Non-ASD outcomes at 36 months in siblings at familial risk for autism spectrum disorder (ASD): A baby siblings research consortium (BSRC) study.
We characterized developmental outcomes of a large sample of siblings at familial high-risk of autism spectrum disorder (ASD), who themselves did not have ASD (n = 859), and low-risk controls with no family history of ASD (n = 473). We report outcomes at age 3 years using the Mullen Scales of Early Learning, the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview-Revised (ADI-R) and adaptive functioning on the Vineland Adaptive Behavior Scales. Around 11% of high-risk siblings had mild-to-moderate levels of developmental delay, a rate higher than the low-risk controls. The groups did not differ in the proportion of toddlers with mild-to-moderate language delay. Thirty percent of high-risk siblings had elevated scores on the ADOS, double the rate seen in the low-risk controls. High-risk siblings also had higher parent reported levels of ASD symptoms on the ADI-R and lower adaptive functioning on the Vineland. Males were more likely to show higher levels of ASD symptoms and lower levels of developmental ability and adaptive behavior than females across most measures but not mild-to-moderate language delay. Lower maternal education was associated with lower developmental and adaptive behavior outcomes. These findings are evidence for early emerging characteristics related to the "broader autism phenotype" (BAP) previously described in older family members of individuals with ASD. There is a need for ongoing clinical monitoring of high-risk siblings who do not have an ASD by age 3 years, as well as continued follow-up into school age to determine their developmental and behavioral outcomes. Autism Res 2017, 10: 169-178. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.


Evolution of a polymorphic regulatory element in interferon-gamma through transposition and mutation.
Mammalian transposable elements have intrinsic regulatory elements that can activate neighboring genes, and it is speculated that they can also carry extrinsic transactivating DNA sequences to new genomic locations. We have identified a polymorphic segment of the human interferon-gamma promoter region where two adjacent binding sites for NF-kappaB and NFAT originated from the insertion of an Alu element approximately 22-34 MYA. Both binding sites lie outside the Alu consensus sequence but within the boundaries of the insertion, suggesting that this segment of DNA was comobilized when the Alu element moved from another part of the genome. Sequence comparisons and examination of DNA-protein interactions across nine different primate species indicate that the inserted sequence contained the intact NFAT binding site, whereas the ability to bind NF-kappaB evolved through a series of mutations after the insertion. These observations are consistent with the notion that retropseudogenes can comobilize intact regulatory sequences to new locations and thereby influence the evolution of gene regulatory networks; however, the extent to which such events have shaped the evolution of gene regulation remains unknown.


Molecular cloning and analysis of abundant and stage-specific mRNAs from Puccinia graminis.
To characterize highly expressed mRNAs from germinated urediniospores of Puccinia graminis f. sp. tritici, we isolated 68 cDNA clones of abundant mRNA species belonging to at least six homology groups. The two most abundant homology groups, HG1 and HG2, contained 54 of the 68 cDNA clones and accounted for 2.4 and 0.6% of the poly(A)+ RNA in germinated urediniospores, respectively. By sampling different developmental stages of the uredinial cycle, we showed that the uam transcript, corresponding to HG2, accumulated in all stages of hyphal and urediniospore development, whereas the accumulation of usp transcript, corresponding to HG1, was specific to the sporulation stage. Southern blot analysis indicated that usp is a small gene family consisting of three to four members. Sequence analysis of 10 cDNA clones indicated that two different members of the usp gene family were expressed in germinated urediniospores. This gene family encodes small hydrophobic polypeptides of 113 amino acids with an unusual amino acid composition, in that alanine, glycine, leucine, and proline represent 48% of the protein. These polypeptides are predicted to be localized extracellular because they contain a putative signal sequence and may be functionally related to hydrophobins, a family of small hydrophobic proteins abundantly expressed during sporulation in Schizophyllum commune and Aspergillus nidulans. The uam and usp genes deserve further investigation, including isolation of genomic clones. The regulatory regions of the uam gene, which is highly expressed in hyphae, may be useful in the construction of a transformation vector for rust fungi.


Studies on the performance of bentonite and its composite as phosphate adsorbent and phosphate supplementation for plant.
Organo-bentonite (OrB) was prepared by modifying bentonite with chitosan, and natural surfactant extracted from Sapindus rarak fruit. The physical alteration post-modification, performance of phosphates (Pi) adsorption, and possibility as a Pi-supplementation for plants of OrB were assessed and compared to acid-activated bentonite (AAB). The physical alteration due to modification of bentonite was characterized. SEM images were not indicating significant morphology differences between OrB and AAB. Existence of chitosan layers in OrB causes a decrease in basal spacing as characterized using XRD. The BET surface area of OrB was decreased compared to AAB due to pore coverage by chitosan. Adsorption studies reveal that OrB has a higher adsorption capacity towards Pi than AAB, which is 97.608 and 131.685 mg/g at 323 K for AAB and OrB, respectively. The H-shape isotherm curve indicates that chemisorption is dominantly controlling the adsorption. The isotherm and kinetics adsorption were well fitted to Langmuir and Pseudo-second order models, respectively. Performance of AAB and OrB as Pi-supplementation was assessed based on growth phenotypes of Arabidopsis thaliana; seedlings show that supplementation of Pi@AAB and Pi@OrB (at half doses) can promote primary root extension. These results also demonstrate the safety of direct disposal of the materials into the soil.


Molecular simulations of droplet coalescence in oil/water/surfactant systems.
We report a molecular simulation study of the mechanism by which droplets covered with a surfactant monolayer coalesce. We study a model system where the rate-limiting step in coalescence is the rupture of the surfactant film. Our simulations allow us to focus on the stages at the core of the coalescence process: the initial rupture of the two surfactant monolayers, the rearrangement of the surfactant molecules to form a channel connecting the two droplets, and the expansion of the radius of the resulting channel. For our numerical study, we made use of the dissipative particle dynamics method. We used a coarse-grained description of the oil, water, and surfactant molecules. The rupture of the surfactant film is a rare event on the molecular time scale. To enhance the sampling of the rupture of the surfactant film, we used forward flux sampling (FFS). FFS not only allows us to estimate coalescence rates, it also provides insight into the molecular structure and free energy of the "transition" state. For an oil-water-oil film without surfactant, the rupture rate decreases exponentially with increasing film thickness. The critical state is different in thin and thick films: Thin films break following a large enough thickness fluctuation. Thicker films break only after a sufficiently large hole fluctuation-they can heal. Next, we designed surfactant molecules with positive, zero, and negative natural curvatures. For a water film between two surfactant-covered oil droplets, the rupture rate is highest when the surfactant has a negative natural curvature, lowest when it has zero natural curvature, and lying in between when it has a positive natural curvature. This nonmonotonic variation with curvature stems from two effects: First, the surfactants with a large absolute value of the natural curvature have lower interfacial tension and bending rigidity. This promotes the interfacial fluctuations required to nucleate a channel. Second, the sign of the natural curvature determines whether there is a critical channel radius at which the channel free energy has a maximum. The latter is in agreement with the hole-nucleation theory of Kabalnov and Wennerstrom [Langmuir 12, 276 (1996)]. Our simulations seriously overestimate the relative stability of surfactant free emulsions. We argue that this is due to the fact that our model does not allow for nanobubble formation and capillary evaporation-processes that are presumably of key importance in the coalescence of surfactant-free emulsions.


Generalized stokes parameters of random electromagnetic beams.
A generalization of the Stokes parameters of a random electromagnetic beam is introduced. Unlike the usual Stokes parameters, which depend on one spatial variable, the generalized Stokes parameters, depend on two spatial variables. They obey precise laws of propagation, both in free space and in any linear medium, whether deterministic or random. With the help of the generalized Stokes parameters, the changes in the ordinary Stokes parameters upon propagation can be determined. Numerical examples of such changes are presented. The generalized Stokes parameters contain information not only about the polarization properties of the beam but also about its coherence properties. We illustrate this fact by expressing the degree of coherence of the electromagnetic beam in terms of one of the generalized Stokes parameters.


What is colitis? Statistical approach to distinguishing clinically important inflammatory change in rectal biopsy specimens.
Measurements of mucosal dimension, architecture, and cell counts in both lamina propria and epithelium were made on rectal biopsy specimens from 20 patients with irritable bowel syndrome ("normal" controls); 54 patients with ulcerative colitis, Crohn's disease, and non-specific proctitis; eight patients with small bowel Crohn's disease; and 34 in whom the rectal biopsy specimen was not diagnostic. Discriminant analysis was applied to multiple variables based on the measurements, and three variables were identified as of high predictive value. The most powerful discriminant was increased lamina propria cellularity in all forms of chronic colitis. The ratios of surface length to mucosal length and of surface epithelial height to crypt epithelial height also emerged as discriminants. Chronic inflammatory bowel disease was distinguished from normal in 95% of cases with a definite pathological diagnosis, and 85% of borderline cases were correctly classified as either normal or inflammatory when judged by the final diagnosis after follow up. This study provides a basis for automated diagnosis of rectal biopsy specimens and provides objectively validated criteria which can also be applied in routine histological diagnosis.


