The relationship between peripherally matched invariant hues and unique hues: a cone-contrast approach.
A characteristic shift in hue and saturation occurs when colored targets are viewed peripherally compared with centrally. Four hues, one in each of the red, blue, green, and yellow regions of color space, remain unchanged when presented in the peripheral field. Apart from green, these peripherally invariant hues correspond almost exactly in color space with the unique hues. We explore this puzzling observation using asymmetric color-matching and color-naming experiments and computing cone contrasts for peripheral and central stimuli. We find that the difference between cone contrasts for the peripheral and central stimuli reaches a maximum at the chromatic axis corresponding to peripherally invariant green. We speculate that the effect is linked to a weakened signal from M-cones and probably associated with a reduced number of M-cones in peripheral retina.


Development of novel self-assembled polymeric micelles from partially hydrolysed poly(2-ethyl-2-oxazoline)-co-PEI-b-PCL block copolymer as non-viral vectors for plasmid DNA in vitro transfection.
A new efficient, non-viral gene delivery cationic polymeric micellar system was developed by partial hydrolysis of poly(2-ethyl-2-oxazoline) (PEtOx) with two different hydrolysis percentages of PEtOx (30% and 60%) to reduce the disadvantages of the PEI. These self-assemble amphiphilic cationic micelles prepared from poly(2-ethyl-2-oxazoline)30%-co-poly(ethyleneimine)-block-poly(ɛ-caprolactone) (PEtOx30%-co-PEI-b-PCL) (PPP30) and poly(2-ethyl-2-oxazoline) 60%-co-poly(ethyleneimine)-block-poly(ɛ-caprolactone) (PEtOx60%-co-PEI-b-PCL) (PPP60) block copolymers were successfully condensed with pEGFP-C3 plasmid DNA via electrostatic interactions to form micelle/DNA complexes with desirable particle sizes. All formulations showed low critical micelle concentration (CMC) values that means highly stable in serum containing medium. Polymeric micelles were also evaluated for their stability in the presence of serum and nuclease as well as cytotoxicity and transfection efficiency. All our results proved that our novel polymeric micellar system prepared by PPP60 block copolymer offer to be an efficient promising carrier for gene delivery applications. Moreover, these findings contribute to design and development of novel gene vectors with tunable and functionality features and also to reduce the cytotoxicity of PEI by partial hydrolysis of PEtOx an alternative synthesis method to produce linear PEI.


Radial and tangential neuronal migration pathways in the human fetal brain: anatomically distinct patterns of diffusion MRI coherence.
Corticogenesis is underpinned by a complex process of subcortical neuroproliferation, followed by highly orchestrated cellular migration. A greater appreciation of the processes involved in human fetal corticogenesis is vital to gaining an understanding of how developmental disturbances originating in gestation could establish a variety of complex neuropathology manifesting in childhood, or even in adult life. Magnetic resonance imaging modalities offer a unique insight into anatomical structure, and increasingly infer information regarding underlying microstructure in the human brain. In this study we applied a combination of high-resolution structural and diffusion-weighted magnetic resonance imaging to a unique cohort of three post-mortem fetal brain specimens, aged between 19 and 22 post-conceptual weeks. Specifically, we sought to assess patterns of diffusion coherence associated with subcortical neuroproliferative structures: the pallial ventricular/subventricular zone and subpallial ganglionic eminence. Two distinct three-dimensional patterns of diffusion coherence were evident: a clear radial pattern originating in ventricular/subventricular zone, and a tangentio-radial patterns originating in ganglionic eminence. These patterns appeared to regress in a caudo-rostral and lateral-ventral to medial-dorsal direction across the short period of fetal development under study. Our findings demonstrate for the first time distinct patterns of diffusion coherence associated with known anatomical proliferative structures. The radial pattern associated with dorsopallial ventricular/subventricular zone and the tangentio-radial pattern associated with subpallial ganglionic eminence are consistent with reports of radial-glial mediated neuronal migration pathways identified during human corticogenesis, supported by our prior studies of comparative fetal diffusion MRI and histology. The ability to assess such pathways in the fetal brain using MR imaging offers a unique insight into three-dimensional trajectories beyond those visualized using traditional histological techniques. Our results suggest that ex-vivo fetal MRI is a potentially useful modality in understanding normal human development and various disease processes whose etiology may originate in aberrant fetal neuronal migration.


Role of 5-HT₂C receptors in effects of monoamine releasers on intracranial self-stimulation in rats.
Many monoamine releasers are abused by humans and produce abuse-related facilitation of intracranial self-stimulation (ICSS) in rats. Facilitation of ICSS in rats can be limited by monoamine releaser-induced serotonin (5-HT) release, but receptors that mediate 5-HT effects of monoamine releasers are unknown. The aim of this study is to investigate whether 5-HT2C receptor activation is necessary for rate-decreasing effects produced in an ICSS procedure in rats by the 5-HT-selective monoamine releaser fenfluramine and the non-selective releasers napthylisopropylamine (PAL-287) and (+)-3,4-methylenedioxymethamphetamine ((+)-MDMA). Adult male Sprague-Dawley rats with electrodes implanted in the medial forebrain bundle were trained to lever press for brain stimulation under a "frequency-rate" ICSS procedure. Effectiveness of the 5-HT2C antagonist SB 242,084 was evaluated to block rate-decreasing effects produced by (1) the 5-HT2C agonist Ro 60-0175, (2) the 5-HT-selective releaser fenfluramine, and (3) the mixed-action dopamine (DA)/norepinephrine (NE)/5-HT releasers PAL-287 (1.0-5.6 mg/kg) and (+)-MDMA (1.0-3.2 mg/kg). For comparison, effectiveness of SB 242,084 to alter rate-decreasing effects of the kappa-opioid receptor agonist U69,593 and rate-increasing effects of the DA>5-HT releaser amphetamine was also examined. SB 242,084 pretreatment blocked rate-decreasing effects of Ro 60-0175 and fenfluramine, but not the rate-decreasing effects of U69,593 or the rate-increasing effects of amphetamine. SB 242,084 blunted the rate-decreasing effects and enhanced expression of rate-increasing effects of PAL-287 and (+)-MDMA. These data suggest that 5-HT2C receptor activation contributes to rate-decreasing effects that are produced by selective and mixed-action 5-HT releasers in rats and that may oppose and limit the expression of abuse-related ICSS facilitation by these compounds.


Distinct developmental profiles in typical speech acquisition.
Three- to five-year-old children produce speech that is characterized by a high level of variability within and across individuals. This variability, which is manifest in speech movements, acoustics, and overt behaviors, can be input to subgroup discovery methods to identify cohesive subgroups of speakers or to reveal distinct developmental pathways or profiles. This investigation characterized three distinct groups of typically developing children and provided normative benchmarks for speech development. These speech development profiles, identified among 63 typically developing preschool-aged speakers (ages 36-59 mo), were derived from the children's performance on multiple measures. These profiles were obtained by submitting to a k-means cluster analysis of 72 measures that composed three levels of speech analysis: behavioral (e.g., task accuracy, percentage of consonants correct), acoustic (e.g., syllable duration, syllable stress), and kinematic (e.g., variability of movements of the upper lip, lower lip, and jaw). Two of the discovered group profiles were distinguished by measures of variability but not by phonemic accuracy; the third group of children was characterized by their relatively low phonemic accuracy but not by an increase in measures of variability. Analyses revealed that of the original 72 measures, 8 key measures were sufficient to best distinguish the 3 profile groups.


Genetic characterization of pilin glycosylation in Neisseria meningitidis.
Pili of Neisseria meningitidis are a key virulence factor, being the major adhesin of this capsulate organism and contributing to specificity for the human host. Pili are post-translationally modified by addition of an O-linked trisaccharide, Gal(beta1-4)Gal(alpha1-3)2,4-diacetimido-2,4,6-trideoxyhexose++ +. In a previous study the authors identified and characterized a gene, pglA, encoding a galactosyltransferase involved in pilin glycosylation. In this study a set of random genomic sequences from N. meningitidis strain MC58 was used to search for further genes involved in pilin glycosylation. Initially, an open reading frame was identified, and designated pglD (pilin glycosylation gene D), which was homologous to genes involved in polysaccharide biosynthesis. The region adjacent to this gene was cloned and nucleotide sequence analysis revealed two further genes, pglB and pglC, which were also homologous with genes involved in polysaccharide biosynthesis. Insertional mutations were constructed in pglB, pglC and pglD in N. meningitidis C311#3, a strain with well-defined LPS and pilin-linked glycan structures, to determine whether these genes had a role in the biosynthesis of either of these molecules. Analysis of these mutants revealed that there was no alteration in the phenotype of LPS in any of the mutant strains as judged by SDS-PAGE gel migration. In contrast, increased gel migration of the pilin subunit molecules of pglB, pglC and pglD mutants by Western analysis was observed. Pilin from each of the pglB, pglC and pglD mutants did not react with a terminal-galactose-specific stain, confirming that the gel migration differences were due to the alteration or absence of the pilin-linked trisaccharide structure in these mutants. In addition, antisera specific for the C311#3 trisaccharide failed to react with pilin from the pglB, pglC, pglD and galE mutants. Analysis of nucleotide sequence homologies has suggested specific roles for pglB, pglC and pglD in the biosynthesis of the 2,4-diacetimido-2,4,6-trideoxyhexose structure.


