Rationale, Design, and Implementation of Intensive Risk Factor Treatment in the CREST2 Trial.
The CREST2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis) is comparing intensive medical management (IMM) alone to IMM plus revascularization with carotid endarterectomy or transfemoral carotid artery stenting for preventing stroke or death within 44 days after randomization or ipsilateral ischemic stroke thereafter. There are extensive clinical trial data on outcomes after revascularization of asymptomatic carotid stenosis, but not for IMM. As such, the experimental treatment in CREST2 is IMM, which is described in this article. IMM consists of aspirin 325 mg/day and intensive risk factor management, primarily targeting systolic blood pressure <130 mm Hg (initially systolic blood pressure <140 mm Hg) and LDL (low-density lipoprotein) cholesterol <70 mg/dL. Secondary risk factor targets focus on tobacco smoking, non-HDL (high-density lipoprotein), HbA1c (hemoglobin A1c), physical activity, and weight. Risk factor management is performed by site personnel and a lifestyle coaching program delivered by telephone. We report interim risk factor data on 1618 patients at baseline and last follow-up through 24 months. The mean baseline LDL of 80.5 mg/dL improved to 66.7 mg/dL. The mean baseline systolic blood pressure of 139.7 mm Hg improved to 130.3 mm Hg. The proportion of patients in-target improved from 43% to 61% for systolic blood pressure <130 mm Hg and from 45% to 67% for LDL<70 mg/dL (both changes P<0.001). The rigorous multimodal approach to intensive stroke risk factor management in CREST2 has resulted in significant improvements in risk factor control that will enable a comparison of cutting-edge medical care to revascularization in patients with asymptomatic carotid stenosis. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02089217.


The Relationship between Vitamin C and Periodontal Diseases: A Systematic Review.
Vitamin C is important for preventing and slowing the progression of many diseases. There is significant evidence linking periodontal disease and vitamin C. We aimed to systematically review the studies addressing the relationship between vitamin C and periodontal disease, and the preventive ability of vitamin C against periodontal disease. Electric searches were performed using PubMed, EMBASE, Cochrane Library, and Web of Science. Studies addressing the relationships between periodontal disease and vitamin C in adults aged over 18 years were included. Quality assessment was done using the Critical Appraisal Skills Program guideline and GRADE-CERQual. There were 716 articles that were retrieved and 14 articles (seven cross-sectional studies, two case-control studies, two cohort studies, and three randomized controlled trials (RCT)) were selected after reviewing all of the articles. The vitamin C intake and blood levels were negatively related to periodontal disease in all seven cross-sectional studies. The subjects who suffer from periodontitis presented a lower vitamin C intake and lower blood-vitamin C levels than the subjects without periodontal disease in the two case-control studies. The patients with a lower dietary intake or lower blood level of vitamin C showed a greater progression of periodontal disease than the controls. The intervention using vitamin C administration improved gingival bleeding in gingivitis, but not in periodontitis. Alveolar bone absorption was also not improved. The present systematic review suggested that vitamin C contributes to a reduced risk of periodontal disease.


Decontamination efficacy of three commercial-off-the-shelf (COTS) sporicidal disinfectants on medium-sized panels contaminated with surrogate spores of Bacillus anthracis.
In the event of a wide area release and contamination of a biological agent in an outdoor environment and to building exteriors, decontamination is likely to consume the Nation's remediation capacity, requiring years to cleanup, and leading to incalculable economic losses. This is in part due to scant body of efficacy data on surface areas larger than those studied in a typical laboratory (5×10-cm), resulting in low confidence for operational considerations in sampling and quantitative measurements of prospective technologies recruited in effective cleanup and restoration response. In addition to well-documented fumigation-based cleanup efforts, agencies responsible for mitigation of contaminated sites are exploring alternative methods for decontamination including combinations of disposal of contaminated items, source reduction by vacuuming, mechanical scrubbing, and low-technology alternatives such as pH-adjusted bleach pressure wash. If proven effective, a pressure wash-based removal of Bacillus anthracis spores from building surfaces with readily available equipment will significantly increase the readiness of Federal agencies to meet the daunting challenge of restoration and cleanup effort following a wide-area biological release. In this inter-agency study, the efficacy of commercial-of-the-shelf sporicidal disinfectants applied using backpack sprayers was evaluated in decontamination of spores on the surfaces of medium-sized (∼1.2 m2) panels of steel, pressure-treated (PT) lumber, and brick veneer. Of the three disinfectants, pH-amended bleach, Peridox, and CASCAD evaluated; CASCAD was found to be the most effective in decontamination of spores from all three panel surface types.


Antenna excited state decay kinetics establish primary electron transfer in reaction centers as heterogeneous.
The decay of the excited primary electron donor P* in bacterial photosynthetic reaction centers (both membrane-bound and detergent-isolated) has been observed to be nonexponential on a time scale of some tens of picoseconds. Although the multipicosecond nonexponentiality of P* has been ascribed to heterogeneity in teh rate of primary electron transfer (PET), the decay kinetics can be interpreted equally well using homogeneous models. To address this ambiguity, we studied the decay of excited bacteriochlorophyll (Bchl) in the membrane-bound core antenna/reaction center complexes of wild-type and mutant reaction center strains of Rhodobacter capsulatus. Reaction centers isolated from these same strains display a range of multiexponentiality in primary charge separation. The mutant strains carry substitutions of amino acids residing near the monomeric Bchl on the active and/or inactive sides of the reaction center. Transient absorption measurements monitoring the Qy bleach of antenna Bchls require at least two exponential components to fit all decays. The wild type was fitted with equal-amplitude components whose lifetimes are 24 and 65 ps. The shortest-lived component is relatively insensitive to mutation, in contrast to the longer-lived component(s) whose amplitude and magnitude were dramatically perturbed by amino acid substitutions. Unlike the situation with isolated reaction centers, here the only kinetic models consistent with the data are those in which the primary electron-transfer rate constant is heterogeneous, suggesting at least two structural populations of RCs. PET in the population with the shortest-lived antenna decay causes the kinetics to be transfer-to-trap-limited, whereas the kinetics in the other population(s)--having longer-lived antenna decays--are limited by the rate of PET. Observation of both types of kinetic limitation within a single light-harvesting system is unexpected and complicates any discussion of the rate-limiting step of light energy utilization in photosynthesis.


Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.
Understanding the transcriptional changes that are engaged in stress resilience may reveal novel antidepressant targets. Here we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB-Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in prefrontal cortex neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB-Zfp189 interactions in mediating a central transcriptional network of resilience.


Red cell transfusion for the management of upper gastrointestinal haemorrhage.
Upper gastrointestinal haemorrhage affects 50 to 150 per 100,000 adults per year and has a high mortality. Red blood cell transfusions are frequently given, but their impact on rebleeding rates and mortality is not known. To assess the effects of red blood cell transfusion in adults with upper gastrointestinal haemorrhage. We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register to February 2008, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1950 to February 2008), EMBASE (1974 to February 2008), the Systematic Review Initiative database of randomised controlled trials, haematology and gastroenterology conference proceedings, and reference lists of articles. We also searched databases of ongoing clinical trials. Randomised and quasi-randomised studies comparing red blood cell transfusion and standard care with other intravenous fluid and standard care regimens in haemodynamically stable and haemodynamically unstable adults with upper gastrointestinal haemorrhage. Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Three trials involving 126 patients were included in the review, with complete data available for 93 patients. The participants were heterogeneous and none of the three studies examined exactly the same interventions or measured the same outcomes. Only two trials reported mortality data and the summary relative risk for mortality of the intervention was 5.4 (95% CI 0.27 to 107.09). One trial reported increased coagulation times in the transfused group, and reported these patients to have increased rates of rebleeding. None of the studies reported adverse events directly related to red blood cell transfusion. Methodological deficiencies, including allocation concealment, generation of random sequences and blinding, simply compound the uncertainty surrounding analysis. None of the studies were appropriately powered and in the largest study less than half the participants were included in the final analysis.One randomised controlled trial of restrictive versus liberal red blood cell transfusion, which aims to recruit 860 patients, has yet to be completed. There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed randomised controlled trials of sufficient power are urgently needed.


Exchange of spacer regions between rRNA operons in Escherichia coli.
The Escherichia coli rRNA operons each have one of two types of spacer separating the 16S and 23S coding regions. The spacers of four operons encode tRNA(Glu2) and the other three encode both tRNA(Ile) and tRNA(Ala1B). We have prepared a series of mutants in which the spacer region of a particular rrn operon has been replaced by the opposite type. Included among these were a mutant retaining only a single copy of the tRNA(Glu2) spacer (at rrnG) and another retaining only a single copy of the tRNA(Ile)-tRNA(Ala1B) spacer (at rrnA). While both mutants grew more slowly than controls, the mutant deficient in tRNA(Glu2) spacers was more severely affected. At a frequency of 6 X 10(-5), these mutants phenotypically reverted to faster growing types by increasing the copy number of the deficient spacer. In most of these phenotypic revertants, the deficient spacer type appeared in a rrn operon which previously contained the surplus type, bringing the ratio of spacer types closer to normal. In a few cases, these spacer changes were accompanied by an inversion of the chromosomal material between the donor and recipient rrn operons. Two examples of inversion of one-half of the E. coli chromosome between rrnG and rrnH were observed. The correlation of spacer change with inversion indicated that, in these particular cases, the change was due to an intrachromatid gene conversion event accompanied by a reciprocal crossover rather than reciprocal exchange between sister chromatids.


