Evaluation of left ventricular function by bedside ultrasound in acute toxic myocarditis.
Myocarditis can be difficult to diagnose in the Emergency Department (ED) due to the lack of classic symptoms and the wide variation in presentations. Poor cardiac contractility is a common finding in myocarditis and can be evaluated by bedside ultrasound. To demonstrate the utility of fractional shortening measurements as an estimation of left ventricular function during bedside cardiac ultrasound evaluation in the ED. A 54-year-old man presented to the ED complaining of 3 days of chest tightness, palpitations, and dyspnea, as well as persistent abdominal pain and vomiting. An electrocardiogram (ECG) showed sinus tachycardia with presumably new ST-segment elevation and signs of an incomplete right bundle branch block. A bedside echocardiogram was performed by the emergency physician that showed poor left ventricular function by endocardial fractional shortening measurements. On further questioning, the patient revealed that for the past 2 weeks he had been regularly huffing a commercially available compressed air duster. Based on these history and examination findings, the patient was given a presumptive diagnosis of toxic myocarditis. A follow-up echocardiogram approximately 7 weeks later demonstrated resolution of the left ventricular systolic dysfunction and his ECG findings normalized. Cardiac ultrasound findings of severely reduced global function measured by endocardial fractional shortening were seen in this patient and supported the diagnosis of myocarditis. Endocardial fractional shortening is a useful means of easily evaluating and documenting left ventricular function and can be performed at the bedside in the ED.


Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.
Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.


A Second Look at Automatic Theory of Mind: Reconsidering Kovács, Téglás, and Endress (2010).
In recent work, Kovács, Téglás, and Endress (2010) argued that human adults automatically represented other agents' beliefs even when those beliefs were completely irrelevant to the task being performed. In a series of 13 experiments, we replicated these previous findings but demonstrated that the effects found arose from artifacts in the experimental paradigm. In particular, the critical findings demonstrating automatic belief computation were driven by inconsistencies in the timing of an attention check, and thus do not provide evidence for automatic theory of mind in adults.


The Vestibular Drive for Balance Control Is Dependent on Multiple Sensory Cues of Gravity.
Vestibular signals, which encode head movement in space as well as orientation relative to gravity, contribute to the ongoing muscle activity required to stand. The strength of this vestibular contribution changes with the presence and quality of sensory cues of balance. Here we investigate whether the vestibular drive for standing balance also depends on different sensory cues of gravity by examining vestibular-evoked muscle responses when independently varying load and gravity conditions. Standing subjects were braced by a backboard structure that limited whole-body sway to the sagittal plane while load and vestibular cues of gravity were manipulated by: (a) loading the body downward at 1.5 and 2 times body weight (i.e., load cues), and/or (b) exposing subjects to brief periods (20 s) of micro- (<0.05 g) and hyper-gravity (∼1.8 g) during parabolic flights (i.e., vestibular cues). A stochastic electrical vestibular stimulus (0-25 Hz) delivered during these tasks evoked a vestibular-error signal and corrective muscles responses that were used to assess the vestibular drive to standing balance. With additional load, the magnitude of the vestibular-evoked muscle responses progressively increased, however, when these responses were normalized by the ongoing muscle activity, they decreased and plateaued at 1.5 times body weight. This demonstrates that the increased muscle activity necessary to stand with additional load is accompanied a proportionally smaller increase in vestibular input. This reduction in the relative vestibular contribution to balance was also observed when we varied the vestibular cues of gravity, but only during an absence (<0.05 g) and not an excess (∼1.8 g) of gravity when compared to conditions with normal 1 g gravity signals and equivalent load signals. Despite these changes, vestibular-evoked responses were observed in all conditions, indicating that vestibular cues of balance contribute to upright standing even in the near absence of a vestibular signal of gravity (i.e., micro-gravity). Overall, these experiments provide evidence that both load and vestibular cues of gravity influence the vestibular signal processing for the control of standing balance.


Combating pertussis resurgence: One booster vaccination schedule does not fit all.
Pertussis has reemerged as a major public health concern in many countries where it was once considered well controlled. Although the mechanisms responsible for continued pertussis circulation and resurgence remain elusive and contentious, many countries have nevertheless recommended booster vaccinations, the timing and number of which vary widely. Here, using a stochastic, age-stratified transmission model, we searched for cost-effective booster vaccination strategies using a genetic algorithm. We did so assuming four hypothesized mechanisms underpinning contemporary pertussis epidemiology: (I) insufficient coverage, (II) frequent primary vaccine failure, (III) waning of vaccine-derived protection, and (IV) vaccine "leakiness." For scenarios I-IV, successful booster strategies were identified and varied considerably by mechanism. Especially notable is the inability of booster schedules to alleviate resurgence when vaccines are leaky. Critically, our findings argue that the ultimate effectiveness of vaccine booster schedules will likely depend on correctly pinpointing the causes of resurgence, with misdiagnosis of the problem epidemiologically ineffective and economically costly.


Gamma-radiation induced formation of chromium oxide nanoparticles from dissolved dichromate.
The formation of chromium oxide nanoparticles by gamma radiolysis of Cr(VI) (CrO(4)(2-) or Cr(2)O(7)(2-)) solutions was investigated as a function of pH and initial Cr(VI) concentration by measuring [Cr(VI)], the particle concentration ([Cr(III)(col)]) and [H(2)], and by characterizing the particles using TEM, Raman, FTIR and XPS. The results show that Cr(VI) is easily reduced to Cr(III) by a homogeneous aqueous reaction with ˙e(aq)(-), but, due to the stability of Cr(III) colloids, the growth of the Cr(OH)(3) particles is very slow. As the particles grow the interior of the particle dehydrates to form Cr(2)O(3) while the outer layer remains hydrated. When most of the Cr(VI) that is initially present in the solution is converted to Cr(OH)(3) further redox reactions of chromium species occur on the particle surfaces. The redox system reaches a pseudo-equilibrium state due to cyclic reactions of Cr(III) with ˙OH and H(2)O(2), and reactions of Cr(VI) with ˙e(aq)(-) and H(2)O(2). The size distribution of the particles that are formed is controlled by these solution-solid interface reactions.


Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment.
Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [(11) C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Parietal and occipital lobar CMBs counts were higher in PiB(+) ADCI with moderate WMH than PiB(+) ADCI with minimal WMH, whereas PiB(-) patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs.


Dietary intake and food sources of EPA, DPA and DHA in Australian children.
Secondary analysis of the 2007 Australian National Children's Nutrition and Physical Activity survey was undertaken to assess the intake and food sources of EPA, DPA and DHA (excluding supplements) in 4,487 children aged 2-16 years. An average of two 24-h dietary recalls was analysed for each child and food sources of EPA, DPA and DHA were assessed using the Australian nutrient composition database called AUSNUT 2007. Median (inter quartile range, IQR) for EPA, DPA and DHA intakes (mg/day) for 2-3, 4-8, 9-13, 14-16 year were: EPA 5.3 (1.5-14), 6.7 (1.8-18), 8.7 (2.6-23), 9.8 (2.7-28) respectively; DPA 6.2 (2.2-14), 8.2 (3.3-18), 10.8 (4.3-24), 12.2 (5-29) respectively; and DHA 3.9 (0.6-24), 5.1 (0.9-26), 6.8 (1.1-27), 7.8 (1.5-33) respectively. Energy-adjusted intakes of EPA, DPA and DHA in children who ate fish were 7.5, 2 and 16-fold higher, respectively (P < 0.001) compared to those who did not eat fish during the 2 days of the survey. Intake of total long chain n-3 PUFA was compared to the energy adjusted suggested dietary target (SDT) for Australian children and 20 % of children who ate fish during the 2 days of the survey met the SDT. Fish and seafood products were the largest contributors to DHA (76 %) and EPA (59 %) intake, while meat, poultry and game contributed to 56 % DPA. Meat consumption was 8.5 times greater than that for fish/seafood. Australian children do not consume the recommended amounts of long chain omega-3 fatty acids, especially DHA, which could be explained by low fish consumption.


Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies.
To understand how excitable tissues give rise to arrhythmias, it is crucially necessary to understand the electrical dynamics of cells in the context of their environment. Multicellular monolayer cultures have proven useful for investigating arrhythmias and other conduction anomalies, and because of their relatively simple structure, these constructs lend themselves to paired computational studies that often help elucidate mechanisms of the observed behavior. However, tissue cultures of cardiomyocyte monolayers currently require the use of neonatal cells with ionic properties that change rapidly during development and have thus been poorly characterized and modeled to date. Recently, Kirkton and Bursac demonstrated the ability to create biosynthetic excitable tissues from genetically engineered and immortalized HEK293 cells with well-characterized electrical properties and the ability to propagate action potentials. In this study, we developed and validated a computational model of these excitable HEK293 cells (called "Ex293" cells) using existing electrophysiological data and a genetic search algorithm. In order to reproduce not only the mean but also the variability of experimental observations, we examined what sources of variation were required in the computational model. Random cell-to-cell and inter-monolayer variation in both ionic conductances and tissue conductivity was necessary to explain the experimentally observed variability in action potential shape and macroscopic conduction, and the spatial organization of cell-to-cell conductance variation was found to not impact macroscopic behavior; the resulting model accurately reproduces both normal and drug-modified conduction behavior. The development of a computational Ex293 cell and tissue model provides a novel framework to perform paired computational-experimental studies to study normal and abnormal conduction in multidimensional excitable tissue, and the methodology of modeling variation can be applied to models of any excitable cell.


