Clinical and procedural implications of congenital vena cava anomalies in adults: A systematic review.
Although congenital vena cava (CVC) anomalies in adults have implications for surgical and radiological interventions, the literature is scare and disparate. The aim of this systematic review was to assess cardiovascular clinical and procedural implications of CVC anomalies in adults without congenital heart disease. We searched PubMed and EMBASE from database conception through October 2018 for English-language studies describing the epidemiology of CVC anomalies or their clinical or procedural implications in humans. Two independent reviewers screened 7093 records and identified 16 relevant studies. We found two major implications of CVC anomalies: 1) congenital inferior vena cava (CIVC) anomalies are associated with a 50-100-fold higher risk of deep venous thrombosis, particularly among younger patients, and 2) persistent left superior vena cava (PLSVC) is associated with a 2-3-fold higher risk of supraventricular arrhythmias. PLSVC also poses technical challenges to cardiovascular electronic device implantation, requiring alterations in surgical approach and lengthening procedure and X-ray exposure times. Due to the large disparity in reported prevalence rates of CIVC anomalies, we performed a meta-analysis of CIVC anomaly prevalence including 8 studies, which showed a weighted prevalence of 6.8% (95% CI, 4.5-9.2%). These findings challenge the notion that CVC anomalies are rare and asymptomatic in adults. Rather, the literature indicates that CVC anomalies are not uncommon and have important clinical and procedural implications. To further understand the prevalence and implications of CVC anomalies, a robust US population-based study and nationwide registry is warranted in the current era of venous interventions.


The effect of diabetes mellitus on histopathological changes in the tissues under denture base bearing masticatory pressure.
The effect of streptozotocin-induced diabetes mellitus on histopathological changes in tissues bearing masticatory pressure exerted through an experimental denture base has been studied in animal specimens. Experimental dentures, which prescribed the masticatory pressure by the amount of subsidence of the denture base (100, 50 or 13 microm), were constructed for the hard palate of the molar regions of rats. It was revealed that streptozotocin-induced diabetes mellitus (1) weakened the intercellular junctions in the epithelium and gradually enhanced this state with time, (2) lessened the atrophic and proliferative reactions in the epithelial ridge and prolonged their appearance period, (3) enhanced the compression of lamina propria mucosae and prolonged the appearance period of this reaction, (4) enhanced the inflammatory change and extended its appearance period, (5) lowered the threshold for the inflammatory reaction induced by the masticatory pressure, (6) increased the number of osteoclasts and prolonged the period of their presence, (7) lowered the threshold for osteoclastic bone resorption induced by the masticatory pressure, (8) inhibited the appearance of osteoblasts following the disappearance of osteoclasts and (9) accelerated the decline rate of masticatory pressure exerted to the denture supporting tissues. Therefore, it can be concluded that the streptozotocin-induced diabetes mellitus in the animals tested deteriorated the tolerance of the denture supporting tissues to masticatory pressure.


BACE1 overexpression regulates amyloid precursor protein cleavage and interaction with the ShcA adapter.
The amyloid precursor protein (APP) is a cell surface protein with a large extracellular N-terminal domain, a single transmembrane segment, and a short cytoplasmic tail. Its location and structural features are characteristic of a receptor for signal transduction. Yet, the physiological function of APP is unclear, although it is well documented that APP's proteolytic processing, through the formation of membrane-bound C-terminal fragments (CTFs) and of beta-amyloid peptides, likely influences the development of Alzheimer's disease (AD). There is evidence that BACE1 is the enzyme responsible for beta-site cleavage of the APP and for the generation of CTFs. BACE1 expression is upregulated in AD brain, and we have recently shown in human brain and in vitro that BACE product CTFs, when phosphorylated in tyrosine residues, interact with the adaptor proteins ShcA and Grb2, which usually are involved in signal transduction pathways. We investigated the interaction between ShcA, APP, and CTFs in the H4 human cell line that overexpresses BACE1 to clarify the significance of such interactions in vitro and for AD generation. Our result show that the APP, CTF, and ShcA interaction is induced only upon overexpression of BACE1 either transiently or in stable cell lines. In particular, although BACE1 drives the formation of C99 and C89 CTFs, only C99 interacts with the ShcA adaptor protein. Therefore, our data suggest that BACE1 activity influences APP processing and its intracellular signaling through the ShcA adaptor protein.


Professional or administrative value patterns? Clinical pathways in medical problem-solving processes.
A health-care organization simultaneously belongs to two different institutional value patterns: a professional and an administrative value pattern. At the administrative level, medical problem-solving processes are generally perceived as the efficient application of familiar chains of activities to well-defined problems; and a low task uncertainty is therefore assumed at the work-floor level. This assumption is further reinforced through clinical pathways and other administrative guidelines. However, studies have shown that in clinical practice such administrative guidelines are often considered inadequate and difficult to implement mainly because physicians generally perceive task uncertainty to be high and that the guidelines do not cover the scope of encountered deviations. The current administrative level guidelines impose uniform structural features that meet the requirement for low task uncertainty. Within these structural constraints, physicians must organize medical problem-solving processes to meet any task uncertainty that may be encountered. Medical problem-solving processes with low task uncertainty need to be organized independently of processes with high task uncertainty. Each process must be evaluated according to different performance standards and needs to have autonomous administrative guideline models. Although clinical pathways seem appropriate when there is low task uncertainty, other kinds of guidelines are required when the task uncertainty is high.


Considerations of critical quality attributes in the analytical comparability assessment of biosimilar products.
Based on experience in clinical trial approvals and marketing authorizations for biosimilar products in Korea, we suggest principles for the analytical comparability assessment of biosimilar products with respect to regulatory considerations. The composition and manufacturing processes of biosimilar products can differ from those of the reference product depending on the information available for the reference product and the time of product development; however, the analytical characteristics of biosimilar products should be highly similar to those of the reference product. Although manufacturing an identical product in terms of the quality profile is nearly impossible due to the high molecular weight and complex structure of biological products, the developer of the biosimilar product should attempt to establish a quality level as similar to that of the reference product as possible. When comparing the similarity of quality attributes, the criticality of the quality attributes and the characteristics of orthogonal quality attributes need to be considered carefully. Based on the results from the analytical comparability assessment, the comparability results of non-clinical and clinical studies should be evaluated before claiming biosimilarity to the reference product. In this review, we focus on quality attribute evaluation based on our regulatory experience.


Translating research on brain aging into public health: a new type of immunotherapy for Alzheimer's disease.
The identification of disease-causing mutations in Alzheimer's disease has contributed greatly to the understanding of the pathogenesis of this disease. The amyloid-β (Aβ) peptide has come into focus and is believed to be central to the pathogenesis of Alzheimer's disease. With only symptomatic treatment available, efforts to develop new therapeutics aimed at lowering the amount of Aβ peptides in the affected brain have intensified. In particular, immunotherapy against Aβ peptides has attracted considerable interest, as it offers the possibility to generate highly specific molecules targeting highly specific moieties. Due to intense research efforts and massive investments at universities and in the pharmaceutical industry, the outlook for patients and their relatives has never been brighter.


Identification and functional characterisation of Complement Regulator Acquiring Surface Protein-1 of serum resistant Borrelia garinii OspA serotype 4.
B. burgdorferi sensu lato (sl) is the etiological agent of Lyme borreliosis in humans. Spirochetes have adapted themselves to the human immune system in many distinct ways. One important immune escape mechanism for evading complement activation is the binding of complement regulators Factor H (CFH) or Factor H-like protein1 (FHL-1) to Complement Regulator-Acquiring Surface Proteins (CRASPs). We demonstrate that B. garinii OspA serotype 4 (ST4) PBi resist complement-mediated killing by binding of FHL-1. To identify the primary ligands of FHL-1 four CspA orthologs from B. garinii ST4 PBi were cloned and tested for binding to human CFH and FHL-1. Orthologs BGA66 and BGA71 were found to be able to bind both complement regulators but with different intensities. In addition, all CspA orthologs were tested for binding to mammalian and avian CFH. Distinct orthologs were able to bind to CFH of different animal origins. B. garinii ST4 PBi is able to evade complement killing and it can bind FHL-1 to membrane expressed proteins. Recombinant proteins BGA66 can bind FHL-1 and human CFH, while BGA71 can bind only FHL-1. All recombinant CspA orthologs from B. garinii ST4 PBi can bind CFH from different animal origins. This partly explains the wide variety of animals that can be infected by B. garinii.


Optimal machine learning feature selection for assessing the mechanical properties of a zeolite framework.
In this study, 45 and 249 critical features were discovered among 896 zeolite descriptors generated by the matminer package for estimating the shear and bulk moduli of zeolites, respectively. A database containing the mechanical properties of 873 zeolite structures, calculated using density functional theory, was used to train the machine learning regression model. The results of using these critical features with the LightGBM algorithm were rigorously compared with those from other regressors as well as with different sets of features. The comparison results indicate that the surrogate model with critical features increases the prediction accuracy of the bulk and shear moduli of zeolites by 17.3% and 10.6%, respectively, and reduces the prediction uncertainty by one-third of that achieved using previously available features. The suggested features originating from several physical and chemical groups highlight the unveiled relationships between the features and mechanical properties of zeolites. The robustness of the constructed model with 356 features was confirmed by applying a set of different training-test set ratios. We believe that the suggested critical features of zeolites can help to understand the mechanical behavior of a half million unlabeled hypothetical zeolite structures and accelerate the discovery of novel zeolites with unprecedented mechanical properties.


Non-contact long-range magnetic stimulation of mechanosensitive ion channels in freely moving animals.
Among physical stimulation modalities, magnetism has clear advantages, such as deep penetration and untethered interventions in biological subjects. However, some of the working principles and effectiveness of existing magnetic neurostimulation approaches have been challenged, leaving questions to be answered. Here we introduce m-Torquer, a magnetic toolkit that mimics magnetoreception in nature. It comprises a nanoscale magnetic torque actuator and a circular magnet array, which deliver piconewton-scale forces to cells over a working range of ~70 cm. With m-Torquer, stimulation of neurons expressing bona fide mechanosensitive ion channel Piezo1 enables consistent and reproducible neuromodulation in freely moving mice. With its long working distance and cellular targeting capability, m-Torquer provides versatility in its use, which can range from single cells to in vivo systems, with the potential application in large animals such as primates.


