Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients.
Recessively inherited mutations in the base excision repair gene MYH have recently been associated with predisposition to colorectal adenomas and cancer in materials selected for occurrence of multiple adenomas. In particular, variants Y165C and G382D have been shown to play a role in Caucasian patients. To evaluate the contribution of MYH mutations to colorectal cancer burden on the population level, and to examine the MYH-associated phenotype in an unselected series of colorectal cancer patients, we determined the frequencies of Y165C and G382D MYH mutations in a population-based series of 1042 Finnish colorectal cancer patients. Four (0.4%) patients had both MYH alleles mutated. Although all these patients had multiple adenomatous polyps, the phenotypes tended to be less extreme than in previous studies on selected cases. The lowest number of colorectal adenomas at the time of cancer diagnosis was five. Cases with one mutant MYH allele were subjected to sequencing of all exons to detect possible Finnish founder mutations, but no additional changes were detected. The Y165C and G382D variants were not present in 424 Finnish cancer-free controls showing that MYH mutations are not enriched in the population. As evaluated against national Finnish Polyposis Registry data MYH-associated colorectal cancer appears to be as common as colorectal cancer associated with familial adenomatous polyposis.


Stress induces analgesia via orexin 1 receptor-initiated endocannabinoid/CB1 signaling in the mouse periaqueductal gray.
The orexin system consists of orexin A/hypocretin 1 and orexin B/hypocretin 2, and OX1 and OX2 receptors. Our previous electrophysiological study showed that orexin A in the rat ventrolateral periaqueductal gray (vlPAG) induced antinociception via an OX1 receptor-initiated and endocannabinoid-mediated disinhibition mechanism. Here, we further characterized antinociceptive effects of orexins in the mouse vlPAG and investigated whether this mechanism in the vlPAG can contribute to stress-induced analgesia (SIA) in mice. Intra-vlPAG (i.pag.) microinjection of orexin A in the mouse vlPAG increased the hot-plate latency. This effect was mimicked by i.pag. injection of WIN 55,212-2, a CB1 agonist, and antagonized by i.pag. injection of the antagonist of OX1 (SB 334867) or CB1 (AM 251), but not OX2 (TCS-OX2-29) or opioid (naloxone), receptors. [Ala(11), D-Leu(15)]-orexin B (i.pag.), an OX2 selective agonist, also induced antinociception in a manner blocked by i.pag. injection of TCS-OX2-29, but not SB 334867 or AM 251. Mice receiving restraint stress for 30 min showed significantly longer hot-plate latency, more c-Fos-expressing orexin neurons in the lateral hypothalamus and higher orexin levels in the vlPAG than unrestrained mice. Restraint SIA in mice was prevented by i.pag. or intraperitoneal injection of SB 334867 or AM 251, but not TCS-OX2-29 or naloxone. These results suggest that during stress, hypothalamic orexin neurons are activated, releasing orexins into the vlPAG to induce analgesia, possibly via the OX1 receptor-initiated, endocannabinoid-mediated disinhibition mechanism previously reported. Although activating either OX1 or OX2 receptors in the vlPAG can lead to antinociception, only OX1 receptor-initiated antinociception is endocannabinoid-dependent.


Nutrition education, farm production diversity, and commercialization on household and individual dietary diversity in Zimbabwe.
Nutrition education is crucial for improved nutrition outcomes. However, there are no studies to the best of our knowledge that have jointly analysed the roles of nutrition education, farm production diversity and commercialization on household, women and child dietary diversity. This article jointly analyses the role of nutrition education, farm production diversity and commercialization on household, women and children dietary diversity in Zimbabwe. In addition, we analyze separately the roles of crop and livestock diversity and individual agricultural practices on dietary diversity. Data were collected from 2,815 households randomly selected in eight districts. Negative binomial regression was used for model estimations. Nutrition education increased household, women, and child dietary diversity by 3, 9 and 24%, respectively. Farm production diversity had a strong and positive association with household and women dietary diversity. Crop diversification led to a 4 and 5% increase in household and women dietary diversity, respectively. Furthermore, livestock diversification and market participation were positively associated with household, women, and children dietary diversity. The cultivation of pulses and fruits increased household, women, and children dietary diversity. Vegetable production and goat rearing increased household and women dietary diversity. Nutrition education and improving access to markets are promising strategies to improve dietary diversity at both household and individual level. Results demonstrate the value of promoting nutrition education; farm production diversity; small livestock; pulses, vegetables and fruits; crop-livestock integration; and market access for improved nutrition.


Association of excessive GWG with adiposity indicators and metabolic diseases of their offspring: systematic review.
It has been reported that excessive gestational weight gain (GWG) during pregnancy is associated with an increase in adiposity indicators and metabolic disorders of the offspring. The objective of this review, using the Institute of Medicine (IOM) criteria, was to analyze the association of excessive GWG in prospective studies with the adiposity indicators and metabolic diseases of the offspring, and the association of excessive GWG with adiposity indicators and metabolic disease of the ≥ 15 years offspring. An electronic search was conducted in the MEDLINE/PubMed, EMBASE, and CINAHL databases of prospective cohort studies published from January 2004 to September 2014. Selection was restricted to prospective cohort studies where the definition of GWG was used according to the IOM-recommendations; and prospective cohort studies including offspring ≥ 15 years, independent of using the definition for excessive GWG. Nine prospective cohort studies meet the inclusion criteria. Five studies used the IOM-recommendations for assessing GWG, and six studies assessed adiposity or metabolic indicators of their offspring at ≥ 15 years. In seven of the nine studies, excessive GWG was associated with adiposity and metabolic diseases. Due to the limitations found, the evidence of the association was shown to be low. The results of this review showed, that independently of the criteria used to diagnose excessive GWG, all the included studies, consistently showed an association of excessive GWG with adiposity indicators or other components of metabolic disease early in life, during adolescence or adulthood. However, due to the limitations of the studies the strength of the evidence was low. Better designed studies are warranted to confirm a stronger evidence.


Current insights in obstetric antiphospholipid syndrome.
Antiphospholipid syndrome (APS) is defined as the association of thrombotic events and/or obstetric morbidity in patients persistently positive for antiphospholipid antibodies (aPL). In this review, we will highlight the most important clinical presentations of APS with a focus on the obstetric morbidity, the current management strategies and the outlook for the future. The use of aspirin and heparin has improved the pregnancy outcome in obstetric APS and approximately 70% of pregnant women with APS have a successful pregnancy outcome. Unfortunately, the current standard of care does not prevent all pregnancy complications as the current treatment fails in 20-30% of APS pregnancies. This therefore highlights the need for alternative treatments to improve obstetrical outcome. Other treatment options are currently explored and retrospective studies show that pravastatin for example is beneficial in women with aPL-related early preeclampsia. Moreover, the immunmodulator hydroxychloroquine may play a beneficial role in the prevention of aPL-related pregnancy complications. APS is among the most frequent acquired risk factors for a treatable cause of recurrent pregnancy loss and increases the risk of conditions associated with ischaemic placental dysfunction, such as fetal growth restriction, preeclampsia, premature birth and intrauterine death. Current treatment is mainly based on aspirin and heparin. Studies to inform on alternative treatment options are urgently needed.


Cyclic AMP analog blocks kinase activation by stabilizing inactive conformation: conformational selection highlights a new concept in allosteric inhibitor design.
The regulatory (R) subunit of protein kinase A serves to modulate the activity of protein kinase A in a cAMP-dependent manner and exists in two distinct and structurally dissimilar, end point cAMP-bound "B" and C-subunit-bound "H"-conformations. Here we report mechanistic details of cAMP action as yet unknown through a unique approach combining x-ray crystallography with structural proteomics approaches, amide hydrogen/deuterium exchange and ion mobility mass spectrometry, applied to the study of a stereospecific cAMP phosphorothioate analog and antagonist((Rp)-cAMPS). X-ray crystallography shows cAMP-bound R-subunit in the B form but surprisingly the antagonist Rp-cAMPS-bound R-subunit crystallized in the H conformation, which was previously assumed to be induced only by C-subunit-binding. Apo R-subunit crystallized in the B form as well but amide exchange mass spectrometry showed large differences between apo, agonist and antagonist-bound states of the R-subunit. Further ion mobility reveals the apo R-subunit as an ensemble of multiple conformations with collisional cross-sectional areas spanning both the agonist and antagonist-bound states. Thus contrary to earlier studies that explained the basis for cAMP action through "induced fit" alone, we report evidence for conformational selection, where the ligand-free apo form of the R-subunit exists as an ensemble of both B and H conformations. Although cAMP preferentially binds the B conformation, Rp-cAMPS interestingly binds the H conformation. This reveals the unique importance of the equatorial oxygen of the cyclic phosphate in mediating conformational transitions from H to B forms highlighting a novel approach for rational structure-based drug design. Ideal inhibitors such as Rp-cAMPS are those that preferentially "select" inactive conformations of target proteins by satisfying all "binding" constraints alone without inducing conformational changes necessary for activation.


Fibroblast growth factor 10 haploinsufficiency causes chronic obstructive pulmonary disease.
Genetic factors influencing lung function may predispose to chronic obstructive pulmonary disease (COPD). The fibroblast growth factor 10 (FGF10) signalling pathway is critical for lung development and lung epithelial renewal. The hypothesis behind this study was that constitutive FGF10 insufficiency may lead to pulmonary disorder. Therefore investigation of the pulmonary functions of patients heterozygous for loss of function mutations in the FGF10 gene was performed. The spirometric measures of lung function from patients and non-carrier siblings were compared and both groups were related to matched reference data for normal human lung function. The patients show a significant decrease in lung function parameters when compared to control values. The average FEV1/IVC quota (FEV1%) for the patients is 0.65 (80% of predicted) and reversibility test using Terbutalin resulted in a 3.7% increase in FEV1. Patients with FGF10 haploinsufficiency have lung function parameters indicating COPD. A modest response to Terbutalin confirms an irreversible obstructive lung disease. These findings support the idea that genetic variants affecting the FGF10 signalling pathway are important determinants of lung function that may ultimately contribute to COPD. Specifically, the results show that FGF10 haploinsufficiency affects lung function measures providing a model for a dosage sensitive effect of FGF10 in the development of COPD.