Effects of interferon alpha on human osteoprogenitor cell growth and differentiation in vitro.
The specific effects of interferon alpha (IFNalpha), on the differentiation pathways of human osteogenic cells are not known. The aim of this study was to investigate possible effects of IFNalpha on osteogenic development by investigating cell differentiation, colony formation (colony forming unit-fibroblastic, CFU-F), cell proliferation, and gene expression, in particular bone morphogenetic protein (BMP) expression, of human bone marrow osteoprogenitor cells. Human bone marrow fibroblasts were cultured with or without the addition of IFNalpha (5-1,000 IU/ml) in the presence and absence of dexamethasone (10 nM) and ascorbate (100 microM), which are agents known to affect osteogenic differentiation. IFNalpha produced a significant dose-dependent inhibition of cell proliferation and alkaline phosphatase specific activity at concentrations as low as 50 IU/ml. IFNalpha (50-1,000 IU/ml) inhibited the stimulation of alkaline phosphatase specific activity induced by ascorbate and dexamethasone. Examination of CFU-F showed dose- and time-dependent inhibitions of colony formation and reductions in both colony size and alkaline phosphatase-positive CFU-F colonies particularly at earlier times. Reactivity with an antibody specific for osteoprogenitors (HOP-26), was reduced in IFNalpha-treated cultures. Northern blot analysis showed a significant dose-dependent up-regulation of BMP-2 mRNA, estrogen receptor alpha mRNA and osteocalcin mRNA expression in ascorbate/dexamethasone cultures. In contrast, IFNalpha significantly inhibited BMP-2 mRNA expression in the absence of ascorbate and dexamethasone. In conclusion, IFNalpha inhibits human osteoprogenitor cell proliferation, CFU- F formation, HOP-26 expression, and alkaline phosphatase specific activity and modulates BMP-2 gene expression. These results suggest a role for IFNalpha in local bone turnover through the specific and direct modulation of osteoprogenitor proliferation and differentiation.


Intra- and interpersonal emotion regulation and adjustment symptoms in couples: The role of co-brooding and co-reappraisal.
Adult emotion regulation is not only occurring within the person but includes strategies that happen in social interactions and that are framed as co-regulating. The current study investigates the role of the interpersonal emotion regulation strategies of co-reappraisal and co-brooding in couples for adjustment disorder symptoms as the disorder will be outlined in the International Classification of Diseases-11 (ICD-11). Couples registered together in an online questionnaire study reporting whether or not they are adjusting to a major stressor that is psychologically challenging to them. In total, one hundred and forty-six participants (N = 73 male; N = 73 female) reported having experienced a major stressor in the last 12 months and were thus be identified as at risk for adjustment disorder. Those individuals at risk were assessed for adjustment disorder and depressive symptoms; intra- and interpersonal emotion regulation (co-/brooding, co-/reappraisal) were assessed not only in the individual at risk but also in the romantic partner. Regression-based dyadic analyses revealed that above and beyond intrapersonal emotion regulation, interpersonal co-brooding and for the female participants also co-reappraisal were significantly associated with symptoms of adjustment disorder and depression, standardized betas varied between .24 and .36, suggesting medium effect sizes. An association with the female partner's tendency to reappraise with fewer symptoms in the male partner at risk for adjustment disorder could also be observed. Co-brooding and co-reappraisal represent emotion regulation strategies that happen in social interaction and seem to play a relevant role in the context of adjustment disorders above and beyond the commonly assessed intrapersonal emotion regulation strategies.


Different functional loops between cerebral cortex and the subthalmic area in Parkinson's disease.
We investigate the extent to which functional circuits coupling cortical and subthalamic activity are multiple and segregated by frequency in untreated Parkinson's disease (PD). To this end, we recorded EEG and local field potentials (LFPs) from macroelectrodes inserted into the subthalamic nucleus area (SA) in nine awake patients following functional neurosurgery for PD. Patients were studied after overnight withdrawal of medication. Coherence between EEG and SA LFPs was apparent in the theta (3-7 Hz), alpha (8-13 Hz), lower beta (14-20 Hz) and upper beta (21-32 Hz) bands, although activity in the alpha and upper beta bands dominated. Theta coherence predominantly involved mesial and lateral areas, alpha and lower beta coherence the mesial and ipsilateral motor areas, and upper beta coherence the midline cortex. SA LFPs led EEG in the theta band. In contrast, EEG led the depth LFP in the lower and upper beta bands. SA LFP activity in the alpha band could either lead or lag EEG. Thus there are several functional sub-loops between the subthalamic area and cerebral cortical motor regions, distinguished by their frequency, cortical topography and temporal relationships. Tuning to distinct frequencies may provide a means of marking and segregating related processing, over and above any anatomical segregation of processing streams.


Increased expression of tissue factor and protease-activated receptor-1 does not correlate with thrombosis in human lung adenocarcinoma.
A correlation between cancer and hypercoagulability has been described for more than a century. Patients with cancer are at increased risk for thrombotic complications and the clotting initiator protein, tissue factor (TF), is possibly involved in this process. Moreover, TF may promote angiogenesis and tumor growth. In addition to TF, thrombin seems to play a relevant role in tumor biology, mainly through activation of protease-activated receptor-1 (PAR-1). In the present study, we prospectively studied 39 lung adenocarcinoma patients in relation to the tumor expression levels of TF and PAR-1 and their correlation with thrombosis outcome and survival. Immunohistochemical analysis showed TF positivity in 22 patients (56%), most of them in advanced stages (III and IV). Expression of PAR-1 was found in 15 patients (39%), most of them also in advanced stages (III and IV). Remarkably, no correlation was observed between the expression of TF or PAR-1 and risk for thrombosis development. On the other hand, patients who were positive for TF or PAR-1 tended to have decreased long-term survival. We conclude that immunolocalization of either TF or PAR-1 in lung adenocarcinoma may predict a poor prognosis although lacking correlation with thrombosis outcome.


In Amateur Athletes With Type 1 Diabetes, a 9-Day Period of Cycling at Moderate-to-Vigorous Intensity Unexpectedly Increased the Time Spent in Hyperglycemia, Which Was Associated With Impairment in Heart Rate Variability.
In type 1 diabetes, autonomic dysfunction may occur early as a decrease in heart rate variability (HRV). In populations without diabetes, the positive effects of exercise training on HRV are well-documented. However, exercise in individuals with type 1 diabetes, particularly if strenuous and prolonged, can lead to sharp glycemic variations, which can negatively impact HRV. This study explores the impact of a 9-day cycling tour on HRV in this population, with a focus on exercise-induced glycemic excursions. Twenty amateur athletes with uncomplicated type 1 diabetes cycled 1,500 km. HRV and glycemic variability were measured by heart rate and continuous glucose monitoring. Linear mixed models were used to test the effects of exercise on HRV, with concomitant glycemic excursions and subject characteristics considered as covariates. Nighttime HRV tended to decrease with the daily distance traveled. The more time the subjects spent in hyperglycemia, the lower the parasympathetic tone was. This result is striking given that hyperglycemic excursions progressively increased throughout the 9 days of the tour, and to a greater degree on the days a longer distance was traveled, while time spent in hypoglycemia surprisingly decreased. This phenomenon occurred despite no changes in insulin administration and a decrease in carbohydrate intake from snacks. In sports enthusiasts with type 1 diabetes, multiday prolonged exercise at moderate-to-vigorous intensity worsened hyperglycemia, with hyperglycemia negatively associated with parasympathetic cardiac tone. Considering the putative deleterious consequences on cardiac risks, future work should focus on understanding and managing exercise-induced hyperglycemia.


The reliability and validity of physiotherapist visual rating of dynamic pelvis and knee alignment in young athletes.
To investigate visual rating of pelvis and knee position in young athletes during lower extremity functional tests. Pelvis and knee alignment, in 23 athletes, was visually rated by 66 physiotherapists. Peak two-dimensional (2D) and three-dimensional (3D) kinematics were also quantified. Ratings were compared to consensus visual ratings of an expert panel. The consensus ratings were also compared to peak kinematics. Reliability was determined using percentage agreement (PA) and the first order agreement coefficient (AC1). Sensitivity, specificity, diagnostic odds ratio (DOR) and differences in kinematics between groups based on the expert visual ratings were calculated to assess rating validity. Mean intra-rater agreement was substantial (PA: 79-88%, AC1: 0.60-0.78). Inter-rater agreement ranged from fair to substantial (PA: 67-80%; AC1: 0.37-0.61). Sensitivity (≥80%) and specificity (≥50%) were acceptable for all tests except the Drop Jump. Experience (DOR 1.6-2.8 times better) and slower movement (4.9 times better) improved rating accuracy. Peak 3D and 2D kinematics were different between groups rated as having good versus poor alignment by the experts. Visual rating by physiotherapists is a valid tool for identifying young athletes with poor frontal plane dynamic pelvis and knee alignment.


Low-back pain, its origin and risk indicators.
Low-back pain is a common ailment. Much is known of the pain-sensitive structures of the low back, but for a patient with acute low-back pain the cause can rarely be defined. Although the biochemical properties of the intervertebral discs and their degenerative changes have been unraveled, it is difficult to distinguish between pathological degeneration and normal changes due to aging. As a consequence of the problems in diagnosing back diseases, the most common measure of low-back morbidity in epidemiologic studies has been the occurrence of symptoms. A wide spectrum of work- and individual-related factors have been found to be associated with low-back pain, but little is known about the extent to which these factors are etiologic and the extent to which they are symptom-precipitating or symptom-aggravating.