Projection onto Epigraph Sets for Rapid Self-Tuning Compressed Sensing MRI.
The compressed sensing (CS) framework leverages the sparsity of MR images to reconstruct from the undersampled acquisitions. CS reconstructions involve one or more regularization parameters that weigh sparsity in transform domains against fidelity to acquired data. While parameter selection is critical for reconstruction quality, the optimal parameters are subject and dataset specific. Thus, commonly practiced heuristic parameter selection generalizes poorly to independent datasets. Recent studies have proposed to tune parameters by estimating the risk of removing significant image coefficients. Line searches are performed across the parameter space to identify the parameter value that minimizes this risk. Although effective, these line searches yield prolonged reconstruction times. Here, we propose a new self-tuning CS method that uses computationally efficient projections onto epigraph sets of the l1 and total-variation norms to simultaneously achieve parameter selection and regularization. In vivo demonstrations are provided for balanced steady-state free precession, time-of-flight, and T1-weighted imaging. The proposed method achieves an order of magnitude improvement in computational efficiency over line-search methods while maintaining near-optimal parameter selection.


Bisphosphonate prescribing, persistence and cumulative exposure in Ontario, Canada.
We studied new users of oral bisphosphonates and found that less than half persisted with therapy for 2 years, and interruptions in use were common. During a median observation period of 4.7 years, 10% of patients filled only a single prescription, 37% switched therapies and median cumulative exposure was 2.2 years. We sought to describe bisphosphonate prescribing, persistence and cumulative exposure among seniors in Ontario, Canada. We used Ontario Drug Benefit pharmacy claims to identify residents aged ≥ 66 years who initiated oral bisphosphonate therapy between April 1996 and March 2009. The first date of bisphosphonate dispensing was considered the index date. Persistence with therapy was defined as continuous treatment with no interruption exceeding 60 days. We examined persistence with therapy and the number of extended gaps (>60 days) between prescriptions over time periods ranging from 1 to 9 years. We also identified the proportion of patients filling only a single prescription and switching to a different bisphosphonate, and calculated the median days of exposure irrespective of gaps in therapy. A total of 451,113 eligible new bisphosphonate users were identified: mean age = 75.6 years (SD = 6.9), 84% female, and median follow-up length = 4.7 years. Persistence with therapy declined from 63% at 1 year to 46% at 2 years and 12% at 9 years. Among those with at least 5 years of follow-up (n = 213,029), 61% had one or more extended gaps in bisphosphonate therapy. Overall, 10% of patients filled only a single prescription, 37% switched to a different bisphosphonate and the median exposure was 2.2 years. Less than half of patients persisted with bisphosphonate therapy for 2 years and interruptions in therapy were common, with most patients experiencing two or more >60-day gaps in therapy. Interventions are needed to improve persistence with bisphosphonate therapy and reduce the frequency of gaps in treatment.


Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide.
Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft. Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites. The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively. UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.


Genome-scale consequences of cofactor balancing in engineered pentose utilization pathways in Saccharomyces cerevisiae.
Biofuels derived from lignocellulosic biomass offer promising alternative renewable energy sources for transportation fuels. Significant effort has been made to engineer Saccharomyces cerevisiae to efficiently ferment pentose sugars such as D-xylose and L-arabinose into biofuels such as ethanol through heterologous expression of the fungal D-xylose and L-arabinose pathways. However, one of the major bottlenecks in these fungal pathways is that the cofactors are not balanced, which contributes to inefficient utilization of pentose sugars. We utilized a genome-scale model of S. cerevisiae to predict the maximal achievable growth rate for cofactor balanced and imbalanced D-xylose and L-arabinose utilization pathways. Dynamic flux balance analysis (DFBA) was used to simulate batch fermentation of glucose, D-xylose, and L-arabinose. The dynamic models and experimental results are in good agreement for the wild type and for the engineered D-xylose utilization pathway. Cofactor balancing the engineered D-xylose and L-arabinose utilization pathways simulated an increase in ethanol batch production of 24.7% while simultaneously reducing the predicted substrate utilization time by 70%. Furthermore, the effects of cofactor balancing the engineered pentose utilization pathways were evaluated throughout the genome-scale metabolic network. This work not only provides new insights to the global network effects of cofactor balancing but also provides useful guidelines for engineering a recombinant yeast strain with cofactor balanced engineered pathways that efficiently co-utilizes pentose and hexose sugars for biofuels production. Experimental switching of cofactor usage in enzymes has been demonstrated, but is a time-consuming effort. Therefore, systems biology models that can predict the likely outcome of such strain engineering efforts are highly useful for motivating which efforts are likely to be worth the significant time investment.


A map of human microRNA variation uncovers unexpectedly high levels of variability.
MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in a healthy population seems an obvious requirement for future research on miRNA-related pathologies. Data on 14 populations from the 1000 Genomes Project were analyzed, along with new data extracted from 60 exomes of healthy individuals from a population from southern Spain, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.


A switch in infected erythrocyte deformability at the maturation and blood circulation of Plasmodium falciparum transmission stages.
Achievement of malaria elimination requires development of novel strategies interfering with parasite transmission, including targeting the parasite sexual stages (gametocytes). The formation of Plasmodium falciparum gametocytes in the human host takes several days during which immature gametocyte-infected erythrocytes (GIEs) sequester in host tissues. Only mature stage GIEs circulate in the peripheral blood, available to uptake by the Anopheles vector. Mechanisms underlying GIE sequestration and release in circulation are virtually unknown. We show here that mature GIEs are more deformable than immature stages using ektacytometry and microsphiltration methods, and that a switch in cellular deformability in the transition from immature to mature gametocytes is accompanied by the deassociation of parasite-derived STEVOR proteins from the infected erythrocyte membrane. We hypothesize that mechanical retention contributes to sequestration of immature GIEs and that regained deformability of mature gametocytes is associated with their release in the bloodstream and ability to circulate. These processes are proposed to play a key role in P falciparum gametocyte development in the host and to represent novel and unconventional targets for interfering with parasite transmission.


Effects of therapeutic passive exercise of hip and knee joints on the soleus H-reflex.
The effect of passive movement of a leg on alpha-motoneurons of the soleus was investigated while the ankle was immobilized. Electrophysiological parameters of the H-reflex were used. Nineteen fully informed volunteers with no history of neurological or internal disease participated in the study. The mean age across all the experiments was 20.9 years. Contributions to the modulation of the soleus H-reflex by hip and knee joint movements were analyzed in two tasks. These were the most general movement methods used in physical therapy. Soleus H-reflexes were measured six times per experiment. Stimulation intensity was set at the 1.1 x M-wave threshold. 1. In both exercises, H/M decreased as flexion progressed with fast or slow movement. The quadriceps femoris inhibited soleus muscle alpha-motoneurons in both experiments. 2. H/M increased on initiation of extension in the two-joint exercise. In the single-joint exercise, inhibition was retained through the extension phase during both fast and slow movements. Hamstring effects were strong during extension of the leg. 3. In both exercises, the H/M for fast movement was lower than for slow movement at all angles, indicative that H/M decreases with fast movement irrespective of the effects produced by the hip joint.


Intestinal NADPH oxidase 2 activity increases in a neonatal rat model of necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is a complication of prematurity. The etiology is unknown, but is related to enteral feeding, ischemia, infection, and inflammation. Reactive oxygen species production, most notably superoxide, increases in NEC. NADPH oxidase (NOX) generates superoxide, but its activity in NEC remains unknown. We hypothesize that NOX-derived superoxide production increases in NEC. Newborn Sprague-Dawley rats were divided into control, formula-fed, formula/LPS, formula/hypoxia, and NEC (formula, hypoxia, and LPS). Intestinal homogenates were analyzed for NADPH-dependent superoxide production. Changes in superoxide levels on days 0-4 were measured. Inhibitors for nitric oxide synthase (L-NAME) and NOX2 (GP91-ds-tat) were utilized. RT-PCR for eNOS, NOX1, GP91phox expression was performed. Immunofluorescence studies estimated the co-localization of p47phox and GP91phox in control and NEC animals on D1, D2, and D4. NEC pups generated more superoxide than controls on D4, while all other groups were unchanged. NADPH-dependent superoxide production was greater in NEC on days 0, 3, and 4. GP91-ds-tat decreased superoxide production in both groups, with greater inhibition in NEC. L-NAME did not alter superoxide production. Temporally, superoxide production varied minimally in controls. In NEC, superoxide generation was decreased on day 1, but increased on days 3-4. GP91phox expression was higher in NEC on days 2 and 4. NOX1 and eNOS expression were unchanged from controls. GP91phox and p47phox had minimal co-localization in all control samples and NEC samples on D1 and D2, but had increased co-localization on D4. In conclusion, this study proves that experimentally-induced NEC increases small intestinal NOX activity. All components of NEC model are necessary for increased NOX activity. NOX2 is the major source, especially as the disease progresses.


Arteriovenous malformation of mandible: Extracorporeal curettage with immediate replantation technique.
Arteriovenous malformations of jaw are extremely rare conditions that can result in disastrous complications, if handled carelessly. Although various treatment modalities have been advocated in the literature, there seems to be no complete consensus on a suitable treatment in these cases. This report highlights the importance of correct diagnosis and early treatment in management of vascular malformations. Extracorporeal curettage followed by immediate replantation yielded good results in our case and this technique can emerge as a valid alternative, especially in developing countries.


