Dependence receptors: what is the mechanism?
Receptors of diverse primary structure and with diverse ligands have been reported to be capable of stimulating apoptosis in the absence of ligand binding. These receptors are called dependence receptors, and the newest member of this family appears to be the Sonic hedgehog receptor Patched, which has been reported to stimulate apoptosis when expressed in the absence of its ligand. The signaling mechanisms that account for this type of receptor activity are unknown. Several theories behind how dependence receptors may trigger cell death are described.


Modeling health gains and cost savings for ten dietary salt reduction targets.
Dietary salt reduction is included in the top five priority actions for non-communicable disease control internationally. We therefore aimed to identify health gain and cost impacts of achieving a national target for sodium reduction, along with component targets in different food groups. We used an established dietary sodium intervention model to study 10 interventions to achieve sodium reduction targets. The 2011 New Zealand (NZ) adult population (2.3 million aged 35+ years) was simulated over the remainder of their lifetime in a Markov model with a 3 % discount rate. Achieving an overall 35 % reduction in dietary salt intake via implementation of mandatory maximum levels of sodium in packaged foods along with reduced sodium from fast foods/restaurant food and discretionary intake (the "full target"), was estimated to gain 235,000 QALYs over the lifetime of the cohort (95 % uncertainty interval [UI]: 176,000 to 298,000). For specific target components the range was from 122,000 QALYs gained (for the packaged foods target) down to the snack foods target (6100 QALYs; and representing a 34-48 % sodium reduction in such products). All ten target interventions studied were cost-saving, with the greatest costs saved for the mandatory "full target" at NZ$1260 million (US$820 million). There were relatively greater health gains per adult for men and for Māori (indigenous population). This work provides modeling-level evidence that achieving dietary sodium reduction targets (including specific food category targets) could generate large health gains and cost savings for a national health sector. Demographic groups with the highest cardiovascular disease rates stand to gain most, assisting in reducing health inequalities between sex and ethnic groups.


Brain size, sex, and the aging brain.
This study was conducted to examine the statistical influence of brain size on cortical, subcortical, and cerebellar compartmental volumes. This brain size influence was especially studied to delineate interactions with Sex and Age. Here, we studied 856 healthy subjects of which 533 are classified as young and 323 as old. Using an automated segmentation procedure cortical (gray and white matter [GM and WM] including the corpus callosum), cerebellar (GM and WM), and subcortical (thalamus, putamen, pallidum, caudatus, hippocampus, amygdala, and accumbens) volumes were measured and subjected to statistical analyses. These analyses revealed that brain size and age exert substantial statistical influences on nearly all compartmental volumes. Analyzing the raw compartmental volumes replicated the frequently reported Sex differences in compartmental volumes with men showing larger volumes. However, when statistically controlling for brain size Sex differences and Sex × Age interactions practically disappear. Thus, brain size is more important than Sex in explaining interindividual differences in compartmental volumes. The influence of brain size is discussed in the context of an allometric scaling of the compartmental volumes.


Credibility battles in the autism litigation.
That vaccines do not cause autism is now a widely accepted proposition, though a few dissenters remain. An 8-year court process in the US federal vaccine injury compensation court ended in 2010 with rulings that autism was not an adverse reaction to vaccination. There were two sets of trials: one against the measles-mumps-rubella (MMR) vaccine and one against the mercury-based preservative thimerosal. The MMR story is more widely known because of publicity surrounding the main proponent of an MMR-autism link, British doctor Andrew Wakefield, but the story of thimerosal in court is largely untold. This study examines the credibility battles and boundary work in the two cases, illuminating the sustaining world of alternative science that supported the parents, lawyers, researchers, and expert witnesses against vaccines. After the loss in court, the families and their advocates transformed their scientific arguments into an indictment of procedural injustice in the vaccine court. I argue that the very efforts designed to produce legitimacy in this type of lopsided dispute will be counter-mobilized as evidence of injustice, helping us understand why settling a scientific controversy in court does not necessarily mean changing anyone's mind.


Genetic algorithm for optical pattern recognition.
A genetic algorithm is used to generate binary reference functions for optical pattern recognition and classification. Procedures based on the properties of convex functions can be implemented directly on hybrid electro-optical systems. Computer simulations demonstrate the efficiency of this novel approach.


Who spares the rod? Religious orientation, social conformity, and child abuse potential.
Relatively little research has investigated the connection between religiosity and physical child abuse risk. Certain aspects, such as specific religious orientation or beliefs, and cognitive schema, such as socially conformist beliefs, may account for the connection that some have claimed increase religious parents' abuse potential. The current study examined whether greater Extrinsic religiosity, but not Intrinsic religiosity, was associated with elevated physical abuse potential. Those who hold a literal interpretation of the Bible and attend church more frequently were also expected to evidence increased abuse risk. Additionally, the role of social conformity in mediating or moderating the association between religiosity and abuse potential was investigated. Two hundred and seven regularly attending Christians of various denominations completed self-report measures of religiosity, social conformity, and child abuse potential. Findings indicate that Extrinsic religiosity was associated with increased physical abuse potential, with greater social conformity further moderating this association. Intrinsic religious orientation was not associated with abuse risk. Further, those who consider the Bible to be literally true were more socially conformist and evidenced greater abuse risk. For those working with religious parents, the particular nature of religiosity needs to be considered when interpreting a connection between religiosity and abuse risk, as well as the potential attitudes the parent holds regarding the need for conformity. Given the complexity of religiosity, future research should explore other potential mediating and moderating factors that could further clarify its connection to physical abuse risk. Clarifying how religiosity relates to child abuse risk has implications for professionals working with the vast numbers of parents for whom religion is a visible force in their daily lives. Findings from the present study suggest that professionals should consider the underlying motivation for an individual's religion as well as the importance the individual places on conformity. Religiosity per se may not be as critical to predicting physical abuse risk as selected approaches to religion or particular attitudes the religious individual assumes in their daily life.


Polygalacturonase and polygalacturonase inhibitor protein: gene isolation and transcription in Glycine max-Heterodera glycines interactions.
The cell wall acts as the first line of defense during pathogen invasion. Polygalacturonases (PGs) are a class of cell-wall-modifying enzymes with precise temporal and organ-specific expression. A 350-bp fragment with high homology to PGs was identified by differential display (DD) analysis of soybean cyst nematode (SCN) race 3 resistant PI 437654 and susceptible cultivar Essex. The fragment was strongly expressed in Essex, 2 days after inoculation (DAI). Complete coding sequences of two PG cDNAs, PG1 and PG2, were isolated by 3' and 5' rapid amplification of cDNA ends polymerase chain reaction (RACE PCR). PI 437654 and Essex had identical PG1 and PG2 sequences. A transversion from A to C created a PstI restriction site in the PG2 cDNA that was used to distinguish the two PG cDNAs by cleaved amplified polymorphic sequence (CAPS) analysis. A cDNA encoding a polygalacturonase-inhibitor protein (PGIP) that is 89% identical to the Phaseolus vulgaris PGIP was isolated from soybean roots by reverse transcription (RT)-PCR. Steady-state levels of PG and PGIP were investigated by RNA gel blot analysis in roots 1 to 5 DAI and in hypocotyls and leaves. Differences in the constitutive levels of PG mRNAs were observed in roots of different soybean genotypes. Steady-state levels of PG mRNAs were enhanced during compatible interactions with SCN and reduced in incompatible interactions and in mechanically wounded roots. Enhanced PGIP transcription was observed in response to mechanical wounding in both PI 437654 and Essex, but only in compatible interactions with SCN, suggesting uncoupling of PGIP functions in developmental and stress cues. Constitutive expression in incompatible interactions shows PGIP is not a factor in SCN resistance. Thus, the up-regulation of endogenous PG transcription in soybean roots early after SCN infection could facilitate successful parasitism by SCN.


Perovskite-inspired materials for photovoltaics and beyond-from design to devices.
Lead-halide perovskites have demonstrated astonishing increases in power conversion efficiency in photovoltaics over the last decade. The most efficient perovskite devices now outperform industry-standard multi-crystalline silicon solar cells, despite the fact that perovskites are typically grown at low temperature using simple solution-based methods. However, the toxicity of lead and its ready solubility in water are concerns for widespread implementation. These challenges, alongside the many successes of the perovskites, have motivated significant efforts across multiple disciplines to find lead-free and stable alternatives which could mimic the ability of the perovskites to achieve high performance with low temperature, facile fabrication methods. This Review discusses the computational and experimental approaches that have been taken to discover lead-free perovskite-inspired materials, and the recent successes and challenges in synthesizing these compounds. The atomistic origins of the extraordinary performance exhibited by lead-halide perovskites in photovoltaic devices is discussed, alongside the key challenges in engineering such high-performance in alternative, next-generation materials. Beyond photovoltaics, this Review discusses the impact perovskite-inspired materials have had in spurring efforts to apply new materials in other optoelectronic applications, namely light-emitting diodes, photocatalysts, radiation detectors, thin film transistors and memristors. Finally, the prospects and key challenges faced by the field in advancing the development of perovskite-inspired materials towards realization in commercial devices is discussed.


Motivation in educational contexts: does gender matter?
Girls and women now outperform boys and men on many indices of academic achievement. Gender differences in motivation may underlie these trends. In this chapter, I review and integrate research on gender differences in self-evaluation, self-regulation, and achievement goals. I argue for the existence of gendered tendencies "to prove" versus "to try and to improve," whereby males tend to orient to demonstrating and defending their abilities, and females to working hard and addressing deficiencies. I discuss how these motivations develop within social and educational contexts of learning, and intersect with gendered patterns of socialization, values, and behaviors in other arenas, especially relational ones. Recurring themes include the costs and benefits of differential emphases on competition and self-promotion versus affiliation and consideration of others in the family, peer group, and classroom. I conclude with some recommendations for creating classroom environments that might promote optimal motivation among all students, regardless of gender.