Do Immigrants Assimilate More Slowly Today than in the Past?
Using millions of historical census records and modern birth certificates, we document that immigrants assimilated into US society at similar rates in the past and present. We measure cultural assimilation as immigrants giving their children less foreign names after spending more time in the United States, and show that immigrants erase about one-half of the naming gap with natives after 20 years both historically and today. Immigrants from poorer countries choose more foreign names upon first arrival in both periods but are among the fastest to shift toward native-sounding names. We find substantial cultural assimilation for immigrants of all education levels.


Speciation with gene flow could be common.
The likelihood of speciation in the face of homogenizing gene flow (i.e. without complete geographical isolation) is one of the most debated topics in evolutionary biology. Demonstrating this phenonemon is hampered by the difficulty of isolating the effects of time since population divergence vs. gene flow on levels of molecular genetic differentiation. For example, weak genetic differentiation between taxa could be due to recent divergence, gene flow, or a combination of these factors. Nonetheless, a number of convincing examples of speciation with gene flow have recently emerged, owing in part to the development of new analytical methods designed to estimate gene flow specifically. A recent example of speciation with gene flow in salamanders (Niemiller et al. 2008) further advances our understanding of this phenonemon, by showing that gene flow between cave and spring salamanders was ongoing during speciation, rather than having occurred after a long period of allopatric divergence. Future work on the ecological and genetic factors reducing gene flow will likely increase our understanding of the conditions that faciliate divergence in the face of gene flow.


Predictive value of primate models for AIDS.
A number of obstacles remain in the search for an animal model for HIV infection and pathogenesis that can serve to predict efficacy in humans. HIV-1 fails to replicate and cause disease except in humans or chimpanzees, thereby limiting our ability to evaluate compounds or vaccines prior to human testing. Despite this limitation, nonhuman primate lentivirus models have been established that recapitulate the modes of infection, disease course, and antiviral immunity that is seen in HIV infection of humans. These models have been utilized to understand key aspects of disease and to evaluate concepts in therapies and vaccine development. By necessity, animal models can only be validated after successful trials in humans and the determination of correlates of protection. Because the only vaccine product tested in phase III trials in humans failed to achieve the desired protective threshold, we are as yet unable to validate any of the currently used nonhuman primate models for vaccine research. In the absence of a validated model, many experts in the field have concluded that prophylactic vaccines and therapeutic concepts should bypass primate models, and rely solely upon the systematic testing of each individual and combined vaccine element in human phase I or I/II trials to determine their relative merits. Indeed, a large effort is underway to expand efforts to test all products as part of an international effort termed "The HIV Vaccine Enterprise", with major contributions from the Bill and Melinda Gates Foundation. This Herculean task could potentially be reduced if it were possible to utilize even partially validated nonhuman primate models as part of the screening efforts. The purpose of this article is to review the data from nonhuman primate models that have contributed to our understanding of lentivirus infection and pathogenesis, and to critically evaluate how well these models have predicted outcomes in humans. Key features of the models developed to date are described and their contributions to HIV pathogenesis, therapeutics, and vaccines, are compared. This analysis shows that many of the models at hand have yielded data on drug action and immune responses to vaccines that are congruent with clinical data. This finding suggests that primate models are valuable as adjunctive testing systems to prioritize future therapeutic and vaccine strategies. Nonhuman primate testing of vaccine approaches in particular has provided valuable information and can significantly enhance and accelerate the evaluation of novel concepts necessary to achieve acceptable levels of efficacy. Because major gaps remain in the quest for fully effective vaccines and therapies, it seems prudent to continue aggressive research programs in the nonhuman primate models.


Polyunsaturated fatty acids modulate the effect of TCF7L2 gene variants on postprandial lipemia.
The transcription factor 7-like 2 (TCF7L2) has been recently associated with diabetes risk, and it may exert its effect through metabolic syndrome (MetS)-related traits and be subjected to modification by environmental factors. We investigated the effect of single nucleotide polymorphisms (SNP), rs7903146 and rs12255372, within the TCF7L2 locus on postprandial lipemia and other MetS-related traits and their modulation by dietary fat. Data were collected from 1083 European Americans participating in the Genetics of Lipid Lowering Drugs and Diet Network Study. Carriers of the minor T allele at the C/T rs7903146 SNP had higher fasting plasma glucose (P = 0.012), lower homeostasis model assessment of beta cell function (P = 0.041), higher plasma VLDL (P = 0.035), and lower large LDL particle (P = 0.007) concentrations and higher risk of MetS (P = 0.011) than CC individuals. Moreover, we identified significant interactions between this SNP and PUFA intake modulating fasting VLDL particle concentrations (P = 0.016) and postprandial triglycerides (TG) (P = 0.028), chylomicrons (P = 0.025), total VLDL (P = 0.026), and large VLDL (P = 0.018) concentrations. Thus, only T allele carriers with a PUFA intake > or = 7.36% of energy had elevated fasting plasma VLDL concentrations and postprandial TG-rich lipoproteins. These variables did not differ in T allele carriers and noncarriers in the low-PUFA intake group. Moreover, these significant interactions were due exclusively to (n-6) PUFA intake. In summary, high (n-6) PUFA intakes (> or = 6.62% of energy intake) were associated with atherogenic dyslipidemia in carriers of the minor T allele at the TCF7L2 rs7903146 SNP and may predispose them to MetS, diabetes, and cardiovascular disease.


Intestinal parasites isolated in a large teaching hospital, Italy, 1 May 2006 to 31 December 2008.
Intestinal parasites account for the majority of parasitic diseases, particularly in endemic areas. Most are transmitted via contaminated food. Because of increased immigration and travel, enteric parasitoses are now distributed worldwide. Between May 2006 and December 2008, we examined stool specimens from 5,351 patients (4,695 Italians, 656 non-Italians) for ova and parasites using microscopy, culture techniques, and molecular methods. Stools from 594 patients (11.1%) were contaminated and for all patients samples combined, a total of 700 intestinal parasites were counted. Ninety of the 594 infected patients had more than one parasite in their stools. Parasites causing intestinal disease occurred in 8.8% of patients. The prevalence was over twice as high among non-Italians (26.8% vs 8.9% in Italians, p<0.001) and higher in males (13.0% vs 9.5% in females, p=0.003). Most isolates were pathogenic protozoa, including in decreasing order of frequency: Blastocystis hominis, Giardia intestinalis, Entamoeba histolytica, and Cyclospora cayetanensis. The latter two species tended to be more common in Italians, although not at significant level (3.6% (15/418) vs 1.7% (3/176) in non-Italians, OR: 2.15; 95%CI: 0.60–11.70, p=0.22). Helminthes were found in 28 patients, mainly non-Italians (5.7% (10/176) vs 4.3% (18/418), OR: 1.34; 95%CI: 0.54–3.13, p=0.47). Ascaris lumbricoides and Hymenolepis nana were the most common. Strongyloides stercoralis, Enterobius vermicularis, Taenia spp. and Trichuris trichiura were also found. Intestinal parasites are a serious problem in developing countries, but should not be underestimated in industrialised countries.


Multi-omics data integration methods and their applications in psychiatric disorders.
To study mental illness and health, in the past researchers have often broken down their complexity into individual subsystems (e.g., genomics, transcriptomics, proteomics, clinical data) and explored the components independently. Technological advancements and decreasing costs of high throughput sequencing has led to an unprecedented increase in data generation. Furthermore, over the years it has become increasingly clear that these subsystems do not act in isolation but instead interact with each other to drive mental illness and health. Consequently, individual subsystems are now analysed jointly to promote a holistic understanding of the underlying biological complexity of health and disease. Complementing the increasing data availability, current research is geared towards developing novel methods that can efficiently combine the information rich multi-omics data to discover biologically meaningful biomarkers for diagnosis, treatment, and prognosis. However, clinical translation of the research is still challenging. In this review, we summarise conventional and state-of-the-art statistical and machine learning approaches for discovery of biomarker, diagnosis, as well as outcome and treatment response prediction through integrating multi-omics and clinical data. In addition, we describe the role of biological model systems and in silico multi-omics model designs in clinical translation of psychiatric research from bench to bedside. Finally, we discuss the current challenges and explore the application of multi-omics integration in future psychiatric research. The review provides a structured overview and latest updates in the field of multi-omics in psychiatry.


Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome.
High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors.


HSP90 Inhibitor Improves Lung Protection in Porcine Model of Donation After Circulatory Arrest.
Ischemia-reperfusion associated with prolonged warm ischemia during donation after circulatory death (DCD) induces acute lung injury. The objective of this study was to combine ex vivo lung perfusion (EVLP) and a heat shock protein-90 inhibitor (HSP90i) to recondition DCD organs and prevent primary graft dysfunction. Pigs (55 to 65 kg) were anesthetized, ventilated, and hemodynamically monitored. Cardiac arrest was induced with potassium chloride, and animals were left nonventilated for 2 hours. Lungs were procured and perfused in an EVLP platform for 4 hours by using a cellular perfusate. In the study group, the perfusate contained HSP90i and its transport vehicle (n = 4). In the control group, the perfusate contained only the transport vehicle (n = 4). Gas exchange, airway pressures, and compliance were measured. Pulmonary edema was assessed by bronchoscopy and weight measurement. Lung biopsy samples were obtained for histologic analyses and protein expression measurements. The use of HSP90i reduced lung weight gain to 8.4 ± 3.4% vs 26.6 ± 6.2% in the control group (P < .05). There was reduced edema formation. The ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen at the end of EVLP was 423 ± 65 in the study group vs 339 ± 25 mm Hg in the control group, but this difference was not statistically significant. Lactate metabolism, pulmonary vascular resistance, and pulmonary arterial pressure improved during EVLP with the use of the HSP90i. The use of HSP90i with EVLP improves the lung reconditioning process. Further research is required to confirm whether these findings translate to benefit once transplanted and observed in vivo. Successful pharmacologic inhibitors may expand the donor pool in the context of DCD donors.


