Segment-specific carotid intima-media thickness and cardiovascular risk factors in Koreans: the Healthy Twin Study.
Increased carotid intima-media thickness is associated with higher cardiovascular disease risk. This study aimed to evaluate the contributions of cardiovascular risk factors and inheritance to segment-specific carotid intima-media thickness. Cross-sectional observational study. A total of 706 Korean adults was selected from the Healthy Twin Study. The intima-media thickness of common, carotid bifurcation, and internal carotid artery were measured using B-mode ultrasound. Behavioral and biological cardiovascular risk factors were measured. Quantitative genetic and linear mixed analyses were performed to examine inherited and environmental contributions to intima-media thickness variation. Heritability of intima-media thickness was moderately high with estimates (95% confidence intervals) of 0.48 (0.37, 0.59), 0.38(0.27, 0.49), and 0.45(0.34, 0.55) for common, carotid bifurcation, and internal carotid artery, respectively. The additive genetic cross-trait correlations between the segments ranged between 0.43 and 0.75, suggesting a shared genetic influence on the three carotid segments. Additive inherited effects contributed 21% and 31% (common and internal carotid, respectively) to the total variance of the intima-media thickness, while measured cardiovascular risk factors accounted for 46% and 26% (common and internal carotid, respectively). The cardiovascular risk factors significantly associated with carotid intima-media thickness were as follows: in men, alcohol use (bifurcation); physical activity (common and internal); BMI (all segments); diabetes (bifurcation and internal); hypertension (internal); and HDL-cholesterol (common and bifurcation); and in women, smoking (bifurcation), hypertension (common), total and LDL cholesterol (bifurcation and internal), and hs-CRP (common and internal). Individual cardiovascular risk factors were differentially associated with carotid intima-media thickness by segments and sex. Inherited effects made a heterogeneous contribution to intima-media thickness by segment. These findings may explain the differences in cardiovascular disease occurrence between men and women.


Integrated genomics of susceptibility to alkylator-induced leukemia in mice.
Therapy-related acute myeloid leukemia (t-AML) is a secondary, generally incurable, malignancy attributable to chemotherapy exposure. Although there is a genetic component to t-AML susceptibility in mice, the relevant loci and the mechanism(s) by which they contribute to t-AML are largely unknown. An improved understanding of susceptibility factors and the biological processes in which they act may lead to the development of t-AML prevention strategies. In this work we applied an integrated genomics strategy in inbred strains of mice to find novel factors that might contribute to susceptibility. We found that the pre-exposure transcriptional state of hematopoietic stem/progenitor cells predicts susceptibility status. More than 900 genes were differentially expressed between susceptible and resistant strains and were highly enriched in the apoptotic program, but it remained unclear which genes, if any, contribute directly to t-AML susceptibility. To address this issue, we integrated gene expression data with genetic information, including single nucleotide polymorphisms (SNPs) and DNA copy number variants (CNVs), to identify genetic networks underlying t-AML susceptibility. The 30 t-AML susceptibility networks we found are robust: they were validated in independent, previously published expression data, and different analytical methods converge on them. Further, the networks are enriched in genes involved in cell cycle and DNA repair (pathways not discovered in traditional differential expression analysis), suggesting that these processes contribute to t-AML susceptibility. Within these networks, the putative regulators (e.g., Parp2, Casp9, Polr1b) are the most likely to have a non-redundant role in the pathogenesis of t-AML. While identifying these networks, we found that current CNVR and SNP-based haplotype maps in mice represented distinct sources of genetic variation contributing to expression variation, implying that mapping studies utilizing either source alone will have reduced sensitivity. The identification and prioritization of genes and networks not previously implicated in t-AML generates novel hypotheses on the biology and treatment of this disease that will be the focus of future research.


Major complications of tibial tuberosity advancement in 1613 dogs.
To report major postoperative complications in 1613 dogs with tibial tuberosity advancement (TTA). Retrospective case series. Dogs (n = 1613) with cranial cruciate ligament deficiency treated with TTA. Medical records of TTAs performed between December 2007-2013 were reviewed for age, sex, weight, contralateral stifle surgery, surgical approach, duration of preoperative lameness, presence of meniscal damage, concurrent patellar luxation and simultaneous bilateral TTA. Major postoperative complications were defined as surgical site infection (SSI) (superficial, deep, or organ/space), implant failure, fracture, patellar luxation, and meniscal tear. Major complications were recorded in 13.4% of cases. Superficial SSI (incisional irritation) was diagnosed in 6.9% cases, requiring only antimicrobial therapy. Other complications included postliminary medial meniscal tear (2% incidence), deep SSI (incisional dehiscence, 1.1%), implant failure (1%), patellar luxation (1.2%), fracture (0.9%), and organ/space SSI (septic arthritis, 0.4%). Dogs with normal menisci were less likely to develop postliminary meniscal tears if the medial meniscus was released at the time of TTA (P < .0001). No association was detected between recorded parameters and complications, although dogs >8 years old approached significance (P = .05) in terms of predisposition to major complications. Major complications after TTA are uncommon, even in dogs with concurrent patellar luxation or bilateral simultaneous procedures. In spite of its morbidity, medial meniscal release may prevent postliminary meniscal tears.


Patterns of perspectives on fall-prevention beliefs by community-dwelling older adults: a Q method investigation.
Falling has high incidence and reoccurrence rates and is an essential factor contributing to accidental injury or death for older adults. Enhancing the participation of community-dwelling older adults in fall-prevention programs is crucial. Understanding fall-prevention beliefs will be beneficial for developing a community-based fall-prevention program. The aim of the present study was to identify the distinct types of subjective views on the fall-prevention beliefs of community-dwelling older adults aged 80 years and older by applying the Q method. The Q method was adopted to investigate the pattern of perception on fall-prevention beliefs. Forty-two older adults aged 80 - 92 years from a community care center in Northern Taiwan were recruited and requested to complete a Q-sorting. A series of Q-sorts was performed by the participants to rank 30 statements into a normal distribution Q-sort grid. The Q-sorts were subjected to principal component analysis by using PQMethod software Version 2.35. Four statistically independent perspectives were derived from the analysis and reflected distinct viewpoints on beliefs related to fall prevention. Participants in the Considerate perspective believed that health problems caused by falling were serious and fall prevention could decrease the burden they place on their family. Participants in the Promising perspective believed that existing health problems could cause a fall and that fall prevention contributed to their well-being. Participants in the Adaptable perspective perceived low barriers to execute fall prevention and displayed self-confidence and independence in preventing falls. Participants in the Ignorance perspective believed that they could not prevent falls and perceived barriers to fall prevention. By combining theoretical constructs and the Q methodology approach, this study identified four distinct perspectives on fall prevention among community-dwelling older adults. Critical reflection on older adult personal perspectives and interpretations of the required responsive approach is a key element for appropriating fall-prevention support.


Effects of three hydrogen-rich liquids on hemorrhagic shock in rats.
Hydrogen-rich saline provides a high concentration of hydrogen, which selectively reduces levels of hydroxyl radicals and alleviates acute oxidative stress in many models. We investigated the protective effects and mechanisms of three different hydrogen-rich liquid resuscitation preparations on lung injury-induced uncontrolled-hemorrhagic shock (UHS) in rats. A UHS rat model was prepared using the method of Capone et al. of arterial bleeding and tail amputation. Healthy male Wistar rats were randomly divided into seven groups (10 per group) to receive: sham treatment; Ringer solution; hydrogen-rich Ringer solution (H-Ringer solution); hydroxyethyl starch (HES); hydrogen-rich hydroxyethyl starch (H-HES); hypertonic saline/hydroxyethyl starch (HSH); and hydrogen-rich hypertonic saline/hydroxyethyl starch (H-HSH). At 72 h after successful resuscitation, lung tissue was Hematoxylin Eosin stained to score any pathologic changes. We also determined wet-to-dry (W/D) lung weight ratios and lung tissue concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-10, malondialdehyde (MDA), and superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. Compared with the non-H groups, polymorphonuclear neutrophil accumulation in alveoli in the H groups was significantly reduced (P value), and capillary leakage and wall edema were ameliorated. Compared with the sham group, pathologic pulmonary injury scores, W/D ratios, IL-6, TNF-α, IL-10, MDA concentrations, and MPO activity in the other groups were all increased, whereas SOD activity was decreased (P < 0.01). Comparing the H-Ringer, H-HES, and H-HSH groups respectively with the Ringer, HES, and HSH groups, pathologic pulmonary injury scores, W/D ratios, IL-6, TNF-α, MDA concentrations, and MPO activity were all reduced, whereas IL-10 concentrations and SOD activity were increased (P < 0.01). Each hydrogen-rich liquid resuscitation preparation could protect the lung against acute injury secondary to UHS. These mechanisms may be associated with hydrogen inhibiting the release of pro-inflammatory cytokines, promoting anti-inflammatory cytokine release, and reducing oxidative damage.


The dynamin GTPase OPA1: more than mitochondria?
The studies addressing the molecular mechanisms governing mitochondrial fusion and fission have brought to light a small group of dynamin-like GTPases (Guanosine-Triphosphate hydrolase) as central regulators of mitochondrial morphology and cristae remodeling, apoptosis, calcium signaling, and metabolism. One of them is the mammalian OPA1 (Optic atrophy 1) protein, which resides inside the mitochondrion anchored to the inner membrane and, in a cleaved form, is associated to oligomeric complexes, in the intermembrane space of the organelle. Here, we review the studies that have made OPA1 emerge as the best understood regulator of mitochondrial inner membrane fusion and cristae remodeling. Further, we re-examine the findings behind the recent claim that OPA1 mediates adrenergic control of lipolysis by functioning as a cytosolic A-kinase anchoring protein (AKAP), on the hemimembrane that envelops the lipid droplet. This article is part of a Special Issue entitled: Mitochondrial dynamics and physiology.


