Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis.
Dysregulation of the blood-brain barrier (BBB) and transendothelial migration of immune cells are among the earliest central nervous system changes partaking in lesion formation in both multiple sclerosis (MS) and its early clinical form, the clinically isolated syndrome. Evidence for the anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors within the central nervous system arose from studies demonstrating that statins improve clinical signs in the animal model of MS and reduce the number of gadolinium-enhancing lesions in MS. We sought to describe the impact of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor treatment on the physiology and immunology of human BBB-derived endothelial cells (ECs). We demonstrate that lovastatin and simvastatin induce a 50 to 60% reduction in the diffusion rates of bovine serum albumin and [(14)C]-sucrose across human BBB-ECs in vitro through abrogation of isoprenylation processes, but independent of the expression of the tight junction molecules occludin, VE-cadherin, JAM-1, zonula occluden-1, and zonula occluden-2. Simvastatin and lovastatin were equipotent in reducing BBB permeability in vitro, with median effective concentration (EC(50)) of 9.5 x 10(-8) and 1.0 x 10(-7)M, respectively. We further demonstrate that lovastatin and simvastatin treatment of BBB-ECs significantly restricts the migration of clinically isolated syndrome-derived and MS-derived monocytes and lymphocytes across the human BBB in vitro, through a specific reduction in the secretion of the chemokines monocyte chemotactic protein-1/CCL2 and interferon-gamma-inducible protein-10/CXCL10 by BBB-ECs. Our data parallel the previously reported magnetic resonance imaging-based radiological findings and suggest an effect of statins that could be beneficial in early MS, restricting the diffusion of molecular tracers and the migration of immune cells across the human BBB.


Encoding of direction of fingertip forces by human tactile afferents.
In most manipulations, we use our fingertips to apply time-varying forces to the target object in controlled directions. Here we used microneurography to assess how single tactile afferents encode the direction of fingertip forces at magnitudes, rates, and directions comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to a standard site on the fingertip while recording impulse activity in 196 tactile afferents with receptive fields distributed over the entire terminal phalanx. Forces were applied in one of five directions: normal force and forces at a 20 degrees angle from the normal in the radial, distal, ulnar, or proximal directions. Nearly all afferents responded, and the responses in most slowly adapting (SA)-I, SA-II, and fast adapting (FA)-I afferents were broadly tuned to a preferred direction of force. Among afferents of each type, the preferred directions were distributed in all angular directions with reference to the stimulation site, but not uniformly. The SA-I population was biased for tangential force components in the distal direction, the SA-II population was biased in the proximal direction, and the FA-I population was biased in the proximal and radial directions. Anisotropic mechanical properties of the fingertip and the spatial relationship between the receptive field center of the afferent and the stimulus site appeared to influence the preferred direction in a manner dependent on afferent type. We conclude that tactile afferents from the whole terminal phalanx potentially contribute to the encoding of direction of fingertip forces similar to those that occur when subjects manipulate objects under natural conditions.


Anxious Imagery in Children With and Without Autism Spectrum Disorder: An Investigation into Occurrence, Content, Features and Implications for Therapy.
Mental imagery has been implicated in anxiety disorders in adults, but has not been investigated in child and adolescent populations. Anxiety is highly prevalent in autism spectrum disorder (ASD), and as people with ASD are often thought of as 'visual thinkers', the potential role of distressing imagery in children with ASD merits exploration. Participants aged 8-16 years were grouped as follows: ASD/high anxiety, ASD/low anxiety, non-ASD/high anxiety and non-ASD/low anxiety. Imagery and associated features were assessed using an interview. Group differences were found in number and frequency of images experienced. There were few differences between the groups in the characteristics of the spontaneous images, which included emotional valence, vividness, controllability and realism. Implications for treatment are discussed.


Multidrug resistance protein MdtM adds to the repertoire of antiporters involved in alkaline pH homeostasis in Escherichia coli.
In neutralophilic bacteria, monovalent metal cation/H+ antiporters play a key role in pH homeostasis. In Escherichia coli, only four antiporters (NhaA, NhaB, MdfA and ChaA) are identified to function in maintenance of a stable cytoplasmic pH under conditions of alkaline stress. We hypothesised that the multidrug resistance protein MdtM, a recently characterised homologue of MdfA and a member of the major facilitator superfamily, also functions in alkaline pH homeostasis. Assays that compared the growth of an E. coli ΔmdtM deletion mutant transformed with a plasmid encoding wild-type MdtM or the dysfunctional MdtM D22A mutant at different external alkaline pH values (ranging from pH 8.5 to 10) revealed a potential contribution by MdtM to alkaline pH tolerance, but only when millimolar concentrations of sodium or potassium was present in the growth medium. Fluorescence-based activity assays using inverted vesicles generated from transformants of antiporter-deficient (ΔnhaA, ΔnhaB, ΔchaA) E. coli TO114 cells defined MdtM as a low-affinity antiporter that catalysed electrogenic exchange of Na+, K+, Rb+ or Li+ for H+. The K+/H+ antiport reaction had a pH optimum at 9.0, whereas the Na+/H+ exchange activity was optimum at pH 9.25. Measurement of internal cellular pH confirmed MdtM as contributing to maintenance of a stable cytoplasmic pH, acid relative to the external pH, under conditions of alkaline stress. Taken together, the results support a role for MdtM in alkaline pH tolerance. MdtM can therefore be added to the currently limited list of antiporters known to function in pH homeostasis in the model organism E. coli.


Fine mapping and identification of candidate pulmonary adenoma susceptibility 1 genes using advanced intercross lines.
In the present study, we used newly developed F(11) generation mouse advanced intercross lines (AIL) to fine map Pas1-3 quantitative trait loci (QTL). The (A/J x C57BL/6) F(11) AIL mouse population was created by crossing lung tumor-resistant C57BL/6 mice with lung tumor-susceptible A/J mice. By selectively genotyping 30% of the population, we have confirmed the Pas1 QTL and narrowed it to an interval of approximately 1.0 cM or 1.3 Mb in the vicinity of the Kras2 gene. The Pas2 QTL was detected by both ANOVA and regression analysis but not by MapMaker EXP/QTL software. In addition, an interaction between the Pas1 and Pas2 QTLs was revealed. However, the Pas3 QTL was not confirmed in this study. It was either lost during the development of the AIL or too weak to be detected using AIL. The Pas1 locus is now sufficiently fine-mapped that candidate gene(s) for the Pas1 locus can be characterized by positional cloning. In this study, all 27 of the known or predicted genes located in the Pas1 candidate region were characterized as possible candidate Pas genes. Six genes were selected for additional analyses because of their relevant function in tumorigenesis or allelic changes between A/J and C57BL/6 mice. The Lrmp gene bears amino acid polymorphisms among various mouse strains that are highly correlated with the Pas1 allele status. The Pas1c1 gene (RIKEN Ak016641), encoding an intermediate filament tail domain-containing protein, produces alternatively spliced transcripts across inbred strains of mice, and its splicing pattern cosegregates with the Pas1 allele. The genetic and expression data support these two genes as strong candidates for the Pas1 locus. Of the other four genes (Eca39, RIKEN Ak015530, mHoj-1, and Krag), no functional polymorphisms or differential gene expression were found in Eca39, mHoj-1, and Krag between lung tumor-susceptible and -resistant strains. The Ak015530 carries an amino acid polymorphism, but this polymorphism does not cosegregate with mouse lung tumor susceptibility. Thus, these 4 genes are less likely candidates for the Pas1 locus.


Lysine Methylation of the Valosin-Containing Protein (VCP) Is Dispensable for Development and Survival of Mice.
Valosin-containing protein (VCP) is a homohexameric ATPase involved in a multitude cellular processes and it was recently shown that VCP is trimethylated at lysine 315 by the VCP lysine methyltransferase (VCPKMT). Here, we generated and validated a constitutive knockout mouse by targeting exon 1-4 of the Vcpkmt gene. We show that Vcpkmt is ubiquitously expressed in all tissues examined and confirm the sub-cellular localization to the cytoplasm. We show by (I) mass spectrometric analysis, (II) VCPKMT-mediated in vitro methylation of VCP in cell extracts and (III) immunostaining with a methylation specific antibody, that in Vcpkmt-/- mice the methylation of lysine 315 in VCP is completely abolished. In contrast, VCP is almost exclusively trimethylated in wild-type mice. Furthermore, we investigated the specificity of VCPKMT with in vitro methylation assays using as source of substrate protein extracts from Vcpkmt-/- mouse organs or three human Vcpkmt-/- cell lines. The results show that VCPKMT is a highly specific enzyme, and suggest that VCP is its sole substrate. The Vcpkmt-/- mice were viable, fertile and had no obvious pathological phenotype. Their body weight, life span and acute endurance capacity were comparable to wild-type controls. Overall the results show that VCPKMT is an enzyme required for methylation of K315 of VCP in vivo, but VCPKMT is not essential for development or survival under unstressed conditions.