Prevalence and correlates of psychological distress among diabetes mellitus adults in the Jilin province in China: a cross-sectional study.
Psychological disorders are common in diabetes mellitus (DM) patients, and the aim of this study was to estimate the prevalence of psychological distress and to determine the influence factors associated with psychological distress among DM patients in the Jilin province of China. Multistage, stratified cluster sampling was used in this cross-sectional study. The 12-item General Health Questionnaire (GHQ-12) was used to assess psychological status with the total score of ≥4 as the threshold for psychological distress. A total of 1,956 subjects with DM were included in the study. Out of this total diabetic participants, 524 (26.8%) had psychological distress. Multiple logistic regression analysis showed that low educational level, divorce or separation from one's spouse, low family average monthly income, short sleep duration, being aware of DM status, and multiple co-morbidities are positively associated with psychological distress (all P < 0.05). This study revealed a high rate of psychological distress among DM population in Jilin province. Low educational level, divorce or separation from one's spouse, low family average monthly income, short sleep duration, awareness of DM status, and multiple co-morbidities are all associated with psychological distress among our study subjects. Interventions to control these factors are needed to address the psychological problems among diabetics in Jilin Province.


Manzamine A Exerts Anticancer Activity against Human Colorectal Cancer Cells.
Marine sponges are known to produce numerous bioactive secondary metabolites as defense strategies to avoid predation. Manzamine A is a sponge-derived β-carboline-fused pentacyclic alkaloid with various bioactivities, including recently reported anticancer activity on pancreatic cancer. However, its cytotoxicity and mode of action against other tumors remain unclear. In this study, we exhibit that manzamine A reduced cell proliferation in several colorectal cancer (CRC) cell lines. To further investigate the manzamine A triggered molecular regulation, we analyzed the gene expression with microarray and revealed that pathways including cell cycle, DNA repair, mRNA metabolism, and apoptosis were dysregulated. We verified that manzamine A induced cell cycle arrest at G₀/G₁ phase via inhibition of cyclin-dependent kinases by p53/p21/p27 and triggered a caspase-dependent apoptotic cell death through mitochondrial membrane potential depletion. Additionally, we performed bioinformatics analysis and demonstrated that manzamine A abolished epithelial⁻mesenchymal transition process. Several mesenchymal transcriptional factors, such as Snail, Slug, and Twist were suppressed and epithelial marker E-cadherin was induced simultaneously in HCT116 cells by manzamine A, leading to the epithelial-like phenotype and suppression of migration. These findings suggest that manzamine A may serve as a starting point for the development of an anticancer drug for the treatment of metastatic CRC.


Treatment of pseudotumors after metal-on-metal hip resurfacing based on magnetic resonance imaging, metal ion levels and symptoms.
Peri-prosthetic pseudotumor formation can be a severe complication following Metal-on-Metal hip resurfacing arthroplasty (MoMHRA), with limited data on the optimal management of this complication. The aims of this study were (1) to evaluate the prevalence and severity of pseudotumors in a consecutive cohort of 248 MoMHRA (214 patients, mean follow-up 4.6 years, range: 1 - 8.2), and (2) to present a clinical guideline for their treatment based on severity grading with Metal Artefact Reduction Sequence Magnetic Resonance Imaging, metal ion levels and symptoms. Pseudotumor prevalence was 36.3%: 61 mild, 25 moderate and four were graded severe. Five revisions followed, all in symptomatic patients with elevated metal ion levels. Pseudotumor severity grading allowed us to be conservative with revision surgery for mild and moderate MoM disease.


Structures of soluble guanylate cyclase: implications for regulatory mechanisms and drug development.
Activation of cGMP synthesis leads to vasodilation, and is an important mechanism in clinical treatment of angina, heart failure, and severe peripheral and pulmonary hypertension. The nitric oxide-responsive sGC (soluble guanylate cyclase) has been the target of recent drug discovery efforts. The present review surveys recent data on the structure and regulation of sGC, and the prospects of new avenues for therapeutic intervention.


"One for all and all for one": consensus-building within communities in rural India on their health microinsurance package.
This study deals with consensus by poor persons in the informal sector in rural India on the benefit-package of their community-based health insurance (CBHI). In this article we describe the process of involving rural poor in benefit-package design and assess the underlying reasons for choices they made and their ability to reach group consensus. The benefit-package selection process entailed four steps: narrowing down the options by community representatives, plus three Choosing Healthplans All Together (CHAT) rounds conducted among female members of self-help groups. We use mixed-methods and four sources of data: baseline study, CHAT exercises, in-depth interviews, and evaluation questionnaires. We define consensus as a community resolution reached by discussion, considering all opinions, and to which everyone agrees. We use the coefficient of unalikeability to express consensus quantitatively (as variability of categorical variables) rather than just categorically (as a binomial Yes/No). The coefficient of unalikeability decreased consistently over consecutive CHAT rounds, reaching zero (ie, 100% consensus) in two locations, and confirmed gradual adoption of consensus. Evaluation interviews revealed that the wish to be part of a consensus was dominant in all locations. The in-depth interviews indicated that people enjoyed the participatory deliberations, were satisfied with the selection, and that group decisions reflected a consensus rather than majority. Moreover, evidence suggests that pre-selectors and communities aimed to enhance the likelihood that many households would benefit from CBHI. The voluntary and contributory CBHI relies on an engaging experience with others to validate perceived priorities of the target group. The strongest motive for choice was the wish to join a consensus (more than price or package-composition) and the intention that many members should benefit. The degree of consensus improved with iterative CHAT rounds. Harnessing group consensus requires catalytic intervention, as the process is not spontaneous.


Human H5N2 avian influenza infection in Japan and the factors associated with high H5N2-neutralizing antibody titer.
H5N2 avian influenza virus infection of humans has not been reported thus far. The first H5N2 avian influenza infection of poultry in Japan occurred in Ibaraki. The subjects were workers at 35 chicken farms in Ibaraki Prefecture, where the H5N2 virus or antibody was isolated from chickens. None of the subjects exhibited influenza symptoms. The H5N2-neutralizing antibody titers of the first and second paired sera samples were compared. To investigate the possible factors for this increase, the H5N2-neutralizing antibody titer (1:40 or more) was calculated for the second samples. A logistic regression analysis was performed to examine the association of these factors with H5N2-neutralizing antibody positivity. We performed Wilcoxon matched-pairs signed-ranked test on data collected from 257 subjects, and determined that the H5N2 antibody titers of the second paired sera samples were significantly higher than those of the first samples (P < 0.001). The H5N2 antibody titers of paired sera of 13 subjects without a history of seasonal influenza vaccination within the previous 12 months increased 4-fold or more. The percentage of antibody positivity was 32% for subjects with a history of seasonal influenza vaccination (28% of all subjects) and 13% for those without a history of the same. The adjusted odds ratio of H5N2-neutralizing antibody positivity was 4.6 (95% confidence interval: 1.6-13.7) for those aged over 40 and 3.1 (95% confidence interval: 1.6-6.1) for those with a history of seasonal influenza vaccination within the previous 12 months. The results suggest that this may have been the first avian influenza H5N2 infection of poultry to affect humans. A history of seasonal influenza vaccination might be associated with H5N2-neutralizing antibody positivity.


Dorsal Root Ganglion Stimulation Modulates Cortical Gamma Activity in the Cognitive Dimension of Chronic Pain.
A cognitive task, the n-back task, was used to interrogate the cognitive dimension of pain in patients with implanted dorsal root ganglion stimulators (DRGS). Magnetoencephalography (MEG) signals from thirteen patients with implanted DRGS were recorded at rest and while performing the n-back task at three increasing working memory loads with DRGS-OFF and the task repeated with DRGS-ON. MEG recordings were pre-processed, then power spectral analysis and source localization were conducted. DRGS resulted in a significant reduction in reported pain scores (mean 23%, p = 0.001) and gamma oscillatory activity (p = 0.036) during task performance. DRGS-induced pain relief also resulted in a significantly reduced reaction time during high working memory load (p = 0.011). A significant increase in average gamma power was observed during task performance compared to the resting state. However, patients who reported exacerbations of pain demonstrated a significantly elevated gamma power (F(3,80) = 65.011612, p < 0.001, adjusted p-value = 0.01), compared to those who reported pain relief during the task. Our findings demonstrate that gamma oscillatory activity is differentially modulated by cognitive load in the presence of pain, and this activity is predominantly localized to the prefrontal and anterior cingulate cortices in a chronic pain cohort.


Eccentric exercise: acute and chronic effects on healthy and diseased tendons.
Eccentric exercise can influence tendon mechanical properties and matrix protein synthesis. mRNA for collagen and regulatory factors thereof are upregulated in animal tendons, independent of muscular contraction type, supporting the view that tendon, compared with skeletal muscle, is less sensitive to differences in type and/or amount of mechanical stimulus with regard to expression of collagen, regulatory factors for collagen, and cross-link regulators. In overused (tendinopathic) human tendon, eccentric exercise training has a beneficial effect, but the mechanism by which this is elicited is unknown, and slow concentric loading appears to have similar beneficial effects. It may be that tendinopathic regions, as long as they are subjected to a certain magnitude of load at a slow speed, independent of whether this is eccentric or concentric in nature, can reestablish their normal tendon fibril alignment and cell morphology.


Analyte and matrix problems in the calibration and quality assessment of the bromocresol green method for albumin in serum.
Different batches of bromocresol green were used in a study of several modifications of the bromocresol green method for serum albumin. No major batch variation was observed. Lyophilized animal sera and a certain batch of lyophilized human sera, however, responded differently from a pool of fresh human sera when the method was modified. These phenomena should be taken into account in calibration procedures and in quality assessment.


Long-distance dispersal of plants.
Long-distance dispersal (LDD) of plants poses challenges to research because it involves rare events driven by complex and highly stochastic processes. The current surge of renewed interest in LDD, motivated by growing recognition of its critical importance for natural populations and communities and for humanity, promises an improved, quantitatively derived understanding of LDD. To gain deep insights into the patterns, mechanisms, causes, and consequences of LDD, we must look beyond the standard dispersal vectors and the mean trend of the distribution of dispersal distances. "Nonstandard" mechanisms such as extreme climatic events and generalized LDD vectors seem to hold the greatest explanatory power for the drastic deviations from the mean trend, deviations that make the nearly impossible LDD a reality.