Effect of an adipose-derived stem cell and nerve growth factor-incorporated hydrogel on recovery of erectile function in a rat model of cavernous nerve injury.
Postprostatectomy erectile dysfunction (ED) is the major problem for patients with clinically localized prostate cancer. Recently, gene and stem cell-based therapy of the corpus cavernosum has been attempted for postprostatectomy ED, but those therapies are limited by rapid blood flow and disruption of the normal architecture of the corpus cavernosum. In this study, we attempted to regenerate the damaged cavernous nerve (CN), which is the main cause of ED. We investigated the effectiveness of human adipose-derived stem cell (hADSC) and nerve growth factor-incorporated hyaluronic acid-based hydrogel (NGF-hydrogel) application on the CN in a rat model of bilateral cavernous nerve crush injury. Four weeks after the operation, erectile function was assessed by detecting the intracavernous pressure (ICP)/arterial pressure level by CN electrostimulation. The ICP was significantly increased by application of hADSC with NGF-hydrogel compared to the other experimental groups. CN and penile tissue were collected for histological examination. PKH-26 labeled hADSC colocalized with beta III tubulin were shown in CN tissue sections. hADSC/NGF-hydrogel treatment prevented smooth muscle atrophy in the corpus cavernosum. In addition, the hADSC/NGF-hydrogel group showed increased endothelial nitric oxide synthase protein expression. This study suggests that application of hADSCs with NGF-hydrogel on the CN might be a promising treatment for postprostatectomy ED.


Perspectives on a 'Sit Less, Move More' Intervention in Australian Emergency Call Centres.
Prolonged sitting is associated with increased risk of chronic diseases. Workplace programs that aim to reduce sitting time (sit less) and increase physical activity (move more) have targeted desk-based workers in corporate and university settings with promising results. However, little is known about 'move more, sit less' programs for workers in other types of jobs and industries, such as shift workers. This formative research examines the perceptions of a 'sit less, move more' program in an Australian Emergency Call Centre that operates 24 hours per day, 7 days per week. Participants were employees (N = 39, 72% female, 50% aged 36-55 years) recruited from Emergency Services control centres located in New South Wales, Australia. The 'sit less, move more' intervention, consisting of emails, posters and timer lights, was co-designed with the management team and tailored to the control centre environment and work practices, which already included electronic height-adjustable sit-stand workstations for all call centre staff. Participants reported their perceptions and experiences of the intervention in a self-report online questionnaire, and directly to the research team during regular site visits. Questionnaire topics included barriers and facilitators to standing while working, mental wellbeing, effects on work performance, and workplace satisfaction. Field notes and open-ended response data were analysed in an iterative process during and after data collection to identify the main themes. Whilst participants already had sit-stand workstations, use of the desks in the standing position varied and sometimes were contrary to expectations (e.g, less tired standing than sitting; standing when experiencing high call stress). Participants emphasised the "challenging" and "unrelenting" nature of their work. They reported sleep issues ("always tired"), work stress ("non-stop demands"), and feeling mentally and physically drained due to shift work and length of shifts. Overall, participants liked the initiative but acknowledged that their predominantly sitting habits were entrenched and work demands took precedence. This study demonstrates the low acceptability of a 'sit less, move more' program in shift workers in high stress environments like emergency call centres. Work demands take priority and other health concerns, like poor sleep and high stress, may be more salient than the need to sit less and move more during work shifts.


Drug utilization patterns and healthcare resource use and costs in patients with neurogenic bladder in the United Kingdom: A retrospective primary care database study.
To characterize patients with neurogenic bladder (NGB), their treatment patterns, healthcare resource utilization, and associated costs based on records from a primary care database in the United Kingdom. This was a retrospective, descriptive, observational study of anonymized data from the Clinical Practice Research Datalink and Hospital Episode Statistics databases (selection period, 1 January 2004 to 31 December 2016). Adults with a definitive or probable diagnosis of NGB and ≥1 referral to a urologist were included. The study cohort included 3913 patients with definitive (n = 363) or probable (n = 3550) NGB. Patients had a mean of 8.6 (standard deviation [SD], 7.6) comorbidities, and mean Anticholinergic Cognitive Burden Scale score of 6.6 (SD, 5.9). During 12 months' follow-up, urinary tract infection (UTI) and urinary incontinence were the most common complications. Most patients (92.2%) received ≥1 prescription for an antimuscarinic agent or mirabegron, and 53.9% of patients received prescriptions for UTI-specific antibiotics. The mean number of visits to a general practitioner for any cause was 67.7 (SD, 42.6) per individual. Almost half (46.7%) of the study cohort visited a specialist during the 12-month follow-up period, and 11.0% had ≥1 hospital admission. Total mean per patient costs for healthcare resource utilization was £2395. The burden of illness, healthcare resource needs, and associated costs among patients with NGB are considerable. Drug prescribing patterns are consistent with the symptoms and complications of NGB, although increased awareness of drugs with anticholinergic activity among prescribers may help to reduce the cumulative anticholinergic burden in this vulnerable population.


Quantitative evaluation of boron-induced disorder in multilayers containing silicon nanocrystals in an oxide matrix designed for photovoltaic applications.
The effect of doping by boron on optical properties of multilayers containing Si-NCs were studied by means of photoluminescence (PL), time-resolved PL, photoluminescence excitation (PLE), transmission and reflection measurements. It was found that PL decay is strongly non-single exponential and can be described by means of Laplace transform of log-normal decay rates distribution. It was also proposed that changes observed in the distribution central moments reflect the disorder induced by boron-doping.


Modes of transmission and evidence for viral latency from studies of human T-cell lymphotrophic virus type I in Japanese migrant populations in Hawaii.
Human T-cell lymphotrophic virus type I (HTLV-I) seroprevalence was 20% among Hawaiian Japanese migrants (issei) and their offspring (nisei) from Okinawa compared to 35% in similarly aged men who were lifetime residents of Okinawa. A control group of migrants from a nonendemic area of Japan, Niigata, had low rates of HTLV-I antibodies, suggesting that Hawaii per se is not an endemic area for HTLV-I. Factors that were significantly associated with seropositivity in the Okinawa migrant groups were years of residence in Japan before migration (issei) and age for offspring of Okinawa migrants (nisei). Antibody titer was highest in Okinawa lifetime residents, intermediate in migrants (issei), and significantly lower in offspring of Okinawa migrants (nisei), with increasing titer observed with advancing age in the offspring of the migrant group. Based on these data, infection within the household occurring early in life appears to be a major route of HTLV-I transmission and may help to explain the curious geographic clustering of this virus in certain locales. As yet to be defined cofactors, including sexual transmission and/or environmental exposures (e.g., particularly before age 20), also may contribute to HTLV-I seropositivity. The pattern of rising seroprevalence and titer with age in the offspring of migrants who resided all of their lives in Hawaii raises the possibility that HTLV-I infection acquired early in life may become dormant and reexpressed with reactivation of latently infected T cells. The importance of this model in the process of viral leukemogenesis is supported by recent reports of adult T-cell leukemia in offspring (nisei) of Okinawa migrants.


An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.
To survey of the structure, processes and organisation of renal satellite units (RSUs) in England and Wales (Phase 1), and to compare the effectiveness, acceptability, accessibility and economic impact of chronic haemodialysis performed in RSUs compared to main renal units (MRUs) (Phase 2). Phase 1: all renal satellite units in England and Wales. Phase 2: haemodialysis patients in a representative sample (based on geography, site, private--public ownership, medical input) of 12 RSUs and their MRUs. Phase 1 consisted of a questionnaire survey. Semi-structured interviews were held in a representative sample of 24 RSUs with the senior clinician, senior nurse and manager. Phase 2 consisted of a cross-sectional comparison of patients in these RSUs and patients in the parent MRUs deemed suitable for satellite care by senior staff. Clinical information was obtained from medical notes and unit computer systems. Generic and disease specific health-related quality of life (HRQoL) measures were used. Co-morbidity was assessed by the Wright/Khan Index, the Lister/Chandna score, the Modified Charlson Index, and the Karnofsky Performance Score. Statistical analyses compared RSU versus MRU patients and took account of the paired and clustered nature of the data. In Phase 1, responses were received from 74/80 (93%) of RSUs; 2600 patients were being treated in these RSUs. The interviews were generally positive about the impact of RSUs in terms of improved accessibility and a better environment for chronic haemodialysis (HD) patients, and in expanding renal replacement therapy patients (RRT) capacity. In Phase 2, some 82% of eligible patients took part, 394 patients in the 12 RSUs and 342 in the parent MRUs. The response rate was similar in both groups. There were no significant differences in clinical processes of care. Most clinical outcomes were similar, especially after pooled analysis, although a few parameters were statistically significantly different -- notably the proportion achieving Renal Association Standards for adequacy of dialysis as measured by the urea reduction ratio (URR) was higher in the RSU patients. Patient-specific quality of life did not differ except on the patient satisfaction questions from the KDQOL, which were scored higher by the RSU sample. Strength of preference for health status on and off dialysis was very similar between the groups, as were EQ-5D utilities. Major adverse events were not common in the RSU patients, although there were many hypotensive episodes on HD, a proportion of which affected the duration of the HD session. Of the costs measured, the only difference that was statistically significant was for District Nurse visits. Of particular note was that despite the MRU group having a higher proportion of patients hospitalised, this did not translate into a statistically significant budgetary impact in terms of the total cost per patient of hospitalisations or mean cost per patient per hospitalisation. This study has shown that RSUs are an effective alternative to MRU HD for a wide spectrum of patients. They improve geographic access for more dispersed areas and reduce patients' travel time, and are generally more acceptable to patients on several criteria. There does not seem to be an adverse impact of care in the RSUs although comparative long-term prospective data are lacking. The evidence suggests that satellite development could be successfully expanded; not all MRUs have any satellites and many have only a few. No single RSU model can be recommended but key factors would include local geography, the likely catchment population and the type of patients to be treated. There is a need for more basic budgetary information linking activity and expenditure to be available and more transparent, to perform at least an insightful top-down costing of the two care settings. Other areas suggested for further research include: a comparison of adverse events occurring in MRUs and RSUs with longer duration and larger numbers to identify more severe events, along with the more research into the scope for preventing such events, and a study into the patients deemed ineligible for satellite care. International comparisons of satellite care would also be useful.