Adult stem cells and multiple sclerosis.
Multiple sclerosis (MS) is a common neurological disease and a major cause of disability, particularly affecting young adults. It is characterized by patches of damage occurring throughout the brain and spinal cord, with loss of myelin sheaths - the insulating material around nerve fibres that allows normal conduction of nerve impulses - accompanied by loss of cells that make myelin (oligodendrocytes). In addition, we now know that there is damage to nerve cells (neurones) and their fibres (axons) too, and that this occurs both within these discrete patches and in tissue between them. The cause of MS remains unknown, but an autoimmune reaction against oligodendrocytes and myelin is generally assumed to play a major role, and early acute MS lesions almost invariably show prominent inflammation. Efforts to develop cell therapy in MS have long been directed towards directly implanting cells capable of replacing lost oligodendrocytes and regenerating myelin sheaths. Accordingly, the advent of techniques to generate large numbers of oligodendrocytes from embryonic stem cells appeared a significant step towards new stem cell treatments for MS; while the emerging consensus that adult stem cells from, for example, the bone marrow had far less potential to turn into oligodendrocytes was thought to cast doubt on their potential value in this disease. A number of scientific and medical concerns, not least the risk of tumour formation associated with embryonic stem cells, have however, prevented any possible clinical testing of these cells in patients. More recently, increasing understanding of the complexity of tissue damage in MS has emphasized that successful cell therapy may need to achieve far more than simply offering a source of replacement myelin-forming cells. The many and varied reparative properties of bone marrow-derived (mesenchymal) stem cells may well offer new and attractive possibilities for developing cell-based treatments for this difficult and disabling condition.


Uniqueness, advantages, challenges, solutions, and perspectives in therapeutics applying RNA nanotechnology.
The field of RNA nanotechnology is rapidly emerging. RNA can be manipulated with the simplicity characteristic of DNA to produce nanoparticles with a diversity of quaternary structures by self-assembly. Additionally RNA is tremendously versatile in its function and some RNA molecules display catalytic activities much like proteins. Thus, RNA has the advantage of both worlds. However, the instability of RNA has made many scientists flinch away from RNA nanotechnology. Other concerns that have deterred the progress of RNA therapeutics include the induction of interferons, stimulation of cytokines, and activation of other immune systems, as well as short pharmacokinetic profiles in vivo. This review will provide some solutions and perspectives on the chemical and thermodynamic stability, in vivo half-life and biodistribution, yield and production cost, in vivo toxicity and side effect, specific delivery and targeting, as well as endosomal trapping and escape.


Bioinformatic discovery of a toxin family in Chryseobacterium piperi with sequence similarity to botulinum neurotoxins.
Clostridial neurotoxins (CNTs), which include botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT), are the most potent toxins known to science and are the causative agents of botulism and tetanus, respectively. The evolutionary origins of CNTs and their relationships to other proteins remains an intriguing question. Here we present a large-scale bioinformatic screen for putative toxin genes in all currently available genomes. We detect a total of 311 protein sequences displaying at least partial homology to BoNTs, including 161 predicted toxin sequences that have never been characterized. We focus on a novel toxin family from Chryseobacterium piperi with homology to BoNTs. We resequenced the genome of C. piperi to confirm and further analyze the genomic context of these toxins, and also examined their potential toxicity by expression of the protease domain of one C. piperi toxin in human cells. Our analysis suggests that these C. piperi sequences encode a novel family of metalloprotease toxins that are distantly related to BoNTs with similar domain architecture. These toxins target a yet unknown class of substrates, potentially reflecting divergence in substrate specificity between the metalloprotease domains of these toxins and the related metalloprotease domain of clostridial neurotoxins.


Role of water reuse for enhancing integrated water management in Europe and Mediterranean countries.
Recycling water is an important aspect of water resource and environment management policies, ensuring reliable alternative water resources, reducing environmental pollution and achieving a more sustainable form of development. This paper focuses on wastewater reuse as a strategy for integrated water management. Key economic, financial, regulatory, social and technical factors that help to make water reuse projects successful are reviewed. Selected examples from Northern and Western Europe and arid and semi-arid Mediterranean regions illustrate the contribution of wastewater reuse to integrated management of water resources.


A censored quantile regression approach for the analysis of time to event data.
The commonly used statistical model for studying time to event data, the Cox proportional hazards model, is limited by the assumption of a constant hazard ratio over time (i.e., proportionality), and the fact that it models the hazard rate rather than the survival time directly. The censored quantile regression model, defined on the quantiles of time to event, provides an alternative that is more flexible and interpretable. However, the censored quantile regression model has not been widely adopted in clinical research, due to the complexity involved in interpreting its results properly and consequently the difficulty to appreciate its advantages over the Cox proportional hazards model, as well as the absence of adequate validation procedure. In this paper, we addressed these limitations by (1) using both simulated examples and data from National Wilms' Tumor clinical trials to illustrate proper interpretation of the censored quantile regression model and the differences and the advantages of the model compared to the Cox proportional hazards model; and (2) developing a validation procedure for the predictive censored quantile regression model. The performance of this procedure was examined using simulation studies. Overall, we recommend the use of censored quantile regression model, which permits a more sensitive analysis of time to event data together with the Cox proportional hazards model.


Molecular epidemiology of malaria in Yaounde, Cameroon II. Baseline frequency of point mutations in the dihydropteroate synthase gene of Plasmodium falciparum.
Sulfadoxine-pyrimethamine is one of the alternative antimalarial drugs used to treat chloroquine-resistant Plasmodium falciparum malaria. The molecular target of sulfadoxine, an analog of p-aminobenzoic acid that inhibits the folate biosynthetic pathway, is dihydropteroate synthase (DHPS). The nucleotide sequence of the DHPS gene was determined in 32 clinical isolates obtained in Yaounde, Cameroon, and compared with the sequence of reference clones and Cambodian strains of P. falciparum. Of the 32 Cameroonian isolates, 31 displayed one of the sulfadoxine-sensitive mutation patterns: Ala-436/Ala-437/Ala-581/Ala-613 (n = 20), Ser-436/Gly-437/Ala-581/Ala-613 (n = 6), Ser-436/Ala-437/Ala-581/Ala-613 (n = 4), and Ala-436/Gly-437/Ala-581/Ala-613 (n = 1). One isolate had a sulfadoxine-resistant profile characterized by a double mutation: Phe-436/Ala-437/Ala-581/Ser-613. Although the majority of the isolates had a sulfadoxine-sensitive genetic profile, further studies are needed to correlate the mutation patterns and in vitro and in vivo sulfadoxine sensitivity.


Molecular functions and significance of the MTA family in hormone-independent cancer.
The members of the metastasis-associated protein (MTA) family play pivotal roles in both physiological and pathophysiological processes, especially in cancer development and metastasis, and their role as master regulators has come to light. Due to the fact that they were first identified as crucial factors in estrogen receptor-mediated breast cancer metastasis, most of the early studies focused on their hormone-dependent functions. However, the accumulating evidence shows that the members of MTA family are deregulated in most, if not all, the cancers studied so far. Therefore, the levels as well as the activities of the MTA family members are widely accepted as potential biomarkers for diagnosis, prognosis, and predictors of overall survival. They function differently in different cancers with specific mechanisms. p53 and HIF-1α appear to be the respectively common upstream and downstream regulator of the MTA family in both development and metastasis of a wide spectrum of cancers. Here, we review the expression and clinical significance of the MTA family, focusing on hormone-independent cancers. To illustrate the molecular mechanisms, we analyze the MTA family-related signaling pathways in different cancers. Finally, targeting the MTA family directly or the pathways involved in the MTA family indirectly could be invaluable strategies in the development of cancer therapeutics.


Can you deliver accurate tidal volume by manual resuscitator?
One of the problems with manual resuscitators is the difficulty in achieving accurate volume delivery. The volume delivered to the patient varies by the physical characteristics of the person and method. This study was designed to compare tidal volumes delivered by the squeezing method, physical characteristics and education and practice levels. 114 individuals trained in basic life support and bag-valve-mask ventilation participated in this study. Individual characteristics were obtained by the observer and the education and practice level were described by the subjects. Ventilation was delivered with a manual resuscitator connected to a microspirometer and volumes were measured. Subjects completed three procedures: one-handed, two-handed and two-handed half-compression. The mean (standard deviation) volumes for the one-handed method were 592.84 ml (SD 117.39), two-handed 644.24 ml (SD 144.7) and two-handed half-compression 458.31 ml (SD 120.91) (p<0.01). Tidal volume delivered by two hands was significantly greater than that delivered by one hand (r = 0.398, p<0.01). The physical aspects including hand size, volume and grip power had no correlation with the volume delivered. There were slight increases in tidal volume with education and practice, but correlation was weak (r = 0.213, r = 0.281, r = 0.131, p<0.01). The tidal volume delivered by a manual resuscitator shows large variations. There were significant differences in the volume delivered by compression methods, but physical characteristics are not a predictor of tidal volume delivery. The manual resuscitator is not a suitable device for accurate ventilation.


Trial watch: Peptide-based vaccines in anticancer therapy.
Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen.