Synthesis and properties of porous polymers synthesized by Michael addition reactions of multi-functional acrylate, diamine, and dithiol compounds.
Porous polymers have been synthesized by Michael addition reactions of multi-functional acrylate and diamine or dithiol compounds. Aza-Michael addition reaction of multi-functional acrylate, trimethylolpropane propoxylate triacrylate (TPT) and hexamethylene diamine (HDA) in dimethyl sulfoxide (DMSO) successfully yielded the porous polymer. The porous structure was characterized by connected globules or co-continuous structure, and could be controlled by the reaction conditions. Mechanical properties of the porous polymers were investigated by compression test. The porous polymers with co-continuous structure showed higher Young's modulus than those with connected globules. The porous polymer absorbed some organic solvents, especially CHCl3. The porous polymer as prepared in DMSO state showed coloring induced by Christiansen filter effect depending on the reaction time and observation temperature. The thio-Michael addition reaction of TPT and 1,6-hexanedithiol (HDT) in DMSO using different base catalysts also yielded the porous polymer. The porous structure could be controlled by the catalysts amount when the reaction was initiated by a photo-base generator as the base catalyst. The present reaction systems make it possible to synthesize the porous polymers with simple process without phase separator.


Low incidence of hepatitis B e antigen seroconversion in patients treated with oral nucleos(t)ides in routine practice.
Treatment end-point of therapy for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) includes HBeAg seroconversion, which ranges from 15% to 22% after 1 year of oral nucleos(t)ides according to clinical trials. Our goal was to determine the incidence and predictors of HBeAg seroconversion in such patients in routine clinical practice because they may differ than reported rates. We conducted a retrospective cohort study of 333 consecutive treatment-naïve HBeAg-positive patients who were treated for CHB between 1/2000 and 6/2010 at three gastroenterology and liver clinics in the USA. Primary study end-point was HBeAg seroconversion-loss of HBeAg and antibody to HBeAg (anti-HBe) development. The majority of patients were Asian (96%). Median treatment duration prior to HBeAg seroconversion was 50 (range 26-52) weeks. Of the 333 study patients, 25% received lamivudine, 16% adefovir, 51% entecavir, and 8% tenofovir. HBeAg seroconversion at month 12 was 8.2%. On multivariate analysis inclusive of age, gender, and antiviral agents, independent predictors for HBeAg seroconversion at month 12 were hepatitis B virus DNA < 7.5 log10 IU/mL (hazard ratio [HR] = 2.59 [1.04-6.44]), P = 0.041) and alanine transaminase (ALT) > 1.5 × upper normal limit (HR = 2.86 [1.05-7.81], P = 0.040), but not the choice of nucleos(t)ides. The HBeAg seroconversion rate seen in clinical settings for oral nucleos(t)ides appears much lower than those reported in pivotal trials, especially in patients with lower ALT and higher HBV DNA levels. HBeAg-positive patients should be counseled about the high possibility of the long treatment duration required to achieve recommended treatment end-points.


Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains.
Most variants associated with complex phenotypes in genome-wide association studies (GWAS) do not directly index coding changes affecting protein structure. Instead they are hypothesized to influence gene regulation, with common variants associated with disease being enriched in regulatory domains including enhancers and regions of open chromatin. There is interest, therefore, in using epigenomic annotation data to identify the specific regulatory mechanisms involved and prioritize risk variants. We quantified lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - across the genome in entorhinal cortex samples using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). H3K27ac peaks were called using high quality reads combined across all samples and formed the basis of partitioned heritability analysis using LD score regression along with publicly-available GWAS results for seven psychiatric and neurodegenerative traits. Heritability for all seven brain traits was significantly enriched in these H3K27ac peaks (enrichment ranging from 1.09-2.13) compared to regions of the genome containing other active regulatory and functional elements across multiple cell types and tissues. The strongest enrichments were for amyotrophic lateral sclerosis (ALS) (enrichment = 2.19; 95% CI = 2.12-2.27), autism (enrichment = 2.11; 95% CI = 2.05-2.16) and major depressive disorder (enrichment = 2.04; 95% CI = 1.92-2.16). Much lower enrichments were observed for 14 non-brain disorders, although we identified enrichment in cortical H3K27ac domains for body mass index (enrichment = 1.16; 95% CI = 1.13-1.19), ever smoked (enrichment = 2.07; 95% CI = 2.04-2.10), HDL (enrichment = 1.53; 95% CI = 1.45-1.62) and trigylcerides (enrichment = 1.33; 95% CI = 1.24-1.42). These results indicate that risk alleles for brain disorders are preferentially located in regions of regulatory/enhancer function in the cortex, further supporting the hypothesis that genetic variants for these phenotypes influence gene regulation in the brain.


Aspirin better than clopidogrel on major adverse cardiovascular events reduction after ischemic stroke: A retrospective nationwide cohort study.
Several clinical trials reported that clopidogrel was superior to aspirin in secondary stroke prevention by reducing the risk of major adverse cardiovascular events (MACE). We aimed to compare the efficacy of clopidogrel with aspirin in reducing one-year risk of MACE based on real-world evidence from Taiwan Health Insurance Database. We identified ischemic stroke patients between 2000 and 2012 who took aspirin or clopidogrel within 7 days of stroke onset for 1-year follow-up. The primary outcome was one-year MACE including recurrent stroke, acute myocardial infarction, and death. Propensity score matching and conditional Cox proportional hazards regression were conducted to control the confounding factors. From 9,089 ischemic stroke patients, we found 654 patients on aspirin and 465 patients on clopidogrel who met the selective inclusion criteria. After propensity score matching, 379 patients were selected from each group. The clopidogrel group had a 1.78-fold MACE risk compared with the aspirin group at one-year follow-up (95% CI = 1.41-2.26, p<0.01). The MACE-free rate in the aspirin group was 15.74% higher than in the clopidogrel group at one-year follow-up. Sub-analysis of the three components of MACE showed that clopidogrel conferred higher risk of recurrent stroke (OR 1.43, 95% CI = 1.06-1.92, p 0.02) and acute myocardial infarction (OR 3.72, 95% CI = 1.04-13.3, p 0.04), but no different risk of death than that of aspirin. Among first-ever ischemic stroke patients, secondary stroke prevention using clopidogrel was associated with higher rates of MACE than aspirin. Aspirin might have better efficacy in secondary stroke prevention and was associated with lower risk of MACE. The real-world evidence raises the need to re-assess the current therapeutic options in secondary stroke prevention applying aspirin vs. clopidogrel.


Fabrication of living soft matter by symbiotic growth of unicellular microorganisms.
We report the fabrication of living soft matter made as a result of the symbiotic relationship of two unicellular microorganisms. The material is composed of bacterial cellulose produced in situ by acetobacter (Acetobacter aceti NCIMB 8132) in the presence of photosynthetic microalgae (Chlamydomonas reinhardtii cc-124), which integrates into a symbiotic consortium and gets embedded in the produced cellulose composite. The same concept of growing living materials can be applied to other symbiotic microorganism pairs similar to the combination of algae and fungi in lichens, which is widespread in Nature. We demonstrate the in situ growth and immobilisation of the C. reinhardtii cells in the bacterial cellulose matrix produced by the simultaneous growth of acetobacter. The effect of the growth media composition on the produced living materials was investigated. The microstructure and the morphology of the produced living biomaterials were dependent on the shape of the growth culture container and media stirring conditions, which control the access to oxygen. As the photosynthetic C. reinhardtii cells remain viable and produce oxygen as they spontaneously integrate into the matrix of the bacterial cellulose generated by the acetobacter, such living materials have the potential for various applications in bio-hydrogen generation from the immobilised microalgae. The proposed approach for building living soft matter can provide new ways of immobilising other commercially important microorganisms in a bacterial cellulose matrix as a result of symbiosis with acetobacter without the use of synthetic binding agents and in turn increase their production efficiency.


Macrophages elicited with heat-killed bacillus Calomette-Guérin protect C57BL/6J mice against a syngeneic melanoma.
We have demonstrated that a murine cytotoxic peritoneal cell can be elicited by intraperitoneal immunization with heat-killed Mycobacterium bovis, strain Bacillus Calmette-Guérin (BCG). When these cells are injected together with cells of clone B(5)59 of B16 melanoma in a Winn-type transfer assay into syngeneic C57BL/6J mice, the tumorigenic potential of the melanoma is completely abrogated. Similarly, mice immunized intraperitoneally with dead BCG are protected against intraperitoneal challenge with a number of B16 melanoma cells sufficient to cause tumors in 100% of control mice. However, mice immunized intraperitoneally with dead BCG are not protected against tumor formation when B16 melanoma cells are injected subcutaneously. Co-injection of BCG-elicited peritoneal cells with B16 melanoma cells into nude or sublethally irradiated (650 rad) mice inhibits tumor formation in > 85% of the mice, indicating that additional participation of host bone marrow- or thymus-derived leukocytes is not required to eradicate the tumor implant. The effector cell in the BCG-induced peritoneal exudate is adherent and phagocytic and is a mononuclear phagocyte. Nonadherent lymphoid cells from the same BCG-induced peritoneal exudate and from thioglycollate-broth-elicited granylocytes and macrophages neither prevent nor delay B16 tumor formation.


Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia.
Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.


