Child functioning in rural and nonrural areas: how does it compare when using the service program site as the level of analysis?
The current study uses data from the national evaluation of the Comprehensive Community Mental Health Services for Children and Their Families Program to examine child functioning in rural (n = 8) as compared to nonrural (n = 18) system-of-care communities across the United States. In this study, the topic of rural versus nonrural differences is approached from a community-level perspective with aggregated functional impairment scores as the dependent variable of interest in weighted least squares regression. The demographic characteristics of children, particularly age, were more important predictors of functional impairment than geographic locale (i.e., rural vs nonrural). Specifically, while children served in nonrural communities were older than those served in rural communities, after controlling for this difference functional impairment levels were similar. It appears from these analyses that youth served in rural and nonrural communities with systems of care were more similar than they were different with regard to their level of functional impairment. This lack of aggregate functional difference between the rural and nonrural sites reminds policymakers and funding agents that youth in rural areas need equity in both access and resource for mental health services. As indicated by the findings in the current investigation youth in rural areas are not immune to the types of mental health challenges often publicized by researchers examining youth in nonrural areas.


Immunoreactivity for calretininin interneurons of the hippocampal CA1 field and dentate gyrus in adult rats after administration of habanero peppers (Capsicum chinense Jacq.).
Calretinin (CR), a calcium-binding protein from EF-hand family, is localised in non-pyramidal GABA-ergic interneurons of the hippocampus. CR takes part in maintaining calcium binding homeostasis, which suggests its neuroprotective role. Hippocampal neurons contain membrane transient receptor potential vanilloid 1 (TRPV1) which binds to capsaicin (CAP) contained in habanero pepper fruits. Few in vivo studies have revealed the effect of CAP on interneurons containing CR. The aim of the present study was to investigate the CR immunoreac- tivity in interneurons of the hippocampal CA1 field and dentate gyrus (DG) in adult rats after intragastric admin- istration of the habanero pepper fruits. Wistar rats received a peanut oil - control group (C), and oil suspension of habanero pepper fruits at doses of 0.025 g dm/kg b.w. - group I and 0.08 g dm/kg b.w. - group II for 28 days. After euthanasia, the brains were collected and embedded in paraffin blocks using a routine histological tech- nique. Frontal hippocampal sections were immunohistochemically stained for CR by using a peroxidase-antiper- oxidase method. CR immunoreactive (CR-IR) interneurons were morphologically and morphometrically ana- lyzed under a light microscope. The results showed similar shapes and distribution of cells in both areas of the brain in group C and I of animals. However, CR-IR interneurons in the hippocampal CA1 field and in DG were occasionally observed in the group II of rats. The results of morphometric studies did not reveal statistically significant differences in the surface area and shape index of cells between examined brain regions from groups I and II compared to group C. Only in group II of rats, an increase in the digital immunostaining intensity of CR-IR interneurons was found in DG. Low number of CR-IR interneurons in the hippocampal CA1 field and in the DG, under the influence of a large dose of habanero pepper fruits containing CAP, may be caused by the activation of TRPV1 receptors and the increase in Ca2+ ions in these cells. This phenomenon may ultimately lead to neuronal death and may disturb neuronal conduction.


Outcome following staphylococcal peritonitis.
Staphylococcus spp predominate as the causative pathogen of continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis.This study evaluated the difference in morbidity and mortality between peritonitis caused by S. aureus and coagulase-negative staphylococci (CoNS). Prospective observational study. A single regional dialysis unit in a teaching hospital. Thirty-seven patients had S. aureus peritonitis and 65 patients had CoNS peritonitis between July 1990 and November 1995. Using the first recorded episode of peritonitis, survival analysis was performed for time to (1) death, (2) removal of peritoneal dialysis catheter, and (3) change to hemodialysis. Abdominal complications were recorded for the first and subsequent episodes. No difference in time to death was demonstrated for the two groups (p = 0.79), although two deaths that occurred during therapy for peritonitis were attributable to S. aureus infection. In addition, 5 patients developed serious abdominal complications related to an episode of S. aureus peritonitis. Patients with S. aureus peritonitis had a shorter time to both peritoneal dialysis catheter removal (p = 0.004) and change to hemodialysis (p = 0.014). The change in mode of dialysis was independent of catheter loss. This study highlights the serious nature of S. aureus peritonitis and confirms the need for effective preventive measures against infection by this pathogen.


Use and perceived benefits of complementary therapies by cancer patients receiving conventional treatment in Italy.
In Italy, data regarding the use of complementary therapies (CTs) among patients with cancer are sparse and discordant. The present study aimed to investigate the demographic and psychological characteristics of Italian cancer patients who use CTs and the perceived benefit of users. Eight hundred three patients from six Italian oncology departments were interviewed about CT use and completed two questionnaires to explore psychological distress and the resilience trait called sense of coherence (SOC). Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. At the time of measurement, 37.9% of patients were using one or more types of CTs. The most commonly used CTs were diets and dietary supplements (27.5%), herbs (10.8%), homeopathy (6.4%), and mind-body therapies (5.5%). The Italian context is characterized by a high percentage of patients who informed their physicians about CT use (66.3%) and who experienced benefits (89.6%); 75.2% of the patients had used CTs in the past. Multivariate analysis revealed that young, female patients, who previously used complementary and alternative medicine in the past, appear more likely to use at least one type of CT in the present. Predictors of the use of CTs varied according to the type of CT. Among psychological factors, SOC was positively associated with both past and present CT use. Overall prevalence of CTs among Italian cancer patients is high and is in accordance with the European average. In addition to clinical and sociodemographic factors, the resilience trait SOC also was associated with CT use.


Translational research for bone marrow failure patients.
Bone marrow failure syndromes encompass a range of inherited and acquired hematological diseases that result in insufficient blood cell production, which leads to severe complications including anemia, weakening of the immune system, impaired coagulation, and increased risk of cancer. Within inherited bone marrow failure syndromes, a number of genetically distinct diseases have been described including Shwachman-Diamond syndrome and Fanconi anemia. Given the genetic complexity and poor prognosis of these inherited bone marrow failure syndromes, there is increasing interest in both characterizing the genetic landscapes of these diseases and developing novel gene therapies to effectively monitor and cure patients. These topics were the focus of the winter 2021 International Society for Experimental Hematology New Investigator Webinar, which featured presentations by Dr. Akiko Shimamura and Dr. Paula Río. Here, we review the topics covered within this webinar.


Utility of near-infrared light devices for pediatric peripheral intravenous cannulation: a systematic review and meta-analysis.
We investigated the utility of near-infrared (NIR) light devices for peripheral intravenous cannulation (PIVC) in pediatric patients. We searched three databases, MEDLINE, EMBASE, and the Cochrane CENTRAL. Randomized controlled trials that compared PIVC using NIR light devices and the "traditional" method (with no assistive device) were included. The primary outcome was a failure rate at the first attempt, and the effect size was measured by the risk ratio for failure. Subgroup analysis was performed according to control group risk for failure at first attempt as an indicator of difficult procedure (low vs. high). Eleven studies were included in the meta-analysis. There was no significant difference in the primary outcome between the two methods (risk ratio 1.03, confidence interval 0.89-1.20, I 2 = 48 %). In a subgroup analysis, the subgroup difference between subsets of low and high control group risk was significant (I 2 = 83 %). In the subset of the high control group risk, using NIR light devices showed a lower risk for failure than the traditional method (risk ratio 0.81, confidence interval 0.64-1.01, I 2 = 0 %). Using NIR light devices did not have an impact on overall failure rate at the first attempt at PIVC in pediatric patients. What is Known: • Near-infrared light devices have been used to help vascular access especially for the pediatric patients. But, their utilities reported in previous studies were conflicting. What is New: • From this study, we could not find out overall benefit of using near-infrared light devices for pediatric peripheral intravenous cannulation. But, this device might be useful for the patients in a difficult condition of successful cannulation.


Prognostic validation of a non-laboratory and a laboratory based cardiovascular disease risk score in multiple regions of the world.
To evaluate the performance of the non-laboratory INTERHEART risk score (NL-IHRS) to predict incident cardiovascular disease (CVD) across seven major geographic regions of the world. The secondary objective was to evaluate the performance of the fasting cholesterol-based IHRS (FC-IHRS). Using measures of discrimination and calibration, we tested the performance of the NL-IHRS (n=100 475) and FC-IHRS (n=107 863) for predicting incident CVD in a community-based, prospective study across seven geographic regions: South Asia, China, Southeast Asia, Middle East, Europe/North America, South America and Africa. CVD was defined as the composite of cardiovascular death, myocardial infarction, stroke, heart failure or coronary revascularisation. Mean age of the study population was 50.53 (SD 9.79) years and mean follow-up was 4.89 (SD 2.24) years. The NL-IHRS had moderate to good discrimination for incident CVD across geographic regions (concordance statistic (C-statistic) ranging from 0.64 to 0.74), although recalibration was necessary in all regions, which improved its performance in the overall cohort (increase in C-statistic from 0.69 to 0.72, p<0.001). Regional recalibration was also necessary for the FC-IHRS, which also improved its overall discrimination (increase in C-statistic from 0.71 to 0.74, p<0.001). In 85 078 participants with complete data for both scores, discrimination was only modestly better with the FC-IHRS compared with the NL-IHRS (0.74 vs 0.73, p<0.001). External validations of the NL-IHRS and FC-IHRS suggest that regionally recalibrated versions of both can be useful for estimating CVD risk across a diverse range of community-based populations. CVD prediction using a non-laboratory score can provide similar accuracy to laboratory-based methods.


Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts.
The present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine-derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.


Zygotic expression of Exostosin1 (Ext1) is required for BMP signaling and establishment of dorsal-ventral pattern in Xenopus.
Exostosin 1 (EXT1) is a glycosyltransferase that contributes to the biosynthesis of heparan sulfate proteoglycans (HSPG). Loss of ext1 function leads to the human genetic disorder hereditary multiple exostoses (HME) and inhibits development in mouse, zebrafish and Drosophila. In Xenopus, loss of maternal EXT1 leads to impaired wnt11 signaling, resulting in a loss of dorsal embryonic development (Tao et al., 2005), but the functions of zygotic ext1 have not been elucidated. In this study, morpholino oligonucleotides were used to generate a zygotic partial loss of function for ext1, in order to evaluate the requirements for ext1 function in gastrulation and paracrine signaling. Transcriptional profiling was carried out by microarray. Validation and subsequent analyses of gene expression were performed using Q-RT-PCR and in situ hybridization. Western blots were used to assess paracrine signaling pathway activity. Introduction of ext1 MO led to gastrulation defects, which were partially rescued by co-injection of ext1 mRNA. Microarray-based comparisons of gene expression in control vs. Ext1 MO embryos identified several developmentally significant genes that are dependent upon Ext1 function, including brachyury (Xbra). In addition, decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern.


Do internists, pediatricians, and psychiatrists feel competent in obesity care?: using a needs assessment to drive curriculum design.
Physicians must effectively evaluate and treat obesity. To design a needs-driven curriculum intended to improve patient outcomes, physicians were surveyed about their self-perceived knowledge and skills. The objective of this study was to determine the expressed needs of residents and faculty regarding obesity care training across three specialties. The study used a survey given to faculty and residents in General Internal Medicine, Pediatrics, and Psychiatry. Survey questions were generated from comprehensive nutrition curriculum and clinical recommendations, administered online, and then organized around a validated behavioral health framework-the 5As (assess, advise, agree, assist, arrange). Analyses were conducted to evaluate differences in perceived knowledge and skills between specialties and across training levels. From an overall response rate of 65% (65 residents and 250 faculty members), nearly 20% reported inadequate competency in every item with 48% of respondents reporting an inability to adequately counsel patients about common treatment options. Internists reported the lowest competency in arranging referrals and follow-up. Psychiatrists reported the lowest competency in assessment skills. This survey demonstrated a critical need for training in specific areas of obesity care. The proposed curriculum targets these areas taking into consideration observed differences across specialties.


HIF-1α stimulates aromatase expression driven by prostaglandin E2 in breast adipose stroma.
The majority of postmenopausal breast cancers are estrogen-dependent. Tumor-derived factors, such as prostaglandin E2 (PGE2), stimulate CREB1 binding to cAMP response elements (CREs) on aromatase promoter II (PII), leading to the increased expression of aromatase and biosynthesis of estrogens within human breast adipose stromal cells (ASCs). Hypoxia inducible factor-1α (HIF-1α), a key mediator of cellular adaptation to low oxygen levels, is emerging as a novel prognostic marker in breast cancer. We have identified the presence of a consensus HIF-1α binding motif overlapping with the proximal CRE of aromatase PII. However, the regulation of aromatase expression by HIF-1α in breast cancer has not been characterized. This study aimed to characterize the role of HIF-1α in the activation of aromatase PII. HIF-1α expression and localization were examined in human breast ASCs using quantitative PCR (QPCR), Western blotting, immunofluorescence and high content screening. QPCR and tritiated water-release assays were performed to assess the effect of HIF-1α on aromatase expression and activity. Reporter assays and chromatin immunoprecipitation (ChIP) were performed to assess the effect of HIF-1α on PII activity and binding. Treatments included PGE2 or DMOG ((dimethyloxalglycine), HIF-1α stabilizer). Double immunohistochemistry for HIF-1α and aromatase was performed on tissues obtained from breast cancer and cancer-free patients. Results indicate that PGE2 increases HIF-1α transcript and protein expression, nuclear localization and binding to aromatase PII in human breast ASCs. Results also demonstrate that HIF-1α significantly increases PII activity, and aromatase transcript expression and activity, in the presence of DMOG and/or PGE2, and that HIF-1α and CREB1 act co-operatively on PII. There is a significant increase in HIF-1α positive ASCs in breast cancer patients compared to cancer-free women, and a positive association between HIF-1α and aromatase expression. This study is the first to identify HIF-1α as a modulator of PII-driven aromatase expression in human breast tumor-associated stroma and provides a novel mechanism for estrogen regulation in obesity-related, post-menopausal breast cancer. Together with our on-going studies on the role of AMP-activated protein kinase (AMPK) in the regulation of breast aromatase, this work provides another link between disregulated metabolism and breast cancer.


Mortality results from a randomized prostate-cancer screening trial.
The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)


Data availability, reusability, and analytic reproducibility: evaluating the impact of a mandatory open data policy at the journal Cognition.
Access to data is a critical feature of an efficient, progressive and ultimately self-correcting scientific ecosystem. But the extent to which in-principle benefits of data sharing are realized in practice is unclear. Crucially, it is largely unknown whether published findings can be reproduced by repeating reported analyses upon shared data ('analytic reproducibility'). To investigate this, we conducted an observational evaluation of a mandatory open data policy introduced at the journal Cognition. Interrupted time-series analyses indicated a substantial post-policy increase in data available statements (104/417, 25% pre-policy to 136/174, 78% post-policy), although not all data appeared reusable (23/104, 22% pre-policy to 85/136, 62%, post-policy). For 35 of the articles determined to have reusable data, we attempted to reproduce 1324 target values. Ultimately, 64 values could not be reproduced within a 10% margin of error. For 22 articles all target values were reproduced, but 11 of these required author assistance. For 13 articles at least one value could not be reproduced despite author assistance. Importantly, there were no clear indications that original conclusions were seriously impacted. Mandatory open data policies can increase the frequency and quality of data sharing. However, suboptimal data curation, unclear analysis specification and reporting errors can impede analytic reproducibility, undermining the utility of data sharing and the credibility of scientific findings.


Dynamics of resistance development to imatinib under increasing selection pressure: a combination of mathematical models and in vitro data.
In the last decade, cancer research has been a highly active and rapidly evolving scientific area. The ultimate goal of all efforts is a better understanding of the mechanisms that discriminate malignant from normal cell biology in order to allow the design of molecular targeted treatment strategies. In individual cases of malignant model diseases addicted to a specific, ideally single oncogene, e.g. Chronic myeloid leukemia (CML), specific tyrosine kinase inhibitors (TKI) have indeed been able to convert the disease from a ultimately life-threatening into a chronic disease with individual patients staying in remission even without treatment suggestive of operational cure. These developments have been raising hopes to transfer this concept to other cancer types. Unfortunately, cancer cells tend to develop both primary and secondary resistance to targeted drugs in a substantially higher frequency often leading to a failure of treatment clinically. Therefore, a detailed understanding of how cells can bypass targeted inhibition of signaling cascades crucial for malignant growths is necessary. Here, we have performed an in vitro experiment that investigates kinetics and mechanisms underlying resistance development in former drug sensitive cancer cells over time in vitro. We show that the dynamics observed in these experiments can be described by a simple mathematical model. By comparing these experimental data with the mathematical model, important parameters such as mutation rates, cellular fitness and the impact of individual drugs on these processes can be assessed. Excitingly, the experiment and the model suggest two fundamentally different ways of resistance evolution, i.e. acquisition of mutations and phenotype switching, each subject to different parameters. Most importantly, this complementary approach allows to assess the risk of resistance development in the different phases of treatment and thus helps to identify the critical periods where resistance development is most likely to occur.


