Selective serotonergic excitation of callosal projection neurons.
Serotonin (5-HT) acting as a neurotransmitter in the cerebral cortex is critical for cognitive function, yet how 5-HT regulates information processing in cortical circuits is not well understood. We tested the serotonergic responsiveness of layer 5 pyramidal neurons (L5PNs) in the mouse medial prefrontal cortex (mPFC), and found three distinct response types: long-lasting 5-HT(1A) (1A) receptor-dependent inhibitory responses (84% of L5PNs), 5-HT(2A) (2A) receptor-dependent excitatory responses (9%), and biphasic responses in which 2A-dependent excitation followed brief inhibition (5%). Relative to 5-HT-inhibited neurons, those excited by 5-HT had physiological properties characteristic of callosal/commissural (COM) neurons that project to the contralateral cortex. We tested whether serotonergic responses in cortical pyramidal neurons are correlated with their axonal projection pattern using retrograde fluorescent labeling of COM and corticopontine-projecting (CPn) neurons. 5-HT generated excitatory or biphasic responses in all 5-HT-responsive layer 5 COM neurons. Conversely, CPn neurons were universally inhibited by 5-HT. Serotonergic excitation of COM neurons was blocked by the 2A antagonist MDL 11939, while serotonergic inhibition of CPn neurons was blocked by the 1A antagonist WAY 100635, confirming a role for these two receptor subtypes in regulating pyramidal neuron activity. Selective serotonergic excitation of COM neurons was not layer-specific, as COM neurons in layer 2/3 were also selectively excited by 5-HT relative to their non-labeled pyramidal neuron neighbors. Because neocortical 2A receptors are implicated in the etiology and pathophysiology of schizophrenia, we propose that COM neurons may represent a novel cellular target for intervention in psychiatric disease.


Apoptosis in the genesis and prevention of cancer.
A strong rationale exists for developing cancer control strategies designed to suppress or reverse the development of precancerous lesions in order to reduce the occurrence and recurrence of this disease. Whereas numerous agents have been identified that inhibit tumor development, little is known about how they work. Recently the hypothesis has been raised that misregulation of apoptosis results in a failure of tissue size regulation that contributes to the development of cancer. If validated, this concept has important implications for the prevention of carcinogenesis and could lead to the development of new cancer control approaches that have as their basis the restoration of competence to regulate tissue size. Thus, it is essential to consider the role of cell loss in the tumorigenic process. In this regard investigation of the role of specific types of cell death in tumorigenesis, particularly the role of apoptotic cell death in maintenance of tissue homeostasis, has been neglected. The fact that apoptosis is a highly conserved, specific, and selective means of controlling tissue mass and shape also suggests that it can be exploited for the prevention or control of cancer.


High mortality and low access to care following incident acute myocardial infarction in individuals with schizophrenia.
The primary objective of this study was to compare mortality following incident acute myocardial infarction (AMI) among individuals with and without schizophrenia. A secondary objective was to compare the likelihood to receive cardiac procedures and cardiologist visits. This retrospective cohort study took place in Ontario, Canada. We studied incident AMI patients who were alive at hospitalization discharge from January 1, 2002 to December 31, 2006. 71,668 subjects were included in the study (402 subjects were excluded because of missing data). The main exposure was a diagnosis of schizophrenia. The main outcome measure was 30-day mortality post-discharge. Secondary outcomes included receipt of cardiac procedures and cardiologist visits within 30 days post-discharge. After risk adjustment, individuals with schizophrenia were 56% more likely to die within 30 days of discharge (OR 1.56, 95% CI 1.08-2.23; p=0.02), but approximately 50% less likely to receive cardiac procedures (OR 0.48, 95% CI 0.40-0.56; p<0.001) or to see a cardiologist within 30 days of discharge (OR 0.53, 95% CI 0.43-0.65; p<0.001). Individuals with schizophrenia have a significant risk of dying following incident AMI. Despite the elevated mortality risk, individuals with schizophrenia are less likely to receive specialist care and cardiac procedures. Inequities in access to AMI care may be an important point of intervention for individuals with schizophrenia.


Design, implementation, and quality control in the Pathways American-Indian multicenter trial.
Pathways was the first multicenter American-Indian school-based study to test the effectiveness of an obesity prevention program promoting healthy eating and physical activity. Pathways employed a nested cohort design in which 41 schools were randomized to intervention or control conditions and students within these schools were followed as a cohort (1,704 third graders at baseline). The study's primary endpoint was percent body fat. Secondary endpoints were levels of fat in school lunches; time spent in physical activity; and knowledge, attitudes, and behaviors regarding diet and exercise. Quality control (QC) included design of data management systems which provided standardization and quality assurance of data collection and processing. Data QC procedures at study centers included manuals of operation, training and certification, and monitoring of performance. Process evaluation was conducted to monitor dose and fidelity of the interventions. Registration and tracking systems were used for students and schools. No difference in mean percent body fat at fifth grade was found between the intervention and control schools. Percent of calories from fat and saturated fat in school lunches was significantly reduced in the intervention schools as was total energy intake from 24-hour recalls. Significant increases in self-reported physical activity levels and knowledge of healthy behaviors were found for the intervention school students. The Pathways study results provide evidence demonstrating the role schools can play in public health promotion. Its study design and QC systems and procedures provide useful models for other similar school based multi- or single-site studies.


Dr. Jekyll and Mr. Hyde: ApoE explains opposing effects of neuronal LRP1.
Alzheimer's disease (AD) is the leading cause of dementia, and its pathogenesis is initiated by the accumulation of amyloid-β (Aβ) into extracellular plaques. Apolipoprotein E4 (ApoE4) is the largest genetic risk factor for sporadic AD and contributes to AD pathogenesis by influencing clearance and seeding of the initial aggregation of Aβ. In this issue of the JCI, Tachibana et al. investigated the relationship between neuronal LRP1 expression and ApoE4-mediated seeding of Aβ and showed that knockout of neuronal LRP1 prevents the increase in Aβ pathology caused by ApoE4 expression. These findings give insight into potential therapeutic targets for the preclinical phase of AD and the pathogenesis of Aβ pathology.


[Developing Japanese version of the eHealth Literacy Scale (eHEALS)].
With the rapid developing an internet society, ehealth literacy, defined as the ability to seek, find, understand, and appraise and apply the knowledge gained to addressing or solving a health problem, becomes important to promote and aid health care at the individual level. However, the eHealth Literacy Scale (eHEALS) was only a scale developed to assess the ehealth literacy. Thus, the present study was conducted to evaluated the validity and reliability of a Japanese version of the eHEALS (J-eHEALS), and examine the association of ehealth literacy with demographic attributes and characteristics on health information searching among Japanese adults. Data were analyzed for 3,000 Japanese adults (males: 50.0%,mean age: 39.6 + 10.9 years) who responded to an Internet-based cross-sectional survey. The J-eHEALS, 6 demographic attributes, resources for obtaining health information (health resources), and contents of health information obtained from internet (ehealth contents) were obtained with a questionnaire. Confirmatory factor analysis and correlation with the communicative and critical health literacy scale were utilized to assess construct validity and criterion validity. Cronbach alpha and correlation coefficients were computed for internal consistency and test-retest reliability. Also, differences in J-eHEALS scores with each demographic attribute were examined with ANOVA and the independent t-test. Finally, chi-square tests were used to determine differences in the proportions of ehealth literacy groups (high or low) classified with a median split within health resources and ehealth contents. Principal components analysis produced a single factor solution and confirmatory factor analysis for the 8-items model demonstrated high indices (GFI = .988, CFI = .993, RMSEA= .056). A significant positive correlation was found between the J-eHEALS and communicative and critical health literacy scores. Cronbach alpha was 0.93 (P < .01), and test-retest reliability was r = 0.63 (P < .01). The J-eHEALS scores were significantly higher in women, the 40-and 50-year age group, those with high income, and individuals with a high frequency of internet searching. Furthermore, the high ehealth literacy group used many health resources and obtained a greater variety of ehealth contents as compared with the low literacy group. The most frequent resource was the internet in the high group, and television/radio in the low group. However, these results could be subject to bias because of the non-representative nature of the Internet population. The results indicate the J-eHEALS to be a highly validated and reliable scale. The present study suggests that enhancement of ehealth literacy will be important to utilize the increasing amount of health information on the internet effectively and appropriately.


Genome rearrangements and pervasive meiotic drive cause hybrid infertility in fission yeast.
Hybrid sterility is one of the earliest postzygotic isolating mechanisms to evolve between two recently diverged species. Here we identify causes underlying hybrid infertility of two recently diverged fission yeast species Schizosaccharomyces pombe and S. kambucha, which mate to form viable hybrid diploids that efficiently complete meiosis, but generate few viable gametes. We find that chromosomal rearrangements and related recombination defects are major but not sole causes of hybrid infertility. At least three distinct meiotic drive alleles, one on each S. kambucha chromosome, independently contribute to hybrid infertility by causing nonrandom spore death. Two of these driving loci are linked by a chromosomal translocation and thus constitute a novel type of paired meiotic drive complex. Our study reveals how quickly multiple barriers to fertility can arise. In addition, it provides further support for models in which genetic conflicts, such as those caused by meiotic drive alleles, can drive speciation.DOI: http://dx.doi.org/10.7554/eLife.02630.001.


Unexpected Complications of Novel Deep Brain Stimulation Treatments: Ethical Issues and Clinical Recommendations.
Innovative neurosurgical treatments present a number of known risks, the natures and probabilities of which can be adequately communicated to patients via the standard procedures governing obtaining informed consent. However, due to their novelty, these treatments also come with unknown risks, which require an augmented approach to obtaining informed consent. This paper aims to discuss and provide concrete procedural guidance on the ethical issues raised by serious unexpected complications of novel deep brain stimulation treatments. We illustrate our analysis using a case study of the unexpected development of recurrent stereotyped events in patients following the use of deep brain stimulation (DBS) to treat severe chronic pain. Examining these unexpected complications in light of medical ethical principles, we argue that serious complications of novel DBS treatments do not necessarily make it unethical to offer the intervention to eligible patients. However, the difficulty the clinician faces in determining whether the intervention is in the patient's best interests generates reasons to take extra steps to promote the autonomous decision making of these patients. We conclude with clinical recommendations, including details of an augmented consent process for novel DBS treatment.