First myocardial infarctions in Asian and white men.
To compare the presentation and natural course of first myocardial infarctions in immigrant Asians and the indigenous white population in Britain and the subsequent risk states of the two groups. Prospective ethnic comparison of consecutive patients with first myocardial infarctions. Secondary referrals to a coronary care unit of a district general hospital. 128 Men (77 white, 54 Asian) presenting consecutively with a first myocardial infarction diagnosed on the basis of clinical, biochemical, and electrocardiographic findings. Identification of mechanisms accounting for the increased rate of ischaemic heart disease in Asians. Infarct size was assessed by measuring the release of creatine phosphokinase (all patients), radionuclide ventriculography (50), and contrast ventriculography (103). Risk states after infarction were assessed from the degree of ventricular dysfunction as determined by exercise electrocardiography (82 patients) and from the extent of coronary atheroma as determined by coronary arteriography (103). Glucose state was measured in fasting venous blood samples. Overall the relative rate of infarction was 4.9 times higher in Asians (95% confidence interval 3.4 to 6.9) than in the white population. Moreover, the relative rate of infarction was higher in Asians in all 10 year age groups, the greatest difference being in 30-39 year olds. The mean age of the Asian denominator population was 47.1 years compared with 49.5 years in the white population. Age at infarction was less in Asians (50.2 years) than in white patients (55.5 years; mean difference 5.5 years (95% confidence interval 2.5 to 7.1]. In Asians the mean creatine phosphokinase activity was 777 (95% confidence interval 155 to 1399) U/1 higher, radionuclide ejection fraction 8.9% (1.0% to 16.9%) lower, and left ventricular fractional shortening 4.8% (1.4% to 8.2%) lower than in white patients. The extent of coronary atheroma was significantly greater in Asians. The mean numbers of plaques in vessels not associated with infarction were 3.66 (median 3.0, range 0-10) in Asians compared with 1.97 (median 2.0, range 0-6) in white patients (p less than 0.001), and a higher proportion of Asians had three vessel coronary artery disease (p less than 0.001). Asians with diabetes or impaired glucose tolerance did not differ from those with normal blood glucose values. Atherogenesis arises earlier in Asians, contributing to premature first myocardial infarctions. The increased incidence of diabetes in Asians may not in itself be relevant in the greater propensity to coronary atheroma in Asians.


Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis.
Global spread and limited genetic variation are hallmarks of M. tuberculosis, the agent of human tuberculosis. In contrast, Mycobacterium canettii and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology are restricted to East Africa. Here, we sequenced and analyzed the whole genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4-5× coverage), 454/Roche (13-18× coverage) and/or Illumina DNA sequencing (45-105× coverage). We show that STB isolates are highly recombinogenic and evolutionarily early branching, with larger genome sizes, higher rates of genetic variation, fewer molecular scars and distinct CRISPR-Cas systems relative to M. tuberculosis. Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse infection experiments showed that STB strains are less persistent and virulent than M. tuberculosis. We conclude that M. tuberculosis emerged from an ancestral STB-like pool of mycobacteria by gain of persistence and virulence mechanisms, and we provide insights into the molecular events involved.


A model that accounts for activity prior to sensory inputs and responses during matching-to-sample tasks.
Neural network models were examined during delayed matching-to-sample tasks (DMS), and neurons in a monkey's prefrontal cortex were studied during the performance of comparable tasks. In DMS, various input stimuli follow a sample stimulus, and an output should occur whenever the sample reappears. Our previous models have been restricted to certain kinds of inputs, outputs, and temporal patterns. Here, we generalized the models by training them on both spatial and nonspatial inputs, spatial and nonspatial outputs, and both fixed and variable interstimulus intervals. Two versions of DMS were presented to both the model and the monkey, both involving nonspatial samples: (1) Two stimuli simultaneously appeared at a variable interval after the sample; and (2) A series of single stimuli appeared at fixed intervals after the sample. Both versions required identical spatial responses, reflecting the direction (left or right) of the matching stimulus relative to a central origin. Thus, these two versions of DMS involved the same samples, memory, and responses, but established different response contexts. Our analysis focused on unit activity prior to stimuli, as well as that prior to responses, termed anticipatory and response-related activity, respectively. In both the model and the monkey, anticipatory activity occurred only for fixed interstimulus intervals. In the model, we could determine that anticipatory activity acted either like a filter to suppress inappropriate responses or it served to enhance the network's general readiness to respond. As for response-related activity, units in both the model and the monkey showed directional selectivity and had a strong dependence on response context. In the model, we could show that this activity contributed both to the suppression of inappropriate responses and to the generation of correct ones. None of the model's hidden units contributed exclusively to computing the direction of match output. Instead, their response-related activity contributed to the computation of both the match decision and the correct response direction.


Ancient hybridization patterns between bighorn and thinhorn sheep.
Whole-genome sequencing has advanced the study of species evolution, including the detection of genealogical discordant events such as ancient hybridization and incomplete lineage sorting (ILS). The evolutionary history of bighorn (Ovis canadensis) and thinhorn (Ovis dalli) sheep present an ideal system to investigate evolutionary discordance due to their recent and rapid radiation and putative secondary contact between bighorn and thinhorn sheep subspecies, specifically the dark pelage Stone sheep (O. dalli stonei) and predominately white Dall sheep (O. dalli dalli), during the last ice age. Here, we used multiple genomes of bighorn and thinhorn sheep, together with snow (O. nivicola) and the domestic sheep (O. aries) as outgroups, to assess their phylogenomic history, potential introgression patterns and their adaptive consequences. Among the Pachyceriforms (snow, bighorn and thinhorn sheep) a consistent monophyletic species tree was retrieved; however, many genealogical discordance patterns were observed. Alternative phylogenies frequently placed Stone and bighorn as sister clades. This relationship occurred more often and was less divergent than that between Dall and bighorn. We also observed many blocks containing introgression signal between Stone and bighorn genomes in which coat colour genes were present. Introgression signals observed between Dall and bighorn were more random and less frequent, and therefore probably due to ILS or intermediary secondary contact. These results strongly suggest that Stone sheep originated from a complex series of events, characterized by multiple, ancient periods of secondary contact with bighorn sheep.


Metabolic control as reflected by HbA1c in children, adolescents and young adults with type-1 diabetes mellitus: combined longitudinal analysis including 27,035 patients from 207 centers in Germany and Austria during the last decade.
While the central role of HbA1c levels for the prediction of micro- and macrovascular complications in patients with type 1 diabetes is generally accepted; recommendations in current guidelines and the level of metabolic control actually achieved during routine care differ widely. Limited information is available on factors that influence metabolic control in the pediatric age group and during the transition from pediatric to adult diabetes care. In a large prospective multicenter database (DPV-Wiss), 338,330 individual HbA1c measurements from 27,035 patients with type-1 diabetes (94,074 observation years) were recorded between 1995 and 2005. Data were anonymously transmitted from 207 institutions. HbA1c values were mathematically standardized to the DCCT normal range (4.05-6.05%). The SAS 9.1 software was used for statistical analysis using nonparametric statistics. Median HbA1c for all measurements was 7.8%, with a strong effect of diabetes duration: median HbA1c at onset was 9.1%, during the first 2 years of diabetes 7.1% with a subsequent increase to 7.9% in patients beyond the remission phase (>2 years, 20,314 patients); a strong age dependency was present. HbA1c above the recommended guidelines was found in 23%. For all age groups, girls/women had higher HbA1c values compared to boys (mean difference 0.1%, p<0.0001). Seasonal variation was remarkably small with the lowest HbA1c values in September (mean: 7.86%) and highest values in January (8.08%; p<0.0001). Some improvement in HbA1c was observed comparing three periods: 1995-1997, 1998-2000 and 2001-2005; after remission the median HbA1c decreases from 8.5% to 7.6%. In a multivariate model, a significant influence on HbA1c was detected for age (p<0001), duration of diabetes (p<0.0001), gender (p<0.02), minority status (p<0.0001), season (p<0.0001), treatment period (p<0.0001), insulin therapy (p<0.0001) and center effect (p<0.0001). Both patient-related and treatment-related variables have a strong influence on metabolic control achieved in pediatric and young adult patients with T1DM. In contrast to wide-spread belief, metabolic control is only marginally better in summer compared to winter. Some improvement in metabolic control was observed during the last 10 years.


Pretreatment serum levels of interferon-gamma-inducible protein-10 are associated with virologic response to telaprevir-based therapy.
Telaprevir (TVR) remarkably improves the efficacy of interferon treatment for chronic hepatitis C. Interleukin-28B (IL28B) genotype and interferon-gamma-inducible protein-10 (IP-10) level predict virologic response to peg-interferon (Peg-IFN)/ribavirin (RBV) therapy. We aimed to investigate the usefulness of pretreatment serum IP-10 levels and IL28B genotyping in predicting sustained virologic response (SVR) to TVR-based triple therapy. In this multi-center study, patients infected with hepatitis C virus genotype 1 with high viral load (⩾5.0logIU/mL) were treated with TVR for 12weeks and Peg-IFN/RBV for 24weeks in Japan. IL28B genotype, serum IP-10 levels, other clinical parameters, and drug dosages were assessed before treatment. We included 121 patients who were treated with TVR for at least 8weeks and Peg-IFN/RBV for 24weeks. The median IP-10 levels were significantly lower in rapid virologic response (RVR) or SVR in the IL28B non-TT genotype group, with no significant difference in the TT genotype group. RVR rates were significantly lower in the group with higher serum IP-10 levels (>450pg/mL). In the non-TT IL28B genotype group, RVR and SVR rates were significantly lower in the group with higher IP-10 levels. SVR rates in the group with lower IP-10 levels (<450pg/mL) increased to 82% for those showing RVR, but reduced to 27% in the group with higher IP-10 levels for those not showing RVR. Determination of serum IP-10 levels before treatment could be useful for predicting favorable virologic response to TVR-based triple therapy, especially in patients with IL28B non-TT genotype.