Construction and Utilization of a Neural Network Model to Predict Current Procedural Terminology Codes from Pathology Report Texts.
At our department, each specimen was assigned a tentative current procedural terminology (CPT) code at accessioning. The codes were subject to subsequent changes by pathologist assistants and pathologists. After the cases had been finalized, their CPT codes went through a final verification step by coding staff, with the aid of a keyword-based CPT code-checking web application. Greater than 97% of the initial assignments were correct. This article describes the construction of a CPT code-predicting neural network model and its incorporation into the CPT code-checking application. R programming language was used. Pathology report texts and CPT codes for the cases finalized during January 1-November 30, 2018, were retrieved from the database. The order of the specimens was randomized before the data were partitioned into training and validation set. R Keras package was used for both model training and prediction. The chosen neural network had a three-layer architecture consisting of a word-embedding layer, a bidirectional long short-term memory (LSTM) layer, and a densely connected layer. It used concatenated header-diagnosis texts as the input. The model predicted CPT codes in both the validation data set and the test data set with an accuracy of 97.5% and 97.6%, respectively. Closer examination of the test data set (cases from December 1 to 27, 2018) revealed two interesting observations. First, among the specimens that had incorrect initial CPT code assignments, the model disagreed with the initial assignments in 73.6% (117/159) and agreed in 26.4% (42/159). Second, the model identified nine additional specimens with incorrect CPT codes that had evaded all steps of checking. A neural network model using report texts to predict CPT codes can achieve high accuracy in prediction and moderate sensitivity in error detection. Neural networks may play increasing roles in CPT coding in surgical pathology.


mTOR complex 2 in adipose tissue negatively controls whole-body growth.
Mammalian target of rapamycin (mTOR), a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors, is found in 2 structurally and functionally distinct multiprotein complexes termed mTOR complex 1 (mTORC1) and mTORC2. mTORC2, which consists of rictor, mSIN1, mLST8, and mTOR, is activated by insulin/IGF1 and phosphorylates Ser-473 in the hydrophobic motif of Akt/PKB. Though the role of mTOR in single cells is relatively well characterized, the role of mTOR signaling in specific tissues and how this may contribute to overall body growth is poorly understood. To examine the role of mTORC2 in an individual tissue, we generated adipose-specific rictor knockout mice (rictor(ad-/-)). Rictor(ad-/-) mice are increased in body size due to an increase in size of nonadipose organs, including heart, kidney, spleen, and bone. Furthermore, rictor(ad-/-) mice have a disproportionately enlarged pancreas and are hyperinsulinemic, but glucose tolerant, and display elevated levels of insulin-like growth factor 1 (IGF1) and IGF1 binding protein 3 (IGFBP3). These effects are observed in mice on either a high-fat or a normal diet, but are generally more pronounced in mice on a high-fat diet. Our findings suggest that adipose tissue, in particular mTORC2 in adipose tissue, plays an unexpectedly central role in controlling whole-body growth.


What roles do middle managers play in implementation of innovative practices?
Middle managers play key roles in hospitals as the bridge between senior leaders and frontline staff. Yet relatively little research has focused on their role in implementing new practices. The aim of this study was to expand the understanding of middle managers' influence in organizations by looking at their activities through the lens of two complementary conceptual frameworks. We analyzed qualitative data from 17 Veterans Affairs Medical Centers with high and low potential to change organizational practices. We analyzed 98 interviews with staff ranging from senior leaders to frontline staff to identify themes within an a priori framework reflecting middle manager activities. Analyses yielded 14 emergent themes that allowed us to classify specific expressions of middle manager commitment to implementation of innovative practices (e.g., facilitate improvement innovation, garner staff buy-in). In comparing middle manager behaviors in high and low change potential sites, we found that most emergent themes were present in both groups. However, the activities and interactions described differed between the groups. Middle managers can use the promising strategies identified by our analyses to guide and improve their effectiveness in implementing new practices. These strategies can also inform senior leaders striving to guide middle managers in those efforts.


Social Return on Investment (SROI) methodology to account for value for money of public health interventions: a systematic review.
Increased scarcity of public resources has led to a concomitant drive to account for value-for-money of interventions. Traditionally, cost-effectiveness, cost-utility and cost-benefit analyses have been used to assess value-for-money of public health interventions. The social return on investment (SROI) methodology has capacity to measure broader socio-economic outcomes, analysing and computing views of multiple stakeholders in a singular monetary ratio. This review provides an overview of SROI application in public health, explores lessons learnt from previous studies and makes recommendations for future SROI application in public health. A systematic review of peer-reviewed and grey literature to identify SROI studies published between January 1996 and December 2014 was conducted. All articles describing conduct of public health SROI studies and which reported a SROI ratio were included. An existing 12-point framework was used to assess study quality. Data were extracted using pre-developed codes: SROI type, type of commissioning organisation, study country, public health area in which SROI was conducted, stakeholders included in study, discount rate used, SROI ratio obtained, time horizon of analysis and reported lessons learnt. 40 SROI studies, of varying quality, including 33 from high-income countries and 7 from low middle-income countries, met the inclusion criteria. SROI application increased since its first use in 2005 until 2011, declining afterwards. SROI has been applied across different public health areas including health promotion (12 studies), mental health (11), sexual and reproductive health (6), child health (4), nutrition (3), healthcare management (2), health education and environmental health (1 each). Qualitative and quantitative methods have been used to gather information for public health SROI studies. However, there remains a lack of consensus on who to include as beneficiaries, how to account for counterfactual and appropriate study-time horizon. Reported SROI ratios vary widely (1.1:1 to 65:1). SROI can be applied across healthcare settings. Best practices such as analysis involving only beneficiaries (not all stakeholders), providing justification for discount rates used in models, using purchasing power parity equivalents for monetary valuations and incorporating objective designs such as case-control or before-and-after designs for accounting for outcomes will improve robustness of public health SROI studies.


Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma.
Purpose: Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare locally aggressive neoplasm with endothelial differentiation, which often presents with multiple lesions. These tumors have characteristic SERPINE1-FOSB fusions. We report a 17 years old patient with advanced unresectable PHE with a durable complete remission to the multi-tyrosine kinase inhibitor telatinib. The aim of this study was to generate an in vitro model for PHE, to study the functional consequences of SERPINE1-FOSB in endothelial cells, and its interaction with telatinib, to biologically substantiate the complete response to telatinib.Experimental Design: As the fusion results in overexpression of a truncated form of FOSB, we overexpressed truncated FOSB in normal endothelial cells.Results: Truncated FOSB significantly affected tumor growth in three-dimensional (3D) on matrigel with increased and sustained sprouting. Moreover, truncated FOSB acted as an active transcription factor capable to regulate its own transcription, as well as to upregulate PDGFRA and FLT1 expression (four-fold). Telatinib decreased proliferation and tumor growth in 3D and induced apoptosis. As expected, telatinib blocked VEGF signaling as phosphorylation of ERK was abolished. Interestingly, in FOSB overexpressing cells, telatinib specifically affected PDGFRA, FLT1, and FLT4 signaling and downregulated SERPINE1, thereby affecting the self-regulation of the fusion gene.Conclusions: We provide a biological substantiation of a complete clinical remission that was seen in a patient with PHE, showing that telatinib indirectly interferes with the self-regulated expression of the fusion product. Thus, telatinib or any other currently available VEGFR1-4/PDGFRA inhibitor could be a highly specific treatment option for patients with multifocal unresectable PHE. Clin Cancer Res; 24(11); 2678-87. ©2018 AACR.


A Radical Approach to Anionic Chemistry: Synthesis of Ketones, Alcohols, and Amines.
Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.


CDH11 expression is associated with survival in patients with osteosarcoma.
Previous studies have shown that cadherin-11 (CDH11) may be involved in the metastatic process of osteosarcoma. The correlation of the expression levels of CDH11 in osteosarcoma samples with the risk of disease progression and metastasis was examined. Real time qRT-PCR was used to quantify CDH11 expression in a set of newly established osteosarcoma cell lines, 11 primaries and five metastases, compared to the levels in 12 normal osteoblast cell lines established from healthy bone, and also in a set of 10 snap-frozen osteosarcoma samples. In all cases long term clinical follow-up data was available. The CDH11 expression level decreased gradually from the osteoblast to the primary cell lines (p=0.2184) and further to those established from the tumor metastases (p=0.0275). Importantly, the level of CDH11 expression correlated significantly (p=0.01) with patient survival (Kaplan-Meier survival analysis) in both sample sets (p=0.0128 for the cell lines, p=0.0492 for the biopsies). In conclusion, the results indicate that CDH11 may be useful as a prognostic marker of disease progression and survival in osteosarcoma.


Noisy silence: non-coding RNA and heterochromatin formation at repetitive elements.
A significant fraction of eukaryotic genomes comprises repetitive sequences, including rRNA genes, centromeres, telomeres, and retrotransposons. Repetitive elements are hotspots for recombination and represent a serious challenge for genome integrity. Maintaining these repeated elements in a compact heterochromatic structure suppresses recombination and unwanted mutagenic transposition, and is therefore indispensable for genomic stability. Paradoxically, repetitive elements are not transcriptionally inert, but produce RNA that has important functions in regulating and reinforcing the heterochromatic state. Here, we review the role of non-coding RNA (ncRNA) in recruiting chromatin-modifying enzymes to repetitive genomic loci to establish a repressive chromatin structure that safeguards chromosome integrity and genome stability.


Population-level effects and recovery of aquatic invertebrates after multiple applications of an insecticide.
Standard risk assessment of plant protection products (PPP) combines "worst-case" exposure scenarios with effect thresholds using assessment (safety) factors to account for uncertainties. If needed, risks can be addressed applying more realistic conditions at higher tiers, which refine exposure and/or effect assessments using additional data. However, it is not possible to investigate the wide range of potential scenarios experimentally. In contrast, ecotoxicological mechanistic effect models do allow for addressing a multitude of scenarios. Furthermore, they may aid the interpretation of experiments such as mesocosm studies, allowing extrapolation to conditions not covered in experiments. Here, we explore how to use mechanistic effect models in the aquatic risk assessment of a model insecticide (Modelmethrin), applied several times per season but rapidly dissipating between applications. The case study focuses on potential effects on aquatic arthropods, the most sensitive group for this substance. The models provide information on the impact of a number of short exposure pulses on sensitive and/or vulnerable populations and, when impacted, assess recovery. The species to model were selected based on their sensitivity in laboratory and field (mesocosm) studies. The general unified threshold model for survival (GUTS) model, which describes the toxicokinetics and toxicodynamics of chemicals in individuals, was linked to 3 individual-based models (IBM), translating individual survival of sensitive organisms into population-level effects. The impact of pulsed insecticide exposures on populations were modeled using the spatially explicit IBM metapopulation model for assessing spatial and temporal effects of pesticides (MASTEP) for Gammarus pulex, the Chaoborus IBM for populations of Chaoborus crystallinus, and the "IdamP" model for populations of Daphnia magna. The different models were able to predict the potential effects of Modelmethrin applications to key arthropod species inhabiting different aquatic ecosystems; the most sensitive species were significantly impacted unless respective mitigation measures were implemented (buffer zones resulting in reduced exposure). As expected the impact was stronger in shallow ditches as compared to deeper pond scenarios. Furthermore, as expected, recovery depended on factors such as temperature (affecting population growth rate and number of generations) and the occurence of nonimpacted aquatic ecosystems (their frequency and connectivity). These model predictions were largely in line with field observations and/or the results of a mesocosm study, providing additional evidence on the suitability and reliability of the models for risk assessment purposes. Because of their flexibility, models may predict the likelihood of unacceptable effects-based on previously defined protection goals-for a range of insecticide exposure scenarios and freshwater habitats.