Magnitude and factors associated with nonadherence to antiepileptic drug treatment in Africa: A cross-sectional multisite study.
The epilepsy treatment gap is large in low- and middle-income countries, but the reasons behind nonadherence to treatment with antiepileptic drugs (AEDs) across African countries remain unclear. We investigated the extent to which AEDs are not taken and associated factors in people with active convulsive epilepsy (ACE) identified in cross-sectional studies conducted in five African countries. We approached 2,192 people with a confirmed diagnosis of ACE for consent to give blood voluntarily. Participants were asked if they were taking AEDs, and plasma drug concentrations were measured using a fluorescence polarization immunoassay analyzer. Information about possible risk factors was collected using questionnaire-based clinical interviews. We determined factors associated with nonadherence to AED treatment in children and adults, as measured by detectable and optimal levels, using multilevel logistic regression. In 1,303 samples assayed (43.7% were children), AEDs were detected in 482, but only 287 had optimal levels. Of the 1,303 samples, 532 (40.8%) were from people who had reported they were on AEDs. The overall prevalence of nonadherence to treatment was 63.1% (95% confidence interval [CI] 60.5-65.6%) as measured by detectable AED levels and 79.1% (95% CI 73.3-84.3%) as measured by optimal AED levels; self-reported nonadherence was 65.1% (95% CI 45.0-79.5%). Nonadherence was significantly (p < 0.001) more common among the children than among adults for optimal and detectable levels of AEDs, as was the self-reported nonadherence. In children, lack of previous hospitalization and learning difficulties were independently associated with nonadherence to treatment. In adults, history of delivery at home, absence of burn marks, and not seeking traditional medicine were independently associated with the nonadherence to AED treatment. Only about 20% of people with epilepsy benefit fully from antiepileptic drugs in sub-Saharan Africa, according to optimum AEDs levels. Children taking AEDs should be supervised to promote compliance.


Free energy of a potassium ion in a model of the channel formed by an amphipathic leucine-serine peptide.
We use molecular dynamics simulations to investigate the position-dependent free energy of a potassium ion in a model of an ion channel formed by the synthetic amphipathic leucine-serine peptide, LS3. The channel model is a parallel bundle of six LS3 helices around which are packed 146 methane-like spheres in order to mimic a membrane. At either end of and within the channel are 1051 water molecules, plus four ions (two potassium and two chloride). The free energy of a potassium ion in the channel was estimated using the weighted histogram analysis (WHAM) method. This is the first time to our knowledge that such a calculation has been carried out as a function of the position of an ion in three dimensions within a channel. The results indicate that for this channel, which is lined by hydrophilic serine sidechains, there is a relatively weak dependence of the free energy on the axial/off-axial position of the ion. There are some off-axis local minima, especially in the C-terminal half of the channel. Using the free energy results, a single channel current-voltage curve was estimated using a one-dimensional Nernst-Planck equation. Although reasonable agreement with experiment is achieved for K(+) ions flowing from the N-terminal to the C-terminal mouth, in the opposite direction the current is underestimated. This underestimation may be a consequence of under-sampling of the conformational dynamics of the channel. We suggest that our simulations may have captured, for example, a sub-conductance level (i.e. an incompletely open state) of the LS3 channel.


High mortality rates for very low birth weight infants in developing countries despite training.
The goal was to determine the effect of training in newborn care and resuscitation on 7-day (early) neonatal mortality rates for very low birth weight (VLBW) infants. The study was designed to test the hypothesis that these training programs would reduce neonatal mortality rates for VLBW infants. Local instructors trained birth attendants from 96 rural communities in 6 developing countries in protocol and data collection, the World Health Organization Essential Newborn Care (ENC) course, and a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (NRP), by using a train-the-trainer model. To test the impact of ENC training, data on infants of 500 to 1499 g were collected by using a before/after, active baseline, controlled study design. A cluster-randomized, controlled trial design was used to test the impact of the NRP. A total of 1096 VLBW (500-1499 g) infants were enrolled, and 98.5% of live-born infants were monitored to 7 days. All-cause, 7-day neonatal mortality, stillbirth, and perinatal mortality rates were not affected by ENC or NRP training. Neither ENC nor NRP training of birth attendants decreased 7-day neonatal, stillbirth, or perinatal mortality rates for VLBW infants born at home or at first-level facilities. Encouragement of delivery in a facility where a higher level of care is available may be preferable when delivery of a VLBW infant is expected.


Human thrombin plus 5 per cent ethanolamine oleate injected to sclerose oesophageal varices: a prospective randomized trial.
Fifty cirrhotic Japanese patients with oesophageal varices underwent sclerotherapy in a prospective randomized trial carried out to examine the effects of human thrombin given concomitantly with the sclerosant 5 per cent ethanolamine oleate. The two groups (25 patients each) were comparable with regard to size of the oesophageal varices, and the aetiology and severity of the liver disease. Twenty-five patients, 13 and 12 in the thrombin + and - groups, respectively, had at least one episode of variceal bleeding. The remaining 25 were given prophylactic injections. There was a significantly lower rate of occurrence of bleeding from injection sites when the injection needle was removed at the initial session of sclerotherapy in the thrombin + group, where human thrombin was injected (0.2-0.3 ml, 100-150 units per injection) just before removal of the injection needle. Endoscopy at 1 week after the initial session showed a significantly (P less than 0.05) higher rate of disappearance of red colour signs on varices in the thrombin + group (96 per cent) than in the thrombin - group (72 per cent). Fibrin degradation product E-fraction (FDP-E) values increased 1 h, 1 day and 6 days after the initial session of sclerotherapy in the two groups. The rate of increase in FDP-E values 1 h after sclerotherapy was significantly larger (P less than 0.001) in the thrombin + than in the thrombin - group. There was no clinical sign of disseminated intravascular coagulation. Administration of human thrombin plus a sclerosant seems to be useful and efficacious, especially for patients with huge oesophageal varices.


A conceptual framework and practical guide for assessing fitness-to-operate in the offshore oil and gas industry.
The paper outlines a systemic approach to understanding and assessing safety capability in the offshore oil and gas industry. We present a conceptual framework and assessment guide for understanding fitness-to-operate (FTO) that builds a more comprehensive picture of safety capability for regulators and operators of offshore facilities. The FTO framework defines three enabling capitals that create safety capability: organizational capital, social capital, and human capital. For each type of capital we identify more specific dimensions based on current theories of safety, management, and organizational processes. The assessment guide matches specific characteristics to each element of the framework to support assessment of safety capability. The content and scope of the FTO framework enable a more comprehensive coverage of factors that influence short-term and long-term safety outcomes.


Mitochondrial DNA mutations in human cancer.
Somatic mitochondrial DNA (mtDNA) mutations have been increasingly observed in primary human cancers. As each cell contains many mitochondria with multiple copies of mtDNA, it is possible that wild-type and mutant mtDNA can co-exist in a state called heteroplasmy. During cell division, mitochondria are randomly distributed to daughter cells. Over time, the proportion of the mutant mtDNA within the cell can vary and may drift toward predominantly mutant or wild type to achieve homoplasmy. Thus, the biological impact of a given mutation may vary, depending on the proportion of mutant mtDNAs carried by the cell. This effect contributes to the various phenotypes observed among family members carrying the same pathogenic mtDNA mutation. Most mutations occur in the coding sequences but few result in substantial amino acid changes raising questions as to their biological consequence. Studies reveal that mtDNA play a crucial role in the development of cancer but further work is required to establish the functional significance of specific mitochondrial mutations in cancer and disease progression. The origin of somatic mtDNA mutations in human cancer and their potential diagnostic and therapeutic implications in cancer are discussed. This review article provides a detailed summary of mtDNA mutations that have been reported in various types of cancer. Furthermore, this review offers some perspective as to the origin of these of mutations, their functional consequences in cancer development, and possible therapeutic implications.


Quantitative changes in mast cell populations after left ventricular assist device implantation.
Mast cells have been implicated as important in tissue remodeling and fibrosis. We investigated the effect of mechanical ventricular unloading upon myocardial fibrosis and cardiac mast cell density in patients undergoing left ventricular assist device (LVAD) implantation. Paired myocardial tissue samples were obtained from 30 patients with end-stage cardiomyopathy at the time of LVAD implantation and at the time of removal and were compared with samples taken from donor hearts. Tissue sections were stained and quantitated for mast cells and myocardial fibrosis. Mast cell density (tryptase positive cells) in cardiomyopathy was higher than that in donor hearts (33.5 +/- 3.6 SEM cells/10 fields vs.15.2 +/- 2.0 SEM cells/10 fields respectively, p = 0.04) and was lower than LVAD supported hearts (33.5 +/- 3.6 SEM cells/10 fields vs. 49.8 +/- 5.7 SEM cells/10 fields respectively, p = 0.01). Mast cells are primarily localized in areas of increased interstitial fibrosis adjacent to myocardial cells and not vessels. There was statistically significant correlation between mast cells and interstitial collagen (p = 0.03) in patients before LVAD implantation that did not persist after mechanical support (p = 0.18). These results suggest that mechanical support with left ventricular assist devices induces an increase in mast cell number in the myocardium and an associated decrease in myocardial fibrosis. We believe these data demonstrate a dual role for cardiac mast cells in the increase in fibrosis in heart failure and the decrease after LVAD and its associated cardiac improvement.


Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts.
Cancer-associated fibroblasts (CAF) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we use single-cell RNA sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human and mouse PDAC tumors. We corroborate the presence of myofibroblastic CAFs and inflammatory CAFs and define their unique gene signatures in vivo. Moreover, we describe a new population of CAFs that express MHC class II and CD74, but do not express classic costimulatory molecules. We term this cell population "antigen-presenting CAFs" and find that they activate CD4+ T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Our cross-species analysis paves the way for investigating distinct functions of CAF subtypes in PDAC immunity and progression. SIGNIFICANCE: Appreciating the full spectrum of fibroblast heterogeneity in pancreatic ductal adenocarcinoma is crucial to developing therapies that specifically target tumor-promoting CAFs. This work identifies MHC class II-expressing CAFs with a capacity to present antigens to CD4+ T cells, and potentially to modulate the immune response in pancreatic tumors.See related commentary by Belle and DeNardo, p. 1001.This article is highlighted in the In This Issue feature, p. 983.