UV-induced hydrogen transfer in DNA base pairs promoted by dark nπ* states.
Dark nπ* states were shown to have substantial contribution to the destructive photochemistry of pyrimidine nucleobases. Based on quantum-chemical calculations, we demonstrate that the characteristic hydrogen bonding pattern of the GC base pair could facilitate the formation of a wobble excited-state charge-transfer complex. This entails a barrierless electron-driven proton transfer (EDPT) process which enables damageless photodeactivation of the base pair. These photostabilizing properties are retained even when guanine is exchanged to hypoxanthine. The inaccessibility of this process in the AT base pair sheds further light on the reasons why cytosine is less susceptible to the formation of photodimers in double-stranded DNA.


Use of simulated patient approach to assess the community pharmacists' knowledge of appropriate use of metered dose inhaler.
The pharmacist charged with the responsibility of drug administration and counseling should have the basic knowledge and skills necessary to demonstrate the use of metered dose inhalers (MDIs) to asthma patients for the maximization of treatment outcomes. This study was designed to evaluate the community pharmacists' knowledge of the appropriate use of MDIs in Anambra State, Nigeria. The study was carried out in two major cities in Anambra State, Nigeria, using 41 registered community pharmacists. A simulated patient approach utilizing two adequately trained pharmacy students were used. Obtained data were analyzed using independent t-test and one-way ANOVA through SPSS version 18. The pharmacists had a mean demonstration score of 45.45%. Step number seven of the correct use of MDI, which involves breathing in and depressing the canister was the most demonstrated step (90.2%) while step 4 which involves tilting the head back slightly was the least demonstrated (14.6%) by the pharmacists. Among five identified critical steps in asthma guideline used, two were well demonstrated (75.6% and 90.2%): one averagely demonstrated (51.2%) and two poorly demonstrated (39% and 31.7%). Sociodemographic characteristics did not influence the demonstration ability of the pharmacists in this study. The study indicated that community pharmacists lacked the adequate knowledge of appropriate use of MDI. Training programs for pharmacists focusing on the use of such devices will enable them to educate patients on the effective use of MDIs in patients with asthma.


Insights into Hox protein function from a large scale combinatorial analysis of protein domains.
Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.


Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis.
Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified. To investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes. These findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.


Inheritance of Hippocampal Place Fields Through Hebbian Learning: Effects of Theta Modulation and Phase Precession on Structure Formation.
A place cell is a neuron that fires whenever the animal traverses a particular location of the environment-the place field of the cell. Place cells are found in two regions of the rodent hippocampus: CA3 and CA1. Motivated by the anatomical connectivity between these two regions and by the evidence for synaptic plasticity at these connections, we study how a place field in CA1 can be inherited from an upstream region such as CA3 through a Hebbian learning rule, in particular, through spike-timing-dependent plasticity (STDP). To this end, we model a population of CA3 place cells projecting to a single CA1 cell, and we assume that the CA1 input synapses are plastic according to STDP. With both numerical and analytical methods, we show that in the case of overlapping CA3 input place fields, the STDP learning rule leads to the formation of a place field in CA1. We then investigate the roles of the hippocampal theta modulation and phase precession on the inheritance process. We find that theta modulation favors the inheritance and leads to faster place field formation whereas phase precession changes the drift of CA1 place fields over time.


The pediatrician and disaster preparedness.
For decades, emergency planning for natural disasters, public health emergencies, workplace accidents, and other calamities has been the responsibility of government agencies on all levels and certain nongovernment organizations such as the American Red Cross. In the case of terrorism, however, entirely new approaches to emergency planning are under development for a variety of reasons. Terrorism preparedness is a highly specific component of general emergency preparedness. In addition to the unique pediatric issues involved in general emergency preparedness, terrorism preparedness must consider several additional issues, including the unique vulnerabilities of children to various agents as well as the limited availability of age- and weight-appropriate antidotes and treatments. Although children may respond more rapidly to therapeutic intervention, they are at the same time more susceptible to various agents and conditions and more likely to deteriorate if they are not monitored carefully. This article is designed to provide an overview of key issues for the pediatrician with respect to disaster, terrorism, and public health emergency preparedness. It is not intended to be a complete compendium of didactic content but rather offers an approach to what pediatricians need to know and how pediatricians must lend their expertise to enhance preparedness in every community. To become fully and optimally prepared, pediatricians need to become familiar with these key areas of emergency preparedness: unique aspects of children related to terrorism and other disasters; terrorism preparedness; mental health vulnerabilities and development of resiliency; managing family concerns about terrorism and disaster preparedness; office-based preparedness; hospital preparedness; community, government, and public health preparedness; and advocating for children and families in preparedness planning.


Selective erasure of speckle-multiplexed holograms by use of a double Mach-Zehnder interferometric arrangement.
A novel method to selectively erase and update speckle-multiplexed holograms in photorefractive crystals by use of a double Mach-Zehnder (DMZ) interferometric arrangement is presented. The DMZ arrangement automatically produces a pair of pi-phase-shifted interference patterns used for holographic recording, erasure, and update operations with a fairly simple optical configuration that consists of a commonly used dielectric multilayer beam splitter and two mirrors. The recording and the erasure conditions required for erasing a photorefractive hologram quickly and completely are discussed by calculating the temporal property of the hologram buildup and decay using the time-dependent coupled-wave equations. An experiment is also performed, in which arbitrary holograms in speckle-multiplexed holograms are selectively erased and updated with the simple DMZ optical configuration.


GPU-based visualization and synchronization of 4-D cardiac MR and ultrasound images.
In minimally invasive image-guided interventions, different imaging modalities, such as magnetic resonance imaging (MRI), computed tomography (CT), and 3-D ultrasound (US), can provide complementary, multispectral image information. Dynamic image registration is a well-established approach that permits real-time diagnostic information to be enhanced by placing lower-quality real-time images within a high quality anatomical context. For the guidance of cardiac interventions, it would be valuable to register dynamic MRI or CT with intra-operative US. However, in practice, either the high computational cost prohibits such real-time visualization, or else the resulting image quality is not satisfactory for accurate interventional guidance. Modern graphics processing units (GPUs) provide the programmability, parallelism and increased computational precision to address this problem. In this paper, we first outline our research on dynamic 3-D cardiac MR and US image acquisition, real-time dual-modality registration and US tracking. Next, we describe our contributions on image processing and optimization techniques for 4-D (3-D + time) cardiac image rendering, and our GPU-accelerated methodologies for multimodality 4-D medical image visualization and optical blending, along with real-time synchronization of dual-modality dynamic cardiac images. Finally, multiple transfer functions, various image composition schemes, and an extended window-level setting and adjustment approach are proposed and applied to facilitate the dynamic volumetric MR and US cardiac data exploration and enhance the feature of interest of US image that is usually restricted to a narrow voxel intensity range.


Maternal caffeine intake during pregnancy and risk of pregnancy loss: a categorical and dose-response meta-analysis of prospective studies.
To assess the association between maternal caffeine intake and risk of pregnancy loss using a systematic review and meta-analysis. Categorical and dose-response meta-analysis of prospective studies. Relevant articles were identified by searching MEDLINE and SCOPUS databases through 30 January 2015. Two authors independently extracted information from eligible studies. Random-effects models were used to derive the summary relative risks (RR) and corresponding 95% CI for specific categories of caffeine consumption and for a continuous association using generalized least-squares trend estimation. A total of 130 456 participants and 3429 cases in fourteen included studies. Compared with the reference category with no or very low caffeine intake, the RR (95% CI) of pregnancy loss was 1·02 (0·85, 1·24; I(2)=28·3%) for low intake (50-149 mg/d), 1·16 (0·94, 1·41; I 2=49·6%) for moderate intake (150-349 mg/d), 1·40 (1·16, 1·68; I(2)=18·6%) for high intake (350-699 mg/d) and 1·72 (1·40, 2·13; I(2)=0·0%) for very high intake (≥ 700 mg/d). In the dose-response analysis, each 100 mg/d increment in maternal caffeine intake (~1 cup of coffee) was associated with 7% (95% CI 3%, 12%) higher risk of pregnancy loss. Our results may have been affected by publication bias, but the association remained significant for the subset of larger studies. Furthermore, adjustment for smoking and pregnancy symptoms may have been incomplete, potentially resulting in residual confounding. Albeit inconclusive, higher maternal caffeine intake was associated with a higher risk of pregnancy loss and adherence to guidelines to avoid high caffeine intake during pregnancy appears prudent.


Facial symmetry after closed and open treatment of fractures of the mandibular condylar process.
This study compares vertical measures of mandibular and facial morphology after open or closed treatment for fractures of the mandibular condylar process. One hundred forty-six patients (121 male, 25 female), 81 treated by closed and 65 by open methods, were included in this study. Towne's and panoramic radiographs, taken at several intervals, were used to quantify the displacement of the condylar process fractures. Posteroanterior cephalograms taken at 6 weeks, 6 months, 1 year, and 2 to 3 years after treatment were used to assess posterior facial height and bigonial and occlusal plane angles. Additionally, panoramic radiographs were used to assess ramus height at the same periods. Standard statistical methods were used to assess differences between groups. Patients whose condylar process fractures were treated by closed methods had significantly shorter posterior facial and ramus heights on the side of injury, and more tilting of the occlusal and bigonial planes toward the fractured side, than patients whose fractures were treated by open methods. Most of the asymmetry in patients treated by closed methods was present by 6 weeks after injury. Patients treated by closed methods develop asymmetries characterized by shortening of the face on the side of injury. It is likely that loss of posterior facial height on the side of fracture in these patients is an adaptation that helps reestablish a new temporomandibular articulation.