Reverse enGENEering of Regulatory Networks from Big Data: A Roadmap for Biologists.
Omics technologies enable unbiased investigation of biological systems through massively parallel sequence acquisition or molecular measurements, bringing the life sciences into the era of Big Data. A central challenge posed by such omics datasets is how to transform these data into biological knowledge, for example, how to use these data to answer questions such as: Which functional pathways are involved in cell differentiation? Which genes should we target to stop cancer? Network analysis is a powerful and general approach to solve this problem consisting of two fundamental stages, network reconstruction, and network interrogation. Here we provide an overview of network analysis including a step-by-step guide on how to perform and use this approach to investigate a biological question. In this guide, we also include the software packages that we and others employ for each of the steps of a network analysis workflow.


Structural Dissection of the Maltodextrin Disproportionation Cycle of the Arabidopsis Plastidial Disproportionating Enzyme 1 (DPE1).
The degradation of transitory starch in the chloroplast to provide fuel for the plant during the night requires a suite of enzymes that generate a series of short chain linear glucans. However, glucans of less than four glucose units are no longer substrates for these enzymes, whereas export from the plastid is only possible in the form of either maltose or glucose. In order to make use of maltotriose, which would otherwise accumulate, disproportionating enzyme 1 (DPE1; a 4-α-glucanotransferase) converts two molecules of maltotriose to a molecule of maltopentaose, which can now be acted on by the degradative enzymes, and one molecule of glucose that can be exported. We have determined the structure of the Arabidopsis plastidial DPE1 (AtDPE1), and, through ligand soaking experiments, we have trapped the enzyme in a variety of conformational states. AtDPE1 forms a homodimer with a deep, long, and open-ended active site canyon contained within each subunit. The canyon is divided into donor and acceptor sites with the catalytic residues at their junction; a number of loops around the active site adopt different conformations dependent on the occupancy of these sites. The "gate" is the most dynamic loop and appears to play a role in substrate capture, in particular in the binding of the acceptor molecule. Subtle changes in the configuration of the active site residues may prevent undesirable reactions or abortive hydrolysis of the covalently bound enzyme-substrate intermediate. Together, these observations allow us to delineate the complete AtDPE1 disproportionation cycle in structural terms.


Low Dose Carbon Monoxide Exposure in Idiopathic Pulmonary Fibrosis Produces a CO Signature Comprised of Oxidative Phosphorylation Genes.
Compelling preclinical studies indicate that low-dose carbon monoxide (CO) abrogates experimental lung fibrosis. We recently reported the results of a multicenter, double-blinded, clinical trial of inhaled CO in patients with idiopathic pulmonary fibrosis (IPF). Identifying no significantly changes in metalloproteinase-7 (MMP7) serum concentration, or secondary endpoints of physiologic measurements, hospitalization, death, or patient-reported outcomes. In the present study, we evaluated the effect of low dose CO exposure (100-200 ppm) for 12 weeks on genome-wide gene expression in peripheral blood mononuclear cells (PBMC) derived from these IPF study subjects. We conducted transcriptome profiling on 38 IPF subjects with time points available at 0, 12, and 24 weeks. Total RNA isolated from PBMCs was hybridized onto the Affymetrix Human Gene 2.0 ST Array. We identified 621 genes significantly upregulated in the 24-week CO exposed group compared with the 12-week. Pathway analysis demonstrated association with Oxidative Phosphorylation (adjusted P < 0.05). We identified a clear CO signature dominated with 23 oxidative phosphorylation-related genes (FDR <10%). We confirmed the expression of nine selected gene products using Nanostring's nCounter analysis system. These findings suggest this signature may serve as a potential genomic biomarker for CO exposure and for potential titration of dosage to allow precision testing of therapies in future low dose CO therapeutic studies in IPF.


Sequence-specific DNA binding by the c-Myc protein.
While it has been known for some time that the c-Myc protein binds to random DNA sequences, no sequence-specific binding activity has been detected. At its carboxyl terminus, c-Myc contains a basic--helix-loop-helix (bHLH) motif, which is important for dimerization and specific DNA binding, as demonstrated for other bHLH protein family members. Of those studied, most bHLH proteins bind to sites that contain a CA- -TG consensus. In this study, the technique of selected and amplified binding-sequence (SAAB) imprinting was used to identify a DNA sequence that was recognized by c-Myc. A purified carboxyl-terminal fragment of human c-Myc that contained the bHLH domain bound in vitro in a sequence-specific manner to the sequence, CACGTG. These results suggest that some of the biological functions of Myc family proteins are accomplished by sequence-specific DNA binding that is mediated by the carboxyl-terminal region of the protein.


Paracrine mechanisms of stem cell reparative and regenerative actions in the heart.
Stem cells play an important role in restoring cardiac function in the damaged heart. In order to mediate repair, stem cells need to replace injured tissue by differentiating into specialized cardiac cell lineages and/or manipulating the cell and molecular mechanisms governing repair. Despite early reports describing engraftment and successful regeneration of cardiac tissue in animal models of heart failure, these events appear to be infrequent and yield too few new cardiomyocytes to account for the degree of improved cardiac function observed. Instead, mounting evidence suggests that stem cell mediated repair takes place via the release of paracrine factors into the surrounding tissue that subsequently direct a number of restorative processes including myocardial protection, neovascularization, cardiac remodeling, and differentiation. The potential for diverse stem cell populations to moderate many of the same processes as well as key paracrine factors and molecular pathways involved in stem cell-mediated cardiac repair will be discussed in this review. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".


Sam2bam: High-Performance Framework for NGS Data Preprocessing Tools.
This paper introduces a high-throughput software tool framework called sam2bam that enables users to significantly speed up pre-processing for next-generation sequencing data. The sam2bam is especially efficient on single-node multi-core large-memory systems. It can reduce the runtime of data pre-processing in marking duplicate reads on a single node system by 156-186x compared with de facto standard tools. The sam2bam consists of parallel software components that can fully utilize multiple processors, available memory, high-bandwidth storage, and hardware compression accelerators, if available. The sam2bam provides file format conversion between well-known genome file formats, from SAM to BAM, as a basic feature. Additional features such as analyzing, filtering, and converting input data are provided by using plug-in tools, e.g., duplicate marking, which can be attached to sam2bam at runtime. We demonstrated that sam2bam could significantly reduce the runtime of next generation sequencing (NGS) data pre-processing from about two hours to about one minute for a whole-exome data set on a 16-core single-node system using up to 130 GB of memory. The sam2bam could reduce the runtime of NGS data pre-processing from about 20 hours to about nine minutes for a whole-genome sequencing data set on the same system using up to 711 GB of memory.


Phorbol ester activates CD5+ leukaemic B cells via a T cell-independent mechanism.
B cell chronic lymphocytic leukaemia (B-CLL) is characterized by the proliferation and accumulation of sIgM+ CD5+ lymphocytes that fail to progress to the final stages of B cell development. Stimulation of unfractionated PBL from three patients with B-CLL with the phorbol ester PMA and the mitogens PHA and PWM resulted in significant increases in cell proliferation, RNA synthesis and IgM secretion when compared to unstimulated cell populations. PMA was the most potent inducer of IgM secretion and this occurred irrespective of the presence of residual T cells. PMA-induced proliferation and RNA synthesis was also independent of T cells. However, in the presence of T cells, these parameters of cellular activation were enhanced during in vitro culture. Thus, the inductive ability of PMA on CD5+ CLL B cells was independent of T cells. In contrast, activation and differentiation of the malignant CD5+ B cells into IgM-secreting cells following culture with mitogens did not occur in the absence of T cells.


A Suppressor/Avirulence Gene Combination in Hyaloperonospora arabidopsidis Determines Race Specificity in Arabidopsis thaliana.
The pathosystem of Arabidopsis thaliana and diploid biotrophic oomycete Hyaloperonospora arabidopsidis (Hpa) has been a model for investigating the molecular basis of Flor's gene-for-gene hypothesis. The isolates Hpa-Noks1 and Hpa-Cala2 are virulent on Arabidopsis accession RMX-A02 whilst an F1 generated from a cross between these two isolates was avirulent. The F2 progeny segregated 3,1 (avirulent, virulent), indicating a single major effect AVR locus in this pathogen. SNP-based linkage mapping confirmed a single AVR locus within a 14 kb map interval containing two genes encoding putative effectors. The Hpa-Cala2 allele of one gene, designated H. arabidopsidiscryptic1 (HAC1), encodes a protein with a signal peptide and an RxLR/dEER motif, and triggers a defense response in RMX-A02. The second gene is heterozygous in Hpa-Cala2. One allele, designated Suppressor ofHAC1Cala2 (S-HAC1Cala2 ) encodes a protein with a signal peptide and a dKEE motif with no RxLR motif; the other allele (s-hac1Cala2 ) encodes a protein with a signal peptide, a dEEE motif and is divergent in sequence from the S-HAC1Cala2 allele. In selfed progeny from Hpa-Cala2, dominant S-HAC1Cala2 allele carrying progeny correlates with virulence in RMX-A02, whereas homozygous recessive s-hac1Cala2 carrying progeny were avirulent. Genetic investigations suggested other heterozygous suppressor loci might exist in the Hpa-Cala2 genome.