An investigation into social information processing in young people with Asperger syndrome.
Deficits in social functioning are a core feature of autistic spectrum disorders (ASD), being linked to various cognitive and developmental factors, but there has been little attempt to draw on normative models of social cognition to understand social behaviour in ASD. The current study explored the utility of Crick and Dodge's (1994) information processing model to studying social cognition in ASD, and examined associations between social information processing patterns, theory of mind skills and social functioning. A matched-group design compared young people with Asperger syndrome with typically developing peers, using a social information processing interview previously designed for this purpose. The Asperger syndrome group showed significantly different patterns of information processing at the intent attribution, response generation and response evaluation stages of the information processing model. Theory of mind skills were found to be significantly associated with parental ratings of peer problems in the Asperger syndrome group but not with parental ratings of pro-social behaviour, with only limited evidence of an association between social information processing and measures of theory of mind and social functioning. Overall, the study supports the use of normative social information processing approaches to understanding social functioning in ASD.


An investigation into the impact and implications of published papers from retracted research: systematic search of affected literature.
Analyses of the impact of a body of clinical trial reports subject to research misconduct have been few. Our objective was to examine the impact on clinically relevant research of a group of researchers' trial reports ('affected trial reports') affected by research misconduct, and whether identification of misconduct invoked a reappraisal. In 2016, we used five databases and search engines to identify 'citing publications', that is, guidelines, systematic and other reviews, and clinical trials citing any of 12 affected trial reports, published 1998-2011, eventually retracted for research misconduct. The affected trial reports were assessed more likely to have had impact because they had hip fracture outcomes and were in journals with impact factor >4. Two authors assessed whether findings of the citing publications would change if the affected trial reports were removed. In 2018, we searched for evidence that the citing publications had undertaken a reassessment as a result of the potential influence of the affected trial reports. By 2016 the affected trial reports were cited in 1158 publications, including 68 systematic reviews, meta-analyses, narrative reviews, guidelines and clinical trials. We judged that 13 guidelines, systematic or other reviews would likely change their findings if the affected trial reports were removed, and in another eight it was unclear if findings would change. By 2018, only one of the 68 citing publications, a systematic review, appeared to have undertaken a reassessment, which led to a correction. We found evidence that this group of affected trial reports distorted the evidence base. Correction of these distortions is slow, uncoordinated and inconsistent. Unless there is a rapid, systematic, coordinated approach by bibliographic databases, authors, journals and publishers to mitigate the impact of known cases of research misconduct, patients, other researchers and their funders may continue to be adversely affected.


Epidermal growth factor receptor status of histological sub-types of breast cancer.
The histological breakdown of a consecutive series of 264 surgically resected malignant lesions of the breast was studied. Oestrogen and epidermal growth factor receptor status was quantified and presented along with size and lymph node status of the non-ductal lesions. Those non-ductal tumours containing EGF receptors have all recurred within two years of resection. Twenty-one percent of the lobular carcinomas contained EGF receptors compared to 34% of ductal carcinomas. EGF receptor status appeared to be associated with an increased risk of early recurrence and death whatever the histological sub-type of the breast cancer.


Testosterone treatment and cardiovascular and venous thromboembolism risk: what is 'new'?
In men, testosterone (T) production declines as a function of ageing. Late-onset hypogonadism (LOH) is the most commonly used term to indicate this age-related condition. In LOH, the relative clinical significance and the potential benefit of testosterone treatment (TTh) are still the subject of strong criticisms in the scientific community. The debate is further complicated by the recent position statement of the US Food and Drug Administration (FDA) emphasizing that, in LOH, the benefits and safety of TTh have not been fully established. Hence, the FDA required a labeling change to inform patients about a possible increased cardiovascular (CV) risk of TTh. Similar considerations were previously released by the FDA and by Health Canada concerning a TTh-related venous thromboembolism (VTE) risk. In this review, we will summarize the available evidence concerning a possible link among TTh and CV and VTE risks. For this purpose, data derived from epidemiological studies analyzing relationships between the aforementioned risks and endogenous T levels will be analyzed. In addition, evidence deriving from interventional studies including pharmacoepidemiological and placebo-controlled randomized controlled trials (RCTs) will be examined. Our analysis shows that available data do not support an increased CV risk related to TTh. Similar considerations can be drawn for the relationship between TTh and VTE. The previously reported cases of TTh-related VTE were frequently related to a previously undiagnosed thrombophilia-hypofibrinolysis status. Hence, an anamnestic screening for thrombophilia before starting TTh is recommended, just as it is for the use of oral contraceptives.


Structures, mechanical properties, equations of state, and electronic properties of β-HMX under hydrostatic pressures: a DFT-D2 study.
We report the hydrostatic compression studies of the β-polymorph of a cyclotetramethylene tetranitramine (HMX) energetic molecular crystal using DFT-D2, a first-principles calculation based on density functional theory (DFT) with van der Waals (vdW) corrections. The molecular structure, mechanical properties, electronic properties, and equations of state of β-HMX are investigated. For the first time, we predict the elastic constants of β-HMX using DFT-D2 studies. The equations of state under hydrostatic compression are studied for pressures up to 100 GPa. We found that the N-N bonds along the minor axis are responsible for the sensitivity of β-HMX. The analysis of the charge distribution shows that the electronic charge is transferred from hydrogen atoms to nitro groups with the amount of 0.131 and 0.064e for the nitro groups along the minor axis and major axis, respectively, when pressure changes from 0 GPa to 100 GPa. The electronic energy band gap changes from direct at a pressure of 0 GPa to indirect at a pressure of 50 GPa and higher. The band gap decreases with respect to an increase in pressure, implying that the impact sensitivity increases with compression. Our study suggests that the van der Waals interactions are critically important in modeling the mechanical properties of this molecular crystal.


Myocardial depression. The effect of Ca++ and calcium flux during sepsis.
Previous studies from this laboratory described myocardial depression in an arterially perfused rabbit interventricular septum following perfusion with acute septic plasma. Calcium is critical for maintenance of cardiac contractility on a beat-to-beat basis. We have investigated calcium flux in the septal tissue to determine whether altered calcium flux explains the impaired cardiac function during sepsis. Twenty-two rabbit septa were perfused with control and septic perfusate (cryo-precipitated plasma + RBCs) and calcium flux determined in seven experiments. Perfusate cations (Ca++, Na+, K+, and H+) were measured, tissue function and arterial pressure were monitored. Developed tension decreased 46%, acceleration of tension change fell 42%, and arterial pressure decreased 26%, all highly significant. All septa recovered after return to control perfusate. The septic perfusate Ca++ was significantly lower than control perfusate, while K+ and H+ were significantly elevated. Ion flux studies, however, could not demonstrate altered calcium flux associated with the depressed contractility.


Differential Effects of Integrin αv Knockdown and Cilengitide on Sensitization of Triple-Negative Breast Cancer and Melanoma Cells to Microtubule Poisons.
Low survival rates of patients with metastatic triple-negative breast cancer (TNBC) and melanoma, in which current therapies are ineffective, emphasize the need for new therapeutic approaches. Integrin β1 appears to be a promising target when combined with chemotherapy, but recent data have shown that its inactivation increases metastatic potential owing to the compensatory upregulation of other integrin subunits. Consequently, we analyzed the potential of integrin subunits αv, α3, or α4 as targets for improved therapy in seven TNBC and melanoma cell lines. Experiments performed in an integrin αvβ1-negative melanoma cell line, MDA-MB-435S, showed that knockdown of integrin subunit αv increased sensitivity to microtubule poisons vincristine or paclitaxel and decreased migration and invasion. In the MDA-MB-435S cell line, we also identified a phenomenon in which change in the expression of one integrin subunit changes the expression of other integrins, leading to an unpredictable influence on sensitivity to anticancer drugs and cell migration, referred to as the integrin switching effect. In a panel of six TNBCs and melanoma cell lines, the contribution of integrins αv versus integrins αvβ3/β5 was assessed by the combined action of αv-specific small interfering RNA or αvβ3/β5 inhibitor cilengitide with paclitaxel. Our results suggest that, for TNBC, knockdown of integrin αv in combination with paclitaxel presents a better therapeutic option than a combination of cilengitide with paclitaxel; however, in melanoma, neither of these combinations is advisable because a decreased sensitivity to paclitaxel was observed.


Who comes first? The role of the prefrontal and parietal cortex in cognitive control.
Cognitive control processes enable us to adjust our behavior to changing environmental demands. Although neuropsychological studies suggest that the critical cortical region for cognitive control is the prefrontal cortex, neuro-imaging studies have emphasized the interplay of prefrontal and parietal cortices. This raises the fundamental question about the different contributions of prefrontal and parietal areas in cognitive control. It was assumed that the prefrontal cortex biases processing in posterior brain regions. This assumption leads to the hypothesis that neural activity in the prefrontal cortex should precede parietal activity in cognitive control. The present study tested this assumption by combining results from functional magnetic resonance imaging (fMRI) providing high spatial resolution and event-related potentials (ERPs) to gain high temporal resolution. We collected ERP data using a modified task-switching paradigm. In this paradigm, a situation where the same task was indicated by two different cues was compared with a situation where two cues indicated different tasks. Only the latter condition required updating of the task set. Task-set updating was associated with a midline negative ERP deflection peaking around 470 msec. We placed dipoles in regions activated in a previous fMRI study that used the same paradigm (left inferior frontal junction, right inferior frontal gyrus, right parietal cortex) and fitted their directions and magnitudes to the ERP effect. The frontal dipoles contributed to the ERP effect earlier than the parietal dipole, providing support for the view that the prefrontal cortex is involved in updating of general task representations and biases relevant stimulus-response associations in the parietal cortex.