Economic evaluation in primary health care: the case of Western Kenya community based health care project.
This paper describes the methodology and presents preliminary results of an economic appraisal of a community based health care project in Kenya. Community health workers, trained for 12 weeks and deployed in two locations in Kenya's Western Province, act as first contact providers of basic health care and promoters of selected health, sanitation and nutrition practices. A Cost Benefit Analysis has been undertaken using the Willingness to Pay approach to compare the costs of the project and its benefits. The benefits are in the form of more easily accessible basic health care and are measured as consumer surplus accruing to the community. Gain in consumer surplus is consequent on the fall of average user costs and rise in utilisation of the project established points of first contact with primary health care. The argument for the economic viability of the project is validated by the large Net Present Value and Benefit Cost Ratio obtained for the whole of the project area and for the two locations separately. Although the evaluation technique used faces the problem of valuation of community time, aggregation of health care services at all points of first contact and the partial nature of cost benefit analysis evaluations, the results are strongly in favour of decentralisation of primary health care on similar lines in the rest of the country.


Cristae architecture is determined by an interplay of the MICOS complex and the F1FO ATP synthase via Mic27 and Mic10.
The inner boundary and the cristae membrane are connected by pore-like structures termed crista junctions (CJs). The MICOS complex is required for CJ formation and enriched at CJs. Here, we address the roles of the MICOS subunits Mic27 and Mic10. We observe a positive genetic interaction between Mic27 and Mic60 and deletion of Mic27 results in impaired formation of CJs and altered cristae membrane curvature. Mic27 acts in an antagonistic manner to Mic60 as it promotes oligomerization of the F1FO-ATP synthase and partially restores CJ formation in cells lacking Mic60. Mic10 impairs oligomerization of the F1FO-ATP synthase similar to Mic60. Applying complexome profiling, we observed that deletion of Mic27 destabilizes the MICOS complex but does not impair formation of a high molecular weight Mic10 subcomplex. Moreover, this Mic10 subcomplex comigrates with the dimeric F1FO-ATP synthase in a Mic27-independent manner. Further, we observed a chemical crosslink of Mic10 to Mic27 and of Mic10 to the F1FO-ATP synthase subunit e. We corroborate the physical interaction of the MICOS complex and the F1FO-ATP synthase. We propose a model in which part of the F1FO-ATP synthase is linked to the MICOS complex via Mic10 and Mic27 and by that is regulating CJ formation.


Safety and Immunogenicity of Early Bacillus Calmette-Guérin Vaccination in Infants Who Are Preterm and/or Have Low Birth Weights: A Systematic Review and Meta-analysis.
Bacillus Calmette-Guérin (BCG) vaccination is commonly delayed in infants who are preterm and have low birth weights (LBW) despite the association of early vaccination with better vaccination coverage and potentially nonspecific benefits for survival. To determine the safety, immunogenicity, and protective efficacy against tuberculosis (TB) of BCG vaccination given at or before 7 days after birth vs vaccination more than 7 days after birth among infants who are preterm and/or had LBW. Searches of Medline, Embase, and Global Health databases were conducted from inception until August 8, 2017. Clinical trials, cohort studies, and case-control studies that included infants who were preterm and/or had LBW and reported safety, mortality, immunogenicity, proxies of vaccine take, and/or efficacy against TB. Two authors independently extracted data and assessed the quality of the studies. Data extracted included demographics, covariates, sources of bias, and effect estimates. Meta-analysis was performed using a random-effects model. Safety, mortality, immunogenicity, or other proxies of vaccine take, such as tuberculin skin test (TST) conversion and efficacy against tuberculosis. Forty studies were included in a qualitative synthesis; infants who were preterm (born at 26-37 weeks' gestational age) and/or had LBW (0.69-2.5 kg at birth) were included. The BCG vaccine was administered at or before 7 days to 10 568 clinically stable infants who were preterm and/or had LBW; vaccination was administered to 4310 infants at varying times between 8 days and 12 months after birth. Twenty-one studies reporting safety found no cases of BCG-associated death or systemic disease in 8243 infants. Four studies reported no increase in all-cause mortality for infants who had LBW and who received early BCG vaccination compared with infants who had LBW with later vaccination or BCG-vaccinated infants of normal birth weight. Four studies reported lymphadenitis incidence; combined, these reported 0% to 2.9% incidence of vaccination within 7 days and 0% to 4.2% of vaccination after 7 days. Meta-analysis of 7 studies revealed no differences between early and delayed BCG vaccination for scar formation (n = 515; relative risk [RR], 1.01 [95% CI, 0.95-1.07]) or TST conversion (n = 397; RR, 0.97 [95% CI, 0.84-1.13]). Published data were insufficient to assess immunogenicity or protective efficacy against TB disease. Early BCG vaccination in healthy infants who are preterm and/or had LBW has a similar safety profile, reactogenicity, and TST conversion rate as delayed vaccination. Based on current evidence, early BCG vaccination in stable infants who are preterm and/or have LBW to optimize uptake is warranted.


Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells.
Increased matrix rigidity associated with the fibrotic reaction is documented to stimulate intracellular signalling pathways that promote cancer cell survival and tumour growth. Pancreatic cancer is one of the stiffest of all human solid carcinomas and is characterised by a remarkable desmoplastic reaction. Here we use mouse models, genetically engineered to recapitulate human pancreatic cancer, and several pancreatic cancer cell lines as a model to investigate the effect of matrix stiffness in epithelial-mesenchymal transition (EMT) and resistance to chemotherapeutics. We found that recapitulation of the fibrotic rigidities found in pancreatic cancer tissues promote elements of EMT, including increases in vimentin expression, decreases in E-cadherin expression, nuclear localisation of β-catenin, YAP and TAZ and changes in cell shape towards a mesenchymal phenotype. We also report that stiffness induces chemoresistance to paclitaxel, but not to gemcitabine, both commonly used therapeutics, suggesting that environmental rigidity underlies an aspect of chemoresistance.


Notes from the field: jumpstarting the IRB approval process in multicenter studies.
To identify strategies that facilitate readiness for local Institutional Review Board (IRB) review, in multicenter studies. Eleven acute care hospitals, as they applied to participate in a foundation-sponsored quality improvement collaborative. Case series. Participant observation, supplemented with review of written and oral communications. Applicant hospitals responded positively to efforts to engage them in early planning for the IRB review process. Strategies that were particularly effective were the provisions of application templates, a modular approach to study description, and reliance on conference calls to collectively engage prospective investigators, local IRB members, and the evaluation/national program office teams. Together, these strategies allowed early identification of problems, clarification of intent, and relatively timely completion of the local IRB review process, once hospitals were selected to participate in the learning collaborative. Engaging potential collaborators in planning for IRB review may help expedite and facilitate review, without compromising the fairness of the grant-making process or the integrity of human subjects protection.


Polarization-sensitive and broadband germanium sulfide photodetectors with excellent high-temperature performance.
Layered materials, such as graphene, transition metal dichalcogenides and black phosphorene, have been established rapidly as intriguing building blocks for optoelectronic devices. Here, we introduce highly polarization sensitive, broadband, and high-temperature-operation photodetectors based on multilayer germanium sulfide (GeS). The GeS photodetector shows a high photoresponsivity of about 6.8 × 103 A W-1, an extremely high specific detectivity of 5.6 × 1014 Jones, and broad spectral response in the wavelength range of 300-800 nm. More importantly, the GeS photodetector has high polarization sensitivity to incident linearly polarized light, which provides another degree of freedom for photodetectors. Tremendously enhanced photoresponsivity is observed with a temperature increase, and high responsivity is achievable at least up to 423 K. The establishment of larger photoinduced reduction of the Schottky barrier height will be significant for the investigation of the photoresponse mechanism of 2D layered material-based photodetectors. These attributes of high photocurrent generation in a wide temperature range, broad spectral response, and polarization sensitivity coupled with environmental stability indicate that the proposed GeS photodetector is very suitable for optoelectronic applications.


Balancing selfishness and norm conformity can explain human behavior in large-scale prisoner's dilemma games and can poise human groups near criticality.
Cooperation is central to the success of human societies as it is crucial for overcoming some of the most pressing social challenges of our time; still, how human cooperation is achieved and may persist is a main puzzle in the social and biological sciences. Recently, scholars have recognized the importance of social norms as solutions to major local and large-scale collective action problems, from the management of water resources to the reduction of smoking in public places to the change in fertility practices. Yet a well-founded model of the effect of social norms on human cooperation is still lacking. Using statistical-physics techniques and integrating findings from cognitive and behavioral sciences, we present an analytically tractable model in which individuals base their decisions to cooperate both on the economic rewards they obtain and on the degree to which their action complies with social norms. Results from this parsimonious model are in agreement with observations in recent large-scale experiments with humans. We also find the phase diagram of the model and show that the experimental human group is poised near a critical point, a regime where recent work suggests living systems respond to changing external conditions in an efficient and coordinated manner.


Plasma nicotine levels after cigarette smoking and chewing nicotine gum.
Plasma nicotine levels were measured over seven hours of smoking cigarettes (1-2 mg nicotine) in a single subject under standardised conditions, and were compared with the levels obtained from chewing-gum containing either 2 mg or 4 mg nicotine. Levels comparable to those resulting from smoking were not obtained with the 2-mg gum, but peak levels on the 4-mg gum averaged 40-1 ng/ml from the third gum onwards compared with 49-2ng/ml after cigarettes. Nicotine was absorbed much more slowly from the gum than from cigarettes. It took 15-30 minutes for the 4-mg gum to raise the plasma nicotine by an average of 11-9 ng/ml compared with an average increase of 27-8 ng/ml within two minutes of completing each cigarette. In a sample of 15 smokers attending a withdrawal clinic the average plasma nicotine concentration while taking 2-mg nicotine chewing-gum was only 10-8 ng/ml compared with 30-4 ng/ml two minutes after smoking a cigarette. Although plasma nicotine levels equivalent to those following cigarette smoking may be obtained by chewing at least 10 pieces of 4-mg nicotine gum daily, the slower rate of absorption may limit its therapeutic value as a substitute for cigarette smoking.