Normal saline may promote formation of peritoneal adhesions.
Normal saline is commonly used for rinsing the abdominal cavity and many surgeons claim that it is not harmful to peritoneum. We found in patients treated with laparoscopic surgery, that mean 25% of the instilled fluid is not drained and dwells in the abdominal cavity. Therefore we evaluated changes of the saline biocompatibility during its dwell in the rats abdominal cavity. In 10 anesthetized rats normal saline were instilled into the abdominal cavity and samples of the dwelling solution were collected every 30 minutes, for 4 hours. Inflammatory parameters and effect of the collected samples on in vitro cultured rats mesothelial cells were studied. Low pH of the saline was normalized, but number of cells and % of macrophages and eosinophils, as well as elastase activity and MCP-1 and TGF-β concentration increased, proportionally to the dwell time. Fluid samples tested ex-vivo suppressed proliferation of the mesothelial cells and induced biphasic (stimulation/inhibition) effect on synthesis of MCP-1 in these cells. Similar pattern of release was observed for TF, whereas synthesis of t-PA in the mesothelial cells was strongly suppressed. Mesothelial cells exposed in vivo to normal saline dwelling in the abdominal cavity acquire properties which may accelerate formation of the peritoneal adhesions.


Fluorescence resonance energy transfer as a method for dissecting in vivo mechanisms of transcriptional activation.
The first step in transcriptional activation of protein-coding genes involves the assembly on the promoter of a large PIC (pre-initiation complex) comprising RNA polymerase II and a suite of general transcription factors. Transcription is greatly enhanced by the action of promoter-specific activator proteins (activators) that function, at least in part, by increasing PIC formation. Activator-mediated stimulation of PIC assembly is thought to result from a direct interaction between the activator and one or more components of the transcription machinery, termed the 'target'. The unambiguous identification of direct, physiologically relevant in vivo targets of activators has been a considerable challenge in the transcription field. The major obstacle has been the lack appropriate experimental methods to measure direct interactions with activators in vivo. The development of spectral variants of green fluorescent protein has made it possible to perform FRET (fluorescence resonance energy transfer) analysis in living cells, thereby allowing the detection of direct protein-protein interactions in vivo. Here we discuss how FRET can be used to identify activator targets and to dissect in vivo mechanisms of transcriptional activation.


Atypical colonial morphology and low recoveries of Listeria monocytogenes strains on Oxford, PALCAM, Rapid'L.mono and ALOA solid media.
The performance of four commercial media, polymyxin-acriflavine-LiCl-ceftazidime-aesculin-mannitol (PALCAM), Oxford, Rapid'L.mono (Bio-Rad, Marne la Coquette, France) and Agar Listeria according to Ottaviani and Agosti (ALOA: AES Laboratoire, Combourg, France; Biolife, Milan, Italy), used to detect and enumerate 176 Belgian strains of Listeria monocytogenes of human and food origin, was evaluated. Four strains showed a low recovery and/or atypical colonies on one or more media. These results showed that a combination of these media, especially alternative media (Rapid'L.mono and/or ALOA) with esculin-containing media (PALCAM and/or Oxford), should therefore be recommended to detect or enumerate atypical strains of L. monocytogenes. In outbreak case investigation for example, incubation of plates should be extended to at least 96 h if no colonies are typical or growth does not appear after 48 h. This is a cost/benefit calculation that should be done in the context of recent listeriosis risk assessments.


Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Abu Dhabi cohort of the A1chieve study.
The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Abu Dhabi. A total of 383 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 134), insulin detemir (n = 152), insulin aspart (n = 13), basal insulin plus insulin aspart (n = 42) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 9.4%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naïve: -2.1%, insulin users: -1.8%). SADRs did not occur in any of the study patients. Major hypoglycaemic events remained same as that of baseline (0.1 events/patient-year) for insulin naïve group whereas major hypoglycaemia reduced from 0.1 events/patient-year to 0.0 events/patient-year in insulin users. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.


Congestive heart failure disease management in Medicare-managed care.
In 2001, the Center for Medicare and Medicaid Services began 2 initiatives that encouraged Medicare-managed care plans to introduce congestive heart failure (CHF) disease management programs. Our study was designed to describe the use, structure, and content of these programs. In 2003 to 2004, we invited the representatives of Medicare-managed care plans with > or = 750 enrollees to participate in a survey by mail or telephone. Representatives of 120 plans, 84 (70%) responded. Of the plans, 92% had CHF programs, 45% of which were instituted in 2001 or later, and 42% of which were handled externally by commercial vendors. Vendor use was more common in large programs (> 30,000 Medicare enrollees) than in small programs (< 15,000 Medicare enrollees) (57% vs 24%, P = .05), in national than local programs (50% vs 21%, P = .03), and in for-profit than not-for-profit programs (45% vs 21%, P = .03). Although 87% of CHF programs focused on improving patient self-management, a smaller fraction engaged practicing physicians (eg, 23% provided feedback to physicians concerning whether care was consistent with CHF guidelines). In Medicare-managed care plans, there is widespread use of CHF disease management. However, the programs used primarily focus on patient self-management and not on engaging physicians on medication management and compliance with guidelines. Our findings raise the concern that these programs will not be able to achieve the quality improvement and cost savings previously demonstrated in clinical trials of CHF disease management.


Immunohistochemical profiling of the heat shock response in obese non-diabetic subjects revealed impaired expression of heat shock proteins in the adipose tissue.
Obesity is characterized by a chronic low-grade inflammation and altered stress responses in key metabolic tissues. Impairment of heat shock response (HSR) has been already linked to diabetes and insulin resistance as reflected by decrease in heat shock proteins (HSPs) expression. However, the status of HSR in non-diabetic human obese has not yet been elucidated. The aim of the current study was to investigate whether obesity triggers a change in the HSR pattern and the impact of physical exercise on this pattern at protein and mRNA levels. Two groups of adult non-diabetic human subjects consisting of lean and obese (n = 47 for each group) were enrolled in this study. The expression pattern of HSP-27, DNAJB3/HSP-40, HSP-60, HSC-70, HSP72, HSP-90 and GRP-94 in the adipose tissue was primarily investigated by immunohistochemistry and then complemented by western blot and qRT-PCR in Peripheral blood mononuclear cells (PBMCs). HSPs expression levels were correlated with various physical, clinical and biochemical parameters. We have also explored the effect of a 3-month moderate physical exercise on the HSPs expression pattern in obese subjects. Obese subjects displayed increased expression of HSP-60, HSC-70, HSP-72, HSP-90 and GRP-94 and lower expression of DNAJB3/HSP-40 (P < 0.05). No differential expression was observed for HSP-27 between the two groups. Higher levels of HSP-72 and GRP-94 proteins correlated positively with the indices of obesity (body mass index and percent body fat) and circulating levels of IFN-gamma-inducible protein 10 (IP-10) and RANTES chemokines. This expression pattern was concomitant with increased inflammatory response in the adipose tissue as monitored by increased levels of Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), and RANTES (P < 0.05). Physical exercise reduced the expression of various HSPs in obese to normal levels observed in lean subjects with a parallel decrease in the endogenous levels of IL-6, TNF-α, and RANTES. Taken together, these data indicate that obesity triggers differential regulation of various components of the HSR in non-diabetic subjects and a 3-month physical moderate exercise was sufficient to restore the normal expression of HSPs in the adipose tissue with concomitant attenuation in the inflammatory response.


Processing, characterization, and in vitro/in vivo evaluations of powder metallurgy processed Ti-13Nb-13Zr alloys.
This article presents details of processing, characterization and in vitro as well as in vivo evaluations of powder metallurgy processed Ti-13Nb-13Zr samples with different levels of porosity. Sintered samples were characterized for density, crystalline phases (XRD), and microstructure (SEM and EDX). Samples sintered at 1000 degrees C showed the highest porosity level ( approximately 30%), featuring open and interconnected pores ranging from 50 to 100 mum in diameter but incomplete densification. In contrast, samples sintered at 1300 and 1500 degrees C demonstrated high densification with 10% porosity level distributed in a homogeneous microstructure. The different sintering conditions used in this study demonstrated a coherent trend that is increase in temperature lead to higher sample densification, even though densification represents a drawback for bone ingrowth. Cytotoxicity tests did not reveal any toxic effects of the starting and processed materials on surviving cell percentage. After an 8-week healing period in rabbit tibias, the implants were retrieved, processed for nondecalcified histological evaluation, and then assessed by backscattered electron images (BSEI-SEM) and EDX. Bone growth into the microstructure was observed only in samples sintered at 1000 degrees C. Overall, a close relation between newly formed bone and all processed samples was observed.