Induction of TRPC6 channel in acquired forms of proteinuric kidney disease.
Injury to podocytes and their slit diaphragms typically leads to marked proteinuria. Mutations in the TRPC6 gene that codes for a slit diaphragm-associated, cation-permeable ion channel have been shown recently to co-segregate with hereditary forms of progressive kidney failure. Herein is shown that induced expression of wild-type TRPC6 is a common feature of human proteinuric kidney diseases, with highest induction observed in membranous nephropathy. Cultured podocytes that are exposed to complement upregulate TRPC6 protein. Stimulation of receptor-operated channels in puromycin aminonucleoside-treated podocytes leads to increased calcium influx in a time- and dosage-dependent manner. Mechanistically, it is shown that TRPC6 is functionally connected to the podocyte actin cytoskeleton, which is rearranged upon overexpression of TRPC6. Transient in vivo gene delivery of TRPC6 into mice leads to expression of TRPC6 protein at the slit diaphragm and causes proteinuria. These studies suggest the involvement of TRPC6 in the pathology of nongenetic forms of proteinuric disease.


Contraction-induced skeletal muscle FAT/CD36 trafficking and FA uptake is AMPK independent.
The aim of this study was to investigate the molecular mechanisms regulating FA translocase CD36 (FAT/CD36) translocation and FA uptake in skeletal muscle during contractions. In one model, wild-type (WT) and AMP-dependent protein kinase kinase dead (AMPK KD) mice were exercised or extensor digitorum longus (EDL) and soleus (SOL) muscles were contracted, ex vivo. In separate studies, FAT/CD36 translocation and FA uptake in response to muscle contractions were investigated in the perfused rat hindlimb. Exercise induced a similar increase in skeletal muscle cell surface membrane FAT/CD36 content in WT (+34%) and AMPK KD (+37%) mice. In contrast, 5-aminoimidazole-4-carboxamide ribonucleoside only induced an increase in cell surface FAT/CD36 content in WT (+29%) mice. Furthermore, in the perfused rat hindlimb, muscle contraction induced a rapid (1 min, +15%) and sustained (10 min, +24%) FAT/CD36 relocation to cell surface membranes. The increase in cell surface FAT/CD36 protein content with muscle contractions was associated with increased FA uptake, both in EDL and SOL muscle from WT and AMPK KD mice and in the perfused rat hindlimb. This suggests that AMPK is not essential in regulation of FAT/CD36 translocation and FA uptake in skeletal muscle during contractions. However, AMPK could be important in regulation of FAT/CD36 distribution in other physiological situations.


CDKs Functional Analysis in Low Proliferating Early-Stage Pancreatic Ductal Adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with a poor prognosis and growing incidence. In this study, we explored the potential roles of CDK1, CDK2, CDK4, and CDK6 in the progression of early-stage PDAC. Clinicopathologic and mRNA expression data and treatment information of 140 patients identified with stage I/II PDAC who underwent pancreaticoduodenectomy were obtained from the Cancer Genome Atlas data set. Our bioinformatic analysis showed that higher CDK1, CDK2, CDK4, or CDK6 expression was associated with a shorter median survival of the early-stage PDAC patients. Of note, in the low-proliferating pancreatic cancer group, CDKs expressions were significantly associated with proteins functioning in apoptosis, metastasis, immunity, or stemness. Among the low-proliferating PDAC, higher expression of CDK1 was associated with the shorter survival of patients, suggesting that CDK1 may regulate PDAC progression through cell cycle-independent mechanisms. Our experimental data showed that CDK1 knockdown/inhibition significantly suppressed the expression levels of AHR and POU5F1, two critical proteins functioning in cancer cell metastasis and stemness, in low-proliferating, but not in high-proliferating pancreatic cancer cells. In all, our study suggests that CDKs regulate PDAC progression not only through cell proliferation but also through apoptosis, metastasis, immunity, and stemness.


Evaluation of surface EMG-based recognition algorithms for decoding hand movements.
Myoelectric pattern recognition (MPR) to decode limb movements is an important advancement regarding the control of powered prostheses. However, this technology is not yet in wide clinical use. Improvements in MPR could potentially increase the functionality of powered prostheses. To this purpose, offline accuracy and processing time were measured over 44 features using six classifiers with the aim of determining new configurations of features and classifiers to improve the accuracy and response time of prosthetics control. An efficient feature set (FS: waveform length, correlation coefficient, Hjorth Parameters) was found to improve the motion recognition accuracy. Using the proposed FS significantly increased the performance of linear discriminant analysis, K-nearest neighbor, maximum likelihood estimation (MLE), and support vector machine by 5.5%, 5.7%, 6.3%, and 6.2%, respectively, when compared with the Hudgins' set. Using the FS with MLE provided the largest improvement in offline accuracy over the Hudgins feature set, with minimal effect on the processing time. Among the 44 features tested, logarithmic root mean square and normalized logarithmic energy yielded the highest recognition rates (above 95%). We anticipate that this work will contribute to the development of more accurate surface EMG-based motor decoding systems for the control prosthetic hands.


Raising the quality of rheumatology management recommendations: lessons from the EULAR process 10 years after provision of standard operating procedures.
To increase understanding of how to raise the quality of rheumatology guidelines by reviewing European League Against Rheumatism (EULAR) management recommendations, using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, 10 years after publication of the EULAR standardized operating procedures (SOP) for the production of recommendations. It was hoped that this work could help inform improvements in guideline development by other societies and organizations. The SOP were published in 2004 to ensure the quality of EULAR-endorsed recommendations. We reviewed 27 published EULAR recommendations for management using the AGREE II tool. This provides a framework to assess the quality of guidelines across six broad domains using 23 specific questions. Overall the EULAR recommendations reviewed have been performed to a high standard. There are particular strengths in the methodology and presentation of the guidelines; however, the results indicate areas for development in future recommendations: in particular, stakeholder involvement and applicability of the recommendations. Improvements in quality were evident in recent years, with patient representation in 9 of 15 (60.0%) recommendations published 2010-14 compared with 4 of 12 (33.3%) published 2000-09. In the last 10 years the overall quality of recommendations was good, with standards improving over the decade following publication of the SOP. However, this review process has identified potential areas for improvement, especially in patient representation and provision of implementation tools. The lessons from this work can be applied to the development of rheumatology guidelines by other societies and organizations.


Effect of diet on the shedding of Escherichia coli O157:H7 in a sheep model.
The purpose of this study was to develop a sheep model to investigate reproduction, transmission, and shedding of Escherichia coli O157:H7 in ruminants. In addition, we investigated the effect of diet change on these parameters. Six groups of twin lambs given oral inoculations of 10(5) or 10(9) CFU of E. coli O157:H7 and their nondosed mothers were monitored for colonization by culture of fecal samples. A modified selective-enrichment protocol that detected E. coli O157:H7 at levels as low as 0.06 CFU per g of ovine feces was developed. Horizontal transmission of infection occurred between the lambs and most of the nondosed mothers. When animals were kept in confinement and given alfalfa pellet feed, lambs receiving the higher dose shed the bacteria sooner and longer than all other animals. However, when the animals were released onto a sagebrush-bunchgrass range, every animal, regardless of its previous status (dosed at one of the inoculum levels tested or nondosed) shed E. coli O157:H7 uniformly. Shedding persisted for 15 days, after which all animals tested negative. E. coli O157:H7 reproduction and transmission and the combined effect of diet change and feed withholding were also investigated in a pilot study with experimentally inoculated rams. Withholding feed induced animals to shed the bacteria either by triggering growth of E. coli O157:H7 present in the intestines or by increasing susceptibility to infection. Introduction of a dietary change with brief starvation caused uniform shedding and clearance of E. coli O157:H7, and all animals then tested negative for the bacteria.(ABSTRACT TRUNCATED AT 250 WORDS)


Validation of newborn positioning protocol in Intensive Care Unit.
to verify the positioning indications of newborn sand build a standard operating procedure protocol for newborn positioning in Neonatal Intensive Care Unit (NICU). for protocol validation, the Delphi technique was used ,in which expert nurses in the field reviewed the proposed procedure. we present the results of this validation in a protocol form, to contribute to the discussion about newborn positioning in NICU and standardization of nursing care related to positioning. We evaluated ten indicators, in which there was agreementof100.0% in seven, and of80% in three, above the 60% recommended by the validation technique. given the importance of newborn positioning in NICU for its neuromuscular development, this study contributes to the adoption of an evidence-based practice for nursing.


ATG9A shapes the forming autophagosome through Arfaptin 2 and phosphatidylinositol 4-kinase IIIβ.
ATG9A is a multispanning membrane protein essential for autophagy. Normally resident in Golgi membranes and endosomes, during amino acid starvation, ATG9A traffics to sites of autophagosome formation. ATG9A is not incorporated into autophagosomes but is proposed to supply so-far-unidentified proteins and lipids to the autophagosome. To address this function of ATG9A, a quantitative analysis of ATG9A-positive compartments immunoisolated from amino acid-starved cells was performed. These ATG9A vesicles are depleted of Golgi proteins and enriched in BAR-domain containing proteins, Arfaptins, and phosphoinositide-metabolizing enzymes. Arfaptin2 regulates the starvation-dependent distribution of ATG9A vesicles, and these ATG9A vesicles deliver the PI4-kinase, PI4KIIIβ, to the autophagosome initiation site. PI4KIIIβ interacts with ATG9A and ATG13 to control PI4P production at the initiation membrane site and the autophagic response. PI4KIIIβ and PI4P likely function by recruiting the ULK1/2 initiation kinase complex subunit ATG13 to nascent autophagosomes.