A meta-analysis of reference markers of bone turnover for prediction of fracture.
The aim of this report was to summarize the clinical performance of two reference bone turnover markers (BTMs) in the prediction of fracture risk. We used an updated systematic review to examine the performance characteristics of serum procollagen type I N propeptide (s-PINP) and serum C-terminal cross-linking telopeptide of type I collagen (s-CTX) in fracture risk prediction in untreated individuals in prospective cohort studies. We excluded cross-sectional studies. Ten potentially eligible publications were identified and six included in the meta-analysis. There was a significant association between s-PINP and the risk of fracture. The hazard ratio per SD increase in s-PINP (gradient of risk [GR]) was 1.23 (95 % CI 1.09-1.39) for men and women combined unadjusted for bone mineral density. There was also a significant association between s-CTX and risk of fracture, GR = 1.18 (95 % CI 1.05-1.34) unadjusted for bone mineral density. For the outcome of hip fracture, the association between s-CTX and risk of fracture was slightly higher, 1.23 (95 % CI 1.04-1.47). Thus, there is a modest but significant association between BTMs and risk of future fractures.


Quality of life, psychological wellbeing and treatment needs of trauma and head and neck cancer patients.
There is increasing evidence that patients treated for trauma or cancer of the head and neck may go on to experience psychological distress. We aimed to measure the impact of this on their quality of life (QoL) and to explore their willingness to be referred for psychological support. A total of 96 patients with facial injuries and 124 with cancer of the head and neck completed a self-reported questionnaire to identify psychological distress (Hospital Anxiety and Depression Scale (HADS) and the Acute Stress Disorder (ASD) Scale), quality of life (WHOQoL-BREF), satisfaction with treatment, and willingness to accept psychological support. Thirty-nine percent of patients showed high levels of depressive symptoms and 43% reported high levels of anxiety; 43% in the trauma group and 12% in the cancer group had high ASD scores. Patients with high scores on the HADS reported poorer QoL, and 40% of those with high levels of psychological distress were willing to consider psychological support. Despite the fact that patients report high levels of satisfaction with their medical and surgical care, many have psychological problems and have needs that are not being met. A large proportion would use psychological support services.


Metabolism of triacetin-derived acetate in dogs.
Triacetin is a water-soluble triglyceride that may have a role as a parenteral nutrient. In the present study triacetin was administered intravenously to mongrel dogs (n = 10) 2 wk after surgical placement of blood-sampling catheters in the aorta and in the portal, hepatic, renal, and femoral veins. [1-14C]Acetate was infused to allow quantification of organ uptake of acetate as well as systemic turnover and oxidation. Systemic acetate turnover accounted for approximately 70% of triacetin-derived acetate, assuming complete hydrolysis of the triglyceride. Approximately 80% of systemic acetate uptake was rapidly oxidized. Significant acetate uptake was demonstrated in all tissues (liver, 559 +/- 68; intestine, 342 +/- 23; hindlimb, 89 +/- 7; and kidney, 330 +/- 37 mumol/min). In conclusion, during intravenous administration in dogs, the majority of infused triacetin undergoes intravascular hydrolysis, and the majority of the resulting acetate is oxidized. Thus, energy in the form of short-chain fatty acids can be delivered to a resting gut via intravenous infusion of a short-chain triglyceride.


Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke.
The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion. In a pragmatic, cluster-randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death). The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying-flat group were less likely than patients in the sitting-up group to maintain the position for 24 hours (87% vs. 95%, P<0.001). In a proportional-odds model, there was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the lying-flat group and patients in the sitting-up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying-flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P=0.84). Mortality within 90 days was 7.3% among the patients in the lying-flat group and 7.4% among the patients in the sitting-up group (P=0.83). There were no significant between-group differences in the rates of serious adverse events, including pneumonia. Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for 24 hours and patients assigned to a sitting-up position with the head elevated to at least 30 degrees for 24 hours. (Funded by the National Health and Medical Research Council of Australia; HeadPoST ClinicalTrials.gov number, NCT02162017 .).


Comprehensive analysis of depression-related factors among middle-aged residents in Japan, an Eastern culture: A cross-sectional study.
There is a need to comprehensively identify depression-related factors, including individual and socioeconomic factors, in each country or cultural area, to consider effective measures to address depression within communities. However, there are not enough studies on middle-aged residents in Japan or other Eastern countries to currently achieve this. Thus, the aim of this study was to comprehensively identify factors related to depression in middle-aged residents in Japan, an Eastern country.The study design was cross-sectional. A questionnaire survey was conducted among all community residents aged 40 to 59 in a rural municipality in Western Japan. The questionnaire contained items on demographic characteristics, psychological factors, health-related behaviors, and socioeconomic factors. A Chi-Squared test or Fisher exact test was used to analyze the relationships between depression and each assessed factor. Next, a logistic regression analysis was performed to identify comprehensive relationships between depression and its related factors.Data from 362 participants were analyzed. The average age was 51.5 years; 148 were male. A Chi-Squared test or Fisher exact test demonstrated that many psychological factors, health-related behaviors, and socioeconomic factors ware significantly related to depression. A logistic regression analysis showed that depression was significantly associated with male gender, low sense of coherence, high cognitive stress levels, low help-seeking behavior, poor quality sleep, and a lack of hobbies. Nagelkerke R2 was 51%.This study revealed through multivariate analysis that depression was primarily associated with personal behavioral and psychological factors in Japan, an Eastern country with a holistic cultural background. This result is consistent with findings from Western countries. This study can contribute the promotion and evaluation of preventive measures for depression in Eastern culture that focus on individual behavioral and psychological factors.


A theory of dopamine function and its role in cognitive deficits in schizophrenia.
In spite of extensive research on the biological and behavioral correlates of dopamine (DA) function, little is known about the mechanisms by which DA may produce the cognitive deficits observed in schizophrenia. Neural network simulation models offer a framework for exploring how DA effects at the physiological level may influence behavior. We focus on findings suggesting that DA modulates neuronal activity by enhancing the ability of neurons to transmit signals and reduce distortion by noise. These phenomena can be captured in simulations by increasing the gain of individual units of a network. When gain is increased diffusely, improvement in signal detection performance of such a network parallels the improvement in performance of human subjects receiving DA agonists. Furthermore, decreasing gain in a network module supporting a memory function analogous to that of prefrontal cortex results in deterioration of performance equivalent to that of schizophrenic subjects. A test of predictions made by such networks about the performance of schizophrenic patients in a new variant of the Continuous Performance Test is discussed. Preliminary data are consistent with predictions and support the account of schizophrenic cognitive deficits in terms of the theory of DA function suggested by the models.


Children's eating behavior, feeding practices of parents and weight problems in early childhood: results from the population-based Generation R Study.
Weight problems that arise in the first years of life tend to persist. Behavioral research in this period can provide information on the modifiable etiology of unhealthy weight. The present study aimed to replicate findings from previous small-scale studies by examining whether different aspects of preschooler's eating behavior and parental feeding practices are associated with body mass index (BMI) and weight status -including underweight, overweight and obesity- in a population sample of preschool children. Cross-sectional data on the Child Eating Behaviour Questionnaire, Child Feeding Questionnaire and objectively measured BMI was available for 4987 four-year-olds participating in a population-based cohort in the Netherlands. Thirteen percent of the preschoolers had underweight, 8% overweight, and 2% obesity. Higher levels of children's Food Responsiveness, Enjoyment of Food and parental Restriction were associated with a higher mean BMI independent of measured confounders. Emotional Undereating, Satiety Responsiveness and Fussiness of children as well as parents' Pressure to Eat were negatively related with children's BMI. Similar trends were found with BMI categorized into underweight, normal weight, overweight and obesity. Part of the association between children's eating behaviors and BMI was accounted for by parental feeding practices (changes in effect estimates: 20-43%), while children's eating behaviors in turn explained part of the relation between parental feeding and child BMI (changes in effect estimates: 33-47%). This study provides important information by showing how young children's eating behaviors and parental feeding patterns differ between children with normal weight, underweight and overweight. The high prevalence of under- and overweight among preschoolers suggest prevention interventions targeting unhealthy weights should start early in life. Although longitudinal studies are necessary to ascertain causal directions, efforts to prevent or treat unhealthy child weight might benefit from a focus on changing the behaviors of both children and their parents.


Real-world comparative analysis of bleeding complications and health-related quality of life in patients with haemophilia A and haemophilia B.
Clinical severity and impact of haemophilia on quality of life have been generally considered to be lower for haemophilia B (HB) compared with haemophilia A (HA) patients. To compare annual bleeding rate (ABR), target joint development and health-related quality of life (HRQoL) between adult (≥18 years) severe HA and HB patients using recent data from the Cost of Haemophilia in Europe: a Socioeconomic Survey (CHESS) study. Multivariate generalized linear models (GLM) were constructed to assess the relationship between haemophilia type, ABR, HRQoL (derived from EQ-5D index scores) and the presence of target joints while controlling for covariates. Of the 1225 patients included, 77% (n = 949) had HA and 23% (n = 278) had HB. Of the 514 patients who completed the EQ-5D, 78% (n = 405) had HA, and 22% (n = 110) had HB. Unadjusted mean ABR was 3.79 in HA and 4.60 in HB. The presence of ≥1 target joint was reported in 59% and 54% of patients with HA and HB, respectively. Unadjusted mean EQ-5D index score was 0.78 in HA and 0.76 in HB. Haemophilia type was not a significant predictor of ABR, target joints or HRQoL when adjusted for confounding factors such as BMI, age and replacement therapy regimen. Data suggest comparable ABR, incidence of target joints and HRQoL between patients with HB and HA indicating comparable clinical severity and disease impact on patient quality of life.