Time trends in 20 years of medication use in older adults: Findings from three elderly cohorts in Stockholm, Sweden.
New drugs and expanded drug indications are constantly being introduced. Welfare states strive to provide equity in drug treatment for all of its citizens and todaýs healthcare systems spend financial resources on drugs for the elderly in a higher rate than for any other age group. Drug utilization in elderly persons has an impact in health and wellbeing in older people. It was to describe the changes in medication use including people aged 78 years and over regardless of residence and other characteristics over 20 years. The study population consisted of 4304 participants in three population-based cross-sectional surveys conducted in the Kungsholmen area of central Stockholm, Sweden. The participant's current drug utilization was reviewed by physicians following standardized protocols. Data were statistical analyzed. Logistic regression models was used to estimate odds ratios and 95% confidence intervals for use of analgesics and psychotropic drugs in the cohorts of 2001 and 2007, controlling for age, gender, education and cognition. Results shows that the prevalence of medication use and polypharmacy in older adults has increased dramatically the late 1980s to the 2000s in central Stockholm, Sweden. In particular, the use of analgesics increased significantly, while some drug groups decreased, i.e., antipsychotics. Women used more medication than men in all three cohorts. Older adults living in service buildings used the largest amount of drugs in 1987, whereas those living in institutions were the most frequent users in 2001 and 2007.


Randomized double-blind controlled study with sublingual carbamylated allergoid immunotherapy in mild rhinitis due to mites.
The clinical efficacy of sublingual immunotherapy (SLIT) in mite allergy and in mild disease is still a matter of debate, thus we performed a long-term clinical trial. The study was randomized, double-blind and placebo-controlled. After a 1-year assessment, 68 patients with mild rhinitis with/without asthma due to mites were randomized to drugs + placebo or drugs + SLIT for 2 years. Sublingual immunotherapy was given as soluble tablets of monomeric carbamylated allergoid. Clinical scores for asthma and rhinitis (0, absent to 3, severe) and drug consumption were assessed by diary card in the period November-February. Quality of life was assessed before and after each observation period and pharmaco-economy data were evaluated as well. Fifty-six patients completed the study. The rate of dropouts was similar in the two groups. No relevant side effect was reported. There was a significant reduction of total clinical scores (P < 0.05) in the active group vs placebo at the first year, but not at the second whereas nasal obstruction significantly improved in both years (P < 0.05). The reduction of drug intake score was significant only at the first year. No change was observed concerning most of the Short Form-36 items, because at baseline all patients displayed a normal profile. A significant change in SLIT group was seen for the item 'change in health status'. The need for extra visits was significantly lower in the active group (25%vs 43%). Sublingual immunotherapy was clinically effective and safe in mite-induced mild disease.


Cloning and characterization of an inversion breakpoint at 6q23.3 suggests a role for Map7 in sacral dysgenesis.
Here we report on a male patient with sacral dysgenesis (SD) and constitutional pericentric inversion of chromosome 6 (p11.2;q23.3). SD is a heterogeneous group of congenital anomalies with complex genetic etiology. Previously, a patient with sacral abnormalities and an interstitial deletion of 6q23-->q25 region has been described. We speculated that a susceptibility gene for SD lies in 6q23.3 region (disrupted in both patients), and therefore, cloning of the breakpoint in our patient would lead to the identification of the disrupted gene. We performed FISH analysis followed by Southern blot analysis and inverse PCR to clone the breakpoint. The 6p11.2 breakpoint mapped very close to the centromere, and the 6q23.3 breakpoint localized in the ninth intron of the MAP7 gene. We then evaluated the involvement of MAP7 in SD by further screening of the gene in several patients with a similar phenotype. Two nucleotide changes causing Ile257Asn and Glu571Ala substitutions in the protein, both affecting amino acid residues conserved in the mouse homolog, were identified in two patients. Both changes are either very rare polymorphisms or true mutations, since they were not detected in 167 normal individuals nor found in the SNP database. Therefore, our study suggests MAP7 as a candidate gene for SD. However, we were unable to detect any sacral defects in the MAP7 knockout mice.


DBD-Hunter: a knowledge-based method for the prediction of DNA-protein interactions.
The structures of DNA-protein complexes have illuminated the diversity of DNA-protein binding mechanisms shown by different protein families. This lack of generality could pose a great challenge for predicting DNA-protein interactions. To address this issue, we have developed a knowledge-based method, DNA-binding Domain Hunter (DBD-Hunter), for identifying DNA-binding proteins and associated binding sites. The method combines structural comparison and the evaluation of a statistical potential, which we derive to describe interactions between DNA base pairs and protein residues. We demonstrate that DBD-Hunter is an accurate method for predicting DNA-binding function of proteins, and that DNA-binding protein residues can be reliably inferred from the corresponding templates if identified. In benchmark tests on approximately 4000 proteins, our method achieved an accuracy of 98% and a precision of 84%, which significantly outperforms three previous methods. We further validate the method on DNA-binding protein structures determined in DNA-free (apo) state. We show that the accuracy of our method is only slightly affected on apo-structures compared to the performance on holo-structures cocrystallized with DNA. Finally, we apply the method to approximately 1700 structural genomics targets and predict that 37 targets with previously unknown function are likely to be DNA-binding proteins. DBD-Hunter is freely available at http://cssb.biology.gatech.edu/skolnick/webservice/DBD-Hunter/.


Deep learning-based automated speech detection as a marker of social functioning in late-life depression.
Late-life depression (LLD) is associated with poor social functioning. However, previous research uses bias-prone self-report scales to measure social functioning and a more objective measure is lacking. We tested a novel wearable device to measure speech that participants encounter as an indicator of social interaction. Twenty nine participants with LLD and 29 age-matched controls wore a wrist-worn device continuously for seven days, which recorded their acoustic environment. Acoustic data were automatically analysed using deep learning models that had been developed and validated on an independent speech dataset. Total speech activity and the proportion of speech produced by the device wearer were both detected whilst maintaining participants' privacy. Participants underwent a neuropsychological test battery and clinical and self-report scales to measure severity of depression, general and social functioning. Compared to controls, participants with LLD showed poorer self-reported social and general functioning. Total speech activity was much lower for participants with LLD than controls, with no overlap between groups. The proportion of speech produced by the participants was smaller for LLD than controls. In LLD, both speech measures correlated with attention and psychomotor speed performance but not with depression severity or self-reported social functioning. Using this device, LLD was associated with lower levels of speech than controls and speech activity was related to psychomotor retardation. We have demonstrated that speech activity measured by wearable technology differentiated LLD from controls with high precision and, in this study, provided an objective measure of an aspect of real-world social functioning in LLD.


Glycosylation of simian virus 40 T antigen and localization of glycosylated T antigen in the nuclear matrix.
Evidence has been obtained for the glycosylation of simian virus 40 (SV40) T antigen in SV40-infected TC7 cells. Both [3H]mannose and [3H]glucosamine are incorporated into T antigen in cells grown and labeled in medium containing fructose instead of glucose. In addition, T antigen is visualized by a carbohydrate stain specific for mannose and/or glucose residues. Finally, lectin binding studies suggest that T antigen contains galactose and/or galactosamine, since T antigen is specifically eluted from soybean lectin by 0.2 M galactose. When gel-purified, [3H]glucosamine-labeled T antigen is subjected to tryptic peptide mapping, label is found in only one peptide, thought to correspond to the methionine-containing peptide extending from Asn-653 to Arg-691, near the carboxy-terminal end of T antigen. Insensitivity to tunicamycin and the localization of the glycosylation site in the carboxy-terminus of T antigen, and not at Asn-153, suggest that T antigen is not N-glycosylated. Cell fractionation studies show that [3H]glucosamine-labeled T antigen is preferentially associated with the nuclear matrix of SV40-infected TC7 cells.


Bioorthogonal Chemistry for the Isolation and Study of Newly Synthesized Histones and Their Modifications.
The nucleosome is an octamer containing DNA wrapped around one histone H3-H4 tetramer and two histone H2A-H2B dimers. Within the nucleosome, histones are decorated with post-translational modifications. Previous studies indicate that the H3-H4 tetramer is conserved during DNA replication, suggesting that old tetramers serve as a template for the modification of newly synthesized tetramers. Here, we present a method that merges bioorthogonal chemistry with mass spectrometry for the study of modifications on newly synthesized histones in mammalian cells. HeLa S3 cells are dually labeled with the methionine analog azidohomoalanine and heavy (13)C6,(15)N4 isotope labeled arginine. Heavy amino acid labeling marks newly synthesized histones while azidohomoalanine incorporation allows for their isolation using bioorthogonal ligation. Labeled mononucleosomes were covalently linked via a copper catalyzed reaction to a FLAG-GGR-alkyne peptide, immunoprecipitated, and subjected to mass spectrometry for quantitative modification analysis. Mononucleosomes containing new histones were successfully isolated using this approach. Additionally, the development of this method highlights the potential deleterious effects of azidohomoalanine labeling on protein PTMs and cell cycle progression, which should be considered for future studies utilizing bioorthogonal labeling strategies in mammalian cells.