Rural Surgery--A Crisis in Wisconsin.
Recruitment of general surgeons to practice in rural environments is challenging. We believe that innovative training programs focusing on the specific needs and experiences of rural surgical practice can play an important role in addressing this clinical workforce issue. For practical reasons, our program will start out small, but if 50 centers around the nation were to establish a similar rural track, we could see a substantial collective impact over time. We hope our new program will serve as a model for the development of other university-based residency training programs with similar opportunities. We are grateful to have received state funding to support the development and early implementation of this program (see Table). We commend the state for understanding the importance of primary care surgery, and we look forward to measuring and reporting the impact of our rural training program on rural surgical care in Wisconsin.


NPA: an R package for computing network perturbation amplitudes using gene expression data and two-layer networks.
High-throughput gene expression technologies provide complex datasets reflecting mechanisms perturbed in an experiment, typically in a treatment versus control design. Analysis of these information-rich data can be guided based on a priori knowledge, such as networks of related proteins or genes. Assessing the response of a specific mechanism and investigating its biological basis is extremely important in systems toxicology; as compounds or treatment need to be assessed with respect to a predefined set of key mechanisms that could lead to toxicity. Two-layer networks are suitable for this task, and a robust computational methodology specifically addressing those needs was previously published. The NPA package ( https://github.com/philipmorrisintl/NPA ) implements the algorithm, and a data package of eight two-layer networks representing key mechanisms, such as xenobiotic metabolism, apoptosis, or epithelial immune innate activation, is provided. Gene expression data from an animal study are analyzed using the package and its network models. The functionalities are implemented using R6 classes, making the use of the package seamless and intuitive. The various network responses are analyzed using the leading node analysis, and an overall perturbation, called the Biological Impact Factor, is computed. The NPA package implements the published network perturbation amplitude methodology and provides a set of two-layer networks encoded in the Biological Expression Language.


Risk factors for adverse perinatal outcomes in imprisoned pregnant women: a systematic review.
Imprisoned pregnant women constitute an important obstetric group about whom relatively little is known. This systematic review was conducted to identify the risk factors associated with adverse pregnancy outcome present in this group of women. The review was conducted according to a prespecified protocol. Studies of any design were included if they described information on any of the pre-specified risk factors. We calculated the results as summary percentages or odds ratios where data was available on both cases and population controls. The search strategy identified 27 relevant papers of which 13 met the inclusion criteria, involving 1504 imprisoned pregnant women and 4571 population control women. Imprisoned women are more likely to be single, from an ethnic minority, and not to have completed high school. They are more likely to have a medical problem which could affect the pregnancy outcome and yet less likely to receive adequate antenatal care. They are also more likely to smoke, drink alcohol to excess and take illegal drugs. Imprisoned women are clearly a high risk obstetric group. These findings have important implications for the provision of care to this important group of women.


Hog1 mitogen-activated protein kinase (MAPK) interrupts signal transduction between the Kss1 MAPK and the Tec1 transcription factor to maintain pathway specificity.
In Saccharomyces cerevisiae, the mating, filamentous growth (FG), and high-osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) signaling pathways share components and yet mediate distinct responses to different extracellular signals. Cross talk is suppressed between the mating and FG pathways because mating signaling induces the destruction of the FG transcription factor Tec1. We show here that HOG pathway activation results in phosphorylation of the FG MAPK, Kss1, and the MAPKK, Ste7. However, FG transcription is not activated because HOG signaling prevents the activation of Tec1. In contrast to the mating pathway, we find that the mechanism involves the inhibition of DNA binding by Tec1 rather than its destruction. We also find that nuclear accumulation of Tec1 is not affected by HOG signaling. Inhibition by Hog1 is apparently indirect since it does not require any of the consensus S/TP MAPK phosphorylation sites on Tec1, its DNA-binding partner Ste12, or the associated regulators Dig1 or Dig2. It also does not require the consensus MAPK sites of the Ste11 activator Ste50, in contrast to a recent proposal for a role for negative feedback in specificity. Our results demonstrate that HOG signaling interrupts the FG pathway signal transduction between the phosphorylation of Kss1 and the activation of DNA binding by Tec1.


Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM).
Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease.


Humidity effect on ion behaviors of moisture-driven CO2 sorbents.
Ion hydration is a fundamental process in many natural phenomena. This paper presents a quantitative analysis, based on atomistic modeling, of the behavior of ions and the impact of hydration in a novel CO2 sorbent. We explore moisture-driven CO2 sorbents focusing on diffusion of ions and the structure of ion hydration complexes forming inside water-laden resin structures. We show that the stability of the carbonate ion is reduced as the water content of the resin is lowered. As the hydration cloud of the carbonate ion shrinks, it becomes energetically favorable to split a remaining water molecule and form a bicarbonate ion plus a hydroxide ion. These two ions bind less water than a single, doubly charged carbonate ion. As a result, under relatively dry conditions, more OH- ions are available to capture CO2 than in the presence of high humidity. Local concentrations of dissolved inorganic carbon and water determine chemical equilibria. Reaction kinetics is then driven to a large extent by diffusion rates that allow water and anions to move through the resin structure. Understanding the basic mechanics of chemical equilibria and transport may help us to rationally design next-generation efficient moisture-driven CO2 sorbents.


Nocturnal Video Assessment of Infant Sleep Environments.
Reports describing factors associated with sleep-related infant death rely on caregiver report or postmortem findings. We sought to determine the frequency of environmental risk factors by using nocturnal sleep videos of infants. Healthy, term newborns were recruited for a parent study examining the role of parenting in the development of nighttime infant sleep patterns. For 1 night at ages 1, 3, and 6 months, video recordings were conducted within family homes. Videos were coded for sudden infant death syndrome risk factors in post hoc secondary analyses after the parent study was completed. Among 160 one-month-olds, initially 21% were placed to sleep on nonrecommended sleep surfaces and 14% were placed nonsupine; 91% had loose/nonapproved items on their sleep surface, including bedding, bumper pads, pillows, stuffed animals, and sleep positioners. Among 151 three-month-olds, 10% were initially placed on a nonrecommended sleep surface, 18% were placed nonsupine, and 87% had potentially hazardous items on their sleep surface. By 6 months, 12% of the 147 infants initially slept on a nonrecommended surface, 33% were placed to bed nonsupine, and 93% had loose/nonrecommended items on their surface. At 1, 3, and 6 months, 28%, 18%, and 12% changed sleep locations overnight, respectively, with an increased likelihood of bed-sharing and nonsupine position at the second location at each time point. Most parents, even when aware of being recorded, placed their infants in sleep environments with established risk factors. If infants were moved overnight, the second sleep environment generally had more hazards.


[Multimodal iatrogenic apathy].
The present paper reports on five patients who developed apathy as a peculiar side effect of antidepressants. Their behavioral and psychopathological changes were primarily due to the near-absence of emotional experience, a key characteristic that distinguishes apathy from avolition and abulia. The emergence of apathy in the course of an antidepressant treatment should raise the suspicion of an adverse effect of the drug and lead to its prompt withdrawal. A sample of the relevant clinical evidence favoring the distinction of apathy confined to a single sensory domain ("unimodal apathy") from apathy confined to more than one sensory realm ("multimodal apathy") is reviewed. From a pathophysiological standpoint, it would appear that neural nets centered in the amygdala-temporo polar cortex are critical for the integration of sensory perceptions and mental imagery with appropriate emotional tone and quality as well as with their accompanying somatic markers, as they receive afferents from the major projection systems of the prosencephalon and lie in nodes strategic to modify the ongoing activity of multiple parallel brain systems. The fact that one common symptom can be produced by such a heterogeneous family of substances points to a shared neurochemical mechanism of action. At present, discrete cerebral serotoninergic circuits would appear to be suitable candidates for such a role. Cases as these may be critical for the understanding of the cerebral organization of emotions in man, lending support to the notion that distinct neurochemical systems mediate discrete psychopathological symptoms.


Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.
Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10 ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCORΔE9-10). While BcorΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9-10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1+/- ;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly up-regulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1+/- ;BcorΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.