Burden of illness and costs among paediatric haemophilia patients with and without central venous access devices treated in US hospitals.
Central venous access devices (CVADs) facilitate repeated or urgent treatments for paediatric haemophilia patients, but are associated with complications. This study examined the burden of illness, healthcare utilization and costs for CVADs in a real-world hospital setting. This study included haemophilia patients ages ≤18 years with discharges during 2006-2014 in the US Premier Healthcare Database. Haemophilia was identified using ICD-9 diagnosis codes and CVAD exposure using billing information. After matching haemophilia patients with and without CVADs on demographic and clinical characteristics, we compared infection, thrombosis, length of stay (LOS), inflation-adjusted hospital cost (2014 $USD) and readmission outcomes using generalized estimating equation models adjusted for hospital teaching status. Among 4793 paediatric haemophilia patients treated at one of 548 hospitals, a total of 197 patients were identified with CVAD exposure. The matched sample included 310 haemophilia patients (155 CVAD and 155 non-CVAD). CVAD cases had greater frequencies of all-cause infections (29% vs 17%, P = .01) and thrombosis (6% vs 1%, P = .06), longer adjusted mean LOS (9.5 vs 4.7 days, P = .002), higher adjusted mean inpatient total hospitalization costs ($47200 vs $25389, P = .02) as well as more inpatient and outpatient visits at 30-, 60- and 90-days (P < .05 for all differences) compared with non-CVAD patients. Paediatric haemophilia patients with CVADs experienced greater infection rates, healthcare utilization and higher hospitalization costs compared with non-CVAD patients. The results of this study may inform further research efforts to understand the costs and benefits of novel treatment alternatives for young haemophilia patients requiring CVADs.


Partial metamorphosis in Anomia simplex.
Many larvae of the common bivalve, Anomia simplex, when grown under laboratory conditions, exhibited a partial metamorphosis. They attained a considerably larger size than that at which larvae normally set. The partial metamorphosis was also characterized by the disappearance of velum, but the retention of a functional foot. Moreover, these organisms were not able to attach to the substratum, and their shells showed a distinct demarcation line between larval and adult portions


Children's enjoyment of play during school lunchtime breaks: an examination of intraday and interday reliability.
Enjoyment and play during school lunchtime are correlated with children's physical activity. Despite this, there is an absence of studies reporting children's enjoyment of play during school lunchtime breaks. The purpose of this study was to examine the intraday and interday reliability of children's enjoyment of school lunchtime play. Surveys used to assess children's enjoyment of lunchtime play were distributed to and completed by 197 children (112 males, 85 females), aged 8-12 years attending an elementary school in Victoria, Australia. Children completed the surveys during class before lunch (expected enjoyment) and after lunch (actual enjoyment) for 5 days. The intra- and interday enjoyment of school lunchtime play reliability were determined using a weighted kappa. Intraday kappa values ranged from fair (0.31) to substantial (0.75) within each of the 5 days (median kappa = 0.41). In comparison, "expected" (0.09-0.40; median 0.30) and "actual" (0.05-0.46; median 0.28) interday enjoyment of lunchtime play displayed low reliability. Children's enjoyment of lunchtime play appears to be more consistent within days than across days. The findings suggest that assessment of children's enjoyment of lunchtime play once on a single day would be representative of a particular day but not necessarily that particular school week.


Doxorubicin Changes Bax /Bcl-xL Ratio, Caspase-8 and 9 in Breast Cancer Cells.
Doxorubicin is administrated as a single agent in first-line therapy of breast cancer to induce apoptosis in tumor cells. Bax, Bcl-xL, Caspase-8 and 9 proteins are involved in induction of apoptosis. The present study describes Bax, Bcl-xL gene expression and Caspase-8 and 9 protein levels in MCF-7 cells incubated with doxorubicin at different doses an incubation times. The cytotoxic effects of doxorubicin were studied using MTT assay. MCF-7 cells were treated with three concentrations of doxorubicin (0.1, 0.5, 1 μM) and incubated for 24, 48 and 72 hours then expression levels of Bax and Bcl-xL genes were elucidated by Real-time RT-PCR technique and protein levels of caspase-8 and caspase-9 proteins were measured using ELISA method. Morphological modifications of the cells were also monitored via light microscopic images. Doxorubicin decreased the anti-apoptotic Bcl-xL and increased pro-apoptotic Bax mRNA levels. Doxorubicin induced a significant increase in Bax /Bcl-xL ratio in all doses and incubation times (p<0.05). Highest (more than 10 fold) increase in Bax /Bcl-xL ratio was revealed after 48 h incubation of the cells with in all doses of doxorubicin. Doxorubicin also increased caspase-9 level in a time and dose-dependent manner, while caspase-8 level didn't follow time and dose dependency pattern. Our results confirm that doxorubicin induces mitochondrial-dependent apoptosis by down-regulation of Bcl-xL and up- regulation of Bax and caspase-9 expressions.


Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women.
Sugar-sweetened beverage (SSB) consumption had substantially increased across successive US birth cohorts until 2000, and adolescents and young adults under age 50 years have the highest consumption. However, the link between SSBs and early-onset colorectal cancer (EO-CRC) remains unexamined. In the Nurses' Health Study II (1991-2015), we prospectively investigated the association of SSB intake in adulthood and adolescence with EO-CRC risk among 95 464 women who had reported adulthood beverage intake using validated food frequency questionnaires (FFQs) every 4 years. A subset of 41 272 participants reported beverage intake at age 13-18 years using a validated high school-FFQ in 1998. Cox proportional hazards models were used to estimate relative risks (RRs) with 95% CIs. We documented 109 EO-CRC cases. Compared with individuals who consumed <1 serving/week of SSBs in adulthood, women who consumed ≥2 servings/day had a more than doubled risk of EO-CRC (RR 2.18; 95% CI 1.10 to 4.35; ptrend=0.02), with a 16% higher risk (RR 1.16; 95% CI 1.00 to 1.36) per serving/day increase. Each serving/day increment of SSB intake at age 13-18 years was associated with a 32% higher risk of EO-CRC (RR 1.32; 95% CI 1.00 to 1.75). Replacing each serving/day of adulthood SSB intake with that of artificially sweetened beverages, coffee, reduced fat milk or total milk was associated with a 17%-36% lower risk of EO-CRC. Higher SSB intake in adulthood and adolescence was associated with a higher risk of EO-CRC among women. Reduction of SSB consumption among adolescents and young adults may serve as a potential strategy to alleviate the growing burden of EO-CRC.


Falls among adult patients hospitalized in the United States: prevalence and trends.
The purpose of this study was to provide normative data on fall prevalence in U.S. hospitals by unit type and to determine the 27-month secular trend in falls before the implementation of the Centers for Medicare and Medicaid Service (CMS) rule, which does not reimburse hospitals for care related to injury resulting from hospital falls. We used data from the National Database of Nursing Quality Indicators (NDNQI) collected between July 1, 2006, and September 30, 2008, to estimate prevalence and secular trends of falls occurring in adult medical, medical-surgical, and surgical nursing units. More than 88 million patient days (pd) of observation were contributed from 6100 medical, surgical, and medical-surgical nursing units in 1263 hospitals across the United States. A total of 315,817 falls occurred (rate = 3.56 falls/1000 pd) during the study period, of which, 82,332 (26.1%) resulted in an injury (rate = 0.93/1000 pd). Both total fall and injurious fall rates were highest in medical units (fall rate = 4.03/1000 pd; injurious fall rate = 1.08/1000 pd) and lowest in surgery units (fall rate = 2.76/1000 pd; injurious fall rate = 0.67/1000 pd). Falls (0.4% decrease per quarter, P < 0.0001) and injurious falls (1% decrease per quarter, P < 0.0001) both decreased over the 27-month study. In this large sample, fall and injurious fall prevalence varied by nursing unit type in U.S. hospitals. Over the 27-month study, there was a small, but statistically significant, decrease in falls (P < 0.0001) and injurious falls (P < 0.0001).


Tranexamic acid for gastrointestinal bleeding: A systematic review with meta-analysis of randomized clinical trials.
Acute gastrointestinal bleeding is a common life-threatening emergent condition. Immediate tranexamic acid is useful for reducing hemorrhage following operation and bleeding trauma, but evidence on the effects of tranexamic acid in patients with gastrointestinal bleeding is limited or highly heterogeneous. It is still unclear about using tranexamic acid in the emergent condition of gastrointestinal bleeding. This study, therefore, aimed to determine whether or not tranexamic acid should be used in gastrointestinal bleeding management through systematic review and meta-analysis. We searched three biomedical databases for relevant randomized controlled trials on this topic. Two authors independently selected studies and extracted data for bias assessment and meta-analysis of bleeding, further intervention, mortality, transfusion, and intensive care unit admission. Available data were pooled using a random-effects model, and the results were presented as risk ratios (RRs) with 95% confidence intervals (CIs). Heterogeneity and small study effects were also assessed. Thirteen randomized controlled trials (n = 2271) were included in the present synthesis. Our meta-analysis revealed that tranexamic acid significantly reduced the rates of continued bleeding (RR = 0.60; 95%CI, 0.43-0.84), urgent endoscopic intervention (RR = 0.35; 95%CI, 0.24-0.50), and mortality (RR = 0.60; 95%CI, 0.45-0.80) compared with the placebo. According to the available evidence, the present synthesis confirms that tranexamic acid is an effective medication for patients with upper gastrointestinal bleeding. Early administration of tranexamic acid may be worth to be recommended for treating upper gastrointestinal bleeding in the emergency department. However, the effects of tranexamic acid on lower gastrointestinal bleeding warrant further clarification.


History of surgery for cerebrovascular disease in children. Part II. Vein of Galen malformations.
Vein of Galen aneurysmal malformations are a mixed group of lesions characterized by an abnormal fistula between abnormal distal branches of the choroidal and/or posterior cerebral arteries and the great vein of Galen. In this paper the authors trace the historical evolution of the current approach to diagnosis and treatment, and the literature is reviewed comprehensively. During the historical era, vein of Galen malformations were described in individual case reports and an early classification system was developed. In the early era of treatment, open surgery was the preferred approach, although morbidity and mortality rates were high. The development of neurointerventional techniques allowed the introduction of occlusive materials into the fistula, with pronounced improvements in clinical outcome.