US cost effectiveness of darunavir/ritonavir 600/100 mg bid in treatment-experienced, HIV-infected adults with evidence of protease inhibitor resistance included in the TITAN Trial.
The phase III TITAN trial evaluated the use of darunavir with low-dose ritonavir (DRV/r) 600/100 mg twice daily (bid) compared with lopinavir with low-dose ritonavir (LPV/r) in treatment-experienced, lopinavir-naive patients. This study estimates the cost effectiveness of DRV/r from a US societal perspective when compared with LPV/r in treatment-experienced patients with a profile similar to those TITAN patients who had one or more International AIDS Society - USA (IAS-USA) primary protease inhibitor (PI) resistance-associated mutations (RAMs) at baseline. This population had less advanced HIV disease and a broader range of previous PI exposure/failure (0 - ≥ 2 PIs) at enrollment than those in the darunavir phase IIb POWER trials. An existing Markov model containing six health states defined by CD4 cell count range (>500, 351-500, 201-350, 101-200, 51-100 and 0-50 cells/mm³) and an absorbing state of death was adapted. Baseline demographics, CD4 cell count distribution and antiretroviral drug usage, virological response (at week 24), and immunological response estimates and matching transition probabilities were based on data collected directly from the one or more IAS-USA PI mutation subpopulation during the first 48 weeks of the TITAN trial, as well as from published literature. Patients were assumed to switch to a regimen containing tipranavir plus an optimized background regimen after treatment failure. For each CD4 cell count range or health state, the utility values, HIV and non-HIV-related mortality rates, and non-antiretroviral-related cost of HIV care estimates were derived from published literature. Unit costs were derived from official local sources. A lifetime horizon was taken in the base-case analysis. The base-case analysis predicted discounted quality-adjusted survival gains of 0.493 quality-adjusted life-years (QALYs) for DRV/r compared with LPV/r, resulting in an incremental cost-effectiveness ratio (ICER) of US$23,057 per QALY gained over a lifetime horizon. Probabilistic sensitivity analysis indicated a 0.754 probability of an ICER below the threshold of US$50,000 per QALY gained. DRV/r remained cost effective over all parameter ranges tested in extensive one-way sensitivity analyses and variability analyses, which examined the impact of input parameter uncertainty and changes in model assumptions and treatment patterns, respectively. Shortening the model time horizon had the largest impact on the ICER, reducing it most notably to US$4919 with a 10-year time horizon. From a US societal perspective and based on an analysis of the patients with primary IAS-USA PI RAMs enrolled in the darunavir phase III TITAN trial, a highly active antiretroviral therapy (HAART) regimen containing DRV/r 600/100 mg bid is estimated to be a cost-effective therapy when compared with a HAART regimen containing LPV/r, for the management of treatment-experienced, PI-resistant, HIV-infected adults with a broad range of previous PI use/failure.


Supervised team management, with or without structured psychotherapy, in heavy users of a mental health service with borderline personality disorder: a two-year follow-up preliminary randomized study.
Individuals affected by severe Borderline Personality Disorder (BPD) are often heavy users of Mental Health Services (MHS). Short-term treatments currently used in BPD therapy are useful to target disruptive behaviors but they are less effective in reducing heavy MHS use. Therefore, alternative short-term treatments, less complex than long-term psychodynamic psychotherapies but specifically oriented to BPD core problems, need to be developed to reduce MHS overuse. This study aimed to evaluate the efficacy of adding Sequential Brief Adlerian Psychodynamic Psychotherapy (SB-APP) to Supervised Team Management (STM) in BPD treatment compared to STM alone in a naturalistic group of heavy MHS users with BPD. Effectiveness was evaluated 6 times along a two-year follow-up. Thirty-five outpatients who met inclusion criteria were randomly assigned to two treatment groups (STM = 17; SB-APP = 18) and then compared. Clinical Global Impression (CGI) and CGI-modified (CGI-M) for BPD, Global Assessment of Functioning (GAF), State-Trait Anger Expression Inventory (STAXI), and Symptom Checklist-90 Revised (SCL-90-R) were administered at T1, T3, T6, T12, T18 and T24. At T12 the Working Alliance Inventory-Short Form (WAI-S) was also completed. At the one-year follow-up, SB-APP group did not receive any additional individual psychological support. MHS team was specifically trained in BPD treatment and had regular supervisions. All patients improved on CGI, GAF, and STAXI scores after 6 and 12 months, independently of treatment received. SB-APP group showed better outcome on impulsivity, suicide attempts, chronic feelings of emptiness, and disturbed relationships. We found a good stabilization at the one year follow-up, even after the interruption of brief psychotherapy in the SB-APP group. Although STM for BPD applied to heavy MHS users was effective in reducing symptoms and improving their global functioning, adding a time-limited and focused psychotherapy was found to achieve a better outcome. In particular, focusing treatment on patients' personality with a specific psychotherapeutic approach (i.e. SB-APP) seemed to be more effective than STM alone. ClinicalTrials.gov: NCT1356069.


Antileishmanial and immunomodulatory potential of Ocimumsanctum Linn. and Cocosnucifera Linn. in murine visceral leishmaniasis.
The role of immunomodulation in the therapeutic treatment of visceral leishmaniasis has gained eminence in view of moderate to severe drawbacks of the currently available drugs like toxicity, drug resistance and prohibitive costs. The potential for modulation of the immune system of many herbal plants can be tapped to address these problems. We conducted the present research study to investigate the antileishmanial and immunomodulatory effects of Ocimum sanctum Linn. and Cocos nucifera Linn. during the progression of visceral leishmaniasis in BALB/c mouse model. The IC50 values of the ethanolic leaf extract of O. sanctum and that of the aqueous husk-fibre extract of C. nucifera against the sodium stibogluconate (SSG) susceptible strain (MHOM/IN/80/Dd8) were found to be 73.3 and 62 µg/ml respectively. On treatment of infected BALB/c mice with the extracts, we observed a reduction in hepatic parasite load by 43.63 % (O. sanctum), 65.42 % (C. nucifera) and 75.61 % (O. sanctum + C. nucifera) at 1st post treatment day (p.t.d.), while at 15th p.t.d., the reduction was 73.61 % (O. sanctum), 76.59 % (C. nucifera) and 94.12 % (O. sanctum + C. nucifera). This was accompanied by an up-scaling of the DTH response, skewing of the humoral response towards Th1 type and hepatoprotection in the form of normalization of liver function tests. Overall, administration of the extracts of these two plants in combination as compared to their administration alone rescued the affected mice from the disease greatly, which can be attributed to their antileishmanial and immunomodulatory activities.


An Experimenter's Influence on Motor Enhancements: The Effects of Letter Congruency and Sensory Switch-Costs on Multisensory Integration.
Multisensory integration can alter information processing, and previous research has shown that such processes are modulated by sensory switch costs and prior experience (e.g., semantic or letter congruence). Here we report an incidental finding demonstrating, for the first time, the interplay between these processes and experimental factors, specifically the presence (vs. absence) of the experimenter in the testing room. Experiment 1 demonstrates that multisensory motor facilitation in response to audiovisual stimuli (circle and tone with no prior learnt associations) is higher in those trials in which the sensory modality switches than when it repeats. Those participants who completed the study while alone exhibited increased RT variability. Experiment 2 replicated these findings using the letters "b" and "d" presented as unisensory stimuli or congruent and incongruent multisensory stimuli (i.e., grapheme-phoneme pairs). Multisensory enhancements were inflated following a sensory switch; that is, congruent and incongruent multisensory stimuli resulted in significant gains following a sensory switch in the monitored condition. However, when the participants were left alone, multisensory enhancements were only observed for repeating incongruent multisensory stimuli. These incidental findings therefore suggest that the effects of letter congruence and sensory switching on multisensory integration are partly modulated by the presence of an experimenter.


Safety assessment of 1,2-glycols as used in cosmetics.
Caprylyl glycol and related 1,2-glycols are used mostly as skin and hair conditioning agents and viscosity agents in cosmetic products, and caprylyl glycol and pentylene glycol also function as cosmetic preservatives. The Cosmetic Ingredient Review (CIR) Expert Panel noted that, while these ingredients are dermally absorbed, modeling data predicted decreased skin penetration of longer chain 1,2-glycols. Because the negative oral toxicity data on shorter chain 1,2-glycols and genotoxicity data support the safety of the 1,2-glycols reviewed in this safety assessment, the Panel concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment.


Hemodynamic changes that accompany the pressor response to propranolol in urethane anesthetized rats subjected to alpha-blockade.
It has been shown that a paradoxical pressor response to a beta-blocker occurs in rats given an alpha-blocker. The dual-isotope microsphere technique was used to investigate the hemodynamic changes that accompany the pressor response to propranolol in phentolamine-treated, urethane-anesthetized rats. Rats were divided into four groups (n = 8 per group): group I received 10 min of saline infusion; group II received intravenous infusion of phentolamine (300 micrograms/kg/min) for 10 min; group III received intravenous injection of propranolol (100 micrograms/kg) after 20 min of phentolamine infusion, and group IV received intravenous injection of saline after 20 min of phentolamine infusion. In groups I and IV, saline did not cause any significant hemodynamic changes. In group II, phentolamine decreased the mean arterial pressure (MAP) and total peripheral resistance (TPR) by 34 +/- 3 mm Hg and 0.28 +/- 0.07 mm Hg/min/ml, respectively. Arterial conductances in the skeletal muscle and skin were increased to 157 and 165% of control values, respectively. Cardiac output and conductances in other tissues and organs were not significantly affected. In rats given phentolamine (group III), propranolol raised MAP (+40 +/- 2 mm Hg) by increasing TPR (+0.41 +/- 0.03 mm Hg/min/ml). Vascular conductances in the skeletal muscle, skin and kidneys were decreased to 38, 57 and 69% of control values, respectively. Conductances in other tissues and organs were not significantly affected. Our results show that propranolol raised MAP by increasing flow resistance, primarily via the reversal of the vasodilator effects of phentolamine in the muscle and skin.


Can Botulinum Toxin A Still Have a Role in Treatment of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia Through Inhibition of Chronic Prostatic Inflammation?
Patients with benign prostatic hyperplasia (BPH) can exhibit various lower urinary tract symptoms (LUTS) owing to bladder outlet obstruction (BOO), prostatic inflammation, and bladder response to BOO. The pathogenesis of BPH involves an imbalance of internal hormones and chronic prostatic inflammation, possibly triggered by prostatic infection, autoimmune responses, neurogenic inflammation, oxidative stress, and autonomic dysfunction. Botulinum toxin A (BoNT-A) is well recognized for its ability to block acetylcholine release at the neuromuscular junction by cleaving synaptosomal-associated proteins. Although current large clinical trials have shown no clinical benefits of BoNT-A for the management of LUTS due to BPH, BoNT-A has demonstrated beneficial effects in certain subsets of BPH patients with LUTS, especially in males with concomitant chronic prostatitis/chronic pelvic pain syndrome and smaller prostate. We conducted a review of published literature in Pubmed, using Botulinum toxin, BPH, BOO, inflammation, LUTS, and prostatitis as the key words. This article reviewed the mechanisms of BPH pathogenesis and anti-inflammatory effects of BoNT-A. The results suggested that to achieve effectiveness, the treatment of BPH with BoNT-A should be tailored according to more detailed clinical information and reliable biomarkers.


