Temporal stability and determinants of white blood cell DNA methylation in the breakthrough generations study.
Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures and disease risk. However, little is known about the variation of methylation markers in the population and their stability over time, both important factors in the design and interpretation of EWAS. We aimed to identify stable variable methylated probes (VMP), i.e., markers that are variable in the population, yet stable over time. We estimated the intraclass correlation coefficient (ICC) for each probe on the Illumina 450K methylation array in paired samples collected approximately 6 years apart from 92 participants in the Breakthrough Generations Study. We also evaluated relationships with age, reproductive and hormonal history, weight, alcohol intake, and smoking. Approximately 17% of probes had an ICC > 0.50 and were considered stable VMPs (stable-VMPs). Stable-VMPs were enriched for probes located in "shores" bordering CpG islands, and at approximately 1.3 kb downstream from the transcription start site in the transition between the unmethylated promoter and methylated gene body. Both cross-sectional and longitudinal data analyses provided strong evidence for associations between changes in methylation levels and aging. Smoking-related probes at 2q37.1 and AHRR were stable-VMPs and related to time since quitting. We also observed associations between methylation and weight changes. Our results provide support for the use of white blood cell DNA methylation as a biomarker of exposure in EWAS. Larger studies, preferably with repeated measures over time, will be required to establish associations between specific probes and exposures.


Effect of energy dependence of the density of states on pressure-dependent rate constants.
The FE integral for the normalized Boltzmann-weighted number of unimolecular states above the threshold energy is the key quantity for computing the collision efficiency in the pressure-dependent unimolecular rate theory developed by Troe, who calls this the energy dependence factor of the density of states. By using the Whitten-Rabinovitch approximation and assuming that the Whitten-Rabinovitch a(E) function is independent of energy, FE can be approximated by an analytical formula; this approximate formula is widely used because of its convenience and computational efficiency. Here we test its validity by comparing the rate constants computed by using the approximate FE to the ones determined by using the numerically integrated FE. For small-sized molecules and for reactions with high threshold energies E0, the differences are negligible at all temperatures, but in other cases, the approximate formula tends to underestimate FE and thus overestimates the collision efficiency, and this leads to smaller pressure falloff. When a(E) at high energies differs appreciably from a(E0), we find that the underestimation of pressure-dependent rate constants by using the approximate formula can be greater than a factor of 5 at high temperatures. The physical insight we draw from this study is that, for reactions with threshold energies below about 30 kcal mol-1, the rate of collisional energy transfer can be appreciably slowed down by the increase in the density of states at higher energies, and this increases the falloff effect by which finite-pressure rate constants become lower than the high-pressure limit, especially at higher temperatures.


MDM2 is a central node in the p53 pathway: 12 years and counting.
Twelve years ago, the Mdm2 oncogene was shown to bind to and inhibit the tumor suppressor protein, p53. During the past 12 years, both genetic and biochemical studies have demonstrated that Mdm2 is a key negative regulator of the tumor suppressor p53. Mdm2 and p53 form an oscillating auto-regulatory feedback loop, which is tightly controlled to allow the appropriate response to environmental stresses in order to suppress tumor formation. When Mdm2 activity is inappropriately heightened, as it is in many human tumors, p53 activity is attenuated and tumor susceptibility arises. The p53 gene is mutated in 50% of all human tumors, but in those tumors that retain wild type p53, inhibiting Mdm2 activity could activate p53 tumor suppression and therefore provide a therapeutic strategy for the treatment of cancer.


Approach to the Diagnosis of Hepatocutaneous Syndrome in Dogs: A Retrospective Study and Literature Review.
Superficial necrolytic dermatitis (SND) is a rare and often fatal disease in dogs that has been associated with pancreatic neuroendocrine neoplasia (SND/EN) and hepatocutaneous syndrome (SND/HCS). Although various combinations of diagnostics have been used to differentiate these two causes of SND, there are currently no data on which combination would enable the most timely and noninvasive way to diagnose HCS. Medical records were reviewed retrospectively (2004-2018) for dogs with SND/HCS (n = 24) and SND/EN (n = 1). These data were compared with cases found by review of the literature of dogs with SND/HCS (n = 105) and SND/EN (n = 13). The most consistent findings with SND were dermatological lesions affecting paw pads or mucocutaneous junctions (143/143, 100%) and marked plasma hypoaminoacidemia (58/58, 100%). On ultrasound, a honeycomb liver was seen in 62/63 (98%) dogs with SND/HCS but none with SND/EN. Six out of 23 (26%) dogs in the retrospective study with SND/HCS had marked keratinocyte apoptosis, a finding that was associated with diabetes mellitus. This study suggests that in dogs with characteristic skin lesions, an amino acid profile permits a noninvasive diagnosis of SND. An abdominal ultrasound can then assist in the differentiation of SND/HCS and SND/EN.


Are there bilingual advantages on nonlinguistic interference tasks? Implications for the plasticity of executive control processes.
It has been proposed that the unique need for early bilinguals to manage multiple languages while their executive control mechanisms are developing might result in long-term cognitive advantages on inhibitory control processes that generalize beyond the language domain. We review the empirical data from the literature on nonlinguistic interference tasks to assess the validity of this proposed bilingual inhibitory control advantage. Our review of these findings reveals that the bilingual advantage on conflict resolution, which by hypothesis is mediated by inhibitory control, is sporadic at best, and in some cases conspicuously absent. A robust finding from this review is that bilinguals typically outperform monolinguals on both compatible and incompatible trials, often by similar magnitudes. Together, these findings suggest that bilinguals do enjoy a more widespread cognitive advantage (a bilingual executive processing advantage) that is likely observable on a variety of cognitive assessment tools but that, somewhat ironically, is most often not apparent on traditional assays of nonlinguistic inhibitory control processes.


Mixed methods grant applications in the health sciences: An analysis of reviewer comments.
Our aim was to understand how reviewers appraise mixed methods research by analyzing reviewer comments for grant applications submitted primarily to the National Institutes of Health. We requested scholars and consultants in the Mixed Methods Research Training Program (MMRTP) for the Health Sciences to send us summary statements from their mixed methods grant applications and obtained 40 summary statements of funded (40%) and unfunded (60%) mixed methods grant applications. We conducted a document analysis using a coding rubric based on the NIH Best Practices for Mixed Methods Research in the Health Sciences and allowed inductive codes to emerge. Reviewers favorably appraised mixed methods applications demonstrating coherence among aims and research design elements, detailed methods, plans for mixed methods integration, and the use of theoretical models. Reviewers identified weaknesses in mixed methods applications that lacked methodological details or rationales, had a high participant burden, and failed to delineate investigator roles. Successful mixed methods applications convey assumptions behind the methods chosen to accomplish specific aims and clearly detail the procedures to be taken. Investigators planning to use mixed methods should remember that reviewers are looking for both points of view.


RelEx: Visualization for Actively Changing Overlay Network Specifications.
We present a network visualization design study focused on supporting automotive engineers who need to specify and optimize traffic patterns for in-car communication networks. The task and data abstractions that we derived support actively making changes to an overlay network, where logical communication specifications must be mapped to an underlying physical network. These abstractions are very different from the dominant use case in visual network analysis, namely identifying clusters and central nodes, that stems from the domain of social network analysis. Our visualization tool RelEx was created and iteratively refined through a full user-centered design process that included a full problem characterization phase before tool design began, paper prototyping, iterative refinement in close collaboration with expert users for formative evaluation, deployment in the field with real analysts using their own data, usability testing with non-expert users, and summative evaluation at the end of the deployment. In the summative post-deployment study, which entailed domain experts using the tool over several weeks in their daily practice, we documented many examples where the use of RelEx simplified or sped up their work compared to previous practices.


Acute and transient psychotic disorders: precursors, epidemiology, course and outcome.
ICD-10 has introduced the diagnostic group acute and transient psychotic disorders (ATPDs; F23). To validate the nosological distinctiveness of ICD-10 ATPDs by following up an inception cohort with first-episode psychosis. All patients with first-episode psychosis identified in Nottingham between 1992 and 1994 and diagnosed using ICD-10 criteria were reassessed 3 years later. ATPD outcomes were compared with schizophrenia and affective psychosis. Multivariate analyses were conducted to determine whether acute onset and early remission predicted favourable 3-year outcome in first-episode psychosis. Of 168 cases of first-episode psychosis, 32 (19%) received an intake diagnosis of ATPD. The diagnosis of ATPD was stable in women over 3 years, but not in men. Outcomes in ATPD were better than in schizophrenia and similar to affective psychosis. In non-affective psychoses, favourable outcomes were a function of gender and premorbid functioning rather than acute onset and early remission. The ICD-10 criteria for ATPDs identify a diagnostically unstable group of disorders. Acute onset and early remission do not independently predict favourable outcome over 3 years in first-episode psychosis.