Prenatal exposure to polychlorinated biphenyls and breastfeeding: opposing effects on auditory P300 latencies in 9-year-old Dutch children.
Effects of perinatal exposure to polychlorinated biphenyls (PCBs) on auditory P300 latencies and amplitudes were evaluated in children from a Rotterdam cohort. From this cohort of healthy, term babies, the 26 lowest and 26 highest prenatally PCB-exposed children from the breastfed and the formula-fed groups (n=104) were invited for P300 assessment when they were 9 years of age. For P300 assessment an auditory simple odd-ball paradigm was used. In the 83 participating children, 60 assessments (32 males, 28 females) satisfied the measurement criteria and were included in the data analyses. After adjusting for confounding variables, children with high prenatal exposure were found to have longer P300 latencies than children with low prenatal exposure. Lactational exposure to PCBs through breastfeeding milk was not related to P300 latencies. P300 latencies were shorter in children breast-fed for at least 16 weeks than in children breastfed for 6 to 16 weeks and formula-fed children. P300 amplitudes were not related to perinatal PCB exposure nor breastfeeding. Results of this exploratory study suggest that prenatal exposure to environmental levels of PCBs and related compounds delays mechanisms in the central nervous system that evaluate and process relevant stimuli, whereas breastfeeding accelerates these mechanisms.


Posttranslational processing of concanavalin A precursors in jackbean cotyledons.
Metabolic labeling of immature jackbean cotyledons with 14C-amino acids was used to determine the processing steps involved in the assembly of concanavalin A. Pulse-chase experiments and analyses of immunoprecipitated lectin forms indicated a complex series of events involving seven distinct species. The structural relatedness of all of the intermediate species was confirmed by two-dimensional mapping of 125I-tryptic peptides. An initial glycosylated precursor was deglycosylated and cleaved into smaller polypeptides, which subsequently reannealed over a period of 10-27 h. NH2-terminal sequencing of the abundant precursors confirmed that the intact subunit of concanavalin A was formed by the reannealing of two fragments, since the alignment of residues 1-118 and 119-237 was reversed in the final form of the lectin identified in the chase and the precursor first labeled. When the tissue was pulse-chased in the presence of monensin, processing of the glycosylated precursor was inhibited. The weak bases NH4Cl and chloroquine were without effect. Immunocytochemical studies showed that monensin treatment caused the accumulation of immunoreactive material at the cell surface and indicated that the ionophore had induced the secretion of a component normally destined for deposition within the protein bodies. Consideration of the tertiary structure of the glycosylated precursor and mature lectin showed that the entire series of processing events could occur without significant refolding of the initial translational product. Proteolytic events included removal of a peptide from the surface of the precursor molecule that connected the NH2- and COOH-termini of the mature protein. This processing activated the carbohydrate-binding activity of the lectin. The chase data suggest the occurrence of a simultaneous cleavage and formation of a peptide bond, raising the possibility that annealment of the fragments to give rise to the mature subunit involves a transpeptidation event rather than cleavage and subsequent religation.


Examining the Process of Modal Choice for Everyday Travel Among Older People.
Modal choice is a prominent concept within transport studies. However, the term is often used quite loosely, with little known about the factors lying behind the choice, the alternatives available to a person, and whether the person had a 'choice' to begin with. This study draws on a travel survey among older people living in Sweden's large metropolitan regions. The questions posed as part of this survey facilitate a greater insight into the processes at play behind modal choice. An analysis of the differences between: (1) the range of modal options available to respondents and (2) the modes selected from this range (modal choice) is presented. An analysis of the respondents' reasoning for choosing the modes they did and not the others they could have chosen is also presented. It was found that more than a quarter of respondents have the option to use and actually use all modes for everyday travel. The car is more inclined to be selected among those who have a range of different modal options. Suitability and comfort are the two main reasons given for modal choice. More positive reasons are given for actively selecting walking and cycling, whereas the motives behind the selection of the car instead tend to be framed as reasons for not selecting other modes. Adaptive preference and adjustment effects are also apparent in the selection processes. This study gives us a deeper understanding of the intricate mechanisms and reasoning at play behind the process of modal choice among this group. In this way, we have a better basis for shaping and implementing measures to promote and encourage sustainable mobility, in such a way that the well-being of older people is also supported.


Effects of synthetic atrial natriuretic peptides on sodium-potassium transport in human erythrocytes.
The effects of synthetic human and rat atrial peptides on sodium and potassium ion transport has been investigated in intact human erythrocytes. The effects of these peptides have been tested on the active, sodium pump-dependent (ouabain-sensitive) and on the sodium-potassium cotransport system (bumetanide-sensitive) with 86Rb used as a tracer. Human (alpha-ANP, 28 amino acids) or rat (atriopeptin III) atrial peptides, over a wide range of concentrations, did not influence the uptake of 86Rb in either the ouabain-sensitive or the bumetanide-sensitive transport system. These results suggest that the natriuretic effect of the atrial peptides is not mediated through inhibition of the sodium pump or the loop-diuretic-sensitive Na-K cotransport.


Self-efficacy as a predictor of adult adjustment to sickle cell disease: one-year outcomes.
The present study prospectively investigated the role of self-efficacy in predicting disease symptomatology and health services utilization for adult patients with sickle cell disease. These data are derived from a 12-month prospective cohort study of African American adults with sickle cell disease. Disease-specific perceptions of coping self-efficacy and indices of disease severity, health care utilization, and psychosocial adjustment were assessed by use of standardized questionnaires administered by trained clinicians. Perceptions of self-efficacy for coping with sickle cell disease were moderately stable across the 12-month study period. At baseline (N = 147), significant inverse relationships, measured with Pearson correlations, were noted between self-efficacy and the following variables: physical symptoms, psychological symptoms, pain severity, and number of physician visits over the preceding 12 months (p <.01). Similar relationships with self-efficacy were noted at the 1-year follow-up (N = 104) period for measures of physical symptoms, psychological symptoms, and pain severity (p <.01). In multiple-regression models, baseline self-efficacy scores predicted changes over the 1-year study period in physical and psychological sickle cell disease symptomatology. Moreover, changes in self-efficacy from baseline to 1-year follow-up were significantly and independently related to changes in physical symptoms, psychological symptoms, and pain ratings from baseline to 1-year follow-up. Self-efficacy beliefs among African American adults with sickle cell disease are inversely related to reported disease symptomatology, and these relationships persist across time. Future investigations should examine the mechanisms through which relationships between self-efficacy and adjustment to sickle cell disease are effected, as well as the feasibility and effectiveness of enhancing self-efficacy beliefs as a means of improving adjustment to sickle cell disease.


Reclaiming the community: the strengths perspective and deinstitutionalization.
In the past decade, concern for the plight of severely mentally ill people has centered on such issues as mental illness among the homeless population, the burden placed on families who care for ill loved ones, and the impoverished quality of life experienced by those who attempt to survive on their own. Some have called for a rethinking of the abandonment of the asylum and a relaxation of civil commitment laws, while others have advocated for increasing community-based services that specifically target severely mentally ill people. This article discusses these issues and considers how the response to severe mental illness has overrelied on pathology-based models of helping. The strengths perspective provides an alternative. Although severe mental illness presents a formidable obstacle to the afflicted, mentally challenged individuals have strengths and abilities that can be tapped to foster their continued integration in community settings. This adjustment is best conducted through the use of naturally occurring community resources rather than specialized, segregated programs.


Rifampin use and safety in hospitalized infants.
This study aims to examine the use and safety of rifampin in the hospitalized infants. Observational study of clinical and laboratory adverse events among infants exposed to rifampin from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Overall, 2,500 infants received 4,279 courses of rifampin; mean gestational age was 27 weeks (5th, 95th percentile; 23, 36) and mean birth weight was 1,125 g (515; 2,830). Thrombocytopenia (121/1,000 infant days) and conjugated hyperbilirubinemia (25/1,000 infant days) were the most common laboratory adverse events. The most common clinical adverse events were medical necrotizing enterocolitis (64/2,500 infants, 3%) and seizure (60/2,500 infants, 2%). The overall incidence of adverse events among infants receiving rifampin appears low; however, additional studies to further evaluate safety and dosing of rifampin in this population are needed.


Identification of a novel polyomavirus from patients with acute respiratory tract infections.
We report the identification of a novel polyomavirus present in respiratory secretions from human patients with symptoms of acute respiratory tract infection. The virus was initially detected in a nasopharyngeal aspirate from a 3-year-old child from Australia diagnosed with pneumonia. A random library was generated from nucleic acids extracted from the nasopharyngeal aspirate and analyzed by high throughput DNA sequencing. Multiple DNA fragments were cloned that possessed limited homology to known polyomaviruses. We subsequently sequenced the entire virus genome of 5,229 bp, henceforth referred to as WU virus, and found it to have genomic features characteristic of the family Polyomaviridae. The genome was predicted to encode small T antigen, large T antigen, and three capsid proteins: VP1, VP2, and VP3. Phylogenetic analysis clearly revealed that the WU virus was divergent from all known polyomaviruses. Screening of 2,135 patients with acute respiratory tract infections in Brisbane, Queensland, Australia, and St. Louis, Missouri, United States, using WU virus-specific PCR primers resulted in the detection of 43 additional specimens that contained WU virus. The presence of multiple instances of the virus in two continents suggests that this virus is geographically widespread in the human population and raises the possibility that the WU virus may be a human pathogen.