Estrogen up-regulates hepatic expression of suppressors of cytokine signaling-2 and -3 in vivo and in vitro.
Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-alpha, ERbeta, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERbeta knockout mice but not in those lacking ERalpha or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P < 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P < 0.05) in constructs containing a region between nucleotides -1862 and -855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ERalpha, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.


Comparative study of the smooth muscle contractor activity of airborne dusts and of dustiness in cotton, flax, and jute mills.
A bioassay technique using isolated guinea-pig ileum was employed to compare the smooth muscle contractor activity of various dusts from mills in which the prevalence of byssinosis was known. The activity of dust from a mill spinning a coarse grade of cotton was several times greater than that in dust from a mill processing a fine grade of cotton. There was a similar order in the difference of the prevalence of byssinosis in these mills. However, the activities of fine cotton, flax, and jute dusts were very similar to each other, in spite of marked differences in the prevalence of byssinosis in these mills. For cotton dust, smooth muscle contractor activity was associated with all particle sizes, although the lowest level of activity was found in the largest sized fraction (less than 2 mm). Activity in the cotton dust extracts was not correlated with nitrogen, carbohydrate, or potassium content. However, about one-fifth of the activity of a cotton dust extract was associated with an insoluble particulate fraction. The possible chemical nature of the water-soluble contractor agent is discussed. It is concluded that, until the role of this agent in the pathogenesis of byssinosis has been established, the bioassay technique cannot be employed as a means of assessing the byssinogenic potential of cotton dust.


Prospective technical validation and assessment of intra-tumour heterogeneity of a low density array hypoxia gene profile in head and neck squamous cell carcinoma.
Tumour hypoxia is associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC), however there is no accepted method for assessing hypoxia clinically. We aimed to conduct a technical validation of a hypoxia gene expression signature using the TaqMan Low Density Array (TLDA) platform to investigate if this approach reliably identified hypoxic tumours. Tumour samples (n=201) from 80 HNSCC patients were collected prospectively from two centres. Fifty-three patients received pimonidazole prior to surgery. TaqMan Low Density Array-Hypoxia Scores (TLDA-HS) were obtained by quantitative real-time PCR (qPCR) using a 25-gene signature and customised TLDA cards. Assay performance was assessed as coefficient of variation (CoV). The assay was sensitive with linear reaction efficiencies across a 4 log(10) range of inputted cDNA (0.001-10 ng/μl). Intra- (CoV=6.9%) and inter- (CoV=2.0%) assay reproducibility were excellent. Intra-tumour heterogeneity was lower for TLDA-HS (23.2%) than for pimonidazole (67.2%) or single gene measurements of CA9 (62.2%), VEGFA (45.0%) or HIG2 (39.4%). TLDA-HS in HNSCC cell lines increased with decreasing pO(2). TLDA-HS correlated with Affymetrix U133 Plus 2.0 microarray HS (p<0.01) and positive pimonidazole scores (p=0.005). Gene expression measurements of hypoxia using a 25-gene signature and TLDA cards are sensitive, reproducible and associated with lower intra-tumour heterogeneity than assaying individual genes or pimonidazole binding. The approach is suitable for further assessment of prognostic and predictive capability in clinical trial material.


Organisation and function of the primary motor cortex in chronic pain: protocol for a systematic review and meta-analysis.
Primary motor cortical (M1) adaptation in the form of altered organisation and function is hypothesised to underpin motor dysfunction observed in chronic pain. The aim of this review is to assess the evidence for altered M1 organisation and function in chronic pain. Systematic review and meta-analysis. We will search electronic databases with predetermined search terms to identify relevant studies and evaluate the studies for inclusion and risks of bias. Two independent reviewers will extract data. Any disagreement will be resolved through a third reviewer. Cross-sectional or prospective studies published in English before May 2015 that investigate M1 organisation and function in chronic pain will be included if they meet the eligibility criteria. Primary outcomes will include M1 cortical excitability, spatial cortical representation, the function of inhibitory and facilitatory intracortical networks, cortical reactivity and cortical glucose metabolism. Clinical measures such as pain and disability will be included where the correlation with the primary outcomes of M1 organisation and function were investigated in the included studies. This systematic review does not require ethical approval. The results of this review will be submitted for peer-reviewed publication regardless of outcome and will be presented at relevant conferences. Our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42015014823).


Regulation of glycogen metabolism in primary cultures of rat hepatocytes. Restoration of acute effects of glucose in cells from diabetic rats involves protein synthesis.
Defective acute regulation of hepatic glycogen synthase by glucose and insulin, caused by severe insulin deficiency, can be corrected in adult rat hepatocytes in primary culture by inclusion of insulin, triiodothyronine, and cortisol in a chemically defined serum-free culture medium over a 3-day period (Miller, T. B., Jr., Garnache, A. K., Cruz, J., McPherson, R. K., and Wolleben, C. (1986) J. Biol. Chem. 261, 785-790). Using primary cultures of hepatocytes isolated from normal and diabetic rats in the same serum-free chemically defined medium, the present study addresses the effects of cycloheximide and actinomycin D on the chronic actions of insulin, triiodothyronine, and cortisol to facilitate the direct effects of glucose on the short-term activation of glycogen synthase. The short-term presence (1 h) of the protein synthesis blockers had no effect on acute activation of glycogen synthase by glucose in primary hepatocyte cultures from normal rats. Normal cells maintained in the presence of cycloheximide or actinomycin D for 2 and 3 days exhibited unimpaired responsiveness to glucose activation of synthase. The protein synthesis inhibitors were effective at blocking the restoration of glucose activation of synthase in diabetic cells in media which restored the activation in their absence. Restoration of glycogen synthase phosphatase activity by insulin, triiodothyronine, and cortisol in primary cultures of diabetic hepatocytes was also blocked by cycloheximide or actinomycin D. These data clearly demonstrate that restoration of acute glycogen synthase activation by glucose and restoration of glycogen synthase phosphatase activity in primary cultures of hepatocytes from adult diabetic rats are dependent upon the synthesis of new protein.


Seed predation increases from the Arctic to the Equator and from high to low elevations.
Species interactions have long been predicted to increase in intensity toward the tropics and low elevations because of gradients in climate, productivity, or biodiversity. Despite their importance for understanding global ecological and evolutionary processes, plant-animal interaction gradients are particularly difficult to test systematically across large geographic gradients, and evidence from smaller, disparate studies is inconclusive. By systematically measuring postdispersal seed predation using 6995 standardized seed depots along 18 mountains in the Pacific cordillera, we found that seed predation increases by 17% from the Arctic to the Equator and by 17% from 4000 meters above sea level to sea level. Clines in total predation, likely driven by invertebrates, were consistent across treeline ecotones and within continuous forest and were better explained by climate seasonality than by productivity, biodiversity, or latitude. These results suggest that species interactions play predictably greater ecological and evolutionary roles in tropical, lowland, and other less seasonal ecosystems.


Influence of Solvation and Dynamics on the Mechanism and Kinetics of Nucleophilic Aromatic Substitution Reactions in Liquid Ammonia.
The role of the solvent and the influence of dynamics on the kinetics and mechanism of the SNAr reaction of several halonitrobenzenes in liquid ammonia, using both static calculations and dynamic ab initio molecular dynamics simulations, are investigated. A combination of metadynamics and committor analysis methods reveals how this reaction can change from a concerted, one-step mechanism in gas phase to a stepwise pathway, involving a metastable Meisenheimer complex, in liquid ammonia. This clearly establishes, among others, the important role of the solvent and highlights the fact that accurately treating solvation is of crucial importance to correctly unravel the reaction mechanism. It is indeed shown that H-bond formation of the reacting NH3 with the solvent drastically reduces the barrier of NH3 addition. The halide elimination step, however, is greatly facilitated by proton transfer from the reacting NH3 to the solvent. Furthermore, the free energy surface strongly depends on the halide substituent and the number of electron-withdrawing nitro substituents.


Plasmid Interactions Can Improve Plasmid Persistence in Bacterial Populations.
It is difficult to understand plasmid maintenance in the absence of selection and theoretical models predict the conditions for plasmid persistence to be limited. Plasmid-associated fitness costs decrease bacterial competitivity, while imperfect partition allows the emergence of plasmid-free cells during cell division. Although plasmid conjugative transfer allows mobility into plasmid-free cells, the rate of such events is generally not high enough to ensure plasmid persistence. Experimental data suggest several factors that may expand the conditions favorable for plasmid maintenance, such as compensatory mutations and accessory genes that allow positive selection. Most of the previous studies focus on bacteria that carry a single plasmid. However, there is increasing evidence that multiple plasmids inhabit the same bacterial population and that interactions between them affect their transmission and persistence. Here, we adapt previous mathematical models to include multiple plasmids and perform computer simulations to study how interactions among them affect plasmid maintenance. We tested the contribution of different plasmid interaction parameters that impact three biological features: host fitness, conjugative transfer and plasmid loss - which affect plasmid persistence. The interaction affecting conjugation was studied in the contexts of intracellular and intercellular interactions, i.e., the plasmids interact when present in the same cell or when in different cells, respectively. First, we tested the effect of each type of interaction alone and concluded that only interactions affecting fitness (epistasis) prevented plasmid extinction. Although not allowing plasmid maintenance, intracellular interactions increasing conjugative efficiencies had a more determinant impact in delaying extinction than the remaining parameters. Then, we allowed multiple interactions between plasmids and concluded that, in a few cases, a combined effect of (intracellular) interactions increasing conjugation and fitness lead to plasmid maintenance. Our results show a hierarchy among these interaction parameters. Those affecting fitness favor plasmid persistence more than those affecting conjugative transfer and lastly plasmid loss. These results suggest that interactions between different plasmids can favor their persistence in bacterial communities.