An estrogen receptor pathway regulates the telogen-anagen hair follicle transition and influences epidermal cell proliferation.
The hair follicle is a cyclic, self renewing epidermal structure which is thought to be controlled by signals from the dermal papilla, a specialized cluster of mesenchymal cells within the dermis. Topical treatments with 17-beta-estradiol to the clipped dorsal skin of mice arrested hair follicles in telogen and produced a profound and prolonged inhibition of hair growth while treatment with the biologically inactive stereoisomer, 17-alpha-estradiol, did not inhibit hair growth. Topical treatments with ICI 182,780, a pure estrogen receptor antagonist, caused the hair follicles to exit telogen and enter anagen, thereby initiating hair growth. Immunohistochemical staining for the estrogen receptor in skin revealed intense and specific staining of the nuclei of the cells of the dermal papilla. The expression of the estrogen receptor in the dermal papilla was hair cycle-dependent with the highest levels of expression associated with the telogen follicle. 17-beta-Estradiol-treated epidermis demonstrated a similar number of 5-bromo-2'-deoxyuridine (BrdUrd) S-phase cells as the control epidermis above telogen follicles; however, the number of BrdUrd S-phase basal cells in the control epidermis varied according to the phase of the cycle of the underlying hair follicles and ranged from 2.6% above telogen follicles to 7.0% above early anagen follicles. These findings indicate an estrogen receptor pathway within the dermal papilla regulates the telogen-anagen follicle transition and suggest that diffusible factors associated with the anagen follicle influence cell proliferation in the epidermis.


Identification of a renal proximal tubular cell-specific enhancer in the mouse 25-hydroxyvitamin d 1alpha-hydroxylase gene.
The active form of vitamin D is synthesized by 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha-hydroxylase), which is expressed predominantly in renal proximal tubular cells. To clarify the mechanism of cell-specific gene expression of this enzyme, the 5'-flanking region of the mouse 1alpha-hydroxylase gene was investigated. Investigation began with mRNA expression of 1alpha-hydroxylase in cultured cells, including LLC-PK1, NIH/3T3, HepG2, MDCK, and OK cells. Expression of 1alpha-hydroxylase mRNA was restricted in LLC-PK1 cells. Several lengths of the 5'-flanking region of 1alpha-hydroxylase gene were linked to a pGL3-basic luciferase vector and introduced into these cells. Only LLC-PK1 cells had a substantial luciferase activity. Deletion analyses revealed that luciferase activity was detected in constructs extending from the transcription initiation site to -1652 to -105 bp, whereas further deletion to -80 bp resulted in a marked decrease in activity. The region from -105 to -80 bp contained two ternary complex factor-1 (TCF-1) sites, and mutations in the proximal TCF-1 site decreased the activity. Electrophoretic mobility shift assay demonstrated binding of LLC-PK1 nuclear proteins to this region. Tests of enhancer function in LLC-PK1 cells indicated that the 26-bp fragment behaved as a classical enhancer, i.e., independently of position and orientation. Moreover, a decoy oligonucleotide corresponding to this region substantially inhibited the promoter activity of 1alpha-hydroxylase gene. This study suggests that the -105 to -80 bp element of mouse 1alpha-hydroxylase gene contains an enhancer to be necessary for renal proximal tubular cell-specific expression.


Sustainable primary health care services in rural and remote areas: innovation and evidence.
To highlight how evidence from studies of innovative rural and remote models of service provision can inform global health system reform in order to develop appropriate, accessible and sustainable primary health care (PHC) services to 'difficult-to-service' communities. The paper synthesises evidence from remote and rural PHC health service innovations in Australia. There is a strong history of PHC innovation in Australia. Successful health service models are 'contextualised' to address diverse conditions. They also require systemic solutions, which address a range of interlinked factors such as governance, leadership and management, adequate funding, infrastructure, service linkages and workforce. An effective systemic approach relies on alignment of changes at the health service level with those in the external policy environment. Ideally, every level of government or health authority needs to agree on policy and funding arrangements for optimal service development. A systematic approach in addressing these health system requirements is also important. Service providers, funders and consumers need to know what type and level of services they can reasonably expect in different community contexts, but there are gaps in agreed indicators and benchmarks for PHC services. In order to be able to comprehensively monitor and evaluate services, as well as benchmarks, we need adequate national information systems. Despite the gaps in our knowledge, we do have a significant amount of information about what works, where and why. At a time of global PHC reform, applying this knowledge will contribute significantly to the development of appropriate, sustainable PHC services and improving access.


Developmentally regulated mRNAs in 3T3-adipocytes: analysis of transcriptional control.
We have investigated the regulation of mRNA synthesis during 3T3-adipocyte differentiation by measuring the transcription of specific genes in isolated preadipocyte and adipocyte nuclei. Transcription was assayed by hybridization of newly synthesized RNA to cDNA clones coding for glycerophosphate dehydrogenase (GPD), the induced protein of 13K which is shown here to be related to myelin protein P-2, the induced protein of 28K, actin, and two RNAs that are not developmentally regulated. Transcription of GPD and 13K was observed in adipocyte but not preadipocyte nuclei. Actin was transcribed in both types of nuclei but at a lower level in adipocytes. For most of the RNAs examined, there was a consistent relationship between amounts of nuclear transcription and the abundance of the corresponding cytoplasmic mRNA in adipocytes. However, 13K and 28K mRNAs are 10-100 times more abundant than would be predicted by their nuclear transcription alone. Preliminary mRNA turnover experiments in which 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole was used to inhibit mRNA synthesis suggest that these mRNAs are much more stable in the adipocyte cytoplasm than the other mRNAs examined. These results indicate that the transcription of specific genes is increased during adipocyte differentiation and suggest that other levels of control, particularly mRNA stability, may contribute to the relative abundance of certain developmentally-regulated mRNAs in adipocytes.


Design-functionality relationships for adhesion/growth-regulatory galectins.
Glycan-lectin recognition is assumed to elicit its broad range of (patho)physiological functions via a combination of specific contact formation with generation of complexes of distinct signal-triggering topology on biomembranes. Faced with the challenge to understand why evolution has led to three particular modes of modular architecture for adhesion/growth-regulatory galectins in vertebrates, here we introduce protein engineering to enable design switches. The impact of changes is measured in assays on cell growth and on bridging fully synthetic nanovesicles (glycodendrimersomes) with a chemically programmable surface. Using the example of homodimeric galectin-1 and monomeric galectin-3, the mutual design conversion caused qualitative differences, i.e., from bridging effector to antagonist/from antagonist to growth inhibitor and vice versa. In addition to attaining proof-of-principle evidence for the hypothesis that chimera-type galectin-3 design makes functional antagonism possible, we underscore the value of versatile surface programming with a derivative of the pan-galectin ligand lactose. Aggregation assays with N,N'-diacetyllactosamine establishing a parasite-like surface signature revealed marked selectivity among the family of galectins and bridging potency of homodimers. These findings provide fundamental insights into design-functionality relationships of galectins. Moreover, our strategy generates the tools to identify biofunctional lattice formation on biomembranes and galectin-reagents with therapeutic potential.


H-2-linked genetic control of murine T-cell-mediated lympholysis to autologous cells modified with low concentrations of trinitrobenzene sulfonate.
Spleen cells from B10.BR and C57BL/10 (B10) mice were compared for their ability to generate primary in vitro cytotoxic responses to syngeneic cells modified with different concentrations (from 10 to 0.031 mM) of trinitrobenzene sulfonate (TNBS) (TNP-self). Although both strains generated effector cells to TNP-self in the range of 10-0.25 mM TNBS modification, effector activity of B10 cells was weaker than that of B10.BR cells. B10 spleen cells did not respond to syngeneic stimulating cells modified at 0.1 mM or lower, whereas B10.BR cells generated effector activity even when stimulated by TNP-self modified with as low as 0.031 mM TNBS. Fluorescence analysis of the modified cells using the FACS II indicated that equivalent quantities of TNP were conjugated to the surfaces of B10.BR and B10 spleen cells for any given concentration of TNBS modification. Similar strain-dependent differences were observed when the TNP was diluted out in the cultures by reducing the number of stimulating cells modified with 10 mM TNBS. These response patterns were verified by stimulating cultures of B10.BR and B10 spleen cells either with TNP conjugated to bovine serum albumin or bovine gamma globulin (B10.BR but not B10 cells responded to TNP-conjugated proteins) or with TNBS-modified glass-adherent spleen cells. The strain-dependent differences could also be detected at the effector phase, because optimally stimulated B10.BR, but not B10 effector cells, could lyse 0.1 mM TNBS-modified syngeneic target cells. The genetic parameters associated with the response and nonresponse patterns of B10.BR and B10 mice were further investigated by comparing the cytotoxic responses to low doses of TNP-self of spleen cells from the following strains: (a) C3H/HeJ (H-2k) and C3H.SW (H-2b); (b) BALB.K (H-2k) and BALb.b (h-2b); and (c) B10.A (H-2a) and B10.D2 (H-2d). The H-2k and H-2a, but not the H-2b and H-2d, strains generated cytotoxic responses to TNP-self when the syngeneic stimulators were modified with 0.1 mM TNBS. Further studies using (B10 X B10.BR)F1 responding cells and parental or F1-modified stimulating cells, indicated that the F1 cells generated cytotoxic activity to low doses of TNP in association with H-2k but not in association with H-2b self products. The results of this study indicate that H-2-linked genetic factors, expressed in the target as well as in the responding and/or stimulating cell populations, control the ability of inbred mouse strains to generate cytotoxic effector cells to low doses of TNP-self. Such dose-dependent genetic effects may be important in the regulation of immune responses activated in vivo by chronic exposure to infectious agents.