Faecal tritium excretion after intravenous administration of 3H-25-hydroxyvitamin D3 in control subjects and in patients with malabsorption.
Faecal tritium excretion after intravenous 3H-25-hydroxyvitamin D3 administration was measured in three control subjects and in six patients with small intestine resection or bypass. The mean daily faecal tritium excretion over four to six days ranged from 0.8-1.6% of the injected dose in the controls (mean 1.2) and 0.9-6.8% in the patients (mean 3.7). There was a significant positive correlation between stool volume and the mean daily faecal tritium excretion. No correlation was found between the faecal tritium excretion and the plasma 25-hydroxyvitamin D concentration. Between 2.5 and 19.0% of faecal radioactivity eluted as 3H-25-hydroxyvitamin D3 on silicic acid chromatography. We conclude that faecal loss of endogenous 25-hydroxyvitamin D may be increased after small intestinal resection or bypass. Although the amount lost by this route is relatively small, it may contribute to the development of vitamin D deficiency in patients with malabsorption when endogenous vitamin D3 synthesis is also reduced.


Disparities in Access to Revascularization: Evidence from New York.
Purpose: To quantify and compare citywide disparities in the performance of coronary revascularization procedures in New York residents diagnosed with ischemic heart disease (IHD) by the characteristics of the patients and their neighborhood of residence in 2000-2002 and 2011-2013. Methods: We identify the number of hospitalizations for patients with diagnoses of IHD and/or congestive heart failure (CHF) and the number of revascularization procedures performed on the population 45 years and older, relying on hospital administrative data for New York City, by area of residence, from the Statewide Planning and Research Cooperative System (SPARCS). We conduct multiple logistic regressions to analyze the factors associated with revascularization for hospitalized patients admitted with IHD and CHF over the two time periods. Results: Despite any decline in population health status, both the age-adjusted rates of inpatient hospital discharges for acute myocardial infarction, for IHD and for CHF, decreased as did the rates of revascularization procedures. Racial and ethnic disparities were much smaller in the later period than those documented earlier. However, there were persistent gender, insurance status, and neighborhood-level disparities in the treatment of heart disease. Conclusions: With the declines in rates of heart disease, our findings point to the need for more clinical and population-based research to improve the understanding of why race/ethnicity, gender, insurance status, and neighborhood-level disparities persist in the treatment of heart disease.


Chronic hepatitis C virus (HCV) disease burden and cost in the United States.
Hepatitis C virus (HCV) infection is a leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. A better understanding of HCV disease progression and the associated cost can help the medical community manage HCV and develop treatment strategies in light of the emergence of several potent anti-HCV therapies. A system dynamic model with 36 cohorts was used to provide maximum flexibility and improved forecasting. New infections incidence of 16,020 (95% confidence interval, 13,510-19,510) was estimated in 2010. HCV viremic prevalence peaked in 1994 at 3.3 (2.8-4.0) million, but it is expected to decline by two-thirds by 2030. The prevalence of more advanced liver disease, however, is expected to increase, as well as the total cost associated with chronic HCV infection. Today, the total cost is estimated at $6.5 ($4.3-$8.4) billion and it will peak in 2024 at $9.1 ($6.4-$13.3) billion. The lifetime cost of an individual infected with HCV in 2011 was estimated at $64,490. However, this cost is significantly higher among individuals with a longer life expectancy. This analysis demonstrates that US HCV prevalence is in decline due to a lower incidence of infections. However, the prevalence of advanced liver disease will continue to increase as well as the corresponding healthcare costs. Lifetime healthcare costs for an HCV-infected person are significantly higher than for noninfected persons. In addition, it is possible to substantially reduce HCV infection through active management. (HEPATOLOGY 2013;57:2164-2170).


Evaluation of an interactive educational tool for primary care researchers.
This paper describes an evaluation of a computer-assisted learning (CAL) resource for primary care researchers. A two-phase approach was adopted involving a questionnaire survey and follow-up telephone interviews with a purposive sample of respondents. Results indicate wide support for this approach to self-directed learning, particularly for those with less experience. Respondents emphasized the flexibility and accessibility of the resource, with Internet links encouraging users to branch out. Potential barriers included securing protected learning time and lack of interaction with peers.


[Aortocoronary bypass surgery at Tygerberg Hospital, 1978 - 1980].
Between January 1978 and December 1980. 118 patients underwent saphenous vein bypass surgery for obstructive coronary artery disease at Tygerberg Hospital. Sixteen patients in addition to bypass surgery underwent mitral and/or aortic valve replacement or resection of a ventricular aneurysm. The operative and hospital mortality was 3,0% (4/134) for all patients and 3,3% (4/118) for patients who had aortocoronary bypass surgery as the sole procedure. Follow-up of the surviving patients for a mean period of 16,4 months revealed a low incidence of late myocardial infarction of 3.6% (4/112) resulting in the death of only 1 patient; 89.1% of patients were free of angina pectoris and the majority of these resumed their normal work or enjoyed their retirement.


Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML).
Mutations of the nucleophosmin (NPM1) gene have recently been described in patients with acute myeloid leukemia (AML). To clarify the prevalence as well as the clinical impact of this mutation, we investigated 1485 patients with AML for NPM1 exon 12 mutations using fragment analysis. A 4 bp insert was detected in 408 of 1485 patients (27.5%). Sequence analysis revealed known mutations (type A, B, and D) as well as 13 novel alterations in 229 analyzed cases. NPM1 mutations were most prevalent in patients with normal karyotype (NK) (324 of 709; 45.7%) compared with 58 of 686 with karyotype abnormalities (8.5%; P < .001) and were significantly associated with several clinical parameters (high bone marrow [BM] blasts, high white blood cell [WBC] and platelet counts, female sex). NPM1 alterations were associated with FLT3-ITD mutations, even if restricted to patients with NK (NPM1-mut/FLT3-ITD: 43.8%; versus NPM1-wt/FLT3-ITD: 19.9%; P < .001). The analysis of the clinical impact in 4 groups (NPM1 and FLT3-ITD single mutants, double mutants, and wild-type [wt] for both) revealed that patients having only an NPM1 mutation had a significantly better overall and disease-free survival and a lower cumulative incidence of relapse. In conclusion, NPM1 mutations represent a common genetic abnormality in adult AML. If not associated with FLT3-ITD mutations, mutant NPM1 appears to identify patients with improved response toward treatment.


Prevalence of factor V G1691A (Leiden) and prothrombin G20210A polymorphisms among apparently healthy Jordanians.
Factor V Leiden and prothrombin G20210A are related genetic risk factors for venous thromboembolism (VTE). Analysis for both mutations is increasingly being performed on patients exhibiting hypercoagulability. The objective of this study was to determine the prevalence of factor V Leiden (FVL), prothrombin-G20210A (PT-G20210A) polymorphisms and their coexistence among apparently healthy Jordanians. One thousand apparently healthy individuals from representative regions of Jordan with no previous history of VTE participated in this study. The mean age of participants was 28.5+/-6.4 years (age range 18-45 years). Two hundred and eighteen subjects were APC resistant with an APC-R mean of 85.52+/-15.35 seconds; the non-resistant subjects had an APC-R mean of 159.90+/-26.96 seconds. A multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the simultaneous detection of FVL and prothrombin G20210A was used to analyze the 218 DNA samples that were APC-R resistant. Both mutations generate HindIII RFLPs and the prothrombin amplicon contains an invariant HindIII recognition sites. The multiplex PCR-RFLP of Factor V for those 218-samples was: 41 wild-type, 169 heterozygous mutant, and eight homozygous mutant individuals. For prothrombin G20210A, the multiplex PCR-RFLP identified 215 wild-type and three heterozygous mutant individuals. Factor V positive individuals (n=50) had a mean F-V activity of 78.04%+/-25.81. F-V activity among wild type (n=41), F-V Leiden heterozygous (n=169) and F-V Leiden homozygous (n=8) were 92.93%+/-16.17, 87.02%+/-15.21 and 96.14%+/-12.32, respectively. Factor II positive subjects (n=47) had a mean factor II activity of 127.96%+/-21.37. F-II activity among carriers (heterozygous, n=3) and non-carriers (normal, n=215) of PT-G20210A mutation were 107.67%+/-9.29 and 105.00%+/-17.79, respectively. The prevalence of FVL was 21.8% and there is a little likelihood of the co-inheritance of the FVL and PT-G20210A among healthy young adults, since only few cases were found to be carriers for the two alleles.


Early versus traditional postoperative feeding in patients undergoing resectional gastrointestinal surgery: a meta-analysis.
A meta-analysis evaluating surgical outcomes following nutritional provision provided proximal to the anastomosis within 24 hours of gastrointestinal surgery compared with traditional postoperative management was conducted. Databases were searched to identify randomized controlled trials comparing the outcomes of early and traditional postoperative feeding. Trials involving gastrointestinal tract resection followed by patients receiving nutritionally significant oral or enteral intake within 24 hours after surgery were included for analysis. Fifteen studies involving a total of 1240 patients were analyzed. A statistically significant reduction (45%) in relative odds of total postoperative complications was seen in patients receiving early postoperative feeding (odds ratio [OR] 0.55; confidence interval [CI], 0.35 -0.87, P = .01). No effect of early feeding was seen with relation to anastomotic dehiscence (OR 0.75; CI, 0.39-1.4, P = .39), mortality (OR 0.71; CI, 0.32-1.56, P = .39), days to passage of flatus (weighted mean difference [WMD] -0.42; CI, -1.12 to 0.28, P = .23), first bowel motion (WMD -0.28; CI, -1.20 to 0.64, P = .55), or reduced length of stay (WMD -1.28; CI, -2.94 to 0.38, P = .13); however, the direction of clinical outcomes favored early feeding. Nasogastric tube reinsertion was less common in traditional feeding interventions (OR 1.48; CI, 0.93-2.35, P = .10). Early postoperative nutrition is associated with significant reductions in total complications compared with traditional postoperative feeding practices and does not negatively affect outcomes such as mortality, anastomotic dehiscence, resumption of bowel function, or hospital length of stay.