Variability in spatio-temporal pattern of trapezius activity and coordination of hand-arm muscles during a sustained repetitive dynamic task.
The spatio-temporal distribution of muscle activity has been suggested to be a determinant of fatigue development. Pursuing this hypothesis, we investigated the pattern of muscular activity in the shoulder and arm during a repetitive dynamic task performed until participants' rating of perceived exertion reached 8 on Borg's CR-10 scale. We collected high-density surface electromyogram (HD-EMG) over the upper trapezius, as well as bipolar EMG from biceps brachii, triceps brachii, deltoideus anterior, serratus anterior, upper and lower trapezius from 21 healthy women. Root-mean-square (RMS) and mean power frequency (MNF) were calculated for all EMG signals. The barycenter of RMS values over the HD-EMG grid was also determined, as well as normalized mutual information (NMI) for each pair of muscles. Cycle-to-cycle variability of these metrics was also assessed. With time, EMG RMS increased for most of the muscles, and MNF decreased. Trapezius activity became higher on the lateral side than on the medial side of the HD-EMG grid and the barycenter moved in a lateral direction. NMI between muscle pairs increased with time while its variability decreased. The variability of the metrics during the initial 10 % of task performance was not associated with the time to task termination. Our results suggest that the considerable variability in force and posture contained in the dynamic task per se masks any possible effects of differences between subjects in initial motor variability on the rate of fatigue development.


Novel GM1 ganglioside-like peptide mimics prevent the association of cholera toxin to human intestinal epithelial cells in vitro.
Cholera is an acute diarrheal disease caused by infection in the gastrointestinal tract by the gram-negative bacterium, Vibrio cholerae, and is a serious public health threat worldwide. There has not been any effective treatment for this infectious disease. Cholera toxin (CT), which is secreted by V. cholerae, can enter host cells by binding to GM1, a monosialoganglioside widely distributed on the plasma membrane surface of various animal epithelial cells. The present study was undertaken to generate peptides that are conformationally similar to the carbohydrate epitope of GM1 for use in the treatment of cholera and related bacterial infection. For this purpose, we used cholera toxin B (CTB) subunit to select CTB-binding peptides that structurally mimic GM1 from a dodecamer phage-display library. Six GM1-replica peptides were selected by biopanning based on CTB recognition. Five of the six peptides showed inhibitory activity for GM1 binding to CTB. To test the potential of employing the peptide mimics for intervening with the bacterial infection, those peptides were examined for their binding capacity, functional inhibitory activity and in vitro effects using a human intestinal epithelial cell line, Caco-2 cells. One of the peptides, P3 (IPQVWRDWFKLP), was most effective in inhibiting cellular uptake of CTB and suppressing CT-stimulated cyclic adenosine monophosphate production in the cells. Our results thus provide convincing evidence that GM1-replica peptides could serve as novel agents to block CTB binding on epithelial cells and prevent the ensuing physiological effects of CT.


Brain white matter tract integrity as a neural foundation for general intelligence.
General intelligence is a robust predictor of important life outcomes, including educational and occupational attainment, successfully managing everyday life situations, good health and longevity. Some neuronal correlates of intelligence have been discovered, mainly indicating that larger cortices in widespread parieto-frontal brain networks and efficient neuronal information processing support higher intelligence. However, there is a lack of established associations between general intelligence and any basic structural brain parameters that have a clear functional meaning. Here, we provide evidence that lower brain-wide white matter tract integrity exerts a substantial negative effect on general intelligence through reduced information-processing speed. Structural brain magnetic resonance imaging scans were acquired from 420 older adults in their early 70s. Using quantitative tractography, we measured fractional anisotropy and two white matter integrity biomarkers that are novel to the study of intelligence: longitudinal relaxation time (T1) and magnetisation transfer ratio. Substantial correlations among 12 major white matter tracts studied allowed the extraction of three general factors of biomarker-specific brain-wide white matter tract integrity. Each was independently associated with general intelligence, together explaining 10% of the variance, and their effect was completely mediated by information-processing speed. Unlike most previously established neurostructural correlates of intelligence, these findings suggest a functionally plausible model of intelligence, where structurally intact axonal fibres across the brain provide the neuroanatomical infrastructure for fast information processing within widespread brain networks, supporting general intelligence.


Blood lead levels and risk factors for lead poisoning among children in Jakarta, Indonesia.
The phase-out of leaded gasoline began in Jakarta, Indonesia on July 1, 2001. We evaluated mean blood lead levels (BLLs) and the prevalence of elevated BLLs of Jakarta school children and assessed risk factors for lead exposure in these children before the beginning of the phase-out activities. The study involved a population-based, cross-sectional blood lead survey that included capillary blood lead sampling and a brief questionnaire on risk factors for lead poisoning. A cluster survey design was used. Forty clusters, defined as primary schools in Jakarta, and 15 2nd- and 3rd-grade children in each cluster were randomly selected for participation in the study. The average age of children in this study was 8.6 years (range 6-12) and the geometric mean BLL of the children was 8.6 microg/dl (median: 8.6 microg/dl; range: 2.6-24.1 microg/dl) (n=397). Thirty-five percent of children had BLLs > or =10 microg/dl and 2.4% had BLLs > or =20 microg/dl. Approximately one-fourth of children had BLLs 10-14.9 microg/dl. In multivariate models, level of education of the child's primary caregiver, water collection method, home varnishing and occupational recycling of metals, other than lead, by a family member were predictors of log BLLs after adjustment for age and sex. BLLs of children who lived near a highway or major intersection were significantly higher than those of children who lived near a street with little or no traffic when level of education was not included in the model. Water collection method was a significant predictor of BLLs > or =10 microg/dl after adjustment for age and sex. BLLs in children in this study were moderately high and consistent with BLLs of children in other countries where leaded gasoline is used. With the phase-out of leaded gasoline, BLLs of children in Jakarta are expected to rapidly decline as they have in other countries that have phased lead out of gasoline.


Needle versus tube thoracostomy in a swine model of traumatic tension hemopneumothorax.
Traumatic tension hemopneumothorax is fatal if not treated rapidly. However, whether prehospital decompression is better achieved by chest tube or needle thoracostomy is unknown. We conducted this study to compare the immediate results and prolonged effectiveness of two methods of treatment for traumatic tension hemopneumothorax in a swine model. Ten percent of calculated total blood volume was instilled into the hemithorax of spontaneously ventilating swine (n = 5 per group, 40 +/- 3 kg). A Veres needle and insufflator were used to induce tension hemopneumothorax. Animals were randomized to one of four groups: 1) needle thoracostomy with 14-gauge intravenous catheter; 2) needle thoracostomy with Cook catheter; 3) 32-F chest tube thoracostomy; or 4) no intervention (control). Serial chest x-rays were obtained to document mediastinal shift before and after treatment. Arterial blood gas values and physiologic data were recorded. Postoperatively, thoracoscopy was performed to detect possible pulmonary injury from the procedure and/or catheter kinking or clotting. Positive intrapleural pressure was rapidly relieved in all treated animals. Four-hour survival was 100% in the 14-gauge needle and chest tube thoracostomy groups, 60% in the Cook catheter group, and 0% in the control animals (p < 0.05). There were no significant differences in survival or physiologic measurements among the treated animals (p > 0.05). In this animal model, needle thoracostomy using a 14-gauge or Cook catheter was as successful as chest tube thoracostomy for relieving tension hemopneumothorax.


Mutations affecting internal TEA blockade identify the probable pore-forming region of a K+ channel.
The active site of voltage-activated potassium channels is a transmembrane aqueous pore that permits ions to permeate the cell membrane in a rapid yet highly selective manner. A useful probe for the pore of potassium-selective channels is the organic ion tetraethylammonium (TEA), which binds with millimolar affinity to the intracellular opening of the pore and blocks potassium current. In the potassium channel encoded by the Drosophila Shaker gene, an amino acid residue that specifically affects the affinity for intracellular TEA has now been identified by site-directed mutagenesis. This residue is in the middle of a conserved stretch of 18 amino acids that separates two locations that are both near the external opening of the pore. These findings suggest that this conserved region is intimately involved in the formation of the ion conduction pore of voltage-activated potassium channels. Further, a stretch of only eight amino acid residues must traverse 80 percent of the transmembrane electric potential difference.