Combined small RNA and degradome sequencing reveals novel miRNAs and their targets in response to low nitrate availability in maize.
MicroRNAs (miRNAs) play an important role in the responses and adaptation of plants to many stresses including low nitrogen (LN). Characterizing relevant miRNAs will improve our understanding of nitrogen (N) use efficiency and LN tolerance and thus contribute to sustainable maize production. The objective of this study was to identify novel and known miRNAs and their targets involved in the response and adaptation of maize (Zea mays) to LN stress. MiRNAs and their targets were identified by combined analysis of deep sequencing of small RNA and degradome libraries. The identity of target genes was confirmed by gene-specific RNA ligase-mediated rapid amplification of 5' cDNA ends (RLM-RACE) and by quantitative expression analysis. Over 150 million raw reads of small RNA and degradome sequence data were generated. A total of 46 unique mature miRNA sequences belonging to 23 maize miRNA families were sequenced. Eighty-five potentially new miRNAs were identified, with corresponding miRNA* also identified for 65 of them. Twenty-five new miRNAs showed >2-fold relative change in response to LN. In addition to known miR169 species, two novel putative miR169 species were identified. Deep sequencing of miRNAs and the degradome, and RLM-RACE and quantitative polymerase chain reaction (PCR) analyses of their targets showed that miRC10- and miRC68-mediated target cleavage may play a major role among miR169 families in the adaptation to LN by maize seedlings. Small RNA and degradome sequencing combined with quantitative reverse transcription-PCR and RLM-RACE verification enabled the efficient identification of miRNAs and their target genes. The generated data sets and the two novel miR169 species that were identified will contribute to our understanding of the physiological basis of adaptation to LN stress in maize plants.


Cartilage nominal strain correlates with shear modulus and glycosaminoglycans content in meniscectomized joints.
Postmeniscectomy osteoarthritis (OA) is hypothesized to be the consequence of abnormal mechanical conditions, but the relationship between postsurgical alterations in articular cartilage strain and in vivo biomechanical/biochemical changes in articular cartilage is unclear. We hypothesized that spatial variations in cartilage nominal strain (percentile thickness change) would correlate with previously reported in vivo articular cartilage property changes following meniscectomy. Cadevaric sheep knees were loaded in cyclic compression which was previously developed to mimic normal sheep gait, while a 4.7 T magnetic resonance imaging (MRI) imaged the whole joint. 3D cartilage strain maps were compared with in vivo sheep studies that described postmeniscectomy changes in shear modulus, phase lag, proteoglycan content and collagen organization/content in the articular cartilage. The area of articular cartilage experiencing high (overloaded) and low (underloaded) strain was significantly increased in the meniscectomized tibial compartment by 10% and 25%, respectively, while no significant changes were found in the nonmeniscectomized compartment. The overloaded and underloaded regions of articular cartilage in our in vitro specimens correlated with regions of in vivo shear modulus reduction. Glycosaminoglycans (GAG) content only increased at the underloaded articular cartilage but decreased at the overloaded articular cartilage. No significant correlation was found in phase lag and collagen organization/content changes with the strain variation. Comparisons between postsurgical nominal strain and in vivo cartilage property changes suggest that both overloading and underloading after meniscectomy may directly damage the cartilage matrix stiffness (shear modulus). Disruption of superficial cartilage by overloading might be responsible for the proteoglycan (GAG) loss in the early stage of postmeniscectomy OA.


Central effects of thyronamines on glucose metabolism in rats.
Thyronamines are naturally occurring, chemical relatives of thyroid hormone. Systemic administration of synthetic 3-iodothyronamine (T(1)AM) and - to a lesser extent - thyronamine (T(0)AM), leads to acute bradycardia, hypothermia, decreased metabolic rate, and hyperglycemia. This profile led us to hypothesize that the central nervous system is among the principal targets of thyronamines. We investigated whether a low dose i.c.v. infusion of synthetic thyronamines recapitulates the changes in glucose metabolism that occur following i.p. thyronamine administration. Plasma glucose, glucoregulatory hormones, and endogenous glucose production (EGP) using stable isotope dilution were monitored in rats before and 120 min after an i.p. (50 mg/kg) or i.c.v. (0.5 mg/kg) bolus infusion of T(1)AM, T(0)AM, or vehicle. To identify the peripheral effects of centrally administered thyronamines, drug-naive rats were also infused intravenously with low dose (0.5 mg/kg) thyronamines. Systemic T(1)AM rapidly increased EGP and plasma glucose, increased plasma glucagon, and corticosterone, but failed to change plasma insulin. Compared with i.p.-administered T(1)AM, a 100-fold lower dose administered centrally induced a more pronounced acute EGP increase and hyperglucagonemia while plasma insulin tended to decrease. Both systemic and central infusions of T(0)AM caused smaller increases in EGP, plasma glucose, and glucagon compared with T(1)AM. Neither T(1)AM nor T(0)AM influenced any of these parameters upon low dose i.v. administration. We conclude that central administration of low-dose thyronamines suffices to induce the acute alterations in glucoregulatory hormones and glucose metabolism following systemic thyronamine infusion. Our data indicate that thyronamines can act centrally to modulate glucose metabolism.


Photosynthetic symmetry of sun and shade leaves of different orientations.
The photosynthetic responses to light of leaves irradiated on the adaxial or abaxial surfaces, were measured for plants with contrasting leaf orientations. For vertical-leaf species of open habitats (Eryngium yuccifolium and Silphium terebinthinaceum), photosynthetic rates were identical when irradiated on either surface. However, for horizontal-leaf species of open habitats (Ambrosia trifida and Solidago canadensis), light-saturated rates of photosynthesis for adaxial irradiation were 19 to 37% higher than rates for abaxial irradiation. Leaves of understory plants (Asarum canadense and Hydrophyllum canadense) were functionally symmetrical although they had horizontal orientation. Photosynthetic rates were measured at saturating CO2, thus differences in the response to incident irradiance presumably resulted from complex interactions of light and leaf optical properties rather than from stomatal effects. Differences in absorptance (400-700 nm) among leaf surfaces were evident for horizontal-leaf species but the primary determinant of functional symmetry was leaf anatomy. Functionally symmetrical leaves had upper and lower palisade layers of equal thickness (vertical leaves of open habitats) or were composed primarily of a single layer of photosynthetic cells (horizontal leaves of understory habitats). Photosynthetic symmetry of vertical-leaf species may be an adaptation to maximize daily integrated carbon gain and water-use efficiency, whereas asymmetry of horizontal-leaf species may be an adaptation to maximize daily integrated carbon gain and photosynthetic nutrient-use efficiency.


Low carbohydrate diets improve atherogenic dyslipidemia even in the absence of weight loss.
Because of its effect on insulin, carbohydrate restriction is one of the obvious dietary choices for weight reduction and diabetes. Such interventions generally lead to higher levels of dietary fat than official recommendations and have long been criticized because of potential effects on cardiovascular risk although many literature reports have shown that they are actually protective even in the absence of weight loss. A recent report of Krauss et al. (AJCN, 2006) separates the effects of weight loss and carbohydrate restriction. They clearly confirm that carbohydrate restriction leads to an improvement in atherogenic lipid states in the absence of weight loss or in the presence of higher saturated fat. In distinction, low fat diets seem to require weight loss for effective improvement in atherogenic dyslipidemia.


Ciguatoxin (CTX-1) modulates single tetrodotoxin-sensitive sodium channels in rat parasympathetic neurones.
The actions of the marine neurotoxin, ciguatoxin-1 (CTX-1), were investigated in isolated parasympathetic neurones from neonatal rat intracardiac ganglia using patch-clamp recording techniques. Under current clamp conditions, bath application of 1-10 nM CTX-1 caused gradual membrane depolarization and tonic action potential firing. Action potential firing ceased with depolarization beyond approximately -35 mV and application of 300 nM tetrodotoxin (TTX) repolarized the cell to its control resting potential. In cell-attached membrane patches, 1-10 nM CTX-1 in the patch pipette markedly increased the open probability of single TTX-sensitive Na+ channels in response to depolarizing voltage steps but did not alter the unitary conductance (10 pS) or reversal potential. Under steady-state conditions, CTX-1 caused spontaneous opening of single Na+ channels which did not inactivate at hyperpolarized membrane potentials. CTX-1 increases neuronal excitability by shifting the voltage of activation of TTX-sensitive Na+ channels to more negative potentials.


Trimmomatic: a flexible trimmer for Illumina sequence data.
Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.php?page=trimmomatic firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Outcome of endovascular treatment of traumatic aortic transection.
The purpose of this study was to analyze our experience of thoracic endovascular aortic repair (TEVAR) in patients with traumatic aortic transection. This was a single-center consecutive case series that was conducted at the Uppsala University Hospital, Tertiary Referral Center. There were a total of 17 consecutive patients undergoing TEVAR for traumatic thoracic aortic transection. All patients undergoing TEVAR for aortic transection were registered prospectively and their medical records were reviewed regarding technical details, mechanism of injury, and concomitant injuries. Long-term outcome was analyzed with respect to need for reintervention and survival. Between 2001 and 2010, 17 patients underwent TEVAR for traumatic aortic injury. Median age was 42 years (range, 18-77 years), and 15 of 17 patients (88%) were men. Fourteen patients had been involved in motor vehicle accidents, two had fallen from heights, and one fell off a bicycle on a slope. In all cases, the aortic injury was located in the proximity of the origin of the left subclavian artery. All patients had concomitant injuries. In all patients, a single stent graft was sufficient to exclude the injured part of the aorta. The median cover length was 120 mm (range, 100-200 mm). In-hospital mortality was 24% (4 of 17 patients). One patient died perioperatively and three postoperatively, two from brain injuries and one from multiorgan failure. After a median follow-up of 36 months (range, 10-98 months), three patients underwent reintervention (18%), each patient only once; one for a type I endoleak, and two for pseudocoarctation secondary to stent graft infolding. Two were treated endovascularly, and one had a stent graft explantation. Endovascular repair allows rapid and minimally invasive therapy in patients with traumatic aortic injury with good technical results. The outcome is highly dependent on the severity of other concurrent injuries.