[Balneotherapy and spa therapy of rheumatic diseases in Turkey: a systematic review].
Turkey has a lot of thermal and mineral springs and is looking back on a still vivid tradition of spa therapy and balneotherapy, applied especially for the treatment of rheumatic diseases. This tradition is predominantly empiric and intuitive, however, it has assumed some important aspects of modern balneotherapeutic methods as well. This article is aimed at presenting the characteristics of traditional and modern balneological and spa therapy forms in Turkey. The studies which have been conducted between 1990 and 2000 in different spas in Turkey on the efficacy and effectiveness of spa therapy and balneotherapy for rheumatic diseases have been searched and analyzed independent of their design. A descriptive evaluation of the studies was carried out. A total of 15 published studies have been found and analyzed. The investigations have been carried out in 8 different spa resorts in Turkey. In these studies the effectiveness and efficacy of different balneological and spa therapies on a variety of rheumatic diseases (from osteoarthritis to fibromyalgia and from rheumatoid arthritis to low back pain) could be shown. Nearly all studied balneotherapeutic modalities were applied as bathing cures. Only in one study peloid therapy was applied. Balneotherapeutic therapy was applied in a modern and traditional way, and both open and stationary spa therapy forms were used at the same time. The review has shown the effectiveness of the investigated spa therapy and balneotherapy forms. It could be concluded that nearly all forms of spa therapy and balneotherapy used for the treatment of rheumatic diseases in Turkey are effective. A definitive conclusion, however, is not possible because of the heterogeneity of the study designs, methodological flaws, and the publication bias. In future good quality randomized controlled trials are needed.


Effectiveness of a primary care-based intervention to reduce sitting time in overweight and obese patients (SEDESTACTIV): a randomized controlled trial; rationale and study design.
There is growing evidence suggesting that prolonged sitting has negative effects on people's weight, chronic diseases and mortality. Interventions to reduce sedentary time can be an effective strategy to increase daily energy expenditure. The purpose of this study is to evaluate the effectiveness of a six-month primary care intervention to reduce daily of sitting time in overweight and mild obese sedentary patients. The study is a randomized controlled trial (RCT). Professionals from thirteen primary health care centers (PHC) will randomly invite to participate mild obese or overweight patients of both gender, aged between 25 and 65 years old, who spend 6 hours at least daily sitting. A total of 232 subjects will be randomly allocated to an intervention (IG) and control group (CG) (116 individuals each group). In addition, 50 subjects with fibromyalgia will be included.Primary outcome is: (1) sitting time using the activPAL device and the Marshall questionnaire. The following parameters will be also assessed: (2) sitting time in work place (Occupational Sitting and Physical Activity Questionnaire), (3) health-related quality of life (EQ-5D), (4) evolution of stage of change (Prochaska and DiClemente's Stages of Change Model), (5) physical inactivity (catalan version of Brief Physical Activity Assessment Tool), (6) number of steps walked (pedometer and activPAL), (7) control based on analysis (triglycerides, total cholesterol, HDL, LDL, glycemia and, glycated haemoglobin in diabetic patients) and (8) blood pressure and anthropometric variables. All parameters will be assessed pre and post intervention and there will be a follow up three, six and twelve months after the intervention. A descriptive analysis of all variables and a multivariate analysis to assess differences among groups will be undertaken. Multivariate analysis will be carried out to assess time changes of dependent variables. All the analysis will be done under the intention to treat principle. If the SEDESTACTIV intervention shows its effectiveness in reducing sitting time, health professionals would have a low-cost intervention tool for sedentary overweight and obese patients management. A service of the U.S. National Institutes of Health. Developed by the National Library of Medicine. ClinicalTrials.gov NCT01729936.


33rd international mammalian genome conference: meeting highlights.
Scientists from 12 countries met at the International Mammalian Genome Conference (IMGC) to share advances in mammalian genetics and genomics research. The event was held in Strasbourg, France and represents the city's second time hosting the IMGC. A diverse attendance of pre-doctoral and post-doctoral trainees, young investigators, established researchers, clinicians, bioinformaticians, and computational biologists enjoyed a rich scientific program of 63 oral presentations, 65 posters, and 5 workshops in the fields of epigenetics, system genetics, developmental biology, cancer, human disease modeling, technical advances, and bioinformatics. This report presents selected highlights of this meeting which illustrate how recent advances in mammalian genetic approaches have improved our ability to decipher complex biological mechanisms.


A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk.
The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288-300. ©2016 AACR.


Poly-N-acetyllactosamine-specific tomato lectin interacts with gastric parietal cells. Identification of a tomato-lectin binding 60-90 X 10(3) Mr membrane glycoprotein of tubulovesicles.
The cytoplasmic tubulovesicular and canalicular membranes of gastric parietal cells are intimately involved in hydrochloric acid secretion. To characterise the glycoproteins of these membranes, we examined a panel of lectins for reactivity with parietal cells in paraffin sections of rat, dog and pig stomach. The poly-N-acetyllactosamine-specific lectin from Lycopersicon esculentum (tomato) and from Solanum tuberosum (potato), and the galactose-specific lectin Ricinus communis agglutinin (RCA120), showed strong cytoplasmic binding of parietal cells of all three species, with a pattern indicative of an intracellular membrane network. Binding to parietal cells was confirmed by double-labelling studies with parietal cell auto-antibodies from patients with autoimmune gastritis. Mucous cells and mucin also bound these lectins strongly. Other gastric cell types did not stain with either tomato or potato lectin, but stained weakly with RCA120. Electron-microscopic examination of lectin binding sites using biotinylated tomato lectin or RCA120 and streptavidin-gold, revealed specific binding to the luminal face of parietal cell tubulovesicular and canalicular membranes as well as the contents of mucous cell secretory granules. Tomato lectin and RCA120 reacted by lectin blotting with a major species of apparent molecular weight 60-90 X 10(3) Mr from rat, dog and pig gastric membranes. A tubulovesicular membrane fraction, enriched 10-fold for K(+)-dependent phosphatase activity, was also enriched three-fold for tomato lectin binding as assessed by a solid-phase lectin assay. The 60-90K (K = 10(3) Mr) component, in 125I-labelled detergent extracts of dog tubulovesicular membranes, bound to an affinity support of tomato lectin-Sepharose and was specifically eluted with N,N',N'-triacetylchitotriose. Digestion with N-glycanase collapsed the 60-90K component into a sharp 35K band. We conclude that: (1) a 60-90K membrane glycoprotein localised on the luminal face of tubulovesicles and canaliculi of parietal cells interacts strongly with tomato lectin and RCA120; and (2) the glycoprotein is composed of a 35K core protein glycosylated with N-glycans probably containing poly-N-acetyllactosamine sequences with terminal galactosyl residues. The properties of this 60-90K glycoprotein are identical to a major parietal cell autoantigen recognised by sera of patients with autoimmune gastritis.(ABSTRACT TRUNCATED AT 400 WORDS)


Application-based management of perioperative anticoagulant therapy: description of POPACTApp.
Perioperative management of oral anticoagulation (OAC) is a constant challenge in interventional and surgical procedures. When deciding to discontinue OAC, the risk of thromboembolic events must be balanced against the risk of bleeding during and after the planned procedure. These risks differ across patients and must be considered individually. POPACTApp, an application for the perioperative or peri-interventional management of oral anticoagulants, was developed using a human-centered design process (ISO 9241-210:2010). The treatment concept developed here can be adapted to a patient's individual risk profile. POPACTApp provides recommendations based on guidelines, consensus statements, and study data. After entering patient-specific risk factors, the attending physician using POPACTApp receives a clear and direct presentation of a periprocedural treatment concept, which should enable the efficient use of the program in everyday clinical practice. The perioperative treatment concept is presented via a timeline, including (1) the decision on whether to interrupt OAC, (2) the timing of the last preoperative administration of OAC in cases of interruption, (3) the decision on whether and how to bridge with heparins, and (4) the decision about when to reinitiate anticoagulation. A task-based survey to evaluate POPACTApp's usability conducted with 20 surgeons showed that all clinicians correctly interpreted the recommendations provided by the app. Further, a questionnaire using a 7-point Likert scale from - 3 (negative) to + 3 (positive) revealed the following results to three specific questions: (1) satisfaction with the current standard procedure in the respective unit of the participant (0.15; SD = 1.57), (2) individual satisfaction with the POPACTApp application (2.7; SD = 0.47), and (3) estimation of the usefulness of POPACTApp for clinical practice (2.7; SD = 0.47). POPACTApp provides clinicians with an individual risk-optimized treatment concept for the perioperative or peri-interventional management of OAC based on current guidelines, consensus statements, and study data, enabling the standardized perioperative handling of OAC in daily clinical practice.