Availability and Use of Therapeutic Interchange Policies in Managing Antimicrobial Shortages among South African Public Sector Hospitals; Findings and Implications.
Abstract: Background: Therapeutic interchange policies in hospitals are useful in dealing with antimicrobial shortages and minimising resistance rates. The extent of antimicrobial shortages and availability of therapeutic interchange policies is unknown among public sector hospitals in South Africa. This study aimed to ascertain the extent of and rationale for dealing with antimicrobial shortages, describe policies or guidelines available, and the role of pharmacists in the process. A quantitative and descriptive study was conducted with a target population of 403 public sector hospitals. Data were collected from hospital pharmacists using an electronic questionnaire via SurveyMonkeyTM. The response rate was 33.5% and most (83.3%) hospitals had experienced shortages in the previous six months. Antimicrobials commonly reported as out of stock included cloxacillin (54.3%), benzathine benzylpenicillin (54.2%), and erythromycin (39.6%). Reasons for shortages included pharmaceutical companies with supply constraints (85.3%) and an inefficient supply system. Only 42.4% had therapeutic interchange policies, and 88.9% contacted the prescriber, when present, for substitution. Antimicrobial shortages are prevalent in South African public sector hospitals with the most affected being penicillins and cephalosporins. Therapeutic interchange policies are not available at most hospitals. Effective strategies are required to improve communication between pharmacists and prescribers to ensure that safe, appropriate, and therapeutically equivalent alternatives are available.


Self-monitoring of Physical Activity After Hospital Discharge in Patients Who Have Undergone Gastrointestinal or Lung Cancer Surgery: Mixed Methods Feasibility Study.
Self-monitoring of physical activity (PA) using an accelerometer is a promising intervention to stimulate PA after hospital discharge. This study aimed to evaluate the feasibility of PA self-monitoring after discharge in patients who have undergone gastrointestinal or lung cancer surgery. A mixed methods study was conducted in which 41 patients with cancer scheduled for lobectomy, esophageal resection, or hyperthermic intraperitoneal chemotherapy were included. Preoperatively, patients received an ankle-worn accelerometer and the corresponding mobile health app to familiarize themselves with its use. The use was continued for up to 6 weeks after surgery. Feasibility criteria related to the study procedures, the System Usability Scale, and user experiences were established. In addition, 6 patients were selected to participate in semistructured interviews. The percentage of patients willing to participate in the study (68/90, 76%) and the final participation rate (57/90, 63%) were considered good. The retention rate was acceptable (41/57, 72%), whereas the rate of missing accelerometer data was relatively high (31%). The mean System Usability Scale score was good (77.3). Interviewed patients mentioned that the accelerometer and app were easy to use, motivated them to be more physically active, and provided postdischarge support. The technical shortcomings and comfort of the ankle straps should be improved. Self-monitoring of PA after discharge appears to be feasible based on good system usability and predominantly positive user experiences in patients with cancer after lobectomy, esophageal resection, or hyperthermic intraperitoneal chemotherapy. Solving technical problems and improving the comfort of the ankle strap may reduce the number of dropouts and missing data in clinical use and follow-up studies.


An experimental clinical evaluation of EIT imaging with ℓ1 data and image norms.
Electrical impedance tomography (EIT) produces an image of internal conductivity distributions in a body from current injection and electrical measurements at surface electrodes. Typically, image reconstruction is formulated using regularized schemes in which ℓ2-norms are used for both data misfit and image prior terms. Such a formulation is computationally convenient, but favours smooth conductivity solutions and is sensitive to outliers. Recent studies highlighted the potential of ℓ1-norm and provided the mathematical basis to improve image quality and robustness of the images to data outliers. In this paper, we (i) extended a primal-dual interior point method (PDIPM) algorithm to 2.5D EIT image reconstruction to solve ℓ1 and mixed ℓ1/ℓ2 formulations efficiently, (ii) evaluated the formulation on clinical and experimental data, and (iii) developed a practical strategy to select hyperparameters using the L-curve which requires minimum user-dependence. The PDIPM algorithm was evaluated using clinical and experimental scenarios on human lung and dog breathing with known electrode errors, which requires a rigorous regularization and causes the failure of reconstruction with an ℓ2-norm solution. The results showed that an ℓ1 solution is not only more robust to unavoidable measurement errors in a clinical setting, but it also provides high contrast resolution on organ boundaries.


Flow analysis on microcasting with degassed polydimethylsiloxane micro-channels for cell patterning with cross-linked albumin.
Patterned cell culturing is one of the most useful techniques for understanding the interaction between geometric conditions surrounding cells and their behaviors. The authors previously proposed a simple method for cell patterning with an agarose gel microstructure fabricated by microcasting with a degassed polydimethylsiloxane (PDMS) mold. Although the vacuum pressure produced from the degassed PDMS can drive a highly viscous agarose solution, the influence of solution viscosity on the casting process is unknown. This study investigated the influences of micro-channel dimensions or solution viscosity on the flow of the solution in a micro-channel of a PDMS mold by both experiments and numerical simulation. It was found experimentally that the degassed PDMS mold was able to drive a solution with a viscosity under 575 mPa·s. A simulation model was developed which can well estimate the flow rate in various dimensions of micro-channels. Cross-linked albumin has low viscosity (1 mPa·s) in aqueous solution and can undergo a one-way dehydration process from solution to solid that produces cellular repellency after dehydration. A microstructure of cross-linked albumin was fabricated on a cell culture dish by the microcasting method. After cells were seeded and cultivated on the cell culture dish with the microstructure for 7 days, the cellular pattern of mouse skeletal myoblast cell line C2C12 was observed. The microcasting with cross-linked albumin solution enables preparation of patterned cell culture systems more quickly in comparison with the previous agarose gel casting, which requires a gelation process before the dehydration process.


Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system.
The plasma protein apolipoprotein (apo) E is an important determinant of lipid transport and metabolism in mammals. In the present study, immunocytochemistry has been used to identify apo E in specific cells of the central and peripheral nervous systems of the rat. Light microscopic examination revealed that all astrocytes, including specialized astrocytic cells (Bergmann glia of the cerebellum, tanycytes of the third ventricle, pituicytes of the neurohypophysis, and Müller cells of the retina), possessed significant concentrations of apo E. In all of the major subdivisions of the central nervous system, the perinuclear region of astrocytic cells, as well as their cell processes that end on basement membranes at either the pial surface or along blood vessels, were found to be rich in apo E. Extracellular apo E was present along many of these same surfaces. The impression that apo E is secreted by astrocytic cells was confirmed by electron microscopic immunocytochemical studies, which demonstrated the presence of apo E in the Golgi apparatus. Apo E was not present in neurons, oligodendroglia, microglia, ependymal cells, and choroidal cells. In the peripheral nervous system, apo E was present within the glia surrounding sensory and motor neurons; satellite cells of the dorsal root ganglia and superior cervical sympathetic ganglion as well as the enteric glia of the intestinal ganglia were reactive. Apo E was also present within the non-myelinating Schwann cells but not within the myelinating Schwann cells of peripheral nerves. These results suggest that apo E has an important, previously unsuspected role in the physiology of nervous tissue.


Combining high-resolution contact data with virological data to investigate influenza transmission in a tertiary care hospital.
Contact patterns and microbiological data contribute to a detailed understanding of infectious disease transmission. We explored the automated collection of high-resolution contact data by wearable sensors combined with virological data to investigate influenza transmission among patients and healthcare workers in a geriatric unit. Proof-of-concept observational study. Detailed information on contact patterns were collected by wearable sensors over 12 days. Systematic nasopharyngeal swabs were taken, analyzed for influenza A and B viruses by real-time polymerase chain reaction, and cultured for phylogenetic analysis. An acute-care geriatric unit in a tertiary care hospital. Patients, nurses, and medical doctors. A total of 18,765 contacts were recorded among 37 patients, 32 nurses, and 15 medical doctors. Most contacts occurred between nurses or between a nurse and a patient. Fifteen individuals had influenza A (H3N2). Among these, 11 study participants were positive at the beginning of the study or at admission, and 3 patients and 1 nurse acquired laboratory-confirmed influenza during the study. Infectious medical doctors and nurses were identified as potential sources of hospital-acquired influenza (HA-Flu) for patients, and infectious patients were identified as likely sources for nurses. Only 1 potential transmission between nurses was observed. Combining high-resolution contact data and virological data allowed us to identify a potential transmission route in each possible case of HA-Flu. This promising method should be applied for longer periods in larger populations, with more complete use of phylogenetic analyses, for a better understanding of influenza transmission dynamics in a hospital setting.


Design of hybrid sol-gel films for direct x-ray and electron beam nanopatterning.
New epoxy based sol-gel organic inorganic materials, showing lithographic resist-like properties without the addition of any photocatalysts, are presented. To obtain a material sensitive to radiation, specific sol-gel syntheses based on an organically modified alkoxide containing an epoxy ring, 3-glycidoxypropyltrimethoxysilane (GPTMS), have been developed. The synthesis and the patternability of hybrid materials have been obtained controlling the inorganic crosslinking degree and with an almost total absence of organic polymerization. Two examples of directly patternable hybrid films, called GB and GGe, have been synthesized using acidic (GGe) and basic (GB) conditions and obtaining different compositions. After electron beam lithography (EBL) or x-ray synchrotron radiation lithography (XRL) the polymerization of the organic component of the sol-gel film occurs, generating a hardening of the structure after post-exposure baking. The exposed polymerized material becomes insoluble, determining a negative resist-like behaviour of the film: the lithographic process of nanopatterning results from the dissolution of the unexposed areas in proper solvents (developers). Spatial resolution of the order of 200 nm is reported and a contrast of 2.2 is achieved. The novelty of this work is that epoxy based materials, which have enhanced thermomechanical stability with respect to the more usual acrylic based resins, are directly nanopatterned for the first time by electron beam (EB) and/or x-ray beam radiation exposure without the aid of catalysts for polymerization. In contrast to common resists that are sacrificial layers of the fabrication process, direct patternable sol-gel hybrids constitute the final material of the devices. In fact, an example of doping with a light emitting dye is reported together with the achievement of directly patterned structures by EBL and XRL.