An ancient defense system eliminates unfit cells from developing tissues during cell competition.
Developing tissues that contain mutant or compromised cells present risks to animal health. Accordingly, the appearance of a population of suboptimal cells in a tissue elicits cellular interactions that prevent their contribution to the adult. Here we report that this quality control process, cell competition, uses specific components of the evolutionarily ancient and conserved innate immune system to eliminate Drosophila cells perceived as unfit. We find that Toll-related receptors (TRRs) and the cytokine Spätzle (Spz) lead to NFκB-dependent apoptosis. Diverse "loser" cells require different TRRs and NFκB factors and activate distinct pro-death genes, implying that the particular response is stipulated by the competitive context. Our findings demonstrate a functional repurposing of components of TRRs and NFκB signaling modules in the surveillance of cell fitness during development.


CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens.
Congenital bilateral aplasia of the vas deferens (CBAVD) was suggested to be a mild form of cystic fibrosis (CF). Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in males with CBAVD revealed that in some males CBAVD is caused by two defective CFTR alleles. The genetic basis of CBAVD in the other males and its association with CF remained unclear. We undertook this study to test the hypothesis of commonality of CBAVD and CF by haplotype analysis, in the CFTR locus, of males suffering from CBAVD and of their families. According to the hypothesis of commonality of CBAVD and CF, two brothers with CBAVD are expected to carry the same two CFTR alleles, while their fertile brothers are expected to carry at least one different allele. Eleven families were studied, of which two families, with unidentified CFTR mutations, did not support this hypothesis. In these families two brothers with CBAVD inherited different CFTR alleles. Their fertile brothers inherited the same CFTR alleles as their brothers with CBAVD. These results provide evidence for genetic heterogeneity in CBAVD. Though in some families CBAVD is associated with two CFTR mutations, we suggest that in others it is caused by other mechanisms, such as mutations at other loci or homozygosity or heterozygosity for partially penetrant CFTR mutations.


Nationwide longitudinal analysis of acute liver failure in taiwan.
Acute liver failure (ALF) is uncommon but fatal. Current management is based mostly on clinical experience. We aimed to investigate the incidence, etiology, outcomes, and prognostic factors of ALF in Taiwan. Patients with the admission diagnosis of ALF between January 2005 and September 2007 were identified from the Longitudinal Health Insurance Database of Taiwan. ALF was further confirmed by disease severity based on laboratory orders, prescriptions, and duration of hospital stay, and acute onset without prior liver disease. Prognostic factors were identified using Cox regression analysis. During the study period, 218 eligible cases were identified from 28,078 potential eligible ALF patients. The incidence was 80.2 per million person-years in average and increased with age. The mean age was 57.9 ± 17.1 years and median survival was 171 days. The most common etiologies were viral (45.4%, mainly hepatitis B virus) and followed by alcohol/toxin (33.0%). Independent prognostic factors included alcohol consumption (hazard ratio, HR, 1.67 [1.01-2.77]), malignancy (HR 2.90 [1.92-4.37]), frequency of checkups per week for total bilirubin (HR 1.57 [1.40-1.76]), sepsis (HR 1.85 [1.20-2.85]), and the use of hemodialysis/hemofiltration (HR 2.12 [1.15-3.9]) and proton pump inhibitor (HR 0.94 [0.90-0.98]). Among the 130 patients who survived ≥90 days, 66 (50.8%) were complicated by liver cirrhosis. Eight (3.7%) were referred for liver transplantation evaluation, but only 1 received transplantation and survived. ALF in Taiwan is mainly due to viral infection. Patients with malignancy and alcohol exposure have worst prognosis. The use of proton pump inhibitor is associated with improved survival. Half of the ALF survivors have liver cirrhosis.


Antiviral combinations for severe influenza.
Observational data suggest that the treatment of influenza infection with neuraminidase inhibitors decreases progression to more severe illness, especially when treatment is started soon after symptom onset. However, even early treatment might fail to prevent complications in some patients, particularly those infected with novel viruses such as the 2009 pandemic influenza A H1N1, avian influenza A H5N1 virus subtype, or the avian influenza A H7N9 virus subtype. Furthermore, treatment with one antiviral drug might promote the development of antiviral resistance, especially in immunocompromised hosts and critically ill patients. An obvious strategy to optimise antiviral therapy is to combine drugs with different modes of action. Because host immune responses to infection might also contribute to illness pathogenesis, improved outcomes might be gained from the combination of antiviral therapy with drugs that modulate the immune response in an infected individual. We review available data from preclinical and clinical studies of combination antiviral therapy and of combined antiviral-immunomodulator therapy for influenza. Early-stage data draw attention to several promising antiviral combinations with therapeutic potential in severe infections, but there remains a need to substantiate clinical benefit. Combination therapies with favourable experimental data need to be tested in carefully designed aclinical trials to assess their efficacy.


PCB Emissions from Paint Colorants.
Polychlorinated biphenyls (PCBs) are known human carcinogens that are byproducts of pigment manufacturing and found in colorants used to tint consumer paints sold in the United States and elsewhere. PCBs have the potential to be emitted from paint containing these pigments. To quantify the gas-phase emissions of ∑PCBs, we used polyurethane foam (PUF) to capture emissions from freshly applied colorants. Some PCB emissions were detected on the PUF after 1 day. After 6 weeks, all PCBs found in the colorant were also found on the PUF. Even the fully chlorinated PCB209 was emitted from green colorant. Mono- and dichlorinated PCBs were released from the colorant at a faster rate than the higher chlorinated congeners. By the end of the experiment, all the lower chlorinated congeners were absent from the colorant while more than 75% of the higher chlorinated congeners remained in the sample. The rate of PCB emissions from paint colorants is a function of the surface/air equilibrium coefficient, and the presence of water accelerates the emissions. Although concentrations of PCBs in colorants are less than 285 ng g-1, PCB emissions from colorants in paint can cause environmentally relevant concentrations of ≥500 pg m-3 within hours of painting a room.


Context Dependent Fuzzy Associated Statistical Model for Intensity Inhomogeneity Correction From Magnetic Resonance Images.
In this paper, a novel context-dependent fuzzy set associated statistical model-based intensity inhomogeneity correction technique for magnetic resonance image (MRI) is proposed. The observed MRI is considered to be affected by intensity inhomogeneity and it is assumed to be a multiplicative quantity. In the proposed scheme the intensity inhomogeneity correction and MRI segmentation is considered as a combined task. The maximum a posteriori probability (MAP) estimation principle is explored to solve this problem. A fuzzy set associated Gibbs' Markov random field (MRF) is considered to model the spatio-contextual information of an MRI. It is observed that the MAP estimate of the MRF model does not yield good results with any local searching strategy, as it gets trapped to local optimum. Hence, we have exploited the advantage of variable neighborhood searching (VNS)-based iterative global convergence criterion for MRF-MAP estimation. The effectiveness of the proposed scheme is established by testing it on different MRIs. Three performance evaluation measures are considered to evaluate the performance of the proposed scheme against existing state-of-the-art techniques. The simulation results establish the effectiveness of the proposed technique.


Changes in coronary sinus pH during dipyridamole stress in patients with hypertrophic cardiomyopathy.
The presence of angina pectoris and myocardial scarring in patients with hypertrophic cardiomyopathy (HCM) suggests that myocardial ischemia is a factor in the pathophysiology of the disease. The clinical evaluation of ischaemia is problematic in HCM as baseline electrocardiographic abnormalities are frequent and thallium-201 perfusion abnormalities correlate poorly with anginal symptoms. Coronary sinus pH measurement using a catheter mounted pH electrode is a validated sensitive technique for the detection of myocardial ischaemia. 11 patients with HCM and chest pain (eight men; mean (SD) (range) age 36 (11) (19-53) years) and six controls (two men; mean (SD) (range) age 49 (11) (31-62) years) with atypical pain and normal coronary angiograms were studied. Eight patients with HCM had baseline ST segment depression of > or = 1 mm and four had reversible perfusion defects during stress 201TI scintigraphy. A catheter mounted hydrogen ion sensitive electrode was introduced into the coronary sinus and pH monitored continuously during dipyridamole infusion (0.56 mg/kg over four min). The maximal change in coronary sinus pH during dipyridamole stress was greater in patients with HCM than in controls (0.082 (0.083) (0 to -0.275) v 0.005 (0.006) (0 to -0.012), P = 0.02). In six patients (four men; mean (SD) (range) age 29 (9) (19-40 years) the development of chest pain was associated with a gradual decline in coronary sinus pH (mean 0.123 (0.089)), peaking at 442 (106) s. There were no relations among left ventricular dimensions, maximal wall thickness, and maximum pH change. In patients with HCM there was a correlation between maximum pH change and maximum heart rate during dipyridamole infusion (r = 0.70, P = 0.02). This study provides further evidence that chest pain in patients with HCM is caused by myocardial ischaemia. The role of myocardial ischaemia in the pathophysiology of the disease remains to be determined but coronary sinus pH monitoring provides a method for quantifying and prospectively assessing its effects on clinical presentation and prognosis.