Assessing Potential Impact of Bt Eggplants on Non-Target Arthropods in the Philippines.
Studies on potential adverse effects of genetically engineered crops are part of an environmental risk assessment that is required prior to the commercial release of these crops. Of particular concern are non-target organisms (NTOs) that provide important ecosystem services. Here, we report on studies conducted in the Philippines over three cropping seasons with Bt eggplants expressing Cry1Ac for control of the eggplant fruit and shoot borer (EFSB), Leucinodes orbonalis, to examine potential effects on field abundance, community composition, structure and biodiversity of NTO's, particularly non-target arthropod (NTA) communities. We document that many arthropod taxa are associated with Bt eggplants and their non-Bt comparators and that the number of taxa and their densities varied within season and across trials. However, we found few significant differences in seasonal mean densities of arthropod taxa between Bt and non-Bt eggplants. As expected, a lower abundance of lepidopteran pests was detected in Bt eggplants. Higher abundance of a few non-target herbivores was detected in non-Bt eggplants as were a few non-target beneficials that might control them. Principal Response Curve (PRC) analyses showed no statistically significant impact of Bt eggplants on overall arthropod communities through time in any season. Furthermore, we found no significant adverse impacts of Bt eggplants on species abundance, diversity and community dynamics, particularly for beneficial NTAs. These results support our previous studies documenting that Bt eggplants can effectively and selectively control the main pest of eggplant in Asia, the EFSB. The present study adds that it can do so without adverse effects on NTAs. Thus, Bt eggplants can be a foundational component for controlling EFSB in an Integrated Pest Management (IPM) program and dramatically reduce dependence on conventional insecticides.


Interactions of CD55 with non-complement ligands.
Decay Accelerating Factor (or CD55) is a major regulator of the alternative and classical pathways of complement activation and is expressed on all serum-exposed cells. It is commonly hijacked by invading pathogens, including many enteroviruses and uropathogenic Escherichia coli, to promote cellular attachment prior to infection. This review will attempt to summarize our knowledge about these interactions between CD55 and various pathogens and also what is known about the non-complement interaction between CD55 and CD97.


Fate of vasopressin perfused into nephrons of Wistar and Brattleboro (diabetes insipidus) rats.
1. Iodinated vasopressin was microinjected into early proximal or distal tubules or Wistar and Brattleboro (diabetes insipidus) rats. Sites of infusion were determined by the lissamine green transit time method. 2. Urinary recovery of 125I after proximal and distal injections was 89 +/- SE 1.7% and 94 +/- 1.0% in Wistar rats (corrected for inulin) and 81 +/- 2.0 and 92 +/- 2.0% in Brattleboro rats (uncorrected); injection of hormone into vascular stars resulted in similar 125I recoveries from punctured and contralateral kidneys. 3. Radioactive substances excreted after perfusing proximal and distal sites in Brattleboro animals, and 125I-labelled hormone added to urine from the contralateral kidney, bound similarly to a specific arginine vasopressin antiserum and demonstrated similar radioactive elution profiles after passage through Sephadex G25 columns. 4. Incubation of labelled and unlabelled vasopressin with rat kidney homogenates resulted in similar and complete degradation of the hormone. 5. Results indicate that most of the vasopressin injected into either proximal or distal nephrons enters the urine intact, and no evidence of tubular secretion was found when perfusing vascular stars. Enzymes in rat renal tissue degrade labelled vasopressin, but the ability of the proximal tubule to hydrolyse the 125I-labelled vasopressin is limited, especially when compared with that reported for several linear peptide hormones.


Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration.
Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNFR2, an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNFR2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.


Growth of surface undulations at the Rosensweig instability.
We investigate the growth of a pattern of liquid crests emerging in a layer of magnetic liquid when subjected to a magnetic field oriented normally to the fluid surface. After a steplike increase of the magnetic field, the temporal evolution of the pattern amplitude is measured by means of a Hall-sensor array. The extracted growth rate is compared with predictions from linear stability analysis by taking into account the proper nonlinear magnetization curve M(H) . The remaining discrepancy can be resolved by numerical calculations via the finite-element method. By starting with a finite surface perturbation, it can reproduce the temporal evolution of the pattern amplitude and the growth rate. The investigations are performed for two magnetic liquids, one with low and one with high viscosity.


Benchmarking the clinical prosthetic dental literature on MEDLINE.
The utility of evidence-based clinical prosthetic dental decision making is, in part, predicated on the availability of high-quality clinical trials and the use of current best evidence. With literature or outcomes continually evolving, it is difficult to know how much information is available, how fast it changes, or where it is located. This study identified and quantified the availability of high-quality prosthetic dental clinical trials, determined the dynamics of literature increase, and identified the location of relevant literature published within a specific decade. A search strategy based on the Medical Subject Headings (MeSH) vocabulary for prosthetic dentistry was developed to examine MEDLINE with use of the Ovid Web Gateway search engine between the years 1990-1999. Specific and sensitive methodologic search filters identified 4 categories of information: etiology, diagnosis, therapy, and prognosis. The identified studies were limited to human subjects and to articles written in English. The results were subdivided by year to identify trends and location of the literature. This evaluation did not include the following: (1) other databases or languages or (2) an evaluation of the validity or clinical applicability of the literature. The first factor would increase the estimated number of relevant articles, whereas the second factor would decrease it. Between 1990 and 1999, MEDLINE identified 10,258 articles published in English on human prosthodontic issues. When subdivided by clinical category, the number of articles per year (mean +/- SD) for specific and sensitive searches, respectively, was as follows: etiology, 10 +/- 6 and 95 +/- 27; diagnosis, 11 +/- 5 and 77 +/- 21; therapy, 6 +/- 2 and 153 +/- 52; and prognosis, 13 +/- 6 and 91 +/- 27. For sensitive searches, this amounted to approximately 416 articles per year. The time-course analysis indicated that the number of articles in each category increased by approximately 7% per year. The articles were published in more than 60 different journals: approximately 50% of the articles were published in 14 journals, whereas the remaining articles were published in 46 journals. There appears to be substantial clinical prosthetic dental literature upon which to base clinical decisions. With the sensitive search strategy used as an estimate, to stay current, one would need to read and absorb approximately 8 articles per week, 52 weeks per year, across 60 different journals. Increases in the volume of literature each year make access even more difficult. These trends suggest the need for computer-based clinical knowledge systems.


Refraction and band isotropy in 2D square-like Archimedean photonic crystal lattices.
In this paper we theoretically study refraction effects in the 2D square-like Archimedean photonic crystals (3(2), 4, 3, 4) and (4, 8(2)) made of dielectric rods in air. In addition, we investigated a band isotropy and band gap structure in these lattices. We compared the square and square-like structures as well, their refraction characteristics, zone structures and the level of band and band gap isotropy (bandwidth and band gap dependence on the wave vector). We found that square-like structures can have some advantages over the square ones regarding the completeness of the gap, its isotropy and the gap width. Also, due to the same square primitive unit cell and the first Brillouin zone, the square and square-like lattices have similar optical response in lower bands.


Neural Responses to Truth Telling and Risk Propensity under Asymmetric Information.
Trust is multi-dimensional because it can be characterized by subjective trust, trust antecedent, and behavioral trust. Previous research has investigated functional brain responses to subjective trust (e.g., a judgment of trustworthiness) or behavioral trust (e.g., decisions to trust) in perfect information, where all relevant information is available to all participants. In contrast, we conducted a novel examination of the patterns of functional brain activity to a trust antecedent, specifically truth telling, in asymmetric information, where one individual has more information than others, with the effect of varying risk propensity. We used functional magnetic resonance imaging (fMRI) and recruited 13 adults, who played the Communication Game, where they served as the "Sender" and chose either truth telling (true advice) or lie telling (false advice) regarding the best payment allocation for their partner. Our behavioral results revealed that subjects with recreational high risk tended to choose true advice. Moreover, fMRI results yielded that the choices of true advice were associated with increased cortical activation in the anterior rostral medial and frontopolar prefrontal cortices, middle frontal cortex, temporoparietal junction, and precuneus. Furthermore, when we specifically evaluated a role of the bilateral amygdala as the region of interest (ROI), decreased amygdala response was associated with high risk propensity, regardless of truth telling or lying. In conclusion, our results have implications for how differential functions of the cortical areas may contribute to the neural processing of truth telling.


Bacteria from solid tumours.
Bacteria were grown from 63 (69%) of 91 specimens from necrotic tumours in 63 patients. Of the tumours, 14 were abdominal, 5 pelvic, 23 of the head and neck, 4 of the lungs, 4 mediastinal, 2 lymphatic, 3 of the breast, and 8 were miscellaneous. Aerobic or facultatively anaerobic bacteria only were present in 12 (19%) specimens, anaerobes only in 10 (16%), and mixed aerobic and anaerobic bacteria in 41 (65%). A total of 83 anaerobic and 47 aerobic and facultatively anaerobic bacteria were isolated. The predominant anaerobic bacteria were Bacteroides spp. (36 isolates), and anaerobic cocci (21) and Propionibacterium acnes (22). The aerobic and facultatively anaerobic bacteria most frequently isolated were Staphylococcus aureus, alpha-haemolytic streptococci, Escherichia coli (seven isolates each), S. epidermidis, Klebsiella pneumoniae and Pseudomonas aeruginosa (five isolates each). These data demonstrate that infection of tumours is usually polymicrobial.