Evaluation of different approaches for confounding in nonrandomised observational data: a case-study of antipsychotics treatment.
Although randomised controlled trials are regarded as the gold standard for treatments efficacy, evidence from observational studies remains relevant. To address the problem of possible confounding in these studies, investigators must employ analysis methods that adjust for confounders and lead to an unbiased estimation of the treatment effect. In this paper, the authors describe two relevant statistical methods. The first method represents the classical approach consisting of a multiple regression model including the effects of treatment and covariates. This approach considers the relation between prognostic factors and the outcome variable as a relevant criterion for adjustment. The second method is based on the propensity score, and focuses on the relation between prognostic factors and treatment assignment. These approaches were applied to a cohort of 183 French schizophrenic patients who were followed for a 2-year period (from 1998 to 2000). The probability of relapse according to antipsychotic treatment exposure was modelled using Cox regression models with the two statistical methods. Goodness-of-fit criteria were used to compare the modelling approaches. This study demonstrates that the propensity score, a predicted probability, has an important balancing property that underscores its value in strengthening the results of nonrandomised observational studies.


Environmental constraints drive the partitioning of the soundscape in fishes.
The underwater environment is more and more being depicted as particularly noisy, and the inventory of calling fishes is continuously increasing. However, it currently remains unknown how species share the soundscape and are able to communicate without misinterpreting the messages. Different mechanisms of interference avoidance have been documented in birds, mammals, and frogs, but little is known about interference avoidance in fishes. How fish thus partition the soundscape underwater remains unknown, as acoustic communication and its organization have never been studied at the level of fish communities. In this study, passive acoustic recordings were used to inventory sounds produced in a fish community (120 m depth) in an attempt to understand how different species partition the acoustic environment. We uncovered an important diversity of fish sounds, and 16 of the 37 different sounds recorded were sufficiently abundant to use in a quantitative analysis. We show that sonic activity allows a clear distinction between a diurnal and a nocturnal group of fishes. Moreover, frequencies of signals made during the day overlap, whereas there is a clear distinction between the different representatives of the nocturnal callers because of a lack of overlap in sound frequency. This first demonstration, to our knowledge, of interference avoidance in a fish community can be understood by the way sounds are used. In diurnal species, sounds are mostly used to support visual display, whereas nocturnal species are generally deprived of visual cues, resulting in acoustic constraints being more important.


Operative versus nonoperative treatment of leg pain in adults with scoliosis: a retrospective review of a prospective multicenter database with two-year follow-up.
Retrospective review of a prospective, multicenter study. The purpose of this study was to assess the prevalence and severity of leg pain in adults with scoliosis and to assess whether surgery significantly improved leg pain compared with nonoperative management. Patients with adult scoliosis characteristically present with pain. The presence of leg pain is an independent predictor of a patient's choice for operative over nonoperative care. Data were extracted from a prospective, multicenter database for adult spinal deformity. At enrollment and follow-up, patients complete the Oswestry Disability Index (ODI) and assessment of leg pain using the numerical rating scale (NRS) score, with 0 and 10 representing no pain and unbearable pain, respectively. Plan for operative or nonoperative treatment was made at enrollment. The vast majority of adult scoliosis patients seen in our surgical clinics have received nonoperative therapies and are being seen for a surgical evaluation. Patients are counseled regarding operative and nonoperative management options and are in general encouraged to maximize nonoperative treatments. Two hundred eight (64%) of 326 adults with scoliosis had leg pain at presentation (mean NRS score = 4.7). Ninety-six patients with leg pain (46%) were managed operatively and 112 were treated nonoperatively. The operative group had higher baseline mean NRS score for leg pain (5.4 vs. 4.1, P < 0.001) and higher mean ODI (41 vs. 30, P < 0.001). At 2-year follow-up, nonoperative patients had no significant change in ODI or NRS score for leg pain (P = 0.2). In contrast, at 2-year follow-up surgically treated patients had significant improvement in mean NRS score for leg pain (5.4 vs. 2.2, P < 0.001) and ODI (41 vs. 24, P < 0.001). Compared with nonsurgically treated patients, at 2-year follow-up operative patients had lower mean NRS score for leg pain (2.2 vs. 3.8, P < 0.001) and mean ODI (24 vs. 31, P = 0.005). Despite having started with significantly greater leg pain and disability, surgically treated patients at 2-year follow-up had significantly less leg pain and disability than nonoperatively treated patients. Surgical treatment has the potential to provide significant improvement of leg pain in adults with scoliosis.


Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci.
Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.


Connections of the subthalamic nucleus with ventral striatopallidal parts of the basal ganglia in the rat.
The present study was undertaken to establish the precise anatomical relationship of the subthalamic nucleus (STh) with limbic lobe-afferented parts of the basal ganglia in the rat. The anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L), injected in the STh, the globus pallidus, the ventral pallidum, the ventral striatum, and the parafascicular thalamic nucleus, and the retrograde tracers Fluoro-Gold (FG) and cholera toxin B (CTb), injected in the globus pallidus, the ventral pallidum, the ventral striatum, and the ventral mesencephalon, were used for this purpose. The results of these tracing experiments confirm the general notion of reciprocal connections between the STh and pallidal areas. Thus the dorsomedial part of the STh is connected with the subcommisural ventral pallidum, whereas a more ventral and lateral part of the medial STh is related to the medial globus pallidus. The lateral hypothalamic area, directly adjacent to the STh, containing neurons with a morphology quite similar to those in the STh, projects to parts of the ventral pallidum related to the olfactory tubercle. The reciprocal projection from this pallidal area to subthalamic regions appears to be very sparse. The medial STh sends strong projections to the medial part of the entopeduncular nucleus and the adjacent lateral hypothalamic area. Sparser projections from the medial STh reach the rostral and medial part of the caudate-putamen and the nucleus accumbens. The nucleus accumbens sends a very sparse projection back to the medial STh. The projections of the medial STh to the ventral mesencephalon appear also to be topographically organized. The lateral hypothalamus and a few cells in the most medial part of the STh project to the ventral tegmental area, whereas progressively more lateral parts of the ventral mesencephalon, in particular the substantia nigra, receive input from successively more lateral and caudal parts of the STh. In addition, a number of STh fibers reach the midbrain extrapyramidal area. The lateral part of the parafascicular thalamic nucleus projects to the lateral part of the STh, whereas parafascicular neurons medial to the fasciculus retroflexus project to the dorsomedial portion of the STh. The medial part of the STh and the adjacent lateral hypothalamus are intimately connected with limbic parts of the basal ganglia in a way similar and parallel to the connections of the lateral STh with motor-related parts of the basal ganglia. These findings suggest a role for the STh in nonmotor functions of the basal ganglia.


Utilization of physical therapy services in Germany.
Physical therapy plays an important role in health care and is listed as a therapy in many clinical guidelines. Claims data gathered by statutory health insurers demonstrate that in Germany physical therapy accounts for more than 70% of the reimbursable costs of all non-medical treatments comprising physical therapy, logopaedics, occupational therapy and podiatry. In monetary terms, this equates to about EUR 4.4 billion annually. According to self-reports of the respondents of GEDA 2014/2015-EHIS on their utilization of physical therapy services 25.5% of women and 17.7% of men used physical therapy services within the 12 months that preceded the interview. This rate increases significantly with age, reaching its peak among the 50-to-59 year age group, at 30.7% among women and 20.1% among men. People with a high level of education and those with private health insurance use physical therapy services more frequently. Moreover, people living in the eastern part of Germany use physical therapy services more often than those living in the western federal states.


Rotavirus within day care centres in Oxfordshire, UK: characterization of partial immunity.
Repeated measures data for rotavirus infection in children within 14 day care centres (DCCs) in the Oxfordshire area, UK, are used to explore aspects of rotavirus transmission and immunity. A biologically realistic model for the transmission of infection is presented as a set of probability models suitable for application to the data. Two transition events are modelled separately: incidence and recovery. The complexity of the underlying mechanistic model is reflected in the choice of the fixed variables in the probability models. Parameter estimation was carried out using a Bayesian Markov chain Monte Carlo method. We use the parameter estimates obtained to build a profile of the natural history of rotavirus reinfection in an individual child. We infer that rotavirus transmission in children in DCCs is dependent on the DCC prevalence, with symptomatic infection of longer duration, but no more infectious per day of infectious period, than asymptomatic infection. There was evidence that a recent previous infection reduces the risk of disease and, to a lesser extent, reinfection, but not duration of infection. The results provide evidence that partial immunity to rotavirus infection develops over several time scales.


The adenylate cyclase toxin of Bordetella pertussis binds to target cells via the alpha(M)beta(2) integrin (CD11b/CD18).
The adenylate cyclase toxin (CyaA) of Bordetella pertussis is a major virulence factor required for the early phases of lung colonization. It can invade eukaryotic cells where, upon activation by endogenous calmodulin, it catalyzes the formation of unregulated cAMP levels. CyaA intoxication leads to evident toxic effects on macrophages and neutrophils. Here, we demonstrate that CyaA uses the alpha(M)beta(2) integrin (CD11b/CD18) as a cell receptor. Indeed, the saturable binding of CyaA to the surface of various hematopoietic cell lines correlated with the presence of the alpha(M)beta(2) integrin on these cells. Moreover, binding of CyaA to various murine cell lines and human neutrophils was specifically blocked by anti-CD11b monoclonal antibodies. The increase of intracellular cAMP level and cell death triggered by CyaA intoxication was also specifically blocked by anti-CD11b monoclonal antibodies. In addition, CyaA bound efficiently and triggered intracellular cAMP increase and cell death in Chinese hamster ovary cells transfected with alpha(M)beta(2) (CD11b/CD18) but not in cells transfected with the vector alone or with the alpha(X)beta(2) (CD11c/CD18) integrin. Thus, the cellular distribution of CD11b, mostly on neutrophils, macrophages, and dendritic and natural killer cells, supports a role for CyaA in disrupting the early, innate antibacterial immune response.