Radiation dose and mortality risk to children undergoing therapeutic interventional cardiology.
Children undergoing interventional cardiology procedures deserve special concern due to the greater radiation sensitivity of their tissues and more remaining years of life during which a radiation-induced cancer may develop. To determine the patient radiation dose for pediatric therapeutic interventional cardiology and to estimate the patient effective dose and lifetime mortality risk to children associated with five common procedures. Ninety children with congenital heart defects undergoing interventional therapy were enrolled in this study. Data regarding fluoroscopy and radiography time, dose-area product (DAP) and peak skin dose (PSD) for each case were measured. Patients were divided into five groups. The patient effective dose (E) was calculated using a multiplicative model of ICRP 60. The overall lifetime mortality risk was evaluated using appropriate risk coefficients. The mean, median, standard deviation, and range of time, PSD, DAP, and E were presented for the five study groups. When these metrics were considered, there were wide variations for different cases within the same group and statistically significant differences between the five groups. The PSD correlated significantly with DAP (Pearson r = 0.70; P < 0.01), but the correlation in individual cases was poor. For all cases, the range of E was found to be between 0.44 and 66.7 mSv. The corresponding risk of lifetime mortality was 1.16 per thousand. The current study provides overall data on the time, PSD, E, and lifetime mortality risk for pediatric therapeutic interventional cardiology. Radio frequency ablation showed the highest radiation risk.


Pathogen-tick-host interactions: Borrelia burgdorferi and TBE virus.
Both tick-borne encephalitis (TBE) virus and Borrelia burgdorferi depend for their survival on a tick-borne transmission cycle involving diverse vertebrate hosts and ixodid (primarily Ixodes) tick species. Increasing evidence strongly suggests that a key factor in successful transmission is the ability of these pathogens to exploit the pharmacological properties of their vector tick's saliva. Proteins and other chemicals, secreted in tick saliva, control the vertebrate hosts' haemostatic, inflammatory and immune responses in order to facilitate blood-feeding. Such bioactive saliva molecules include immunoglobulin-binding proteins, histamine-binding proteins, natural killer cell and interferon regulators, and complement inhibitors. By unravelling the contents of tick saliva and understanding their interactions with host and pathogen, we may identify new strategies for disease control.


Lysis of measles virus-infected cells by the purified cytolytic alternative complement pathway and antibody.
The dependence of antibody-and-complement-mediated lysis of virus-infected cells on the alternative pathway was examined utilizing the isolated cytolytic alternative pathway--a system consisting of the six purified proteins of the alternative pathway of activation (C3, factors B and D, beta 1H, C3b inactivator and properdin), and the five proteins of the membrane attack pathway (C5--9) of complement. HeLa cells acutely infected with measles virus were lysed by anti-viral IgG and the isolated cytolytic alternative pathway with an efficiency comparable to whole human serum. IgG and its F(ab')2 fragment were equally effective in inducing lysis by the isolated cytolytic alternative pathway, binding of approximately equal to 5 X 10(7) molecules per cell being required for 50% lysis; in contrast, no lysis occurred when equivalen or greater amounts of Fab' were bound to the virus-infected cell. Properdin was required for lysis. No lysis occurred if properdin was deleted from the isolated cytolytic alternative pathway, and lysis was diminished by 80% in properdin-depleted serum. Uptake of [125I]C3b from the isolated alternative pathway onto measles virus-infected cells occurred in the absence of properdin, but was accelerated in the presence of properdin. The 11 proteins of the isolated cytolytic alternative pathway are thus sufficient for lysis of measles virus-infected cells bearing anti-viral IgG or F(ab')2 without any other serum protein.


Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide.
We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group. Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness. Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43). In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.


Biosynthesis of fructo-oligosaccharides by Sporotrichum thermophile during submerged batch cultivation in high sucrose media.
Biosynthesis of fructo-oligosaccharides (FOS) was observed during growth of the thermophilic fungus Sporotrichum thermophile on media containing high sucrose concentrations. Submerged batch cultivation with the optimum initial sucrose concentration of 250 g/l allowed the production of 12.5 g FOS/l. The FOS mixture obtained was composed of three sugars, which were isolated by size-exclusion chromatography. They were characterized by acid hydrolysis and HPLC as 1-kestose, 6-kestose and neokestose. The mechanism of osmotic adaptation of S. thermophile was investigated and sugars and amino acids were found to be the predominant compatible solutes. The fungus accumulated glutamic acid, arginine, alanine, leucine and lysine, in order to balance the outer osmotic pressure. Fatty acid analysis of the membrane lipids showed a relatively high percentage of unsaturated lipids, which is known to be associated with high membrane fluidity.


Type IX collagen NC1 domain peptides can trimerize in vitro without forming a triple helix.
Synthetic peptides of the three chains of type IX collagen consisting of the carboxyl-terminal end of the COL1 domain and the complete NC1 domain were characterized by circular dichroism spectroscopy and analyzed for their ability to assemble into trimers. In vitro association and oxidation result in disulfide-linked oligomers as shown by molecular sieve chromatography and SDS-polyacrylamide electrophoresis. Whereas the individual peptides show a tendency to self-associate, when an equimolar amount of the three peptides was oxidized, a heterotrimer of the three chains was observed. This heterotrimer is recognized by a monoclonal antibody against the disulfide-linked NC1 domain of chicken type IX collagen, indicating the correct formation of the disulfide bonds. Circular dichroism measurements show that under the association conditions used, a triple helix does not form between the chains. These results indicate that these peptides contain all the necessary information for chain selection and assembly.


Factors that trigger emergency physicians to contact a poison centre: findings from a Swiss study.
Poison centres offer rapid and comprehensive support for emergency physicians managing poisoned patients. This study investigates institutional, case-specific and poisoning-specific factors which influence the decision of emergency physicians to contact a poison centre. Retrospective, consecutive review of all poisoning-related admissions to the emergency departments (EDs) of a primary care hospital and a university hospital-based tertiary referral centre during 2007. Corresponding poison centre consultations were extracted from the poison centre database. Data were matched and analysed by logistic regression and generalised linear mixed models. 545 poisonings were treated in the participating EDs (350 (64.2%) in the tertiary care centre, 195 (35.8%) in the primary care hospital). The poison centre was consulted in 62 (11.4%) cases (38 (61.3%) by the tertiary care centre and 24 (38.7%) by the primary care hospital). Factors significantly associated with poison centre consultation included gender (female vs male) (OR 2.99; 95% CI 1.69 to 5.29; p<0.001), number of ingested substances (>1 vs 1) (OR 2.84; 95% CI 1.65 to 4.9; p<0.001) and situation (accidental vs intentional) (OR 2.76; 95% CI 1.05 to 7.25; p=0.039). In contrast, age, medical history and hospital size did not influence poison centre consultation. Poison centre consultation was significantly higher during the week, and significantly less during night shifts. The poison centre was consulted significantly more when patients were admitted to intensive care units (OR 5.81; 95% CI 3.25 to 10.37; p<0.001). Asymptomatic and severe versus mild cases were associated with more frequent consultation (OR 4.48; 95% CI 1.78 to 11.26; p=0.001 and OR 2.76; 95% CI 1.42 to 5.38; p=0.003). We found low rates of poison centre consultation by emergency physicians. It appears that intensive care unit admission and other factors reflecting either complexity or uncertainty of the clinical situation are the strongest predictors for poison centre consultation. Hospital size did not influence referral behaviour.


Pitfalls of merging GWAS data: lessons learned in the eMERGE network and quality control procedures to maintain high data quality.
Genome-wide association studies (GWAS) are a useful approach in the study of the genetic components of complex phenotypes. Aside from large cohorts, GWAS have generally been limited to the study of one or a few diseases or traits. The emergence of biobanks linked to electronic medical records (EMRs) allows the efficient reuse of genetic data to yield meaningful genotype-phenotype associations for multiple phenotypes or traits. Phase I of the electronic MEdical Records and GEnomics (eMERGE-I) Network is a National Human Genome Research Institute-supported consortium composed of five sites to perform various genetic association studies using DNA repositories and EMR systems. Each eMERGE site has developed EMR-based algorithms to comprise a core set of 14 phenotypes for extraction of study samples from each site's DNA repository. Each eMERGE site selected samples for a specific phenotype, and these samples were genotyped at either the Broad Institute or at the Center for Inherited Disease Research using the Illumina Infinium BeadChip technology. In all, approximately 17,000 samples from across the five sites were genotyped. A unified quality control (QC) pipeline was developed by the eMERGE Genomics Working Group and used to ensure thorough cleaning of the data. This process includes examination of sample and marker quality and various batch effects. Upon completion of the genotyping and QC analyses for each site's primary study, eMERGE Coordinating Center merged the datasets from all five sites. This larger merged dataset reentered the established eMERGE QC pipeline. Based on lessons learned during the process, additional analyses and QC checkpoints were added to the pipeline to ensure proper merging. Here, we explore the challenges associated with combining datasets from different genotyping centers and describe the expansion to eMERGE QC pipeline for merged datasets. These additional steps will be useful as the eMERGE project expands to include additional sites in eMERGE-II, and also serve as a starting point for investigators merging multiple genotype datasets accessible through the National Center for Biotechnology Information in the database of Genotypes and Phenotypes. Our experience demonstrates that merging multiple datasets after additional QC can be an efficient use of genotype data despite new challenges that appear in the process.


Investing in the future: lessons learnt from communicating the results of HSV/ HIV intervention trials in South Africa.
Communicating the results of randomised controlled trials may present challenges for researchers who have to work with communities and policy-makers to anticipate positive outcomes, while being aware that results may show no effect or harm. We present a case study from the perspective of researchers in South Africa about the lessons learnt from communicating the results of four trials evaluating treatment for herpes simplex virus type 2 (HSV-2) as a new strategy for HIV prevention. We show that contextual factors such as misunderstandings and mistrust played an important role in defining the communications response. Use of different approaches in combination was found to be most effective in building understanding, credibility and trust in the research process. During the communication process, researchers acted beyond their traditional role of neutral observers and became agents of social change. This change in role is in keeping with a global trend towards increased communication of research results and presents both opportunities and challenges for the conduct of future research. Despite disappointing trial results which showed no benefit of HSV-2 treatment for HIV prevention, important lessons were learnt about the value of the communication process in building trust between researchers, community members and policy-makers, and creating an enabling environment for future research partnerships.