Analysis of a polyadenine tract of the transforming growth factor-beta type II receptor gene in colorectal cancers by non-gel-sieving capillary electrophoresis.
We developed a method to analyze a polyadenine tract, the (A)10 repeat, within the cysteine-rich domain of the transforming growth factor-beta (TGF-beta) type II receptor gene using a non-gel-sieving capillary electrophoresis technique and applied it to the DNA diagnosis of colorectal cancers. This method consists of single-strand DNA amplification of the (A)10 repeat by an asymmetric PCR technique and capillary electrophoresis. A higher concentration of dATP in the PCR reaction mixture led to more specific amplification of the (A)10 repeat. Under the optimal electrophoretic conditions, one nucleotide difference could be determined in 8 to 32 nucleotides. One or two base deletions of the (A)10 repeat in colorectal cancers could be detected under these conditions within 30 min, and the results coincided with those obtained on DNA sequencing analyses. According to a sensitivity study, we could detect the deleted sequence if it was present in 12.5% or more of the wild-type allele. The reproducibility of this technique was satisfactory because the intraassay imprecision (CV) (n = 10) was 1.4%. These results indicate that capillary electrophoretic analysis of small repeated sequences results in easier handling and more feasible automation, compared with conventional gel electrophoretic analysis.


Protection from endotoxemia by adenoviral-mediated gene transfer of human bactericidal/permeability-increasing protein.
Sepsis represents a growing concern in high-risk patients and there has been a lack of effective preventives and therapies. Bacterial/permeability increasing protein (BPI) is a human neutrophil granule-associated defense molecule specific for Gram-negative bacteria and their products. To develop a BPI-transgene-based prophylactic or therapeutic modality, we have developed a recombinant, replication-deficient adenoviral vector expressing full-length human BPI protein (AdhBPI). The expression of BPI is under control of a murine cytomegalovirus (CMV) promoter. Using in vitro and in vivo systems, AdhBPI-mediated gene transfer led to extracellular secretion of BPI protein, which effectively neutralized endotoxin (lipopolysaccharide [LPS]) and markedly reduced the production of proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and macrophage inflammatory protein 2 (MIP-2) by freshly isolated murine alveolar macrophages. By using a mouse model of nonlethal sepsis elicited with LPS, we demonstrated that in vivo gene transfer of BPI was able to markedly inhibit the effect of a large dose of LPS on cytokine responses when injected intraperitoneally. Furthermore, such in vivo BPI gene transfer also improved the survival of mice suffering from lethal septic shock elicited by intraperitoneal injection of d-galactosamine and LPS. Thus, our results suggest that human BPI gene transfer vector has the potential to be used as a therapeutic agent for septic conditions.


The impact of smoke exposure on the clinical phenotype of alpha-1 antitrypsin deficiency in Ireland: exploiting a national registry to understand a rare disease.
Individuals with Alpha-1 antitrypsin deficiency (AATD) have mutations in the SERPINA1 gene causing genetic susceptibility to early onset lung and liver disease that may result in premature death. Environmental interactions have a significant impact in determining the disease phenotype and outcome in AATD. The aim of this study was to assess the impact of smoke exposure on the clinical phenotype of AATD in Ireland. Clinical demographics and available thoracic computerised tomography (CT) imaging were detected from 139 PiZZ individuals identified from the Irish National AATD Registry. Clinical information was collected by questionnaire. Data was analysed to assess AATD disease severity and evaluate predictors of clinical phenotype. Questionnaires were collected from 107/139 (77%) and thoracic CT evaluation was available in 72/107 (67.2%). 74% of respondents had severe Chronic Obstructive Pulmonary Disease (COPD) (GOLD stage C or D). Cigarette smoking was the greatest predictor of impairment in FEV1 and DLCO (%predicted) and the extent of emphysema correlated most significantly with DLCO. Interestingly the rate of FEV1 decline was similar in ex-smokers when compared to never-smokers. Passive smoke exposure in childhood resulted in a greater total pack-year smoking history. Radiological evidence of bronchiectasis was a common finding and associated with increasing age. The Irish National AATD Registry facilitates clinical and basic science research of this condition in Ireland. This study illustrates the detrimental effect of smoke exposure on the clinical phenotype of AATD in Ireland and the benefit of immediate smoking cessation at any stage of lung disease.


TEST FUSION IN ADULT FORAMINIFERA: A REVIEW WITH NEW OBSERVATIONS OF AN EARLY EOCENE NUMMULITES SPECIMEN.
In foraminifera, so-called "double tests" usually arise due to abnormal growth originating mainly from twinning, but may also be caused by irregularities in the early chambers and by regeneration after test injury that modifies the direction of growth. A fourth cause of double tests has only rarely been reported: the fusion of the tests of two adult individuals. We studied an early Eocene Nummulites double test consisting of two adult individuals that fused after an extended period of independent growth. The specimen was studied using computed tomography with micrometric resolution (micro-CT) that allowed bi- and three-dimensional visualization of the internal structure. Before fusion each individual test had 30-36 chambers, which, by comparison with growth rates in recent nummulitids, implies at least three months of independent growth. After fusion, the compound test grew in two spirals that fused after about one whorl and then continued in a single spiral. To fuse their tests, either adult individuals have to be forced to do so or the allorecognition (ability to distinguish between self and another individual) mechanisms must fail. A possible explanation for the merged Nummulites tests in this study is forced fusion in attached individuals after surviving ingestion and digestion by a metazoan. Alternatively, environmental stress could lead to a failure of allorecognition mechanisms and/or foraminiferal motility. Once fused, subsequent growth seems to be determined mainly by the relative orientation of individual tests. In any case, the frequency in which adult fusion occurs remains unknown.


Pazopanib, a novel multitargeted kinase inhibitor, shows potent in vitro antitumor activity in gastric cancer cell lines with FGFR2 amplification.
Pazopanib is an orally bioavailable, ATP-competitive, multitargeted tyrosine kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, but the biologic sequences of pazopanib activities beyond antiangiogenesis are poorly defined. We used a panel of 38 gastric cancer cell lines to test the efficacy of pazopanib. In a growth inhibition assay, genomic changes indicated that pazopanib had differential effects on cell growth. Treatment of the KATO-III, OCUM-2M, SNU-16, and HSC-39 gastric cancer cell lines harboring FGFR2 amplification with pazopanib resulted in marked decreases of cell survival with IC50 in ranges of 0.1 to 2.0 μmol/L, whereas the same treatment of those cell lines without FGFR2 amplification had no growth-inhibitory effects. In the ectopic FGFR2-expressing model, treatment with the indicated concentrations of pazopanib significantly inhibited cell growth and colony formation by FGFR2-expressing NIH 3T3 cells with wild-type (WT) FGFR2 and mutant FGFR2 (S252W). Pazopanib also selectively suppressed constitutive FGFR2 signaling and phosphorylation of downstream effectors. In cell-cycle analysis, FGFR2-amplified cells underwent cell-cycle arrest at the G1-S phase after pazopanib treatment, whereas there were no significant effects on cell-cycle progression in cells without FGFR2 amplification treated with pazopanib. In addition, pazopanib increased a substantial fraction of sub-G1 only in FGFR2-amplified cells. These findings show that the activation of FGFR2 signaling by amplification may be a critical mediator of cell proliferation in a small subset of gastric cancer patients and that pazopanib may provide genotype-correlated clinical benefits beyond the setting of highly vascular tumors.


Reduction of tar, nicotine and carbon monoxide intake in low tar smokers.
Blood nicotine, cotinine, and carboxyhaemoglobin (COHb) concentrations were measured in 392 smokers (255 women and 137 men) of "middle tar" (17-22 mg), "low to middle" (11-16 mg), and "low tar" (less than 11 mg) cigarettes. Since tar intake cannot yet be measured directly, we devised an index to estimate it based on the use of measured levels of an intake marker (eg, blood nicotine) and the ratio of the tar to marker yields of the cigarettes. This approach was validated by its ability to enhance the prediction of levels of one marker by use of another. In a practical test, using COHb and the CO/nicotine yield ratio of the cigarettes, the mean blood nicotine concentration of the low tar smokers was predicted to be 31.9 ng/ml compared with the measured mean of 31.8 ng/ml. Our main findings were that despite substantial compensatory increases in inhalation, the low tar smokers took in about 25% less tar, about 15% less nicotine, and about 10% less carbon monoxide than smokers of middle and low to middle tar cigarettes. These results indicate that low tar cigarettes of the type available in Britain since the late 1970s are likely to prove less harmful than other brands. Monitoring of smoke intakes could supplement epidemiological approaches and provide earlier evidence of whether changing cigarette designs lead to any significant dosage reduction that could affect the risk of disease.


A new povidone-iodine cream for the treatment of burns. Comparison with a standard topical regimen.
A remarkable improvement in the rate of burn healing has been achieved with a mixture of povidone-iodine ointment (Betadine) and malic, benzoic and salicylic acids (MBS) (Aserbine). A study was undertaken to compare the effects of a new povidone-iodine formulation (Betadine cream) with and without MBS with povidone-iodine ointment plus MBS. All preparations were easy to apply and were readily removed, causing only mild discomfort on application in the majority of cases. A significant difference in healing times was observed between povidone-iodine cream and povidone-iodine cream plus MBS. There was also a significant difference in the decrease in the number of positive bacterial cultures between these two treatments. This applied to both superficial and deep burns. No skin sensitivity reactions were reported with any of the preparations. The addition of MBS to povidone-iodine cream did not produce as significant an improvement in results as its addition to povidone-iodine ointment.


Immunology: Dendritic Cells Pull the T Cell's Strings.
Cells communicate by sensing diffusible or surface-associated chemical signals, with the surface-associated molecules also providing mechanical cues. New work now shows that both chemical and mechanical signals are critical for the communication between T cells and antigen-presenting dendritic cells in the initiation and maintenance of immune responses.


Parental depression, family functioning and obesity among African American children.
Obesity has reached an epidemic level in America (National Center for Health Statistics [NCHS] 1999), and this epidemic is more acute for African Americans than for other groups of Americans. In this study, 44 parent-child dyads completed measurements of height, depression, and body fat composition. In addition, parents completed a demographic questionnaire, and instruments, which measured family functioning, parental psychopathology, child behavior, and cardiovascular risks. Several models emerged for predicting childhood and parental body mass index, parental depression, and child behavioral problems. Findings indicated a role for parental depression in childhood obesity. These findings are discussed in light of Bandura's Social Cognitive Theory, and the family's role in childhood obesity.