Advance Care Planning in Glioblastoma Patients.
Despite multimodal treatment with surgery, radiotherapy and chemotherapy, glioblastoma is an incurable disease with a poor prognosis. During the disease course, glioblastoma patients may experience progressive neurological deficits, symptoms of increased intracranial pressure such as drowsiness and headache, incontinence, seizures and progressive cognitive dysfunction. These patients not only have cancer, but also a progressive brain disease. This may seriously interfere with their ability to make their own decisions regarding treatment. It is therefore warranted to involve glioblastoma patients early in the disease trajectory in treatment decision-making on their future care, including the end of life (EOL) care, which can be achieved with Advance Care Planning (ACP). Although ACP, by definition, aims at timely involvement of patients and proxies in decision-making on future care, the optimal moment to initiate ACP discussions in the disease trajectory of glioblastoma patients remains controversial. Moreover, the disease-specific content of these ACP discussions needs to be established. In this article, we will first describe the history of patient participation in treatment decision-making, including the shift towards ACP. Secondly, we will describe the possible role of ACP for glioblastoma patients, with the specific aim of treatment of disease-specific symptoms such as somnolence and dysphagia, epileptic seizures, headache, and personality changes, agitation and delirium in the EOL phase, and the importance of timing of ACP discussions in this patient population.


Efficient gate-tunable light-emitting device made of defective boron nitride nanotubes: from ultraviolet to the visible.
Boron nitride is a promising material for nanotechnology applications due to its two-dimensional graphene-like, insulating, and highly-resistant structure. Recently it has received a lot of attention as a substrate to grow and isolate graphene as well as for its intrinsic UV lasing response. Similar to carbon, one-dimensional boron nitride nanotubes (BNNTs) have been theoretically predicted and later synthesised. Here we use first principles simulations to unambiguously demonstrate that i) BN nanotubes inherit the highly efficient UV luminescence of hexagonal BN; ii) the application of an external perpendicular field closes the electronic gap keeping the UV lasing with lower yield; iii) defects in BNNTS are responsible for tunable light emission from the UV to the visible controlled by a transverse electric field (TEF). Our present findings pave the road towards optoelectronic applications of BN-nanotube-based devices that are simple to implement because they do not require any special doping or complex growth.


Polymer scaling laws of unfolded and intrinsically disordered proteins quantified with single-molecule spectroscopy.
The dimensions of unfolded and intrinsically disordered proteins are highly dependent on their amino acid composition and solution conditions, especially salt and denaturant concentration. However, the quantitative implications of this behavior have remained unclear, largely because the effective theta-state, the central reference point for the underlying polymer collapse transition, has eluded experimental determination. Here, we used single-molecule fluorescence spectroscopy and two-focus correlation spectroscopy to determine the theta points for six different proteins. While the scaling exponents of all proteins converge to 0.62 ± 0.03 at high denaturant concentrations, as expected for a polymer in good solvent, the scaling regime in water strongly depends on sequence composition. The resulting average scaling exponent of 0.46 ± 0.05 for the four foldable protein sequences in our study suggests that the aqueous cellular milieu is close to effective theta conditions for unfolded proteins. In contrast, two intrinsically disordered proteins do not reach the Θ-point under any of our solvent conditions, which may reflect the optimization of their expanded state for the interactions with cellular partners. Sequence analyses based on our results imply that foldable sequences with more compact unfolded states are a more recent result of protein evolution.


The making of a moral economy: women's views of monetary transactions in an 'egg sharing for research' scheme.
There are growing debates about the appropriateness of offering money in exchange for the provision of bodily materials for clinical treatment and research. The bioethics literature and many practice guidelines have generally been opposed to such entanglement, depicting the use of money as contaminating, creating undue inducement, exploitation and commodification of the human body. However, two elements have been missing from these debates: (i) the perspectives of those people providing bodily materials when money is offered; and (ii) systematic empirical engagement with the notion of 'money' itself. This article seeks to fill those gaps in knowledge by providing detailed insights from a project investigating the views and experiences of women who volunteered to provide eggs for research in exchange for reduced fees for fertility treatment. Analysis of 29 semi-structured interviews reveals multiple ways in which volunteers reason through the involvement of 'money' in this domain and shows how their accounts diverge from pessimistic understandings of the role of monies in everyday life. When volunteers speak in detail about the monetary aspects of their participation they draw major, recurring, distinctions in five overlapping areas: their depiction of the monetized world of fertility treatment; their views of the different forms that money can take; a distancing of their actions from their understandings of how markets and commodities work; their location of the transactions within a particular clinic, and the ongoing importance of their eggs, post-transaction. This article: (i) responds to calls for concrete case studies to assist understandings of the inter-relationships of money and specific aspects of social life; (ii) adds to the sociology of money literature by providing empirical insights into how notions of money are deployed; (iii) presents much-needed perspectives from providers of bodily materials; and (iv) contributes to ongoing conversations between bioethics and sociology.


Comparison of diagnostic value of multi-slice spiral CT and MRI for different pathological stages of prostate cancer.
Diagnostic value of magnetic resonance imaging (MRI) and multi-slice spiral CT (MSCT) for different pathological stages of prostate cancer was compared. A total of 112 patients with prostate cancer who underwent surgical pathology in The Affiliated Yantai Yuhuangding Hospital of Qingdao University from February 2014 to January 2016 were enrolled as prostate cancer group, and another 100 patients who received physical health examinations during the same period as the normal group. MSCT and MRI scanning were performed on patients in both groups to analyze their diagnostic value for stages A/B and C/D of prostate cancer. Based on the apparent diffusion coefficient (ADC) value generated by the diffusion-weighted imaging (DWI) in MRI, there was a significant difference in the ADC value between different stages of prostate cancer (P<0.05); the pathological stage was negatively correlated with the ADC value (r=-0.7629, P<0.05), and the higher the stage was, the lower the ADC value was. The sensitivity was significantly higher in the MRI group than that in the MSCT group (92.0 vs. 79.5%, P<0.05), and the specificity was significantly higher in the MRI group than that in the MSCT group (90.0 vs. 70.0%, P<0.05). In the diagnosis of stage A and B of prostate cancer, the diagnostic coincidence rate was 86.7% in the MRI group, and 57.8% in the MSCT group (P<0.05); the misdiagnosis rate and missed diagnosis rate were significantly lower in the MRI group than those in the MSCT group (P<0.05). The accuracy of MRI is higher than that of MSCT in the diagnosis of early prostate cancer. Both MRI and MSCT can accurately detect stages C and D of prostate cancer, but the ADC value in MRI has great clinical significance for judging the risk of the tumor. Therefore, MRI is more valuable than MSCT in the diagnosis of patients with different pathological stages of prostate cancer.


Segmental hair analysis for differentiation of tilidine intake from external contamination using LC-ESI-MS/MS and MALDI-MS/MS imaging.
Segmental hair analysis has been used for monitoring changes of consumption habit of drugs. Contamination from the environment or sweat might cause interpretative problems. For this reason, hair analysis results were compared in hair samples taken 24 h and 30 days after a single tilidine dose. The 24-h hair samples already showed high concentrations of tilidine and nortilidine. Analysis of wash water from sample preparation confirmed external contamination by sweat as reason. The 30-day hair samples were still positive for tilidine in all segments. Negative wash-water analysis proved incorporation from sweat into the hair matrix. Interpretation of a forensic case was requested where two children had been administered tilidine by their nanny and tilidine/nortilidine had been detected in all hair segments, possibly indicating multiple applications. Taking into consideration the results of the present study and of MALDI-MS imaging, a single application as cause for analytical results could no longer be excluded. Interpretation of consumption behaviour of tilidine based on segmental hair analysis has to be done with caution, even after typical wash procedures during sample preparation. External sweat contamination followed by incorporation into the hair matrix can mimic chronic intake. For assessment of external contamination, hair samples should not only be collected several weeks but also one to a few days after intake. MALDI-MS imaging of single hair can be a complementary tool for interpretation. Limitations for interpretation of segmental hair analysis shown here might also be applicable to drugs with comparable physicochemical and pharmacokinetic properties.


Delay time in suspected acute myocardial infarction and the importance of its modification.
This paper summarizes the present knowledge of delay time in suspected acute myocardial infarction. More than 50% of deaths in acute myocardial infarction occur outside of the hospital setting. Recent experiences indicate that early and even late mortality can be dramatically reduced by intervention in the early phase. This points up the importance of bringing patients with suspected acute myocardial infarction to the hospital as early in the course of MI as possible. The predominating cause of delay is the time it takes for the patient to decide to go to hospital regardless of a previous history of cardiovascular disease. Patients arriving in hospital in later stages of MI are at a very high risk of mortality. Therefore one of the most important problems to be resolved is how to reduce delay time in suspected acute myocardial infarction. Such efforts have been surprisingly few. Limited experiences indicate that public education can reduce delay time dramatically.


Autism risk in offspring can be assessed through quantification of male sperm mosaicism.
De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.