Brønsted acid-catalyzed intramolecular nucleophilic substitution of the hydroxyl group in stereogenic alcohols with chirality transfer.
The hydroxyl group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols has been intramolecularly displaced by uncharged O-, N-, and S-centered nucleophiles to yield enantioenriched tetrahydrofuran, pyrrolidine, and tetrahydrothiophene derivatives with phosphinic acid catalysis. The five-membered heterocyclic products are generated in good to excellent yields, with high degree of chirality transfer, and water as the only side-product. Racemization experiments show that phosphinic acid does not promote SN1 reactivity. Density functional theory calculations corroborate a reaction pathway where the phosphinic acid operates as a bifunctional catalyst in the intramolecular substitution reaction. In this mechanism, the acidic proton of the phosphinic acid protonates the hydroxyl group, enhancing the leaving group ability. Simultaneously, the oxo group of phosphinic acid operates as a base abstracting the nucleophilic proton and thus enhancing the nucleophilicity. This reaction will open up new atom efficient techniques that enable alcohols to be used as nucleofuges in substitution reactions in the future.


The role of directionally selective neurons in the perception of global motion.
Dynamic random dot targets consisting of many localized motion vectors have been used to study the pooling of local motion signals into a global motion percept (Williams and Sekuler, 1984). In such displays, the dots are displaced with a constant step size and the direction of motion for each dot is chosen at random from a specified distribution. When the distribution extends over 360 deg, the display consists only of local random motion of individual dots and no coherent motion is reported. However, when the distribution is less than 360 deg (biased), the stimulus appears to flow in a single direction. We examined the effects of reducing the number of directionally selective (DS) cortical neurons on this integration process. Normal cats and cats with severely reduced proportions of DS neurons were trained on 2 direction discrimination tasks. The discrimination of opposite directions was examined while varying either the range of directions of local motion, or the proportion of dots moving with biased distribution. When all dots in the display were directionally biased, cats with reduced numbers of DS neurons performed the task as well as normal cats and humans (threshold range: 280-320 deg). However, when the proportion of biased dots decreased, these animals had severe deficits. Thus, in the absence of noise, even a very small number of DS neurons can perform spatial pooling of local directional signals, and support normal discrimination of opposite directions. However, a full complement of directional detectors appears necessary when the motion signal is masked by noise. The discrimination of small differences in direction revealed far more severe deficits, even when all the dots in the display were directionally biased (no noise).(ABSTRACT TRUNCATED AT 250 WORDS)


Genotypic Variation in the Root and Shoot Metabolite Profiles of Wheat (Triticum aestivum L.) Indicate Sustained, Preferential Carbon Allocation as a Potential Mechanism in Phosphorus Efficiency.
Changes in the levels of plant metabolites in response to nutrient deficiency is indicative of how plants utilize scarce resources. In this study, changes in the metabolite profile of roots and shoots of wheat genotypes differing in phosphorus use efficiency (PUE) was investigated. Under low P supply and at 28 days after sowing (DAS), the wheat breeding line, RAC875 (P efficient) produced 42% more shoot biomass than the wheat variety, and Wyalkatchem (P inefficient). Significant changes in the metabolite profile in leaves and roots were observed under low P supply and significant genotypic variation was evident. Under low P supply, an increase in raffinose and 1-kestose was evident in roots of both wheat genotypes, with RAC875 accumulating more when compared to Wyalkatchem. There was no significant increase in raffinose and 1-kestose in leaves when plants were grown under P deficiency. P deficiency had no significant impact on the levels of sucrose, maltose, glucose and fructose in both genotypes, and while phosphorylated sugars (glucose-6-P and fructose-6-P) remained unchanged in RAC875, in Wyalkatchem, glucose-6-P significantly decreased in roots, and fructose-6-P significantly decreased in both leaves and roots. Glycerol-3-P decreased twofold in roots of both wheat genotypes in response to low P. In roots, RAC875 exhibited significantly lower levels of fumarate, malate, maleate and itaconate than Wyalkatchem, while low P enhanced organic acid exudation in RAC875 but not in Wyalkatchem. RAC875 showed greater accumulation of aspartate, glutamine and β-alanine in leaves than Wyalkatchem under low P supply. Greater accumulation of raffinose and 1-kestose in roots and aspartate, glutamine and β-alanine in leaves appears to be associated with enhanced PUE in RAC875. Glucose-6-P and fructose-6-P are important for glycolysis, thus maintaining these metabolites would enable RAC875 to maintain carbohydrate metabolism and shoot biomass under P deficiency. The work presented here provides evidence that differences in metabolite profiles can be observed between wheat varieties that differ in PUE and key metabolic pathways are maintained in the efficient genotype to ensure carbon supply under P deficiency.


A CA repeat polymorphism of the IFN-gamma gene is associated with susceptibility to type 1 diabetes.
Recent studies have shown that loci outside the HLA region are involved in determining susceptibility to type 1 diabetes. Polymorphisms in the coding and noncoding regions of the genes encoding cytokines may be involved in modulating the immune response to self and nonself antigens. There is increasing evidence that an imbalance and disruption of the Thl and Th2 T cell subsets play a key role in the development of experimental and clinical type 1 diabetes. The aim of this study was to investigate the frequency of a CA dinucleotide repeat polymorphism in the interferon-gamma (IFN-gamma) gene (IFNG) and a C(-590)T polymorphism of the interleukin-4 (IL-4) gene in 236 Caucasoid patients with type 1 diabetes. There was a highly significant increase in the 3/3 IFNG genotype in the patients compared with normal healthy controls (34.3% vs. 13.5%, p<0.0001) as well as a significant increase in allele 3 of the IFNG locus in the patients compared with controls (51.9% vs. 31.7%, p<0.00001). In contrast, no significant differences were found in the frequency of the C(-590)T IL-4 polymorphism between patients and controls. These results suggest that polymorphisms of the IFNG gene may modify the function of this proinflammatory mediator and the response to pancreatic islet beta cells.


Laparotomic vs laparoscopic ovariectomy: comparing the two methods. The ovariectomy in the bitch in laparoscopic era.
The aim of the present work is to evaluate the effectiveness of the use of ultrasound scalpel during laparoscopic ovariectomy in the bitch. Two groups of 10 subjects each, of different races and ages, were compared. In the first group, ovariectomy was performed laparoscopically, using harmonic scalpel to remove ovary. In the second group surgery was performed by means of classical laparotomy. Pre-operative time was similar in both groups. Total operative time, from incision to skin suture, showed significant difference between the two groups, being laparoscopy faster than laparotomy. Partial operative time for bilateral oophorectomy resulted lower using open technique, but, considering each ovary, there was no significant difference in both groups. The use of harmonic scalpel to perform ovariectomy during laparoscopy is an effective time-sparing surgical approach compared to the already great practicality of laparotomy.


Epidemiological situation of malaria in Madagascar: baseline data for monitoring the impact of malaria control programmes using serological markers.
The aim of this study was to provide baseline information of the epidemiological situation of malaria in Madagascar using serological markers. We carried out cross-sectional studies in schoolchildren from eight sites in the four different malarious epidemiological strata of Madagascar. We studied the prevalence of anti-MSP1 antibodies to assess the burden, and anti-CSP antibodies to estimate the transmission intensity, of malaria. The overall prevalence of each antibody tested was 46.1% for anti-PfMSP-1, 15.2% for anti-PvMSP-1, 14.9% for anti-PfCSP, 4.9% for anti-PvCSP and 2.4% for anti-PmCSP. The prevalence of the five antibodies varied significantly between the sites (P<10(-6)). We also found significant effects of ethnic origin on the prevalence of anti-PfMSP1 antibodies. With regular testing in the same target populations, this data will be particularly useful for managing the elimination strategy supported by the Malagasy Government.


Quinols as novel therapeutic agents. 2.(1) 4-(1-Arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents.
A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones(1) with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI(50) value of 16 nM and a mean LC(50) value of 2.24 muM in the NCI 60-cell-line screen, with LC(50) activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.


Collaborative healthcare education programmes for continuing professional education in low and middle-income countries: A Best Evidence Medical Education (BEME) systematic review. BEME Guide No. 65.
Large discrepancies exist between standards of healthcare provision in high-income (HICs) and low and middle-income countries (LMICs). The root cause is often financial, resulting in poor infrastructure and under-resourced education and healthcare systems. Continuing professional education (CPE) programmes improve staff knowledge, skills, retention, and practice, but remain costly and rare in low-resource settings. One potential solution involves healthcare education collaborations between institutions in HICs and LMICs to provide culturally appropriate CPE in LMICs. To be effective, educational partnerships must address the challenges arising from differences in cultural norms, language, available technology and organisational structures within collaborating countries. Seven databases and other sources were systematically searched on 7 July 2020 for relevant studies. Citations, abstracts, and studies were screened and consensus was reached on which to include within the review. 54 studies were assessed regarding the type of educational programme involved, the nature of HIC/LMIC collaboration and quality of the study design. Studies varied greatly regarding the types and numbers of healthcare professionals involved, pedagogical and delivery methods, and the ways in which collaboration was undertaken. Barriers and enablers of collaboration were identified and discussed. The key findings were: 1. The methodological quality of reporting in the studies was generally poor. 2. The way in which HIC/LMIC healthcare education collaboration is undertaken varies according to many factors, including what is to be delivered, the learner group, the context, and the resources available. 3. Western bias was a major barrier. 4. The key to developing successful collaborations was the quality, nature, and duration of the relationships between those involved. This review provides insights into factors that underpin successful HIC/LMIC healthcare CPE collaborations and outlines inequities and quality issues in reporting.