Adapting the severe mental illness physical Health Improvement Profile for use in primary care.
People with severe mental illness (SMI) have a higher incidence of long-term physical conditions, including diabetes and cardiovascular disease. This can dramatically reduce their life expectancy. In the UK, it is the duty of health-care professionals in primary care to monitor the physical health of this group of people. However, these professionals have been given no specific training in order to do this effectively. The Northampton Physical Health and Well-Being Project has been developed in order to reduce the mortality of people with SMI, improve their physical and emotional health, and increase their support network. We have adapted the Health Improvement Profile (a tool to help mental health nurses profile the physical health of people with SMI) for use in primary care by creating a manual and website and will provide bespoke training in its use to the health-care professionals.


The morphology of heart development in Xenopus laevis.
We have used serial histological sections to document heart formation in Xenopus laevis, from the formation of a linear heart tube to the appearance of morphologically distinct atrial and ventricular chambers. 3D reconstruction techniques have been used to derive accurate models from digital images, revealing the morphological changes that accompany heart differentiation. To demonstrate the utility of this approach in analysing cardiac gene expression, we have reexamined the distribution of Hand1 transcripts in the linear and looped heart tube. Our results demonstrate that prior to looping, an initial asymmetric, left-sided pattern is replaced by more symmetrical localisation of transcripts to the ventral portion of the myocardium. After the onset of looping, Hand1 expression is restricted to the ventral ventricular myocardium and extends along the entire length of the single ventricle.


Application of Silver Nanoparticles in the Multicomponent Reaction Domain: A Combined Catalytic Reduction Methodology to Efficiently Access Potential Hypertension or Inflammation Inhibitors.
The catalytic efficacy of silver nanoparticles was investigated toward the chemoselective reduction of nitro-tetrazole or amino acid-substituted derivatives into the corresponding amines in high isolated yields. This highly efficient protocol was thereafter applied toward the multicomponent reaction synthesis of heterocyclic dihydroquinoxalin-2-ones with high isolated yields. The reaction proceeds with low catalyst loading (0.8-1.4 mol %) and under mild catalytic conditions, a very good functional-group tolerance, and high yields and can be easily scaled up to more than 1 mmol of product. Thus, the present catalytic methodology highlights a useful synthetic application. Different molecules are designed and accordingly synthesized with the current protocol that could play the role of inhibitors of the soluble epoxide hydrolase, an important target for therapies against hypertension or inflammation.


A proposed method to determine fumonisin exposure from maize consumption in a rural South African population using a culturally appropriate FFQ.
To develop an FFQ for estimating culture-specific maize intake that can distinguish between home-grown and commercial maize. Home-grown maize is more likely to be contaminated with fumonisins, mycotoxins that are associated with increased risk of oesophageal cancer. An existing FFQ developed for use in urban Xhosa populations was used as the initial framework for the maize-specific FFQ (M-FFQ). The existing questionnaire contained 126 food items divided into ten food groups (bread, cereals, vegetables, fruit, meat, dairy, snacks, condiments, beverages and fat). The M-FFQ was developed based on additional data obtained from a literature search, 24 h recalls (n 159), in-depth interviews (n 4), focus group discussions (n 56) and expert consultation. Food items available in local shops (n 3) were compared with information obtained from focus group discussions. Five villages in two rural isiXhosa-speaking areas of the Eastern Cape Province, known to have a high incidence of oesophageal cancer, were randomly selected. Women aged 18-55 years were recruited by snowball sampling and invited to participate. The final M-FFQ comprised twenty-one maize-based food items, including traditional Xhosa dishes and beverages. The questionnaire focused on maize-specific dishes and distinguished between home-grown maize and commercial maize consumption. A culturally specific dietary assessment method was designed to determine maize consumption and therefore fumonisin exposure. The questionnaire will be tested against 24 h recalls and other methods to determine its validity, after which it will be used in various epidemiological studies to determine fumonisin exposure.


Combination of aminocaproic acid and nicardipine in treatment of aneurysmal subarachnoid hemorrhage.
Antifibrinolytic drugs reduce the risk of rebleeding during the first 2 weeks after aneurysmal subarachnoid hemorrhage. However, they do not lower overall mortality, largely because of an increased incidence of cerebral ischemia. The usefulness of antifibrinolytic drugs might be increased if a method to prevent or control vasospasm in patients were to be developed. We recently completed late Phase I and Phase II studies of the calcium ion blocking drug nicardipine in 67 patients treated within 1 week of subarachnoid hemorrhage. Of these 67 patients, 42 had delayed operations and were treated concomitantly with the antifibrinolytic drug aminocaproic acid (1.5 g/hr) for an average of 6 days before surgery. The outcome of these 42 patients is the subject of this report. Fifteen of 42 patients were treated with the lower dosage levels of nicardipine (0.4-4.5 mg/m2/hr), and 27 patients were treated at the highest dosage level (6.0 mg/m2/hr). Using the World Federation of Neurological Surgeons scale for subarachnoid hemorrhage, at admission 18 patients were Grade I, 15 were Grade II, 6 were Grade III, and 3 were Grade IV. Five patients (12%) developed clinical signs of deterioration suggestive of cerebral ischemia with concomitant evidence of vasospasm on arteriography. These patients were all treated with hypervolemic hypertensive therapy. Only one patient (2%) developed an infarction from vasospasm. Two patients developed symptomatic hydrocephalus requiring ventriculoperitoneal shunting, and a third patient required a temporary ventriculostomy. The 3-month postoperative outcomes were excellent. Three patients (7%) rebled. Three patients died, two from rebleeding of the aneurysm and one who never regained consciousness from the initial hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)


Growth and self-assembly of ultrathin Au nanowires into expanded hexagonal superlattice studied by in situ SAXS.
We report the self-assembly of gold nanowires into hexagonal superlattices in liquid phase followed by in situ small-angle X-ray scattering and give new insights into their growth mechanism. The unprecedented large interwire distance of 8 nm strongly suggests the stabilization of the ultrathin gold nanowires by a ligand's double layer composed of oleylamine and oleylammonium chloride. The one-dimensional growth is discussed, opening perspectives toward the control growth and self-assemblies of metallic nanowires.


A 10-Year Longitudinal Study of Effects of a Multifaceted Residency Spiritual Care Curriculum: Clinical Ability, Professional Formation, End of Life, and Culture.
Although spiritual care (SC) is recognized as important in whole-person medicine, physicians infrequently address patients' spiritual needs, citing lack of training. Although many SC curricula descriptions exist, few studies report effects on physicians. To broadly examine immediate and long-term effects of a required, longitudinal, residency SC curriculum, which emphasized inclusive patient-centered SC, compassion, and spiritual self-care. We conducted in-depth individual interviews with 26 physicians (13 intervention; 13 comparison) trained at a 13-13-13 residency. We interviewed intervention physicians three times over 10 years-1) preintervention, as PGY1s, 2) postintervention, as PGY3s, 3) eight-year postintervention, as practicing physicians. We interviewed comparison physicians as PGY3s. Interviews were audio-recorded, transcribed, and analyzed by four researchers. Forty-nine interviews were analyzed. General: Both groups were diverse regarding personal importance of spirituality/religion. All physicians endorsed the value of SC, sharing rich patient stories particularly related to end of life and cultural diversity. Curricular effects: 1) skills/barriers-intervention physicians demonstrated progressive improvements in clinical approach, accompanied by diminishing worries related to SC. PGY3 comparison physicians struggled with SC skills and worries more than PGY3 intervention physicians, 2) physician formation-most physicians described residency as profoundly challenging and transformative. Even after eight years, many intervention physicians noted that reflection on their diverse beliefs and values in safety, coupled with compassion shown to them through this curriculum, had deeply positive effects. High impact training: patient-centered spiritual assessment; chaplain rounds; spiritual self-care workshop/retreats; multicultural SC framework. A longitudinal, multifaceted residency SC curriculum can have lasting positive effects on physicians' SC skills and their professional/personal formation.


Exercise effects in Huntington disease.
Huntington disease (HD) is a relentlessly progressive neurodegenerative disorder with symptoms across a wide range of neurological domains, including cognitive and motor dysfunction. There is still no causative treatment for HD but environmental factors such as passive lifestyle may modulate disease onset and progression. In humans, multidisciplinary rehabilitation has a positive impact on cognitive functions. However, a specific role for exercise as a component of an environmental enrichment effect has been difficult to demonstrate. We aimed at investigating whether endurance training (ET) stabilizes the progression of motor and cognitive dysfunction and ameliorates cardiovascular function in HD patients. Twelve male HD patients (mean ± SD, 54.8 ± 7.1 years) and twelve male controls (49.1 ± 6.8 years) completed 26 weeks of endurance training. Before and after the training intervention, clinical assessments, exercise physiological tests, and a body composition measurement were conducted and a muscle biopsy was taken from M. vastus lateralis. To examine the natural course of the disease, HD patients were additionally assessed 6 months prior to ET. During the ET period, there was a motor deficit stabilization as indicated by the Unified Huntington's Disease Rating Scale motor section score in HD patients (baseline: 18.6 ± 9.2, pre-training: 26.0 ± 13.7, post-training: 26.8 ± 16.4). Peak oxygen uptake ([Formula: see text]) significantly increased in HD patients (∆[Formula: see text] = +0.33 ± 0.28 l) and controls (∆[Formula: see text] = +0.29 ± 0.41 l). No adverse effects of the training intervention were reported. Our results confirm that HD patients are amenable to a specific exercise-induced therapeutic strategy indicated by an increased cardiovascular function and a stabilization of motor function.


Metabolic Acidosis in CKD: A Review of Recent Findings.
Metabolic acidosis is fairly common in patients with chronic kidney disease (CKD). The prevalence of metabolic acidosis increases with worsening kidney function and is observed in ∼40% of those with stage 4 CKD. For the past 2 decades, clinical practice guidelines have suggested treatment of metabolic acidosis to counterbalance adverse effects of metabolic acidosis on bone and muscle. Studies in animal models of CKD also demonstrated that metabolic acidosis causes kidney fibrosis. During the past decade, results from observational studies identified associations between metabolic acidosis and adverse kidney outcomes, and results from interventional studies support the hypothesis that treating metabolic acidosis with sodium bicarbonate preserves kidney function. However, convincing data from large-scale, double-blinded, placebo-controlled, randomized trials have been lacking. This review discusses findings from recent interventional trials of alkali therapy in CKD and new findings linking metabolic acidosis with cardiovascular disease in adults and CKD progression in children. Finally, a novel agent that treats metabolic acidosis in patients with CKD by binding hydrochloric acid in the gastrointestinal tract is discussed.