The nutritional environment determines which and how intestinal stem cells contribute to homeostasis and tumorigenesis.
Sporadic colon cancer accounts for approximately 80% of colorectal cancer (CRC) with high incidence in Western societies strongly linked to long-term dietary patterns. A unique mouse model for sporadic CRC results from feeding a purified rodent Western-style diet (NWD1) recapitulating intake for the mouse of common nutrient risk factors each at its level consumed in higher risk Western populations. This causes sporadic large and small intestinal tumors in wild-type mice at an incidence and frequency similar to that in humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts and decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumor development. Here we establish that NWD1 transcriptionally reprograms Lgr5hi cells, and that nutrients are interactive in reprogramming. Furthermore, the DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, paralleled by reduced accumulation of relevant somatic mutations detected by single-cell exome sequencing. In compensation, NWD1 also reprograms Bmi1+ cells to function and persist as stem-like cells in mucosal homeostasis and tumor development. The data establish the key role of the nutrient environment in defining the contribution of two different stem cell populations to both mucosal homeostasis and tumorigenesis. This raises important questions regarding impact of variable human diets on which and how stem cell populations function in the human mucosa and give rise to tumors. Moreover, major differences reported in turnover of human and mouse crypt base stem cells may be linked to their very different nutrient exposures.


Nordihydroguaiaretic acid, an inhibitor of lipoxygenase, also inhibits cytochrome P-450-mediated monooxygenase activity in rat epidermal and hepatic microsomes.
Nordihydroguaiaretic acid (NDGA), a plant lignan and phenolic antioxidant, is a known lipoxygenase inhibitor. In this study, we investigated the effect of NDGA on rat epidermal and hepatic monooxygenase activity and its interaction with rat hepatic microsomal cytochrome P-450. The addition of NDGA to epidermal microsomes prepared from control and 3-methylcholanthrene (3-MC)-pretreated rats and hepatic microsomal preparations from control, 3-MC-pretreated, and phenobarbital (PB)-pretreated rats resulted in a concentration-dependent inhibition of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase (ERD) activities. The 50% inhibitory dose for NDGA ranged from 4.1 x 10(-5) to 13.1 x 10(-5) M for AHH and ERD activities in these microsomal preparations. The addition of NDGA to hepatic microsomes prepared from PB-pretreated rats resulted in spectral changes characterized by absorbance maxima at 380 nm and minima at 414 nm, typical of type I binding difference spectra. It also showed time- and concentration-dependent inhibition of the binding of carbon monoxide to dithionite or NADPH-reduced cytochrome P-450. We speculate that perhaps hydroxyl groups present in NDGA play an important role in inhibiting the monooxygenase activity and suggest that NDGA may have potential as an antimutagen and/or anticarcinogen. Furthermore, caution must be exercised in elucidating the role of lipoxygenase in metabolic pathways based solely on the criterion of inhibition by NDGA.


Lipoprotein(a), fibrin binding, and plasminogen activation.
Lipoprotein(a) (Lp[a]) is a complex plasma lipoprotein in which apolipoprotein (apo) B-100 is covalently linked by a disulfide bridge to a unique apolipoprotein, apo(a). The cDNA of apo(a) has recently been isolated and sequenced, and a remarkable homology to human plasminogen has been noted. In this report, we demonstrate that, like plasminogen, Lp(a) binds to fibrin. In addition, Lp(a) competes with plasminogen and tissue-type plasminogen activator for fibrin binding. As a functional consequence of these binding properties, we show that Lp(a) attenuates the fibrin-dependent enhancement of tissue-type plasminogen activator activity against the native substrate, and does so as an uncompetitive inhibitor (Ki = 15 nM). Finally, we show that in a plasma milieu, Lp(a) attenuates clot lysis induced by tissue-type plasminogen activator. None of these effects was noted with low density lipoprotein free of apo(a). These data suggest that Lp(a) influences the fibrinolytic system and probably does so by virtue of the fibrin binding properties conferred by the kringle repeats of apo(a).


Outcome of Pancreatic Cancer Surveillance Among High-Risk Individuals Tested for Germline Mutations in BRCA1 and BRCA2.
Germline mutations in BRCA1/2 are risk factors for pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether results of surveillance for PDAC in high risk individuals (HRI) differ between those with and without a pathogenic BRCA1/2 mutation. This prospective study was conducted within the Pancreatic Tumor Registry at a major cancer center. There were 83 HRIs with ≥1 first-degree relative with PDAC who underwent surveillance and testing for pathogenic germline mutations in BRCA1/2 A secondary analysis includes 18 HRIs with known mutations in BRCA1/2 but with weaker family history. HRIs were evaluated over time using magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound when indicated by MRCP findings. We reviewed imaging results, blinded to mutation status. Demographic information was obtained from interviewer-administered questionnaires. The outcome was the proportion with any pancreatic abnormality identified at initial or follow-up surveillance. Among the 83 HRIs in the main analysis, 48 had a mutation in BRCA1/2 and 35 did not. Overall, 16 of 48 (33%) BRCA1/2-positive and 13 of 35 (37%) BRCA1/2-negative participants had pancreatic abnormalities on imaging; in each group, all but one finding was an intraductal papillary mucinous neoplasm. Among those with pathogenic mutations but weaker family history, results were similar: 7 of 18 (39%) with pancreatic abnormalities. Results of surveillance for pancreatic abnormalities on imaging are similar regardless of BRCA1/2 mutation status. While the results from this small study need confirmation in other studies, at present there does not appear to be increased yield from targeting individuals with BRCA1/2 mutations for surveillance.


Integrated approach for biofouling control.
Despite extensive research efforts, past and present strategies to control biofouling problems in spiral-wound nanofiltration and reverse osmosis membranes have not been successful under all circumstances. Gaining insight in the biofouling process is a first necessity. Based on recent insights, an overview is given of 12 potential complementary approaches to solve biofouling. Combinations of approaches may be more efficient in biofouling control than a single approach. A single approach must be 100% effective, while in combination each individual approach can be partially effective while the combination is still efficient. An integrated Approach for Biofouling Control (ABC) is proposed, based on three corner stones: (i) equipment design and operation, (ii) biomass growth conditions, and (iii) cleaning agents as a framework to control biofouling. While past and present strategies addressed mainly membranes and microorganisms, i.e. removal or inactivation of biomass, this ABC-approach addresses the total membrane filtration system. It is anticipated that this integral approach will enable a more rational and effective control of biofouling. Although in this stage chemical cleaning and biofouling inhibitor dosage seem unavoidable to control biofouling, it is expected that in future--because of sustainability and costs reasons--membrane systems will be developed without or with minimal need for chemical cleaning and dosing. Three potential scenarios for biofouling control are proposed based on (i) biofouling tolerant spiral wound membrane systems, (ii) capillary membranes, and (iii) phosphate limitation.


Grandparents driving grandchildren: an evaluation of child passenger safety and injuries.
To compare restraint-use practices and injuries among children in crashes with grandparent versus parent drivers. This was a cross-sectional study of motor vehicle crashes that occurred from January 15, 2003, to November 30, 2007, involving children aged 15 years or younger, with cases identified via insurance claims and data collected via follow-up telephone surveys. We calculated the relative risk of significant child-passenger injury for grandparent-driven versus parent-driven vehicles. Logistic regression modeling estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for several child occupant, driver, vehicle, and crash characteristics. Children driven by grandparents comprised 9.5% of the sample but resulted in only 6.6% of the total injuries. Injuries were reported for 1302 children, for an overall injury rate of 1.02 (95% CI: 0.90-1.17) per 100 child occupants. These represented 161 weighted injuries (0.70% injury rate) with grandparent drivers and 2293 injuries (1.05% injury rate) with parent drivers. Although nearly all children were reported to have been restrained, children in crashes with grandparent drivers used optimal restraint slightly less often. Despite this, children in grandparent-driven crashes were at one-half the risk of injuries as those in parent-driven crashes (OR: 0.50 [95% CI: 0.33- 0.75]) after adjustment. Grandchildren seem to be safer in crashes when driven by grandparents than by their parents, but safety could be enhanced if grandparents followed current child-restraint guidelines. Additional elucidation of safe grandparent driving practices when carrying their grandchildren may inform future child-occupant driving education guidelines for all drivers.


Dual flaA1 flaB1 mutant of Serpulina hyodysenteriae expressing periplasmic flagella is severely attenuated in a murine model of swine dysentery.
The motility imparted by the periplasmic flagella (PF) of Serpulina hyodysenteriae is thought to play a pivotal role in the enteropathogenicity of this spirochete. The complex PF are composed of multiple class A and class B polypeptides. Isogenic strains containing specifically disrupted flaAl or flaB1 alleles remain capable of expressing PF, although such mutants display aberrant motility in vitro. To further examine the role that these proteins play in the maintenance of periplasmic flagellar structural integrity, motility, and fitness for intestinal colonization, we constructed a novel strain of S. hyodysenteriae which is deficient in both FlaA1 and FlaB1. To facilitate construction of this strain, a chloramphenicol gene cassette, with general application as a selectable marker in prokaryotes, was developed. The cloned flaAl and flaB1 genes were disrupted by replacement of internal fragments with chloramphenicol and kanamycin gene cassettes, respectively. The inactivated flagellar genes were introduced into S. hyodysenteriae, and allelic exchange at the targeted chromosomal flaA1 and flaB1 loci was verified by PCR analysis. Immunoblots or cell lysates with antiserum raised against purified FlaA or FlaB confirmed the absence of the corresponding sheath and core proteins in this dual flagellar mutant. These mutations selectively abolished the expression of the targeted genes without affecting the synthesis of other immunologically related FlaB proteins. The resulting flaA1 flaB1 mutant exhibited altered motility in vitro. Surprisingly, it was capable of assembling periplasmic flagella that were morphologically normal as evidenced by electron microscopy. The virulence of this strain was assessed in a murine model of swine dysentery by determining the incidence of cecal lesions and the persistence of S. hyodysenteriae in the gut. Mice challenged with the wild-type strain or a passage control strain showed a dose-related response to the challenge organism. The dual flagellar mutant was severely attenuated in murine challenge experiments, suggesting that the FlaA1 and FlaB1 proteins are dispensable for flagellar assembly but critical for normal flagellar function and colonization of mucosal surfaces of the gastrointestinal tract. This strain represents the first spirochete engineered to contain specifically defined mutations in more than one genetic locus.