Label-free DNA sensors using ultrasensitive diamond field-effect transistors in solution.
Charge detection biosensors have recently become the focal point of biosensor research, especially field-effect-transistors (FETs) that combine compactness, low cost, high input, and low output impedances, to realize simple and stable in vivo diagnostic systems. However, critical evaluation of the possibility and limitations of charge detection of label-free DNA hybridization using silicon-based ion-sensitive FETs (ISFETs) has been introduced recently. The channel surface of these devices must be covered by relatively thick insulating layers ( SiO2, Si3N4, Al2O3, or Ta2O5) to protect against the invasion of ions from solution. These thick insulating layers are not suitable for charge detection of DNA and miniaturization, as the small capacitance of thick insulating layers restricts translation of the negative DNA charge from the electrolyte to the channel surface. To overcome these difficulties, thin-gate-insulator FET sensors should be developed. Here, we report diamond solution-gate FETs (SGFETs), where the DNA-immobilized channels are exposed directly to the electrolyte solution without gate insulator. These SGFETs operate stably within the large potential window of diamond (>3.0 V). Thus, the channel surface does not need to be covered by thick insulating layers, and DNA is immobilized directly through amine sites, which is a factor of 30 more sensitive than existing Si-ISFET DNA sensors. Diamond SGFETs can rapidly detect complementary, 3-mer mismatched (10 pM) and has a potential for the detection of single-base mismatched oligonucleotide DNA, without biological degradation by cyclically repeated hybridization and denature.


Concentration-dependent mortality of chloroquine in overdose.
Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1-17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.


Leaning Into the Bite: The piRNA Pathway as an Exemplar for the Genetic Engineering Need in Mosquitoes.
The piRNA pathway is a specialized small RNA interference that in mosquitoes is mechanistically distant from analogous biology in the Drosophila model. Current genetic engineering methods, such as targeted genome manipulation, have a high potential to tease out the functional complexity of this intricate molecular pathway. However, progress in utilizing these methods in arthropod vectors has been geared mostly toward the development of new vector control strategies rather than to study cellular functions. Herein we propose that genetic engineering methods will be essential to uncover the full functionality of PIWI/piRNA biology in mosquitoes and that extending the applications of genetic engineering on other aspects of mosquito biology will grant access to a much larger pool of knowledge in disease vectors that is just out of reach. We discuss motivations for and impediments to expanding the utility of genetic engineering to study the underlying biology and disease transmission and describe specific areas where efforts can be placed to achieve the full potential for genetic engineering in basic biology in mosquito vectors. Such efforts will generate a refreshed intellectual source of novel approaches to disease control and strong support for the effective use of approaches currently in development.


Assessment of vascular function: flow-mediated constriction complements the information of flow-mediated dilatation.
To determine whether vascular function assessed by low-flow-mediated constriction (L-FMC), a novel non-invasive method, complements the information obtained with "traditional" flow-mediated dilatation (FMD). In protocol 1, 12 healthy young volunteers underwent FMD and L-FMC measurements at rest and immediately after isometric exercise of the same hand. In protocol 2, 24 patients with coronary artery disease, 24 with congestive heart failure, 24 hypertensive patients and 64 healthy volunteers were enrolled to undergo L-FMC and FMD measurements. In protocol 1, exercise was associated with mean (SD) increases in radial artery blood flow, diameter and L-FMC (from -5.1 (1.5)% to -7.8 (3.4)%, p<0.05), while FMD was significantly blunted (from 6.0 (2.4)% to 3.0 (3.2)%, p<0.05). In protocol 2, both FMD and L-FMC were blunted in the patient groups. Receiver operating curve analysis showed that, as compared with FMD alone, the combination of L-FMC and FMD significantly improved the sensitivity and specificity in detecting patients diagnosed with cardiovascular disease (p<0.05). In the first protocol, FMD and L-FMC were shown to be reciprocally regulated. A blunted FMD may, in certain cases, be an expression of increased resting vascular activation and not only of impaired endothelial function. In the second protocol, a statistical approach showed that implementation of L-FMC provides a better characterisation than FMD of vascular function in cardiovascular disease. Vascular (endothelial) function is a complex phenomenon which requires a multifaceted approach; it is suggested that a combination of L-FMC and FMD will provide additive and complementary information to "traditional" FMD measurements.


Teledermatology to Improve Access to and Quality of Skin Care in Eastern Indonesia.
Skin diseases are a major public health concern in Indonesia, although access to specialized care in remote areas is limited. We initiated a low-cost teledermatology service in Sumba, a remote island in eastern Indonesia. Eighteen healthcare workers (HCWs) at five primary healthcare centers received training to manage common skin diseases and submit clinical cases beyond their expertise to an online platform. Submitted cases were reviewed by at least one dermatologist. Diagnostic agreement between HCWs and dermatologists was calculated. The HCWs participated in a satisfaction survey 2 years after project initiation. Since October 2020, of 10,384 patients presenting with skin complaints in a 24-month period, 307 (3%) were submitted for a teledermatology consultation. The most frequent skin diseases were infections and infestations (n = 162, 52.8%) and eczematous (85, 27.7%) and inflammatory (17, 5.5%) conditions. Fifty-three patients (17.3%) were diagnosed with a neglected tropical skin disease, including leprosy and scabies. Dermatologist advice was provided within a median of 50 minutes (interquartile range, 18-255 minutes), with 91.9% of consultations occurring within 24 hours. The diagnostic agreement level between HCWs and dermatologists significantly improved over time, from 46.9% in the first 6-month period (κ = 0.45; 95% CI, 0.37-0.54) to 77.2% in the last 6-month period (κ = 0.76; 95% CI, 0.67-0.86; global P < 0.001). The HCWs reported that the teledermatology service was extremely/very useful in supporting daily practice (100%) and improved their knowledge of skin diseases tremendously/a lot (92%). Teledermatology can improve accessibility and quality of skin services in medically underserved areas, providing opportunities for scalability and knowledge transfer to frontline HCWs.


Dynamic model of time-dependent complex networks.
The characterization of the "most connected" nodes in static or slowly evolving complex networks has helped in understanding and predicting the behavior of social, biological, and technological networked systems, including their robustness against failures, vulnerability to deliberate attacks, and diffusion properties. However, recent empirical research of large dynamic networks (characterized by irregular connections that evolve rapidly) has demonstrated that there is little continuity in degree centrality of nodes over time, even when their degree distributions follow a power law. This unexpected dynamic centrality suggests that the connections in these systems are not driven by preferential attachment or other known mechanisms. We present an approach to explain real-world dynamic networks and qualitatively reproduce these dynamic centrality phenomena. This approach is based on a dynamic preferential attachment mechanism, which exhibits a sharp transition from a base pure random walk scheme.


Antiarrhythmic, electrophysiologic and hemodynamic effects of ACC-9358.
The antiarrhythmic, electrophysiologic and hemodynamic effects of a new antiarrhythmic agent, ACC-9358, were evaluated. In anesthetized dogs, ACC-9358 converted ouabain-induced ventricular tachycardia to normal sinus rhythm at a cumulative dose equal to encainide or flecainide and less than disopyramide. In 24-hr coronary artery ligated dogs, ACC-9358 suppressed spontaneous ventricular arrhythmias for up to 6 hr after oral or i.v. administration. The antiarrhythmic effect and plasma concentrations of ACC-9358 correlated well for both oral (r = 0.88) and i.v. (r = 0.87) administration. ACC-9358, flecainide and disopyramide were equieffective in converting crush-stimulation-induced atrial flutter in anesthetized dogs to normal sinus rhythm. In alpha-chloralose-anesthetized, closed-chest dogs, ACC-9358 slowed impulse conduction through the atria, atrioventricular node, His-Purkinje system and ventricles and prolonged atrial functional refractory period. In conscious dogs, ACC-9358 increased heart rate, reduced stroke volume and had no effect on mean arterial pressure, systemic vascular resistance or cardiac output. In alpha-chloralose-anesthetized dogs, ACC-9358-induced sinus tachycardia was unaffected by propranolol but was blocked by hexamethonium or vagotomy. In isolated cat ventricular muscle, the IC50 for the negative inotropic effect of ACC-9358 was significantly greater than flecainide or disopyramide. These results indicate that ACC-9358 is a potent, broad-spectrum, long-acting, orally and intravenously active class Ic antiarrhythmic agent that 1) may be devoid of active metabolites, 2) exerts little or no vascular effects and 3) has less direct cardiodepressant activity than flecainide or disopyramide.


Phase I clinical study of LL-D49194 alpha 1 with retrospective pharmacokinetic investigations in mice and humans. The EORTC ECTG.
LL-D49194 alpha 1 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D49194 alpha 1 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.


Management of asthma exacerbations.
The 1997 Expert Panel Report 2 from the National Asthma Education and Prevention Program details principles and goals for managing asthma exacerbations, based on scientific literature and the opinion of the panel. The panel's recommendations are summarized here, along with approaches to the evaluation and management of patients with asthma exacerbations. Methods to assess and classify the severity of asthma exacerbations are discussed, and treatment objectives for mild, moderate, and severe exacerbations are presented, along with a discussion of postinfectious acute airway hyperresponsiveness. A review of pharmacologic agents used in the treatment of asthma exacerbations is also included. Key points in the management of asthma exacerbations include the notion that early treatment is the best strategy for management. Important elements of early treatment include recognition of early signs of worsening asthma, a written action plan to guide patient self-management, appropriate intensification of therapy, and prompt communication between patient and provider about deterioration in asthma control. Other key points include the use of inhaled beta 2-adrenergic agonists to provide prompt relief of airflow obstruction, the early use of systemic corticosteroids for patients with moderate to severe exacerbations or for patients who fail to respond promptly and completely to an inhaled beta 2-adrenergic agonist, and monitoring response to therapy with serial measurements of lung function.