Comet assay and flow cytometry analysis of DNA repair in normal and cancer cells treated with known mutagens with different mechanisms of action.
In order to determine differences in repair after treatment with DNA damaging agents, normal and cancer cells were selected for analysis of single strand breaks and DNA crosslinks using the Comet assay. Normal human lymphocytes, human colorectal adenocarcinoma SW620 cells, lung carcinoma A549, and H460 cell lines were exposed to an ethylating agent (ethylmethane sulfonate [EMS]), and a cross-linking agent (mitomycin C [MMC]). Differences in repair profiles of DNA damage demonstrated using the comet assay were observed in human lymphocytes and tumour cell lines with both mutagens. Results were also indicative that MMC repair is concentration-dependent. It was also apparent that normal cells repair DNA damage more readily than tumour cells. Repair also varied between different cell lines. To investigate the mechanistic differences of these two chemicals, flow cytometry studies were undertaken in tumour cells, namely cell cycle analysis and frequency of micronuclei induction (FMN). A G2M phase block was clearly evident following treatment with EMS at all concentrations tested. With MMC, an initial arrest of cells in G2M was accompanied by a build-up in S-phase over longer exposure periods. Also, at the highest mutagen doses there were different patterns of micronuclei induction. Thus, using the mutagens with different mechanisms of action highlighted the differences in repair patterns between normal and tumour cells.


Bottlenecks and hubs in inferred networks are important for virulence in Salmonella typhimurium.
Recent advances in experimental methods have provided sufficient data to consider systems as large networks of interconnected components. High-throughput determination of protein-protein interaction networks has led to the observation that topological bottlenecks, proteins defined by high centrality in the network, are enriched in proteins with systems-level phenotypes such as essentiality. Global transcriptional profiling by microarray analysis has been used extensively to characterize systems, for example, examining cellular response to environmental conditions and effects of genetic mutations. These transcriptomic datasets have been used to infer regulatory and functional relationship networks based on co-regulation. We use the context likelihood of relatedness (CLR) method to infer networks from two datasets gathered from the pathogen Salmonella typhimurium: one under a range of environmental culture conditions and the other from deletions of 15 regulators found to be essential in virulence. Bottleneck and hub genes were identified from these inferred networks, and we show for the first time that these genes are significantly more likely to be essential for virulence than their non-bottleneck or non-hub counterparts. Networks generated using simple similarity metrics (correlation and mutual information) did not display this behavior. Overall, this study demonstrates that topology of networks inferred from global transcriptional profiles provides information about the systems-level roles of bottleneck genes. Analysis of the differences between the two CLR-derived networks suggests that the bottleneck nodes are either mediators of transitions between system states or sentinels that reflect the dynamics of these transitions.


Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels.
Serotonin [5-hydroxytryptamine (5-HT)] is a major therapeutic target of psychiatric disorders. Tryptophan hydroxylase (TPH) catalyzes the rate-limiting reaction in the biosynthesis of 5-HT. Two isoforms (TPH1 and TPH2) having tryptophan hydroxylating activity were identified. Association studies have revealed possible TPH1 involvement in psychiatric conditions and behavioral traits. However, TPH1 mRNA was reported to be mainly expressed in the pineal gland and the periphery and to be barely detected in the brain. Therefore, contribution of TPH1 to brain 5-HT levels is not known, and the mechanisms how TPH1 possibly contributes to the pathogenesis of psychiatric disorders are not understood. Here, we show an unexpected role of TPH1 in the developing brain. We found that TPH1 is expressed preferentially during the late developmental stage in the mouse brain. TPH1 showed higher affinity to tryptophan and stronger enzyme activity than TPH2 in a condition reflecting that of the developing brainstem. Low 5-HT contents in the raphe nucleus were seen during development in New Zealand white (NZW) and SWR mice having common functional polymorphisms in the TPH1 gene. However, the 5-HT contents in these mice were not reduced in adulthood. In adult NZW and SWR mice, depression-related behavior was observed. Considering an involvement of developmental brain disturbance in psychiatric disorders, TPH1 may act specifically on development of 5-HT neurons, and thereby influence behavior later in life.


Photophysical and structural investigation of a (Py)A-modified adenine cluster: its potential use for fluorescent DNA probes exhibiting distinct emission color changes.
In this study, we found a (Py)A-modified adenine cluster (A-cluster), a minimum fluorescent unit for significant emission wavelength changes, and investigated its photophysical and structural properties. The basic A-cluster unit was an adenine-pentad duplex containing stacked (Py)A pairs in the center aligned in an antiparallel manner. Spectral analysis of the A-cluster revealed remarkable reddish fluorescence with a large Stokes shift (∼195 nm) and a long life-time constant (31 ns), originated from exciton states formed by (Py)A pairs and neighboring adenines. Structurally, the exciton state of the A-cluster exhibited unusually high stability, relative to that of other five-mismatched duplexes, as a result of stabilization through strong stacking interactions (zipper-like structure) of the mismatched A-A and (Py)A pairs, rather than through traditional Watson-Crick base pairing. These spectral and structural properties of the A-clusters were specific to the adenine bases and highly disturbed by introducing other bases (T, G, and especially C) or an abasic site into the A-cluster, whereas they were enhanced through synergistic effects in systems containing multiple A-clusters. As a minimum unit for these unique properties, finally, the A-cluster was exploited as a fluorescent probing system for specific nucleic acid sequences, such as miR-21, accompanying distinct fluorescence color changes from blue to red. These findings indicated the potential utility of the A-cluster as a part of fluorescent probes exhibiting clear signaling upon micro-environmental changes.


Effect of transcranial direct-current stimulation on cognitive function in stroke patients: A systematic review and meta-analysis.
Transcranial direct-current stimulation (tDCS) is a noninvasive approach that can alter brain excitability. Several studies have shown the effectiveness of tDCS in improving language and movement function in stroke patients. However, the effect of tDCS on cognitive function after stroke remains uncertain. We searched Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the China National Knowledge Infrastructure, the China Science and Technology Journal Database, and the Wanfang Data Knowledge Service Platform from inception to April 2, 2019. Two reviewers independently screened the studies, extracted the data, and evaluated the quality of the included studies using the Cochrane Collaboration Risk of Bias Tool. All statistical analyses were performed in RevMan 5.3, and the mean difference (MD) or standard mean difference (SMD) were used as the pooled statistics. Fifteen studies involving 820 participants were included. When compared with passive tDCS, anodal tDCS was associated with improved general cognitive performance as examined by the Minimum Mental State Examination or Montreal Cognitive Assessment (SMD = 1.31, 95% CI 0.91-1.71, P < 0.00001), attention performance (SMD = 0.66, 95% CI 0.11-1.20, P = 0.02). There was no significant difference in memory performance (SMD = 0.41, 95% CI -0.67-1.50, P = 0.46). tDCS is likely to be effective for patients with cognitive impairment after stroke. The evidence for different effects based on population characteristics and stimulation methods was limited, but a real effect cannot be ruled out. More high-quality research in this field is required to determine the potential benefits of tDCS in the treatment of cognitive deficits after stroke and to establish the optimal treatment program.


Predation and drift of lotic macroinvertebrates during colonization.
A field experiment was carried out to determine the effect of an invertebrate predator on the colonization and drift of benthic macroinvertebrates in experimental stream channels. Lotic invertebrates colonized four replicate channels: two controls with no predators, and two channels with low densities (2.8 m-2) of predatory stonefly nymphs, Doroneuria baumanni (Perlidae). Immigration rates were measured at the inflow of two other channels. Drift rates of invertebrates immigrating to and emigrating from channels were measured daily, and benthic samples were collected every five days. Over a 25-day colonization period, benthic densities of Baetis nymphs and larval Chironomidae were reduced by D. baumanni. Colonization curves were fit with a power function and significantly different colonization rates were indicated for both Baetis and chironomids in predation and control channels. A predator-induced drift response was exhibited by Baetis only and this response was size-dependent. In the presence of D. baumanni, large Baetis drifted more frequently than small nymphs and, correspondingly, small nymphs were more frequent in the benthos. Net predator impacts on invertebrate densities in channel substrates were partitioned into predator-induced drift and prey consumption. These estimates suggest that predator avoidance by Baetis is a prominent mechanism causing density reductions in the presence of predators. Reductions in the density of Chironomidae, however, were attributed to prey consumption only. A rainstorm during the experiment demonstrated that stream flow disruptions can override the influence of predators on benthic invertebrates, at least temporarily, and re-set benthic densities.


Effect of plaque accumulation and salivary factors on enamel demineralization and plaque composition in situ.
This study evaluated the effect of some plaque and salivary factors on caries progression in situ. The salivary secretion rate, buffering capacity and mutans streptococci counts from 13 volunteers were determined. For three distinct periods of time, 4, 7 and 10 days, each of them wore a palatal appliance containing 4 bovine enamel blocks. They used a non-fluoridated dentifrice during the experiment and a 20% sucrose solution was dripped onto the blocks 10 times a day. Mutans streptococci (MS), calcium (Ca), and insoluble polysaccharide (IP) were quantified in the dental plaque formed on the enamel blocks, after each period. Enamel demineralization was assessed by surface microhardness, and the percentage of surface microhardness change (%SMC) in relation to the baseline values was calculated. Enamel demineralization occurred after each period of plaque accumulation (p < 0.05), and the %SMC increased with time (from 13.8 to 48.3%). The concentrations of Ca and IP in plaque were not statistically different among the experimental times, but significant correlations were found between these concentrations and %SMC. Neither the salivary factors assessed initially nor mutans streptococci in plaque presented statistically significant correlations to %SMC. The results suggest that enamel demineralization is time-dependent and is more related to the composition of the biofilm formed than to the salivary factors studied.