Detection of Chlamydia trachomatis antigens in urine as an alternative to swabs and cultures.
By using commercially available spectrophotometric and immunofluorescent immunoassays, Chlamydia trachomatis antigens were detected in first-void urine (FVU) sediments from 224 men attending a sexually transmitted disease clinic at a frequency of 81.6%-86.8% compared with 86.8% (33/38) positive by urethral swab culture (P less than .05). Endocervical cultures from 228 women attending a gynecology clinic yielded 92.3% (12/13) positive compared with 61.5%-76.9% for urine samples in three antigen-detection assays. Culturing urine from either gender yielded low positivity rates (23.7% for men, 15.4% for women). Defining truly infected patients as positive by culture or by any two of the three antigen tests, all assays were 100% specific. Immunodiagnostic testing of male FVU sediment appears to be a reliable, rapid, nontraumatic method for diagnosing chlamydia infection.


Breaking the Cycle: Understanding the Needs of Women Involved in the Criminal Justice System and the Role of Mentoring in Promoting Desistance.
An increasingly popular gender-specific intervention to assist women involved in the criminal justice system (e.g., ex-prisoners) is mentoring. However, despite the growing popularity of mentoring, there is a dearth of literature that has explored the intervention's efficacy, particularly as it relates to women involved in the criminal justice system. In the current study, client files of 64 women in a one-to-one mentoring program in Australia were examined to identify (a) the social and practical needs and obstacles faced by women overcoming their involvement with the justice system, and (b) the extent to which mentoring addressed these needs and obstacles. The results show that consistent with previous research, many of the women experienced a range of social and practical difficulties that impeded the desistance process. For a large portion of the women, however, mentoring helped overcome some difficulties by enhancing positive social capital in their lives. These findings are discussed in the context of how mentoring relationships can act as key turning points in the lives of women involved in the criminal justice system.


Acute necrotizing encephalopathy in caucasian children: two cases and review of the literature.
Acute necrotizing encephalopathy is a fulminant neurologic disease seen predominantly in Japan and Taiwan. We present two cases diagnosed at a Canadian center within the same year in Caucasian children. Both were previously well, developed an acute viral illness with fever and vomiting, and progressed to brain death within 2 to 4 days. Neuroimaging and postmortem examination demonstrated the unique features of bilateral and severe necrosis of deep gray- and subcortical white-matter structures. The first case was associated with extensive, but transient, hepatic involvement, recent varicella and rotavirus infections, and detailed metabolic studies, including mitochondrial functional analysis, were normal. The second case tested positive for influenza A infection, whereas evidence of liver damage was lacking. Both children demonstrated early lymphopenia and myocardial necrosis, two features not previously associated with acute necrotizing encephalopathy. These cases are unique in their occurrence in non-Japanese children and are among the first published reports in Canada.


Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation.
A common characteristic of allergens is that they contain proteases that can activate protease-activated receptor (PAR-2); however the mechanism by which PAR-2 regulates allergic airway inflammation is unclear. Mice (wild type and PAR-2-deficient) were sensitized using German cockroach (GC) feces (frass), the isolated protease from GC frass, or through adoptive transfer of GC frass-treated bone marrow-derived dendritic cells (BMDC) and measurements of airway inflammation (cellular infiltration, cytokine expression, and mucin production), serum IgE levels and airway hyperresponsiveness (AHR) were assessed. BMDC were cultured, treated with GC frass and assessed for cytokine production. PAR-2 expression on pulmonary mDCs was determined by flow cytometry. Exposure to GC frass induced AHR and airway inflammation in wild type mice; however PAR-2-deficient mice had significantly attenuated responses. To directly investigate the role of the protease, we isolated the protease from GC frass and administered the endotoxin-free protease into the airways of mice in the presence of OVA. GC frass proteases were sufficient to promote the development of AHR, serum IgE, and Th2 cytokine production. PAR-2 expression on mDC was upregulated following GC frass exposure, but the presence of a functional PAR-2 did not alter antigen uptake. To determine if PAR-2 activation led to differential cytokine production, we cultured BMDC in the presence of GM-CSF and treated these cells ex vivo with GC frass. PAR-2-deficient BMDC released significantly less IL-6, IL-23 and TNFα compared to BMDC from wild type mice, suggesting PAR-2 activation was important in Th2/Th17 skewing cytokine production. To determine the role for PAR-2 on mDCs on the initiation of allergic airway inflammation, BMDCs from wild type and PAR-2-deficient mice were treated in the presence or absence of GC frass and then adoptively transferred into the airway of wild type mice. Importantly, GC frass-stimulated wild type BMDCs were sufficient to induce AHR and allergic airway inflammation, while GC frass-stimulated PAR-2-deficient BMDC had attenuated responses. Together these data suggest an important role for allergen activation of PAR-2 on mDCs in mediating Th2/Th17 cytokine production and allergic airway responses.


Hemorrhagic intramedullary hemangioblastoma of the cervical spinal cord presenting with acute-onset quadriparesis: case report and review of the literature.
Hemangioblastomas of the spinal cord are uncommon vascular tumors. Patients commonly present with subtle neurologic findings that are thought to represent growth of the lesion over time. Hemorrhage of an intramedullary hemangioblastoma presenting as acute neurologic deficit is an extremely rare occurrence. Although the cervical spine is the most common location for hemangioblastoma of the spinal cord, there have been no previously published cases in the literature of intramedullary hemorrhage from such a lesion. A 22-year-old woman with a previously undiagnosed spinal cord hemangioblastoma presented with sudden-onset dense quadriparesis due to intramedullary hemorrhage in the cervical spinal cord. The patient did not have any clinical findings of von-Hippel Lindau disease. Laminoplasty from C5 to T2 and posterior midline myelotomy for resection of the intramedullary tumor with hematoma evacuation were completed without complication. Intramedullary hemangioblastoma of the spinal cord is uncommon, and hemorrhage from a cervical spinal cord lesion has not previously been reported. Symptoms from these usually indolent lesions are commonly associated with tumor growth, edema, or associated syrinx, whereas devastating acute neurologic deficit from hemorrhage is exceedingly rare. Microsurgical resection should be done in cases of symptomatic lesions and considered in isolated symptomatic lesions without the known diagnosis of von Hippel-Lindau disease.


Functional analysis of subunit e of the F1Fo-ATP synthase of the yeast Saccharomyces cerevisiae: importance of the N-terminal membrane anchor region.
Mitochondrial F1Fo-ATP synthase complexes do not exist as physically independent entities but rather form dimeric and possibly oligomeric complexes in the inner mitochondrial membrane. Stable dimerization of two F1Fo-monomeric complexes involves the physical association of two membrane-embedded Fo-sectors. Previously, formation of the ATP synthase dimeric-oligomeric network was demonstrated to play a critical role in modulating the morphology of the mitochondrial inner membrane. In Saccharomyces cerevisiae, subunit e (Su e) of the Fo-sector plays a central role in supporting ATP synthase dimerization. The Su e protein is anchored to the inner membrane via a hydrophobic region located at its N-terminal end. The hydrophilic C-terminal region of Su e resides in the intermembrane space and contains a conserved coiled-coil motif. In the present study, we focused on characterizing the importance of these regions for the function of Su e. We created a number of C-terminal-truncated derivatives of the Su e protein and expressed them in the Su e null yeast mutant. Mitochondria were isolated from the resulting transformant strains, and a number of functions of Su e were analyzed. Our results indicate that the N-terminal hydrophobic region plays important roles in the Su e-dependent processes of mitochondrial DNA maintenance, modulation of mitochondrial morphology, and stabilization of the dimer-specific Fo subunits, subunits g and k. Furthermore, we show that the C-terminal coiled-coil region of Su e functions to stabilize the dimeric form of detergent-solubilized ATP synthase complexes. Finally, we propose a model to explain how Su e supports the assembly of the ATP synthase dimers-oligomers in the mitochondrial membrane.


MALDI-imaging enables direct observation of kinetic and thermodynamic products of mixed peptide fiber assembly.
Controlling the self-assembly of multicomponent systems provides a key to designing new materials and understanding the molecular complexity of biology. Here, we demonstrate the first use of MALDI-imaging to characterize a multicomponent self-assembling peptide fiber. Observations of mixed peptide systems over time demonstrate how simple sequence variation can change the balance between kinetic and thermodynamic products.


Genetic Association Analysis of Drusen Progression.
Age-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of AMD pathogenesis. Exome chip data was made available through the International AMD Genomics Consortium (IAMDGC). Drusen quantification was carried out with color fundus photographs using an automated drusen detection and quantification algorithm. A genetic risk score (GRS) was calculated per subject by summing risk allele counts at 19 common genetic risk variants weighted by their respective effect sizes. Pathway analysis of drusen progression was carried out with the software package Pathway Analysis by Randomization Incorporating Structure. We observed significant correlation with drusen baseline area and the GRS in the age-related eye disease study (AREDS) dataset (ρ = 0.175, P = 0.006). Measures of association were not statistically significant between drusen progression and the GRS (P = 0.54). Pathway analysis revealed the cell adhesion molecules pathway as the most highly significant pathway associated with drusen progression (corrected P = 0.02). In this study, we explored the potential influence of known common AMD genetic risk factors on drusen progression. Our results from the GRS analysis showed association of increasing genetic burden (from 19 AMD associated loci) to baseline drusen load but not drusen progression in the AREDS dataset while pathway analysis suggests additional genetic contributors to AMD risk.