Retinal prosthetics, optogenetics, and chemical photoswitches.
Three technologies have emerged as therapies to restore light sensing to profoundly blind patients suffering from late-stage retinal degenerations: (1) retinal prosthetics, (2) optogenetics, and (3) chemical photoswitches. Prosthetics are the most mature and the only approach in clinical practice. Prosthetic implants require complex surgical intervention and provide only limited visual resolution but can potentially restore navigational ability to many blind patients. Optogenetics uses viral delivery of type 1 opsin genes from prokaryotes or eukaryote algae to restore light responses in survivor neurons. Targeting and expression remain major problems, but are potentially soluble. Importantly, optogenetics could provide the ultimate in high-resolution vision due to the long persistence of gene expression achieved in animal models. Nevertheless, optogenetics remains challenging to implement in human eyes with large volumes, complex disease progression, and physical barriers to viral penetration. Now, a new generation of photochromic ligands or chemical photoswitches (azobenzene-quaternary ammonium derivatives) can be injected into a degenerated mouse eye and, in minutes to hours, activate light responses in neurons. These photoswitches offer the potential for rapidly and reversibly screening the vision restoration expected in an individual patient. Chemical photoswitch variants that persist in the cell membrane could make them a simple therapy of choice, with resolution and sensitivity equivalent to optogenetics approaches. A major complexity in treating retinal degenerations is retinal remodeling: pathologic network rewiring, molecular reprogramming, and cell death that compromise signaling in the surviving retina. Remodeling forces a choice between upstream and downstream targeting, each engaging different benefits and defects. Prosthetics and optogenetics can be implemented in either mode, but the use of chemical photoswitches is currently limited to downstream implementations. Even so, given the high density of human foveal ganglion cells, the ultimate chemical photoswitch treatment could deliver cost-effective, high-resolution vision for the blind.


Anti-thrombotic strategies for microfluidic blood processing.
The redundant mechanisms involved in blood coagulation are crucial for rapid hemostasis. Yet they also create challenges in blood processing in medical devices and lab-on-a-chip systems. In this work, we investigate the effects of both shear stress and hypothermic blood storage on thrombus formation in microfluidic processing. For fresh blood, thrombosis occurs only at high shear, and the glycoprotein IIb/IIIa inhibitor tirofiban is highly effective in preventing thrombus formation. Blood storage generally activates platelets and primes them towards thrombosis via multiple mechanisms. Thrombus formation of stored blood at low shear can be adequately inhibited by glycoprotein IIb/IIIa inhibitors. At high shear, von Willebrand factor-mediated thrombosis contributes significantly and requires additional treatments with thiol-containing antioxidants-such as N acetylcysteine and reduced glutathione-that interfere with von Willebrand factor polymerization. We further demonstrate the effectiveness of these anti-thrombotic strategies in microfluidic devices made of cyclic olefin copolymer, a popular material used in the healthcare industry. This work identifies effective anti-thrombotic strategies that are applicable in a wide range of blood- and organ-on-a-chip applications.


Senescence surveillance of pre-malignant hepatocytes limits liver cancer development.
Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.


Role of circulating platelets and granulocytes in PAF-induced pulmonary dysfunction in awake sheep.
The effects of a single intravascular bolus injection of platelet-activating factor (PAF) on pulmonary hemodynamics, lung mechanics, and lung fluid and solute exchange were studied in 13 chronically instrumented unanesthetized sheep. Since PAF has profound effects on both platelets and granulocytes, we investigated the effects of platelet and granulocyte depletion on the sheep's response to exogenous PAF. Sheep received PAF when granulocyte and platelets counts were normal and after platelet depletion with rabbit antisheep platelet antibodies (n = 5) or granulocyte depletion with hydroxyurea (n = 5). Sheep served as their own controls, and the order of experimentation was varied. Bolus injections of PAF had reproducible effects on pulmonary hemodynamics (pulmonary arterial pressure increased acutely to 85 +/- 3.7 cmH2O) and lung mechanics (dynamic compliance of the lungs decreased to 24.5 +/- 3.8% of base line and resistance to airflow across the lungs increased greater than 10-fold) and caused marked increases in lung lymph concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha. The single bolus injection of PAF also caused marked prolonged elevations in lung lymph flow and increases in the lymph-to-plasma protein concentration ratio for 3 h after PAF. PAF had profound effects despite platelet and granulocyte depletion. Platelet depletion slightly attenuated the pulmonary hypertension observed after PAF injection. Platelet depletion also attenuated the increases in thromboxane B2 concentrations in lung lymph, and lung mechanics normalized more rapidly in platelet-depleted sheep. There were no statistically significant effects of granulocyte depletion to less than 200 granulocytes/mm3 on any of the measured variables.(ABSTRACT TRUNCATED AT 250 WORDS)


Light scattering by polydispersions of randomly oriented spheroids with sizes comparable to wavelengths of observation.
We report the results of an extensive study of the scattering of light by size and size-shape distributions of randomly oriented prolate and oblate spheroids with the index of refraction 1.5 + 0.02i typical of some mineral terrestrial aerosols. The scattering calculations have been carried out with Waterman's T-matrix approach, as developed recently by Mishchenko [J. Opt. Soc. Am. A 8, 871 (1991); Appl. Opt. 32, 4562 (1993)]. Our main interest is in light scattering by polydisperse models of nonspherical particles because averaging over sizes provides more realistic modeling of natural ensembles of scattering particles and washes out the interference structure and ripple typical of monodisperse scattering patterns, thus enabling us to derive meaningful conclusions about the effects of particle nonsphericity on light scattering. Following Hansen and Travis [Space Sci. Rev. 16, 527 (1974)], we show that scattering properties of most physically plausible size distributions of randomly orientednonspherical part cles depend primarily on the effective equivalent-sphere radius and effective variance of the distribution, the actual shape of the distribution having a minor influence. To minimize the computational burden, we have adopted a computationally convenient power law distribution of particle equivalent-sphere radii n(r) α r(-3),r(1) ≤ r≤r(2). The effective variance of the size distribution is fixed at 0.1, and the effective size parameter continuously varies from 0 to 15. We present results of computer calculations for 24 prolate and oblate spheroidal shapes with aspect ratios from 1.1 to 2.2. The elements of the scattering matrix for the whole range of size parameters and scattering angles are displayed in the form of contour plots. Computational results are compared with analogous calculations for surface-equivalent spheres, and the effects of particle shape on light scattering are discussed in detail.


A worksite obesity intervention: results from a group-randomized trial.
We used a participatory process to develop an obesity intervention appropriate for elementary school personnel. A randomized controlled trial included 16 school worksites (8 intervention, 8 control). Intervention schools formed committees to develop and implement health promotion activities for employees. Anthropometric and self-report data were collected at baseline and postintervention (2 years later). The primary outcome measures were body mass index (BMI), waist-hip ratio, physical activity, and fruit and vegetable consumption. After adjustment for age, ethnicity, and job classification, employees in intervention schools reduced their BMI by an average of 0.04 kg/m2, and those in control schools increased their BMI by an average of 0.37 kg/m2. Comparisons for waist-hip ratio, weekly physical activity minutes, and fruit and vegetable consumption were not significant. The participatory process appeared to be an effective means for stimulating change. The intervention may have slowed and perhaps reversed the tendency of adults to gain weight progressively with age.


Social status, gonadal state, and the adrenal stress response in the lizard, Anolis carolinensis.
Adult males of the small arboreal iguanid lizard, Anolis carolinensis, form social dominance hierarchies when placed in habitats with limited resources. Skin color changes occur during hierarchy formation, most conspicuously in subordinates, who appear darker (more brown) than dominants (more green). Because skin color in this species is under the control of hormones frequently associated with physiological stress, radioimmunoassay of plasma levels of the principal reptilian adrenal steroid, corticosterone, was performed. To examine the influence of gonadal androgen, known to influence the aggression that attends hierarchy formation, lizard pairs were constituted in which one or both members were castrated. Corticosterone levels of intact subordinates were significantly elevated, whereas those of castrated subordinates or dominants showed levels comparable to those of isolates. No significant differences in spermatogenic stage could be detected between intact dominants or subordinates.


Proteins of bovine ephemeral fever virus.
The proteins of bovine ephemeral fever virus (BEFV) were examined in purified virions and in infected BHK-21 cells. Five structural proteins were named L (180K), G (81K), N (52K), M1 (43K) and M2 (29K). The 81K G protein incorporated [3H]glucosamine, was removed from virions by treatment with Triton X-100 and bound monoclonal antibodies which were both neutralizing and protective. Treatment of virions with Triton X-100 and 0.2 to 1.0 M-NaCl progressively released L, M1 and M2. The N protein remained associated with nucleocapsids in up to 2.5 M-NaCl. The glycoprotein (G), nucleoprotein (N) and matrix protein (M2) were phosphorylated. In BEFV-infected BHK-21 cells, five virus-induced proteins were detected from 12 h post-infection. The L, N, M1 and M2 proteins corresponded to those detected in virions whereas the G protein existed in two forms. In tunicamycin-treated cells these occurred as 67K and 71K non-glycosylated precursors. In the absence of tunicamycin, 77K and 79K glycosylated forms were further modified to produce the 81K virion G protein and a 90K cell-associated form. Five viral proteins were also detected in cells infected with the closely related Berrimah virus; the Berrimah virus G protein was also present in two forms.


Emerging electrochemical energy conversion and storage technologies.
Electrochemical cells and systems play a key role in a wide range of industry sectors. These devices are critical enabling technologies for renewable energy; energy management, conservation, and storage; pollution control/monitoring; and greenhouse gas reduction. A large number of electrochemical energy technologies have been developed in the past. These systems continue to be optimized in terms of cost, life time, and performance, leading to their continued expansion into existing and emerging market sectors. The more established technologies such as deep-cycle batteries and sensors are being joined by emerging technologies such as fuel cells, large format lithium-ion batteries, electrochemical reactors; ion transport membranes and supercapacitors. This growing demand (multi billion dollars) for electrochemical energy systems along with the increasing maturity of a number of technologies is having a significant effect on the global research and development effort which is increasing in both in size and depth. A number of new technologies, which will have substantial impact on the environment and the way we produce and utilize energy, are under development. This paper presents an overview of several emerging electrochemical energy technologies along with a discussion some of the key technical challenges.