Can a collapse of global civilization be avoided?
Environmental problems have contributed to numerous collapses of civilizations in the past. Now, for the first time, a global collapse appears likely. Overpopulation, overconsumption by the rich and poor choices of technologies are major drivers; dramatic cultural change provides the main hope of averting calamity.


Siglec-8 antibody reduces eosinophils and mast cells in a transgenic mouse model of eosinophilic gastroenteritis.
Aberrant accumulation and activation of eosinophils and potentially mast cells (MCs) contribute to the pathogenesis of eosinophilic gastrointestinal diseases (EGIDs), including eosinophilic esophagitis (EoE), gastritis (EG), and gastroenteritis (EGE). Current treatment options, such as diet restriction and corticosteroids, have limited efficacy and are often inappropriate for chronic use. One promising new approach is to deplete eosinophils and inhibit MCs with a monoclonal antibody (mAb) against sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8), an inhibitory receptor selectively expressed on MCs and eosinophils. Here, we characterize MCs and eosinophils from human EG and EoE biopsies using flow cytometry and evaluate the effects of an anti-Siglec-8 mAb using a potentially novel Siglec-8-transgenic mouse model in which EG/EGE was induced by ovalbumin sensitization and intragastric challenge. MCs and eosinophils were significantly increased and activated in human EG and EoE biopsies compared with healthy controls. Similar observations were made in EG/EGE mice. In Siglec-8-transgenic mice, anti-Siglec-8 mAb administration significantly reduced eosinophils and MCs in the stomach, small intestine, and mesenteric lymph nodes and decreased levels of inflammatory mediators. In summary, these findings suggest a role for both MCs and eosinophils in EGID pathogenesis and support the evaluation of anti-Siglec-8 as a therapeutic approach that targets both eosinophils and MCs.


The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations.
Environmental and genetic correlates of inflammatory marker variability are incompletely understood. In the family-based Framingham Heart Study, we investigated heritability and candidate gene associations of systemic inflammatory biomarkers. In offspring participants (n=3710), we examined 11 inflammatory biomarkers (CD40 ligand, C-reactive protein, intercellular adhesion molecule-1, interleukin-6, urinary isoprostanes, monocyte chemoattractant protein-1, myeloperoxidase, P-selectin, tumor necrosis factor-alpha, tumor necrosis factor receptor II, fibrinogen). Heritability and bivariate genetic and environmental correlations were assessed by Sequential Oligogenic Linkage Analysis routines in 1012 family members. We examined 1943 tagging single-nucleotide polymorphisms in 233 inflammatory pathway genes with >or=5 minor allele carriers using a general genetic linear model. Clinical correlates explained 2.4% (CD40 ligand) to 28.5% (C-reactive protein) of the variability in inflammatory biomarkers. Estimated heritability ranged from 10.9% (isoprostanes) to 44.8% (P-selectin). Most correlations between biomarkers were weak although statistically significant. A total of 45 single-nucleotide polymorphism-biomarker associations met the q-value threshold of 0.25. Novel top single-nucleotide polymorphisms were observed in ICAM1 gene in relation to intercellular adhesion molecule-1 concentrations (rs1799969, P=1.32 x 10(-8)) and MPO in relation to myeloperoxidase (rs28730837, P=1.9 x 10(-5)). Lowest P values for trans-acting single-nucleotide polymorphisms were observed for APCS with monocyte chemoattractant protein-1 concentrations (rs1374486, P=1.01 x 10(-7)) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, P=3.36 x 10(-5)). Novel potential candidates (APCS, MPO) need to be replicated. Our community-based data support the relevance of clinical and genetic factors for explaining variation in inflammatory biomarker traits.


The neglected role of distress in pain management: qualitative research on a gastrointestinal ward.
Background and aims Pain management for hospital inpatients remains suboptimal. Previously identified barriers to optimal pain management include staff communication difficulties, confusion around pain management roles and a lack of suitable resources for clinical staff. The emotional, relational and contextual complexities of gastrointestinal (GI) pain create particular challenges for frontline clinical staff attempting to implement a biopsychosocial approach to its management. The current study took place over 2 years, comprised an ethnographic and a feedback phase, and aimed to examine pain management processes with clinical staff in order to generate hypotheses and initiatives for improvement. This paper focuses on two overarching themes identified in the ethnographic phase of the study, centred on the neglected role of both staff and patient distress in GI pain management. Methods Grounded theory and thematic analysis methods were used as part of action research, which involves collaborative working with clinical staff. The study took place on a 60 bed GI ward in a university hospital in London. Participants were clinical staff who were either ward-based or involved in the care of particular patients. This latter group included doctors, nurses, psychologists and physiotherapists from the Acute and Complex Pain Teams. Qualitative data on pain management processes was gathered from staff interviews, consultation groups, and observations of patient-staff interactions. Recruitment was purposive and collaborative in that early participants suggested targets and staff groups for subsequent enquiry. Following the identification of initial ethnographic themes, further analysis and the use of existing literature led to the identification of two overarching pain management processes. As such the results are divided into three sections: (i) illustration of initial ethnographic themes, (ii) summary of relevant theory used, (iii) exploration of hypothesised overarching processes. Results Initially, two consultation groups, five nursing staff and five junior doctors, provided key issues that were included in subsequent interviews (n=18) and observations (n=5). Initial ethnographic themes were divided into challenges and resources, reflecting the emergent structure of interviews and observations. Drawing on attachment, psychodynamic and evolutionary theories, themes were then regrouped around two overarching processes, centred on the neglected role of distress in pain management. The first process elucidates the lack of recognition during pain assessment of the emotional impact of patient distress on staff decision-making and pain management practice. The second process demonstrates that, as a consequence of resultant staff distress, communication between staff groups was fraught and resources, such as expert team referral and pharmacotherapy, appeared to function, at times, to protect staff rather than to help patients. Interpersonal skills used by staff to relieve patient distress were largely outside systems for pain care. Conclusions Findings suggest that identified "barriers" to optimal pain management likely serve an important defensive function for staff and organisations. Implications Unless the impact of patient distress on staff is recognised and addressed within the system, these barriers will persist.


Obstructive sleep apnea as a risk factor for silent cerebral infarction.
Previous studies have suggested that obstructive sleep apnea (OSA) may be a risk factor for stroke. In this study, we assessed that OSA is an independent risk factor of silent cerebral infarction (SCI) in the general population, and in a non-obese population. This study recruited a total of 746 participants (252 men and 494 women) aged 50-79 years as part of the Korean Genome and Epidemiology Study (KoGES); they underwent polysomnography, brain magnetic resonance imaging and health screening examinations. SCI was assessed by subtypes and brain regions, and lacunar infarction represented lesions <15 mm in size in the penetrating arteries. Moderate-severe OSA was determined by apnea-hypopnea index ≥15. The results indicated that 12.06% had moderate-severe OSA, 7.64% of participants had SCI and 4.96% had lacunar infarction. Moderate-severe OSA was associated positively with SCI [odds ratio (OR): 2.44, 95% confidence interval (CI): 1.03-5.80] and lacunar infarction (OR: 3.48, 95% CI: 1.31-9.23) in the age ≥65-year group compared with those with non-OSA. Additionally, in the basal ganglia, OSA was associated with an increase in the odds for SCI and lacunar infarction in all age groups, and especially in the ≥65-year age group. In the non-obese participants, OSA was also associated positively with SCI in the ≥65-year age group, lacunar infarction in all age groups, and especially in the ≥65-year age group. There was also a positive association with the basal ganglia. Moderate-severe OSA was associated positively with SCI and lacunar infarction in elderly participants. Treatment of OSA may reduce new first-time cerebrovascular events and recurrences.


Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns.
Nonsense-mediated mRNA decay (NMD) affects the outcome of alternative splicing by degrading mRNA isoforms with premature termination codons. Splicing regulators constitute important NMD targets; however, the extent to which loss of NMD causes extensive deregulation of alternative splicing has not previously been assayed in a global, unbiased manner. Here, we combine mouse genetics and RNA-seq to provide the first in vivo analysis of the global impact of NMD on splicing patterns in two primary mouse tissues ablated for the NMD factor UPF2. We developed a bioinformatic pipeline that maps RNA-seq data to a combinatorial exon database, predicts NMD-susceptibility for mRNA isoforms and calculates the distribution of major splice isoform classes. We present a catalog of NMD-regulated alternative splicing events, showing that isoforms of 30% of all expressed genes are upregulated in NMD-deficient cells and that NMD targets all major splicing classes. Importantly, NMD-dependent effects are not restricted to premature termination codon+ isoforms but also involve an abundance of splicing events that do not generate premature termination codons. Supporting their functional importance, the latter events are associated with high intronic conservation. Our data demonstrate that NMD regulates alternative splicing outcomes through an intricate web of splicing regulators and that its loss leads to the deregulation of a panoply of splicing events, providing novel insights into its role in core- and tissue-specific regulation of gene expression. Thus, our study extends the importance of NMD from an mRNA quality pathway to a regulator of several layers of gene expression.


