Global and regional estimates of COPD prevalence: Systematic review and meta-analysis.
The burden of chronic obstructive pulmonary disease (COPD) across many world regions is high. We aim to estimate COPD prevalence and number of disease cases for the years 1990 and 2010 across world regions based on the best available evidence in publicly accessible scientific databases. We conducted a systematic search of Medline, EMBASE and Global Health for original, population-based studies providing spirometry-based prevalence rates of COPD across the world from January 1990 to December 2014. Random effects meta-analysis was conducted on extracted crude prevalence rates of COPD, with overall summaries of the meta-estimates (and confidence intervals) reported separately for World Health Organization (WHO) regions, the World Bank's income categories and settings (urban and rural). We developed a meta-regression epidemiological model that we used to estimate the prevalence of COPD in people aged 30 years or more. Our search returned 37 472 publications. A total of 123 studies based on a spirometry-defined prevalence were retained for the review. From the meta-regression epidemiological model, we estimated about 227.3 million COPD cases in the year 1990 among people aged 30 years or more, corresponding to a global prevalence of 10.7% (95% confidence interval (CI) 7.3%-14.0%) in this age group. The number of COPD cases increased to 384 million in 2010, with a global prevalence of 11.7% (8.4%-15.0%). This increase of 68.9% was mainly driven by global demographic changes. Across WHO regions, the highest prevalence was estimated in the Americas (13.3% in 1990 and 15.2% in 2010), and the lowest in South East Asia (7.9% in 1990 and 9.7% in 2010). The percentage increase in COPD cases between 1990 and 2010 was the highest in the Eastern Mediterranean region (118.7%), followed by the African region (102.1%), while the European region recorded the lowest increase (22.5%). In 1990, we estimated about 120.9 million COPD cases among urban dwellers (prevalence of 13.2%) and 106.3 million cases among rural dwellers (prevalence of 8.8%). In 2010, there were more than 230 million COPD cases among urban dwellers (prevalence of 13.6%) and 153.7 million among rural dwellers (prevalence of 9.7%). The overall prevalence in men aged 30 years or more was 14.3% (95% CI 13.3%-15.3%) compared to 7.6% (95% CI 7.0%-8.2%) in women. Our findings suggest a high and growing prevalence of COPD, both globally and regionally. There is a paucity of studies in Africa, South East Asia and the Eastern Mediterranean region. There is a need for governments, policy makers and international organizations to consider strengthening collaborations to address COPD globally.


Guidelines for Management of Urgent Symptoms in Patients with Cholangiocarcinoma and Biliary Stents or Catheters using the Modified RAND/UCLA Delphi Process.
Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20-40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The goal was to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: Thirteen expert physicians from relevant specialties, geography, and practice settings were recruited for the panel. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a scale from 1-9 and classified as appropriate, inappropriate, or uncertain. Scenarios with greater than 2 (>2) ratings of 1-3 (inappropriate) and greater than 2 (>2) ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions and the UK (8%) and had practiced for a mean 16.5 years (4-33 years). Panelists rated 480 scenarios before the meeting and re-rated 288 of the clinical scenarios after the meeting. The panelists agreed that ongoing treatment with chemotherapy did not influence decision-making and, therefore, 192 scenarios were excluded from the final list. Disagreement decreased from 37.5% before to 10.4% after the meeting. Consensus on stent/tube manipulation and inpatient antibiotic therapy was obtained and summarized in patients as "appropriate" or "maybe appropriate" based on a patient's bilirubin level at presentation. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in the urgent management of ascending cholangitis in patients with cholangiocarcinoma.


Haptic information stabilizes and destabilizes coordination dynamics.
Goal-directed, coordinated movements in humans emerge from a variety of constraints that range from 'high-level' cognitive strategies based on perception of the task to 'low-level' neuromuscular-skeletal factors such as differential contributions to coordination from flexor and extensor muscles. There has been a tendency in the literature to dichotomize these sources of constraint, favouring one or the other rather than recognizing and understanding their mutual interplay. In this experiment, subjects were required to coordinate rhythmic flexion and extension movements with an auditory metronome, the rate of which was systematically increased. When subjects started in extension on the beat of the metronome, there was a small tendency to switch to flexion at higher rates, but not vice versa. When subjects were asked to contact a physical stop, the location of which was either coincident with or counterphase to the auditory stimulus, two effects occurred. When haptic contact was coincident with sound, coordination was stabilized for both flexion and extension. When haptic contact was counterphase to the metronome, coordination was actually destabilized, with transitions occurring from both extension to flexion on the beat and from flexion to extension on the beat. These results reveal the complementary nature of strategic and neuromuscular factors in sensorimotor coordination. They also suggest the presence of a multimodal neural integration process - which is parametrizable by rate and context - in which intentional movement, touch and sound are bound into a single, coherent unit.