Coastal coal pollution increases Cd concentrations in the predatory gastropod Hexaplex trunculus and is detrimental to its health.
Parameters of environmental health, including paracellular permeability of external epithelia, functional state of lysosomes and the level of metallothioneins (MTs), were examined using fluorescent markers and vital microfluorometry in different tissues of the marine gastropod, Hexaplex trunculus, from a coal-polluted and coal-free site. Vital microfluorometrical examinations exhibited enhanced paracellular permeability of external epithelia to the anionic marker, fluorescein (FLU), lower lysosomal accumulation of neutral red (NR) as well as higher levels of MTs, when compared with epithelia of gastropods from the coal-free site. Those differences were particularly marked in the foot epithelium, which is in direct contact with the substrate. In addition, cadmium was measured by ICP-AES in the hepatopancreas of gastropods sampled from the coal-polluted site and two coal-free sites. Significantly higher levels of Cd were found in gastropod hepatopancreas from the coal-polluted site. In addition, two months feeding experiments conducted in aquaria containing: (a) coal pieces covered by barnacles; (b) natural rocks covered by barnacles; and (c) natural rocks with barnacles + bare coal pieces, demonstrated significant increase of Cd concentration in the hepatopancreas of the gastropods exposed to coal. We suggest that coal in the marine environment has detrimental effects on marine gastropods, both directly through contact with the organisms and indirectly through the food web.


A discrete time-space geography for epidemiology: from mixing groups to pockets of local order in pandemic simulations.
The World Health Organization urges all nations to develop and maintain national influenza preparedness plans. Important components of such plans are forecasts of morbidity and mortality based on local social and geographic conditions. Most methodologies for simulations of epidemic outbreaks are implicitly based on the assumption that the frequency and duration of social contacts that lead to disease transmission is affected by geography, i.e. the spatial distribution of physical meeting places. In order to increase the effectiveness of the present methods for simulation of infectious disease outbreaks, the aim of this study is to examine two social geographic issues related to such models. We display how the social geographic characteristics of mixing networks, in particular when these significantly deviate from the random-mixing norm, can be represented in order to enhance the understanding and prediction of epidemic patterns in light of a possible future destructive influenza pandemic. We conclude that social geography, social networks and simulation models of directly transmitted infectious diseases are fundamentally linked.


Effects of increasing and decreasing physiological arousal on anticipation timing performance during competition and practice.
The aim of this study was to investigate if the effects of changes in physiological arousal on timing performance can be accurately predicted by the catastrophe model. Eighteen young adults (8 males, 10 females) volunteered to participate in the study following ethical approval. After familiarisation, coincidence anticipation was measured using the Bassin Anticipation Timer under four incremental exercise conditions: Increasing exercise intensity and low cognitive anxiety, increasing exercise intensity and high cognitive anxiety, decreasing exercise intensity and low cognitive anxiety and decreasing exercise intensity and high cognitive anxiety. Incremental exercise was performed on a treadmill at intensities of 30%, 50%, 70% and 90% heart rate reserve (HRR) respectively. Ratings of cognitive anxiety were taken at each intensity using the Mental Readiness Form 3 (MRF3) followed by performance of coincidence anticipation trials at speeds of 3 and 8 mph. Results indicated significant condition × intensity interactions for absolute error (AE; p = .0001) and MRF cognitive anxiety intensity scores (p = .05). Post hoc analysis indicated that there were no statistically significant differences in AE across exercise intensities in low-cognitive anxiety conditions. In high-cognitive anxiety conditions, timing performance AE was significantly poorer and cognitive anxiety higher at 90% HRR, compared to the other exercise intensities. There was no difference in timing responses at 90% HRR during competitive trials, irrespective of whether exercise intensity was increasing or decreasing. This study suggests that anticipation timing performance is negatively affected when physiological arousal and cognitive anxiety are high.


Development of a freshwater aquatic toxicity database for ambient water quality criteria for methyl tertiary-butyl ether.
The detection of methyl tertiary-butyl ether (MTBE) in groundwater and surface water in recent years has drawn attention to its potential effects in aquatic ecosystems. To address concerns regarding MTBE environmental effects and to establish safe concentrations in surface waters, a collaborative effort was initiated in 1997 to develop aquatic toxicity databases sufficient to derive ambient water quality criteria for MTBE consistent with United States Environmental Protection Agency (U.S. EPA) requirements. Acute toxicity data for six species, chronic toxicity data for a fish and an invertebrate, and plant toxicity data were developed in order to complete the freshwater database. The toxicity tests followed U.S. EPA and American Society for Testing and Materials (ASTM, Philadelphia, PA, USA) procedures and were conducted in accordance with U.S. EPA Good Laboratory Practice guidelines. Based on measured exposure concentrations, acute toxicity endpoints ranged from 472 to 1742 mg MTBE/L, while chronic endpoints (IC25) were 57 to 308 mg MTBE/L. Aquatic invertebrates were generally more sensitive than fish to MTBE in both acute and chronic exposures. Acute-to-chronic ratios for fathead minnows and Daphnia magna were 3.4 and 11.3, respectively. The measured acute and chronic toxicity were within a 10-fold factor of toxicity predicted from quantitative structure-activity relationships for baseline toxicity or nonpolar narcosis typical of ether compounds. The data developed in this study were consistent with existing data and showed that MTBE has low acute and chronic toxicity to freshwater organisms. Reported environmental concentrations of MTBE are several orders of magnitude lower than concentrations observed to cause effects in freshwater organisms.


Implementing case-based teaching strategies in a decentralised nursing management programme in South Africa.
Case-based education has a long history in the disciplines of education, business, law and the health professions. Research suggests that students who learn via a case-based method have advanced critical thinking skills and a greater ability for application of knowledge in practice. In medical education, case-based methodology is widely used to facilitate knowledge transfer from theoretical knowledge to application in patient care. Nursing education has also adopted case-based methodology to enhance learner outcomes and critical thinking. The objectives of the study was to describe a decentralised nursing management education programme located in Durban, South Africa and describe the perceptions of nursing faculty facilitators regarding implementation of this teaching method. Data was collected through the use of one-on-one interviews and also focus groups amongst the fifteen facilitators who were using a case-based curriculum to teach the programme content. The average facilitator was female, between 41 and 50 years of age, working part-time, educated with a baccalaureate degree, working as a professional nurse for between 11 and 20 years; slightly more than half had worked as a facilitator for three or more years. The facilitators identified themes related to the student learners, the learning environment, and strengths and challenges of using facilitation to teach the content through cases. Decentralised nursing management educational programmes can meet the needs of nurses who are located in remote areas which are characterised by poor transportation patterns and limited resources and have great need for quality healthcare services. Nursing faculty facilitators need knowledgeable and accessible contact with centrally based full-time nursing faculty in order to promote high quality educational programmes.


Host cell phosphatidylcholine is a key mediator of malaria parasite survival during liver stage infection.
During invasion, Plasmodium, the causative agent of malaria, wraps itself in a parasitophorous vacuole membrane (PVM), which constitutes a critical interface between the parasite and its host cell. Within hepatocytes, each Plasmodium sporozoite generates thousands of new parasites, creating high demand for lipids to support this replication and enlarge the PVM. Here, a global analysis of the total lipid repertoire of Plasmodium-infected hepatocytes reveals an enrichment of neutral lipids and the major membrane phospholipid, phosphatidylcholine (PC). While infection is unaffected in mice deficient in key enzymes involved in neutral lipid synthesis and lipolysis, ablation of rate-limiting enzymes in hepatic PC biosynthetic pathways significantly decreases parasite numbers. Host PC is taken up by both P. berghei and P. falciparum and is necessary for correct localization of parasite proteins to the PVM, which is essential for parasite survival. Thus, Plasmodium relies on the abundance of these lipids within hepatocytes to support infection.


Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis.
Angiogenesis promotes tumor development. Understanding the crucial factors regulating tumor angiogenesis may reveal new therapeutic targets. Human GT198 (PSMC3IP or Hop2) is an oncoprotein encoded by a DNA repair gene that is overexpressed in tumor stromal vasculature to stimulate the expression of angiogenic factors. Here we show that pericytes expressing GT198 give rise to tumor cells through angiogenesis. GT198+ pericytes and perivascular cells are commonly present in the stromal compartment of various human solid tumors and rodent xenograft tumor models. In human oral cancer, GT198+ pericytes proliferate into GT198+ tumor cells, which migrate into lymph nodes. Increased GT198 expression is associated with increased lymph node metastasis and decreased progression-free survival in oral cancer patients. In rat brain U-251 glioblastoma xenografts, GT198+ pericytes of human tumor origin encase endothelial cells of rat origin to form mosaic angiogenic blood vessels, and differentiate into pericyte-derived tumor cells. The net effect is continued production of glioblastoma tumor cells from malignant pericytes via angiogenesis. In addition, activation of GT198 induces the expression of VEGF and promotes tube formation in cultured U251 cells. Furthermore, vaccination using GT198 protein as an antigen in mouse xenograft of GL261 glioma delayed tumor growth and prolonged mouse survival. Together, these findings suggest that GT198-expressing malignant pericytes can give rise to tumor cells through angiogenesis, and serve as a potential source of cells for distant metastasis. Hence, the oncoprotein GT198 has the potential to be a new target in anti-angiogenic therapies in human cancer.