Combining users' needs with health behavior models in designing an internet- and mobile-based intervention for physical activity in cardiac rehabilitation.
Internet-based physical activity interventions have great potential in supporting patients in cardiac rehabilitation. Health behavior change theories and user input are identified as important contributors in the effectiveness of the interventions, but they are rarely combined in a systematic way in the design of the interventions. The aim of this study is to identify the appropriate theoretical framework, along with the needs of the users of a physical activity intervention for cardiac rehabilitation, and to combine them into an effective Internet- and mobile-based intervention. We explain the theoretical framework of the intervention in a narrative overview of the existing health behavior change literature as it applies to physical activity. We also conducted a focus group with 11 participants of a cardiac rehabilitation program and used thematic analysis to identify and analyze patterns of meaning in the transcribed data. We chose stage-based approaches, specifically the transtheoretical model and the health action process approach as our main framework for tailoring, supplemented with other theoretical concepts such as regulatory focus within the appropriate stages. From the thematic analysis of the focus group data, we identified seven themes: (1) social, (2) motivation, (3) integration into everyday life, (4) information, (5) planning, (6) monitoring and feedback, and (7) concerns and potential problems. The final design of the intervention was based on both the theoretical review and the user input, and it is explained in detail. We applied a combination of health behavioral theory and user input in designing our intervention. We think this is a promising design approach with the potential to combine the high efficacy of theory-based interventions with the higher perceived usefulness of interventions designed according to user input. Clinicaltrials.gov NCT01223170; http://clinicaltrials.gov/show/NCT01223170 (Archived by WebCite at http://www.webcitation.org/6M5FqT9Q2).


Longitudinal Trajectory of Exposure to Psychological Interpersonal Violence.
Psychological intimate partner violence (P-IPV) refers to verbal abuse from one partner to another and abuse of power or control from one partner to another. To date, no studies have examined the longitudinal course of P-IPV exposure among mothers or the effect that witnessing P-IPV can have on their children. Using latent class growth analysis, the current study identified five trajectory groups with the following intercept and growth characteristics: low stable, low-increasing, moderate-decreasing, high-decreasing, and consistently elevated. Membership in the four groups characterized by higher P-IPV exposure was predicted by maternal race and exposure to physical abuse. The children of mothers in the low-increasing and consistently elevated groups had elevated scores on the Internalizing and Externalizing scales of the Childhood Behavior Checklist. These findings remained after controlling for child sex, race, cumulative trauma exposure, and maternal depression.


Carcinogenesis Induced by Low-dose Radiation.
Although the effects of high dose radiation on human cells and tissues are relatively well defined, there is no consensus regarding the effects of low and very low radiation doses on the organism. Ionizing radiation has been shown to induce gene mutations and chromosome aberrations which are known to be involved in the process of carcinogenesis. The induction of secondary cancers is a challenging long-term side effect in oncologic patients treated with radiation. Medical sources of radiation like intensity modulated radiotherapy used in cancer treatment and computed tomography used in diagnostics, deliver very low doses of radiation to large volumes of healthy tissue, which might contribute to increased cancer rates in long surviving patients and in the general population. Research shows that because of the phenomena characteristic for low dose radiation the risk of cancer induction from exposure of healthy tissues to low dose radiation can be greater than the risk calculated from linear no-threshold model. Epidemiological data collected from radiation workers and atomic bomb survivors confirms that exposure to low dose radiation can contribute to increased cancer risk and also that the risk might correlate with the age at exposure. Understanding the molecular mechanisms of response to low dose radiation is crucial for the proper evaluation of risks and benefits that stem from these exposures and should be considered in the radiotherapy treatment planning and in determining the allowed occupational exposures.


A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression.
Repetitive transcranial magnetic stimulation (rTMS) has been reported to be as effective as electroconvulsive therapy (ECT) for major depression. The authors conducted a multicenter randomized, controlled trial to test the equivalence of rTMS with ECT. Forty-six patients with major depression referred for ECT were randomly assigned to either a 15-day course of rTMS of the left dorsolateral prefrontal cortex (N=24) or a standard course of ECT (N=22). The primary outcome measures were the score on the 17-item Hamilton Depression Rating Scale (HAM-D) and the proportion of patients with remissions (Hamilton score, <or=8) at the end of treatment. Secondary outcomes included mood self-ratings on the Beck Depression Inventory-II and visual analogue mood scales, Brief Psychiatric Rating Scale (BPRS) score, and both self-reported and observer-rated cognitive changes. The patients were followed up after 6 months. HAM-D scores at the end of treatment were significantly lower for ECT, with 13 patients (59.1%) achieving remission in the ECT group and four (16.7%) in the rTMS group. However, at 6 months the HAM-D scores did not differ between groups. Beck scale, visual analogue mood scale, and BPRS scores were lower for ECT at the end of treatment and remained lower after 6 months. Self- and observer-rated cognitive measures were similar in the two groups. rTMS was not as effective as ECT, and ECT was substantially more effective for the short-term treatment of depression.


Control of the function of substrate-bound C4b-C3b by the complement receptor Cr1.
The complement fragments C3b and C4b are the main ligands for the membrane receptor CR1. We showed elsewhere that CR1 functions as an essential cofactor for the factor I-mediated enzymatic breakdown of membrane-bound C3b (*C3b) into C3c and * C3dg . One of the main findings of the present paper is that CR1 also promotes the degradation of bound C4b (*C4b) into C4c and *C4d. On a weight basis, the cofactor activity of CR1 in the cleavage of *C4b present on the cell intermediate EAC14 is 10(3)-fold greater than that of the serum cofactor C4-binding protein ( C4bp ). An additional finding is that the effect of CR1 on either *C3b or *C4b is modulated by the presence of the other ligand in its vicinity; that is, *C4b degradation by CR1 plus I is enhanced by neighboring *C3b and vice versa. For example, upon uptake of optimal amounts of *C3b onto EAC142 and the assembly of the C3-convertase EAC1423 , the activity of CR1 in generating C4c is enhanced 5-10 times further. Conversely, when the number of *C3b molecules on EAC1423 is relatively small (or when EAC1423 has been converted by I plus H into EAC1423i ), the presence of neighboring *C4b enhances the conversion of *C3b (or *iC3b) into C3c plus * C3dg . The enhancing effect of *C3b on the cleavage of *C4b by I is observed only if the cofactor of this reaction is CR1. Indeed, the activity of I or I plus C4bp on *C4b is significantly inhibited when *C3b is fixed and the main product of the reaction is * iC4b . Taken together, these findings suggest that degradation of *C4b will be more effective when enough C3b molecules are fixed nearby, thus facilitating the interaction of *C4b*3b clusters with CR1-bearing cells, and that under physiological conditions, *C4b activity can be efficiently controlled by CR1.


Comparison of bismuth citrate and 5-aminosalicylic acid enemas in distal ulcerative colitis: a controlled trial.
An enema that contained a complex of bismuth citrate and polyacrylate was compared with 5-aminosalicylic acid (5-ASA) enemas for treatment of distal ulcerative colitis. The multicentre trial involving 63 patients was randomised and double blind with enemas given over four weeks; clinical, sigmoidoscopic, and histological assessments were made. Improvements were seen in both treatment groups. Clinical remission was seen in 18 of 32 patients treated with 5-ASA and 12 of 31 patients treated with bismuth citrate-carbomer (chi 2 1.94; p = 0.16). Sigmoidoscopic remission occurred in 20 of 32 patients in the 5-ASA group and 15 of 31 patients given bismuth (chi 2 1.27; p = 0.26). Improvement of rectal biopsy histology by at least one grade was seen in 16 of 32 patients in the 5-ASA group and 14 of 31 patients with bismuth (chi 2 0.15; p = 0.70). Analysis of covariance gave no significant difference between groups, although there was a trend favouring 5-ASA. There was no evidence of bismuth accumulation during the trial. Bismuth enemas may offer a new therapeutic option in distal ulcerative colitis.


[Current possibilities of using antimyocotic drugs in the treatment of various skin disorders].
Current possibilities of using antimycotic drugs in the treatment of various skin disorders. The purpose of this article is to review the literature data on the therapeutic protocols and the results of using some antimycotics in different skin diseases. In addition to the antimycotic action, particular antifungal drugs such as itraconazole, ketoconazole and terbinafine exhibit anti-inflammatory activity by inhibiting the synthesis of 5-lipooxygenase metabolites. As these metabolites are involved in a number of inflammatory and immunoreactive processes the dual action of the drugs may be suitably exploited in the treatment of some skin diseases which are otherwise difficult to cure. Another rationale for the use of antimycotics in certain skin disorders is their action against Malassezia. It has been recently demonstrated that Malassezia, present as a commensal in the epidermis, may play an important role in inducing certain inflammatory processes by stimulating cytokine production by keratinocytes. The antimycotics proved to be useful in the therapy of the following skin conditions: seborrheic dermatitis, Malassezia folliculitis, perioral dermatitis and papulopustular rosacea, as well as adult atopic dermatitis. The use of antimycotic drugs in amicrobial palmoplantar pustulosis and sebopsoriasis remains controversial. These medications are also an alternative in the treatment of leishmaniosis.


A member of a new Picornaviridae genus is shed in pig feces.
During a study of the fecal microbiomes from two healthy piglets using high-throughput sequencing (HTS), we identified a viral genome containing an open reading frame encoding a predicted polyprotein of 2,133 amino acids. This novel viral genome displayed the typical organization of picornaviruses, containing three structural proteins (VP0, VP3, and VP1), followed by seven nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C(pro), and 3D(pol)). Given its particular relationship with Parechovirus, we propose to name it "Pasivirus" for Parecho sister clade virus, with "Swine pasivirus 1" (SPaV1) as the type species. Fecal samples collected at an industrial farm from healthy sows and piglets from the same herd (25 and 75, respectively) with ages ranging from 4 to 28 weeks were analyzed for the presence of SPaV1 by one-step reverse transcription (RT)-PCR targeting a 3D region of 151 bp. SPaV1 was detected in fecal samples from 51/75 healthy piglets (68% of the animals) and in none of the 25 fecal samples from healthy sows, indicating that SPaV1 circulates through enteric infection of healthy piglets. We propose that SPaV1 represents the first member of a novel Picornaviridae genus related to parechoviruses.