Improved responsiveness and reduced sample size requirements of PROMIS physical function scales with item response theory.
The Health Assessment Questionnaire Disability Index (HAQ) and the SF-36 PF-10, among other instruments, yield sensitive and valid Disability (Physical Function) endpoints. Modern techniques, such as Item Response Theory (IRT), now enable development of more precise instruments using improved items. The NIH Patient Reported Outcomes Measurement Information System (PROMIS) is charged with developing improved IRT-based tools. We compared the ability to detect change in physical function using original (Legacy) instruments with Item-Improved and PROMIS IRT-based instruments. We studied two Legacy (original) Physical Function/Disability instruments (HAQ, PF-10), their item-improved derivatives (Item-Improved HAQ and PF-10), and the IRT-based PROMIS Physical Function 10- (PROMIS PF 10) and 20-item (PROMIS PF 20) instruments. We compared sensitivity to detect 12-month changes in physical function in 451 rheumatoid arthritis (RA) patients and assessed relative responsiveness using P-values, effect sizes (ES), and sample size requirements. The study sample was 81% female, 87% Caucasian, 65 years of age, had 14 years of education, and had moderate baseline disability. All instruments were sensitive to detecting change (< 0.05) in physical function over one year. The most responsive instruments in these patients were the Item-Improved HAQ and the PROMIS PF 20. IRT-improved instruments could detect a 1.2% difference with 80% power, while reference instruments could detect only a 2.3% difference (P < 0.01). The best IRT-based instruments required only one-quarter of the sample sizes of the Legacy (PF-10) comparator (95 versus 427). The HAQ outperformed the PF-10 in more impaired populations; the reverse was true in more normal populations. Considering especially the range of severity measured, the PROMIS PF 20 appears the most responsive instrument. Physical Function scales using item improved or IRT-based items can result in greater responsiveness and precision across a broader range of physical function. This can reduce sample size requirements and thus study costs.


Duodenal perforation in a 12-month old child with severe malaria.
Peptic ulcer disease (PUD) in children remains rare and difficult to diagnose before the onset of complications. We report on a case of a 12-month child with perforated duodenal ulcer, association with malaria. The severity of the febrile presentation and the positive laboratory confirmation of malaria delayed the diagnosis of PUD. Surgical intervention was successful and without significant sequelae. An awareness of the possibility, and a lower threshold for considering PUD in children may help prevent complications.


Simulations of dynamically cross-linked actin networks: Morphology, rheology, and hydrodynamic interactions.
Cross-linked actin networks are the primary component of the cell cytoskeleton and have been the subject of numerous experimental and modeling studies. While these studies have demonstrated that the networks are viscoelastic materials, evolving from elastic solids on short timescales to viscous fluids on long ones, questions remain about the duration of each asymptotic regime, the role of the surrounding fluid, and the behavior of the networks on intermediate timescales. Here we perform detailed simulations of passively cross-linked non-Brownian actin networks to quantify the principal timescales involved in the elastoviscous behavior, study the role of nonlocal hydrodynamic interactions, and parameterize continuum models from discrete stochastic simulations. To do this, we extend our recent computational framework for semiflexible filament suspensions, which is based on nonlocal slender body theory, to actin networks with dynamic cross linkers and finite filament lifetime. We introduce a model where the cross linkers are elastic springs with sticky ends stochastically binding to and unbinding from the elastic filaments, which randomly turn over at a characteristic rate. We show that, depending on the parameters, the network evolves to a steady state morphology that is either an isotropic actin mesh or a mesh with embedded actin bundles. For different degrees of bundling, we numerically apply small-amplitude oscillatory shear deformation to extract three timescales from networks of hundreds of filaments and cross linkers. We analyze the dependence of these timescales, which range from the order of hundredths of a second to the actin turnover time of several seconds, on the dynamic nature of the links, solvent viscosity, and filament bending stiffness. We show that the network is mostly elastic on the short time scale, with the elasticity coming mainly from the cross links, and viscous on the long time scale, with the effective viscosity originating primarily from stretching and breaking of the cross links. We show that the influence of nonlocal hydrodynamic interactions depends on the network morphology: for homogeneous meshworks, nonlocal hydrodynamics gives only a small correction to the viscous behavior, but for bundled networks it both hinders the formation of bundles and significantly lowers the resistance to shear once bundles are formed. We use our results to construct three-timescale generalized Maxwell models of the networks.


Microbiological water quality requirements for salad irrigation in the United Kingdom.
The growth in United Kingdom salad production is dependent on irrigation to maintain product quality. There are concerns that irrigation with poor-quality water could pose a disease risk. This article examines the key issues in the emerging debate on the microbiological quality of water used for salad irrigation in the United Kingdom. The links between irrigation water quality and foodborne disease, and the current international guidance on irrigation water quality, are firstly reviewed. The findings indicate that a number of recent food-poisoning outbreaks have been linked to the consumption of fresh fruits and vegetables and that unhygienic product handling is implicated as the principal source of contamination. There is also credible evidence that salads contaminated in the field, including by irrigation water, can pose a small disease risk at the point of sale. Although irrigation water-quality standards exist in various forms internationally, there is no nationally agreed on standard used in the United Kingdom. This paper then describes the results of a survey conducted in 2003 of United Kingdom irrigation practices that might influence the microbiological quality of salads. The survey showed that surface water is the principal irrigation water source, that overhead irrigation predominates, that the gap between the last irrigation and harvest may be < 24 h in many cases, and that current water-quality monitoring practices are generally very limited in scope. This paper concludes with a discussion of the issues emerging from the review and survey, including the need for improved water-quality monitoring, and the problems associated with establishing water-quality standards that could be either too strict or too lax.


Biased and less sensitive: A gamified approach to delay discounting in heroin addiction.
People with addiction will continue to use drugs despite adverse long-term consequences. We hypothesized (a) that this deficit persists during substitution treatment, and (b) that this deficit might be related not only to a desire for immediate gratification, but also to a lower sensitivity for optimal decision making. We investigated how individuals with a history of heroin addiction perform (compared to healthy controls) in a virtual reality delay discounting task. This novel task adds to established measures of delay discounting an assessment of the optimality of decisions, especially in how far decisions are influenced by a general choice bias and/or a reduced sensitivity to the relative value of the two alternative rewards. We used this measure of optimality to apply diffusion model analysis to the behavioral data to analyze the interaction between decision optimality and reaction time. The addiction group consisted of 25 patients with a history of heroin dependency currently participating in a methadone maintenance program; the control group consisted of 25 healthy participants with no history of substance abuse, who were recruited from the Western Sydney community. The patient group demonstrated greater levels of delay discounting compared to the control group, which is broadly in line with previous observations. Diffusion model analysis yielded a reduced sensitivity for the optimality of a decision in the patient group compared to the control group. This reduced sensitivity was reflected in lower rates of information accumulation and higher decision criteria. Increased discounting in individuals with heroin addiction is related not only to a generally increased bias to immediate gratification, but also to reduced sensitivity for the optimality of a decision. This finding is in line with other findings about the sensitivity of addicts in distinguishing optimal from nonoptimal choice options.


Regulation of toxin and virulence gene transcription in Bacillus thuringiensis.
Bacillus thuringiensis is a spore-forming bacterium well known for its insecticidal properties and its ability to produce a crystal inclusion during sporulation. The specific activity of B. thuringiensis against insect larvae is due to the crystal proteins (Cry proteins). Two different transcriptional mechanisms (dependent and independent of sporulation) are responsible for cry gene transcription during the stationary phase. In addition to these specific insecticidal toxins, B. thuringiensis produces potential virulence factors including haemolysins, degradative enzymes and enterotoxins. A pleiotropic regulator (PlcR) that activates the transcription of various genes encoding such extracellular proteins has been identified. Its expression at the onset of the stationary phase is dependent on the growth medium and is controlled by the transition state regulator, SpoOA.


Increased C reactive protein and cardiac enzyme levels after coronary stent implantation. Is there protection by remote ischaemic preconditioning?
To investigate whether remote ischaemic preconditioning (RIPC) can attenuate the inflammatory response and enzyme leakage that can occur after uncomplicated routine percutaneous coronary intervention (PCI). 41 consecutive normotensive patients with stable angina and single-vessel disease were assigned to be exposed to RIPC (n = 20) or not (control group; n = 21) before elective PCI with stent implantation. RIPC was induced by three cycles of 5-min ischaemia-reperfusion of both upper limbs (inflation/deflation of blood pressure cuff). C reactive protein (CRP), creatine phosphokinase (CK), CK cardiac isoenzyme (CK-MB) and troponin I (TNI) were serially measured for 48 h. No difference in baseline values was observed between the groups. The CRP rose significantly (p<0.001) and at 48 h was similarly increased (>fourfold) in both groups (15.7 (2.6) v 14.0 (3.3) mg/l, RIPC v control; p = NS). However, sub-group analysis on the basis of statin use showed that the highest rise was in the group of patients with RIPC not taking statins and was significantly greater than in patients with RIPC taking statins (23.8 (3.71) v 11.4 (3.0) mg/l, respectively, p<0.01). Both CK-MB and TNI leakage were raised (slightly but significantly) after PCI in controls at 24 h compared with baseline values. However, this small rise was significantly worse after RIPC (CK-MB, 1.33 (0.27) v 3.57 (0.97) ng/ml, p<0.01; TNI, 0.255 (0.059) v 0.804 (0.232) ng/ml, p<0.05, respectively at 24 h). The increase was more marked in the RIPC subgroup not taking statins. RIPC does not reduce, but exacerbates, the enzyme and TNI release from the heart after single-vessel angioplasty with stent. Furthermore, the increased circulating CRP remains raised. It seems that there is an enhanced inflammatory response after RIPC in the absence of statin treatment.


Tuberculosis in renal transplant recipients: the evidence for prophylaxis.
Tuberculosis (TB) remains a leading cause of death in endemic countries and is 20 to 70 times more common in renal transplant recipients, where it contributes to both increased morbidity and mortality. This review will focus on the epidemiology of TB in renal transplant recipients and critically appraise the published literature on isoniazid prophylaxis in renal transplantation. A literature search for randomized and nonrandomized studies investigating the use of isoniazid prophylaxis in renal transplant recipients was conducted using Ovid MEDLINE, the Cochrane Library, the Transplant Library, and EMBASE. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis of the randomized controlled trials (RCTs) was performed with a fixed-effects model. Eleven relevant studies were identified; six nonrandomized and five RCTs. The nonrandomized studies indicate a reduced risk of TB with isoniazid prophylaxis. The RCTs demonstrated conflicting results, with two studies finding a reduction in TB with prophylaxis and two studies finding no difference. Meta-analysis of the 709 patients from the four RCTs demonstrated a reduced risk of TB with isoniazid prophylaxis (RR, 0.31; 95% CI, 0.19-0.51). No significant difference was found in the incidence of hepatitis (RR, 1.22; 95% CI, 0.91-1.65). Both randomized and nonrandomized studies support the value of isoniazid as TB prophylaxis in renal transplant recipients at risk of active infection. Clinicians should consider prophylaxis in renal transplant recipients in endemic areas or in recipients in nonendemic countries who are at risk. However, the evidence for the benefit of isoniazid prophylaxis in renal transplantation is not robust and there is still a need for a large multicenter trial of isoniazid prophylaxis in kidney transplantation in an endemic area.