Cortical overexpression of neuronal calcium sensor-1 induces functional plasticity in spinal cord following unilateral pyramidal tract injury in rat.
Following trauma of the adult brain or spinal cord the injured axons of central neurons fail to regenerate or if intact display only limited anatomical plasticity through sprouting. Adult cortical neurons forming the corticospinal tract (CST) normally have low levels of the neuronal calcium sensor-1 (NCS1) protein. In primary cultured adult cortical neurons, the lentivector-induced overexpression of NCS1 induces neurite sprouting associated with increased phospho-Akt levels. When the PI3K/Akt signalling pathway was pharmacologically inhibited the NCS1-induced neurite sprouting was abolished. The overexpression of NCS1 in uninjured corticospinal neurons exhibited axonal sprouting across the midline into the CST-denervated side of the spinal cord following unilateral pyramidotomy. Improved forelimb function was demonstrated behaviourally and electrophysiologically. In injured corticospinal neurons, overexpression of NCS1 induced axonal sprouting and regeneration and also neuroprotection. These findings demonstrate that increasing the levels of intracellular NCS1 in injured and uninjured central neurons enhances their intrinsic anatomical plasticity within the injured adult central nervous system.


Systematic review to inform prevention and management of chronic disease for Indigenous Australians: overview and priorities.
To describe the main characteristics of systematic reviews addressing questions of chronic disease and related risk factors for Indigenous Australians. We searched databases for systematic reviews meeting inclusion criteria. Two reviewers assessed quality and extracted characteristics using pre-defined tools. We identified 14 systematic reviews. Seven synthesised evidence about health intervention effectiveness; four addressed chronic disease or risk factor prevalence; and six conducted critical appraisal as per current best practice. Only three reported steps to align the review with standards for ethical research with Indigenous Australians and/or capture Indigenous-specific knowledge. Most called for more high-quality research. Systematic review is an under-utilised method for gathering evidence to inform chronic disease prevention and management for Indigenous Australians. Relevance of future systematic reviews could be improved by: 1) aligning questions with community priorities as well as decision maker needs; 2) involvement of, and leadership by, Indigenous researchers with relevant cultural and contextual knowledge; iii) use of critical appraisal tools that include traditional risk of bias assessment criteria and criteria that reflect Indigenous standards of appropriate research. Systematic review method guidance, tools and reporting standards are required to ensure alignment with ethical obligations and promote rigor and relevance.


Off-Axis Dipole Forces in Optical Tweezers by an Optical Analog of the Magnus Effect.
It is shown that a circular dipole can deflect the focused laser beam that induces it and will experience a corresponding transverse force. Quantitative expressions are derived for Gaussian and angular top hat beams, while the effects vanish in the plane wave limit. The phenomena are analogous to the Magnus effect, pushing a spinning ball onto a curved trajectory. The optical case originates in the coupling of spin and orbital angular momentum of the dipole and the light. In optical tweezers the force causes off-axis displacement of the trapping position of an atom by a spin-dependent amount up to λ/2π, set by the direction of a magnetic field. This suggests direct methods to demonstrate and explore these effects, for instance, to induce spin-dependent motion.


Ice sheets. Volume loss from Antarctic ice shelves is accelerating.
The floating ice shelves surrounding the Antarctic Ice Sheet restrain the grounded ice-sheet flow. Thinning of an ice shelf reduces this effect, leading to an increase in ice discharge to the ocean. Using 18 years of continuous satellite radar altimeter observations, we have computed decadal-scale changes in ice-shelf thickness around the Antarctic continent. Overall, average ice-shelf volume change accelerated from negligible loss at 25 ± 64 cubic kilometers per year for 1994-2003 to rapid loss of 310 ± 74 cubic kilometers per year for 2003-2012. West Antarctic losses increased by ~70% in the past decade, and earlier volume gain by East Antarctic ice shelves ceased. In the Amundsen and Bellingshausen regions, some ice shelves have lost up to 18% of their thickness in less than two decades.


Academic performance in adolescents aged 15-16 years born after frozen embryo transfer compared with fresh embryo transfer: a nationwide registry-based cohort study.
To assess academic performance in singletons aged 15-16 years conceived after frozen embryo transfer (FET) compared with singletons born after fresh embryo transfer (ET) in Danish cohorts born from 1995 to 2001. Danish national registry-based cohort study. Danish national registries. All 6495 singletons conceived after assisted reproductive technology (ART) treatment in Denmark from 1995 to 2001 [FET (n) = 423; fresh ET (n) = 6072]. Mean test scores on a national standardised and international comparable grading-scale. Comparisons of test score were first made in univariate analysis (Model 1) and secondly in a multivariate linear model (Model 2) adjusting for relevant reproductive and socio-demographic covariates such as the occupational and educational level of the parents. Sensitivity analyses on FET-IVF (in vitro fertilisation) versus fresh ET-IVF and FET-ICSI (intracytoplasmic sperm injection) versus fresh ET-ICSI were made. Linear mixed models were used to account for the correlation in test scores of siblings for continuous outcome. Mean overall test score and test score in Danish, mathematics, English, and physics/chemistry. Crude and adjusted mean test scores were similar for adolescents conceived after FET compared with fresh ET. The crude mean difference was +0.11 (95% CI -0.11; 0.34), and the adjusted mean difference was +0.12 (95% CI -0.09; 0.34). Adolescents conceived after FET had similar academic performance at 15-16 of years of age compared with children conceived after fresh ET. Using frozen embryos in fertility treatment does not affect school performance in Danish adolescents aged 15-16 years.


Monocular 3D reconstruction of locally textured surfaces.
Most recent approaches to monocular nonrigid 3D shape recovery rely on exploiting point correspondences and work best when the whole surface is well textured. The alternative is to rely on either contours or shading information, which has only been demonstrated in very restrictive settings. Here, we propose a novel approach to monocular deformable shape recovery that can operate under complex lighting and handle partially textured surfaces. At the heart of our algorithm are a learned mapping from intensity patterns to the shape of local surface patches and a principled approach to piecing together the resulting local shape estimates. We validate our approach quantitatively and qualitatively using both synthetic and real data.


2,5-Hexanedione excretion after occupational exposure to n-hexane.
The urinary excretion of the n-hexane metabolite 2,5-hexanedione (HD) was determined in four shoe factory workers during four workingdays that were preceded by four free days and followed by two free days. The correlation between excretion of HD and the n-hexane concentrations in the workroom air was evaluated. The air concentrations of n-hexane and those of acetone, toluene, and other organic solvents were monitored with charcoal tubes. All the urine from each worker was collected at freely chosen intervals during the experimental period and the following two free days. The samples were analysed by gas chromatography. The relative excretion of HD increased as the exposure to n-hexane increased, although it seemed that HD accumulated progressively in the body at the highest n-hexane concentrations and at higher total solvent concentrations.


Breastfeeding, Cognitive and Noncognitive Development in Early Childhood: A Population Study.
There is mixed evidence from correlational studies that breastfeeding impacts children's development. Propensity score matching with large samples can be an effective tool to remove potential bias from observed confounders in correlational studies. The aim of this study was to investigate the impact of breastfeeding on children's cognitive and noncognitive development at 3 and 5 years of age. Participants included ∼8000 families from the Growing Up in Ireland longitudinal infant cohort, who were identified from the Child Benefit Register and randomly selected to participate. Parent and teacher reports and standardized assessments were used to collect information on children's problem behaviors, expressive vocabulary, and cognitive abilities at age 3 and 5 years. Breastfeeding information was collected via maternal report. Propensity score matching was used to compare the average treatment effects on those who were breastfed. Before matching, breastfeeding was associated with better development on almost every outcome. After matching and adjustment for multiple testing, only 1 of the 13 outcomes remained statistically significant: children's hyperactivity (difference score, -0.84; 95% confidence interval, -1.33 to -0.35) at age 3 years for children who were breastfed for at least 6 months. No statistically significant differences were observed postmatching on any outcome at age 5 years. Although 1 positive benefit of breastfeeding was found by using propensity score matching, the effect size was modest in practical terms. No support was found for statistically significant gains at age 5 years, suggesting that the earlier observed benefit from breastfeeding may not be maintained once children enter school.


Participatory health research with migrants: Opportunities, challenges, and way forwards.
Migration is one of the most politically pressing issues of the 21st century but migrant health remains an under-researched area. The International Collaboration for Participatory Health Research (ICPHR) working group on migration developed this position statement to address opportunities and challenges in relation to migrant health. It aims to contribute to a shift from a deficit model that sees migrants as passively affected by policies to their reconceptualization as citizens who are engaged in the co-creation of solutions. This paper examines the opportunities and challenges posed by the use of PHR with migrants. It draws on a broad literature to provide examples of successful PHR with migrants and highlights critical issues for consideration. Successful initiatives illustrate the value of engaging migrants in the definition of the research agenda, the design and implementation of health interventions, the identification of health-protective factors and the operationalization and validation of indicators to monitor progress. Within increasingly super diverse contexts, fragmented community landscapes that are not necessarily constructed along ethnicity traits, inadequate structures of representation, local tensions and operational barriers can hamper meaningful PHR with migrants. For each research context, it is essential to gauge the 'optimal' level and type of participation that is more likely to leverage migrants' empowerment. The development of Monitoring and Evaluation tools and methodological strategies to manage inter-stakeholder discrepancies and knowledge translation gaps are steps in this direction. This paper draws from contributions of migrant populations and other stakeholders to policymaking.