Development of pemphigus vulgaris-like lesions in severe combined immunodeficiency disease mice reconstituted with lymphocytes from patients.
Pemphigus vulgaris is an autoimmune blistering disease that is induced by binding of antibodies to a 130/85-kD protein complex on epidermal keratinocytes. An in vivo experimental model of this disease was developed by reconstituting severe combined immunodeficiency (SCID) mice with 1-10 x 10(7) PBL from patients with naturally occurring pemphigus vulgaris. Of 49 reconstituted mice, 34 (69%) produced human IgG levels of > 0.1 mg/ml. Circulating anti-pemphigus antibodies were found in 20 of the 34 successfully reconstituted mice; 44% of these animals had deposits of human IgG in their own skin after it was traumatized by either heat or cold. Spontaneous pemphigus vulgaris-like blisters associated with human IgG deposits were rarely found in mouse skin. By contrast, allogeneic human skin grafted to 10 to 12 mice before reconstitution with patients' PBL developed pemphigus vulgaris-like lesions containing human IgG deposits. These results demonstrate that SCID mice can serve as a model of an antibody-mediated human autoimmune skin disease.


Dual role of BSA for synthesis of MnO2 nanoparticles and their mediated fluorescent turn-on probe for glutathione determination and cancer cell recognition.
A MnO2 nanoparticle (MnO2 NP)-mediated fluorescent turn-on probe for sensitively and selectively detecting glutathione (GSH) and recognizing cancer cells was established in this work. MnO2 NPs were synthesized simply and quickly through an in situ redox reaction by mixing bovine serum albumin (BSA) and KMnO4, in which BSA served the dual roles of template and reductant. It was found that the MnO2 NPs served as an effective energy acceptor and quenched the fluorescence intensity of carbon dots (CDs), owing to the fluorescence resonance energy transfer (FRET) process. Further, the addition of GSH triggered the decomposition of MnO2, breaking the FRET between MnO2 NPs and CDs and thus restoring the fluorescence intensity of CDs. Based on this mechanism, quantitative determination of GSH was performed. Under optimal conditions, a satisfactory linear range of 0.05-90 μM and limit of detection of 39 nM were obtained, and GSH content in human serum samples was detected. Moreover, taking advantage of the higher levels of GSH in cancer cells than in normal cells, the MnO2 NP-CD probe was applied to distinguish SMMC-7721 cancer cells from L02 normal cells. The FRET was interrupted by GSH in cancer cells, and strong fluorescence was observed. This work provides a facile approach for synthesizing MnO2 NPs, and this rapid, low-cost method with no need for reductants makes synthesis green and convenient. The MnO2 NP-mediated fluorescent turn-on response to GSH could improve the MnO2 nanomaterial-based biochemical analysis applications.


Corticosteroids as a therapy for bacterial keratitis: an evidence-based review of 'who, when and why'.
Corticosteroids have been proposed as an adjunct to antibiotics for the treatment of bacterial keratitis, with significant controversy regarding the appropriate use of this therapy. Recent prospective randomised controlled trials have provided additional evidence to guide clinical decision-making. A review of the epidemiology and mechanisms of pathogenesis, preliminary animal studies, retrospective human studies and prospective randomised clinical trials that address the potential risks and benefits of corticosteroids in patients with bacterial keratitis was performed. Four prospective randomised controlled trials were identified. Three small studies found no benefit of topical corticosteroids, but were underpowered to evaluate adverse events. The Steroids for Corneal Ulcers Trial (SCUT) study and subgroup analyses provide evidence for a relative gain of one line of best spectacle-corrected visual acuity in patients with non-Nocardia bacterial keratitis, especially when corticosteroids were initiated within 3 days of presentation; no increase in adverse events was noted. No evidence was found to support the concern for corneal thinning attributable to corticosteroids in the absence of an inadequately treated infectious process. In patients with culture-proven non-Nocardia bacterial keratitis, corticosteroids provide one line of vision improvement over antimicrobials alone, with no increase in adverse events. This benefit should not be extrapolated to patients with other aetiologies of keratitis, such as fungus, herpes viruses, acanthamoeba or atypical mycobacteria, and these entities should be excluded before considering adjunctive steroid therapy.


Enterobacter spp.: Update on Taxonomy, Clinical Aspects, and Emerging Antimicrobial Resistance.
The genus Enterobacter is a member of the ESKAPE group, which contains the major resistant bacterial pathogens. First described in 1960, this group member has proven to be more complex as a result of the exponential evolution of phenotypic and genotypic methods. Today, 22 species belong to the Enterobacter genus. These species are described in the environment and have been reported as opportunistic pathogens in plants, animals, and humans. The pathogenicity/virulence of this bacterium remains rather unclear due to the limited amount of work performed to date in this field. In contrast, its resistance against antibacterial agents has been extensively studied. In the face of antibiotic treatment, it is able to manage different mechanisms of resistance via various local and global regulator genes and the modulation of the expression of different proteins, including enzymes (β-lactamases, etc.) or membrane transporters, such as porins and efflux pumps. During various hospital outbreaks, the Enterobacter aerogenes and E. cloacae complex exhibited a multidrug-resistant phenotype, which has stimulated questions about the role of cascade regulation in the emergence of these well-adapted clones.


Labral penetration rate in a consecutive series of 300 hip arthroscopies.
Intraoperative labral injury during the establishment of the first portal in hip arthroscopy has been reported to be as high as 20%. The purpose of the study was to prospectively identify the incidence of acetabular labral injuries that occurred while using a current technique for the establishment of portals during hip arthroscopy. Case series; Level of evidence, 4. Between the years 2008 and 2010, data were prospectively collected for all patients undergoing hip arthroscopic surgery. Patients with previous labral resection or Tonnis grade greater than 1 were excluded. Patients were positioned supine, traction was applied, and portals were established. The anterolateral portal was created first by venting the joint with a spinal needle and then re-entering the joint with the same needle with the bevel side facing the labrum. Next, the midanterior portal was created under vision. A thorough examination of the acetabular labrum was conducted arthroscopically through multiple viewing portals, and labral injuries related to the establishment of portals were identified and noted. A total of 300 patients were included in the study; only 2 patients (0.67%) suffered intraoperative labral injuries at the study period. One injury occurred during revision arthroscopy, while the second involved a hyperplastic labrum in a dysplastic hip. No patient with normal hip morphological characteristics undergoing a hip arthroscopy suffered a labral tear as a result of portal placement. The incidence of iatrogenic labral injury during hip arthroscopy can be as low as 0.67% when using the described technique.


Lower-limb lengthening in short stature. An electrophysiological and clinical assessment of peripheral nerve function.
We assessed peripheral nerve function during and after lower-limb lengthening by callotasis in 14 patients with short stature, using motor conduction studies. Four patients with short stature of varying aetiology showed unilateral and one showed bilateral weakness of foot dorsiflexion. Both clinical and electrophysiological abnormalities consistent with involvement of the peroneal nerve were observed early after starting tibial callotasis. There was some progressive electrophysiological improvement despite continued bone distraction, but two patients with Turner's syndrome had incomplete recovery. A greater percentage increase in tibial length did not correspond to a higher rate of peroneal nerve palsy. The function of the posterior leg muscles and the conduction velocity of the posterior tibial nerve were normal throughout the monitoring period. The F-wave response showed a longer latency at the end of the bone distraction than in basal conditions; this is probably related to the slowing of conduction throughout the entire length of the nerve.


Parasitic oligosaccharide residues recognized by patients with mucocutaneous and localized cutaneous leishmaniasis.
Humoral immune responses were studied in 118 Venezuelan patients with either active mucocutaneous (MCL) or localized cutaneous leishmaniasis (LCL). Most patients had elevated antibody levels to the six promastigote oligosaccharide residues studied: galactosyl(alpha 1-2)galactose, galactosyl(alpha 1-3)galactose, galactosyl(alpha 1-6)galactose, galactosyl(alpha 1-3)mannose, galactofuranosyl(beta 1-3)mannose, and galactocerebroside. Significantly higher antibody levels were found in patients with MCL against galactosyl(alpha 1-3)galactose and Leishmania tropica glycoinositol phospholipid (GIPL)-1, GIPL-2, and GIPL-3 compared with patients with LCL. For both clinical forms of American cutaneous leishmaniasis (ACL), the most reactive antigen was galactosyl(alpha 1-3)galactose, with elevated levels found in 63% and 79% of MCL and LCL patients, respectively. In patients with MCL and LCL, no significant relationship was found between antibody levels against a given oligosaccharide residue and clinical parameters such as age, leishmanin diameter, number of skin lesions, or time of evolution. It is noteworthy that 33% and 15% of MCL and LCL patients, respectively, did not have elevated antibody levels against the six different oligosaccharide residues studied. This suggests the presence of a subpopulation of non-humoral immunoreactive ACL patients. The relationship between abnormal levels of oligosaccharide antibodies and the final outcome of the disease remains to be established.