Natural transmission of Leishmania infantum through experimentally infected Phlebotomus perniciosus highlights the virulence of Leishmania parasites circulating in the human visceral leishmaniasis outbreak in Madrid, Spain.
A human leishmaniasis outbreak is occurring in the Madrid region, Spain, with the parasite and vector involved being Leishmania infantum and Phlebotomus perniciosus respectively. The aim of this study was to investigate the virulence of L. infantum isolates from the focus using a natural transmission model. Hamsters were infected by intraperitoneal inoculation (IP) or by bites of sand flies experimentally infected with L. infantum isolates obtained from P. perniciosus collected in the outbreak area (IPER/ES/2012/BOS1FL1 and IPER/ES/2012/POL2FL6) and a well characterized L. infantum strain JPCM5 (MCAN/ES/98/LLM-877). Hamster infections were monitored by clinical examination, serology, culture, parasite burden, Giemsa-stained imprints, PCR, histopathology and xenodiagnostic studies. Establishment of infection of L. infantum was achieved with the JPCM5 strain and outbreak isolates by both P. perniciosus infective bites or IP route. However, high virulence of BOS1FL1 and POL2FL6 isolates was highlighted by the clinical outcome of disease, high parasite detection in spleen and liver, high parasitic loads and positivity of Leishmania serology. Transmission by bite of POL2FL6 infected flies generated a slower progression of clinical disease than IP infection, but both groups were infective to P. perniciosus by xenodiagnosis at 2 months post-infection. Conversely, hamsters inoculated with JPCM5 were not infective to sand flies. Histopathology studies confirmed the wide spread of POL2FL6 parasites to several organs. A visceral leishmaniasis model that mimics the natural transmission in nature allowed us to highlight the high virulence of isolates that are circulating in the focus. These findings contribute to a better understanding of the outbreak epidemiology.


White Book on Physical and Rehabilitation Medicine (PRM) in Europe. Chapter 10. Science and research in PRM: specificities and challenges.
In the context of the White Book of Physical and Rehabilitation Medicine (PRM), this paper deals with Research, the future of PRM. PRM students and specialists are mainly involved in biomedical research, investigating the biological processes, the causes of diseases, their medical diagnosis, the evaluation of their consequences on functioning, disability and health and the effects of health interventions at an individual and a societal level. Most of the current PRM research, often interdisciplinary, originates from applied research which, using existing knowledge, is directed towards specific goals. Translational medical research, research and development, implementation research and clinical impact research are in this field. PRM physicians, mainly master or PhD students, are nowadays increasing their participation in basic research and in pre-clinical trials. PRM physicians are involved in primary research, which is an original first hand research, but also in secondary research, which is the analysis and interpretation of primary research publications in a field, with a specific methodology. Secondary research remains an important activity of the UEMS PRM section and it will be the field of the new created Cochrane Rehabilitation. Secondary research with interest for persons with disabilities, will be developed world wide on the basis of evidence based medicine, with the participation of PRM physicians and of all other health and social professionals involved in rehabilitation. The development of research activities with interest for PRM in Europe is a challenge for the future, which has to be faced now. The European PRM schools, the European master and PhD program with their supporting research and clinical facilities, the European PRM organizations with their websites, the PRM scientific journals and European congresses are a strong basis to develop research activities, together with the development of Cochrane Rehabilitation field and of our cooperation with European high level research facilities, European and international scientific societies in different fields. PRM will be a leader in this field of research.


PhySIC_IST: cleaning source trees to infer more informative supertrees.
Supertree methods combine phylogenies with overlapping sets of taxa into a larger one. Topological conflicts frequently arise among source trees for methodological or biological reasons, such as long branch attraction, lateral gene transfers, gene duplication/loss or deep gene coalescence. When topological conflicts occur among source trees, liberal methods infer supertrees containing the most frequent alternative, while veto methods infer supertrees not contradicting any source tree, i.e. discard all conflicting resolutions. When the source trees host a significant number of topological conflicts or have a small taxon overlap, supertree methods of both kinds can propose poorly resolved, hence uninformative, supertrees. To overcome this problem, we propose to infer non-plenary supertrees, i.e. supertrees that do not necessarily contain all the taxa present in the source trees, discarding those whose position greatly differs among source trees or for which insufficient information is provided. We detail a variant of the PhySIC veto method called PhySIC_IST that can infer non-plenary supertrees. PhySIC_IST aims at inferring supertrees that satisfy the same appealing theoretical properties as with PhySIC, while being as informative as possible under this constraint. The informativeness of a supertree is estimated using a variation of the CIC (Cladistic Information Content) criterion, that takes into account both the presence of multifurcations and the absence of some taxa. Additionally, we propose a statistical preprocessing step called STC (Source Trees Correction) to correct the source trees prior to the supertree inference. STC is a liberal step that removes the parts of each source tree that significantly conflict with other source trees. Combining STC with a veto method allows an explicit trade-off between veto and liberal approaches, tuned by a single parameter.Performing large-scale simulations, we observe that STC+PhySIC_IST infers much more informative supertrees than PhySIC, while preserving low type I error compared to the well-known MRP method. Two biological case studies on animals confirm that the STC preprocess successfully detects anomalies in the source trees while STC+PhySIC_IST provides well-resolved supertrees agreeing with current knowledge in systematics. The paper introduces and tests two new methodologies, PhySIC_IST and STC, that demonstrate the interest in inferring non-plenary supertrees as well as preprocessing the source trees. An implementation of the methods is available at: http://www.atgc-montpellier.fr/physic_ist/.


Crystallization behavior of supercooled smectic cholesteryl myristate nanoparticles containing phospholipids as stabilizers.
Supercooled smectic nanoparticles based on physiological cholesterol esters are under investigation as a potential novel carrier system for lipophilic drugs. The present study investigates the very complex crystallization behavior of such nanoparticles stabilized with the aid of phospholipids. Phospholipid and phospholipid/bile salt stabilized cholesteryl myristate dispersions were prepared by high-pressure melt homogenization and characterized by particle size measurements, differential scanning calorimetry, X-ray diffraction and electron microscopy. To obtain fractions with very small smectic nanoparticles, selected dispersions were ultracentrifuged. A mixture of cholesteryl myristate and the phospholipid used for the stabilization of the dispersions was also investigated by light microscopy. The nanoparticles usually display a bimodal crystallization event which depends on the thermal treatment and cannot be attributed to crystalline polymorphism. The ratio of the particle fractions crystallizing in the two successive steps strongly depends on the particle size of the dispersions. The presence of larger particles leads to an increased fraction crystallizing at higher temperature and a higher recrystallization tendency upon storage. The observed peculiarities of the crystallization behavior seem to be mainly caused by the presence of particles with different shapes (cylindrical and spherical) as observed in electron microscopy. Alterations in the composition of the nanoparticles may also play a role.


Mycophenolate mofetil use is associated with decreased risk of late acute rejection in adult liver transplant recipients.
Mycophenolate mofetil (MMF) used in a triple-drug regimen has been shown to decrease acute rejection rates, compared to a double-drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described. To investigate the risk of LAR (rejection > or = 6 months post-transplantation) data from the Scientific Registry of Transplant Recipients (SRTR) were used. We studied adult primary liver transplant recipients transplanted between June 1, 1995, and April 30, 2004, with hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) or a nonviral (n = 5740) primary cause of liver disease who were recorded as receiving continuous 3-(MMF + Tacro + steroids) versus 2-drug (Tacro + steroids) therapy for at least 6 months immediately post transplantation. Kaplan-Meier analysis showed significantly lower LAR rates 4 years post-transplant in 3- versus 2-drug HCV, HBV and nonviral disease patients. Multivariate regression confirmed 3- versus 2-drug therapy to be associated with a decreased risk of LAR. Late graft survival was significantly lower at 4 years post-transplant for patients with LAR 6-12 months post-transplantation versus patients with early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001). Three-drug versus 2-drug therapy for a minimum of 6 months may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.


Transcriptional elucidation of tumor necrosis factor-α-mediated nuclear factor-κB1 activation in breast cancer cohort of Pakistan.
Initiation, promotion, progression, and metastasis of mammary tumors are mediated by dysregulation of multiple genes involved in various signaling pathways. Expressional variation of these molecules significantly influences cancer cell proliferation in breast cancer. In the current study, tumor necrosis factor-alpha (TNF-α) and its downstream effector nuclear factor kappa-B1 (NF-κB1) mean transcript levels were explored and associated with molecular subtypes in breast cancer cohort of Pakistan. Freshly excised tumors (n = 150) along with background tissues were collected for RNA isolation and cDNA synthesis. Quantitative polymerase chain reaction was carried out for quantification of TNF-α, NF-κB1, and β-actin gene transcripts along with estrogen receptor, progesterone receptor, HER2, and Ki-67, followed by statistical analysis. For TNF-α and NF-κB1, 95% and 77% of the cohort was found to be positive, respectively. Both of these molecules were found to be significantly upregulated in tumors when compared against their respective controls (P < 0.0001). Association of TNF-α and NF-κB1 with late clinical stages, poorly differentiated tumors, increased tumor size, nodal involvement, and metastasis was observed to be statistically significant (P < 0.05). Strong positive correlation was established between TNF-α and NF-κB1(r = 0.465, P< 0.05). Moreover, mean transcript levels of TNF-α and NF-κB1 were significantly elevated in Luminal A and Luminal B subtypes of breast cancer patients, respectively. Strong positive correlation between TNF-α and NF-κB1 proposed the putative role of these molecules as prognostic biomarkers in breast cancer.