Independent effects of youth and poor diabetes control on responses to hypoglycemia in children.
To evaluate the effects of childhood and poorly controlled insulin-dependent diabetes mellitus (IDDM) on counterregulatory hormone and symptomatic responses to hypoglycemia, we studied 16 nondiabetic children (13 +/- 2 yr), 19 nondiabetic adults (26 +/- 3 yr), and 13 children with IDDM (14 +/- 2 yr, HbA, 15.1 +/- 3.3%) during a gradual reduction in plasma glucose with the glucose-clamp technique. Plasma glucose was reduced from approximately 5 to approximately 2.8 mM over 240 min with serial assessment of counterregulatory hormone levels and symptom awareness. The plasma glucose level that triggered a sustained rise in plasma epinephrine was consistently higher in nondiabetic children than in adults (3.9 +/- 0.06 vs. 3.2 +/- 0.06 mM, P less than 0.001). Poorly controlled IDDM further elevated the glucose threshold for epinephrine release to normoglycemic levels (4.9 +/- 0.2 mM, P less than 0.001 vs. both control groups). Age and IDDM also produced an upward shift in the glucose level at which growth hormone release and symptom awareness were initiated. In contrast to the effect on glucose thresholds, maximal epinephrine responses and symptom scores were increased only by age and not IDDM (2-fold higher in children). We conclude that childhood and poor diabetes control independently contribute to an upward shift in glucose thresholds for counterregulatory hormone release and symptom awareness during mild hypoglycemia. Normoglycemic counterregulation may interfere with efforts to control diabetes in young patients.


Eating local: influences of habitat on the diet of little brown bats (Myotis lucifugus).
We employ molecular methods to profile the diet of the little brown bat, Myotis lucifugus, and describe spatial and temporal changes in diet over their maternity season. We identified 61 prey species of insects and 5 species of arachnid. The largest proportion of prey (∼32%) were identified as species of the mass-emerging Ephemeroptera (mayfly) genus Caenis. Bats roosting in agricultural settings had lower dietary richness than those occupying a roost located on a forest fragment in a conservation area. We detected temporal fluctuations in diet over the maternity season. Dipteran (fly) species dominated the diet early in the season, replaced later by species of mayfly. Because our methodology provides species-level identification of prey, we were able to isolate environmental indicator species in the diet and draw conclusions about the location and type of their foraging habitat and the health of these aquatic systems. The species detected suggested that the bats use variable habitats; members of one agricultural roost foraged on insects originating in rivers or streams while those in another agricultural roost and the forest roost fed on insects from pond or lake environments. All source water for prey was of fair to good quality, though no species detected are intolerant of pollution thus the habitat cannot be classified as pristine. Our study outlines a model system to investigate the abiotic and biotic interactions between habitat factors through this simple food chain to the top predator.


A new approach to the biobleaching of flax pulp with laccase using natural mediators.
The phenols syringaldehyde (SA), acetosyringone (AS) and p-coumaric acid (PCA) were used as natural laccase mediators in combination with a laccase from Pycnoporus cinnabarinus to bleach flax fibres. Their performance was compared with 1-hydroxybenzotriazole (HBT) in terms of enzyme stability, and pulp and effluent properties. HBT and PCA were found to inactivate laccase in the absence of pulp. However, in the presence of unbleached flax pulp stability was increased; for example with PCA, laccase retained 77% of its initial activity, in contrast with complete inactivation in the absence of pulp. This suggests a protective effect of the pulp against denaturalization of the enzyme. All natural mediators resulted in a reduced kappa number after the subsequent alkaline treatment with hydrogen peroxide; the reduction being especially marked with SA (about 2 units - with respect to the control sample) and comparable to that obtained by HBT. Brightness was significantly increased by all natural mediators, but especially by AS and SA (23% with both), which performed very similarly to HBT in this respect. Natural mediators therefore might constitute an effective alternative to synthetic mediators for flax pulp biobleaching. This paper demonstrates for the first time the use of natural mediators in the laccase-assisted delignification of flax pulp and their effect on the properties of the resulting effluents.


Effects of larval exposure to sublethal concentrations of the ecdysteroid agonists RH-5849 and tebufenozide (RH-5992) on male reproductive physiology in Spodoptera litura.
Sublethal concentrations of the bisacylhydrazine moulting hormone agonists, RH-5849, and tebufenozide (RH-5992) were fed to sixth (final) instar larvae of Spodoptera litura. Both RH-5849 and tebufenozide adversely affected the mating success of S. litura when the surviving treated males were crossed with normal females. The ecdysone agonists decreased the longevity of treated males and of untreated females when crossed with treated males. The number of eggs laid by untreated females mated to treated males was decreased, and the fertility (percentage of hatching success) of the resulting eggs was reduced. These effects on male reproductive success were at least in part explained by a reduction in the number of sperm transferred during mating. The adverse effects of tebufenozide on male reproductive function were qualitatively the same as those of RH-5849, but tebufenozide was active at lower concentrations. To understand the reason for these adverse effects on male reproduction, we investigated the effects of the insecticides on male reproductive physiology. Male reproductive tract development and testicular volume of resulting adult moths were adversely affected by sublethal larval exposure to the ecdysone agonists. Dose-dependent reductions occurred in the production of eupyrene and apyrene spermatozoa in the adult testes, and in the number of spermatozoa released from the testes into the male reproductive tract. The descent into the male tract of both eupyrene and apyrene sperm was found to start at the normal stage of development in both normal and treated insects, but the daily rhythm of sperm descent was subsequently disturbed in the insecticide-treated moths. This affected the numbers of sperm in the upper vas deferens (UVD), seminal vesicle (SV), and duplex (duplex). Injections of RH-5849 given to pharate adult or newly emerged adult S. litura also caused drastic reduction in the number of sperm in the upper regions of the male tract, when measured 24 h after injection. The possible importance of pest population reduction through the sublethal anti-reproductive effects of insecticides is discussed.


Polymorphism in myristoylpalmitoylphosphatidylcholine.
This study focuses on the mixed-chain lipid myristoylpalmitoylphosphatidylcholine (MPPC) near full hydration. The lipid, synthesized according to the procedure of (Mason et al., 1981a, has a low degree of acyl chain migration. When MPPC is temperature-jumped (T-jumped) from the L alpha phase (T = 38 degrees C) to T = 20 degrees C or below, a subgel phase forms; this formation takes less than 1 h at a temperature below T = 12 degrees C. The subgel remains stable up to T = 29 degrees C. When MPPC is T-jumped from the L alpha phase to T = 24 degrees C or above, a ripple phase forms with coexisting ripple wavelengths of 240 A and 130 A. In contrast, when MPPC is melted from the subgel phase, the ripple phase is characterized by bilayers having a single ripple wavelength of 130 A. In agreement with earlier studies (Stumpel et al., 1983; Serrallach et al., 1984. Structure and thermotropic properties of mixed-chain phosphatidylcholine bilayer membranes. Biochemistry 23:713-720.), no stable gel phase was observed. Instead, an ill-defined low-angle X-ray pattern is initially observed, which gradually transforms into the subgel phase below 20 degrees C, or into the ripple phase above 24 degrees C. In the wide-angle X-ray diffraction, a single peak is observed, similar to the ripple phase wide-angle pattern, that either persists above 24 degrees C or transforms into a multi-peaked subgel wide-angle pattern below 20 degrees C. The absence of a gel phase can be understood phenomenologically as the relative dominance of the subgel phase in mixed-chain PCs compared to same-chain PCs. The subgel structure and molecular interactions responsible for this comparative behavior are interesting open issues.


Miniaturization of holographic Fourier-transform spectrometers.
Wave propagation equations in the stationary-phase approximation have been used to identify the theoretical bounds of a miniature holographic Fourier-transform spectrometer (HFTS). It is demonstrated that the HFTS throughput can be larger than for a scanning Fourier-transform spectrometer. Given room- or a higher-temperature constraint, a small HFTS has the potential to outperform a small multichannel dispersive spectrograph with the same resolving power because of the size dependence of the signal-to-noise ratio. These predictions are used to analyze the performance of a miniature HFTS made from simple optical components covering a broad spectral range from the UV to the near IR. The importance of specific primary aberrations in limiting the HFTS performance has been both identified and verified.


Sapropterin dihydrochloride for phenylketonuria.
Phenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most natural foods are excluded from diet and supplements are used to supply other nutrients. Recent publications report a decrease in blood phenylalanine concentration in some patients treated with sapropterin dihydrochloride. We examined the evidence for the use of sapropterin dihydrochloride to treat phenylketonuria. To assess the safety and efficacy of sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Date of last search: 29 June 2012.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 23 July 2012.We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials. Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. Two authors independently assessed trials and extracted outcome data. Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 μmol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 μmol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group. There is evidence of short-term benefit from using sapropterin in some patients with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term.There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.


[Significance of genome-wide association study in cancer].
The single-nucleotide polymorphism (SNP)-based genome-wide association study (GWAS) is now widely performed because of the development of new SNP genotyping technologies from 2007 onward. The GWAS provides a powerful approach to identify regions of the genome that harbor genetic variants conferring risk for disease without prior knowledge of location or function. During the past few years, the GWAS has identified numerous robust associations between specific chromosomal loci and different types of cancer. For nearly all regions identified in the GWAS, the per allele effect sizes estimated are < 1.5 and the mechanism of SNP in carcinogenesis was not clear. Consequently, GWAS findings underscore the complex nature of cancer. The combined effects may be sufficiently great to be useful for risk prediction, targeted screening, and prevention, particularly as more loci are identified. Some loci, such as 8q24, were identified as a cancer susceptibility region for many unrelated cancers, and therefore an investigation of those loci may disclose new mechanisms of carcinogenesis or unknown genes including noncoding RNA. Furthermore, the development of new strategies for GWAS analysis is expected.