Magnetic resonance imaging of cerebrospinal fluid outflow after low-rate lateral ventricle infusion in mice.
The anatomical routes for the clearance of cerebrospinal fluid (CSF) remain incompletely understood. However, recent evidence has given strong support for routes leading to lymphatic vessels. A current debate centers upon the routes through which CSF can access lymphatics, with evidence emerging for either direct routes to meningeal lymphatics or along cranial nerves to reach lymphatics outside the skull. Here, a method was established to infuse contrast agent into the ventricles using indwelling cannulae during imaging of mice at 2 and 12 months of age by magnetic resonance imaging. As expected, a substantial decline in overall CSF turnover was found with aging. Quantifications demonstrated that the bulk of the contrast agent flowed from the ventricles to the subarachnoid space in the basal cisterns. Comparatively little contrast agent signal was found at the dorsal aspect of the skull. The imaging dynamics from the 2 cohorts revealed that the contrast agent was cleared from the cranium through the cribriform plate to the nasopharyngeal lymphatics. On decalcified sections, we confirmed that fluorescently labeled ovalbumin drained through the cribriform plate and could be found within lymphatics surrounding the nasopharynx. In conclusion, routes leading to nasopharyngeal lymphatics appear to be a major efflux pathway for cranial CSF.


Sarcopenia, Obesity and Sarcopenia Obesity in Comparison: Prevalence, Metabolic Profile, and Key Differences: Results from WCHAT Study.
To identify the prevalence, lifestyle factors, chronic disease status, and assessing the metabolic profile, comparing key differences in a cohort of subjects with non-sarcopenia/non-obesity (H), sarcopenia/non-obesity (S), non-sarcopenia/obesity (O) and sarcopenia obesity (SO) in a multi-ethnic population in west China. A cross-sectional study. The communities in Yunnan, Guizhou, Sichuan, and Xinjiang provinces. We included 4,500 participants aged 50 years or older who did bioelectrical impedance in our analysis from West China Health and Aging Trend (WCHAT) study. We measured gait speed, handgrip strength and muscle mass by using bioelectrical impedance analysis (BIA) for all participants. We defined sarcopenia using the diagnostic algorithm recommended by the Asian Working Group for Sarcopenia (AWGS). Obesity was defined as the highest sex-specific quintile of the percentage body fat. Different variables like anthropometry measures, life styles, chronic disease and blood test were collected. Analysis of variance and a multinomial logistic regression analysis adjusting for covariates were used to assess the differences of metabolic profiles among different groups. Of 4500 participants aged 50 years old or older, the proportions of H, O, S, SO were 63.0%, 17.7%, 16.7% and 2.6%, respectively. And the prevalence of S subjects in men was 18.3% and 15.7% in women, while the prevalence of SO was 3.7% in men and 2.0% in women. Data showed that the prevalence of S and SO has an aging increase pattern which was opposite with O. Both S and SO tends to be older, lower educational level, without spouse, smoking, comorbidity of chronic disease, poor nutrition status, depression and cognitive decline compared to H and S seems to be worse than SO. Compared to H, S cohort showed a decrease in Vitamin D, triglyceride, albumin, fasting glucose, insulin, creatinine, ALT, nutrition scores and increase in HDL. SO cohort were observed for an increase in cholesterol, LDL, total protein and decrease in vitamin D. While O cohort showed an increase in triglyceride, cholesterol, LDL, total protein, glucose, insulin, WBC, uric acid, ALT and nutrition scores, but a decrease in HDL and vitamin D level. Among individuals aged 50 years old or older in West China. S, O and SO participants demonstrate distinct differences in the life-styles, chronic disease profile, and metabolic profiles. The prevalence of S and SO has an aging increase pattern contrary to O. Both S and SO tend to be older, lower educational level, without spouse, smoking, comorbidity of chronic disease, poor nutrition status, depression and cognitive decline compared to H and S looks like to be worse than SO. Besides, the S subjects seem to have more metabolic index changes than SO compared to H. While O subjects have some contrary metabolic index to S subjects.


Olive oil and the haemostatic system.
Interest in the Mediterranean diet (MD) has grown worldwide due to its link with greater longevity and lower cardiovascular disease rate, cancer and age cognitive decline. Despite the high complexity of its nutrients composition, olive oil emerges as its principal food, since it provides the higher percent of energy and a lot of bioactive compounds. In this review we will discuss the benefits of diets enriched in virgin olive oil, whose effects are probably due not only to its oleic acid content but also to its other potentially health-promoting components. Traditionally, the benefits of MD were linked to its effect on lipoprotein metabolism but today we realise that there exists a whole sheaf of other benefits, including the components of haemostasis: platelet function, thrombogenesis and fibrinolysis. A diet enriched in virgin olive oil can reduce the sensitivity of platelets to aggregation, decreasing von Willebrand and tromboxane B2 plasma levels. Moreover a particular interest has arisen about its capacity to decrease fasting Factor VII plasma levels and to avoid or modulate its postprandial activation. Also Tissue Factor expression in mononuclear cells could be reduced with the chronic intake of virgin olive oil and finally, studies performed in different experimental situation have shown that it could also increase fibrinolytic activity, reducing plasma concentration of Plasma Activator Inhibitor type-1.


Water consumption patterns in rural Bangladesh: are we underestimating total arsenic load?
Risk related to the ingestion of any water contaminants depends on many factors, including the daily per capita amount of consumed water relative to body weight. This study explored the water consumption pattern of a rural arsenic-affected population in Bangladesh. The study findings are likely to contribute to the risk estimation attributable to ingestion of arsenic and other drinking water contaminants. A total of 640 individuals participated in this cross-sectional study carried out in an arsenic-affected rural population in Bangladesh. In this study daily per capita water consumption for drinking purposes was found to be 73.04 ml/kg/d (range = 71.24-74.84 ml/kg/d), which is higher than for both the US and Taiwan populations. This difference in per capita drinking water consumption might contribute to much higher lifetime cancer mortality and other morbidity risks from arsenic among the Bangladesh population compared to either the US or Taiwan populations. Arsenic is also ingested through cooking water which, if considered, might increase the risk further. The findings of this study highlight the urgent need for a holistic water supply programme for Bangladesh, with special emphasis on the arsenic-affected population.


Management of faecal incontinence and constipation in adults with central neurological diseases.
People with central neurological disease or injury have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine line between the two symptoms, with any management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical, with a limited research base. This is an update of a Cochrane review first published in 2001 and subsequently updated in 2003 and 2006. The review is relevant to individuals with any disease directly and chronically affecting the central nervous system (post-traumatic, degenerative, ischaemic or neoplastic), such as multiple sclerosis, spinal cord injury, cerebrovascular disease, Parkinson's disease and Alzheimer's disease. To determine the effects of management strategies for faecal incontinence and constipation in people with a neurological disease or injury affecting the central nervous system. We searched the Cochrane Incontinence Group Trials Register (searched 8 June 2012), which includes searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In-Process as well as handsearching of journals and conference proceedings; and all reference lists of relevant articles. Randomised and quasi-randomised trials evaluating any type of conservative or surgical intervention for the management of faecal incontinence and constipation in people with central neurological disease or injury were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction were also considered. At least two review authors independently assessed the risk of bias of eligible trials and independently extracted data from the included trials using a range of pre-specified outcome measures. Twenty trials involving 902 people were included. Oral medications There was evidence from individual small trials that people with Parkinson's disease had a statistically significant improvement in the number of bowel motions or successful bowel care routines per week when fibre (psyllium) (mean difference (MD) -2.2 bowel motions, 95% confidence interval (CI) -3.3 to -1.4) or oral laxative (isosmotic macrogol electrolyte solution) (MD 2.9 bowel motions per week, 95% CI 1.48 to 4.32) are used compared with placebo. One trial in people with spinal cord injury showed statistically significant improvement in total bowel care time comparing intramuscular neostigmine-glycopyrrolate (anticholinesterase plus an anticholinergic drug) with placebo (MD 23.3 minutes, 95% CI 4.68 to 41.92).Five studies reported the use of cisapride and tegaserod in people with spinal cord injuries or Parkinson's disease. These drugs have since been withdrawn from the market due to adverse effects; as they are no longer available they have been removed from this review. Rectal stimulants One small trial in people with spinal cord injuries compared two bisacodyl suppositories, one polyethylene glycol-based (PGB) and one hydrogenated vegetable oil-based (HVB). The trial found that the PGB bisacodyl suppository significantly reduced the mean defaecation period (PGB 20 minutes versus HVB 36 minutes, P < 0.03) and mean total time for bowel care (PGB 43 minutes versus HVB 74.5 minutes, P < 0.01) compared with the HVB bisacodyl suppository.Physical interventions There was evidence from one small trial with 31 participants that abdominal massage statistically improved the number of bowel motions in people who had a stroke compared with no massage (MD 1.7 bowel motions per week, 95% CI 2.22 to 1.18). A small feasibility trial including 30 individuals with multiple sclerosis also found evidence to support the use of abdominal massage. Constipation scores were statistically better with the abdominal massage during treatment although this was not supported by a change in outcome measures (for example the neurogenic bowel dysfunction score).One small trial in people with spinal cord injury showed statistically significant improvement in total bowel care time using electrical stimulation of abdominal muscles compared with no electrical stimulation (MD 29.3 minutes, 95% CI 7.35 to 51.25).There was evidence from one trial with a low risk of bias that for people with spinal cord injury transanal irrigation, compared against conservative bowel care, statistically improved constipation scores, neurogenic bowel dysfunction score, faecal incontinence score and total time for bowel care (MD 27.4 minutes, 95% CI 7.96 to 46.84). Patients were also more satisfied with this method.Other interventions In one trial in stroke patients, there appeared to be a short term benefit (less than six months) to patients in terms of the number of bowel motions per week with a one-off educational intervention from nurses (a structured nurse assessment leading to targeted education versus routine care), but this did not persist at 12 months. A trial in individuals with spinal cord injury found that a stepwise protocol did not reduce the need for oral laxatives and manual evacuation of stool.Finally, one further trial reported in abstract form showed that oral carbonated water (rather than tap water) improved constipation scores in people who had had a stroke. There is still remarkably little research on this common and, to patients, very significant issue of bowel management. The available evidence is almost uniformly of low methodological quality. The clinical significance of some of the research findings presented here is difficult to interpret, not least because each intervention has only been addressed in individual trials, against control rather than compared against each other, and the interventions are very different from each other.There was very limited evidence from individual trials in favour of a bulk-forming laxative (psyllium), an isosmotic macrogol laxative, abdominal massage, electrical stimulation and an anticholinesterase-anticholinergic drug combination (neostigmine-glycopyrrolate) compared to no treatment or controls. There was also evidence in favour of transanal irrigation (compared to conservative management), oral carbonated (rather than tap) water and abdominal massage with lifestyle advice (compared to lifestyle advice alone). However, these findings need to be confirmed by larger well-designed controlled trials which should include evaluation of the acceptability of the intervention to patients and the effect on their quality of life.