Interobserver variation in the assessment of the sarcomatoid and transitional components in biphasic mesotheliomas.
The percentage of sarcomatoid component has an impact on prognosis in patients with biphasic malignant pleural mesothelioma. Recent study showed that the transitional pattern similar to sarcomatoid component of malignant mesothelioma has negative prognostic significance. Practice guidelines recommend quantification of sarcomatoid component despite poor diagnostic reproducibility of biphasic mesothelioma among thoracic pathologists. The aim of this study was to determine the interobserver agreement in the quantification of sarcomatoid component, and in the diagnosis of a transitional component in the biphasic malignant mesothelioma. Thirteen experts in thoracic pathology reviewed the representative H&E and cytokeratin whole-slide images of the 54 biphasic mesotheliomas, without knowledge of BAP1 or p16 deletion status, and completed the survey of 25 questions. The overall interobserver agreement in the assessment of the percentage of the sarcomatoid component in 25% increments was good (wK = 0.62). Excellent agreement was present in 14 of 54 cases (26%), and 3 cases were unanimously scored. Excellent agreement was reached for the cases with 0-24% and > 75% of the sarcomatoid component.The most commonly used criteria for the diagnosis of sarcomatoid component were malignant spindle cells, frank sarcomatoid features and high N/C ratio. The overall interobserver agreement for transitional pattern was fair (wK = 0.40). Unanimous opinion about the absence of transitional pattern was observed in only one case. At least 70% agreement regarding the presence of transitional pattern was observed in 12 cases, with the rest of the cases showing a wide range of disagreement. Morphologic characteristics that favor transitional pattern over non-transitional include sheet-like growth of cohesive, plump, elongated epithelioid cells with well-defined cell borders and a tendency to transition into spindle cells. Our study defined precise morphologic criteria that may be used in the differential diagnosis between transitional pattern and other mesothelioma subtypes including sarcomatoid and epithelioid.


Near-diffraction-limited annular flattop beam shaping with dual phase only liquid crystal spatial light modulators.
We demonstrate the annular flattop beam shaping technique with dual phase only liquid crystal spatial light modulators (LC-SLM) based on the refractive laser beam shaping systems. One LC-SLM redistributes the intensity distribution, and the other restores the initial underlying wave front. Differing from the conventional annular beam shaping technique, the wave front of the output beam can be maintained. The influences of deviations of beam waist and beam shape on the output beam profile are discussed in detail. Experimental results show that approximate 71% of the power is enclosed in a region with less than 7% rms intensity variation. The 4.1mm diameter near-diffraction-limited beam retains an annular flattop intensity distribution without significant diffraction peaks for a working distance of more than 24cm in the near field.


Effects of transfection with the Cu, Zn-superoxide dismutase gene on xanthine/xanthine oxidase-induced cytotoxicity in fibroblasts from rat skin.
The effects of transfection with the human Cu, Zn-superoxide dismutase (hSOD)4 gene on active oxygen-induced cytotoxicity in rat skin fibroblasts (FR) were studied for the purpose of developing the novel delivery system of hSOD using hSOD gene. An expression plasmid for hSOD, pRc/RSV-SOD, was constructed and used to transfect FR cells. Xanthine (X)/xanthine oxidase (XO) system were used to generate active oxygen species. The effects of transfection with the hSOD gene on active oxygen-induced cytotoxicity were assessed by comparing the number of surviving cells and the level of lipid peroxidation in host and transformants after exposure to X/XO system. The cellular SOD activity in RSV-SOD cells transfected with pRc/RSV-SOD was significantly increased in comparison with host or RSV cells transfected with the pRc/RSV plasmid containing no hSOD gene as a control. Furthermore, Western blot analysis using an anti-hSOD antibody indicated the production of hSOD in RSV-SOD cells. On the other hand, although the numbers of surviving cells in both host and RSV-SOD cultures after exposure to X/XO system decreased in a time-dependent manner, the decrease in number of surviving RSV-SOD cells was less than that in host cells. In the presence of catalase, the decreases in number of surviving cells in both host and RSV-SOD cultures after exposure to the X/XO system were also less than those in the absence of catalase. However, the decreases in cell survival in RSV-SOD cultures were significantly less than those in host cells in the presence of catalase. Furthermore, the levels of lipid peroxidation in RSV-SOD cells exposed to the X/XO system in the presence or absence of catalase were lower than those in host cells. These results indicated that the increase in cellular SOD activity by transfection with the hSOD gene protects cells from oxidative stress. Human SOD gene therapy may be useful for treatment of diseases in which oxidative tissue damage is produced.


The Drosophila Wnt protein DWnt-3 is a secreted glycoprotein localized on the axon tracts of the embryonic CNS.
The Wnt gene family encodes highly conserved cysteine-rich proteins which appear to act as secreted developmental signals. Both the mouse Wnt-1 gene and the Drosophila wingless (wg) gene play important roles in central nervous system (CNS) development. wg is also required earlier, in the development of the embryonic metameric body pattern. We have begun to characterize the developmental expression and role of another member of the Drosophila Wnt gene family, DWnt-3. Using antisera raised to the DWnt-3 protein, we show that the protein is secreted in vivo. The early protein expression domains include the limb and appendage primordia. Late expression domains comprise the ventral cord and supraesophageal ganglia of the CNS. Notably, DWnt-3 protein accumulates on the commissural and longitudinal axon tracts of the CNS. Ectopic expression of DWnt-3 in transgenic embryos bearing a HS-DWnt-3 construct leads to specific disruption of the commissural axon tracts of the CNS. We also show that DWnt-3 does not functionally replace wg in an in vivo assay. Experiments with a tissue culture cell line transfected with a construct encoding the DWnt-3 gene show that DWnt-3 protein is efficiently synthesized, glycosylated, proteolytically processed, and transported to the extracellular matrix and medium. DWnt-3, therefore, encodes a secreted protein, which is likely to play a role in development of the Drosophila CNS.


Effects of Different Drying Methods and Storage Time on Free Radical Scavenging Activity and Total Phenolic Content of Cosmos Caudatus.
The present study was conducted to determine the effect of air (AD), oven (OD) and freeze drying (FD) on the free radical scavenging activity and total phenolic content (TPC) of Cosmos caudatus and the effect of storage time by the comparison with a fresh sample (FS). Among the three drying methods that were used, AD resulted in the highest free radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) (IC50 = 0.0223 mg/mL) and total phenolic content (27.4 g GAE/100 g), whereas OD produced the lowest scavenging activity and TPC value. After three months of storage, the dried samples showed a high and consistent free radical scavenging activity when compared to stored fresh material. The drying methods could preserve the quality of C. caudatus during storage and the stability of its bioactive components can be maintained.


From bouncy legs to poisoned arrows: elastic movements in invertebrates.
Elastic mechanisms in the invertebrates are fantastically diverse, yet much of this diversity can be captured by examining just a few fundamental physical principles. Our goals for this commentary are threefold. First, we aim to synthesize and simplify the fundamental principles underlying elastic mechanisms and show how different configurations of basic building blocks can be used for different functions. Second, we compare single rapid movements and rhythmic movements across six invertebrate examples - ranging from poisonous cnidarians to high-jumping froghoppers - and identify remarkable functional properties arising from their underlying elastic systems. Finally, we look to the future of this field and find two prime areas for exciting new discoveries - the evolutionary dynamics of elastic mechanisms and biomimicry of invertebrate elastic materials and mechanics.


FRNA Bacteriophages as Viral Indicators of Faecal Contamination in Mexican Tropical Aquatic Systems.
A particular challenge to water safety in populous intertropical regions is the lack of reliable faecal indicators to detect microbiological contamination of water, while the numerical relationships of specific viral indicators remain largely unexplored. The aim of this study was to investigate the numerical relationships of FRNA-bacteriophage genotypes, adenovirus 41, and human adenoviruses (HADV) in Mexican surface water systems to assess sewage contamination. We studied the presence of HADV, HADV41 and FRNA bacteriophage genotypes in water samples and quantified by qPCR and RT-qPCR. Virus and water quality indicator variances, as analyzed by principal component analysis and partial least squared regression, followed along the major percentiles of water faecal enterococci. FRNA bacteriophages adequately deciphered viral and point source water contamination. The strongest correlation for HADV was with FRNA bacteriophage type II, in water samples higher than the 50th percentiles of faecal enterococci, thus indicating urban pollution. FRNA bacteriophage genotypes I and III virus indicator performances were assisted by their associations with electrical conductivity and faecal enterococci. In combination, our methods are useful for inferring water quality degradation caused by sewage contamination. The methods used have potential for determining source contamination in water and, specifically, the presence of enteric viruses where clean and contaminated water have mixed.


The genome of Syntrophomonas wolfei: new insights into syntrophic metabolism and biohydrogen production.
Syntrophomonas wolfei is a specialist, evolutionarily adapted for syntrophic growth with methanogens and other hydrogen- and/or formate-using microorganisms. This slow-growing anaerobe has three putative ribosome RNA operons, each of which has 16S rRNA and 23S rRNA genes of different length and multiple 5S rRNA genes. The genome also contains 10 RNA-directed, DNA polymerase genes. Genomic analysis shows that S. wolfei relies solely on the reduction of protons, bicarbonate or unsaturated fatty acids to re-oxidize reduced cofactors. Syntrophomonas wolfei lacks the genes needed for aerobic or anaerobic respiration and has an exceptionally limited ability to create ion gradients. An ATP synthase and a pyrophosphatase were the only systems detected capable of creating an ion gradient. Multiple homologues for β-oxidation genes were present even though S. wolfei uses a limited range of fatty acids from four to eight carbons in length.Syntrophomonas wolfei, other syntrophic metabolizers with completed genomic sequences, and thermophilic anaerobes known to produce high molar ratios of hydrogen from glucose have genes to produce H(2) from NADH by an electron bifurcation mechanism. Comparative genomic analysis also suggests that formate production from NADH may involve electron bifurcation. A membrane-bound, iron-sulfur oxidoreductase found in S. wolfei and Syntrophus aciditrophicus may be uniquely involved in reverse electron transport during syntrophic fatty acid metabolism. The genome sequence of S. wolfei reveals several core reactions that may be characteristic of syntrophic fatty acid metabolism and illustrates how biological systems produce hydrogen from thermodynamically difficult reactions.