Validation and simplification of Fournier's gangrene severity index.
To validate the predictive value of Fournier's Gangrene Severity Index in patients with Fournier gangrene and to facilitate patient mortality risk-stratification by simplifying the Fournier's Gangrene Severity Index. From January 1989 to December 2011, 85 male patients with clinically-documented Fournier's gangrene undergoing intensive treatment and with complete medical records were recruited. The demographic information and nine parameters of Fournier's Gangrene Severity Index were compared between survivors and non-survivors. The parameters that showed a significant difference between the two groups were selected to generate a simplified scoring index. Of the 85 patients recruited, 16 patients died of the disease with mortality rate of 18.8%. The Fournier's Gangrene Severity Index score at initial diagnosis was significantly higher in non-survivors than in survivors. Of the nine parameters of Fournier's Gangrene Severity Index, the scores of serum creatinine level, hematocrit level and serum potassium level were significantly different between the two groups. However, the mean body temperatures, heart rate, respiration rate, white blood cell count, serum sodium and bicarbonate levels were non-significantly different. Of the 12 patients with chronic kidney disease or end-stage renal disease, 10 died of severe sepsis. A simplified scoring index including parameters of creatinine, hematocrit and potassium was generated, which provided sensitivity and specificity of 87% and 77% in predicting patient mortality, respectively. The predictive values of this simplified Fournier's Gangrene Severity Index were shown to be non-inferior to Fournier's Gangrene Severity Index in our patients. The simplified Fournier's Gangrene Severity Index is easy to use at initial diagnosis, and offers a way to compare outcomes in different clinical populations.


Impact of immunization with glycoprotein D2/AS04 on herpes simplex virus type 2 shedding into the genital tract in guinea pigs that become infected.
In recent clinical trials, a vaccine that contained herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) and the adjuvant AS04 afforded HSV-seronegative women significant protection against HSV-2 genital disease and limited protection against infection. Similarly, in guinea pigs, immunization with the vaccine provided significant protection against genital HSV-2 disease but did not prevent mucosal infection. We explored the impact of immunization on the magnitude of latent virus infection and on the frequency and magnitude of virus reactivation as measured by both recurrent disease and viral shedding into the genital tract. Guinea pigs immunized with gD2/AS04 were shown by quantitative polymerase chain reaction (qPCR) analysis to have significantly less latent viral DNA in the ganglia than did naive control guinea pigs and to have a reduced incidence and frequency of recurrent disease. By contrast, all immunized guinea pigs shed virus into the genital tract with a frequency comparable to that seen in control guinea pigs. However, the amount of virus shed was significantly reduced, as measured by qPCR. These data suggest that immunization could affect transmission by altering viral shedding patterns.


Osteoporosis in experimental postmenopausal polyarthritis: the relative contributions of estrogen deficiency and inflammation.
Generalized osteoporosis in postmenopausal rheumatoid arthritis (RA) is caused both by estrogen deficiency and by the inflammatory disease. The relative importance of each of these factors is unknown. The aim of this study was to establish a murine model of osteoporosis in postmenopausal RA, and to evaluate the relative importance and mechanisms of menopause and arthritis-related osteoporosis. To mimic postmenopausal RA, DBA/1 mice were ovariectomized, followed by the induction of type II collagen-induced arthritis. After the mice had been killed, paws were collected for histology, one femur for bone mineral density (BMD) and sera for analyses of markers of bone resorption (RatLaps; type I collagen cross-links, bone formation (osteocalcin) and cartilage destruction (cartilage oligomeric matrix protein), and for the evaluation of antigen-specific and innate immune responsiveness. Ovariectomized mice displayed more severe arthritis than sham-operated controls. At termination of the experiment, arthritic control mice and non-arthritic ovariectomized mice displayed trabecular bone losses of 26% and 22%, respectively. Ovariectomized mice with arthritis had as much as 58% decrease in trabecular BMD. Interestingly, cortical BMD was decreased by arthritis but was not affected by hormonal status. In addition, markers of bone resorption and cartilage destruction were increased in arthritic mice, whereas markers of bone formation were increased in ovariectomized mice. This study demonstrates that the loss of endogenous estrogen and inflammation contribute additively and equally to osteoporosis in experimental postmenopausal polyarthritis. Markers of bone remodeling and bone marrow lymphocyte phenotypes indicate different mechanisms for the development of osteoporosis caused by ovariectomy and arthritis in this model.


Neural topography and content of movement representations.
We have used implicit motor imagery to investigate the neural correlates of motor planning independently from actual movements. Subjects were presented with drawings of left or right hands and asked to judge the hand laterality, regardless of the stimulus rotation from its upright orientation. We paired this task with a visual imagery control task, in which subjects were presented with typographical characters and asked to report whether they saw a canonical letter or its mirror image, regardless of its rotation. We measured neurovascular activity with fast event-related fMRI, distinguishing responses parametrically related to motor imagery from responses evoked by visual imagery and other task-related phenomena. By quantifying behavioral and neurovascular correlates of imagery on a trial-by-trial basis, we could discriminate between stimulus-related, mental rotation-related, and response-related neural activity. We found that specific portions of the posterior parietal and precentral cortex increased their activity as a function of mental rotation only during the motor imagery task. Within these regions, the parietal cortex was visually responsive, whereas the dorsal precentral cortex was not. Response- but not rotation-related activity was found around the left central sulcus (putative primary motor cortex) during both imagery tasks. Our study provides novel evidence on the topography and content of movement representations in the human brain. During intended action, the posterior parietal cortex combines somatosensory and visuomotor information, whereas the dorsal premotor cortex generates the actual motor plan, and the primary motor cortex deals with movement execution. We discuss the relevance of these results in the context of current models of action planning.


A review of UVA-mediated photosensitivity disorders.
A number of skin conditions are characterised by photosensitivity to UVA. Some of these are exclusively UVA-mediated conditions, while others include UVA in the action spectrum which also include UVB and/or visible light. This review aims to describe this diverse range of conditions for non-dermatologist scientists with an interest in this topic. As such, clinical details, including treatments, are brief and succinct. Recent advances in understanding the pathogenesis of these conditions is highlighted.


Positive regulation by GABA(B)R1 subunit of leptin expression through gene transactivation in adipocytes.
The view that γ-aminobutyric acid (GABA) plays a functional role in non-neuronal tissues, in addition to an inhibitory neurotransmitter role in the mammalian central nervous system, is prevailing, while little attention has been paid to GABAergic signaling machineries expressed by adipocytes to date. In this study, we attempted to demonstrate the possible functional expression of GABAergic signaling machineries by adipocytes. GABA(B) receptor 1 (GABA(B)R1) subunit was constitutively expressed by mouse embryonic fibroblasts differentiated into adipocytes and adipocytic 3T3-L1 cells in culture, as well as mouse white adipose tissue, with no responsiveness to GABA(B)R ligands. However, no prominent expression was seen with mRNA for GABA(B)R2 subunit required for heteromeric orchestration of the functional GABA(B)R by any adipocytic cells and tissues. Leptin mRNA expression was significantly and selectively decreased in adipose tissue and embryonic fibroblasts, along with drastically reduced plasma leptin levels, in GABA(B)R1-null mice than in wild-type mice. Knockdown by siRNA of GABA(B)R1 subunit led to significant decreases in leptin promoter activity and leptin mRNA levels in 3T3-L1 cells. Our results indicate that GABA(B)R1 subunit is constitutively expressed by adipocytes to primarily regulate leptin expression at the transcriptional level through a mechanism not relevant to the function as a partner of heterodimeric assembly to the functional GABA(B)R.


Analysis of 4,664 high-quality sequence-finished poplar full-length cDNA clones and their utility for the discovery of genes responding to insect feeding.
The genus Populus includes poplars, aspens and cottonwoods, which will be collectively referred to as poplars hereafter unless otherwise specified. Poplars are the dominant tree species in many forest ecosystems in the Northern Hemisphere and are of substantial economic value in plantation forestry. Poplar has been established as a model system for genomics studies of growth, development, and adaptation of woody perennial plants including secondary xylem formation, dormancy, adaptation to local environments, and biotic interactions. As part of the poplar genome sequencing project and the development of genomic resources for poplar, we have generated a full-length (FL)-cDNA collection using the biotinylated CAP trapper method. We constructed four FLcDNA libraries using RNA from xylem, phloem and cambium, and green shoot tips and leaves from the P. trichocarpa Nisqually-1 genotype, as well as insect-attacked leaves of the P. trichocarpa x P. deltoides hybrid. Following careful selection of candidate cDNA clones, we used a combined strategy of paired end reads and primer walking to generate a set of 4,664 high-accuracy, sequence-verified FLcDNAs, which clustered into 3,990 putative unique genes. Mapping FLcDNAs to the poplar genome sequence combined with BLAST comparisons to previously predicted protein coding sequences in the poplar genome identified 39 FLcDNAs that likely localize to gaps in the current genome sequence assembly. Another 173 FLcDNAs mapped to the genome sequence but were not included among the previously predicted genes in the poplar genome. Comparative sequence analysis against Arabidopsis thaliana and other species in the non-redundant database of GenBank revealed that 11.5% of the poplar FLcDNAs display no significant sequence similarity to other plant proteins. By mapping the poplar FLcDNAs against transcriptome data previously obtained with a 15.5 K cDNA microarray, we identified 153 FLcDNA clones for genes that were differentially expressed in poplar leaves attacked by forest tent caterpillars. This study has generated a high-quality FLcDNA resource for poplar and the third largest FLcDNA collection published to date for any plant species. We successfully used the FLcDNA sequences to reassess gene prediction in the poplar genome sequence, perform comparative sequence annotation, and identify differentially expressed transcripts associated with defense against insects. The FLcDNA sequences will be essential to the ongoing curation and annotation of the poplar genome, in particular for targeting gaps in the current genome assembly and further improvement of gene predictions. The physical FLcDNA clones will serve as useful reagents for functional genomics research in areas such as analysis of gene functions in defense against insects and perennial growth. Sequences from this study have been deposited in NCBI GenBank under the accession numbers EF144175 to EF148838.