Electronic Properties of Transferable Atomically Thin MoSe2/h-BN Heterostructures Grown on Rh(111).
Vertically stacked two-dimensional (2D) heterostructures composed of 2D semiconductors have attracted great attention. Most of these include hexagonal boron nitride (h-BN) as either a substrate, an encapsulant, or a tunnel barrier. However, reliable synthesis of large-area and epitaxial 2D heterostructures incorporating BN remains challenging. Here, we demonstrate the epitaxial growth of nominal monolayer (ML) MoSe2 on h-BN/Rh(111) by molecular beam epitaxy, where the MoSe2/h-BN layer system can be transferred from the growth substrate onto SiO2. The valence band structure of ML MoSe2/h-BN/Rh(111) revealed by photoemission electron momentum microscopy ( kPEEM) shows that the valence band maximum located at the K point is 1.33 eV below the Fermi level ( EF), whereas the energy difference between K and Γ points is determined to be 0.23 eV, demonstrating that the electronic properties, such as the direct band gap and the effective mass of ML MoSe2, are well preserved in MoSe2/h-BN heterostructures.


Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis.
Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor beta signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA)-like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large-joint OA in humans. Ten tag single-nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA. A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta-analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12-1.34), P < 7.5 x 10(-6). For hip OA, the OR was 1.22 (95% CI 1.09-1.36), P < 4.0 x 10(-4). No evidence for heterogeneity was found (I(2) = 0%). Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA.


Locally linear denoising on image manifolds.
We study the problem of image denoising where images are assumed to be samples from low dimensional (sub)manifolds. We propose the algorithm of locally linear denoising. The algorithm approximates manifolds with locally linear patches by constructing nearest neighbor graphs. Each image is then locally denoised within its neighborhoods. A global optimal denoising result is then identified by aligning those local estimates. The algorithm has a closed-form solution that is efficient to compute. We evaluated and compared the algorithm to alternative methods on two image data sets. We demonstrated the effectiveness of the proposed algorithm, which yields visually appealing denoising results, incurs smaller reconstruction errors and results in lower error rates when the denoised data are used in supervised learning tasks.


Registration of Durum Wheat Germplasm Lines with Combined Mutations in SBEIIa and SBEIIb Genes Conferring Increased Amylose and Resistant Starch.
Durum wheat [Triticum turgidum L. subsp. durum (Desf.) Husn.], used in pasta, couscous, and flatbread production, is an important source of starch food products worldwide. The amylose portion of the starch forms resistant starch complexes that resist digestion and contribute to dietary fiber. Increasing the amount of amylose and resistant starch in wheat by mutating the STARCH BRANCHING ENZYME II (SBEII) genes has potential to provide human health benefits. Ethyl methane sulfonate mutations in the linked SBEIIa and SBEIIb paralogs were combined on chromosomes 2A (SBEIIa/b-A; Reg. No. GP-968, PI 670159), 2B (SBEIIa/b-B; Reg. No. GP-970, PI 670161), and on both chromosomes (SBEIIa/b-AB; Reg. No. GP-969, PI 670160) in the tetraploid wheat cultivar Kronos, a semidwarf durum wheat cultivar that has high yield potential and excellent pasta quality. These three double and quadruple SBEII-mutant lines were compared with a control sib line with no SBEII mutations in two field locations in California. The SBEIIa/b-AB line with four mutations showed dramatic increases in amylose (average 66%) and resistant starch (average 753%) relative to the control. However, the SBEIIa/b-AB line also showed an average 7% decrease in total starch and an 8% decrease in kernel weight. The release by the University of California-Davis of the durum wheat germplasm combining four SBEIIa and SBEIIb mutations will accelerate the deployment of these mutations in durum wheat breeding programs and the development of durum wheat varieties with increased resistant starch.


Comparison of midbrain and thalamic space-specific neurons in barn owls.
Spatial receptive fields of neurons in the auditory pathway of the barn owl result from the sensitivity to combinations of interaural time (ITD) and level differences across stimulus frequency. Both the forebrain and tectum of the owl contain such neurons. The neural pathways, which lead to the forebrain and tectal representations of auditory space, separate before the midbrain map of auditory space is synthesized. The first nuclei that belong exclusively to either the forebrain or the tectal pathways are the nucleus ovoidalis (Ov) and the external nucleus of the inferior colliculus (ICx), respectively. Both receive projections from the lateral shell subdivision of the inferior colliculus but are not interconnected. Previous studies indicate that the owl's tectal representation of auditory space is different from those found in the owl's forebrain and the mammalian brain. We addressed the question of whether the computation of spatial cues in both pathways is the same by comparing the ITD tuning of Ov and ICx neurons. Unlike in ICx, the relationship between frequency and ITD tuning had not been studied in single Ov units. In contrast to the conspicuous frequency independent ITD tuning of space-specific neurons of ICx, ITD selectivity varied with frequency in Ov. We also observed that the spatially tuned neurons of Ov respond to lower frequencies and are more broadly tuned to ITD than in ICx. Thus there are differences in the integration of frequency and ITD in the two sound-localization pathways. Thalamic neurons integrate spatial information not only within a broader frequency band but also across ITD channels.


Illegal bowling actions contribute to performance in cricket finger-spin bowlers.
With advances in technology, scientists are now able to more accurately measure elbow displacement changes during the cricket bowling action. This has led to the realization that the majority of bowlers undergo some degree of elbow extension during the forward swing phase of bowling. Consequently, the International Cricket Council were obliged to revise the once zero tolerance for elbow extension threshold to a 15° range. However, it is still not understood if bowling with >15° of elbow extension aids performance or alters other kinematic movements. The purpose of this study was to compare performance and technique measures between legal and illegal finger-spin bowlers. Data were collected from 48 pathway and elite bowlers using a 22-camera motion analysis system. Results indicated that the ball velocity and revolutions at ball release of pathway bowlers with illegal actions showed no significant difference and were similar to elite legal bowlers. Technique differences were also identified, with illegal bowlers being more front-on, forcing a reliance on increased elbow flexion and supination to impart effective ball kinematics at ball release. The performance benefit of greater ball velocity and revolutions is obtained when finger-spin bowlers deliver the ball with more than the allowable 15° of elbow extension, thus reinforcing the validity of the current bowling laws. To counteract bowling with an illegal action, it is recommended that a more side-on technique at back foot impact and rotating the trunk through to the point of ball release will assist bowlers in reducing undesirable elbow extension levels.


Cavity contour segmentation in chest radiographs using supervised learning and dynamic programming.
Efficacy of tuberculosis (TB) treatment is often monitored using chest radiography. Monitoring size of cavities in pulmonary tuberculosis is important as the size predicts severity of the disease and its persistence under therapy predicts relapse. The authors present a method for automatic cavity segmentation in chest radiographs. A two stage method is proposed to segment the cavity borders, given a user defined seed point close to the center of the cavity. First, a supervised learning approach is employed to train a pixel classifier using texture and radial features to identify the border pixels of the cavity. A likelihood value of belonging to the cavity border is assigned to each pixel by the classifier. The authors experimented with four different classifiers:k-nearest neighbor (kNN), linear discriminant analysis (LDA), GentleBoost (GB), and random forest (RF). Next, the constructed likelihood map was used as an input cost image in the polar transformed image space for dynamic programming to trace the optimal maximum cost path. This constructed path corresponds to the segmented cavity contour in image space. The method was evaluated on 100 chest radiographs (CXRs) containing 126 cavities. The reference segmentation was manually delineated by an experienced chest radiologist. An independent observer (a chest radiologist) also delineated all cavities to estimate interobserver variability. Jaccard overlap measure Ω was computed between the reference segmentation and the automatic segmentation; and between the reference segmentation and the independent observer's segmentation for all cavities. A median overlap Ω of 0.81 (0.76 ± 0.16), and 0.85 (0.82 ± 0.11) was achieved between the reference segmentation and the automatic segmentation, and between the segmentations by the two radiologists, respectively. The best reported mean contour distance and Hausdorff distance between the reference and the automatic segmentation were, respectively, 2.48 ± 2.19 and 8.32 ± 5.66 mm, whereas these distances were 1.66 ± 1.29 and 5.75 ± 4.88 mm between the segmentations by the reference reader and the independent observer, respectively. The automatic segmentations were also visually assessed by two trained CXR readers as "excellent," "adequate," or "insufficient." The readers had good agreement in assessing the cavity outlines and 84% of the segmentations were rated as "excellent" or "adequate" by both readers. The proposed cavity segmentation technique produced results with a good degree of overlap with manual expert segmentations. The evaluation measures demonstrated that the results approached the results of the experienced chest radiologists, in terms of overlap measure and contour distance measures. Automatic cavity segmentation can be employed in TB clinics for treatment monitoring, especially in resource limited settings where radiologists are not available.