Spatial and Temporal Dynamics of the Native Banana-Spotting Bug, Amblypelta lutescens lutescens (Hemiptera: Coreidae), in Avocado Crops in North Queensland, Australia.
The native banana-spotting bug, Amblypelta lutescens lutescens Distant, is a major polyphagous insect pest of many tropical and subtropical horticultural crops in Australia, including high-valued commodities such as avocado (Persea americana Mill. (Laurales: lauraceae)). The cryptic nature of A. l. lutescens makes it difficult to sample, and much about its ecology and behavior remains poorly understood. A lure based on the main components of the semiochemicals emitted by male A. l. lutescens, which is attractive to adult males, adult females, and nymphs, has been developed and incorporated into a trap, facilitating sampling of A. l. lutescens in the field. A 2-yr study investigated the spatial and temporal dynamics of the pest in two conventionally managed avocado (cv. Shepard) orchards using a grid (36 m × 36 m) of traps across each. In each year of the study, higher numbers of A. l. lutescens were recorded from October to June. In one field, spatial clustering of adults was detected in close proximity to an adjacent lime [Citrus aurantiifolia (Christm.) (Rutales: rutaceae) Swingle] crop that was not managed with insecticides during the study. Spatial clustering of nymphs was detected adjacent to native riparian vegetation in the other field. The results suggest that source populations of A. l. lutescens could originate from neighboring crops that host A. l. lutescens and from riparian vegetation. Focused sampling of trees at the interface with these vegetation types could lead to early pest detection, timely suppression, and therefore improved pest management.


Long-term follow-up of front-line treatment of hairy cell leukemia with 2-chlorodeoxyadenosine.
Although remission of hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) appears to be long lasting, few reports currently provide results from follow-up exceeding 5 years. We reviewed our HCL patients treated with front-line 2-CdA (by 2-hour infusion) either for 5 consecutive days at 0.14 mg/kg/day (daily subset, n=21) or once a week at 0.14 mg/kg for 5 cycles (weekly subset, n=16). Of the 37 eligible patients, 30 (81%) achieved complete response (CR) and 7 (19%) partial response (PR) (overall response rate, 100%); identical response rates were recorded in the daily and weekly subsets. After a median follow-up of 122 months (range, 54-156), the overall relapse rate was 27% (8/30): 24% (4/17) had relapsed in the subset treated daily whereas 30% (4/13) had done so in the subset treated weekly (p=ns). The projected 13-year overall and the relapse-free survivals are 96% and 52%, respectively. In terms of hematologic toxicity, the weekly 2-CdA schedule was associated with significantly fewer cases of grade 3-4 neutropenia. In HCL patients, a single dose of 2-CdA induces a long-term CR. Over 90% of patients are alive 13 years later and over 50% of patients appear to be clinically cured by this treatment. The weekly schedule seems to be a safer option for neutropenic HCL patients, while apparently providing equivalent results in terms of response rates and long-term outcome.


Adaptive optics scanning ophthalmoscopy with annular pupils.
Annular apodization of the illumination and/or imaging pupils of an adaptive optics scanning light ophthalmoscope (AOSLO) for improving transverse resolution was evaluated using three different normalized inner radii (0.26, 0.39 and 0.52). In vivo imaging of the human photoreceptor mosaic at 0.5 and 10° from fixation indicates that the use of an annular illumination pupil and a circular imaging pupil provides the most benefit of all configurations when using a one Airy disk diameter pinhole, in agreement with the paraxial confocal microscopy theory. Annular illumination pupils with 0.26 and 0.39 normalized inner radii performed best in terms of the narrowing of the autocorrelation central lobe (between 7 and 12%), and the increase in manual and automated photoreceptor counts (8 to 20% more cones and 11 to 29% more rods). It was observed that the use of annular pupils with large inner radii can result in multi-modal cone photoreceptor intensity profiles. The effect of the annular masks on the average photoreceptor intensity is consistent with the Stiles-Crawford effect (SCE). This indicates that combinations of images of the same photoreceptors with different apodization configurations and/or annular masks can be used to distinguish cones from rods, even when the former have complex multi-modal intensity profiles. In addition to narrowing the point spread function transversally, the use of annular apodizing masks also elongates it axially, a fact that can be used for extending the depth of focus of techniques such as adaptive optics optical coherence tomography (AOOCT). Finally, the positive results from this work suggest that annular pupil apodization could be used in refractive or catadioptric adaptive optics ophthalmoscopes to mitigate undesired back-reflections.


Child and Adult Care Food Program: Meal Pattern Revisions Related to the Healthy, Hunger-Free Kids Act of 2010. Final rule.
This final rule updates the meal pattern requirements for the Child and Adult Care Food Program to better align them with the Dietary Guidelines for Americans, as required by the Healthy, Hunger-Free Kids Act of 2010. This rule requires centers and day care homes participating in the Child and Adult Care Food Program to serve more whole grains and a greater variety of vegetables and fruit, and reduces the amount of added sugars and solid fats in meals. In addition, this final rule supports mothers who breastfeed and improves consistency with the Special Supplemental Nutrition Program for Women, Infants, and Children and with other Child Nutrition Programs. Several of the changes are extended to the National School Lunch Program, School Breakfast Program, and Special Milk Program. These changes are based on the Dietary Guidelines for Americans, science-based recommendations made by the National Academy of Medicine (formerly the Institute of Medicine of the National Academies), cost and practical considerations, and stakeholder's input. This is the first major revision of the Child and Adult Care Food Program meal patterns since the Program's inception in 1968. These improvements to the meals served in the Child and Adult Care Food Program are expected to safeguard the health of young children by ensuring healthy eating habits are developed early, and improve the wellness of adult participants.


The P2X7 receptor is not essential for development of imiquimod-induced psoriasis-like inflammation in mice.
Psoriasis is a chronic inflammatory skin disorder, characterised by epidermal hyperplasia (acanthosis) and leukocyte infiltration of the skin. Current therapies are inadequate, highlighting the need for new therapeutic targets. The P2X7 receptor is implicated in the pathogenesis of psoriasis. This study investigated the role of P2X7 in imiquimod (IMQ)-induced psoriasis-like inflammation. Topically applied IMQ caused twofold greater ear swelling in BALB/c mice compared to C57BL/6 mice, which encode a partial loss-of-function missense mutation in the P2RX7 gene. However, there was no difference in histological skin pathology (acanthosis and leukocyte infiltration) between the two strains. IMQ treatment up-regulated P2X7 expression in skin from both mouse strains. Additionally, IMQ induced ATP release from cultured human keratinocytes, a process independent of cell death. Injection of the P2X7 antagonist Brilliant Blue G (BBG) but not A-804598 partly reduced ear swelling compared to vehicle-injected control mice. Neither antagonist altered skin pathology. Moreover, no difference in ear swelling or skin pathology was observed between C57BL/6 and P2X7 knock-out (KO) mice. Flow cytometric analysis of IMQ-treated skin from C57BL/6 and P2X7 KO mice demonstrated similar leukocyte infiltration, including neutrophils, macrophages and T cells. In conclusion, this study demonstrates that P2X7 is not essential for development of IMQ-induced psoriasis-like inflammation but does not exclude a role for this receptor in psoriasis development in humans or other mouse models of this disease.


What causes autism? Exploring the environmental contribution.
Autism is a biologically based disorder of brain development. Genetic factors--mutations, deletions, and copy number variants--are clearly implicated in causation of autism. However, they account for only a small fraction of cases, and do not easily explain key clinical and epidemiological features. This suggests that early environmental exposures also contribute. This review explores this hypothesis. Indirect evidence for an environmental contribution to autism comes from studies demonstrating the sensitivity of the developing brain to external exposures such as lead, ethyl alcohol and methyl mercury. But the most powerful proof-of-concept evidence derives from studies specifically linking autism to exposures in early pregnancy - thalidomide, misoprostol, and valproic acid; maternal rubella infection; and the organophosphate insecticide, chlorpyrifos. There is no credible evidence that vaccines cause autism. Expanded research is needed into environmental causation of autism. Children today are surrounded by thousands of synthetic chemicals. Two hundred of them are neurotoxic in adult humans, and 1000 more in laboratory models. Yet fewer than 20% of high-volume chemicals have been tested for neurodevelopmental toxicity. I propose a targeted discovery strategy focused on suspect chemicals, which combines expanded toxicological screening, neurobiological research and prospective epidemiological studies.


Predicting global change effects on forest biomass and composition in south-central Siberia.
Multiple global changes such as timber harvesting in areas not previously disturbed by cutting and climate change will undoubtedly affect the composition and spatial distribution of boreal forests, which will, in turn, affect the ability of these forests to retain carbon and maintain biodiversity. To predict future states of the boreal forest reliably, it is necessary to understand the complex interactions among forest regenerative processes (succession), natural disturbances (e.g., fire, wind, and insects), and anthropogenic disturbances (e.g., timber harvest). We used a landscape succession and disturbance model (LANDIS-II) to study the relative effects of climate change, timber harvesting, and insect outbreaks on forest composition, biomass (carbon), and landscape pattern in south-central Siberia. We found that most response variables were more strongly influenced by timber harvest and insect outbreaks than by the direct effects of climate change. Direct climate effects generally increased tree productivity and modified probability of establishment, but indirect effects on the fire regime generally counteracted the direct effects of climate on forest composition. Harvest and insects significantly changed forest composition, reduced living aboveground biomass, and increased forest fragmentation. We concluded that: (1) Global change is likely to significantly change forest composition of south-central Siberian landscapes, with some changes taking ecosystems outside the historic range of variability. (2) The direct effects of climate change in the study area are not as significant as the exploitation of virgin forest by timber harvest and the potential increased outbreaks of the Siberian silk moth. (3) Novel disturbance by timber harvest and insect outbreaks may greatly reduce the aboveground living biomass of Siberian forests and may significantly alter ecosystem dynamics and wildlife populations by increasing forest fragmentation.