Challenges to improving case management of childhood pneumonia at health facilities in resource-limited settings.
Effective case management is an important strategy to reduce pneumonia-related morbidity and mortality in children. Guidelines based on sound evidence are available but are used variably. This review outlines current guidelines for childhood pneumonia management in the setting where most child pneumonia deaths occur and identifies challenges for improved management in a variety of settings and different "at-risk" groups. These include appropriate choice of antibiotic, clinical overlap with other conditions, prompt and appropriate referral for inpatient care, and management of treatment failure. Management of neonates, and of HIV-infected or severely malnourished children is more complicated. The influence of co-morbidities on pneumonia outcome means that pneumonia case management must be integrated within strategies to improve overall paediatric care. The greatest potential for reducing pneumonia-related deaths in health facilities is wider implementation of the current guidelines built around a few core activities: training, antibiotics and oxygen. This requires investment in human resources and in equipment for the optimal management of hypoxaemia. It is important to provide data from a variety of epidemiological settings for formal cost-effectiveness analyses. Improvements in the quality of case management of pneumonia can be a vehicle for overall improvements in child health-care practices.


Perinatal health care services for imprisoned pregnant women and associated outcomes: a systematic review.
Women are an increasing minority of prisoners worldwide, and most are of childbearing age. Prisons offer unique opportunities for improving the pregnancy outcomes of these high-risk women, and no systematic review to date has looked at their care. This systematic review identified studies describing models of perinatal health care for imprisoned women which report maternal and child health and care outcomes. We systematically searched for literature published between 1980 and April 2014. Studies were eligible if they included a group of imprisoned pregnant women, a description of perinatal health care and any maternal or infant health or care outcomes. Two authors independently extracted data. We described relevant outcomes in prisons (including jails) under models of care we termed PRISON, PRISON+ and PRISON++, depending on the care provided. Where outcomes were available on a comparison group of women, we calculated odds ratios with 95 % confidence intervals. Eighteen studies were reported, comprising 2001 imprisoned pregnant women. Fifteen were in the US, two in the UK and one in Germany. Nine contained a comparison group of women comprising 849 pregnant women. Study quality was variable and outcome reporting was inconsistent. There was some evidence that women in prisons receiving enhanced prison care, PRISON+, were less likely to have inadequate prenatal care (15.4 % vs 30.7 %, p < 0 · 001), preterm delivery (6.4 % vs 19.0 %, p = 0 · 001) or caesarean delivery (12.9 % vs 26.5 %, p = 0 · 005) compared to women in prisons receiving usual care (PRISON). Women participating in two PRISON++ interventions, that is, interventions which included not only enhanced care in prisons but also coordination of community care on release, demonstrated reductions in long term recidivism rates (summary OR 0 · 37, 95 % CI 0 · 19-0 · 70) compared to pregnant women in the same prisons who did not participate in the intervention. Enhanced perinatal care can improve both short and long-term outcomes but there is a lack of data. Properly designed programmes with rigorous evaluation are needed to address the needs of this vulnerable population. The cost to mothers, children and to society of failing to address these important public health issues are likely to be substantial. PROSPERO registration: CRD42012002384 .


Viral infection and iron metabolism.
Fundamental cellular operations, including DNA synthesis and the generation of ATP, require iron. Viruses hijack cells in order to replicate, and efficient replication needs an iron-replete host. Some viruses selectively infect iron-acquiring cells by binding to transferrin receptor 1 during cell entry. Other viruses alter the expression of proteins involved in iron homeostasis, such as HFE and hepcidin. In HIV-1 and hepatitis C virus infections, iron overload is associated with poor prognosis and could be partly caused by the viruses themselves. Understanding how iron metabolism and viral infection interact might suggest new methods to control disease.


Image reconstruction and image quality evaluation for a dual source CT scanner.
The authors present and evaluate concepts for image reconstruction in dual source CT (DSCT). They describe both standard spiral (helical) DSCT image reconstruction and electrocardiogram (ECG)-synchronized image reconstruction. For a compact mechanical design of the DSCT, one detector (A) can cover the full scan field of view, while the other detector (B) has to be restricted to a smaller, central field of view. The authors develop an algorithm for scan data completion, extrapolating truncated data of detector (B) by using data of detector (A). They propose a unified framework for convolution and simultaneous 3D backprojection of both (A) and (B) data, with similar treatment of standard spiral, ECG-gated spiral, and sequential (axial) scan data. In ECG-synchronized image reconstruction, a flexible scan data range per measurement system can be used to trade off temporal resolution for reduced image noise. Both data extrapolation and image reconstruction are evaluated by means of computer simulated data of anthropomorphic phantoms, by phantom measurements and patient studies. The authors show that a consistent filter direction along the spiral tangent on both detectors is essential to reduce cone-beam artifacts, requiring truncation of the extrapolated (B) data after convolution in standard spiral scans. Reconstructions of an anthropomorphic thorax phantom demonstrate good image quality and dose accumulation as theoretically expected for simultaneous 3D backprojection of the filtered (A) data and the truncated filtered (B) data into the same 3D image volume. In ECG-gated spiral modes, spiral slice sensitivity profiles (SSPs) show only minor dependence on the patient's heart rate if the spiral pitch is properly adapted. Measurements with a thin gold plate phantom result in effective slice widths (full width at half maximum of the SSP) of 0.63-0.69 mm for the nominal 0.6 mm slice and 0.82-0.87 mm for the nominal 0.75 mm slice. The visually determined through-plane (z axis) spatial resolution in a bar pattern phantom is 0.33-0.36 mm for the nominal 0.6 mm slice and 0.45 mm for the nominal 0.75 mm slice, again almost independent of the patient's heart rate. The authors verify the theoretically expected temporal resolution of 83 ms at 330 ms gantry rotation time by blur free images of a moving coronary artery phantom with 90 ms rest phase and demonstrate image noise reduction as predicted for increased reconstruction data ranges per measurement system. Finally, they show that the smoothness of the transition between image stacks acquired in different cardiac cycles can be efficiently controlled with the proposed approach for ECG-synchronized image reconstruction.


Antibody-mediated kidney allograft rejection: therapeutic options and their experimental rationale.
With the advent of novel therapies to directly intervene with B cell immunity and complement activation, antibody-mediated kidney allograft rejection (AMR) has come into the focus of transplant immunologists. Intravenous immunoglobulin, rituximab, bortezomib, and eculizumab have been used to treat patients with acute AMR, apart from the standard treatment of antibody removal with plasma exchange or immunoadsorption and steroid pulses. This article describes the experimental rationale and summarizes the still limited clinical experience with these novel therapies in the transplant setting. Results with the standard treatment for acute AMR, including intense plasmapheresis, intravenous immunoglobulins, and steroids are good with a graft survival of 80% at 18 months. In contrast, patients suffering from chronic AMR have significant irreversible damage in their grafts with substantially impaired graft survival. Thus, the authors propose a step-wise escalation of therapy in refractory cases of acute AMR and advocate an urgent need for controlled therapeutic trials for acute and chronic AMR not to inflict unnecessary harm on our patients by uncontrolled polypragmasy.


Expert consensus document: Advances in the evaluation of anorectal function.
Faecal incontinence and evacuation disorders are common, impair quality of life and incur substantial economic costs worldwide. As symptoms alone are poor predictors of underlying pathophysiology and aetiology, diagnostic tests of anorectal function could facilitate patient management in those cases that are refractory to conservative therapies. In the past decade, several major technological advances have improved our understanding of anorectal structure, coordination and sensorimotor function. This Consensus Statement provides the reader with an appraisal of the current indications, study performance characteristics, clinical utility, strengths and limitations of the most widely available tests of anorectal structure (ultrasonography and MRI) and function (anorectal manometry, neurophysiological investigations, rectal distension techniques and tests of evacuation, including defecography). Additionally, this article provides our consensus on the clinical relevance of these tests.


Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation.
Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus.


Bioactive conformational generation of small molecules: a comparative analysis between force-field and multiple empirical criteria based methods.
Conformational sampling for small molecules plays an essential role in drug discovery research pipeline. Based on multi-objective evolution algorithm (MOEA), we have developed a conformational generation method called Cyndi in the previous study. In this work, in addition to Tripos force field in the previous version, Cyndi was updated by incorporation of MMFF94 force field to assess the conformational energy more rationally. With two force fields against a larger dataset of 742 bioactive conformations of small ligands extracted from PDB, a comparative analysis was performed between pure force field based method (FFBM) and multiple empirical criteria based method (MECBM) hybrided with different force fields. Our analysis reveals that incorporating multiple empirical rules can significantly improve the accuracy of conformational generation. MECBM, which takes both empirical and force field criteria as the objective functions, can reproduce about 54% (within 1Å RMSD) of the bioactive conformations in the 742-molecule testset, much higher than that of pure force field method (FFBM, about 37%). On the other hand, MECBM achieved a more complete and efficient sampling of the conformational space because the average size of unique conformations ensemble per molecule is about 6 times larger than that of FFBM, while the time scale for conformational generation is nearly the same as FFBM. Furthermore, as a complementary comparison study between the methods with and without empirical biases, we also tested the performance of the three conformational generation methods in MacroModel in combination with different force fields. Compared with the methods in MacroModel, MECBM is more competitive in retrieving the bioactive conformations in light of accuracy but has much lower computational cost. By incorporating different energy terms with several empirical criteria, the MECBM method can produce more reasonable conformational ensemble with high accuracy but approximately the same computational cost in comparison with FFBM method. Our analysis also reveals that the performance of conformational generation is irrelevant to the types of force field adopted in characterization of conformational accessibility. Moreover, post energy minimization is not necessary and may even undermine the diversity of conformational ensemble. All the results guide us to explore more empirical criteria like geometric restraints during the conformational process, which may improve the performance of conformational generation in combination with energetic accessibility, regardless of force field types adopted.