The effects of nucleotides on MutS-DNA binding kinetics clarify the role of MutS ATPase activity in mismatch repair.
MutS protein initiates mismatch repair with recognition of a non-Watson-Crick base-pair or base insertion/deletion site in DNA, and its interactions with DNA are modulated by ATPase activity. Here, we present a kinetic analysis of these interactions, including the effects of ATP binding and hydrolysis, reported directly from the mismatch site by 2-aminopurine fluorescence. When free of nucleotides, the Thermus aquaticus MutS dimer binds a mismatch rapidly (k(ON)=3 x 10(6) M(-1) s(-1)) and forms a stable complex with a half-life of 10 s (k(OFF)=0.07 s(-1)). When one or both nucleotide-binding sites on the MutS*mismatch complex are occupied by ATP, the complex remains fairly stable, with a half-life of 5-7 s (k(OFF)=0.1-0.14 s(-1)), although MutS(ATP) becomes incapable of (re-)binding the mismatch. When one or both nucleotide-binding sites on the MutS dimer are occupied by ADP, the MutS*mismatch complex forms rapidly (k(ON)=7.3 x 10(6) M(-1) s(-1)) and also dissociates rapidly, with a half-life of 0.4 s (k(OFF)=1.7 s(-1)). Integration of these MutS DNA-binding kinetics with previously described ATPase kinetics reveals that: (a) in the absence of a mismatch, MutS in the ADP-bound form engages in highly dynamic interactions with DNA, perhaps probing base-pairs for errors; (b) in the presence of a mismatch, MutS stabilized in the ATP-bound form releases the mismatch slowly, perhaps allowing for onsite interactions with downstream repair proteins; (c) ATP-bound MutS then moves off the mismatch, perhaps as a mobile clamp facilitating repair reactions at distant sites on DNA, until ATP is hydrolyzed (or dissociates) and the protein turns over.


New Non-Intravenous Routes for Benzodiazepines in Epilepsy: A Clinician Perspective.
Benzodiazepines represent the first-line treatment for the acute management of epileptic seizures and status epilepticus. The emergency use of benzodiazepines must be timely, and because most seizures occur outside of the hospital environment, there is a significant need for delivery methods that are easy for nonclinical caregivers to use and administer quickly and safely. In addition, the ideal route of administration should be reliable in terms of absorption. Rectal diazepam is the only licensed formulation in the USA, whereas rectal diazepam and buccal midazolam are currently licensed in the EU. However, the sometimes unpredictable absorption with rectal and buccal administration means they are not ideal routes. Several alternative routes are currently being explored. This is a narrative review of data about delivery methods for benzodiazepines alternative to the intravenous and oral routes for the acute treatment of seizures. Unconventional delivery options such as direct delivery to the central nervous system or inhalers are reported. Data show that intranasal diazepam or midazolam and the intramuscular auto-injector for midazolam are as effective as rectal or intravenous diazepam. Head-to-head comparisons with buccal midazolam are urgently needed. In addition, the majority of trials focused on children and adolescents, and further trials in adults are warranted.


On-chip integration of droplet microfluidics and nanostructure-initiator mass spectrometry for enzyme screening.
Biological assays often require expensive reagents and tedious manipulations. These shortcomings can be overcome using digitally operated microfluidic devices that require reduced sample volumes to automate assays. One particular challenge is integrating bioassays with mass spectrometry based analysis. Towards this goal we have developed μNIMS, a highly sensitive and high throughput technique that integrates droplet microfluidics with nanostructure-initiator mass spectrometry (NIMS). Enzyme reactions are carried out in droplets that can be arrayed on discrete NIMS elements at defined time intervals for subsequent mass spectrometry analysis, enabling time resolved enzyme activity assay. We apply the μNIMS platform for kinetic characterization of a glycoside hydrolase enzyme (CelE-CMB3A), a chimeric enzyme capable of deconstructing plant hemicellulose into monosaccharides for subsequent conversion to biofuel. This study reveals NIMS nanostructures can be fabricated into arrays for microfluidic droplet deposition, NIMS is compatible with droplet and digital microfluidics, and can be used on-chip to assay glycoside hydrolase enzyme in vitro.


National study of the nutritional status of Korean older adults with dementia who are living in long-term care settings.
To evaluate the nutritional status of older adults with dementia who were living in long-term care settings. As a secondary analysis, this study used the data from the Nationwide Survey on Dementia Care in Korea that was conducted between December 1, 2010, and August 31, 2011, which surveyed 3472 older adults with dementia, aged ≥60 years (mean age: 81.24 years), who were residing in 248 randomly selected long-term care settings in South Korea. Twenty-three different variables that related to the participants' demographics, diseases, and functional and nutritional characteristics were selected. The nutritional status was assessed by using the Mini Nutritional Assessment (MNA). Descriptive statistics, an ANOVA, and a chi-squared test were used to analyze the data. The mean MNA score of the participants was 17.90. The malnutrition rate was 38.4% (n = 1333), with 54.7% (n = 1900) of the participants at risk for malnutrition. The largest population with malnutrition resided in long-term care hospitals (47.9%), followed by nursing homes (34.1%), and group homes (25.9%). Being older and female, while exhibiting higher cognitive impairment, more neuropsychiatric symptoms, higher functional dependency, and a higher number of disabilities, were associated with poor nutritional status. The nutritional status of older adults with dementia who were living in long-term care settings in South Korea was poor and associated with multiple factors. Paying special attention to recognizing, assessing, preventing, and treating malnutrition in this population is necessary.


Pancreatic VIPoma as a Differential Diagnosis in Chronic Pediatric Diarrhea: A Case Report and Review of the Literature.
Chronic diarrhea is a common chief complaint in the pediatric population with a wide range of diagnostic differentials; as such, whilst suspecting common causes, less prevalent conditions tend to be overlooked, such as neuroendocrine tumor pathologies. VIPomas are characterized by hypersecretion of the vasoactive intestinal peptide (VIP), causing watery diarrhea, hypokalemia, and achlorhydria. Nonetheless, its low incidence rate in children makes it an easily unnoticed pathology. Herein, we report a case of a 14-year-old female patient and a review of relevant literature. The patient complained of 7-month history of watery diarrhea, multiple emetic episodes, and relevant past medical history of multiple hospitalizations. Chronic diarrheal disease work-up studies, including a high VIP scintigram, showed a lesion suggestive of a VIPoma-type neuroendocrine pancreatic tumor. A distal pancreatectomy was performed with a complete resolution of the symptoms. When faced with a pediatric patient presenting with chronic secretory diarrhea and whose work-up studies rule out the most common pathologies, the possible presence of a neuroendocrine tumor as VIPoma should be considered.


Characteristics and effectiveness of diabetes self-management educational programs targeted to racial/ethnic minority groups: a systematic review, meta-analysis and meta-regression.
It is not clear to what extent educational programs aimed at promoting diabetes self-management in ethnic minority groups are effective. The aim of this work was to systematically review the effectiveness of educational programs to promote the self-management of racial/ethnic minority groups with type 2 diabetes, and to identify programs' characteristics associated with greater success. We undertook a systematic literature review. Specific searches were designed and implemented for Medline, EMBASE, CINAHL, ISI Web of Knowledge, Scirus, Current Contents and nine additional sources (from inception to October 2012). We included experimental and quasi-experimental studies assessing the impact of educational programs targeted to racial/ethnic minority groups with type 2 diabetes. We only included interventions conducted in countries members of the OECD. Two reviewers independently screened citations. Structured forms were used to extract information on intervention characteristics, effectiveness, and cost-effectiveness. When possible, we conducted random-effects meta-analyses using standardized mean differences to obtain aggregate estimates of effect size with 95% confidence intervals. Two reviewers independently extracted all the information and critically appraised the studies. We identified thirty-seven studies reporting on thirty-nine educational programs. Most of them were conducted in the US, with African American or Latino participants. Most programs obtained some benefits over standard care in improving diabetes knowledge, self-management behaviors and clinical outcomes. A meta-analysis of 20 randomized controlled trials (3,094 patients) indicated that the programs produced a reduction in glycated hemoglobin of -0.31% (95% CI -0.48% to -0.14%). Diabetes knowledge and self-management measures were too heterogeneous to pool. Meta-regressions showed larger reduction in glycated hemoglobin in individual and face to face delivered interventions, as well as in those involving peer educators, including cognitive reframing techniques, and a lower number of teaching methods. The long-term effects remain unknown and cost-effectiveness was rarely estimated. Diabetes self-management educational programs targeted to racial/ethnic minority groups can produce a positive effect on diabetes knowledge and on self-management behavior, ultimately improving glycemic control. Future programs should take into account the key characteristics identified in this review.