FluidFM: combining atomic force microscopy and nanofluidics in a universal liquid delivery system for single cell applications and beyond.
We describe the fluidFM, an atomic force microscope (AFM) based on hollow cantilevers for local liquid dispensing and stimulation of single living cells under physiological conditions. A nanofluidic channel in the cantilever allows soluble molecules to be dispensed through a submicrometer aperture in the AFM tip. The sensitive AFM force feedback allows controlled approach of the tip to a sample for extremely local modification of surfaces in liquid environments. It also allows reliable discrimination between gentle contact with a cell membrane or its perforation. Using these two procedures, dyes have been introduced into individual living cells and even selected subcellular structures of these cells. The universality and versatility of the fluidFM will stimulate original experiments at the submicrometer scale not only in biology but also in physics, chemistry, and material science.


The SARS-Coronavirus PLnc domain of nsp3 as a replication/transcription scaffolding protein.
Many genetic and mechanistic features distinguish the coronavirus replication machinery from that encoded by most other RNA viruses. The coronavirus replication/transcription complex is an assembly of viral and, most probably, cellular proteins that mediate the synthesis of both the unusually large (approximately 30 kb) RNA genome and an extensive set of subgenomic mRNAs. The viral components of the complex are encoded by the giant replicase gene, which is expressed in the form of two polyproteins (pp1a and pp1ab) that are processed into 16 cleavage products (nonstructural proteins 1-16). Using the combination of yeast two-hybrid screening and GST pull-down assays, we have now analyzed all potential interactions between SARS-Coronavirus nonstructural proteins, which may contribute to the structure and/or function of the viral replication/transcription complex. We demonstrate the existence of a complex network of interactions involving all 16 nonstructural proteins. Our results both confirmed previously described associations and identified novel heterodimerizations. The interaction map thus provides a sum of the interactions that may occur at some point during coronavirus RNA synthesis and provides a framework for future research.


The impact of healthcare-associated methicillin-resistant Staphylococcus aureus infections on post-discharge healthcare costs and utilization.
Healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) infections are a major cause of morbidity, mortality, and cost among hospitalized patients. Little is known about their impact on post-discharge resource utilization. The purpose of this study was to estimate post-discharge healthcare costs and utilization attributable to positive MRSA cultures during a hospitalization. Our study cohort consisted of patients with an inpatient admission lasting longer than 48 hours within the US Department of Veterans Affairs (VA) system between October 1, 2007, and November 30, 2010. Of these patients, we identified those with a positive MRSA culture from microbiology reports in the VA electronic medical record. We used propensity score matching and multivariable regression models to assess the impact of positive culture on post-discharge outpatient, inpatient, and pharmacy costs and utilization in the 365 days following discharge. Our full cohort included 369,743 inpatients, of whom, 3,599 (1.0%) had positive MRSA cultures. Our final analysis sample included 3,592 matched patients with and without positive cultures. We found that, in the 12 months following hospital discharge, having a positive culture resulted in increases in post-discharge pharmacy costs ($776, P<.0001) and inpatient costs ($12,167, P<.0001). Likewise, having a positive culture increased the risk of a readmission (odds ratio [OR]=1.396, P<.0001), the number of prescriptions (incidence rate ratio [IRR], 1.138; P<.0001) and the number of inpatient days (IRR, 1.204; P<.0001,) but decreased the number of subsequent outpatient encounters (IRR, 0.941; P<.008). The results of this study indicate that MRSA infections are associated with higher levels of post-discharge healthcare cost and utilization. These findings indicate that financial benefits resulting from infection prevention efforts may extend beyond the initial hospital stay.


Ganglia of the hand and wrist: a sonographic analysis.
The purpose of this study was to analyze the sonographic appearance of a large series of pathologically proven ganglia. A computer search of sonography and pathology reports for hand and wrist ganglia was performed. All sonography reports and images were reviewed for ganglion size, location, presence of a neck, echogenicity, acoustic enhancement, locules, color Doppler flow, margins, wall thickness, and calcifications and to determine if the ganglion was palpable or collapsed. All pathology reports were reviewed for histologic features that were then correlated with the sonographic images. Ganglia were categorized into three groups: simple, complex cystic, and solid-appearing. Of 60 ganglia, 34 were complex, 91% of which were located within the dorsal or volar wrist; 97% had well-defined margins; 76%, locules; 68%, acoustic enhancement; 47%, a thick wall; 15%, internal reflectors; and 12%, blood flow. Of the 23 simple ganglia, 11 involved the extensor or flexor tendon sheath, 73% of which were simple. Complex ganglia had a larger mean volume than simple. Three ganglia were solid-appearing. A visible neck was seen in 25% of ganglia. Most ganglia are complex rather than simple on sonography. Complex ganglia are larger than simple ganglia; located within the dorsal or volar wrist; and usually have well-defined margins, thick walls, locules, and acoustic enhancement. A small percentage have blood flow and internal reflectors. Simple ganglia are smaller and can occur within the volar or dorsal wrist, or flexor tendon sheath. Most flexor tendon sheath ganglia are simple rather than complex. Solid-appearing ganglia, although unusual, may mimic a benign neoplasm or synovitis.


What is the effect of the weather on trauma workload? A systematic review of the literature.
Hospital admission rates for a number of conditions have been linked to variations in the weather. It is well established that trauma workload displays significant seasonal variation. A reliable predictive model might enable targeting of high-risk groups for intervention and planning of hospital staff levels. To our knowledge there have been no systematic reviews of the literature on the relationship between weather and trauma workload, and predictive models have thus far been informed by the results of single studies. We conducted a systematic review of bibliographic databases and reference lists up to June 2014 to identify primary research papers assessing the effect of specified weather conditions including temperature, rainfall, snow, fog, hail, humidity and wind speed on trauma workload, defined as admission to hospital, fracture or a Road Traffic Accident (RTA) resulting in a seriously injured casualty or fatality. 11,083 papers were found through electronic and reference search. 83 full papers were assessed for eligibility. 28 met inclusion criteria and were included in the final review; 6 of these related to the effect of the weather on trauma admissions, one to ambulance call out for trauma, 13 to fracture rate and 8 to RTAs. Increased temperature is positively correlated with trauma admissions. The rate of distal radius fractures is more sensitive to adverse weather than the rate of hip fractures. Paediatric trauma, both in respect of trauma admissions and fracture rate, is more sensitive to the weather than adult trauma. Adverse weather influences both RTA frequency and severity, but the nature of the relationship is dependent upon the timecourse of the weather event and the population studied. Important methodological differences between studies limit the value of the existing literature in building consensus for a generalisable predictive model. Weather conditions may have a substantial effect on trauma workload independent of the effects of seasonal variation; the population studied and timecourse of weather events appear critical in determining this relationship. Methodological differences between studies limit the validity of conclusions drawn from analysis of the literature, and we identify a number of areas that future research might address.


Maternal transfer and sublethal immune system effects of brevetoxin exposure in nesting loggerhead sea turtles (Caretta caretta) from western Florida.
Blooms of Karenia brevis (also called red tides) occur almost annually in the Gulf of Mexico. The health effects of the neurotoxins (i.e., brevetoxins) produced by this toxic dinoflagellate on marine turtles are poorly understood. Florida's Gulf Coast represents an important foraging and nesting area for a number of marine turtle species. Most studies investigating brevetoxin exposure in marine turtles thus far focus on dead and/or stranded individuals and rarely examine the effects in apparently "healthy" free-ranging individuals. From May-July 2014, one year after the last red tide bloom, we collected blood from nesting loggerhead sea turtles (Caretta caretta) on Casey Key, Florida USA. These organisms show both strong nesting and foraging site fidelity. The plasma was analyzed for brevetoxin concentrations in addition to a number of health and immune-related parameters in an effort to establish sublethal effects of this toxin. Lastly, from July-September 2014, we collected unhatched eggs and liver and yolk sacs from dead-in-nest hatchlings from nests laid by the sampled females and tested these samples for brevetoxin concentrations to determine maternal transfer and effects on reproductive success. Using a competitive enzyme-linked immunosorbent assay (ELISA), all plasma samples from nesting females tested positive for brevetoxin (reported as ng brevetoxin-3[PbTx-3] equivalents [eq]/mL) exposure (2.1-26.7ng PbTx-3eq/mL). Additionally, 100% of livers (1.4-13.3ng PbTx-3eq/mL) and yolk sacs (1.7-6.6ng PbTx-3eq/mL) from dead-in-nest hatchlings and 70% of eggs (<1.0-24.4ng PbTx-3eq/mL) tested positive for brevetoxin exposure with the ELISA. We found that plasma brevetoxin concentrations determined by an ELISA in nesting females positively correlated with gamma-globulins, indicating a potential for immunomodulation as a result of brevetoxin exposure. While the sample sizes were small, we also found that plasma brevetoxin concentrations determined by an ELISA in nesting females significantly correlated with liver brevetoxin concentrations of dead-in-nest hatchlings and that brevetoxins could be related to a decreased reproductive success in this species. This study suggests that brevetoxins can still elicit negative effects on marine life long after a bloom has dissipated. These results improve our understanding of maternal transfer and sublethal effects of brevetoxin exposure in marine turtles.


Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial.
To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS). The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding. The trial was conducted at 4 academic institutions within North America. Patients Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years. BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg). The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses. BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-gamma-producing, myelin-reactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone. In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.