Sustained fitness gains and variability in fitness trajectories in the long-term evolution experiment with Escherichia coli.
Many populations live in environments subject to frequent biotic and abiotic changes. Nonetheless, it is interesting to ask whether an evolving population's mean fitness can increase indefinitely, and potentially without any limit, even in a constant environment. A recent study showed that fitness trajectories of Escherichia coli populations over 50 000 generations were better described by a power-law model than by a hyperbolic model. According to the power-law model, the rate of fitness gain declines over time but fitness has no upper limit, whereas the hyperbolic model implies a hard limit. Here, we examine whether the previously estimated power-law model predicts the fitness trajectory for an additional 10 000 generations. To that end, we conducted more than 1100 new competitive fitness assays. Consistent with the previous study, the power-law model fits the new data better than the hyperbolic model. We also analysed the variability in fitness among populations, finding subtle, but significant, heterogeneity in mean fitness. Some, but not all, of this variation reflects differences in mutation rate that evolved over time. Taken together, our results imply that both adaptation and divergence can continue indefinitely--or at least for a long time--even in a constant environment.


Using care profiles as a catalyst for improving end of life commissioning, involvement and service delivery.
In 2010, Liverpool Primary Care Trust successfully pioneered a care profiles approach to commissioning End of Life (EoL) services. They established service requirements for each stage of the EoL pathway, and set out skill mix, delivery, quality and outcomes. This feature sets out how the approach can also support local work relating to Advance Care Planning, palliative care funding tariffs and patient and public involvement. Local EoL services vary, reflecting geography, history, service models and resources. Few commissioners know in detail how all EoL services and resources systematically inter-relate, particularly those involving non-specialist services. Also, anecdotal evidence indicates that information provided by healthcare professionals to patients and carers is not necessarily consistent or complete. The planned introduction of per patient tariffs for palliative care in 2015 means commissioners must be clear about what EoL services are and what are not covered by the tariffs, and how this might impact on service delivery and contracts. A multi-disciplinary workshop established that by clarifying what services are commissioned locally, EoL care profiles can provide detailed information to ensure patients and carers receive comprehensive, consistent, quality information to support their Advanced Care Planning. They can address gaps in EoL information prescriptions and enable transparent information for patient and public involvement. EoL care profiles enable local services to be commissioned in detail, which is a catalyst and essential precursor for an inclusive and explicit approach to planning and resourcing services for individual patients and the population as a whole.


Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.
There are no proven, effective therapies for polycystic kidney disease (PKD) or polycystic liver disease (PLD). We enrolled 42 patients with severe PLD resulting from autosomal dominant PKD (ADPKD) or autosomal dominant PLD (ADPLD) in a randomized, double-blind, placebo-controlled trial of octreotide, a long-acting somatostatin analogue. We randomly assigned 42 patients in a 2:1 ratio to octreotide LAR depot (up to 40 mg every 28+/-5 days) or placebo for 1 year. The primary end point was percent change in liver volume from baseline to 1 year, measured by MRI. Secondary end points were changes in total kidney volume, GFR, quality of life, safety, vital signs, and clinical laboratory tests. Thirty-four patients had ADPKD, and eight had ADPLD. Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048). Among patients with ADPKD, total kidney volume remained practically unchanged (+0.25%+/-7.53%) in the octreotide group but increased by 8.61%+/-10.07% in the placebo group (P=0.045). Changes in GFR were similar in both groups. Octreotide was well tolerated; treated individuals reported an improved perception of bodily pain and physical activity. In summary, octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile.


Self-reported use of natural health products: a cross-sectional telephone survey in older Ontarians.
The self-reported use of natural health products (NHPs) (herbal products and vitamin and mineral supplements) has increased over the past decade in Canada. Because the elderly population might have comorbidities and concurrently administered medications, there is a need to explore the perceptions and behaviors associated with NHPs in this age group. The goal of this study was to assess the use of NHPs in a cohort of older Canadian residents and the characteristics, perceptions, and behaviors associated with NHP use. Survey participants aged > or = 60 years were randomly selected from telephone listings in the area of greater Hamilton, Ontario, Canada. Data were collected using a standardized computer-assisted telephone interview system. Self-reported data covering 7 domains were collected: (1) demographics; (2) self-reported 12-month NHP use; (3) reasons for NHP use; (4) self-reported 12-month prescription medication use; (5) expenditures on NHPs; (6) patient-reported adverse events and drug-NHP interactions; and (7) perceptions of physicians' attitudes regarding NHPs. Descriptive statistics were used to compare the characteristics of NHP users with those of nonusers and to assess the characteristics of NHP users across these 7 domains. Multivariate regression analysis was conducted to determine the demographic variables that might be associated with NHP user status. Of 2528 persons identified as age > or = 60 years, 1206 (48%) completed the telephone interview. Six hundred sixteen of these respondents (51%) reported the use of > or = 1 NHP during the previous 12 months. On the initial univariate analysis, younger age and higher income were significantly associated with reporting NHP use (mean age, users vs nonusers, 71.1 vs 72.7 years, respectively; 95% CI, 1.02-1.06; P < 0.001; income more than Can $26,000 was 28% and 22% in users and nonusers, respectively; P = 0.028). One hundred seventy of 616 users (28%) used an NHP to treat the same condition for which they were concurrently receiving a prescription medication, and 43 (25%) had not informed their physicians about their NHP use. Patients' characteristics such as sex, education, smoking status, and self-reported health status did not differ significantly between users and nonusers. In individuals who regularly spent money to purchase NHPs (n = 394), the mean cost was $20.38/mo. NHP expenditure was not significantly associated with age, sex, or income. Based on these findings, a substantial proportion of those Ontarians aged > or = 60 years reported NHP use, and there is a need for greater communication with physicians to avoid potential drug-NHP interactions.


Parental desensitization to violence and sex in movies.
To assess desensitization in parents' repeated exposure to violence and sex in movies. A national US sample of 1000 parents living with at least 1 target child in 1 of 3 age groups (6 to 17 years old) viewed a random sequence of 3 pairs of short scenes with either violent or sexual content from popular movies that were unrestricted to youth audiences (rated PG-13 or unrated) or restricted to those under age 17 years without adult supervision (rated R). Parents indicated the minimum age they would consider appropriate to view each film. Predictors included order of presentation, parent and child characteristics, and parent movie viewing history. As exposure to successive clips progressed, parents supported younger ages of appropriate exposure, starting at age 16.9 years (95% confidence interval [CI], 16.8 to 17.0) for violence and age 17.2 years (95% CI, 17.0 to 17.4) for sex, and declining to age 13.9 years (95% CI, 13.7 to 14.1) for violence and 14.0 years (95% CI, 13.7 to 14.3) for sex. Parents also reported increasing willingness to allow their target child to view the movies as exposures progressed. Desensitization was observed across parent and child characteristics, violence toward both human and non-human victims, and movie rating. Those who frequently watched movies were more readily desensitized to violence. Parents become desensitized to both violence and sex in movies, which may contribute to the increasing acceptance of both types of content by both parents and the raters employed by the film industry.


Running-related injury prevention through innate impact-moderating behavior.
The purpose of these experiments was to test the Robbins and Hanna hypothesis, which relates differences in discomfort from localized deformation at certain positions on the plantar surface to protective behavior (intrinsic foot shock absorption). A penetrometer was used to quantify the relations between localized load and pain and between load and depth of deformation. The magnitude of load required to elicit pain varied significantly (P less than 0.005) in relation to position on the plantar surface. With a load of 9 kg and a 10 mm spherical end on the penetrometer, 6% of the sample reported pain at the heelpad, 32% at the distal first digit, and 66% at the first metatarsal-phalangeal joint. This pattern was predicted by the Robbins and Hanna thesis. Two deformation patterns were observed which were best explained by deformation constraint by tight trabecular tethering of the epithelial membrane at the heelpad and distal first digit and unrestricted deformation due to loose trabecular tethering of the epithelial membrane at the first metatarsal-phalangeal joint. These data provide insight into how, when barefoot, the plantar surface resists perforation yet provides protection to local bony structures. These data further support the notion that plantar sensory feedback plays a central role in safe and effective locomotion.