Dendritic cell interactions with Histoplasma and Paracoccidioides.
Fungi are among the most common microbes encountered by humans. More than 100, 000 fungal species have been described in the environment to date, however only a few species cause disease in humans. Fungal infections are of particular importance to immunocompromised hosts in whom disease is often more severe, especially in those with impaired cell-mediated immunity such as individuals with HIV infection, hematologic malignancies, or those receiving TNF-α inhibitors. Nevertheless, environmental disturbances through natural processes or as a consequence of deforestation or construction can expose immunologically competent people to a large number of fungal spores resulting in asymptomatic acquisition to life-threatening disease. In recent decades, the significance of the innate immune system and more importantly the role of dendritic cells (DC) have been found to play a fundamental role in the resolution of fungal infections, such as in dimorphic fungi like Histoplasma and Paracoccidioides. In this review article the general role of DCs will be illustrated as the bridge between the innate and adaptive immune systems, as well as their specific interactions with these 2 dimorphic fungi.


Dissemination of drinking water contamination data to consumers: a systematic review of impact on consumer behaviors.
Drinking water contaminated by chemicals or pathogens is a major public health threat in the developing world. Responses to this threat often require water consumers (households or communities) to improve their own management or treatment of water. One approach hypothesized to increase such positive behaviors is increasing knowledge of the risks of unsafe water through the dissemination of water contamination data. This paper reviews the evidence for this approach in changing behavior and subsequent health outcomes. A systematic review was conducted for studies where results of tests for contaminants in drinking water were disseminated to populations whose water supply posed a known health risk. Studies of any design were included where data were available from a contemporaneous comparison or control group. Using multiple sources >14,000 documents were located. Six studies met inclusion criteria (four of arsenic contamination and two of microbiological contamination). Meta-analysis was not possible in most cases due to heterogeneity of outcomes and study designs. Outcomes included water quality, change of water source, treatment of water, knowledge of contamination, and urinary arsenic. Source switching was most frequently reported: of 5 reporting studies 4 report significantly higher rates of switching (26-72%) among those who received a positive test result and a pooled risk difference was calculate for 2 studies (RD = 0.43 [CI0.4.0-0.46] 6-12 months post intervention) suggesting 43% more of those with unsafe wells switched source compared to those with safe wells. Strength of evidence is low since the comparison is between non-equivalent groups. Two studies concerning fecal contamination reported non-significant increases in point-of-use water treatment. Despite the publication of some large cohort studies and some encouraging results the evidence base to support dissemination of contamination data to improve water management is currently equivocal. Rigorous studies on this topic are needed, ideally using common outcome measures.


Prospective study of paclitaxel and irinotecan for elderly patients with unresectable non-small cell lung cancer.
We conducted a phase II study of combination chemotherapy with paclitaxel (Pac) and irinotecan (CPT) to determine the effects and toxicities in patients 70 years or older with unresectable non-small cell lung cancer (NSCLC). Eligible patients were entered to receive three courses of Pac at 160 mg/m2 and CPT at 60 mg/m2 every 2-3 weeks. Twenty-one patients were registered. Thirteen patients were male and 8 were female, with a median age of 72 years (range: 70-82 years). Eight patients had a performance status (PS) of 0 and the other 13 patients had a PS of 1. Six and 15 patients were stage IIIB and stage IV, respectively. Ten patients received 3 to 6 cycles of the chemotherapy. Of the hematological toxicities, grade 4 neutropenia was observed in 23.8% of the patients. Of the non-hematological toxicities, grade 3 or 4 fatigue, anorexia and nausea were observed in 5, 3 and 4 patients, respectively. Three of 6 patients with infection developed grade 3 pneumonia. Grade 3 allergy with rash occurred in a patient. Cerebral infarction occurred in two patients and grade 3 peripheral neuropathy in one. The outcome of the Pac and CPT regimen in 21 patients was 8 PR, 10 SD and three PD, and the response rate was 38.1% The median survival time was 9.1 months. The one- and 2-year survival rates were 38.1% and 19.0%, respectively. The Pac plus CPT regimen is feasible and active with moderate toxicity for elderly patients with NSCLC.


Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma.
Objective: Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. The majority of patients become resistant to sorafenib, the only approved first-line therapy for advanced cancer, underscoring the need for newer, more effective drugs. The purpose of this study is to expedite identification of novel drugs against sorafenib resistant (SR)-HCC. Methods: We employed a transcriptomics-based drug repurposing method termed connectivity mapping using gene signatures from in vitro-derived SR Huh7 HCC cells. For proof of concept validation, we focused on drugs that were FDA-approved or under clinical investigation and prioritized two anti-neoplastic agents (dasatinib and fostamatinib) with targets associated with HCC. We also prospectively validated predicted gene expression changes in drug-treated SR Huh7 cells as well as identified and validated the targets of Fostamatinib in HCC. Results: Dasatinib specifically reduced the viability of SR-HCC cells that correlated with up-regulated activity of SRC family kinases, its targets, in our SR-HCC model. However, fostamatinib was able to inhibit both parental and SR HCC cells in vitro and in xenograft models. Ingenuity pathway analysis of fostamatinib gene expression signature from LINCS predicted JAK/STAT, PI3K/AKT, ERK/MAPK pathways as potential targets of fostamatinib that were validated by Western blot analysis. Fostamatinib treatment reversed the expression of genes that were deregulated in SR HCC. Conclusion: We provide proof of concept evidence for the validity of this drug repurposing approach for SR-HCC with implications for personalized medicine.


Use of diffusive gradients in thin films to measure cadmium speciation in solutions with synthetic and natural ligands: comparison with model predictions.
The performance of the technique of diffusive gradients in thin films (DGT) was characterized in well-defined systems containing cadmium with chloride and nitrate ions, simple organic ligands (nitrilotriacetic acid and diglycolic acid), and Suwannee river fulvic acid for the pH range 5-8. Cd was fully labile in all Cd, Cl-, and NO3- solutions tested (I= 0.1 and 0.01 M), even atvery low Cd concentrations (10 nM), consistent with there being no binding of Cd to the diffusive gel. Diffusion coefficients of Cd-nitritotriacetic acid (NTA) and Cd-diglycolic acid (DGA) species were measured and found to be ca. 25-30% lower than the equivalent coefficient for free metal ions. These values were used to calculate concentrations of labile Cd from DGT measurements in solutions of Cd with NTA or DGA. Cd-NTA and Cd-DGA species were found to be fully DGT-labile. DGT devices that used a diffusive gel with a reduced pore size, which retarded the passage of fulvic acid species through the gel, were used to estimate the proportion of Cd complexed by fulvic acid. These results were compared with predictions of the solution speciation from models with default parameter values. ECOSAT, incorporating the NICA-Donnan model, correctly predicted the magnitude of the binding and its pH dependence, while predictions from WHAM V (with humic ion binding model V) and WHAM 6 (with humic ion binding model VI) were less satisfactory at predicting the pH dependence. Reasonable fits to the data could be obtained from WHAM 6 when the effective binding constant log K(MA) was changed from 1.6 to 1.5, the value of deltaLK1 from 2.8 to 1.0 to minimize the dependence on pH, and the value of deltaLK2 from 1.48 to 1.0 to decrease the strength of the strong bidentate and tridentate binding sites.


Irregular shape symmetry analysis: theory and application to quantitative galaxy classification.
This paper presents a set of imperfectly symmetric measures based on a series of geometric transformation operations for quantitatively measuring the "amount" of symmetry of arbitrary shapes. The definitions of both bilateral symmetricity and rotational symmetricity give new insight into analyzing the geometrical property of a shape and enable characterizing arbitrary shapes in a new way. We developed a set of criteria for quantitative galaxy classification using our proposed irregular shape symmetry measures. Our study has demonstrated the effectiveness of the proposed method for the characterization of the shape of the celestial bodies. The concepts described in the paper are applicable to many fields, such as mathematics, artificial intelligence, digital image processing, robotics, biomedicine, etc.


Evidence for male dispersal along the coasts but no migration in pelagic waters in dusky dolphins (Lagenorhynchus obscurus).
Using nine nuclear species-specific microsatellite loci and two mitochondrial gene fragments (cytochrome b and control region), we investigated the processes that have shaped the geographical distribution of genetic diversity exhibited by contemporary dusky dolphin (Lagenorhynchus obscurus) populations. A total of 221 individuals from four locations (Peru, Argentina, southern Africa, and New Zealand) were assayed, covering most of the species' distribution range. Although our analyses identify a general demographic decline in the Peruvian dusky dolphin stock (recently affected by high natural and human-induced mortality levels), comparison between the different molecular markers hint at an ancient bottleneck that predates recent El Niño oscillations and human exploitation. Moreover, we find evidence of a difference in dispersal behaviour of dusky dolphins along the South American coast and across the Atlantic. While data in Peruvian and Argentine waters are best explained by male-specific gene flow between these two populations, our analyses suggest that dusky dolphins from Argentina and southern Africa recently separated from an ancestral Atlantic population and, since then, diverged without considerable gene flow. The inclusion of a few New Zealand samples further confirms the low levels of genetic differentiation among most dusky dolphin populations. Only the Peruvian dusky dolphin stock is highly differentiated, especially at mitochondrial loci, suggesting that major fluctuations in its population size have led to an increased rate of genetic drift.