GPGPU Linear Complexity t-SNE Optimization.
In recent years the t-distributed Stochastic Neighbor Embedding (t-SNE) algorithm has become one of the most used and insightful techniques for exploratory data analysis of high-dimensional data. It reveals clusters of high-dimensional data points at different scales while only requiring minimal tuning of its parameters. However, the computational complexity of the algorithm limits its application to relatively small datasets. To address this problem, several evolutions of t-SNE have been developed in recent years, mainly focusing on the scalability of the similarity computations between data points. However, these contributions are insufficient to achieve interactive rates when visualizing the evolution of the t-SNE embedding for large datasets. In this work, we present a novel approach to the minimization of the t-SNE objective function that heavily relies on graphics hardware and has linear computational complexity. Our technique decreases the computational cost of running t-SNE on datasets by orders of magnitude and retains or improves on the accuracy of past approximated techniques. We propose to approximate the repulsive forces between data points by splatting kernel textures for each data point. This approximation allows us to reformulate the t-SNE minimization problem as a series of tensor operations that can be efficiently executed on the graphics card. An efficient implementation of our technique is integrated and available for use in the widely used Google TensorFlow.js, and an open-source C++ library.


Identification of novel inhibitors of the SARS coronavirus main protease 3CLpro.
SARS (severe acute respiratory syndrome) is caused by a newly discovered coronavirus. A key enzyme for the maturation of this virus and, therefore, a target for drug development is the main protease 3CL(pro) (also termed SARS-CoV 3CL(pro)). We have cloned and expressed in Escherichia coli the full-length SARS-CoV 3CL(pro) as well as a truncated form containing only the catalytic domains. The recombinant proteins have been characterized enzymatically using a fluorescently labeled substrate; their structural stability in solution has been determined by differential scanning calorimetry, and novel inhibitors have been discovered. Expression of the catalytic region alone yields a protein with a reduced catalytic efficiency consistent with the proposed regulatory role of the alpha-helical domain. Differential scanning calorimetry indicates that the alpha-helical domain does not contribute to the structural stability of the catalytic domains. Analysis of the active site cavity reveals the presence of subsites that can be targeted with specific chemical functionalities. In particular, a cluster of serine residues (Ser139, Ser144, and Ser147) was identified near the active site cavity and was susceptible to being targeted by compounds containing boronic acid. This cluster is highly conserved in similar proteases from other coronaviruses, defining an attractive target for drug development. It was found that bifunctional aryl boronic acid compounds were particularly effective at inhibiting the protease, with inhibition constants as strong as 40 nM. Isothermal titration microcalorimetric experiments indicate that these inhibitors bind reversibly to 3CL(pro) in an enthalpically favorable fashion, implying that they establish strong interactions with the protease molecule, thus defining attractive molecular scaffolds for further optimization.


Variable direct and indirect effects of a habitat-modifying invasive species on mortality of native fauna.
Habitat-modifying invasive species can influence rates of predation on native prey either directly by providing protective structure or indirectly by modifying traits of prey species responding to the habitat. The alga Caulerpa taxifolia is one of the most successful invasive species of shallow-water marine systems globally, often provisioning habitat in areas previously lacking in vegetated structure. We experimentally evaluated the direct effect of Caulerpa to provide refuge for the native clam Anadara trapezia and how this balances with its influence on two trait-mediated indirect interactions that may increase Anadara's susceptibility to predators. Specifically, Caulerpa's alteration of physical and chemical properties of the surrounding water and sediment deteriorate Anadara's condition and predator resistance properties and also cause Anadara, though normally buried, to project from beneath the sediment, exposing it to predators. Our results show that Anadara are somewhat (but not consistently) protected from predators by living among Caulerpa. Shallow burial depth did not counteract this protective effect. However at times of year when predator activity diminishes and conducive environmental conditions develop, negative effects of Caulerpa habitat such as hypoxia and lowered flow may dominate. Under such situations, poor clam condition accentuates Anadara's susceptibility to mortality. Ultimately, a slight and inconsistent positive effect of Caulerpa to protect Anadara from predators is exceeded by the strong negative effect of Caulerpa on clam mortality, which is heightened by clams' weakened condition produced by chronic exposure to Caulerpa. Our results show that invasive habitat-modifying species can affect mortality of native species not simply through obvious positive direct effects of their protective structure, but indirectly through contrasting negative modification of the traits of prey species responding to the habitat.


Dysmorphic Facial Features and Other Clinical Characteristics in Two Patients with PEX1 Gene Mutations.
Peroxisomal disorders are a group of genetically heterogeneous metabolic diseases related to dysfunction of peroxisomes. Dysmorphic features, neurological abnormalities, and hepatic dysfunction can be presenting signs of peroxisomal disorders. Here we presented dysmorphic facial features and other clinical characteristics in two patients with PEX1 gene mutation. Follow-up periods were 3.5 years and 1 year in the patients. Case I was one-year-old girl that presented with neurodevelopmental delay, hepatomegaly, bilateral hearing loss, and visual problems. Ophthalmologic examination suggested septooptic dysplasia. Cranial magnetic resonance imaging (MRI) showed nonspecific gliosis at subcortical and periventricular deep white matter. Case II was 2.5-year-old girl referred for investigation of global developmental delay and elevated liver enzymes. Ophthalmologic examination findings were consistent with bilateral nystagmus and retinitis pigmentosa. Cranial MRI was normal. Dysmorphic facial features including broad nasal root, low set ears, downward slanting eyes, downward slanting eyebrows, and epichantal folds were common findings in two patients. Molecular genetic analysis indicated homozygous novel IVS1-2A>G mutation in Case I and homozygous p.G843D (c.2528G>A) mutation in Case II in the PEX1 gene. Clinical findings and developmental prognosis vary in PEX1 gene mutation. Kabuki-like phenotype associated with liver pathology may indicate Zellweger spectrum disorders (ZSD).


Estimation of cloud top heights from satellite imagery.
Light coming from a cloud to the detector of a multispectral satellite (Landsat) consists of light reflected from the cloud and light scattered by the layer of atmosphere between the cloud and satellite. Because of the strong wavelength dependence of Rayleigh scattering, the comparison of the signals in two spectral channels allows one to find the thickness of the scattering layer and hence the height of the cloud top.


SNP discovery in European anchovy (Engraulis encrasicolus, L) by high-throughput transcriptome and genome sequencing.
Increased throughput in sequencing technologies has facilitated the acquisition of detailed genomic information in non-model species. The focus of this research was to discover and validate SNPs derived from the European anchovy (Engraulis encrasicolus) transcriptome, a species with no available reference genome, using next generation sequencing technologies. A cDNA library was constructed from four tissues of ten fish individuals corresponding to three populations of E. encrasicolus, and Roche 454 GS FLX Titanium sequencing yielded 19,367 contigs. Additionally, the European anchovy genome was sequenced for the same ten individuals using an Illumina HiSeq2000. Using a computational pipeline for combining transcriptome and genome information, a total of 18,994 SNPs met the necessary minor allele frequency and depth filters. A series of further stringent filters were applied to identify those SNPs likely to succeed in genotyping assays, and for filtering of those in potential duplicated genome regions. A novel method for detecting potential intron-exon boundaries in areas of putative SNPs has also been applied in silico to improve genotyping success. In all, 2,317 filtered putative transcriptome SNPs suitable for genotyping primer design were identified. From those, a subset of 530 were selected, with the genotyping results showing the highest reported conversion and validation rates (91.3% and 83.2%, respectively) reported to date for a non-model species. This study represents a promising strategy to discover genotypable SNPs in the exome of non-model organisms. The genomic resource generated for E. encrasicolus, both in terms of sequences and novel markers, will be informative for research into this species with applications including traceability studies, population genetic analyses and aquaculture.


The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications.
This paper puts the case for the hippocampus as being central to the neuropathology and pathophysiology of schizophrenia. The evidence comes from a range of approaches, both in vivo (neuropsychology, structural and functional imaging) and post mortem (histology, morphometry, gene expression, and neurochemistry). Neuropathologically, the main positive findings concern neuronal morphology, organisation, and presynaptic and dendritic parameters. The results are together suggestive of an altered synaptic circuitry or "wiring" within the hippocampus and its extrinsic connections, especially with the prefrontal cortex. These changes plausibly represent the anatomical component of the aberrant functional connectivity that underlies schizophrenia. Glutamatergic pathways are prominently but not exclusively affected. Changes appear somewhat greater in the left hippocampus than the right, and CA1 is relatively uninvolved compared to other subfields. Hippocampal pathology in schizophrenia may be due to genetic factors, aberrant neurodevelopment, and/or abnormal neural plasticity; it is not due to any recognised neurodegenerative process. Hippocampal involvement is likely to be associated with the neuropsychological impairments of schizophrenia rather than with its psychotic symptoms.