Healthcare resource utilization of second-generation long-acting injectable antipsychotics in schizophrenia: risperidone versus paliperidone palmitate.
This retrospective longitudinal cohort study aimed to compare treatment patterns, healthcare resource utilization (HRU), and costs in patients with schizophrenia treated with second-generation antipsychotic long-acting injectables (SGA-LAIs): biweekly risperidone LAI versus once-monthly paliperidone palmitate. Patients who initiated risperidone LAI or paliperidone palmitate between 1 July 2007 and 31 December 2012 (index date) were identified from the Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases. Outcomes were assessed 12 months after the index date. Propensity score matching (1:1) based on patients' demographics and comorbidities was conducted. Outcome differences between the two cohorts were evaluated using t-tests for continuous variables, chi-square tests for categorical variables, and Wilcoxon rank-sum tests for count and cost variables. Regression models estimated the difference in medication use and adherence, likelihood of HRU, number of HRU events, and healthcare costs when comparing risperidone LAI versus paliperidone palmitate, while further adjusting for patient characteristics and pre-index HRU. Patient characteristics were well balanced between the two cohorts (n = 499 each). Significantly lower discontinuation rates (36.5% vs. 53.3%; p < 0.001) and longer days of LAI coverage (233.6 vs. 131.7 days; p < 0.001) were observed in the paliperidone palmitate cohort versus the risperidone LAI cohort, respectively. Patients treated with paliperidone palmitate were 12.5 (95% confidence interval [CI]: 9.0-17.8) and 11.7 (95% CI: 8.0-17.4) times more likely to be adherent based on medication possession ratio and proportion of days covered, respectively (p < 0.001). Patients treated with paliperidone palmitate had reduced likelihood of hospitalization (adjusted odds ratio [95% CI]: 0.72 [0.55-0.95]), fewer emergency department (ED) visits (adjusted incidence rate ratio [aIRR]: 0.67 [0.61-0.73]) and reduced length of inpatient stay (aIRR: 0.86 [0.82-0.90]), which resulted in lower monthly inpatient hospitalization costs (-$77.58; p = 0.038) and ED visits (-$9.77; p = 0.021) relative to risperidone LAI. Pharmacy costs were derived from health plan payment in the claims data and do not account for any discounts or rebates. This may have overestimated the branded drug costs in this analysis. These findings highlight the value of once-monthly paliperidone palmitate in the treatment of patients with schizophrenia.


Endosomal recycling controls plasma membrane area during mitosis.
The shape and total surface of a cell and its daughters change during mitosis. Many cells round up during prophase and metaphase and reacquire their extended and flattened shape during cytokinesis. How does the total area of plasma membrane change to accommodate these morphological changes and by what mechanism is control of total membrane area achieved? Using single-cell imaging methods, we have found that the amount of plasma membrane in attached cells in culture decreases at the beginning of mitosis and recovers rapidly by the end. Clathrin-based endocytosis is normal throughout all phases of cell division, whereas recycling of internalized membranes back to the cell surface slows considerably during the rounding up period and resumes at the time at which recovery of cell membrane begins. Interference with either one of these processes by genetic or chemical means impairs cell division. The total cell-membrane area recovers even in the absence of a functional Golgi apparatus, which would be needed for export of newly synthesized membrane lipids and proteins. We propose a mechanism by which modulation of endosomal recycling controls cell area and surface expression of membrane-bound proteins during cell division.


Pectoralis major tendon repairs in the active-duty population.
Rupture of the pectoralis major tendon is an uncommon injury that typically occurs in young, active people. Of this injury population, active-duty military personnel represent a unique, athletic subset that is commonly treated with operative repair. For the retrospective case series reported here, we hypothesized that active-duty soldiers with acute and chronic pectoralis major tendon ruptures treated with operative repair would have high levels of patient satisfaction, quick return to work and sports, and few long-term complications. We retrospectively reviewed all pectoralis major tendon rupture repairs performed at our institution between 2000 and 2007. Charts were thoroughly reviewed, and patients were asked to complete DASH (Disabilities of the Arm, Shoulder, and Hand) and supplemental questionnaires. Paired Student's t test was performed, and Ps were calculated to analyze statistical differences between immediate- and delayed-treatment groups. Fourteen patients were identified. The most common mechanism of injury was bench-pressing weights. Overall DASH, Work Module, and Sports Module scores were good to excellent. There was a statistically significant difference between outcomes for the immediate- and delayed- treatment groups, with the immediate-treatment group having better overall DASH and Work Module scores. Patients had a 30% to 40% objective loss of strength after surgery. Active-duty soldiers reported acceptable overall outcomes after both immediate and delayed treatment for pectoralis major tendon ruptures, but a statistically significant difference was found in overall DASH and Work Module scores between the treatment groups.


Comparative characterization of human induced pluripotent stem cells (hiPSC) derived from patients with schizophrenia and autism.
Human induced pluripotent stem cells (hiPSC) provide an attractive tool to study disease mechanisms of neurodevelopmental disorders such as schizophrenia. A pertinent problem is the development of hiPSC-based assays to discriminate schizophrenia (SZ) from autism spectrum disorder (ASD) models. Healthy control individuals as well as patients with SZ and ASD were examined by a panel of diagnostic tests. Subsequently, skin biopsies were taken for the generation, differentiation, and testing of hiPSC-derived neurons from all individuals. SZ and ASD neurons share a reduced capacity for cortical differentiation as shown by quantitative analysis of the synaptic marker PSD95 and neurite outgrowth. By contrast, pattern analysis of calcium signals turned out to discriminate among healthy control, schizophrenia, and autism samples. Schizophrenia neurons displayed decreased peak frequency accompanied by increased peak areas, while autism neurons showed a slight decrease in peak amplitudes. For further analysis of the schizophrenia phenotype, transcriptome analyses revealed a clear discrimination among schizophrenia, autism, and healthy controls based on differentially expressed genes. However, considerable differences were still evident among schizophrenia patients under inspection. For one individual with schizophrenia, expression analysis revealed deregulation of genes associated with the major histocompatibility complex class II (MHC class II) presentation pathway. Interestingly, antipsychotic treatment of healthy control neurons also increased MHC class II expression. In conclusion, transcriptome analysis combined with pattern analysis of calcium signals appeared as a tool to discriminate between SZ and ASD phenotypes in vitro.


Genome-wide characterization of human L1 antisense promoter-driven transcripts.
Long INterspersed Element-1 (LINE-1 or L1) is the only autonomously active, transposable element in the human genome. L1 sequences comprise approximately 17 % of the human genome, but only the evolutionarily recent, human-specific subfamily is retrotransposition competent. The L1 promoter has a bidirectional orientation containing a sense promoter that drives the transcription of two proteins required for retrotransposition and an antisense promoter. The L1 antisense promoter can drive transcription of chimeric transcripts: 5' L1 antisense sequences spliced to the exons of neighboring genes. The impact of L1 antisense promoter activity on cellular transcriptomes is poorly understood. To investigate this, we analyzed GenBank ESTs for messenger RNAs that initiate in the L1 antisense promoter. We identified 988 putative L1 antisense chimeric transcripts, 911 of which have not been previously reported. These appear to be alternative genic transcripts, sense-oriented with respect to gene and initiating near, but typically downstream of, the gene transcriptional start site. In multiple cell lines, L1 antisense promoters display enrichment for YY1 transcription factor and histone modifications associated with active promoters. Global run-on sequencing data support the activity of the L1 antisense promoter. We independently detected 124 L1 antisense chimeric transcripts using long read Pacific Biosciences RNA-seq data. Furthermore, we validated four chimeric transcripts by quantitative RT-PCR and Sanger sequencing and demonstrated that they are readily detectable in many normal human tissues. We present a comprehensive characterization of human L1 antisense promoter-driven transcripts and provide substantial evidence that they are transcribed in a variety of human cell-types. Our findings reveal a new wide-reaching aspect of L1 biology by identifying antisense transcripts affecting as many as 4 % of all human genes.


Are views towards egg farming associated with Brazilian and Chilean egg consumers' purchasing habits?
In many industrialised countries, public rejection of intensive animal production systems has led to the development of legislation and industry actions that have resulted in significant changes in animal care at the farm level. However, little is known about the views of citizens from emerging countries regarding animal production. The aims of this study were to explore the views of Brazilian and Chilean consumers towards egg farming, and to investigate if these views are associated with participants' eggs purchasing habits and reported willingness to pay (WTP) more for eggs produced in the conditions they perceive as important. In an open question, participants (n = 716) were asked to describe an ideal egg production farm and explain their reasons. This was followed by closed questions asking egg purchasing habits, willingness to pay for eggs produced in the conditions they perceive as important and demographic information. Participants main concerns were with animal welfare, naturalness, hygiene, production, and ethical aspects, which many associated with improved health, sensory, and nutritional quality of the eggs. The views of participants towards an ideal egg production farm were associated, to some extent, with type of egg purchasing habits and WTP a premium for organic or free-range eggs. Our results suggest a demand for more natural, animal friendly egg production systems; furthermore, they indicate a disconnect between lay citizens' expectations and industry practices, given that intensive confined systems typically fail to supply many of the expected characteristics.


Comparing the kinetics of NK cells, CD4, and CD8 T cells in murine cytomegalovirus infection.
NK cells recognize virus-infected cells with germline-encoded activating and inhibitory receptors that do not undergo genetic recombination or mutation. Accordingly, NK cells are often considered part of the innate immune response. The innate response comprises rapid early defenders that do not form immune memory. However, there is increasing evidence that experienced NK cells provide increased protection to secondary infection, a hallmark of the adaptive response. In this study, we compare the dynamics of the innate and adaptive immune responses by examining the kinetic profiles of the NK and T cell response to murine CMV infection. We find that, unexpectedly, the kinetics of NK cell proliferation is neither earlier nor faster than the CD4 or CD8 T cell response. Furthermore, early NK cell contraction after the peak of the response is slower than that of T cells. Finally, unlike T cells, experienced NK cells do not experience biphasic decay after the response peak, a trait associated with memory formation. Rather, NK cell contraction is continuous, constant, and returns to below endogenous preinfection levels. This indicates that the reason why Ag-experienced NK cells remain detectable for a prolonged period after adoptive transfer and infection is in part due to the high precursor frequency, slow decay rate, and low background levels of Ly49H(+) NK cells in recipient DAP12-deficient mice. Thus, the quantitative contribution of Ag-experienced NK cells in an endogenous secondary response, with higher background levels of Ly49H(+) NK cells, may be not be as robust as the secondary response observed in T cells.