Treatment for hepatitis C virus-associated mixed cryoglobulinaemia.
Hepatitis C virus (HCV)-associated mixed cryoglobulinaemia is the manifestation of an inflammation of small and medium-sized vessels produced by a pathogenic IgM with rheumatoid factor activity generated by an expansion of B-cells. The immune complexes formed precipitate mainly in the skin, joints, kidneys or peripheral nerve fibres. Current therapeutic approaches are aimed at elimination of HCV infection, removal of cryoglobulins and also of the B-cell clonal expansions. The optimal treatment for it has not been established. This review aims to look at the benefits and harms of the currently available treatment options to treat the HCV-associated mixed cryoglobulinaemia with active manifestations of vasculitis (cutaneous or glomerulonephritis). We searched the Cochrane Kidney and Transplant Specialised Register to 30 November 2017 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. All randomised controlled trials (RCTs) and quasi-RCTs looking at interventions directed at treatment of HCV-associated cryoglobulinaemic vasculitis (immunosuppressive medications and plasma exchange therapy) have been included. Two authors independently assessed the retrieved titles and abstracts. Authors of included studies were contacted to obtain missing information. Statistical analyses were performed using random effects models and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). The planned primary outcomes were kidney disease, skin vasculitis, musculoskeletal symptoms, peripheral joint arthralgia, peripheral neuropathies, liver involvement, interstitial lung involvement, widespread vasculitis and death. Other planned outcomes were: therapy duration, laboratory findings, adverse effects, antiviral therapy failure, B-cell lymphoma, endocrine disorders and costs of treatment. Ten studies were included in the review (394 participants). None of them evaluated direct-acting antivirals. Seven studies were single-centre studies and three were multicentre. The duration of the studies varied from six to 36 months. The risk of bias was generally unclear or low. Three different interventions were examined: use of rituximab (3 studies, 118 participants); interferon (IFN) (IFN compared to other strategies (5 studies, 223 participants); six IFN months versus one year (1 study, 36 participants), and immunoadsorption apheresis versus only immunosuppressive therapy (1 study, 17 participants).The use of rituximab may slightly improve skin vasculitis (2 studies, 78 participants: RR 0.57, 95% CI 0.28 to 1.16; moderate certainty evidence) and made little of no difference to kidney disease (moderate certainty evidence). In terms of laboratory data, the effect of rituximab was uncertain for cryocrit (MD -2.01%, 95% CI -10.29% to 6.27%, low certainty evidence) and HCV replication. Rituximab may slightly increase infusion reactions compared to immunosuppressive medication (3 studies, 118 participants: RR 4.33, 95%CI 0.76 to 24.75, moderate certainty evidence) however discontinuations of the treatment due to adverse reactions were similar (3 studies, 118 participants: RR 0.97, 95% CI 0.22 to 4.36, moderate certainty evidence).Effects of lFN on clinical symptoms were evaluated only in narrative results. When laboratory parameters were assessed, IFN made little or no difference in levels of alanine transaminase (ALT) at six months (2 studies, 39 participants: MD -5.89 UI/L, 95%CI -55.77 to 43.99); rheumatoid factor activity at six months (1 study, 13 participants: MD 97.00 UI/mL, 95%CI -187.37 to 381.37), or C4 levels at 18 months (2 studies, 49 participants: MD -0.04 mg/dL, 95%CI -2.74 to 2.67). On the other hand, at 18 months IFN may probably decrease ALT (2 studies, 39 participants: MD -28.28 UI/L, 95%CI -48.03 to -8.54) and Ig M (-595.75 mg/dL, 95%CI -877.2 to -314.3), but all with low certainty evidence. One study reported infusion reactions may be higher in IFN group compared to immunosuppressive therapy (RR 27.82, 95%CI 1.72 to 449.18), and IFN may lead to higher discontinuations of the treatment due to adverse reactions (4 studies, 148 participants: RR 2.32, 95%CI 0.91 to 5.90) with low certainty evidence. Interferon therapy probably improved skin vasculitis (3 studies, 95 participants: RR 0.60, 95% CI 0.36 to 1.00) and proteinuria (2 studies, 49 participants: MD -1.98 g/24 h, 95% CI -2.89 to -1.07), without changing serum creatinine at 18 months (2 studies, 49 participants: MD -30.32 μmol/L, 95%CI -80.59 to 19.95).Six months versus one year treatment with IFN resulted in differences terms of the maintenance of the response, 89% of patients in the six months group presented a relapse and only 11% maintained a long-term response at one year, while in the one year group only 78% relapsed and long-term response was observed in 22%. The one-year therapy was linked to a higher number of side-effects (severe enough to cause the discontinuation of treatment in two cases) than the six-month schedule.One study reported immunoadsorption apheresis had uncertain effects on skin vasculitis (RR 0.44, 95% CI 0.05 to 4.02), peripheral neuropathies (RR 2.70, 95%CI 0.13 to 58.24), and peripheral joint arthralgia (RR 2.70, 95%CI 0.13 to 58.24), cryocrit (MD 0.01%, 95%CI -1.86 to 1.88) at six months, and no infusion reactions were reported. However when clinical scores were evaluated, they reported changes were more favourable in immunoadsorption apheresis with higher remission of severe clinical complications (80% versus 33%, P = 0.05) compared to immunosuppressive treatment alone.In terms of death, it was not possible to present a pooled intervention effect estimate because most of the studies reported no deaths, or did not report death as an outcome. To treat HCV-associated mixed cryoglobulinaemia, it may be beneficial to eliminate HCV infection by using antiviral treatment and to stop the immune response by using rituximab. For skin vasculitis and for some laboratory findings, it may be appropriate to combine antiviral treatment with deletion of B-cell clonal expansions by using of rituximab. The applicability of evidence reviewed here is limited by the absence of any studies with direct-acting antivirals, which are urgently needed to guide therapy.


BcsQ is an essential component of the Escherichia coli cellulose biosynthesis apparatus that localizes at the bacterial cell pole.
Biofilms are microbial communities characterized by three-dimensional growth resulting from the ability of individual cells to adhere to each other as well as to produce an extracellular matrix that ensures biofilm physical cohesion. Numerous bacteria produce cellulose as a biofilm matrix polymer, a property relying on the expression of bacterial cellulose synthesis (Bcs) proteins and their post-translational activation upon binding of cyclic di-guanosine mono-phosphate second messenger (c-di-GMP) produced by diguanylate cyclases. In Escherichia coli and other Enterobacteriaceae, two genes of unknown function, yhjR and yhjQ, are located upstream of the bcs genes. Here, we show that yhjQ, but not yhjR, is essential for cellulose biosynthesis; it has therefore been renamed bcsQ. Using a green fluorescent protein (GFP) fusion approach, we demonstrate that BcsQ, a MinD homologue, displays a polar localization and that cell-to-cell adhesion is initiated through production of cellulose at the BcsQ-labelled pole. Although we did not detect a similar localization for other Bcs proteins, immunogold labelling of cellulose itself at the pole of individual bacteria indicates the localized activity of the cellulose biosynthesis apparatus. These results therefore suggest that BcsQ could participate in spatial restriction of cellulose biosynthesis activity in Enterobacteriaceae.


Pediatrician identification of Latino children at risk for autism spectrum disorder.
Latino-white disparities in age at autism spectrum disorder (ASD) diagnosis may be modified by primary care pediatrician (PCP) practices and beliefs. The objectives of this study were to assess ASD and developmental screening practices, attitudes toward ASD identification in Latino children, and barriers to ASD identification for Latino children, in a sample of 267 California PCPs. In mail-based PCP survey, we assessed rates of bilingual general developmental and ASD screening, perceptions of parent ASD knowledge in Latino and white families, reports of difficulty assessing for ASDs in Latino and white children, and perceptions of barriers to early ASD identification for Latinos. Although 81% of PCPs offered some form of developmental screening, 29% of PCPs offered Spanish ASD screening per American Academy of Pediatrics guidelines, and only 10% offered both Spanish general developmental and Spanish ASD screening per American Academy of Pediatrics guidelines. Most PCPs thought that Latino (English and Spanish primary family language) parents were less knowledgeable about ASDs than white parents. PCPs had more difficulty assessing ASD risk for Latino children with Spanish primary family language than for white children, even when the PCP conducted recommended ASD screening or had >25% Latino patients. The most frequent barrier to ASD identification in Latinos was access to developmental specialists. Multiple factors in the primary care setting may contribute to delayed ASD identification for Latinos. Promoting language-appropriate screening, disseminating culturally appropriate ASD materials to Latino families, improving the specialist workforce, and providing PCP support in screening and referral of Latino children may be important ways to reduce racial and ethnic differences in care.


Carbon dots: materials, synthesis, properties and approaches to long-wavelength and multicolor emission.
Herein, we summarize recent research developments and progress of carbon dots (CDs), which have been attracting considerable attention as a new type of photoluminescent material. Raw materials, from single carbonaceous compounds to colorful natural substances, for the synthesis of CDs are discussed. A range of diverse synthetic methodologies to achieve better photoluminescence performance and more advanced functions are summarized, and these are basically divided into two classes: top-down and bottom-up. The inspiring properties, mainly including composites, optical properties and cytotoxicity, are listed. In particular, the luminescence mechanism and surface functionalization of the CDs are briefly discussed. Moreover, on the basis of the above, the long-wavelength and multicolor emission properties of CDs and ways to achieve these goals including surface state and size controlled by synthesis strategies, proper precursors, chemical doping and modification, solvatochromic effects and energy transfer are reviewed in detail.


Oncolytic viruses as therapeutic cancer vaccines.
Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity. With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF (such as T-VEC and Pexa-Vec) or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy. Coadministration with a HDAC inhibitor inhibits innate immunity transiently to promote infection and spread of OVs, and significantly enhances anti-tumor immunity and improves the therapeutic index. Local administration or OV mediated-expression of ligands for Toll-like receptors can rescue the function of tumor-infiltrating CD8+ T cells inhibited by the immunosuppressive tumor microenvironment and thus enhances the antitumor effect. Combination with cyclophosphamide further induces ICD, depletes Treg, and thus potentiates antitumor immunity. In summary, OVs properly armed or in rational combinations are potent therapeutic cancer vaccines.


Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity.
Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (THC/CBD, Sativex®, nabiximols) is available in numerous countries worldwide for the treatment of multiple sclerosis (MS)-related moderate to severe spasticity in patients who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. Twelve weeks' therapy with THC/CBD improved MS-related spasticity in patients with an inadequate response to other anti-spasticity agents who had undergone a successful initial trial of THC/CBD therapy, according to the results of a pivotal phase 3 trial. Improvements in spasticity were maintained in the longer term with THC/CBD with no evidence of dose tolerance, and results of real-world studies confirm the effectiveness of THC/CBD in everyday clinical practice. Improvements in health-related quality of life and activities of daily living were also seen with THC/CBD. THC/CBD is generally well tolerated; adverse effects such as dizziness may occur whilst the THC/CBD dosage is being optimized. THC/CBD has low abuse potential and a low risk of psychoactive effects. In conclusion, THC/CBD oromucosal spray is a useful option for the treatment of MS-related spasticity not completely relieved with current anti-spasticity medication.


PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans.
Autophagy is a process by which cells recycle cytoplasm and defective organelles during stress situations such as nutrient starvation. It can also be used by host cells as an immune defense mechanism to eliminate infectious pathogens. Here we describe the use of autophagy as a survival mechanism and virulence-associated trait by the human fungal pathogen Cryptococcus neoformans. We report that a mutant form of C. neoformans lacking the Vps34 PI3K (vps34Delta), which is known to be involved in autophagy in ascomycete yeast, was defective in the formation of autophagy-related 8-labeled (Atg8-labeled) vesicles and showed a dramatic attenuation in virulence in mouse models of infection. In addition, autophagic vesicles were observed in WT but not vps34Delta cells after phagocytosis by a murine macrophage cell line, and Atg8 expression was exhibited in WT C. neoformans during human infection of brain. To dissect the contribution of defective autophagy in vps34Delta C. neoformans during pathogenesis, a strain of C. neoformans in which Atg8 expression was knocked down by RNA interference was constructed and these fungi also demonstrated markedly attenuated virulence in a mouse model of infection. These results demonstrated PI3K signaling and autophagy as a virulence-associated trait and survival mechanism during infection with a fungal pathogen. Moreover, the data show that molecular dissection of such pathogen stress-response pathways may identify new approaches for chemotherapeutic interventions.


Preoperative Neutrophil-Lymphocyte and Lymphocyte-Monocyte Ratios Reflect Immune Cell Population Rearrangement in Resectable Pancreatic Cancer.
Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) may serve as a simple index of the immune function. The aim of this study was to investigate the prognostic significance of NLR, PLR, and LMR in patients with resectable pancreatic ductal adenocarcinoma (PDAC) and to verify whether such biomarkers are associated with changes in populations of lymphoid cells. The prognostic implications of blood count parameters were evaluated in a retrospective cohort of 442 subjects undergoing pancreatic resections for PDAC. Subpopulations of lymphocytes and monocytes in peripheral blood were identified by FACS in a prospective cohort of 54 patients. In the univariate analysis, NLR < 5 and LMR ≥ 3 were associated with significantly longer median survival of 25.7 vs 12.6 months and 29.2 vs 13.1 months, respectively. PLR did not influence survival. The Cox proportional hazards model showed that high NLR (HR 1.66, 95 % CI 1.12 to 2.46, P = 0.012) and low LMR (HR 1.65, 95 % CI 1.06 to 2.58, P = 0.026) were independent predictors of poor prognosis. NLR ≥ 5 and LMR < 3 correlated with an approximately twofold decrease in counts of helper and cytotoxic T cells, B cells, and NK cells. High NLR was also accompanied with increased neutrophil counts, while low LMR showed increased numbers of monocytes, mostly classical. NLR and LMR may carry important prognostic information for patients with resected PDAC. The unfavorable prognosis likely correlates with reduced numbers of immune cells effective against the tumor and increased populations of cells involved in immune suppression.


Construction of a novel shuttle vector for use in Haemophilus influenzae and H. parainfluenzae.
Haemophilus influenzae is an important human pathogen. A number of complete genome sequences of various haemophili are available; however, functional studies have been limited by the lack of an effective shuttle vector which functions in all strains. Here, we have constructed a shuttle vector, pEJ6, which transfers genes between Escherichia coli and H. influenzae and H. parainfluenzae. The vector contains an origin of replication from pLS88 which is functional in E. coli and H. influenzae. In addition it contains an RP4 mobilisation region. The vector can be introduced by electroporation and conjugation into capsulate and non-typeable H. influenzae and is functional for allelic replacement and mutant complementation. The vector will be useful for investigating gene function in Haemophilus spp.


Resveratrol induces sumoylated COX-2-dependent anti-proliferation in human prostate cancer LNCaP cells.
Cyclooxygenase (COX)-2 has been implicated in cancer development. However, resveratrol-induced nuclear accumulation of COX-2 enhances p53-dependent anti-proliferation in different types of cancers. Treatment with resveratrol leads to phosphorylation and nuclear translocation of mitogen-activated protein kinase (ERK1/2), and accumulation of nuclear COX-2 to complex with pERK1/2 and p53. The consequence is Ser-15 phosphorylation of p53 (pSer15-p53), and induction of anti-proliferation in cancer cells. We investigated the mechanisms by which resveratrol-inducible COX-2 facilitates p53-dependent anti-proliferation in prostate cancer LNCaP cells. Resveratrol treatment caused nuclear accumulation and complexing of ERK1/2, pSer15-p53 and COX-2 which was activated ERK1/2-dependent. Knockdown of SUMO-1 by shRNA also reduced nuclear accumulation of COX-2. Inhibition of nuclear accumulation by the COX-2 specific inhibitor, NS-398, inhibited co-localization of nuclear COX-2 and SUMO-1. Similar results were observed in the PD98059-treated cells. Finally, inhibition of SUMO-1 expression also reduced resveratrol-induced expression of pro-apoptotic genes but increased the expression of proliferative genes. In summary, these results demonstrate that inducible COX-2 associates with phosphorylated ERK1/2 to induce the phosphorylation of Ser-15 in p53 and then complexes with p53 and SUMO-1 which binds to p53-responsive pro-apoptotic genes to enhance their expression. The inhibition of COX-2 expression and activity significantly blocks the pro-apoptotic effect of resveratrol.


Endoscopically assisted versus open repair of sagittal craniosynostosis: the St. Louis Children's Hospital experience.
This study investigated the differences in effectiveness and morbidity between endoscopically assisted wide-vertex strip craniectomy with barrel-stave osteotomies and postoperative helmet therapy versus open calvarial vault reconstruction without helmet therapy for sagittal craniosynostosis. Between 2003 and 2010, the authors prospectively observed 89 children less than 12 months old who were surgically treated for a diagnosis of isolated sagittal synostosis. The endoscopic procedure was offered starting in 2006. The data associated with length of stay, blood loss, transfusion rates, operating times, and cephalic indices were reviewed. There were 47 endoscopically treated patients with a mean age at surgery of 3.6 months and 42 patients with open-vault reconstruction whose mean age at surgery was 6.8 months. The mean follow-up time was 13 months for endoscopic versus 25 months for open procedures. The mean operating time for the endoscopic procedure was 88 minutes, versus 179 minutes for the open surgery. The mean blood loss was 29 ml for endoscopic versus 218 ml for open procedures. Three endoscopically treated cases (6.4%) underwent transfusion, whereas all patients with open procedures underwent transfusion, with a mean of 1.6 transfusions per patient. The mean length of stay was 1.2 days for endoscopic and 3.9 days for open procedures. Of endoscopically treated patients completing helmet therapy, the mean duration for helmet therapy was 8.7 months. The mean pre- and postoperative cephalic indices for endoscopic procedures were 68% and 76% at 13 months postoperatively, versus 68% and 77% at 25 months postoperatively for open surgery. Endoscopically assisted strip craniectomy offers a safe and effective treatment for sagittal craniosynostosis that is comparable in outcome to calvarial vault reconstruction, with no increase in morbidity and a shorter length of stay.


Photodynamics of Zr-based MOFs: effect of explosive nitroaromatics.
The present work describes the spectroscopic and photodynamics of two different Zr mixed-linkers MOFs (Zr-NDC/Tz and Zr-NDC/CN) and their interaction with nitroaromatics. Both MOFs exhibit comparable spectroscopic behaviours, with a broad emission band mainly due to the naphthalene excimers within their three-dimensional structure. Flash photolysis experiments show a slow radiative electron-hole (e--h+) recombination, reflected as a large negative absorption band. The interaction with the selected nitroaromatic compounds produces a static fluorescence quenching of Zr-NDC/Tz. Interestingly, the addition of trinitrophenol (TNP) induces the formation of a charge-transfer complex, helped by intermolecular H-bonds formation, as shown by the steady-state and ps-time-resolved emission experiments. Remarkably, the (e--h+) recombination is strongly affected due to the inhibition of the ligand-to-cluster charge transfer process within the MOF. The quenching constants for the nitroaromatics lacking -OH groups are in the order of 102 M-1, while it is two orders of magnitude higher for the TNP (1.8 × 104 M-1). Both MOFs are highly selective toward TNP. We also demonstrate the possibility to recycle these MOFs without significant loses in their ability to detect TNP. Our findings give the clues to understand the fluorescence quenching mechanism of new Zr-based MOFs in presence of explosive-like molecules, opening the way to improve these nanomaterials as highly selective sensor of nitroaromatics.


Merging models and biomonitoring data to characterize sources and pathways of human exposure to organophosphorus pesticides in the Salinas Valley of California.
We characterize cumulative intakes of organophosphorus (OP) pesticides in an agricultural region of California by drawing on human biomonitoring data, California pesticide use reporting (PUR) data, and limited environmental samples together with outputs from the CalTOX multimedia, multipathway, source-to-dose model. The study population is the CHAMACOS cohort of almost 600 pregnant Latina women in the Salinas Valley region. We use model estimates of OP intake and urinary dialkylphosphate (DAP) metabolite excretion to develop premises about relative contributions from different exposure sources and pathways. We evaluate these premises by comparing the magnitude and variation of DAPs in the CHAMACOS cohort with those of the whole U.S. population using data from the National Health and Nutrition Examination Survey (NHANES). This comparison supports the premise that diet is the common and dominant exposure pathway in both populations. Biomarker comparisons and model results support the observation that, relative to NHANES, the CHAMACOS population has a statistically significant (p < 0.001) added intake of OP pesticides with low inter-individual variability. We attribute the magnitude and small variance of this intake to residential nondietary exposures from local agricultural OP uses. These results show that mass-balance models can estimate exposures for OP pesticides within the range measured by biological monitoring.