A hierarchical dynamical map as a basic frame for cortical mapping and its application to priming.
A hierarchical dynamical map is proposed as the basic framework for sensory cortical mapping. To show how the hierarchical dynamical map works in cognitive processes, we applied it to a typical cognitive task known as priming, in which cognitive performance is facilitated as a consequence of prior experience. Prior to the priming task, the network memorizes a sensory scene containing multiple objects presented simultaneously using a hierarchical dynamical map. Each object is composed of different sensory features. The hierarchical dynamical map presented here is formed by random itinerancy among limit-cycle attractors into which these objects are encoded. Each limit-cycle attractor contains multiple point attractors into which elemental features belonging to the same object are encoded. When a feature stimulus is presented as a priming cue, the network state is changed from the itinerant state to a limit-cycle attractor relevant to the priming cue. After a short priming period, the network state reverts to the itinerant state. Under application of the test cue, consisting of some feature belonging to the object relevant to the priming cue and fragments of features belonging to others, the network state is changed to a limit-cycle attractor and finally to a point attractor relevant to the target feature. This process is considered as the identification of the target. The model consistently reproduces various observed results for priming processes such as the difference in identification time between cross-modality and within-modality priming tasks, the effect of interval between priming cue and test cue on identification time, the effect of priming duration on the time, and the effect of repetition of the same priming task on neural activity.


Analysis and inactivation of vha55, the gene encoding the vacuolar ATPase B-subunit in Drosophila melanogaster reveals a larval lethal phenotype.
Vacuolar ATPases play major roles in endomembrane and plasma membrane proton transport in eukaryotes. A Drosophila melanogaster cDNA encoding vha55, the 55-kDa vacuolar ATPase (V-ATPase) regulatory B-subunit, was characterized and mapped to 87C2-4 on chromosome 3R. A fly line was identified that carried a single lethal P-element insertion within the coding portion of gene, and its LacZ reporter gene revealed elevated expression in Malpighian tubules, rectum, antennal palps, and oviduct, regions where V-ATPases are believed to play a plasma membrane, rather than an endomembrane, role. The P-element vha55 insertion was shown to be allelic to a known lethal complementation group l(3)SzA (= l(3)87Ca) at 87C, for which many alleles have been described previously. Deletions of the locus have been shown to be larval lethal, whereas point mutations show a range of phenotypes from subvital to embryonic lethal, implying that severe alleles confer a partial dominant negative phenotype. The P-element null allele of vha55 was shown also to suppress ectopic sex combs in Polycomb males, suggesting that transcriptional silencing may be modulated by genes other than those with known homeotic or DNA binding functions.


Transcriptional trajectories of human kidney injury progression.
The molecular understanding of the progression from acute to chronic organ injury is limited. Ischemia/reperfusion injury (IRI) triggered during kidney transplantation can contribute to progressive allograft dysfunction. Protocol biopsies (n = 163) were obtained from 42 kidney allografts at 4 time points after transplantation. RNA sequencing-mediated (RNA-seq-mediated) transcriptional profiling and machine learning computational approaches were employed to analyze the molecular responses to IRI and to identify shared and divergent transcriptional trajectories associated with distinct clinical outcomes. The data were compared with the response to IRI in a mouse model of the acute to chronic kidney injury transition. In the first hours after reperfusion, all patients exhibited a similar transcriptional program under the control of immediate-early response genes. In the following months, we identified 2 main transcriptional trajectories leading to kidney recovery or to sustained injury with associated fibrosis and renal dysfunction. The molecular map generated by this computational approach highlighted early markers of kidney disease progression and delineated transcriptional programs associated with the transition to chronic injury. The characterization of a similar process in a mouse IRI model extended the relevance of our findings beyond transplantation. The integration of multiple transcriptomes from serial biopsies with advanced computational algorithms overcame the analytical hurdles related to variability between individuals and identified shared transcriptional elements of kidney disease progression in humans, which may prove as useful predictors of disease progression following kidney transplantation and kidney injury. This generally applicable approach opens the way for an unbiased analysis of human disease progression. The study was supported by the California Institute for Regenerative Medicine and by the Swiss National Science Foundation.


Distinctive interactions of the Arabidopsis homolog of the 30 kD subunit of the cleavage and polyadenylation specificity factor (AtCPSF30) with other polyadenylation factor subunits.
The Arabidopsis ortholog of the 30 kD subunit of the mammalian Cleavage and Polyadenylation Specificity Factor (AtCPSF30) is an RNA-binding endonuclease that is associated with other Arabidopsis CPSF subunits (orthologs of the 160, 100, and 73 kD subunits of CPSF). In order to further explore the functions of AtCPSF30, the subcellular distribution of the protein was examined by over-expressing fusion proteins containing fluorescent reporters linked to different CPSF subunits. It was found that AtCPSF30 by itself localizes, not to the nucleus, but to the cytoplasm. AtCPSF30 could be found in the nucleus when co-expressed with AtCPSF160 or AtCPSF73(I), one of the two Arabidopsis orthologs of CPSF73. This re-directing of AtCPSF30 indicates that AtCPSF30 is retained in the nucleus via interactions with either or both of these other CPSF subunits. Co-expression of AtCSPF30 with AtCPSF100 altered the location, not of AtCPSF30, but rather of AtCPSF100, with these proteins residing in the cytoplasm. Deletion of plant-specific N- or C-terminal domains of AtCPSF30 abolished various of the interactions between AtCPSF30 and other CPSF subunits, suggesting that the plant CPSF complex assembles via novel protein-protein interactions. These results suggest that the nuclear CPSF complex in plants is a dynamic one, and that the interactions between AtCPSF30 and other CPSF subunits are different from those existing in other eukaryotes.


Prevention of thromboembolism after spinal cord injury using low-molecular-weight heparin.
To examine the safety and effectiveness of a low-molecular-weight heparin in the prevention of thromboembolism in patients with recent spinal cord injury and complete motor paralysis. Randomized evaluation of two heparin regimens in 41 consecutive patients meeting eligibility requirements for anticoagulant prophylaxis. Daily bedside examinations were supplemented by serial venous flow studies; suspicious or positive tests were confirmed by venography. Standard heparin, 5000 units subcutaneously three times a day; low-molecular-weight heparin 3500 anti-Xa units subcutaneously once daily. Five patients in the standard heparin group had thrombotic events, including two patients with fatal pulmonary embolism; two other patients had bleeding severe enough to necessitate withdrawing the heparin. The cumulative event rate was 34.7% (95% CI, 13.7% to 55.2%). None of the patients treated with low-molecular-weight heparin had thrombosis or bleeding (CI, 0% to 14%). The difference between the two groups was significant (P = 0.006, log-rank test). Low-molecular-weight heparin is safe and effective in the prevention of thromboembolism in selected patients with spinal cord injury and complete motor paralysis, and is superior to standard heparin in fixed doses of 5000 units three times a day.


An open-label phase IB study to evaluate GSK3052230 in combination with paclitaxel and carboplatin, or docetaxel, in FGFR1-amplified non-small cell lung cancer.
GSK3052230 (FP-1039) is a soluble fusion protein that acts as ligand trap sequestering fibroblast growth factors (FGFs) involved in tumor growth and angiogenesis, while sparing the hormonal FGFs. Because of this selectivity, the molecule is predicted to avoid toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Herein we report the results of a phase 1b study where GSK3052330 was administered with standard of care chemotherapy in FGFR1-amplified squamous non-small cell lung cancer (sqNSCLC) patients. Eligible patients with stage IV or recurrent metastatic sqNSCLC harboring FGFR1 gene amplification received escalating doses of GSK3052230 in combination with paclitaxel and carboplatin at the starting doses 200 mg/m2 and AUC of 6, respectively, in the first line setting (Arm A) or docetaxel 75 mg/m2 in second line (Arm B). The primary endpoints of the study were safety and tolerability, to identify a maximum tolerated dose (MTD), and to assess overall response rate (ORR) based on investigator assessment. Twenty-nine patients were enrolled into the study, including 20 patients on Arm A and 9 patients on Arm B. There were no dose limiting toxicities in either Arm and the MTD was not reached. The most common adverse events (AEs) were compatible with the chemotherapy backbone used in each Arm, including neutropenia, alopecia, nausea, arthralgia, asthenia, diarrhea and peripheral neuropathy. The overall response rate and median progression-free survival were 47% and 5.5 months, respectively, for Arm A and 0% and 4.6 months, respectively, for Arm B. GSK3052230 is a novel FGFR pathway inhibitor, which is well tolerated in combination with chemotherapy. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.


A Yellow Mosaic Disease of Soybean in Northern India is Caused by Cotton leaf curl Kokhran virus.
Soybean, Glycine max (L.) Merr., is a protein- and oil-rich crop cultivated in India and abroad. A yellow mosaic disease was observed on soybean with 80 to 90% disease incidence during August 2005 at fields of the National Botanical Research Institute, Lucknow, in northern India. Soybean plants were found to be infested with whiteflies (Bemisia tabaci) suggesting begomovirus etiology. The disease agent was transmitted experimentally by whiteflies, and symptoms developed after 23 days. Total DNA was isolated from 51 leaf samples collected from 42 symptomatic and 9 asymptomatic plants. Polymerase chain reaction was performed using begomovirus coat protein-specific primers 5'-ATGGCGAA GCGACCAG-3' and 5'-TTAATTTGTGACCGAATCAT-3' (AM180920/ AM180921). An amplicon of the expected size (~800 bp) was obtained in all 42 symptomatic leaves but not from any of the nine asymptomatic leaf samples. The amplicon was cloned, and the identical sequence of three clones was submitted to GenBank (Accession No. DQ343283). BLAST search of nucleotide sequences revealed 95% identity with Cotton leaf curl Kokhran virus (CLCKV) (GenBank Accession Nos. AJ002449, AJ002448, AJ496286, and AY456683) and 57% identity with Mungbean yellow mosaic India virus (MYMIV-Sb, GenBank Accession No. AY049772). Results indicated that the virus associated with yellow mosaic disease of soybean is an isolate of CLCKV rather than MYMIV-Sb (1) reported earlier on soybean from northern India. To our knowledge, this is the first report of soybean as a new host of Cotton leaf curl Kokhran virus. Reference: (1) K. S. Usharani et al. Curr. Sci. 86:845, 2004.