A test of the diffusion model explanation for the worst performance rule using preregistration and blinding.
People with higher IQ scores also tend to perform better on elementary cognitive-perceptual tasks, such as deciding quickly whether an arrow points to the left or the right Jensen (2006). The worst performance rule (WPR) finesses this relation by stating that the association between IQ and elementary-task performance is most pronounced when this performance is summarized by people's slowest responses. Previous research has shown that the WPR can be accounted for in the Ratcliff diffusion model by assuming that the same ability parameter-drift rate-mediates performance in both elementary tasks and higher-level cognitive tasks. Here we aim to test four qualitative predictions concerning the WPR and its diffusion model explanation in terms of drift rate. In the first stage, the diffusion model was fit to data from 916 participants completing a perceptual two-choice task; crucially, the fitting happened after randomly shuffling the key variable, i.e., each participant's score on a working memory capacity test. In the second stage, after all modeling decisions were made, the key variable was unshuffled and the adequacy of the predictions was evaluated by means of confirmatory Bayesian hypothesis tests. By temporarily withholding the mapping of the key predictor, we retain flexibility for proper modeling of the data (e.g., outlier exclusion) while preventing biases from unduly influencing the results. Our results provide evidence against the WPR and suggest that it may be less robust and less ubiquitous than is commonly believed.


Detection of highly ciprofloxacin resistance acinetobacter baumannii isolated from patients with burn wound infections in presence and absence of efflux pump inhibitor.
The emergence of fluoroquinolone resistance among A. baumannii isolates is now of particular concern. Phenotypic and genotypic characteristics of resistance to ciprofloxacin among 50 Acinetobacter baumannii isolated from burn wound infections of Tehran were evaluated by E-test and broth microdilution in presence and absence of efflux pump inhibitor phenylalanine- arginine β-naphthylamide (PAβN) and PCR-sequencing methods. All isolates were then typed by REP-PCR fingerprinting to find the clonal relationship between resistant isolates. Our results indicated that resistance to ciprofloxacin among A. baumannii isolated from burn infections in Tehran are high with resistance rate of 100% and ciprofloxacin resistant isolates have a mutation of Serine 83 →Leucine in the quinolone resistance determining region (QRDR) of DNA gyrase subunit A (GyrA). 38% of the isolates showed MIC ranges of 64 to ≥512μg/ml and were considered as highly resistant. We could not detect Par C mutations and plasmid-mediated quinolone resistance A (qnrA) among ciprofloxacin resistant isolates. When we used the efflux pump inhibitor PAbN, MIC of ciprofloxacin was reduced two-to four folds. REP-type A (25/50; 50%), B (20/50; 30%) and C (10/50; 20%) were the most common REP-types among A. baumannii isolates. It seems that mutation in GyrA is the main mechanism of resistant to ciprofloxacin among A. baumannii isolates from burn infections and presence of efflux pumps is just secondary target for ciprofloxacin resistant among A. baumannii in Iran. Regarding with limitation of REP-types detected in this study, we found good correlation between resistance to ciprofloxacin and REP-types A-C.


High-frequency oscillation in adults: a utilization review.
High-frequency oscillation is used for adults with acute lung injury/acute respiratory distress syndrome. Given the uncertain benefits, our objective was to describe contemporary patient selection, high-frequency oscillation utilization, and outcomes. Utilization review. Ten academic centers (Ontario, Canada; January 1, 2005-January 31, 2007). We included 190 consecutive adults treated with high-frequency oscillation and retrospectively abstracted data on patient demographics, gas exchange, hemodynamics, settings during conventional ventilation and high-frequency oscillation, adjunctive therapies, and outcomes. We used logistic regression to explore associations with oxygenation response and hemodynamic and ventilatory complications (2 hrs after high-frequency oscillation initiation) and mortality. Continuous data are reported as mean (sd) or median (quartile 1, quartile 3). None. Patients (60.0% male; mean age, 52; sd 17) had predominantly acute lung injury/acute respiratory distress syndrome (89.8%) and were severely ill (mean Acute Physiology and Chronic Health Evaluation II score, 28; sd, 9) and hypoxemic (mean Pao2/Fio2, 80; sd, 42). High-frequency oscillation was started a median of 2 (1, 8) days after intubation and continued for a median of 3 (2, 7) days. During high-frequency oscillation, adjunctive treatments (neuromuscular blockade, 75.6%; recruitment maneuvers, 49.5%; nitric oxide, 34.0%; steroids, 63.1%) and new barotrauma or chest tube placement (23.5%) were common. Ten patients (5.3%) had technical complications; five required a new ventilator. Reasons for stopping high-frequency oscillation included death or withdrawal of life support (39.1%), significant improvement in respiratory failure (37.6%), and inadequate improvement (23.3%). One hundred and twenty-eight of 189 patients died in hospital. Most (62.5%) had a positive oxygenation response after 2 hrs of high-frequency oscillation (mean absolute increase in PaO₂/FiO₂, 22 [SD, 54]; 95% confidence interval of mean 14-31). A minority had lower PaO₂/FiO₂ (32.5%) or a hemodynamic (27.5%) or ventilatory (30.5%) complication. Older age, Acute Physiology and Chronic Health Evaluation II score, and Paco2 before high-frequency oscillation were independently associated with mortality. Most patients treated with high-frequency oscillation have acute respiratory distress syndrome and severe hypoxemia that modestly improves 2 hrs after high-frequency oscillation application. However, oxygenation worsens in some patients, complications are common, and mortality is high.


Advances in the diagnosis and treatment of dry eye.
The core mechanism of dry eye is the tear film instability. Tear film-oriented diagnosis (TFOD) is a concept to clarify the cause of tear film instability by tear film, and tear film-oriented treatment (TFOT) is a concept to treat dry eye disease by replacing the lacking components of the tear film layer based on the TFOD. In TFOD, the fluorescein breakup pattern of the tear film is important, and the subtype of dry eye can be judged to some extent from the breakup patterns. Current noninvasive devices related to the dynamic analysis of the tear film and visual acuity enabled the diagnosis of dry eye, subtype analysis, and the extent of severity. In Asian countries, secretagogues represent the main treatment in TFOT. Since meibomian gland dysfunction is a factor that greatly affects the tear breakup time, its treatment is also essential in the dry eye treatment strategy. A newly discovered dry eye subtype is the short breakup time-type (BUT) of dry eye. The only abnormal finding in this disease is the short BUT, suggesting a relationship with ocular neuropathic pain and eye strain. Recently, data from many studies have accumulated which show that dry eye is a life-style disease. In addition to the treatment of dry eyes, it is becoming possible to prevent the onset by intervening with the daily habits, diet, exercise and sleep, etc. It has been pointed out that oxidative stress is also involved in the pathology of dry eye, and intervention is being carried out by improving diet and taking supplements. Future research will be needed to link clinical findings to the molecular biological findings in the tear film.


Atomic-level observation of disclination dipoles in mechanically milled, nanocrystalline Fe.
Plastic deformation of materials occurs by the motion of defects known as dislocations and disclinations. High-resolution transmission electron microscopy was used to directly reveal the individual dislocations that constitute partial disclination dipoles in nanocrystalline, body-centered cubic iron that had undergone severe plastic deformation by mechanical milling. The mechanisms by which the formation and migration of such partial disclination dipoles during deformation allow crystalline solids to fragment and rotate at the nanometer level are described. Such rearrangements are important basic phenomena that occur during material deformation, and hence, they may be critical in the formation of nanocrystalline metals by mechanical milling and other deformation processes.


Editors' overview perspectives on teaching social responsibility to students in science and engineering.
Global society is facing formidable current and future problems that threaten the prospects for justice and peace, sustainability, and the well-being of humanity both now and in the future. Many of these problems are related to science and technology and to how they function in the world. If the social responsibility of scientists and engineers implies a duty to safeguard or promote a peaceful, just and sustainable world society, then science and engineering education should empower students to fulfil this responsibility. The contributions to this special issue present European examples of teaching social responsibility to students in science and engineering, and provide examples and discussion of how this teaching can be promoted, and of obstacles that are encountered. Speaking generally, education aimed at preparing future scientists and engineers for social responsibility is presently very limited and seemingly insufficient in view of the enormous ethical and social problems that are associated with current science and technology. Although many social, political and professional organisations have expressed the need for the provision of teaching for social responsibility, important and persistent barriers stand in the way of its sustained development. What is needed are both bottom-up teaching initiatives from individuals or groups of academic teachers, and top-down support to secure appropriate embedding in the university. Often the latter is lacking or inadequate. Educational policies at the national or international level, such as the Bologna agreements in Europe, can be an opportunity for introducing teaching for social responsibility. However, frequently no or only limited positive effect of such policies can be discerned. Existing accreditation and evaluation mechanisms do not guarantee appropriate attention to teaching for social responsibility, because, in their current form, they provide no guarantee that the curricula pay sufficient attention to teaching goals that are desirable for society as a whole.


Magnetization transfer study of HIV encephalitis and progressive multifocal leukoencephalopathy. Groupe d'Epidémiologie Clinique du SIDA en Aquitaine.
To ascertain whether the use of magnetization transfer (MT) in MR imaging can characterize tissue destruction in human immunodeficiency virus (HIV)-positive patients with presumed progressive multifocal leukoencephalopathy (PML) or HIV encephalitis. Brain MR studies that included MT were obtained in three groups: 11 healthy control subjects, 10 HIV-positive patients with clinical and radiologic findings of PML, and 13 HIV-positive patients with HIV encephalitis. MT ratios (MTRs) were calculated in PML and HIV encephalitis lesions and in normal-appearing white matter in the patients and control subjects. PML lesions revealed a dramatic decrease in MTR (22% +/- 2.3). HIV encephalitis lesions had statistically significantly higher MTR values (40% +/- 3.8) than PML lesions. The MTR of normal-appearing white matter was significantly higher in the control subjects (47% +/- 2.3) than in the PML group (46% +/- 3.3) or the HIV encephalitis group (44% +/- 2.6). MTR determinations suggest the possibility of distinguishing PML from HIV encephalitis and of indicating whether HIV encephalitis is involved in white matter that appears normal on conventional MR images.