Comparative Genomics Provides Insights Into the Marine Adaptation in Sponge-Derived Kocuriaflava S43.
Sponge-derived actinomycetes represent a significant component of marine actinomycetes. Members of the genus Kocuria are distributed in various habitats such as soil, rhizosphere, clinical specimens, marine sediments, and sponges, however, to date, little is known about the mechanism of their environmental adaptation. Kocuria flava S43 was isolated from a coastal sponge. Phylogenetic analysis revealed that it was closely related to the terrestrial airborne K. flava HO-9041. In this study, to gain insights into the marine adaptation in K. flava S43 we sequenced the draft genome for K. flava S43 by third generation sequencing (TGS) and compared it with those of K. flava HO-9041 and some other Kocuria relatives. Comparative genomics and phylogenetic analyses revealed that K. flava S43 might adapt to the marine environment mainly by increasing the number of the genes linked to potassium homeostasis, resistance to heavy metals and phosphate metabolism, and acquiring the genes associated with electron transport and the genes encoding ATP-binding cassette (ABC) transporter, aquaporin, and thiol/disulfide interchange protein. Notably, gene acquisition was probably a primary mechanism of environmental adaptation in K. flava S43. Furthermore, this study also indicated that the Kocuria isolates from various marine and hyperosmotic environments possessed common genetic basis for environmental adaptation.


Cognitive and language skills of Turkish children in Germany: a comparison of the second and third generation and mixed generational groups.
The paper compares several generational groups of Turkish children in Germany with respect to cognitive skills and German language skills at an early age. Empirically, children of inter-marriages outperform the other groups of Turkish children in both tests while children with a first generation mother and a second generation father score worse than all others. All group differences regarding children's cognitive skills can be explained by the families' socio-economic status and educational resources. In contrast, with respect to children's language skills also parents' endowment with receiving country specific resources (e.g., parental German language proficiency) needs to be taken into account.


Suicidal or self-harming ideation in military personnel transitioning to civilian life.
Suicides have markedly increased among military personnel in recent years. We used path analysis to examine factors associated with suicidal/self-harming ideation among male Navy and Marine Corps personnel transitioning to civilian life. Roughly 7% of men (Sailors = 5.3%, Marines = 9.0%) reported ideation during the previous 30 days. Results suggest that combat exposure, substance abuse, and resilience are associated with suicidal ideation/self-harming thoughts through the mediation of posttraumatic stress disorder symptoms and/or depression symptoms. Substance abuse plays a moderating role. Resilience had a direct effect only among the Marines. Implications for improving the transition to civilian life are discussed.


Characteristics and survival of young adults who started renal replacement therapy during childhood.
Little is known about the group of children on renal replacement therapy (RRT) who reach the age of 18 years and are transferred from paediatric to adult nephrology services. The aim of this study was to describe patient demographics, primary renal diseases, treatment history and determine the risk factors for mortality of these young adults who started RRT in childhood. We included 1777 young adults who had started RRT during childhood and turned 18 between 1985 and 2004 from nine European renal registries submitting data to the ERA-EDTA Registry. The chi-square test was used to test differences between patient groups and Cox regression analysis to examine patient survival. Young adults who began RRT during childhood increased the total number of adult patients starting RRT by 1.5% per annum. The annual number of children on RRT turning 18, per million persons (Pmarp) reaching the age of 18 years, increased between 1985 and 2004 from 71 to 116. Over time, there was an increase in the percentage of young adults who started RRT at a very young age, a greater number of children with hypoplasia/dysplasia and cystic kidneys and more young adults who started RRT with peritoneal dialysis or pre-emptive transplantation. The unadjusted 5-year patient survival from the 18th birthday was 95.1% (95% CI 93.9-96.0). The average life expectancy was 63 years for young adults with a functioning graft and 38 years for those remaining on dialysis. The number Pmarp of young adults on RRT has increased over time. Their characteristics and treatment history changed. Their survival prospects are good; however, transplant recipients have an expected remaining lifetime that is at least twice as high as for young adults on dialysis.


The mcp element from the Drosophila melanogaster bithorax complex mediates long-distance regulatory interactions.
In the studies reported here, we have examined the properties of the Mcp element from the Drosophila melanogaster bithorax complex (BX-C). We have found that sequences from the Mcp region of BX-C have properties characteristic of Polycomb response elements (PREs), and that they silence adjacent reporters by a mechanism that requires trans-interactions between two copies of the transgene. However, Mcp trans-regulatory interactions have several novel features. In contrast to classical transvection, homolog pairing does not seem to be required. Thus, trans-regulatory interactions can be observed not only between Mcp transgenes inserted at the same site, but also between Mcp transgenes inserted at distant sites on the same chromosomal arm, or even on different arms. Trans-regulation can even be observed between transgenes inserted on different chromosomes. A small 800-bp Mcp sequence is sufficient to mediate these long-distance trans-regulatory interactions. This small fragment has little silencing activity on its own and must be combined with other Polycomb-Group-responsive elements to function as a "pairing-sensitive" silencer. Finally, this pairing element can also mediate long-distance interactions between enhancers and promoters, activating mini-white expression.


Thermodynamics-based metabolic flux analysis.
A new form of metabolic flux analysis (MFA) called thermodynamics-based metabolic flux analysis (TMFA) is introduced with the capability of generating thermodynamically feasible flux and metabolite activity profiles on a genome scale. TMFA involves the use of a set of linear thermodynamic constraints in addition to the mass balance constraints typically used in MFA. TMFA produces flux distributions that do not contain any thermodynamically infeasible reactions or pathways, and it provides information about the free energy change of reactions and the range of metabolite activities in addition to reaction fluxes. TMFA is applied to study the thermodynamically feasible ranges for the fluxes and the Gibbs free energy change, Delta(r)G', of the reactions and the activities of the metabolites in the genome-scale metabolic model of Escherichia coli developed by Palsson and co-workers. In the TMFA of the genome scale model, the metabolite activities and reaction Delta(r)G' are able to achieve a wide range of values at optimal growth. The reaction dihydroorotase is identified as a possible thermodynamic bottleneck in E. coli metabolism with a Delta(r)G' constrained close to zero while numerous reactions are identified throughout metabolism for which Delta(r)G' is always highly negative regardless of metabolite concentrations. As it has been proposed previously, these reactions with exclusively negative Delta(r)G' might be candidates for cell regulation, and we find that a significant number of these reactions appear to be the first steps in the linear portion of numerous biosynthesis pathways. The thermodynamically feasible ranges for the concentration ratios ATP/ADP, NAD(P)/NAD(P)H, and H(extracellular)(+)/H(intracellular)(+) are also determined and found to encompass the values observed experimentally in every case. Further, we find that the NAD/NADH and NADP/NADPH ratios maintained in the cell are close to the minimum feasible ratio and maximum feasible ratio, respectively.


Nonhuman primate models to evaluate vaccine safety and immunogenicity.
When considering preclinical studies to evaluate the safety and immunogenicity of putative vaccine candidates, such as nucleic acid vaccines, species most closely related to humans should be considered. Phylogenetically, the great apes (chimpanzees, orangutans, gorillas, and gibbons) are most closely related to humans. However, the great apes, which diverged from humans over 5 million years ago, represent endangered or threatened species that limits their utility in preclinical studies. In addition, cost considerations for using great apes in biomedical studies represents another serious limitation. The Old World monkeys, (macaques, baboons, mandrills, and mangabeys), diverged from humans over 15 million years ago. A number of the Old World monkey species including rhesus, cynomolgus, and African green monkeys, have also been employed in biomedical research to evaluate vaccine safety and immunogenicity. New World monkeys (aotus, owl, cebus monkeys, and marmosets) are the most phylogenetically divergent from humans, yet they have also been utilized to develop nonhuman primate models for a number of human infectious diseases and tumors. The advantages and disadvantages in selecting a particular nonhuman primate species for studies to evaluate DNA vaccine safety and immunogenicity are briefly discussed. Comparative immunology, reproductive physiology, endogenous infectious agents, and cost considerations are briefly described.


Follow-up testing for ketonuria. Is it necessary?
The authors examined the utility of confirming positive urinary ketones detected by Multistix and the designation of trace ketonuria by Acetest. They also studied whether ketonuria should signal a need for microscopic evaluation. They used Multistix to test for ketones in 4345 urine samples; 108 samples tested positive and were retested using Acetest. The positive predictive value for Multistix was 98% for samples of small amounts or more of ketonuria. Sensitivity and specificity were then assessed on 179 samples tested prospectively by both methods. Multistix specificity was high at 96%, but sensitivity decreased from 87.5% to 63.6% when trace ketonuria was regarded as positive ketonuria. In evaluating the usefulness of positive ketonuria to signal a need for microscopic examination, the authors found 12% of 78 ketotic, but otherwise negative, samples demonstrated positive microscopic findings compared with 15% for 114 chemically negative controls. The authors concluded that using Acetest for confirmation is necessary only for trace ketonuria by Multistix and that confirmatory testing of higher levels of ketonuria incurs increased costs without adding significantly to patient care. Using more sensitive Acetest detection levels does not change these results. In addition, ketonuria does not appear to signal a need for further microscopic evaluation.