Family and infant characteristics in relation to age at walking in Turkey.
The purpose of this study was to assess the onset of independent ambulation relative to possible relationships with maternal and infant characteristics. In a cross-sectional study, the health files of 1,553 Turkish children aged 12-23 months were selected by the multistage sampling method in the Nomenclature of Territorial Units for Statistics (NUTS) regions coded as low, medium and high malnutrition levels in Turkey. Children were selected from health centers by systematic sampling technique in each region. Kaplan-Meier analysis and estimated mean values were used for data description; log-rank test and the Cox multivariable regression analysis were applied for data analysis. Maternal education level, occupation, region of residence, gestational iron supplementation, child's gender, child's nutritional status, and presence of anemia in the infant during the survey period demonstrated significant relationships with walking unassisted in the univariate analysis. However, multivariable analysis showed that high maternal education, absence of parental consanguinity and appropriate weight-for-age Z score were positively associated with earlier age of walking. These findings showed the importance of improvement in girls' education, prevention of postnatal growth retardation and improvement in diet quality for children's gross motor development. In addition, counseling programs should be given to decrease the rate of parental consanguinity.


Prior Dengue Virus Exposure Shapes T Cell Immunity to Zika Virus in Humans.
While progress has been made in characterizing humoral immunity to Zika virus (ZIKV) in humans, little is known regarding the corresponding T cell responses to ZIKV. Here, we investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether preexisting dengue virus (DENV) T cell immunity modulates these responses. We find that memory T cell responses elicited by prior infection with DENV or vaccination with tetravalent dengue attenuated vaccines (TDLAV) recognize ZIKV-derived peptides. This cross-reactivity is explained by the sequence similarity of the two viruses, as the ZIKV peptides recognized by DENV-elicited memory T cells are identical or highly conserved in DENV and ZIKV. DENV exposure prior to ZIKV infection also influences the timing and magnitude of the T cell response. ZIKV-reactive T cells in the acute phase of infection are detected earlier and in greater magnitude in DENV-immune patients. Conversely, the frequency of ZIKV-reactive T cells continues to rise in the convalescent phase in DENV-naive donors but declines in DENV-preexposed donors, compatible with more efficient control of ZIKV replication and/or clearance of ZIKV antigen. The quality of responses is also influenced by previous DENV exposure, and ZIKV-specific CD8 T cells from DENV-preexposed donors selectively upregulated granzyme B and PD1, unlike DENV-naive donors. Finally, we discovered that ZIKV structural proteins (E, prM, and C) are major targets of both the CD4 and CD8 T cell responses, whereas DENV T cell epitopes are found primarily in nonstructural proteins.IMPORTANCE The issue of potential ZIKV and DENV cross-reactivity and how preexisting DENV T cell immunity modulates Zika T cell responses is of great relevance, as the two viruses often cocirculate and Zika virus has been spreading in geographical regions where DENV is endemic or hyperendemic. Our data show that memory T cell responses elicited by prior infection with DENV recognize ZIKV-derived peptides and that DENV exposure prior to ZIKV infection influences the timing, magnitude, and quality of the T cell response. Additionally, we show that ZIKV-specific responses target different proteins than DENV-specific responses, pointing toward important implications for vaccine design against this global threat.


A high-density genetic map of Arachis duranensis, a diploid ancestor of cultivated peanut.
Cultivated peanut (Arachis hypogaea) is an allotetraploid species whose ancestral genomes are most likely derived from the A-genome species, A. duranensis, and the B-genome species, A. ipaensis. The very recent (several millennia) evolutionary origin of A. hypogaea has imposed a bottleneck for allelic and phenotypic diversity within the cultigen. However, wild diploid relatives are a rich source of alleles that could be used for crop improvement and their simpler genomes can be more easily analyzed while providing insight into the structure of the allotetraploid peanut genome. The objective of this research was to establish a high-density genetic map of the diploid species A. duranensis based on de novo generated EST databases. Arachis duranensis was chosen for mapping because it is the A-genome progenitor of cultivated peanut and also in order to circumvent the confounding effects of gene duplication associated with allopolyploidy in A. hypogaea. More than one million expressed sequence tag (EST) sequences generated from normalized cDNA libraries of A. duranensis were assembled into 81,116 unique transcripts. Mining this dataset, 1236 EST-SNP markers were developed between two A. duranensis accessions, PI 475887 and Grif 15036. An additional 300 SNP markers also were developed from genomic sequences representing conserved legume orthologs. Of the 1536 SNP markers, 1054 were placed on a genetic map. In addition, 598 EST-SSR markers identified in A. hypogaea assemblies were included in the map along with 37 disease resistance gene candidate (RGC) and 35 other previously published markers. In total, 1724 markers spanning 1081.3 cM over 10 linkage groups were mapped. Gene sequences that provided mapped markers were annotated using similarity searches in three different databases, and gene ontology descriptions were determined using the Medicago Gene Atlas and TAIR databases. Synteny analysis between A. duranensis, Medicago and Glycine revealed significant stretches of conserved gene clusters spread across the peanut genome. A higher level of colinearity was detected between A. duranensis and Glycine than with Medicago. The first high-density, gene-based linkage map for A. duranensis was generated that can serve as a reference map for both wild and cultivated Arachis species. The markers developed here are valuable resources for the peanut, and more broadly, to the legume research community. The A-genome map will have utility for fine mapping in other peanut species and has already had application for mapping a nematode resistance gene that was introgressed into A. hypogaea from A. cardenasii.


Electron microscopy as a critical tool in the determination of pore forming mechanisms in proteins.
Electron microscopy has consistently played an important role in the description of pore-forming protein systems. The discovery of pore-forming proteins has depended on visualization of the structural pores formed by their oligomeric protein complexes, and as electron microscopy has advanced technologically so has the degree of insight it has been able to give. This review considers a large number of published studies of pore-forming complexes in prepore and pore states determined using single-particle cryo-electron microscopy. Sample isolation and preparation, imaging and image analysis, structure determination and optimization of results are all discussed alongside challenges which pore-forming proteins particularly present. The review also considers the use made of cryo-electron tomography to study pores within their membrane environment and which will prove an increasingly important approach for the future.


Biological significance of gene amplification in carcinogenesis.
K-SAM gene was originally isolated as an amplified gene in a stomach cancer cell line by in-gel DNA renaturation method. K-SAM encodes a membrane receptor with tyrosine kinase and is often amplified in poorly differentiated type of stomach cancer, while c-ERBB-2 is often amplified in well differentiated type of stomach cancer. There are several forms of K-SAM mRNAs which are generated by alternative splicing, and two types of K-SAM protein without transmembrane region. The ligand of K-SAM is considered to be growth factor(s) belonging to fibroblast growth factor (FGF) or heparin binding growth factor (HBFG) family. We have also frequently found amplification of HST-1 or HSTF1 gene in esophageal cancer. HST-1 gene, originally found as a transforming gene, is located on human chromosome 11q13, and it locates 35 kbp apart from its related gene, INT-2. Neither of the genes was expressed even in cancer cells with the co-amplification. By cosmid walking, we have identified at least two genes, designated tentatively as EXP1 and EXP2, on the same amplicon as HST-1 and INT-2, and the mRNAs for EXP1 and EXP2 genes were increased in amounts proportional to the degree of amplification.


Effect of phase coarsening under melt annealing on the electrical performance of polymer composites with a double percolation structure.
The effect of phase coarsening on the evolution of the carbon black (CB) nanoparticle network under quiescent melt annealing and the electrical performance of polypropylene/polystyrene/carbon black (PP/PS/CB) composites with a double percolation structure was investigated. The results showed that when the CB content is low, the coarsening process of PP/PS/CB blends can be divided into two stages. In the first stage, the coarsening rate is fast before the formation of the CB nanoparticle network, and after annealing for a certain time, the evolution of the co-continuous morphology can drive the CB nanoparticles to self-assemble into a complete nanoparticle network. In the second stage, the coarsening rate is slow after the formation of the CB nanoparticle network. When the CB content is high, the CB nanoparticle network can be maintained throughout the whole annealing process, so that the conductivity and morphology of the PP/PS/CB composites are stable. Moreover, the electrical conductivity of the PP/PS/CB composites greatly increases after annealing for a certain time, and a percolation threshold as low as 0.07 vol% can be obtained. These results reveal the relationship between the evolution of the morphology and the conductivity in the conductive polymer composites with a double percolation structure, and provide a more in-depth and comprehensive understanding of the double percolation structure.


Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants.
Modest reduction in brain temperature is a promising therapy to reduce brain damage after neonatal encephalopathy as a result of acute perinatal asphyxia. The efficacy of modest hypothermia may in part be dependent on the stability of the desired brain temperature. The objective of this study was 1) to evaluate in newborn animals a commercially available cooling system (Blanketrol II Hyperthermia-Hypothermia system) to control brain temperature during whole-body hypothermia and 2) to use the results of the animal experiments to perform a pilot study evaluating the feasibility of whole-body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth. In the animal investigation, 3 miniature swine were instrumented and ventilated, and temperature probes were placed in the esophagus and the brain (1 cm and 2 cm beneath the parietal cortical surface and the dura). Body cooling was achieved using the automatic control mode (servo) of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to either normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole-body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of esophageal temperature to 34.5 degrees C for 72 hours followed by slow rewarming. In the animal investigation, body cooling with the animal lying on a single blanket resulted in rapid cooling of the body within 90 minutes. Repetitive cyclical swings in esophageal temperature of 1.7 +/- 0.2 degrees C (mean +/- standard deviation) around the set point of 33.5 degrees C were reduced to 0.7 +/- 0.2 degrees C when a second, larger blanket was attached and suspended. Esophageal temperature was a good marker of deep brain temperature (esophageal to 2-cm brain difference: 0.1 +/- 0.3 degrees C). In the human investigation, the infants were randomized at 4.1 +/- 1.3 hours (mean +/- standard deviation) after birth. Age at randomization was similar in the 2 groups. Cooling was initiated at an average age of 5.3 hours. Target temperature of 34.5 degrees C was achieved within 30 minutes and remained constant throughout the intervention period. Heart rate decreased to 108 +/- 14 beats per minute (bpm) at 60 minutes and remained between 115 and 130 bpm for the duration of cooling compared with 130 to 145 bpm in the normothermia group. Blood pressure was similar in the 2 groups. No adverse events occurred during 72 hours of cooling. The mortality rate and frequency of persistent pulmonary hypertension, renal failure, hepatic dysfunction, and need for pressor support were similar in both groups. Animal studies showed that a simple modification of a commercially available cooling system (2 blankets attached, subject lying on 1 and the second hanging freely) results in stable core body and brain temperature when used in the automatic control mode. The pilot study in term infants with encephalopathy using this cooling system demonstrates feasibility of initiating whole-body hypothermia at <6 hours of age to a constant esophageal temperature using servo control and provides no evidence that hypothermia involved greater hazard than benefit.


Ibuprofen effects on behavioral thermoregulation with microwave radiation in albino rats.
This study determined whether ibuprofen causes a disruptive behavior pattern similar to aspirin yet contrary to acetaminophen regarding thermoregulatory effects. 8 Sprague-Dawley rats (3 males and 5 females) were drawn from a population of rats which had been conditioned to press a lever for food reinforcement in an undergraduate course in operant conditioning. Animals were conditioned in a refrigerated Skinner Box on a fixed-interval 2-min. (FI-2 min.) schedule of microwave radiation (5 sec. of radiation per exposure occasion) in a repeated-measures reversal (within-subjects) design. The rats were injected intraperitoneally with doses of ibuprofen in amounts of 10-50 mg/kg or methyl-cellulose control vehicle of equal volume over 8-hr. daily sessions. A multivariate analysis of variance showed significant differences due to doses (mg/kg) of ibuprofen for number of microwave heat reinforcers per hour and rate of responding (ns) both measures of which were significantly higher during the first 2 hours of the session. Comparative differences in behavioral thermoregulation in humans reflect the likelihood of underlying biochemical mechanisms based on research by Murphy, Badia, Myers, Boecker, and Wright in 1994.


Characterization of soluble dietary fiber from Moringa oleifera seeds and its immunomodulatory effects.
Moringa oleifera (moringa or drumstick) seeds are a potential source of dietary fiber with 6.5% w/w soluble dietary fiber. Biochemical characterization of moringa seed soluble fiber revealed that it is a glycoprotein with 5% neutral sugars. Arabinose and xylose are the major neutral sugars identified by gas liquid chromatography (GLC). Moringa seed soluble fiber was identified as protease resistant-glycoprotein and termed as moringa seed resistant protein (MSRP). MSRP was found to be a homodimer (18kDa) containing two 9kDa monomeric units as revealed by SDS-PAGE analysis with pI 10.8. Immunostimulating activity of MSRP was assessed by murine splenocyte proliferation and production of NO from macrophages. MSRP at low concentration (0.01μg/well) strongly increased proliferation of splenocytes, while MSRP at high concentration weakly responded. MSRP induced 6-fold increase in NO production when compared to the control which indicates the activation of macrophages. MSRP isolated from defatted moringa seed flour is a potent mitogen, enhancing the proliferation of lymphocytes and inducing NO from macrophages. This study concludes that moringa seed is a potential nutritional source to promote the immune system of the host.


A multicentre comparison of a novel surrogate marker for determining the specific potency of anti-tuberculosis drugs.
A model for evaluating the potency of a new anti-tuberculosis drug or a drug combination, based on a decline in the number of viable tubercle bacilli in patient's sputum during 5 days mono-therapy has been reported. One popular measure is based on the analysis of the decline in bacterial counts during the first 48 h of therapy and has been called early bactericidal activity (EBA). Such analyses could detect EBA for only a few drugs and were subject to variations in results obtained in different sites. To address these problems we applied a reiterative exponential decay model to evaluate the data on bacterial counts during 5 days of mono-therapy. The validity of this approach was tested using data from three previously published studies. For patients treated with isoniazid 300 mg daily, the values for the time taken to reduce the viable count by 50% (vt50) measured in days were, from a Kenyan study 0.58 days S.E.M. 0.18, from a Tanzanian study 0.41 days S.E.M. 0.04, and from a United States study 0.55 days s.e.m. 0.12. These differences were not statistically significant (P = 0.77 Kruskal-Wallis non-parametric ANOVA). Mean values of vt50 for all of the major anti-tuberculosis agents showed that there was an overlapping spectrum of activity from isoniazid 300 mg (vt50 0.58 days) to para-amino-salicylic acid (vt50 2.9 days) The variation between column means was greater than could be expected by chance (P = 0.0002 Kruskal-Wallis non-parametric ANOVA). From this, we conclude that the reiterative exponential decay model permits comparison between the data obtained in different centres and would allow the activity of a new drug to be compared with that of the currently available agents.


Truncating variants in p53AIP1 disrupting DNA damage-induced apoptosis are associated with prostate cancer risk.
Germ line mutations in several genes (BRCA1, BRCA2, and CHEK2) whose products are involved in the DNA damage-signaling pathway have been implicated in prostate cancer risk. To identify additional genes in this pathway that might confer susceptibility to this cancer, we analyzed a recently identified DNA damage-response gene, p53AIP1 (a gene encoding for p53-regulated apoptosis-inducing protein 1), for genetic variants in prostate cancer. Five novel germ line variants were identified. The two truncating variants (Ser(32)Stop and Arg(21)insG) were found in 3% (4 of 132) of unselected prostate tumor samples. Genotyping of the two variants in an additional 393 men with sporadic prostate cancer showed a frequency of 3.1% (12 of 393) in contrast to 0.6% (2 of 327) in 327 unaffected men (Fisher's exact test, P = 0.018), with an odds ratio (OR) of 5.1 [95% confidence interval (95% CI), 1.1-23.0]. In addition, two of six tumors carrying the truncating variants were associated with loss of heterozygosity of the wild-type alleles, suggesting that p53AIP1 may act as a tumor suppressor. We also showed that the truncated p53AIP1 was unable to induce apoptosis and suppress cell growth in HeLa and COS-7 cells. These results suggest that loss-of-function variants in p53AIP1 associated with the risk of sporadic prostate cancer and further support the concept that the genetic defects in the DNA damage-response genes play an important role in the development of prostate cancer.


Interaction between DNA Polymerase lambda and RPA during translesion synthesis.
Replication of damaged DNA (translesion synthesis, TLS) is realized by specialized DNA polymerases. Additional protein factors such as replication protein A (RPA) play important roles in this process. However, details of the interaction are unknown. Here we analyzed the influence of the hRPA and its mutant hABCD lacking domains responsible for protein-protein interactions on ability of DNA polymerase lambda to catalyze TLS. The primer-template structures containing varying parts of extended strand (16 and 37 nt) were used as model systems imitating DNA intermediate of first stage of TLS. The 8-oxoguanine disposed in +1 position of the template strand in relation to 3 -end of primer was exploited as damage. It was shown that RPA stimulated TLS DNA synthesis catalyzed by DNA polymerase lambda in its globular but not in extended conformation. Moreover, this effect is dependent on the presence of p70N and p32C domains in RPA molecule.


Occlusion pressures in men rebreathing CO2 under methoxyflurane anesthesia.
The effect of general anesthesia on control of breathing was studied by CO2 rebreathing and occlusion pressure measurements in six normal human subjects under methoxyflurane anesthesia. CO2 was found to increase the amplitude of the occlusion pressure wave without changing its shape, so that CO2 responses in terms of the occlusion pressure developed 100 ms after the onset of inspiration (Po/0.1) gave results equivalent to the responses in terms of Po/1.o or any other parameter of the pressure wave. Methoxyflurane depressed the ventilatory response to CO2 but not the occlusion pressure response, implying that the most important action of the anesthetic was to increase the effective elastance of the respiratory system rather than to depress the respiratory centers. The elastance was further increased by CO2, and this mechanical change had the effect of shifting the "apneic threshold" extrapolated from the ventilatory response curve to a lower PAco2. Frequency of breathing, inspiratory and expiratory times were not altered by CO2 in anesthetized subjects.


Comparative biochemical and histopathological evaluations proved that receptacle is the most effective part of Cynara scolymus against liver and kidney damages.
The liver and kidney are among the most important organs in the body, where metabolic and elimination functions take place. During this process, liver and kidneys may suffer damage due to ingestion or formation of toxic metabolites leading to organ loss and even death. Artichoke (Cynara scolymus L.) leaf has long been recognized as a popular herbal remedy in traditional medicines with beneficial effects on liver. In phytotherapy leaves are the part used to support the liver functions and for treatment of damage induced by various toxins, while fleshy receptacle is cooked as meal to support liver homeostasis. However, effects of other plant parts on liver such as stems, bracts have not much attracted the attention of scientific community so far. In this study we investigated comparatively the hepatoprotective and nephroprotective effects of different plant parts of artichoke, i.e. receptacles, outer bracts, inner bracts, and stems with that of leaves upon paracetamol-induction in rats. Aqueous ethanol (80%) extracts obtained from the different parts of artichoke were administered for five consecutive days after paracetamol induction to rats. At the end of experimental period blood samples from the experimental animals were taken for biochemical tests, while livers and kidneys were removed for further histopathological evaluation. The histopathological examinations of liver and kidney tissues revealed that the receptacle and stem extracts of the artichoke were the most effective parts by improving the experimentally induced pathology in both liver and kidney. Biochemical tests also supported the histopathological data; receptacle, stem and bract extracts reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, but not alkaline phosphatase (ALP), creatinine and blood urea nitrogen (BUN) levels. Histopathological and biochemical studies have shown that receptacle and stem extracts of artichoke were found to exert higher protective activity on liver and kidney damage induced by paracetamol comparing to its bract and leaf extracts, the latest is officially recognized as herbal remedy.