Roux-en-Y divided gastric bypass results in the same weight loss as duodenal switch for morbid obesity.
The 2 weight loss procedures most commonly performed in the United States are Roux-en-Y gastric bypass (RYGBP) and lateral gastrectomy with duodenal switch (BPD/DS). RYGB is a restrictive procedure, whereas BPD/DS relies on mild restriction of intake as well as malabsorption. Many physicians believe that weight loss is greater after BPD/DS than after RYGBP. However, these procedures have not been compared using groups of patients operated on by the same surgeons at the same institution. We compared weight loss (expressed as percent of excess body weight [%EBW]) after 1 and 2 years in patients who underwent open RYGB or BPD/DS at our institution. Average length of stay was longer in BPD/DS patients than in those undergoing RYGBP (8.7 vs. 5.9 days, P <0.05). Anastomotic leaks were higher after BPD/DS (6% vs. 3%), but the difference did not achieve statistical significance. Mortality did not differ between the 2 groups (0.8% vs. 0.9%). In the group of patients followed-up for 1 to 2 years, age and distribution of men and women did not differ. Those patients undergoing BPD/DS had higher body mass index (59 vs. 55, P <0.05). Weight loss expressed as %EBW was similar between the 2 groups: 54% versus 53% at 1 year and 67% versus 64% at 2 years. Our data suggested that weight loss expressed as %EBW is similar between patients undergoing RYGBP and those undergoing BPD/DS. However, BPD/DS was associated with a longer hospital stay.


Vision in annelid worms.
In a first electrophysiological study of worm vision, electroretinograms were measured in two alciopid worms: Torrea, taken at the surface, and deep-sea Vanadis. Both forms possess a primary retina in the focal plane of the lens, and accessory retinas lying beside the lens. Such accessory retinas occur also in deep sea fishes and cephalopods. In Torrea the primary retina peaks in sensitivity at 400 nanometers, the secondary retina at 560 nanometers. Both together could serve as a depth guage, since 560 nanometers attenuates much faster in seawater than 400 nanometers. The Vanadis eyes peaked in sensitivity at 460 to 480 nanometers, a property shared with deep-sea forms of other phyla; and appropriate, since these wavelengths penetrate seawater most deeply, and also are the wavelengths of maximum bioluminescence.


Output power enhancement of a palmtop terahertz-wave parametric generator.
Broadband terahertz (THz) waves were generated by optical parametric processes based on laser light scattering from the polariton mode of a nonlinear crystal. By using the parametric oscillation of a MgO-doped LiNbO3 crystal pumped by a nanosecond Q-switched Nd:YAG laser, we have realized a broadband, high-energy and compact THz-wave source. We report the development of a THz-wave parametric generator (TPG) using a small pump source with a short pulse width and a top-hat beam profile. These characteristics of the pump beam permit high-intensity pumping especially close to the output surface of the THz wave without thermal damage to the crystal surface. We also calculated the outcoupled THz wave for beams with two different intensity profiles: a top-hat beam (in this experiment) and a Gaussian beam (previously reported). The result shows the mechanism of the output energy and/or power enhancement.


Nine-year survival of lymphoblastic lymphoma patients.
This study aimed to analyze the overall survival period of adult lymphoblastic lymphoma patients treated with various therapeutic regimens, and to assess the determinants affecting survival outcome. Twenty-five adult patients with lymphoblastic lymphoma who had been treated at Severance Hospital, Yonsei University College of Medicine, Seoul, Korea from June 1996 to June 2005 were analyzed retrospectively. As an initial remission induction chemotherapy, the hyper-CVAD regimen was performed in eight patients, the Stanford/Northern California Oncology Group (NCOG) regimen in five, the CAVOP regimen in four, the m-BACOP regimen in three, and the CHOP regimen in one patient. Patients were divided into two groups according to their therapeutic modalities. Twenty patients received conventional chemotherapy alone and five received subsequent PBSCT after conventional chemotherapy. Four patients of the PBSCT group underwent autologous PBSCT and one underwent allogeneic PBSCT. The overall response rate was 80% (60% showing a complete response, 20% showing a partial response) and the relapse rate was 73.3%. The overall survival (OS) rate was 55.1% at 1 year, 31.5% at 5 years, and 23.6% at 9 years. The disease-free survival (DFS) rate was 46.7% at 1 year and 30.0% at 7 years. The 5-year OS rate in relation to the regimens was 60% with the Stanford/NCOG regimen, 50% with the CAVOP regimen, and 33.3% with the m-BACOP regimen. The patients treated with the hyper-CVAD regimen had an 18.2% 2-year OS rate, and other patients with CHOP or COPBLAM-V expired early in their course. The OS rate in patients treated with conventional chemotherapy alone was 19.8%, whereas patients treated with subsequent PBSCT after chemotherapy showed 50% overall survival (p=0.25). The age at presentation influenced the outcome of the patients (p=0.01). The Stanford/NCOG regimen is an effective initial choice of therapy for lymphoblastic lymphoma patients, and is superior to the hyper-CVAD regimen in complete response rate and overall survival rate (p =0.36). Addition of PBSCT after chemotherapy may be needed for achieving optimal outcomes.


Covered stents versus Bare-metal stents in chronic atherosclerotic Gastrointestinal Ischemia (CoBaGI): study protocol for a randomized controlled trial.
Chronic mesenteric ischemia (CMI) is the result of insufficient blood supply to the gastrointestinal tract and is caused by atherosclerotic stenosis of one or more mesenteric arteries in > 90% of cases. Revascularization therapy is indicated in patients with a diagnosis of atherosclerotic CMI to relieve symptoms and to prevent acute-on-chronic mesenteric ischemia, which is associated with high morbidity and mortality. Endovascular therapy has rapidly evolved and has replaced surgery as the first choice of treatment in CMI. Bare-metal stents (BMS) are standard care currently, although retrospective studies suggested significantly higher patency rates for covered stents (CS). The Covered stents versus Bare-metal stents in chronic atherosclerotic Gastrointestinal Ischemia (CoBaGI) trial is designed to prospectively assess the patency of CS versus BMS in patients with atherosclerotic CMI. The CoBaGI trial is a randomized controlled, parallel-group, patient- and investigator-blinded, superiority, multicenter trial conducted in six centers of the Dutch Mesenteric Ischemia Study group (DMIS). Eighty-four patients with a consensus diagnosis of atherosclerotic CMI are 1:1 randomized to either a balloon-expandable BMS (Palmaz Blue with rapid-exchange delivery system, Cordis Corporation, Bridgewater, NJ, USA) or a balloon-expandable CS (Advanta V12 over-the-wire, Atrium Maquet Getinge Group, Hudson, NH, USA). The primary endpoint is the primary stent-patency rate at 24 months assessed with CT angiography. Secondary endpoints are primary stent patency at 6 and 12 months and secondary patency rates, freedom from restenosis, freedom from symptom recurrence, freedom from re-intervention, quality of life according the EQ-5D-5 L and SF-36 and cost-effectiveness at 6, 12 and 24 months. The CoBaGI trial is designed to assess the patency rates of CS versus BMS in patients treated for CMI caused by atherosclerotic mesenteric stenosis. Furthermore, the CoBaGI trial should provide insights in the quality of life of these patients before and after stenting and its cost-effectiveness. The CoBaGI trial is the first randomized controlled trial performed in CMI caused by atherosclerotic mesenteric artery stenosis. ClinicalTrials.gov, ID: NCT02428582 . Registered on 29 April 2015.


Treatment of schizophrenia with antipsychotics in Norwegian emergency wards, a cross-sectional national study.
Surveys on prescription patterns for antipsychotics in the Scandinavian public health system are scarce despite the prevalent use of these drugs. The clinical differences between antipsychotic drugs are mainly in the areas of safety and tolerability, and international guidelines for the treatment of schizophrenia offer rational strategies to minimize the burden of side effects related to antipsychotic treatment. The implementation of treatment guidelines in clinical practice have proven difficult to achieve, as reflected by major variations in the prescription patterns of antipsychotics between different comparable regions and countries. The objective of this study was to evaluate the practice of treatment of schizophrenic patients with antipsychotics at discharge from acute inpatient settings at a national level. Data from 486 discharges of patients from emergency inpatient treatment of schizophrenia were collected during a three-month period in 2005; the data were collected in a large national study that covered 75% of Norwegian hospitals receiving inpatients for acute treatment. Antipsychotic treatment, demographic variables, scores from the Global Assessment of Functioning and Health of the Nation Outcome Scales and information about comorbid conditions and prior treatment were analyzed to seek predictors for nonadherence to guidelines. In 7.6% of the discharges no antipsychotic treatment was given; of the remaining discharges, 35.6% were prescribed antipsychotic polypharmacy and 41.9% were prescribed at least one first-generation antipsychotic (FGA). The mean chlorpromazine equivalent dose was 450 (SD 347, range 25-2800). In the multivariate regression analyses, younger age, previous inpatient treatment in the previous 12 months before index hospitalization, and a comorbid diagnosis of personality disorder or mental retardation predicted antipsychotic polypharmacy, while previous inpatient treatment in the previous 12 months also predicted prescription of at least one FGA. Our national survey of antipsychotic treatment at discharge from emergency inpatient treatment revealed antipsychotic drug regimens that are to some degree at odds with current guidelines, with increased risk of side effects. Patients with high relapse rates, comorbid conditions, and previous inpatient treatment are especially prone to be prescribed antipsychotic drug regimens not supported by international guidelines.