Accurate 4Pi single-molecule localization using an experimental PSF model.
Interferometric single-molecule localization microscopy (iPALM, 4Pi-SMS) uses multiphase interferometry to localize single fluorophores and achieves nanometer isotropic resolution in 3D. The current data analysis workflow, however, fails to reach the theoretical resolution limit due to the suboptimal localization algorithm. Here, we develop a method to fit an experimentally derived point spread function (PSF) model to the interference 4Pi-PSF. As the interference phase is not fixed with respect to the shape of the PSF, we decoupled the phase term in the model from the 3D position of the PSF. The fitter can reliably infer the interference period even without introducing astigmatism, reducing the complexity of the microscope. Using a spline-interpolated experimental PSF model and by fitting all phase images globally, we show on simulated data that we can achieve the theoretical limit of 3D resolution, the Cramér-Rao lower bound (CRLB), also for the 4Pi microscope.


The Hand and Wrist: AntImicrobials and Infection (HAWAII) trial.
Hand trauma, comprising injuries to both the hand and wrist, affects over five million people per year in the NHS, resulting in 250 000 operations each year. Surgical site infection (SSI) following hand trauma surgery leads to significant morbidity. Triclosan-coated sutures may reduce SSI in major abdominal surgery but have never been tested in hand trauma. Feasibility needs to be ascertained before a definitive trial can be delivered in hand trauma. A multicentre feasibility RCT of antimicrobial sutures versus standard sutures involving adults undergoing surgery for hand trauma to evaluate feasibility for a definitive trial. Secondary objectives were incidence of SSI in both groups, hand function measured with patient-reported outcome measures, health-related quality of life and change in employment. Randomization was performed on a 1:1 basis, stratified by age of the patient and whether the injury was open or closed, using a secure, centralized, online randomization service. Participants were blinded to allocation. 116 participants were recruited and randomized (60 intervention, 56 control). Of 227 screened, most were eligible (89.5 per cent), and most who were approached agreed to be included in the study (84.7 per cent). Retention was low: 57.5 per cent at 30 days, 52 per cent at 90 days and 45.1 per cent at 6 months. Incidence of SSI was >20 per cent in both groups. Hand function deteriorated after injury but recovered to near pre-injury levels during the study period. Risk of SSI after hand trauma is high. A definitive RCT of antimicrobial sutures in hand trauma surgery is feasible, if retention is improved. ISRCTN10771059.


Silver(I) complexation of linked 2,2'-dipyridylamine derivatives. Synthetic, solvent extraction, membrane transport and X-ray structural studies.
Synthesis of the 2,2'-dipyridylamine derivatives di-2-pyridylaminomethylbenzene 1, 1,2-bis(di-2-pyridylaminomethyl)benzene 2, 1,3-bis(di-2-pyridylaminomethyl)benzene 3, 2,6-bis(di-2-pyridylaminomethyl)pyridine 4, 1,4-bis(di-2-pyridylaminomethyl)benzene 5, and 1,3,5-tris(di-2-pyridylaminomethyl)benzene 6 are reported together with the single-crystal X-ray structures of 2, 3, and 5. Reaction of individual salts of the type AgX (where X = NO(3)(-), PF(6)(-), ClO(4)(-), or BF(4)(-)) with the above ligands has led to the isolation of thirteen Ag(I) complexes, nine of which have also been characterised by X-ray diffraction. In part, the inherent flexibility of the respective ligands has resulted in the adoption of a range of coordination arrangements. A series of liquid-liquid (H(2)O/CHCl(3)) extraction experiments of Ag(I) with varying concentrations of 1-6 in the organic phase have been undertaken, with the counter ion in the aqueous phase being respectively picrate, perchlorate and nitrate. In general, extraction efficiencies for a given ionophore followed the Hofmeister order of picrate > perchlorate > nitrate; in each case the tris-dpa derivative 6 acting as the most efficient extractant of the six systems investigated. Competitive seven-metal bulk membrane transport experiments (H(2)O/CHCl(3)/H(2)O) employing the above ligands as the ionophore in the organic phase and equimolar concentrations of Co(II), Ni(II), Zn(II), Cu(II), Cd(II), Pb(II) and Ag(I) in the aqueous source phase were also undertaken, with transport occurring against a pH gradient. Under the conditions employed 1 and 5 yielded negligible transport of any of the metals present in the source phase while sole transport selectivity for Ag(I) was observed for 2-4 and 6.


The relationship between electronic gaming machine accessibility and police-recorded domestic violence: A spatio-temporal analysis of 654 postcodes in Victoria, Australia, 2005-2014.
An emerging body of research has documented an association between problem gambling and domestic violence in a range of study populations and locations. Yet little research has analysed this relationship at ecological scales. This study investigates the proposition that gambling accessibility and the incidence of domestic violence might be linked. The association between police-recorded domestic violence and electronic gaming machine accessibility is described at the postcode level. Police recorded family incidents per 10,000 and domestic-violence related physical assault offenses per 10,000 were used as outcome variables. Electronic gaming machine accessibility was measured as electronic gaming machines per 10,000 and gambling venues per 100,000. Bayesian spatio-temporal mixed-effects models were used to estimate the associations between gambling accessibility and domestic violence, using annual postcode-level data in Victoria, Australia between 2005 and 2014, adjusting for a range of covariates. Significant associations of policy-relevant magnitudes were found between all domestic violence and EGM accessibility variables. Postcodes with no electronic gaming machines were associated with 20% (95% credibility interval [C.I.]: 15%, 24%) fewer family incidents per 10,000 and 30% (95% C.I.: 24%, 35%) fewer domestic-violence assaults per 10,000, when compared with postcodes with 75 electronic gaming machine per 10,000. The causal relations underlying these associations are unclear. Quasi-experimental research is required to determine if reducing gambling accessibility is likely to reduce the incidence of domestic violence.


Expanding Medicaid, Expanding the Electorate: The Affordable Care Act's Short-Term Impact on Political Participation.
The Affordable Care Act is a landmark piece of social legislation with the potential to reshape health care in the United States. Its potential to reshape politics is also considerable, but existing scholarship suggests conflicting expectations about the law's policy feedbacks, especially given uneven state-level implementation. In this article I focus on the policy feedbacks of the law's Medicaid expansion on political participation, using district-level elections data for 2012 and 2014 US House races and cross-sectional survey data from 2014. I find that the increases in Medicaid enrollment associated with the expansion are related to considerably higher voter turnout and that this effect was likely due to both an increase in turnout for new beneficiaries and a backlash effect among conservative voters opposed to the law and its implementation. These results have important implications for our understanding of the ACA and of the impact of welfare state expansions on political participation, particularly in federalized systems.


Associations among decisional autonomy, fatigue, pain, and well-being in long-term physical disability.
Decisional autonomy-or sense of one's ability to make independent choices about one's life-is especially relevant to individuals who may feel their autonomy is limited due to physical challenges. Past work has found associations between measures of autonomy and quality of life (QoL) in individuals with disability and in older adults. However, it is less clear how decisional autonomy influences the impact of pain and fatigue severity on QoL, especially in adults aging with physical disability. This study examined the relationship of decisional autonomy to QoL and the extent to which autonomy moderates the association between symptom severity and QoL. We used hierarchical linear regression models to examine the associations between autonomy, pain and fatigue, and quality of life in a sample of individuals with long-term disability. In 2 sets of models, we examined individuals reporting some level of fatigue (n = 1,060, Mage = 62.66, SD = 11.88) and some level of pain (n = 964, Mage = 62.79, SD = 11.69). We found that decisional autonomy significantly predicted QoL over and above other measures related to social participation. Decisional autonomy also weakly moderated the associations between fatigue and QoL and the associations between pain and QoL. The findings indicate that levels of decisional autonomy may be important to QoL in individuals aging with physical limitations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Ultrasensitive Reagent for Ratiometric Detection and Detoxification of iAsIII in Water and Mitochondria.
Toxicity induced by inorganic arsenic as AsO33- (iAsIII) is of global concern. Reliable detection of the maximum allowed contaminant level for arsenic in drinking water and in the cellular system remains a challenge for the water quality management and assessment of toxicity in the cellular milieu, respectively. A new Ir(III)-based phosphorescent molecule (AS-1; λExt = 415 nm and λEms = 600 nm, Φ = 0.3) is synthesized for the selective detection of iAsIII in an aqueous solution with a ratiometric luminescence response even in the presence of iAsV and all other common inorganic cations and anions. The relatively higher affinity of the thioimidazole ligand (HPBT) toward iAsIII led to the formation of a fluorescent molecule iAsV-HPBT (λExt = 415 nm and λEms = 466 nm, Φ = 0.28) for the reaction of iAsIII and AS-1. An improved limit of quantitation (LOQ) down to 0.2 ppb is achieved when AS-1 is used in the CTAB micellar system. Presumably, the cationic surfactants favor the localization of AS-1@CTABMicelle in mitochondria of MCF7 cells, and this is confirmed from the images of the confocal laser fluorescence scanning microscopic studies. Importantly, cell viability assay studies confirm that AS-1@CTABMicelle induces dose-dependent detoxification of iAsIII in live cells. Further, luminescence responses at 466 nm could be utilized for developing a hand-held device for the in-field application. Such a reagent that allows for ratiometric detection of iAsIII with LOQ of 2.6 nM (0.5 ppb) in water, as well as helps in visualizing its distribution in mitochondria with a detoxifying effect, is rather unique in contemporary literature.