High-dose hydroxocobalamin administered after H2S exposure counteracts sulfide-poisoning-induced cardiac depression in sheep.
Severe H2S poisoning leads to death by rapid respiratory and cardiac arrest, the latter can occur within seconds or minutes in severe forms of intoxication. To determine the time course and the nature of H2S-induced cardiac arrest and the effects of high-dose hydroxocobalamin administered after the end of sulfide exposure. NaHS was infused in 16 sedated mechanically ventilated sheep to reach concentrations of H2S in the blood, which was previously found to lead to cardiac arrest within minutes following the cessation of H2S exposure. High-dose hydroxocobalamin (5 g) or saline solution was administered intravenously, 1 min after the cessation of NaHS infusion. All animals were still alive at the cessation of H2S exposure. Three animals (18%) presented a cardiac arrest within 90 s and were unable to receive any antidote or vehicle. In the animals that survived long enough to receive either hydroxocobalamin or saline, 71% (5/7) died in the control group by cardiac arrest within 10 min. In all instances, cardiac arrest was the result of a pulseless electrical activity (PEA). In the group that received the antidote, intravenous injection of 5 g of hydroxocobalamin provoked an abrupt increase in blood pressure and blood flow; PEA was prevented in all instances. However, we could not find any evidence for a recovery in oxidative metabolism in the group receiving hydroxocobalamin, as blood lactate remained elevated and even continued to rise after 1 h, despite restored hemodynamics. This, along with an unaltered recovery of H2S kinetics, suggests that hydroxocobalamin did not act through a mechanism of H2S trapping. In this sheep model, there was a high risk for cardiac arrest, by PEA, persisting up to 10 min after H2S exposure. Very high dose of hydroxocobalamin (5 g), injected very early after the cessation of H2S exposure, improved cardiac contractility and prevented PEA.


Opiates suppress a resting sodium-dependent inward current and activate an outward potassium current in locus coeruleus neurons.
The opioid peptide met-enkephalin (met-ENK) produces an outward current with an increase in input conductance in locus coeruleus (LC) neurons. This current has been attributed to an opening of potassium channels. However, the opioid-induced current tends to reverse at potentials more negative than the expected potassium reversal potential (EK) or does not reverse at all. Since lack of reversal can occur if there is a simultaneous increase in one conductance and a decrease in a second conductance, we tested the possible contribution of a second conductance to the opioid-induced outward current in LC neurons. Biochemically, opiates inhibit adenylate cyclase in LC neurons and cAMP-active agents produce a sodium-dependent inward current in these neurons. This current is also present at rest, as sodium substitution hyperpolarizes LC neurons. By inhibiting adenylate cyclase, could opiates be turning off this current? To evaluate this possibility, we used intracellular voltage-clamp technique in rat LC slices, and studied the effect of sodium substitution on the opiate response. Replacement of external sodium (80%) with Tris or choline caused (1) an outward current with a decrease in input conductance and (2) an approximately 50% decrease in the met-ENK-induced outward current with a shift in its reversal potential toward EK. Extracellular Ba2+, a K+ channel blocker, also partially reduced the opiate response, but it shifted its reversal potential away from EK. The met-ENK-induced outward current was almost totally abolished by combined sodium substitution and extracellular Ba2+ in an additive manner.(ABSTRACT TRUNCATED AT 250 WORDS)


Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.
Short-term efficacy of induction therapy with intravenous immunoglobulin (Ig) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is well established. However, data of previous studies on maintenance therapy were limited up to 24-week treatment period. We aimed to investigate the efficacy and safety of longer-term intravenous Ig therapy for 52 weeks. This study was an open-label phase 3 clinical trial conducted in 49 Japanese tertiary centres. 49 patients with CIDP who fulfilled diagnostic criteria were included. After an induction intravenous Ig therapy (0.4 g/kg/day for five consecutive days), maintenance dose intravenous Ig (1.0 g/kg) was given every 3 weeks for up to 52 weeks. The primary outcome measures were the responder rate at week 28 and relapse rate at week 52. The response and relapse were defined with the adjusted Inflammatory Neuropathy Cause and Treatment scale. At week 28, the responder rate was 77.6% (38/49 patients; 95% CI 63% to 88%), and the 38 responders continued the maintenance therapy. At week 52, 4 of the 38 (10.5%) had a relapse (95% CI 3% to 25%). During 52 weeks, 34 (69.4%) of the 49 enrolled patients had a maintained improvement. Adverse events were reported in 94% of the patients; two patients (66-year-old and 76-year-old men with hypertension or diabetes) developed cerebral infarction (lacunar infarct with good recovery), and the other adverse effects were mild and resolved by the end of the study period. Maintenance treatment with 1.0 g/kg intravenous Ig every 3 weeks is an efficacious therapy for patients with CIDP, and approximately 70% of them had a sustained remission for 52 weeks. Thrombotic complications should be carefully monitored, particularly in elderly patients with vascular risk factors. ClinicalTrials.gov (NCT01824251).


Plasticity of hepatic cell differentiation: bipotential adult mouse liver clonal cell lines competent to differentiate in vitro and in vivo.
In fetal liver, bipotential hepatoblasts differentiate into hepatocytes and bile duct cells (cholangiocytes). The persistence of such progenitor cells in adult mouse liver is still debated. In damaged liver of adult murine animals, when hepatocyte proliferation is compromised, bipotential oval cells emerge, probably from bile ducts, proliferate, and differentiate to regenerate the liver. However, treatment to elicit oval cell proliferation is not necessary to obtain bipotential stem cells from adult mouse liver. Here, we have isolated bipotential clonal cell lines from healthy liver of 8-10-week-old C57BL/6 mice. Primary cultures established from hepatocyte-enriched suspensions were characterized by time-lapse image acquisition, immunocytology, and RNA transcript analysis. Although hepatocytes dedifferentiated with loss of apical polarity and other hepatocyte markers, they rapidly activated expression of bile duct/oval cell markers. Reversibility of these processes was achieved in part by culture under dilute Matrigel or by aging of confluent cultures. Cell lines were obtained at high frequency from mass cultures, from isolated colonies, and by primary cloning of the hepatocyte-enriched suspension. Cells of the clonal cell lines do not grow in soft agar and are nontumorigenic, and they express cytokeratin 19, A6 antigen, and alpha6 integrin, as well as a large panel of hepatocyte functions. Furthermore, they can participate in liver regeneration in albumin-urokinase-type plasminogen activator/severe combined immune-deficient mice, where they differentiate in clusters of hepatocytes and occasionally bile ducts. These results demonstrate the existence, in normal adult mouse liver, of a significant pool of clonogenic cells that are (or can become) bipotential.


Adhesion dynamics of Flavobacterium columnare to channel catfish Ictalurus punctatus and zebrafish Danio rerio after immersion challenge.
The adhesion dynamics of Flavobacterium columnare to fish tissues were evaluated in vivo by immersion challenge followed by bacterial plate count and confirmatory observations of gill-adhered bacterial cells using scanning electron microscopy. Adhesion of F. columnare genomovar I (ARS-1) and II (BGFS-27) strains to skin and gill of channel catfish Ictalurus punctactus and gill of zebrafish Danio rerio was compared. At 0.5 h post-challenge, both strains adhered to gill of channel catfish at comparable levels (10(6) colony forming units [CFU] g(-1)), but significant differences in adhesion were found later in the time course. Channel catfish was able to effectively reduce ARS-1 cells on gill, whereas BGFS-27 persisted in gill beyond the first 24 h post-challenge. No significant difference was found between both strains when adhered to skin, but adhered cell numbers were lower (10(3) CFU g(-1)) than those found in gill and were not detectable at 6 h post-challenge. Adhesion of BGFS-27 cells to gill of zebrafish also occurred at high numbers (> 10(6) CFU g(-1)), while only < 10(2) CFU g(-1) of ARS-1 cells were detected in this fish. The results of the present study show that particular strains of F. columnare exhibit different levels of specificity to their fish hosts and that adhesion to fish tissues is not sufficient to cause columnaris disease.


Lack of interest in physical activity - individual and environmental attributes in adults across Europe: The SPOTLIGHT project.
A considerable proportion of European adults report little or no interest in physical activity. Identifying individual-level and environmental-level characteristics of these individuals can help designing effective interventions and policies to promote physical activity. This cross-sectional study additionally explored associations between level of interest and physical activity, after controlling for other individual and environmental variables. Measures of objective and perceived features of the physical environment of residence, self-reported physical activity and other lifestyle behaviors, barriers towards physical activity, general health, and demographics were obtained from 5205 European adults participating in the 2014 online SPOTLIGHT survey. t-Tests, chi-square tests, and generalized estimating equations with negative binomial log-link function were conducted. Adults not interested in physical activity reported a higher BMI and a lower self-rated health, were less educated, and to a smaller extent female and less frequently employed. They were more prone to have less healthy eating habits, and to perceive more barriers towards physical activity. Only minor differences were observed in environmental attributes: the non-interested were slightly more likely to live in neighborhoods objectively characterized as less aesthetic and containing more destinations, and perceived as less functional, safe, and aesthetic. Even after controlling for other individual and environmental factors, interest in physical activity remained a significant correlate of physical activity, supporting the importance of this association. This study is among the first to describe characteristics of individuals with reduced interest in physical activity, suggesting that (lack of) interest is a robust correlate of physical activity in several personal and environmental conditions.