The new agreement of the international RIGA consensus conference on nasal airway function tests.
The report reflects an agreement based on the consensus conference of the International Standardization Committee on the Objective Assessment of the Nasal Airway in Riga, 2nd Nov. 2016. The aim of the conference was to address the existing nasal airway function tests and to take into account physical, mathematical and technical correctness as a base of international standardization as well as the requirements of the Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. Rhinomanometry, acoustic rhinometry, peak nasal inspiratory flow, Odiosoft-Rhino, optical rhinometry, 24-h measurements, computational fluid dynamics, nasometry and the mirrow test were evaluated for important diagnostic criteria, which are the precision of the equipment including calibration and the software applied; validity with sensitivity, specificity, positive and negative predictive values, reliability with intra-individual and inter-individual reproducibility and responsiveness in clinical studies. For rhinomanometry, the logarithmic effective resistance was set as the parameter of high diagnostic relevance. In acoustic rhinometry, the area of interest for the minimal cross-sectional area will need further standardization. Peak nasal inspiratory flow is a reproducible and fast test, which showed a high range of mean values in different studies. The state of the art with computational fluid dynamics for the simulation of the airway still depends on high performance computing hardware and will, after standardization of the software and both the software and hardware for imaging protocols, certainly deliver a better understanding of the nasal airway flux.


Thermodynamics of viscous flow and elasticity of glass forming liquids in the glass transition range.
The elastic moduli of glasses from different chemical systems, including oxide, chalcogenide, oxynitride, and metallic, were investigated through the glass transition (T(g)), typically from 0.4 to 1.3 T(g). These data were used to interpret the temperature sensitivity of the shear viscosity coefficient obtained on the same materials. The relevant Gibbs free activation energy was estimated from the apparent heat of flow by means of the temperature dependence of the shear elastic modulus. The activation entropy associated with the viscous flow was also derived and was found to correlate with the fragile versus strong character of the glass forming liquids. Finally, the physicochemistry of the flow process was described on the basis of the glass network de-structuration which shows up through the temperature dependence of Poisson's ratio, and an expression for the shear viscosity coefficient is proposed which is chiefly based on the high temperature elastic behavior.


Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates.
The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low. Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.


Tocotrienol supplementation improves late-phase fracture healing compared to alpha-tocopherol in a rat model of postmenopausal osteoporosis: a biomechanical evaluation.
This study investigated the effects of α-tocopherol and palm oil tocotrienol supplementations on bone fracture healing in postmenopausal osteoporosis rats. 32 female Sprague-Dawley rats were divided into four groups. The first group was sham operated (SO), while the others were ovariectomised. After 2 months, the right femora were fractured under anesthesia and fixed with K-wire. The SO and ovariectomised-control rats (OVXC) were given olive oil (vehicle), while both the alpha-tocopherol (ATF) and tocotrienol-enriched fraction (TEF) groups were given alpha-tocopherol and tocotrienol-enriched fraction, respectively, at the dose of 60 mg/kg via oral gavages 6 days per week for 8 weeks. The rats were then euthanized and the femora dissected out for bone biomechanical testing to assess their strength. The callous of the TEF group had significantly higher stress parameter than the SO and OVXC groups. Only the SO group showed significantly higher strain parameter compared to the other treatment groups. The load parameter of the OVXC and ATF groups was significantly lower than the SO group. There was no significant difference in the Young's modulus between the groups. In conclusion, tocotrienol is better than α-tocopherol in improving the biomechanical properties of the fracture callous in postmenopausal osteoporosis rat model.


The Vibrio cholerae Minor Pilin TcpB Initiates Assembly and Retraction of the Toxin-Coregulated Pilus.
Type IV pilus (T4P) systems are complex molecular machines that polymerize major pilin proteins into thin filaments displayed on bacterial surfaces. Pilus functions require rapid extension and depolymerization of the pilus, powered by the assembly and retraction ATPases, respectively. A set of low abundance minor pilins influences pilus dynamics by unknown mechanisms. The Vibrio cholerae toxin-coregulated pilus (TCP) is among the simplest of the T4P systems, having a single minor pilin TcpB and lacking a retraction ATPase. Here we show that TcpB, like its homolog CofB, initiates pilus assembly. TcpB co-localizes with the pili but at extremely low levels, equivalent to one subunit per pilus. We used a micropillars assay to demonstrate that TCP are retractile despite the absence of a retraction ATPase, and that retraction relies on TcpB, as a V. cholerae tcpB Glu5Val mutant is fully piliated but does not induce micropillars movements. This mutant is impaired in TCP-mediated autoagglutination and TcpF secretion, consistent with retraction being required for these functions. We propose that TcpB initiates pilus retraction by incorporating into the growing pilus in a Glu5-dependent manner, which stalls assembly and triggers processive disassembly. These results provide a framework for understanding filament dynamics in more complex T4P systems and the closely related Type II secretion system.


A new formulation of protein evolutionary models that account for structural constraints.
Despite the importance of a thermodynamically stable structure with a conserved fold for protein function, almost all evolutionary models neglect site-site correlations that arise from physical interactions between neighboring amino acid sites. This is mainly due to the difficulty in formulating a computationally tractable model since rate matrices can no longer be used. Here, we introduce a general framework, based on factor graphs, for constructing probabilistic models of protein evolution with site interdependence. Conveniently, efficient approximate inference algorithms, such as Belief Propagation, can be used to calculate likelihoods for these models. We fit an amino acid substitution model of this type that accounts for both solvent accessibility and site-site correlations. Comparisons of the new model with rate matrix models and alternative structure-dependent models demonstrate that it better fits the sequence data. We also examine evolution within a family of homohexameric enzymes and find that site-site correlations between most contacting subunits contribute to a higher likelihood. In addition, we show that the new substitution model has a similar mathematical form to the one introduced in Rodrigue et al. (Rodrigue N, Lartillot N, Bryant D, Philippe H. 2005. Site interdependence attributed to tertiary structure in amino acid sequence evolution. Gene 347:207-217), although with different parameter interpretations and values. We also perform a statistical analysis of the effects of amino acids at neighboring sites on substitution probabilities and find a significant perturbation of most probabilities, further supporting the significant role of site-site interactions in protein evolution and motivating the development of new evolutionary models similar to the one described here. Finally, we discuss possible extensions and applications of the new substitution model.


Impact of human migrations on diversity of Helicobacter pylori in Cambodia and New Caledonia.
Helicobacter pylori is a major gastric bacterial pathogen, presumed to have established itself in the human stomach approximately 100,000 years ago. Helicobacter pylori co-evolved with its host, and human migrations shaped the expansion and the diversity of strains around the world. Here, we investigated the population structure and the genomic diversity of H. pylori in New Caledonia and Cambodia, where humans of different origins are living. Both multilocus sequence typing (MLST) and macro-array experiments were performed to assess polymorphism of housekeeping genes and to compare differences in gene contents among strains of H. pylori. The macro-array analysis based on variations of the flexible gene pools was consistent with the contribution of ancestral H. pylori populations to modern strains. Most of the CDS variably present encode proteins of unknown function, selfish DNA, and transposases. In New Caledonia-where humans are of several ethnic origins-strains belonged to four different genetic populations, reflecting the diversity of human populations. Melanesians and Polynesians were infected mainly by strains assigned to hspMaori, whereas Caucasians were infected by hspWAfrica, hpEurope, and hpNEAfrica strains. In contrast, strains from Khmer patients belonged to only two subpopulations: hspEAsia and hpEurope. In the two countries, both ancient and recent human migrations may have influenced the diversity of H. pylori. Our present results are consistent with the possibility of admixture of strains in multiethnic communities. This increases the global polymorphism of H. pylori without evidence of functional change or impact on fitness and virulence.


Evaluation of a nonisotopic DNA assay kit for diagnosing Plasmodium falciparum malaria in Madagascar.
This study evaluated a nonisotopic DNA assay kit for diagnosing Plasmodium falciparum malaria in an area of Madagascar where all Plasmodium species of human malaria are present and where malaria is endemic. Blood samples from 440 healthy children and 20 healthy adults were processed and assayed in a single day in a blind protocol. The parasitemia levels of the four Plasmodium species were determined by microscopic examinations and by counts of numbers of malaria parasites per 1,000 white blood cells. Relative to P. falciparum infections, the DNA assay results agreed with those of microscopy for 207 positive and 239 negative samples; two samples were scored as positive by the DNA probe that were not detected by microscopy, and 12 samples were scored as positive by microscopy but were not detected by the assay. Relative to microscopy, the sensitivity of the assay was 95%, the specificity was 99%, and the effective sensitivity threshold of the DNA probe assay was approximately 30 parasites/mm3 of blood. The assay did not detect infections with either P. vivax, P. malariae, or P. ovale alone, but detected mixed infections of P. falciparum with either P. vivax or P. ovale. With this nonisotopic DNA probe assay, we were able to process large numbers of samples efficiently and to detect P. falciparum malaria infections with high sensitivity and specificity in a population that did not display overt disease symptoms.


Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass.
Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.