The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells.
The adhesion molecule L1, which is extensively characterized in the nervous system, is also expressed in dendritic cells (DCs), but its function there has remained elusive. To address this issue, we ablated L1 expression in DCs of conditional knockout mice. L1-deficient DCs were impaired in adhesion to and transmigration through monolayers of either lymphatic or blood vessel endothelial cells, implicating L1 in transendothelial migration of DCs. In agreement with these findings, L1 was expressed in cutaneous DCs that migrated to draining lymph nodes, and its ablation reduced DC trafficking in vivo. Within the skin, L1 was found in Langerhans cells but not in dermal DCs, and L1 deficiency impaired Langerhans cell migration. Under inflammatory conditions, L1 also became expressed in vascular endothelium and enhanced transmigration of DCs, likely through L1 homophilic interactions. Our results implicate L1 in the regulation of DC trafficking and shed light on novel mechanisms underlying transendothelial migration of DCs. These observations might offer novel therapeutic perspectives for the treatment of certain immunological disorders.


Comparing exercise interventions to increase persistence with physical exercise and sporting activity among people with hypertension or high normal blood pressure: study protocol for a randomised controlled trial.
Increasing physical activity is known to have health benefits for people with hypertension and related conditions. Current general practitioner referrals for gym-based exercise increase physical activity but meta-analyses show that while these are effective the absolute health risk reduction is small due to patients failing to maintain activity levels over time. This study assesses the effectiveness of two sports-oriented interventions that are intended to bridge the intention-behaviour gap and thus increase the likelihood of sustained increases in physical activity. Four-arm randomised controlled trial. The study tests two types of intervention that are intended to increase physical activity among currently inactive 18- to 74-year-old people with hypertension or high-normal blood pressure. This study will assess the effectiveness of a 12-week sports-oriented exercise programme, the efficacy of a web-delivered self-help tool to promote and support sports participation and healthy behaviour change and the effect of these interventions in combination. The control arm will be a standard care general practitioner referral for gym-based exercise. Participants will be allocated using block randomisation. The first author and primary analyst is blinded to participant allocation. The primary outcome measures will be time spent in physical activity assessed in metabolic equivalent minutes per week using the International Physical Activity Questionnaire 1 year after commencement of the intervention. Secondary outcomes include increased involvement in sporting activity and biomedical health outcomes including change in body mass index, and waist and hip measurement and reductions in blood pressure. If proven to be superior to general practitioner referrals for gym-based exercise, these sports-oriented interventions would constitute low-cost alternatives. The next stage would be a full economic evaluation of the interventions. Current Controlled Trials ISRCTN71952900 (7 June 2013).


Sequence and properties of pIM13, a macrolide-lincosamide-streptogramin B resistance plasmid from Bacillus subtilis.
We initiated a study of pIM13, a multicopy, macrolide-lincosamide-streptogramin B (MLS) plasmid first isolated from a strain of Bacillus subtilis and described by Mahler and Halvorson (J. Gen. Microbiol. 120:259-263, 1980). The copy number of this plasmid was about 200 in B. subtilis and 30 in Staphylococcus aureus. The MLS resistance determinant of pIM13 was shown to be highly homologous to ermC, an inducible element on the S. aureus plasmid pE194. The product of the pIM13 determinant was similar in size to that of ermC and immunologically cross-reactive with it. The MLS resistance of pIM13 was expressed constitutively. The complete base sequence of pIM13 is presented. The plasmid consisted of 2,246 base pairs and contained two open reading frames that specified products identified in minicell extracts. One was a protein of 16,000 molecular weight, possibly required for replication. The second was the 29,000-molecular-weight MLS resistance methylase. The regulatory region responsible for ermC inducibility was missing from pIM13, explaining its constitutivity. The remainder of the pIM13 MLS determinant was nearly identical to ermC. The ends of the region of homology between pIM13 and pE194 were associated with hyphenated dyad symmetries. A segment partially homologous to one of these termini on pIM13 and also associated with a dyad was found in pUB110 near the end of a region of homology between that plasmid and pBC16. The entire sequence of pIM13 was highly homologous to that of pE5, an inducible MLS resistance plasmid from S. aureus that differs from pIM13 in copy control.


[Hydredynamic bench for pulsatile flows. Application to hemodynamic studies (author's transl)].
Oscillatory or pulsatile flows are produced on a hydrodynamic bench by a volumetric gear pump. The moto-pump group is an original device which is very different from other systems. It is driven by a wave synthesizing generator which enables any flow rate to be produced especially oscillatory, pulsatile or physiological flow. The synthesizing generator delivers a periodic wave with variable amplitude, shape and frequency. The moto-pump group is controlled by an amplifying comparator; it produces a flow whose rate follows the control signal. A study of the modifications of flow patterns induced by models of vascular stenoses has been performed with this bench. The study of the velocity distribution has been effected with a pulsed Doppler ultrasonic velocimeter.


The Association of Stress, Metabolic Syndrome, and Systemic Inflammation With Neurocognitive Function in the Hispanic Community Health Study/Study of Latinos and Its Sociocultural Ancillary Study.
Identifying sociocultural correlates of neurocognitive dysfunction among Hispanics/Latinos, and their underlying biological pathways, is crucial for understanding disparities in Alzheimer's disease and related dementias. We examined cross-sectional associations between stress and neurocognition, and the role that metabolic syndrome (MetS) and systemic inflammation might play in these associations. Participants included 3,045 adults aged 45-75 (56% female, education 0-20+ years, 86% Spanish-speaking, 23% U.S.-born), enrolled in the Hispanic Community Health Study/Study of Latinos and its Sociocultural Ancillary Study. Global neurocognition was the primary outcome and operationalized as the average of the z scores of measures of learning and memory, word fluency, and processing speed. Stress measures included self-report assessments of stress appraisal (perceived and acculturative stress) and exposure to chronic and traumatic stressors. MetS was defined via established criteria including waist circumference, high blood pressure, elevated triglycerides, fasting plasma glucose, and high levels of high-density lipoprotein cholesterol. Systemic inflammation was represented by high-sensitivity C-reactive protein (hs-CRP). Separate survey multivariable linear regression models adjusting for covariates showed that higher perceived (b = -0.004, SE = 0.002, p < .05) and acculturative stress (b = -0.004, SE = 0.001, p < .0001) were significantly associated with worse global neurocognition, while lifetime exposure to traumatic stressors was associated with better global neurocognition (b = 0.034, SE = 0.009, p < .001). Neither MetS nor hs-CRP were notable pathways in the association between stress and neurocognition; rather, they were both independently associated with worse neurocognition in models including stress measures (ps < .05). These cross-sectional analyses suggest that stress appraisal, MetS, and systemic inflammation may be targets to reduce neurocognitive dysfunction among Hispanics/Latinos.


Controlled propulsion of artificial magnetic nanostructured propellers.
For biomedical applications, such as targeted drug delivery and microsurgery, it is essential to develop a system of swimmers that can be propelled wirelessly in fluidic environments with good control. Here, we report the construction and operation of chiral colloidal propellers that can be navigated in water with micrometer-level precision using homogeneous magnetic fields. The propellers are made via nanostructured surfaces and can be produced in large numbers. The nanopropellers can carry chemicals, push loads, and act as local probes in rheological measurements.


HIV-1: maternal prognosis.
Profound modifications in the profile of patients are currently being observed within the epidemic context of AIDS, especially with respect to pauperization and feminization of the disease. The population most frequently affected is in the reproductive age, and among adults aged 18 to 24 years, the ratio is 1 man to 1 woman, a phenomenon occurring uniformly all over the world. One of the main challenges for HIV-1-infected pregnant women and their doctors is the effect of the interaction between HIV infection and pregnancy. The present article is a review of the literature; and its objective is to assess the influence of HIV-1 infection seen from the maternal perspective, with a discussion of immunologic function, maternal prognosis, and the HIV-abortion interface. At present, we cannot conclude that pregnancy has a short-term effect on the evolution of HIV infection, but the concomitance of HIV and pregnancy may adversely affect the prognosis of gestation, especially in view of its frequent association with increased abortion and puerperal morbidity rates.


Red cell carriage of label: its limiting effect on the exchange of materials in the liver.
The red cell membrane is a permeability barrier that limits the equilibration of a variety of solutes between red cell and plasma water. We utilized the multiple indicator dilution technique to investigate the effect of this barrier on the exchange in the liver of a group of tracer substances that are not removed in net fashion from the hepatic circulation: thiourea, urea, and chloride. We demonstrated that, after preequilibration of the label with red cells, a red cell carriage effect appeared (the trapping and translocation of label in the red cells), that this effect was most marked when the permeability of the red cell was relatively low for the substance under consideration (thiourea), and that the effect became small when the permeability of the red cells was large for the exchanging substance (urea and chloride). We developed a theoretical description of the retarding effect of the red cell permeability barrier on the extravascular exchange of label and were able to use this description to obtain estimates of the red cell permeability from the in vivo dilution curves. We examined the effect of plasma injection, of changing the input in such a fashion that the label was not preequilibrated with red cells, and found both experimentally and theoretically, that for substances of low permeability the transit time from these experiments, if multiplied by the total water flow or solute flux, gave an overestimate of both the apparent total volume of distribution and the mass of traced material in the system. This last effect is of great importance for the practical design of many biological experiments. Reliable volume and mass estimates can be made only when the labeled material has been preequilibrated with red cells.


Lifestyle physical activity for individuals with spinal cord injury: a pilot study.
To evaluate the acceptability and feasibility of a lifestyle physical activity program for people with spinal cord injury (SCI). Sixteen nonexercising adult volunteers with SCI participated in a single group pre-post-test of the "Be Active in Life Program" comprising stage-matched educational materials, home visit by a nurse, construction of a personal plan to increase activity, and four follow-up phone calls. Program acceptability, stage of change, barriers to health-promoting activities, abilities for health practices, health, depression, and muscle strength were rated. Physical activity was monitored using actigraphy and a self-report record. Participants rated the program positively, although some preferred a structured exercise approach. Eighty-one percent of participants progressed in stage of change and 60% increased physical activity. There were significant changes in motivational barriers, exercise self-efficacy, self-rated health, and muscle strength. Lifestyle physical activity is feasible and acceptable and could be effective in promoting greater physical activity among people with SCI.