Vitamin D status predicts 30 day mortality in hospitalised cats.
Vitamin D insufficiency, defined as low serum concentrations of the major circulating form of vitamin D, 25 hydroxyvitamin D (25(OH)D), has been associated with the development of numerous infectious, inflammatory, and neoplastic disorders in humans. In addition, vitamin D insufficiency has been found to be predictive of mortality for many disorders. However, interpretation of human studies is difficult since vitamin D status is influenced by many factors, including diet, season, latitude, and exposure to UV radiation. In contrast, domesticated cats do not produce vitamin D cutaneously, and most cats are fed a commercial diet containing a relatively standard amount of vitamin D. Consequently, domesticated cats are an attractive model system in which to examine the relationship between serum 25(OH)D and health outcomes. The hypothesis of this study was that vitamin D status would predict short term, all-cause mortality in domesticated cats. Serum concentrations of 25(OH)D, together with a wide range of other clinical, hematological, and biochemical parameters, were measured in 99 consecutively hospitalised cats. Cats which died within 30 days of initial assessment had significantly lower serum 25(OH)D concentrations than cats which survived. In a linear regression model including 12 clinical variables, serum 25(OH)D concentration in the lower tertile was significantly predictive of mortality. The odds ratio of mortality within 30 days was 8.27 (95% confidence interval 2.54-31.52) for cats with a serum 25(OH)D concentration in the lower tertile. In conclusion, this study demonstrates that low serum 25(OH)D concentration status is an independent predictor of short term mortality in cats.


A normal psychology of everyday pain.
Proposed is a psychology of pain that focusses on normal psychological reactions to pain. A normal psychology of pain seeks to explain what normal people (those who would not meet any criteria for any psychological disorder) do when faced with pain. Herein, we focus on everyday pain defined as pain that is clinically unimportant that arises from normal everyday activity. Pain functions to interrupt current concerns and promote problem solving typically in the form of escape, pain management, or request for assistance. A model of analgesic problem solving is described. Focussing on pain as an interruption leads us to think about the purpose of analgesics in repairing attention and returning function. New endpoints for analgesic performance are offered. Similarly, a focus on pain as a motivation for analgesia demands that we understand how people self-medicate its relative success, and what influences patterns of self-medication. Finally, the problem of pain in children and adolescents, including self-medication in youth, is discussed. Although there is limited small-scale research on young people and their knowledge about analgesics, very little is known about their beliefs, attitudes to analgesics and their self-medication behaviour. Adolescents in most societies are left largely unguided. There is little child-specific communication about how to manage pain. Most children rely on parental knowledge, although increasingly the internet is becoming a source of advice for young people learning about analgesics.


Neurodevelopmental status of infants and young children treated for brain tumors with preirradiation chemotherapy.
In an effort to reduce the severity of late neurotoxicities associated with cranial irradiation, 14 infants and young children with malignant brain tumors were given preirradiation chemotherapy for 2 to 22 months (median, 8 months). Prospective neurodevelopmental evaluations were routinely conducted and now extend from 35 to 60 months (median, 41 months) postdiagnosis, and 10 to 52 months (median, 31 months) postirradiation in the 12 surviving children. At the initiation of chemotherapy, less than one fourth of the patients displayed normal performance status or mental functioning on age-corrected tests; the majority remained stable or declined while receiving chemotherapy. Declining mental development and adaptive behavior were noted in six patients following radiation therapy with only two patients now functioning in the normal range for age. The analysis suggests that neurodevelopmental progress is a function of multiple factors, including neurologic and sensorimotor deficits associated with the tumor, surgical intervention, and chemotherapy that antedated radiation therapy. This implies that delaying irradiation will not necessarily improve the patients' functional status. Whether the interval of postponement of irradiation evidenced in this sample will translate into an ultimately better quality of life remains unknown. Given the probable interaction of multiple risk factors, well-controlled prospective clinical trials are needed to definitively analyze this issue.


Weight-related teasing in the school environment: associations with psychosocial health and weight control practices among adolescent boys and girls.
Weight-related teasing has been found to be associated with low self-esteem, depressive symptoms, body dissatisfaction, and weight control behaviors in adolescents. While research has typically examined weight-related teasing directed towards the individual, little is known about weight-related teasing at the school level. This study aimed to determine the association between the school-level prevalence of weight-related teasing and psychosocial factors, body dissatisfaction and weight control behaviors in adolescents. Adolescents (N = 2,793; 53.2% female) attending 20 US public middle and high schools were surveyed as part of the Eating and Activity in Teens (EAT) 2010 study. Generalized estimating equations were used to estimate the association between school-level weight-related teasing and health variables, controlling for individual-level weight-related teasing, clustering of individuals within schools, and relevant covariates. A greater school-level prevalence of weight-related teasing was associated with lower self-esteem and greater body fat dissatisfaction in girls, and greater depressive symptoms in boys, over and above individual-level weight-related teasing. Dieting was associated with the school-level prevalence of weight-related teasing in analysis adjusted for covariates in girls, but not following adjustment for individual-level weight-related teasing. Unhealthy weight control behaviors, extreme weight control behaviors, and muscle-enhancing behaviors were not associated with the school-level prevalence of weight-related teasing in girls or boys. Findings from the current study, in conjunction with previous findings showing associations between weight-related teasing, psychological concerns, and weight control behaviors, highlight the importance of implementing strategies to decrease weight-related teasing in schools.


Detection of Variants of Wheat Stem Rust Race Ug99 (Puccinia graminis f. sp. tritici) in Zimbabwe and Mozambique.
The migration of Ug99 variants of Puccinia graminis f. sp. tritici is of concern to global wheat production (1). Seven races have been characterized in the Ug99 lineage (3), three of which occur in South Africa (4). During surveys of wheat fields for Ug99 in Zimbabwe and Mozambique in August and September 2010, high stem rust severities were found at Chiredzi, Chisumbanje, and Birchenough in Zimbabwe and at Rotanda in Mozambique. Stem rust was widespread in the lowlands (<800 m above sea level) of Zimbabwe and trace amounts were present in the mid-altitude areas. In Mozambique, stem rust was only observed at Rotanda (sample Moz1001). Collections from Chiredzi (samples Zim1004 and Zim1005), Chisumbanje (Zim1006), and Birchenough (Zim1009 and Zim1010) yielded viable urediniospores for infection studies. According to race analysis conducted on seedlings of the North American stem rust differential set (2) in a greenhouse at 18 to 25°C, Zim1005 and Zim1006 were typed as PTKST and Zim1004 and Zim1009 as TTKSF. Both TTKSF and PTKST were detected in the Zim1010 sample. Race analysis experiments were conducted three times. Urediniospores of isolate Moz1001 were not viable in infection studies, but yielded fungal DNA for simple sequence repeat (SSR) analysis. Using eight selected SSR primer combinations (4), all six isolates clustered within the Ug99 lineage. Isolates Zim1005, Zim1006, Zim1009, Zim1010, and Moz1001 and the stem rust control races TTKSF, TTKSK, and PTKST grouped into two main clusters, with Zim1009 and Zim1010 clustering together and sharing 88% similarity with the rest of the isolates. Zim1005 and Zim1006 were identical to TTKSF and TTKSK, respectively. Zim1004 shared 96% genetic similarity with the TTKSP control, with these two sharing 74% genetic similarity with the remaining isolates. The SSR data correlated with the infection data, except for Zim1004, which was typed as TTKSF but clustered close to TTKSP. Wheat cvs. SC Nduna, SC Shine, SC Stallion, SC Smart, Kana, Insiza, and Dande are predominant in Zimbabwe. Cv. SC Stallion and other unidentified cultivars were susceptible to P. graminis f. sp. tritici in the field in Zimbabwe. In Mozambique, the tall, local cv. Sitsonko was susceptible to P. graminis f. sp. tritici but no infections were observed on SC Nduna or SC Shine. The similarity in P. graminis f. sp. tritici races in Zimbabwe, South Africa, and Mozambique suggests that inoculum is exchanged within the region and explains the detection of race PTKST in South Africa in 2009. Trajectory models showed winds originating at Birchenough in October 2009, where stem rust was observed, passing directly over KwaZulu-Natal, South Africa within 48 to 72 h. Race PTKST was confirmed from collections in KwaZulu-Natal in November 2009 (4). The confirmation of Sr31 virulence in race PTKST in Zimbabwe is important because it provides new geographical records for an Ug99-related race and puts Southern African cultivars with 1B.1R resistance at risk. References: (1) D. Hodson. Euphytica 179:93, 2011. (2) Y. Jin et al. Plant Dis. 92:923, 2008. (3) R. F. Park et al. Euphytica 179:109, 2011. (4) B. Visser et al. Euphytica 179:119, 2011.


Neural Basis of Early Somatosensory Change Detection: A Magnetoencephalography Study.
The mismatch negativity (MMN) reflects the early detection of changes in sensory stimuli at the cortical level. The mechanisms underlying its genesis remain debated. This magnetoencephalography study investigates the spatio-temporal dynamics and the neural mechanisms of the magnetic somatosensory MMN. Somatosensory evoked magnetic fields elicited by tactile stimulation of the right fingertip (Single), tactile stimulation of the right middle phalanx and fingertip (Double) or omissions (Omitted) of tactile stimuli were studied in different paradigms: in oddballs where Double/Omitted followed a sequence of four Single, in sequences of two stimuli where Double occurred after one Single, and in random presentation of Double only. The predictability of Double occurrence in oddballs was also manipulated. Cortical sources of evoked responses were identified using equivalent current dipole modeling. Evoked responses elicited by Double were significantly different from those elicited by Single at the contralateral secondary somatosensory (cSII) cortex. Double elicited higher cSII cortex responses than Single when preceded by a sequence of four Single, compared to when they were preceded by one Single. Double elicited higher cSII cortex response when presented alone compared to when Double were preceded by one or a sequence of Single. Omitted elicited similar cSII cortex response than Single. Double in oddballs led to higher cSII cortex responses when less predictable. These data suggest that early tactile change detection involves mainly cSII cortex. The predictive coding framework probably accounts for the SII cortex response features observed in the different tactile paradigms.


Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil.
Corticosteroids withdrawal from immunosuppressive regimens has thus far been associated with increased risk of acute rejection episodes. In this study, basiliximab, a chimeric monoclonal interleukin-2 receptor antagonist, added to a maintenance regimen consisting of cyclosporine microemulsion and mycophenolate mofetil was studied for its effectiveness in allowing early corticosteroid withdrawal in de novo renal allograft recipients. Primary renal transplant recipients receiving basiliximab, cyclosporine-microemulsion, and mycophenolate mofetil, were randomized to either corticosteroid withdrawal at day four post-transplantation (n = 40) or standard steroid therapy (n = 43). The primary endpoint was the incidence of biopsy-proven acute rejection episodes. Randomized subjects who underwent transplantation and received at least one dose of basiliximab were analyzed in an intent-to-treat fashion. The incidence of biopsy-proven acute rejection at 12 months was not significantly different between the steroid withdrawal group (20%) and the standard treatment group (16%). Patient and graft survival was 100% in the steroid withdrawal group while one death in a patient with a functioning graft occurred in the standard steroid group. Seventy-two percent of the steroid withdrawal group remained off steroids at 6 months post-transplant. Allograft function and incidence of adverse events and infections were similar between the two groups. Rapid and early corticosteroid withdrawal among renal transplant recipients receiving basiliximab induction and daily therapy with cyclosporine-microemulsion and mycophenolate mofetil was not associated with an increased risk of acute rejection.


Structural and biochemical characterization of VIM-26 shows that Leu224 has implications for the substrate specificity of VIM metallo-β-lactamases.
During the last decades antimicrobial resistance has become a global health problem. Metallo-β-lactamases (MBLs) which are broad-spectrum β-lactamases that inactivate virtually all β-lactams including carbapenems, are contributing to this health problem. In this study a novel MBL variant, termed VIM-26, identified in a Klebsiella pneumoniae isolate was studied. VIM-26 belongs to the Verona integron-encoded metallo-β-lactamase (VIM) family of MBLs and is a His224Leu variant of the well-characterized VIM-1 variant. In this study, we report the kinetic parameters, minimum inhibitory concentrations and crystal structures of a recombinant VIM-26 protein, and compare them to previously published data on VIM-1, VIM-2 and VIM-7. The kinetic parameters and minimum inhibitory concentration determinations show that VIM-26, like VIM-7, has higher penicillinase activity but lower cephalosporinase activity than VIM-1 and VIM-2. The four determined VIM-26 crystal structures revealed mono- and di-zinc forms, where the Zn1 ion has distorted tetrahedral coordination geometry with an additional water molecule (W2) at a distance of 2.6-3.7 Å, which could be important during catalysis. The R2 drug binding site in VIM-26 is more open compared to VIM-2 and VIM-7 and neutrally charged due to Leu224 and Ser228. Thus, the VIM-26 drug binding properties are different from the VIM-2 (Tyr224/Arg228) and VIM-7 (His224/Arg228) structures, indicating a role of these residues in the substrate specificity.


Where are the human speech and voice regions, and do other animals have anything like them?
Modern lesion and imaging work in humans has been clarifying which brain regions are involved in the processing of speech and language. Concurrently, some of this work has aimed to bridge the gap to the seemingly incompatible evidence for multiple brain-processing pathways that first accumulated in nonhuman primates. For instance, the idea of a posterior temporal-parietal "Wernicke's" territory, which is thought to be instrumental for speech comprehension, conflicts with this region of the brain belonging to a spatial "where" pathway. At the same time a posterior speech-comprehension region ignores the anterior temporal lobe and its "what" pathway for evaluating the complex features of sensory input. Recent language models confirm that the posterior or dorsal stream has an important role in human communication, by a reconceptualization of the "where" into a "how-to" pathway with a connection to the motor system for speech comprehension. Others have tried to directly implicate the "what" pathway for speech comprehension, relying on the growing evidence in humans for anterior-temporal involvement in speech and voice processing. Coming full circle, we find that the recent imaging of vocalization and voice preferring regions in nonhuman primates allows us to make direct links to the human imaging data involving the anterior-temporal regions. The authors describe how comparison of the structure and function of the vocal communication system of humans and other animals is clarifying evolutionary relationships and the extent to which different species can model human brain function.


Infant mortality and causes of infant deaths in rural Ethiopia: a population-based cohort of 3684 births.
Ethiopia has made large-scale healthcare investments to improve child health and survival. However, there is insufficient population level data on the current estimates of infant mortality rate (IMR) in the country. The aim of this study was to measure infant mortality rate, investigate risk factors for infant deaths and identify causes of death in a rural population of northern Ethiopia. Live births to a cohort of mothers under the Kilite Awlaelo Health and Demographic Surveillance System were followed up to their first birthday or death, between September 11, 2009 and September 10, 2013. Maternal and infant characteristics were collected at baseline and during the regular follow-up visit. Multiple-Cox regression was used to investigate risk factors for infant death. Causes of infant death were identified using physician review verbal autopsy method. Of the total 3684 infants followed, 174 of them died before their first birthday, yielding an IMR of 47 per 1000 live births (95 % CI: 41, 54) over the four years of follow-up. About 96 % of infants survived up to their first birthday, and 56 % of infant deaths occurred during the neonatal period. Infants born to mothers aged 15-19 years old had higher risk of death (HR = 2.68, 95 % CI: 1. 74, 4.87) than those born to 25-29 years old. Infants of mothers who attained a secondary school and above had 56 % lower risk of death (HR = 0.44, 95 % CI: 0.24, 0.81) compared to those whose mothers did not attend formal education. Sepsis, prematurity and asphyxia and acute lower respiratory tract infections were the commonest causes of death. The IMR for the four-year period was lower than the national and regional estimates. Our findings suggest the need to improve the newborn care, and empower teenagers to delay teenage pregnancy and attain higher levels of education.


Extensive myocytolysis as a marker of sudden cardiac death.
Colliquative myocytolysis, an intracellular vacuolization of myocardial cells, is considered an indicator of acute myocardial ischemia. Although often present in ischemic cardiac death, this lesion is often either overlooked, or not utilized as a criterion for diagnosing ischemia. This study reports light microscopic and ultrastructural studies of six autopsied patients who died suddenly and showed extensive myocytolysis as the only pathologic finding. In two of these patients, the clinical history and electrocardiogram findings documented an acute ischemic episode 1 to 3 hours antemortem. Six control patients with matched age and postmortem intervals did not show the intracellular vacuolization characteristic of myocytolysis. The postmortem intervals ranged from 2 to 12 hours. Ultrastructurally, myocytolysis was seen as a well-defined large intracellular vacuole without any lining membrane and associated with disrupted myofibrils, prominent Z band degeneration, and a few fat droplets. The mitochondria showed swelling and disruption, as well as electron dense amorphous inclusions. The swelling and disruption of mitochondria are well-known postmortem artefacts, and the mitochondrial amorphous inclusions, large intracellular vacuoles, prominent Z band degeneration, and fat droplets are not seen with autolysis. We conclude that myocytolysis, especially if extensive and restricted to an area supplied by a major coronary artery, can be a helpful pathologic marker of myocardial ischemia, particularly in sudden deaths without any other histologic findings.


A2E, a component of lipofuscin, is pro-angiogenic in vivo.
A recent study in vitro demonstrated that a major lipofuscin component, A2E, serves as a retinoic acid receptor ligand. The current study investigated the effects of A2E on retinal pigment epithelial (RPE) cells in vivo and was performed to extend the understanding of the effects of A2E. Firstly, subretinal injection of A2E was performed and 3 weeks after the injection, and it was demonstrated that subretinal injection of A2E induced RPE cell death, and concomitant upregulation of vascular endothelial growth factor (VEGF) in the RPE and choroid. The upregulation of VEGF was attenuated by an RARalpha antagonist. Next we performed laser photocoagulation in mice that accumulated A2E either after subretinal injection, by Ccl2 gene knockout or by aging demonstrated that mice that accumulated A2E in the RPE, which showed higher rates of choroidal neobascularization (CNV) formation after weak laser injury than the controls and the formation of CNV was inhibited by an RARalpha antagonist in all models tested. The data suggest that A2E accumulation induces RPE cell death, and concomitant increase of VEGF. Accumulation of A2E alone is not sufficient to induce CNV in vivo, but induces the expression of VEGF in RPE and choroid. The mice that accumulated A2E in RPE cells are vulnerable to CNV development via RAR activation, at least in part.


Systemic Barriers and Equitable Interventions to Improve Vegetable and Fruit Intake in Children: Interviews with National Food System Actors.
Fruit and vegetable (FV) intake is declining in New Zealand, and over half of New Zealand's children do not meet the recommendation of two serves of fruit and three serves of vegetables daily (with even lower adherence among children in high-deprivation neighbourhoods). The aim of this study was to map the potential causal pathways explaining this decline and possible actions to reverse it. Semi-structured interviews were held in April-May 2018 with 22 national actors from the produce industry, food distribution and retail sector, government, and NGO health organisations. The qualitative systems dynamics method of cognitive mapping was used to explore causal relationships within the food system that result in low FV intake among children. Barriers and solutions identified by participants were analysed using thematic analysis and according to a public health intervention framework. Participants were in agreement with the goal of improving FV intake for health and economic outcomes, and that health promotion strategies had been ineffectual to date due to multiple systemic barriers. Common barriers discussed were poverty, high food prices, low skills/knowledge, unhealthy food environments, climate change, and urbanization. Solutions with the strongest evidence of efficacy identified by the participants were subsidizing FVs and early childhood interventions to improve FV exposure.