Gabapentin add-on for drug-resistant partial epilepsy.
The majority of people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding the antiepileptic drug gabapentin, when used as an add-on treatment for drug-resistant partial epilepsy. To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant partial epilepsy. This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 4. We searched the Cochrane Epilepsy Group's Specialised Register (14 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 4, The Cochrane Library) (April 2013) and MEDLINE (1946 to 14 May 2013). We imposed no language restrictions. Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant partial epilepsy. Trials using an active drug control group or which compared doses of gabapentin were also included in the review. Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (a) seizure frequency and seizure freedom; (b) treatment withdrawal (any reason); (c) adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best and worst-case analyses. We estimated summary risk ratios for each outcome and evaluated dose-response in regression models. Eleven trials were included representing 2125 randomised participants. We combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for 50% or greater reduction in seizure frequency compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55). Dose regression analysis (for trials in adults) shows increasing efficacy with increasing dose, with 25.3% (19.3 to 32.3) of people responding to 1800 mg of gabapentin compared to 9.7% on placebo, a 15.5% increase in response rate (8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49). Adverse effects were significantly associated with gabapentin compared to placebo. Risk ratios were as follows: ataxia 2.01 (99% CI 0.98 to 4.11), dizziness 2.43 (99% CI 1.44 to 4.12), fatigue 1.95 (99% CI 0.99 to 3.82) and somnolence 1.93 (99% CI 1.22 to 3.06). No significant differences were found for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35) or nausea (RR 0.95, 99% CI 0.52 to 1.73). Overall the studies together are rated as low/unclear risk of bias due to information on each risk of bias domain not being available. Gabapentin has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types.


Biosynthesis of cannflavins A and B from Cannabis sativa L.
In addition to the psychoactive constituents that are typically associated with Cannabis sativa L., there exist numerous other specialized metabolites in this plant that are believed to contribute to its medicinal versatility. This study focused on two such compounds, known as cannflavin A and cannflavin B. These prenylated flavonoids specifically accumulate in C. sativa and are known to exhibit potent anti-inflammatory activity in various animal cell models. However, almost nothing is known about their biosynthesis. Using a combination of phylogenomic and biochemical approaches, an aromatic prenyltransferase from C. sativa (CsPT3) was identified that catalyzes the regiospecific addition of either geranyl diphosphate (GPP) or dimethylallyl diphosphate (DMAPP) to the methylated flavone, chrysoeriol, to produce cannflavins A and B, respectively. Further evidence is presented for an O-methyltransferase (CsOMT21) encoded within the C. sativa genome that specifically converts the widespread plant flavone known as luteolin to chrysoeriol, both of which accumulate in C. sativa. These results therefore imply the following reaction sequence for cannflavins A and B biosynthesis: luteolin ► chrysoeriol ► cannflavin A and cannflavin B. Taken together, the identification of these two unique enzymes represent a branch point from the general flavonoid pathway in C. sativa and offer a tractable route towards metabolic engineering strategies that are designed to produce these two medicinally relevant Cannabis compounds.


Comparing the importance of disease rate versus practice style variations in explaining differences in small area hospitalization rates for two respiratory conditions.
Many studies have reported large variations in age- and sex-adjusted rates of hospitalizations across small geographic areas. These variations have often been attributed to differences in medical practice style which are not reflected in differences in health care outcomes. There is, however, another potentially important source of variation that has not been examined much in the literature: geographic differences in the age-sex adjusted size of the pool of patients who present with the disease and are candidates for hospitalization. Previous studies of small area variations in hospitalization rates have only used data on hospitalizations. Thus, it has not been possible to distinguish the extent to which differences in hospitalization rates are due to (i). differences in the chance that patients diagnosed with a disease are admitted to a hospital, which we refer to as the 'practice style effect,' versus (ii). geographic differences in the total amount of diagnosed disease, which we refer to as the 'disease effect.' Elementary methods for estimating the relative strength of the two effects directly from the data can be misleading, since equal amounts of variability in each effect result in unequal impacts on hospitalization rates. In this paper we describe a model-based approach for estimating the relative importance of the practice style effect and the disease effect in explaining variations in hospitalization rates. The key to our approach is the use of data on both inpatient and outpatient visits. We use 1997 Medicare data for two respiratory medical conditions across 71 small areas in Massachusetts: chronic bronchitis and emphysema, and bacterial pneumonia. Based on a Poisson model for the process generating hospitalizations and outpatient visits, we use a Bayesian framework and Gibbs sampling to compute and compare the correlation between the number of people hospitalized and each of these two sources of variation. Our results show that for the two conditions, disease rate variation explains at least as much of the variation in hospitalization rates as does practice style variation.


Application of deterministic model of isothermals for population dynamics of Synthesiomyia nudiseta (Diptera, Muscidae).
The isothermal deterministic model adherence was studied to evaluate the population dynamic of Synthesiomyia nudiseta (Diptera, Muscidae). The linear form of equation obtained for the experiments in the several phases, were for Egg: 1/D = -0.18 + 0.02. T; Larva: 1/D = -0.028 + 0.01. T; Pupa: 1/D = -0.069 + 0.01. T; and Adult: 1/D = -0.4178 + 0.02. T. In function of temperature, S. nudiseta can present from 4.18 to 8.95 and from 4.91 to 8.99 generations per year, when calculated through the equations of development and through the simulations, respectively. And the higher the temperature the larger the generation number. Through variance analysis it was verified the significance for the regression equations in relation to the annual generation number (Ng/year) of S. nudiseta in function of the isothermals, for two studied situations. It was obtained a significance of 0,1%. The regression equations obtained for these situations were: Ng/year = 5.4 + 0.5. T and Ng/year = 5.1 + 0.52. T. The number of generations of S. nudiseta varies linearly with the isothermal. Besides that, the number of annual generations for each isothermal does not differ statistically when calculated through the development equations or through the simulations. Such conditions suggest the adaptation of the deterministic model adopted.


Genetic and environmental modulation of neurotrophic and anabolic stress response: Counterbalancing forces.
The serotonin transporter genetic variant 5HTTLPR influences activation and feedback control of the hypothalamic-pituitary-adrenal axis, and has been shown to influence the effect of stressful life events on behavioral health. We recently reported that 5HTTLPR modulates cortisol response in healthy military men exposed to intense stress. Less is known of its combined effects with environmental factors in this context, or of its effect on neuroprotective stress responses. In this follow-up study, we examined the unique and combined effects of 5HTTLPR and prior trauma exposure on neuroprotective (salivary nerve growth factor [sNGF]), anabolic (dehydroepiandrosterone sulfate [DHEAS] and testosterone), and catabolic (cortisol) stress responses. Ninety-three healthy, active-duty military men were studied before, during, and 24h after a stressful 12-day survival course. Distinct and interactive effects of 5HTTLPR long allele carriage [L] versus homozygous short allele carriage [SS]) and prior trauma exposure (low versus high) were evaluated, after which a priori group comparisons were performed between hypothesized high resilience (L/low) and low resilience (SS/high) groups. For sNGF, L/low produced the greatest sNGF throughout stress exposure while SS/high demonstrated the smallest; L/high and SS/low bisected these two extremes and were nearly identical to each other (i.e., SS/high < SS/low = L/high < L/low). Thus, 5HTTLPR and prior trauma exposure demonstrated counterbalancing (additive) forces. Similar patterns were found for DHEAS. To our knowledge, this study is the first to report counterbalancing genetic and environmental effects on novel biomarkers related to resilience in humans exposed to real-world stress. These findings have profound implications for health, performance and training in high-stress occupational settings.


Therapeutic effects of hydrogen saturated saline on rat diabetic model and insulin resistant model via reduction of oxidative stress.
Molecular hydrogen, as a novel antioxidant, has been proven effective in treating many diseases. This study aimed to evaluate the therapeutic effects of hydrogen saturated saline in treatment of a rat model of diabetes mellitus and a rat model of insulin resistant. A rat diabetes mellitus model was established by feeding a high fat/high carbohydrate diet followed by injection of a small dose of streptozotocin, and an insulin resistant model was induced with a high glucose and high fat diet. Hydrogen saturated saline was administered to rats with both models conditions on a daily basis for eight weeks. A pioglitazone-treated group and normal saline-treated group served as positive and negative controls. The general condition, body weight, blood glucose, blood lipids, and serum insulin levels of rats were examined at the 8th week after treatment. The oxidative stress indices, including serum superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) were also evaluated after eight weeks of treatment using the commercial kits. Hydrogen saturated saline showed great efficiency in improving the insulin sensitivity and lowering blood glucose and lipids. Meanwhile, the therapeutic effects of hydrogen saturated saline were superior to those of pioglitazone. Hydrogen saturated saline markedly attenuated the MDA level and elevated the levels of antioxidants SOD and GSH. Hydrogen saturated saline may improve the insulin resistance and alleviate the symptoms of diabetes mellitus by reducing the oxidative stress and enhancing the anti-oxidant system.