Modeling the space of camera response functions.
Many vision applications require precise measurement of scene radiance. The function relating scene radiance to image intensity of an imaging system is called the camera response. We analyze the properties that all camera responses share. This allows us to find the constraints that any response function must satisfy. These constraints determine the theoretical space of all possible camera responses. We have collected a diverse database of real-world camera response functions (DoRF). Using this database, we show that real-world responses occupy a small part of the theoretical space of all possible responses. We combine the constraints from our theoretical space with the data from DoRF to create a low-parameter empirical model of response (EMoR). This response model allows us to accurately interpolate the complete response function of a camera from a small number of measurements obtained using a standard chart. We also show that the model can be used to accurately estimate the camera response from images of an arbitrary scene taken using different exposures. The DoRF database and the EMoR model can be downloaded at http://www.cs.columbia.edu/CAVE.


The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.
Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is Δ9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors. These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named the CB1 and CB2 cannabinoid receptors. Later, an endogenous molecule that exerts pharmacological effects similar to those described by Δ9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG). Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2- AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT). To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various disturbances, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences.


Prebiotics increase heme iron bioavailability and do not affect non-heme iron bioavailability in humans.
The aim of this study was to establish the effect of a prebiotic mix on heme and non-heme iron (Fe) bioavailability in humans. To this purpose, twenty-four healthy women were randomized into one of two study groups. One group ate one yogurt per day for 12 days with a prebiotic mix (prebiotic group) and the other group received the same yogurt but without the prebiotic mix (control group). Before and after the intake period, the subjects participated in Fe absorption studies. These studies used 55Fe and 59Fe radioactive isotopes as markers of heme Fe and non-heme Fe, respectively, and Fe absorption was measured by the incorporation of radioactive Fe into erythrocytes. The results showed that there were no significant differences in heme and non-heme Fe bioavailability in the control group. Heme Fe bioavailability of the prebiotic group increased significantly by 56% post-prebiotic intake. There were no significant differences in non-heme Fe bioavailability in this group. We concluded that daily consumption of a prebiotic mix increases heme Fe bioavailability and does not affect non-heme iron bioavailability.


Maturational increase in mouse brain creatine kinase reaction rates shown by phosphorus magnetic resonance.
In-vivo phosphorus fluxes in the reaction catalyzed by creatine kinase (CK) were measured in brains of mice from 3 to 40 days of age using high-field (8.45 T) phosphorus magnetic resonance and the saturation transfer technique. This technique gives the ratio of chemical flux to reactant concentration directly and allows the calculation of pseudo-rate constants for the forward direction from PC to ATP (kf) and for the reverse direction (kr). The spin-lattice relaxation times (T1) for phosphocreatine (PC) and for the nucleoside triphosphate (NTP) nuclei, estimated by the progressive saturation technique, did not change during this age period. The PC concentration doubled relative to the NTP concentration over the first month of life. The kf and the flux of phosphorus nuclei in the forward direction increased 2- to 3-fold in the very narrow time period from 12 to 15 days of age. Brain phosphorus flux from PC to ATP thus increased 4- to 6-fold in the first month of life. An increase at least that large occurred in the reverse direction, but the kr could not be measured consistently in the younger animals using the saturation transfer technique. Phosphorus fluxes were equal in the forward and reverse directions in the mature brain. The capacity to increase rates of glycolysis and tissue respiration in response to increased energy demand appears in the same narrow age period as the increase in CK-catalyzed reaction rates in the developing rodent brain. We propose that these coincident changes in brain energy metabolism reflect the maturation of mechanisms for coupling cell energy production to rapid changes in energy requirements.


Identifying key factors associated with aggression on acute inpatient psychiatric wards.
Aggressive behaviour is a critical issue for modern acute psychiatric services, not just because of the adverse impact it has on patients and staff, but also because it puts a financial strain on service providers. The aim of this study was to assess the relationship of patient violence to other variables: patient characteristics, features of the service and physical environment, patient routines, staff factors, the use of containment methods, and other patient behaviours. A multivariate cross sectional design was utilised. Data were collected for a six month period on 136 acute psychiatric wards in 26 NHS Trusts in England. Multilevel modelling was conducted to ascertain those factors most strongly associated with verbal aggression, aggression toward objects, and physical aggression against others. High levels of aggression were associated with a high proportion of patients formally detained under mental health legislation, high patient turnover, alcohol use by patients, ward doors being locked, and higher staffing numbers (especially qualified nurses). The findings suggest that the imposition of restrictions on patients exacerbates the problem of violence, and that alcohol management strategies may be a productive intervention. Insufficient evidence is available to draw conclusions about the nature of the link between staffing numbers and violence.


IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury.
Cytokines IL-4 and IL-13 play important roles in polarization of macrophages/dendritic cells to an M2 phenotype, which is important for recovery from acute kidney injury. Both IL-4 and IL-13 activate JAK3/STAT6 signaling. In mice with diphtheria toxin receptor expression in proximal tubules (selective injury model), a relatively selective JAK3 inhibitor, tofacitinib, led to more severe kidney injury, delayed recovery from acute kidney injury, increased inflammatory M1 phenotype markers and decreased reparative M2 phenotype markers of macrophages/dendritic cells, and development of more severe renal fibrosis after diphtheria toxin administration. Similarly, there was delayed recovery and increased tubulointerstitial fibrosis in these diphtheria toxin-treated mice following tamoxifen-induced deletion of both IL-4 and IL-13, with increased levels of M1 and decreased levels of M2 markers in the macrophages/dendritic cells. Furthermore, deletion of IL-4 and IL-13 led to a decrease of tissue reparative M2a phenotype markers but had no effect on anti-inflammatory M2c phenotype markers. Deletion of IL-4 and IL-13 also inhibited recovery from ischemia-reperfusion injury in association with increased M1 and decreased M2 markers and promoted subsequent tubulointerstitial fibrosis. Thus, IL-4 and IL-13 are required to effectively polarize macrophages/dendritic cells to an M2a phenotype and to promote recovery from acute kidney injury.


The Deferred Consent Model in a Prospective Observational Study Evaluating Myocardial Injury in the Intensive Care Unit.
Informed consent is a hallmark of ethical clinical research. An inherent challenge in critical care research is obtaining consent when patients lack decision-making capacity. One solution is deferred consent, which is often used for studies that are low risk or involve emergency interventions. Our objective was to describe a deferred consent model in a low-risk critical care study. Prognostic Value of Elevated Troponins in Critical Illness Study was a prospective, pilot observational study of critically ill patients in 3 intensive care units, involving serial electrocardiograms and cardiac biomarkers. Newly admitted patients were enrolled over 1 month. When possible, informed consent was obtained a priori from the patient or substitute decision maker (SDM); otherwise, consent was deferred until the patient regained consent capacity or until their SDM was available. Logistic regression analysis was used to determine the association between patient's sex, Acute Physiology and Chronic Health Evaluation II score, study center, person providing consent (patient vs SDM), method of consent (telephone vs in person), and the provision or not of informed consent. The overall consent rate was 80.1% (213 of 266 persons approached). Of the 53 persons declining consent, 37 (69.8%) agreed to the use of data collected up until that point. Over half of all consent encounters were with patients rather than SDMs. Median interval delay between enrollment and the consent encounter was 1 day. On multivariate analysis, the only variable associated with consent was male sex of the patient (odds ratio for males 2.59, confidence interval: 1.19-5.63). Deferred consent facilitates implementation of time-sensitive research protocols until a consent encounter is possible. As a feasible alternative to exclusive a priori consent, the deferred consent model can be useful in low-risk studies in critically ill patients.


Scaling up TB DOTS in a fragile state: post-conflict Afghanistan.
Afghanistan. To describe the results of rapid expansion of the DOTS strategy in a post-conflict environment, with a focus on the experience of the Rural Expansion of Afghanistan's Community-based Healthcare (REACH) Program. Despite the destruction of the National Tuberculosis Program (NTP) and basic health services by war and an uncertain security situation, the NTP, with assistance from many partners and REACH, increased the number of patients receiving DOTS by 136% in 4 years (from 9261 cases in 2001 to 21851 in 2005), with an 86% treatment success rate. By focusing on rapidly expanding the number of facilities capable of providing tuberculosis (TB) diagnostic and treatment services and involving community health workers in case detection, referrals and home-based DOTS, REACH showed a 10-fold rise in the number of facilities providing TB services and a 380% increase in the number of sputum smear-positive pulmonary TB cases detected in 2 years (from 251/month in 2004 to 818/month in 2006) in 13 provinces. At the current rate of expansion, case detection and successful treatment of TB cases in Afghanistan will continue to expand rapidly. The NTP and REACH have demonstrated that expansion of TB services in Afghanistan is possible despite the challenges.


Hydrogen bonding motifs in a hydroxy-bisphosphonate moiety: revisiting the problem of hydrogen bond identification.
Bisphosphonates are important therapeutic agents in bone-related diseases and exhibit complex H-bonding networks. To assess the role of H-bonds in biophosphonate stability, a full conformational search was performed for methylenebisphosphonate (MBP) and 1-hydroxyethylidene-1,1-diphosphonate (HEDP) using the MP2 method in conjunction with the continuum solvation model. The most stable structures and their equilibrium populations were analyzed at two protonation states via assignment of H-bonding motifs to each conformer. Geometrical and topological approaches for the identification and characterization of H-bonds were compared with each other, and some of the important correlations between H-bond features were described over the entire conformational space of a hydroxy-bisphosphonate moiety. The topologically derived H-bond energy obtained from the local density of potential energy at bond critical points shows consistent correlations with other measures such as H-bond frequency shift. An inverse power form without an intercept predicts topological H-bond energies from hydrogen-acceptor distances with an RMS error of less than 1 kcal mol(-1). The consistency of this measure was further checked by building a model that reasonably reproduces the relative stabilities of different conformers from their hydrogen-acceptor distances. In all systems, the predictions of this model are improved by the consideration of weak H-bonds that have no bond critical point.