Screening and testing for endocrine disruption in fish-biomarkers as "signposts," not "traffic lights," in risk assessment.
Biomarkers are currently best used as mechanistic "signposts" rather than as "traffic lights" in the environmental risk assessment of endocrine-disrupting chemicals (EDCs). In field studies, biomarkers of exposure [e.g., vitellogenin (VTG) induction in male fish] are powerful tools for tracking single substances and mixtures of concern. Biomarkers also provide linkage between field and laboratory data, thereby playing an important role in directing the need for and design of fish chronic tests for EDCs. It is the adverse effect end points (e.g., altered development, growth, and/or reproduction) from such tests that are most valuable for calculating adverseNOEC (no observed effect concentration) or adverseEC10 (effective concentration for a 10% response) and subsequently deriving predicted no effect concentrations (PNECs). With current uncertainties, biomarkerNOEC or biomarkerEC10 data should not be used in isolation to derive PNECs. In the future, however, there may be scope to increasingly use biomarker data in environmental decision making, if plausible linkages can be made across levels of organization such that adverse outcomes might be envisaged relative to biomarker responses. For biomarkers to fulfil their potential, they should be mechanistically relevant and reproducible (as measured by interlaboratory comparisons of the same protocol). VTG is a good example of such a biomarker in that it provides an insight to the mode of action (estrogenicity) that is vital to fish reproductive health. Interlaboratory reproducibility data for VTG are also encouraging; recent comparisons (using the same immunoassay protocol) have provided coefficients of variation (CVs) of 38-55% (comparable to published CVs of 19-58% for fish survival and growth end points used in regulatory test guidelines). While concern over environmental xenoestrogens has led to the evaluation of reproductive biomarkers in fish, it must be remembered that many substances act via diverse mechanisms of action such that the environmental risk assessment for EDCs is a broad and complex issue. Also, biomarkers such as secondary sexual characteristics, gonadosomatic indices, plasma steroids, and gonadal histology have significant potential for guiding interspecies assessments of EDCs and designing fish chronic tests. To strengthen the utility of EDC biomarkers in fish, we need to establish a historical control database (also considering natural variability) to help differentiate between statistically detectable versus biologically significant responses. In conclusion, as research continues to develop a range of useful EDC biomarkers, environmental decision-making needs to move forward, and it is proposed that the "biomarkers as signposts" approach is a pragmatic way forward in the current risk assessment of EDCs.


Enhanced maze performance and reduced oxidative stress by combined extracts of zingiber officinale and ginkgo biloba in the aged rat.
Here we assessed the effects of i.g. administration of Zingicomb (ZC), a mixture of zingiber officinale and ginkgo biloba extracts, on learning and memory, and on indicators of oxidative stress in aged rats. Effects of ZC (1 and 10 mg/kg) were investigated in 22-24 months old Wistar rats using the Morris water maze, in which they show deficient performance as compared to 3 months old rats in the undrugged state (days 1 and 2). Treatment was administered on days 3 and 4 of training, then over 7 days with training discontinued, and again on days 5 and 6 when training was resumed. Thereafter chronic treatment was maintained over 5 months. 1 mg/kg ZC improved escape learning in the water maze. The two capital indicators of oxidative stress in brain homogenates, the amount of oxidized proteins (assessed as carbonyl group containing proteins) and lipid peroxidation, were significantly reduced in ZC treated animals. Thus, ZC, which had previously been shown to improve inhibitory avoidance learning and to have anxiolytic properties in adult animals, might also facilitate spatial learning in aged animals, and reduces indices of oxidative stress in brain tissue after chronic treatment.


Nonpharmacologic treatment of functional abdominal pain disorders: a systematic review.
Various nonpharmacologic treatments are available for pediatric abdominal pain-related functional gastrointestinal disorders (AP-FGIDs). Data on efficacy and safety are scarce. The goal of this study was to summarize the evidence regarding nonpharmacologic interventions for pediatric AP-FGIDs: lifestyle interventions, dietary interventions, behavioral interventions, prebiotics and probiotics, and alternative medicine. Searches were conducted of the Medline and Cochrane Library databases. Systematic reviews and randomized controlled trials (RCTs) concerning nonpharmacologic therapies in children (aged 3-18 years) with AP-FGIDs were included, and data were extracted on participants, interventions, and outcomes. The quality of evidence was assessed by using the GRADE approach. Twenty-four RCTs were found that included 1390 children. Significant improvement of abdominal pain was reported after hypnotherapy compared with standard care/wait-list approaches and after cognitive behavioral therapy compared with a variety of control treatments/wait-list approaches. Written self-disclosure improved pain frequency at the 6-month follow-up only. Compared with placebo, Lactobacillus rhamnosus GG (LGG) and VSL#3 were associated with significantly more treatment responders (LGG relative risk: 1.31 [95% confidence interval: 1.08 to 1.59]; VSL#3: P < .05). Guar gum significantly improved irritable bowel syndrome symptom frequency; however, no effect was found for other fiber supplements (relative risk: 1.17 [95% confidence interval: 0.75 to 1.81]) or a lactose-free diet. Functional disability was not significantly decreased after yoga compared with a wait-list approach. No studies were found concerning lifestyle interventions; gluten-, histamine-, or carbonic acid-free diets; fluid intake; or prebiotics. No serious adverse effects were reported. The quality of evidence was found to be very low to moderate. Although high-quality studies are lacking, some evidence shows efficacy of hypnotherapy, cognitive behavioral therapy, and probiotics (LGG and VSL#3) in pediatric AP-FGIDs. Data on fiber supplements are inconclusive.


SHV-12-like extended-spectrum-beta-lactamase-producing strains of Salmonella enterica serotypes Babelsberg and Enteritidis isolated in France among infants adopted from Mali.
From December 2002 to June 2003, 14 cultures of Salmonella enterica serotype Babelsberg and 6 cultures of serotype Enteritidis, isolated in France from internationally adopted children, were identified at the French National Reference Center for Salmonella. All serotype Babelsberg isolates were related, as determined by pulsed-field gel electrophoresis, and all serotype Enteritidis strains displayed the same phage type. All serotype Enteritidis and seven serotype Babelsberg isolates produced an SHV-12-like extended-spectrum beta-lactamase as determined by sequencing of PCR products and by isoelectrofocusing. Some serotype Enteritidis isolates exhibited additional antimicrobial resistance (aminoglycosides, tetracycline, chloramphenicol, sulfonamides, and trimethoprim). Our investigation indicated that these Salmonella isolates were certainly acquired in the same orphanage in Bamako, Mali, before the children were adopted by French families. An inappropriate use of ceftriaxone was probably the cause of the emergence of such strains. There is an urgent need to determine the origin of the contamination and to introduce adequate antibiotic protocols into this orphanage to prevent further transmission and dissemination. Screening for infections and follow-up, adapted to the origin of the internationally adopted children, should be recommended.


First Report of Begonia Elatior Wilt Disease Caused by Fusarium foetens in France.
Fusarium foetens is a destructive vascular pathogen on Begonia, mainly on cultivars of Begonia elatior hybrids (Begonia × hiemalis), which has recently been identified in Europe and Northern America (1,3). This Fusarium species has been responsible for severe damage in the begonia flower industry (1) and is listed as an EPPO A2 quarantine pathogen since 2007. In May 2007, wilted potted plants of B. elatior showing chlorotic leaves and basal stem rot were observed in a nursery located in the west of France (La Flèche, Sarthe). Symptomatic foliar and basal stem pieces were plated on a Fusarium semi selective medium, dichloran chloramphenicol peptone agar (DCPA), and on malt agar medium supplemented with 100 ppm chloramphenicol. Homogeneous mycelium of a Fusarium species developed from both types of tissue and on both media, and was transferred to potato dextrose agar (PDA) and to spezieller nährstoffarmer agar (SNA) media for morphological examination. Microscope slides were then prepared by pressing gently a clear self-adhesive tape onto the surface covered by mycelium and sporodochia, which was further stained with lactic acid/methylene blue. Typical multiseptate (often three septa), hyaline, slightly curved Fusarium macroconidia 29.2 to 41.8 (32.5) × 3.6 to 4.5 (4.3) μm were collected in sporodochia. In the aerial mycelium, long and short conidiophores with mono- or polyphialidic cells bearing false heads of ellipsoidal microconidia were observed. In addition, a pungent distinctive odor was produced by the mycelium grown on PDA. These features were consistent with F. foetens (2). To support the diagnosis, total DNA was further extracted from the pure culture and a partial region of the translation elongation 1 (tef1) gene was amplified by PCR using EF1-EF2 primer pair (4). Nucleotide sequence was determined and deposited on GenBank (Accession No. JX298790). Analysis of the sequence by BLAST showed that it was 100% identical with all the available F. foetens sequences, which confirmed our morphological diagnosis. To our knowledge, this is the first official report of F. foetens in France. Since this first detection, F. foetens was again identified in 2010 in another nursery located in the Pays de la Loire on collapsed B. elatior. Approximately 15 to 20% of the Begonia plants showed typical Fusarium wilt symptoms and the infected lots were systematically destroyed. The origin of these infections could not be traced back since the mother plants tested negative. The disease is considered as eradicated in France but causes major economic losses to Begonia growers and marketers in regions where the disease is established (2). References: (1) H. Huvenne et al. Eur. J. Plant Pathol. 131:705, 2011. (2) H. J. Schroers et al. Mycologia 96:393, 2004. (3) X. L. Tian et al. Plant Dis. 94:1261, 2010. (4) D. Geiser. Eur. J. Plant Pathol. 110:473, 2004.