Increasing dietary calcium moderates experimental gentamicin nephrotoxicity.
Because calcium has been reported to modify gentamicin binding to its proximal tubular brush border membrane receptor, we studied the effects of dietary calcium loading and subsequent hypercalciuria on experimental gentamicin nephrotoxicity. Male Fischer 344 rats were fed one of two diets that were identical except for calcium carbonate content: normal (0.5%) and high (4%). The high-calcium diet made rats hypercalciuric but there were no differences between the two groups in inulin clearance, sodium or osmolar excretion, or serum calcium prior to gentamicin administration. Animals on both diets were treated with gentamicin, 20 mg/kg b.i.d., for periods of 3 to 21 days. Both groups developed acute renal failure, but animals on the high-calcium diet had less severe acute toxic injury, as evidenced by studies of inulin clearance, renal histology, and in vitro cortical uptake of NMN and PAH. Furthermore, calcium-loaded animals tended to have lower peak renal cortical gentamicin levels during the period of acute toxicity. The mechanism by which increased dietary calcium protects against gentamicin nephrotoxicity remains speculative. Calcium and gentamicin may compete for the same brush border receptor or alternatively parathyroid suppression may result in diminution in tubular cell membrane drug binding sites. The possibility that high-calcium diets exert a nonspecific salutory effect on proximal tubular cell integrity has not been excluded.


Time-series analyses of Monterey Bay coastal microbial picoplankton using a 'genome proxy' microarray.
To investigate the temporal, spatial and phylogenetic resolution of marine microbial community structure and variability, we designed and expanded a genome proxy array (an oligonucleotide microarray targeting marine microbial genome fragments and genomes), evaluated it against metagenomic sequencing, and applied it to time-series samples from the Monterey Bay. The expanded array targeted 268 microbial genotypes across much of the known diversity of cultured and uncultured marine microbes. The target abundances measured by the array were highly correlated to pyrosequence-based abundances (linear regression R(2) = 0.85-0.91, P < 0.0001). Fifty-seven samples from ∼4 years in Monterey Bay were examined with the array, spanning the photic zone (0 m), the base of the surface mixed layer (30 m) and the subphotic zone (200 m). A significant portion of the expanded genome proxy array's targets showed signal (95 out of 268 targets present in ≥ 1 sample). The multi-year community survey showed the consistent presence of a core group of common and abundant targeted taxa at each depth in Monterey Bay, higher variability among shallow than deep samples, and episodic occurrences of more transient marine genotypes. The abundance of the most dominant genotypes peaked after strong episodic upwelling events. The genome-proxy array's ability to track populations of closely related genotypes indicated population shifts within several abundant target taxa, with specific populations in some cases clustering by depth or oceanographic season. Although 51 cultivated organisms were targeted (representing 19% of the array) the majority of targets detected and of total target signal (85% and ∼92% respectively) were from uncultivated genotypes, often those derived from Monterey Bay. The array provided a relatively cost-effective approach (∼$15 per array) for surveying the natural history of uncultivated lineages.


A principled dimension-reduction method for the population density approach to modeling networks of neurons with synaptic dynamics.
The population density approach to neural network modeling has been utilized in a variety of contexts. The idea is to group many similar noisy neurons into populations and track the probability density function for each population that encompasses the proportion of neurons with a particular state rather than simulating individual neurons (i.e., Monte Carlo). It is commonly used for both analytic insight and as a time-saving computational tool. The main shortcoming of this method is that when realistic attributes are incorporated in the underlying neuron model, the dimension of the probability density function increases, leading to intractable equations or, at best, computationally intensive simulations. Thus, developing principled dimension-reduction methods is essential for the robustness of these powerful methods. As a more pragmatic tool, it would be of great value for the larger theoretical neuroscience community. For exposition of this method, we consider a single uncoupled population of leaky integrate-and-fire neurons receiving external excitatory synaptic input only. We present a dimension-reduction method that reduces a two-dimensional partial differential-integral equation to a computationally efficient one-dimensional system and gives qualitatively accurate results in both the steady-state and nonequilibrium regimes. The method, termed modified mean-field method, is based entirely on the governing equations and not on any auxiliary variables or parameters, and it does not require fine-tuning. The principles of the modified mean-field method have potential applicability to more realistic (i.e., higher-dimensional) neural networks.


Cortical activity during naturalistic music listening reflects short-range predictions based on long-term experience.
Expectations shape our experience of music. However, the internal model upon which listeners form melodic expectations is still debated. Do expectations stem from Gestalt-like principles or statistical learning? If the latter, does long-term experience play an important role, or are short-term regularities sufficient? And finally, what length of context informs contextual expectations? To answer these questions, we presented human listeners with diverse naturalistic compositions from Western classical music, while recording neural activity using MEG. We quantified note-level melodic surprise and uncertainty using various computational models of music, including a state-of-the-art transformer neural network. A time-resolved regression analysis revealed that neural activity over fronto-temporal sensors tracked melodic surprise particularly around 200ms and 300-500ms after note onset. This neural surprise response was dissociated from sensory-acoustic and adaptation effects. Neural surprise was best predicted by computational models that incorporated long-term statistical learning-rather than by simple, Gestalt-like principles. Yet, intriguingly, the surprise reflected primarily short-range musical contexts of less than ten notes. We present a full replication of our novel MEG results in an openly available EEG dataset. Together, these results elucidate the internal model that shapes melodic predictions during naturalistic music listening.


An essential role for the Zn2+ transporter ZIP7 in B cell development.
Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.


Parental Decision Making Regarding the Disclosure or Nondisclosure of a Mutation-Positive BRCA1/2 Test Result to Minors.
To gain insight into parental decision making regarding the disclosure or nondisclosure of a mutation-positive BRCA1/2 test result to minors. . A qualitative study based on Heidegger hermeneutic phenomenology was undertaken to explore the lived experience of parental decision making regarding high-risk BRCA1/2 disclosure. . The study's recruitment site was a western Canadian hereditary breast and ovarian cancer clinic. . Fifteen female mutation-positive BRCA1/2 carriers who had at least one child aged 6-18 years. . The use of a demographic questionnaire, semistructured interviews, and conversation summaries were employed to gain an understanding of participants' lived experience. van Manen's selective approach was used to conduct a thematic analysis. . Collectively, parents wanted clinicians to discuss implications of disclosing and not disclosing a mutation-positive BRCA1/2 test result to minors in greater detail. The findings were categorized under the following emergent themes. Participants' stories identified the need for auxiliary support pertaining to the decision-making process and suggested ways in which parental support may be coordinated. . Oncology nurses with advanced genetics training should assist mutation-positive BRCA1/2 carriers in meeting their genetic risk information needs; this requires nurses to stay informed about a multitude of issues that affect this population of patients.


Risk of hospitalization or death from ischemic heart disease among British vegetarians and nonvegetarians: results from the EPIC-Oxford cohort study.
Few previous prospective studies have examined differences in incident ischemic heart disease (IHD) risk between vegetarians and nonvegetarians. The objective was to examine the association of a vegetarian diet with risk of incident (nonfatal and fatal) IHD. A total of 44,561 men and women living in England and Scotland who were enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford study, of whom 34% consumed a vegetarian diet at baseline, were part of the analysis. Incident cases of IHD were identified through linkage with hospital records and death certificates. Serum lipids and blood pressure measurements were available for 1519 non cases, who were matched to IHD cases by sex and age. IHD risk by vegetarian status was estimated by using multivariate Cox proportional hazards models. After an average follow-up of 11.6 y, there were 1235 IHD cases (1066 hospital admissions and 169 deaths). Compared with nonvegetarians, vegetarians had a lower mean BMI [in kg/m(2); -1.2 (95% CI: -1.3, -1.1)], non-HDL-cholesterol concentration [-0.45 (95% CI: -0.60, -0.30) mmol/L], and systolic blood pressure [-3.3 (95% CI: -5.9, -0.7) mm Hg]. Vegetarians had a 32% lower risk (HR: 0.68; 95% CI: 0.58, 0.81) of IHD than did nonvegetarians, which was only slightly attenuated after adjustment for BMI and did not differ materially by sex, age, BMI, smoking, or the presence of IHD risk factors. Consuming a vegetarian diet was associated with lower IHD risk, a finding that is probably mediated by differences in non-HDL cholesterol, and systolic blood pressure.


Assessment of environmental improvement measures using a novel integrated model: a case study of the Shenzhen River catchment, China.
Integrated water environmental management in a rapidly urbanizing area often requires combining social, economic and engineering measures in order to be effective. However, in reality, these measures are often considered independently by different planners, and decisions are made in a hierarchical manner; this has led to problems in environmental pollution control and also an inability to devise innovative solutions due to technological lock-in. In this paper, we use a novel coupled system dynamics and water environmental model (SyDWEM) to simulate the dynamic interactions between the socio-economic system, water infrastructure and receiving water in a rapidly urbanizing catchment in Shenzhen, China. The model is then applied to assess the effects of proposed socio-economic or engineering measures on environmental and development indicators in the catchment for 2011-2020. The results indicate that 1) measures to adjust industry structures have a positive effect on both water quantity and quality in the catchment; 2) measures to increase the labor productivity, the water use efficiency, the water transfer quota or the reclaimed wastewater reuse can alleviate the water shortage, but cannot improve water quality in the river; 3) measures to increase the wastewater treatment rate or the pollutant removal rate can improve water quality in the river, but have no effect on water shortage. Based on the effectiveness of the individual measures, a combination of socio-economic and engineering measures is proposed, which can achieve water environmental sustainability in the study area. Thus, we demonstrate that SyDWEM has the capacity to evaluate the effects of both socio-economic and engineering measures; it also provides a tool for integrated decision making by socio-economic and water infrastructure planners.