Flash-quench technique employed to study the one-electron reduction of triiodide in acetonitrile: evidence for a diiodide reaction product.
The one-electron reduction of triiodide (I(3)(-)) by a reduced ruthenium polypyridyl compound was studied in an acetonitrile solution with the flash-quench technique. Reductive quenching of the metal-to-ligand charge-transfer excited state of [Ru(II)(deeb)(3)](2+) by iodide generated the reduced ruthenium compound [Ru(II)(deeb(-))(deeb)(2)](+) and diiodide (I(2)(•-)). The subsequent reaction of [Ru(II)(deeb(-))(deeb)(2)](+) with I(3)(-) indicated that I(2)(•-) was a product that appeared with a second-order rate constant of (5.1 ± 0.2) × 10(9) M(-1) s(-1). After correction for diffusion and some assumptions, Marcus theory predicted a formal potential of -0.58 V (vs SCE) for the one-electron reduction of I(3)(-). The relevance of this reaction to solar energy conversion is discussed.


Neuromuscular Strain Increases Symptom Intensity in Chronic Fatigue Syndrome.
Chronic fatigue syndrome (CFS) is a complex, multisystem disorder that can be disabling. CFS symptoms can be provoked by increased physical or cognitive activity, and by orthostatic stress. In preliminary work, we noted that CFS symptoms also could be provoked by application of longitudinal neural and soft tissue strain to the limbs and spine of affected individuals. In this study we measured the responses to a straight leg raise neuromuscular strain maneuver in individuals with CFS and healthy controls. We randomly assigned 60 individuals with CFS and 20 healthy controls to either a 15 minute period of passive supine straight leg raise (true neuromuscular strain) or a sham straight leg raise. The primary outcome measure was the symptom intensity difference between the scores during and 24 hours after the study maneuver compared to baseline. Fatigue, body pain, lightheadedness, concentration difficulties, and headache scores were measured individually on a 0-10 scale, and summed to create a composite symptom score. Compared to individuals with CFS in the sham strain group, those with CFS in the true strain group reported significantly increased body pain (P = 0.04) and concentration difficulties (P = 0.02) as well as increased composite symptom scores (all P = 0.03) during the maneuver. After 24 hours, the symptom intensity differences were significantly greater for the CFS true strain group for the individual symptom of lightheadedness (P = 0.001) and for the composite symptom score (P = 0.005). During and 24 hours after the exposure to the true strain maneuver, those with CFS had significantly higher individual and composite symptom intensity changes compared to the healthy controls. We conclude that a longitudinal strain applied to the nerves and soft tissues of the lower limb is capable of increasing symptom intensity in individuals with CFS for up to 24 hours. These findings support our preliminary observations that increased mechanical sensitivity may be a contributor to the provocation of symptoms in this disorder.


The program for processing newly synthesized histones H3.1 and H4.
The mechanism by which newly synthesized histones are imported into the nucleus and deposited onto replicating chromatin alongside segregating nucleosomal counterparts is poorly understood, yet this program is expected to bear on the putative epigenetic nature of histone post-translational modifications. To define the events by which naive pre-deposition histones are imported into the nucleus, we biochemically purified and characterized the full gamut of histone H3.1-containing complexes from human cytoplasmic fractions and identified their associated histone post-translational modifications. Through reconstitution assays, biophysical analyses and live cell manipulations, we describe in detail this series of events, namely the assembly of H3-H4 dimers, the acetylation of histones by the HAT1 holoenzyme and the transfer of histones between chaperones that culminates with their karyopherin-mediated nuclear import. We further demonstrate the high degree of conservation for this pathway between higher and lower eukaryotes.


Biological chemistry of carbon monoxide.
Carbon monoxide (CO) has many effects in biology due to its complex biochemical activities. These actions of CO depend primarily on its ability to bind heme proteins (Hp) and to inhibit or alter their biochemical functions. Whether CO is derived from exogenous or endogenous sources, its cellular activity is related to its concentration and the concentration of molecular O(2), as well as to the availability of reduced transition metals such as Fe(II). In this respect, the CO/O(2) ratio and O(2)-dependent changes in local oxidation-reduction state assume critical importance in determining the physiological effects of CO by affecting the functions of specific Hp. By interacting with Hp, CO influences electron-transport reactions in a variety of ways, which can produce either prooxidant or antioxidant effects. Similarly, Hp relationships also govern how changes in CO concentration influence the physiological and pathological effects of nitric oxide and the relationships of the two biologically active gases to metal-catalyzed oxidations. This article provides a brief update on the biochemistry of CO as it relates to Hp binding, chemical oxidative processes, and cellular function.


Learning to love the state action doctrine.
The state action doctrine receives relatively little attention in the Federal Trade Commission/Department of Justice 2004 report on competition in the health care sector. Not surprisingly, the report focuses primarily on urging states to reconsider specific laws that tend to restrict competition in health care markets but that are clearly shielded by the state action doctrine. Relatively little attention is given to the interpretation of the doctrine itself. This article employs the twin themes of institutional choice and market failure to evaluate a number of interpretive proposals affecting the state action doctrine that were available to, but not taken up by, the agencies. It also proposes using the state action doctrine to ease the burden on courts in market-failure cases in which there is an obvious threat to competition and the alternative of publicly accountable regulatory action is available.


Persistent cloaca and caudal duplication in a monovular twin, a rare case report.
A cloaca occurs when genitourinary tract and bowel converge into a common channel. We report a case of partial caudal duplication, persistent cloaca and vestigial appendage in a monovular female twin infant. This is a monochorinonic-diamniotic twin born at 36 weeks with apgars of 9/9. She had a duplicated labia with two clitorises, and a partially formed accessory foot with 2 toes protruding from the right gluteal region. There was anal atresia and a punctate urethral opening in the right genitalia through which she voided spontaneously. X-ray of the accessory foot had rudimentary metatarsals and phalanges. There was left hydroureteronephrosis and a hydrocolpos causing severe mass effect. On the first day of life, she had exploratory laparotomy with a diverting colostomy and mucus fistula and drainage of hydrocolpos. At 6 months of age, she had removal of the accessory foot with flap closure of the perineal defect and vesicostomy. At 15 months of age she had laparotomy for repair of cloaca, excision of presacral pelvic mass and the duplicated vulva. Theories of etiology include failure of regression of Kovalevsky's canal (a communication that connects the amniotic and yolk sac), an incomplete form of twinning through iatrogenic damage to the zona pellucida or a failed triplet formation from a single embryo. Caudal duplication with persistent cloaca and vestigial appendage is a rare and complex malformation. Having a unified surgical and medical team to preserve quality of life and to treat complications is of key importance.


Feverfew for preventing migraine.
This review is an update of a previously published review in the Cochrane Database of Systematic Reviews on 'Feverfew for preventing migraine' (2004, Issue 1). Feverfew (Tanacetum parthenium L.) extract is a herbal remedy, which has been used for preventing attacks of migraine. To systematically review the evidence from double-blind randomised controlled trials (RCTs) assessing the clinical efficacy and safety of feverfew monopreparations versus placebo for preventing migraine. For this updated version of the review we searched CENTRAL, MEDLINE, EMBASE and AMED to January 2015. We contacted manufacturers of feverfew and checked the bibliographies of identified articles for further trials. We included randomised, placebo-controlled, double-blind trials assessing the efficacy of feverfew monopreparations for preventing migraine in patients of any age. We included trials using clinical outcome measures, while we excluded trials focusing exclusively on physiological parameters. There were no restrictions regarding the language of publication. We systematically extracted data on patients, interventions, methods, outcome measures, results and adverse events. We assessed risk of bias using the Cochrane 'Risk of bias' tool and evaluated methodological quality using the Oxford Quality Scale developed by Jadad and colleagues. Two review authors (BW and MHP for this update, MHP and EE for the original version) independently selected studies, assessed methodological quality and extracted data. We resolved disagreements concerning evaluation of individual trials through discussion. We identified one new study for this update, resulting in six trials (561 patients) meeting the inclusion criteria. Five of the six trials reported on the main outcome, migraine frequency. Although five of the trials were generally of good methodological quality, all studies were either of unclear or high risk of bias with regards to sample size. Pooled analysis of the results was not possible due to the lack of common outcome measures and heterogeneity between studies in terms of participants, interventions and designs.The most recent trial added to this version of the review is rigorous and larger (n = 218), using a stable feverfew extract at a dose determined by a previous dose-finding trial. It reports that feverfew reduced migraine frequency by 1.9 attacks from 4.8 to 2.9 and placebo by 1.3 from to 4.8 to 3.5 per month, resulting in a difference in effect between feverfew and placebo of 0.6 attacks per month. For the secondary outcome measures intensity and duration of migraine attacks, incidence and severity of nausea and vomiting, and global assessment no statistically significant differences were reported. Results of previous trials are not convincing: three trials reporting positive effects of feverfew are all of small sample size (17 to 60 participants), while two rigorous trials (n = 50, 147) did not find significant differences between feverfew and placebo. Only mild and transient adverse events, most commonly gastrointestinal complaints and mouth ulcers, were reported in the included trials. Since the last version of this review, one larger rigorous study has been included, reporting a difference in effect between feverfew and placebo of 0.6 attacks per month. This adds some positive evidence to the mixed and inconclusive findings of the previous review. However, this constitutes low quality evidence, which needs to be confirmed in larger rigorous trials with stable feverfew extracts and clearly defined migraine populations before firm conclusions can be drawn. It appears from the data reviewed that feverfew is not associated with any major safety concerns.