Unsupervised identification of the internal states that shape natural behavior.
Internal states shape stimulus responses and decision-making, but we lack methods to identify them. To address this gap, we developed an unsupervised method to identify internal states from behavioral data and applied it to a dynamic social interaction. During courtship, Drosophila melanogaster males pattern their songs using feedback cues from their partner. Our model uncovers three latent states underlying this behavior and is able to predict moment-to-moment variation in song-patterning decisions. These states correspond to different sensorimotor strategies, each of which is characterized by different mappings from feedback cues to song modes. We show that a pair of neurons previously thought to be command neurons for song production are sufficient to drive switching between states. Our results reveal how animals compose behavior from previously unidentified internal states, which is a necessary step for quantitative descriptions of animal behavior that link environmental cues, internal needs, neuronal activity and motor outputs.


Age related changes in biochemical markers of bone metabolism in horses.
Biochemical markers of bone metabolism were analysed in serum samples obtained from 60 horses with no history of orthopaedic disease (age 3 months-20 years). Serum levels of the carboxyterminal propeptide of type I procollagen (PICP), a marker of bone formation and the pyridinoline cross linked telopeptide domain of type I collagen (ICTP), a putative marker of bone resorption, were measured by radioimmunoassay (RIA). Serum levels of the bone specific isoenzyme of alkaline phosphatase (BALP), another marker of bone formation, were measured by a wheatgerm agglutinin affinity (WGA) method. Total alkaline phosphatase levels were also determined. Serum levels of PICP were significantly correlated with bone ALP (r = 0.78, P < 0.0001) and ICTP (r = 0.87, P < 0.0001). ICTP levels also correlated significantly with bone ALP (r = 0.81, P < 0.0001). However, total alkaline phosphatase did not correlate significantly with PICP, ICTP and BALP in horses over 1 year of age. There was an inverse correlation between serum levels of all biochemical markers and age of animals, with the most significant changes seen over the first 2 years. In animals less than 1 year of age, the reference ranges (mean +/- s.d. 1.96) were as follows: PICP 1216-2666 micrograms/l, ICTP 13.8-26.7 micrograms/l, bone ALP 134-288 u/l and total ALP 223-498 u/l. In 2-year-olds, the equivalent reference ranges were: PICP 550-1472 micrograms/l, ICTP 7.96-22.8 micrograms/l, bone ALP 32.7-125 u/l and total ALP 134-238 u/l.(ABSTRACT TRUNCATED AT 250 WORDS)


United Kingdom Prospective Diabetes Study. III. Prevalence of hypertension and hypotensive therapy in patients with newly diagnosed diabetes. A multicenter study.
We measured the blood pressure of 1226 patients with newly diagnosed maturity-onset diabetes, age 25 to 65 years (mean 52 years), mean fasting plasma glucose 11.4 mmol/L. Forty percent of males and 53% of females had hypertension by the World Health Organization criteria of either having blood pressure more than 160/95 mm Hg or receiving hypotensive therapy. Male patients were less obese than female patients (21% and 40% over ideal weight respectively) and a mean 1.3 years younger. Blood pressure was higher in women than men, but it was not significantly greater if age and obesity were taken into account. Twenty-three percent of men and 42% of women had already been informed they were hypertensive, and 12% of men and 26% of women were already receiving hypotensive therapy. The prevalence of hypertension in diabetic white patients was greater than that reported in a sex- and age-matched healthy population. The blood pressure of those taking diuretics was not significantly greater than that of untreated patients, but the 8% of men and 13% of women receiving other hypotensive drugs still had significantly higher blood pressure than the untreated patients. Both patients treated by diuretics and those treated by other hypotensive agents had significantly higher mean plasma urea and creatinine concentrations than untreated patients. This may have been induced by therapy, but one cannot exclude the possibility that treated patients already had renal impairment from diabetic, hypertensive, or other pathology.


Do patients with ulcerative colitis diagnosed at a young age have more severe disease activity than patients diagnosed when older?
To compare the clinical features and disease behavior of ulcerative colitis (UC) according to the age at onset. This retrospective study included 455 patients with UC who were diagnosed and treated between 1990 and 2008 at a single tertiary institution in Korea. The patients were divided into 2 groups according to their age at diagnosis of UC: an elderly group (>or=40 years) and a young group (<40 years). Clinical findings at diagnosis, extent of disease, treatment modalities used, cumulative admission rates, cumulative relapse rates, and surgery rates were analyzed according to these age groups. Two hundred and forty-two patients with UC (53.2%) were diagnosed before the age of 40 years. Disease severity at initial presentation as assessed by diarrhea frequency, the presence of pancolitis, and the use of steroids were higher in the young group; however, clinical disease course including cumulative admission rates, cumulative relapse rates, and surgery rates were not significantly different between the 2 groups. Certain clinical features and the extent of disease in UC patients appear to be more severe when the disease is diagnosed at younger age; however, their disease course and prognosis might not be different from those of their older counterparts.


Radiant properties of strong shock waves in argon.
Measurements of the visible radiation emitted by one dimensional, explosively generated, shock waves in argon initially at 1 atm are reported. A time-resolved spectrograph and calibrated photodetectors were used to measure the intensity of the source at 5450 A and 4050 A. The results show that explosive induced shock waves in argon having shock velocities in the range 8-9 mm/microusec radiate at these wavelengths like a blackbody having a temperature of approximately 23,000 degrees K.


Comparison of subjective and objective analgesic effects of intravenous and intrathecal morphine in chronic pain patients by heat beam dolorimetry.
The pain tolerance latencies of 10 chronic pain patients were evaluated by heat beam dolorimetry (stimulus intensity 15.33 mW.cm-2.sec-1) prior to and following administration of morphine by intrathecal (n = 5) or intravenous (n = 5) routes. Patients not undergoing opiate withdrawal evinced increased baseline pain tolerance latencies prior to drug administration compared with normal volunteers. Two patients undergoing the opiate withdrawal syndrome at the time of test experienced reduced pain tolerance latencies compared with normal volunteers, most probably corresponding to the hyperesthesia symptom of the syndrome. Intravenous morphine infusion (30 mg) induced a time-dependent increase in cutaneous pain tolerance with peak effect occurring 1-2 h after administration. This persisted for up to 4 h and thereafter declined. The time course of subjective pain self-report by visual pain analog scale (VPAS) measurements corresponded to the time course of increasing cutaneous pain tolerance latency assessed by dolorimetry. Pain self-reports following intrathecal morphine infusion (2.25 or 1 mg) followed a similar though slower onset to that reported by patients receiving intravenous morphine and was of lesser degree. In contrast, heat beam dolorimetric evidence of increased cutaneous pain tolerance (which was of lesser degree than following i.v. morphine) did not reach its maximum during the 4 h measuring period. A dissociation was noted therefore between the self-reported relief of endogenous pain and dolorimetrically measured cutaneous analgesia following intrathecal morphine administration. Linear regression correlation analysis characterized this phenomenon as a positive correlation between cutaneous pain tolerance and pain relief self-report following intravenous morphine infusion and a negative correlation following intrathecal administration. We propose that the phenomenon may be due to intrathecal morphine acting via two separate compartments: one spinal and one supraspinal.(ABSTRACT TRUNCATED AT 250 WORDS)


Cellular and molecular determinants of stroke-induced changes in subventricular zone cell migration.
A remarkable aspect of adult neurogenesis is that the tight regulation of subventricular zone (SVZ) neuroblast migration is altered after ischemic stroke and newborn neurons emigrate towards the injury. This phenomenon is an essential component of endogenous repair and also serves to illuminate normal mechanisms and rules that govern SVZ migration. Stroke causes inflammation that leads to cytokine and chemokine release, and SVZ neuroblasts that express their receptors are recruited. Metalloproteinases create pathways and new blood vessels provide a scaffold to facilitate neuroblast migration between the SVZ and the infarct. Most experiments have studied the peri-lesion parenchyma and relatively little is known about SVZ remodeling after stroke. Migration in the SVZ is tightly regulated by cellular interactions and molecular signaling; how are these altered after stroke to allow emigration? Do ependymal cells contribute to this process, given their reported neurogenic potential? How does stroke affect ependymal cell regulation of cerebrospinal fluid flow? Given the heterogeneity of SVZ progenitors, do all types of neuroblasts migrate out, or is this confined to specific subtypes of cells? We discuss these and other questions in our review and propose experiments to address them.


[Low publication of the papers presented at the Congresses of Gastroenterology Society of Peru 1998-2008].
To determine the proportion of abstracts presented at the Congreso Peruano de Gastroenterología (the major Peruvian gastroenterological scientific meeting), that had been published in scientific journals, the date of publication and its associated factors. Longitudinal retrospective and analytic study; the publicationrate of all the abstracts presented in the biennial Congreso Peruano de Gastroenterología between 1998 and 2008 was assessed. Google Scholar engine was used. The searching strategy performed included: ("Study location" AND "population studied" AND "main outcome") AND (autor:First OR autor:Second OR autor:Last). Logistic regression was used, considering p<0.05 statistically significant. Publication rate was 8.2% (34/217), statistically significant differences were found among meeting years (p<0.001). There were also differences between study design, objectives (more in analytic studies) and measurement (more in longitudinal studies (p<0.001). 82.4% were published in the Revista de Gastroenterología del Perú. The median time for publication was 10.8±10.4 months; this variable and the meeting year, study type, journal of publication or accordance between the abstract and publication characteristic showed no statistical differences. The mean authors' number was 5.02±2.4; analytic studies have less authors than the descriptive ones (3.6 vs 6.1; p=0.012). The Congreso Peruano de Gastroenterología presents a low publication rate of the abstracts presented, which can be used as a quality indicator of the abstracts and the reviewing process.