Influence of "diagnostic delay" upon cancer survival: an analysis of five tumour sites.
The aim was to assess the relationship between survival, tumour stage, and the interval from first symptom to diagnosis (SDI, or duration of symptoms). This was a retrospective follow up study of a cohort of patients registered in the tumour registry of the Hospital del Mar (Barcelona). Hospital based tumour registry, with patients derived mainly from the City of Barcelona. 1247 cases of lung, breast, stomach, colon, or rectal cancer were analysed using survival curves and Cox proportional hazards regression. Subjects (mean age 63.6 years) were followed for a median length of 12.9 months after diagnosis. At the time of diagnosis one fourth of patients had disseminated disease. Based on clinical records, a physician registered the onset time of the first symptom attributable to cancer (from which the SDI is computed), as well as the tumour stage at diagnosis. Other measurements followed standard tumour registry procedures. Overall, the crude mean SDI was 5.15 months (SD 8.03, median 2.03); only 24.5% of cases had an SDI less than a month. Crude mean SDIs by anatomical site were as follows: lung cancer 3.07 months; breast 7.44; stomach 5.34; colon 5.74; rectum 5.03. Tumour extension did not appear to be significantly influenced by SDI, only breast cancer showing a distinct pattern of increased extension with increasing SDI. As expected, the probability of survival decreased monotonically with increasing stage in all sites. Tumour site was also a significant predictor of survival, which at one year ranged from 93% for breast cancer to 28% for lung cancer. However, a longer SDI tended sometimes to be associated with a better chance of survival, a fact that was most apparent in colon cancer. All Cox proportional hazards models showed a consistent picture: SDI was not a significant predictor of survival (age and sex adjusted hazard ratios ranging from 0.97 to 1.01), neither was sex; age did predict survival, and so did site and stage. The results provide further evidence of a very weak relationship between SDI and tumour stage at diagnosis (except for breast cancer), and between SDI and survival, thus emphasising some limitations within which early clinical detection operates. They also suggest that in addition to reflecting patient and physician behaviour, as well as the functioning of the health system, SDI may be influenced by the biological behaviour of the tumour.


Amplifying the Pacific climate system response to a small 11-year solar cycle forcing.
One of the mysteries regarding Earth's climate system response to variations in solar output is how the relatively small fluctuations of the 11-year solar cycle can produce the magnitude of the observed climate signals in the tropical Pacific associated with such solar variability. Two mechanisms, the top-down stratospheric response of ozone to fluctuations of shortwave solar forcing and the bottom-up coupled ocean-atmosphere surface response, are included in versions of three global climate models, with either mechanism acting alone or both acting together. We show that the two mechanisms act together to enhance the climatological off-equatorial tropical precipitation maxima in the Pacific, lower the eastern equatorial Pacific sea surface temperatures during peaks in the 11-year solar cycle, and reduce low-latitude clouds to amplify the solar forcing at the surface.


Romo1-Derived Antimicrobial Peptide Is a New Antimicrobial Agent against Multidrug-Resistant Bacteria in a Murine Model of Sepsis.
To overcome increasing bacterial resistance to conventional antibiotics, many antimicrobial peptides (AMPs) derived from host defense proteins have been developed. However, there are considerable obstacles to their application to systemic infections because of their low bioavailability. In the present study, we developed an AMP derived from Romo1 (AMPR-11) that exhibits a broad spectrum of antimicrobial activity. AMPR-11 showed remarkable efficacy against sepsis-causing bacteria, including multidrug-resistant strains, with low toxicity in a murine model of sepsis after intravenous administration. It seems that AMPR-11 disrupts bacterial membranes by interacting with cardiolipin and lipid A. From the results of this study, we suggest that AMPR-11 is a new class of agent for overcoming low efficacy in the intravenous application of AMPs and is a promising candidate to overcome multidrug resistance.IMPORTANCE Abuse of antibiotics often leads to increase of multidrug-resistant (MDR) bacteria, which threatens the life of human beings. To overcome threat of antibiotic resistance, scientists are developing a novel class of antibiotics, antimicrobial peptides, that can eradicate MDR bacteria. Unfortunately, these antibiotics have mainly been developed to cure bacterial skin infections rather than others, such as life-threatening sepsis. Major pharmaceutical companies have tried to develop antiseptic drugs; however, they have not been successful. Here, we report that AMPR-11, the antimicrobial peptide (AMP) derived from mitochondrial nonselective channel Romo1, has antimicrobial activity against Gram-positive and Gram-negative bacteria comprising many clinically isolated MDR strains. Moreover, AMPR-11 increased the survival rate in a murine model of sepsis caused by MDR bacteria. We propose that AMPR-11 could be a novel antiseptic drug candidate with a broad antimicrobial spectrum to overcome MDR bacterial infection.


Clinical presentation of nipah virus infection in Bangladesh.
In Bangladesh, 4 outbreaks of Nipah virus infection were identified during the period 2001-2004. We characterized the clinical features of Nipah virus-infected individuals affected by these outbreaks. We classified patients as having confirmed cases of Nipah virus infection if they had antibodies reactive with Nipah virus antigen. Patients were considered to have probable cases of Nipah virus infection if they had symptoms consistent with Nipah virus infection during the same time and in the same community as patients with confirmed cases. We identified 92 patients with Nipah virus infection, 67 (73%) of whom died. Although all age groups were affected, 2 outbreaks principally affected young persons (median age, 12 years); 62% of the affected persons were male. Fever, altered mental status, headache, cough, respiratory difficulty, vomiting, and convulsions were the most common signs and symptoms; clinical and radiographic features of acute respiratory distress syndrome of Nipah illness were identified during the fourth outbreak. Among those who died, death occurred a median of 6 days (range, 2-36 days) after the onset of illness. Patients who died were more likely than survivors to have a temperature >37.8 degrees C, altered mental status, difficulty breathing, and abnormal plantar reflexes. Among patients with Nipah virus infection who had well-defined exposure to another patient infected with Nipah virus, the median incubation period was 9 days (range, 6-11 days). Nipah virus infection produced rapidly progressive severe illness affecting the central nervous and respiratory systems. Clinical characteristics of Nipah virus infection in Bangladesh, including a severe respiratory component, appear distinct from clinical characteristics reported during earlier outbreaks in other countries.


Immunochemical evidence for a role of cytochrome P-450 in liver microsomal ethanol oxidation.
Antibodies to cytochrome P-450 isozyme 3a, the ethanol-inducible isozyme in rabbit liver, were used to determine the role of this enzyme in the microsomal oxidation of alcohols and the p-hydroxylation of aniline. P-450 isozymes, 2, 3b, 3c, 4, and 6 did not crossreact with anti-3a IgG as judged by Ouchterlony double diffusion, and radioimmunoassays indicated a crossreactivity of less than 1%. Greater than 90% of the activity of purified form 3a toward aniline, ethanol, n-butanol, and n-pentanol was inhibited by the antibody in the reconstituted system. The catalytic activity of liver microsomes from control or ethanol-treated rabbits was unaffected by the addition of either desferrioxamine (up to 1.0 mM) or EDTA (0.1 mM), suggesting that reactions involving the production of hydroxyl radicals from H2O2 and any contaminating iron in the system did not make a significant contribution to the microsomal activity. The addition of anti-3a IgG to hepatic microsomes from ethanol-treated rabbits inhibited the metabolism of ethanol, n-butanol, n-pentanol, and aniline by about 75, 70, 80, and 60%, respectively, while the inhibition of the activity of microsomes from control animals was only about one-half as great. The rate of microsomal H2O2 formation was inhibited to a lesser extent than the formation of acetaldehyde, thus suggesting that the antibody was acting to prevent the direct oxidation of ethanol by form 3a. Under conditions where purified NADPH-cytochrome P-450 reductase-catalyzed substrate oxidations was minimal, the P-450 isozymes other than 3a had low but significant activity toward the four substrates examined. The residual activity at maximal concentrations of the antibody most likely represents the sum of the activities of P-450 isozymes other than 3a present in the microsomal preparations. The results thus indicate that the enhanced monooxygenase activity of liver microsomes from ethanol-treated animals represents catalysis by P-450 isozyme 3a.


How to do a grounded theory study: a worked example of a study of dental practices.
Qualitative methodologies are increasingly popular in medical research. Grounded theory is the methodology most-often cited by authors of qualitative studies in medicine, but it has been suggested that many 'grounded theory' studies are not concordant with the methodology. In this paper we provide a worked example of a grounded theory project. Our aim is to provide a model for practice, to connect medical researchers with a useful methodology, and to increase the quality of 'grounded theory' research published in the medical literature. We documented a worked example of using grounded theory methodology in practice. We describe our sampling, data collection, data analysis and interpretation. We explain how these steps were consistent with grounded theory methodology, and show how they related to one another. Grounded theory methodology assisted us to develop a detailed model of the process of adapting preventive protocols into dental practice, and to analyse variation in this process in different dental practices. By employing grounded theory methodology rigorously, medical researchers can better design and justify their methods, and produce high-quality findings that will be more useful to patients, professionals and the research community.