Inhibitory mechanism of costunolide, a sesquiterpene lactone isolated from Laurus nobilis, on blood-ethanol elevation in rats: involvement of inhibition of gastric emptying and increase in gastric juice secretion.
Basic inhibitory mechanisms of costunolide and its active component, alpha-methylene-gamma-butyrolactone (alpha-MGBL), on blood-ethanol elevation were investigated in rats. In normal rats, blood-ethanol elevation (30 min later) induced by 20% (v/v) ethanol [5 ml/kg, per os (p.o.)] was strongly inhibited by pretreatment (30 min earlier) with costunolide and alpha-MGBL (50 mg/kg, p.o.). In pylorus-ligated rats given ethanol, blood-ethanol level (30 min) was barely elevated compared with that of normal rats. Neither costunolide nor alpha-MGBL affected the blood-ethanol elevation in pylorus-ligated rats or that induced by intraperitoneal and intraduodenal ethanol administration. Moreover, these compounds given orally induced no irreversible changes in alcohol dehydrogenase activity in rat liver. We continuously investigated the rate of gastric emptying in rats given various test meals. Costunolide and alpha-MGBL suppressed gastric emptying in rats given 20% ethanol and 1% sodium carboxymethyl cellulose. alpha-MGBL (50 mg/kg), but not costunolide, suppressed gastric emptying in 20% glucose-loaded rats. In an in vitro experiment, alpha-MGBL contracted the pylorus strip at a high concentration (20 mM), which was the estimated concentration in the stomach when the substance was given orally in vivo. These findings suggested that alpha-MGBL constricted the pylorus and caused delay of gastric emptying. Moreover, both compounds increased gastric fluid secretion with pepsin and mucus. In conclusion, the inhibitory effects of costunolide and alpha-MGBL on blood-ethanol elevation were based on inhibition of gastric emptying and dilution of the ethanol concentration by the increased gastric fluid.


Physical therapy for acute low back pain: associations with subsequent healthcare costs.
Case-control. To examine the association between adherence to the evidence-based recommendation for active physical therapy care and clinical outcomes along with subsequent healthcare utilization and charges for 1 year after completion of physical therapy. Low back pain (LBP) is a common condition associated with high costs. Many patients with acute LBP receive physical therapy. The type of physical therapy care provided may impact subsequent healthcare costs. A retrospective review was undertaken of patients age 18-60 with acute (<90 days) LBP receiving physical therapy covered by 1 insurance provider. Adherence to the recommendation for active care was determined from billing records. Disability (Oswestry) and pain (numerical pain rating) were assessed at the beginning and completion of physical therapy. Subsequent healthcare utilization for LBP and charges were recorded from insurer's databases. Four hundred and seventy-one patients were included (mean age 41.2 years [SD = 11.0], 54% female), 28.0% received adherent care. Patients receiving adherent care had fewer physical therapy visits (mean difference 1.3 visits, P < 0.05) with lower charges (nontransformed mean difference $167, P < 0.05), greater improvement in pain (mean difference 12.3%, 95% confidence interval [CI]: 3.2-21.3) and disability (mean difference 17.6%, 95% CI: 11.1-24.1). During the year after discharge, receiving adherent care was associated with a lower likelihood of receiving prescription medication (46.2% vs. 57.2%, P < 0.05), magnetic resonance imaging (MRI) (8.3% vs. 15.9%, P < 0.05), or epidural injections (5.3% vs. 12.1%, P < 0.05). Adherence to the recommendation for active care was associated with better clinical outcomes and decreased subsequent use of prescription medication, MRI, and injections. Improving adherence to this recommendation may present an opportunity to improve the cost-effectiveness of care for acute LBP.


Neutralizing antibodies are associated with a reduction of interferon-β efficacy during the treatment of Japanese multiple sclerosis patients.
Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Interferon-β (IFN-β) has been used as the first line therapy for MS treatment in Japan, but patients treated with IFN-β may develop antibodies, known as neutralizing antibodies (NAbs), which abrogate its therapeutic effects. Intramuscular IFN-β 1a and subcutaneous IFN-β 1b are currently available in Japan, but large-scale studies evaluating the prevalence and clinical implications of NAbs against these IFN-β preparations in MS patients have only been performed in Caucasian populations. NAbs positivity has been reported to be associated with HLA-DRB1 alleles, suggesting that the positivity might differ among populations with distinct genetic backgrounds. Clinical information and sera were collected from 229 consecutive MS patients treated with IFN-β in 4 centers in Japan. Sera were tested for NAbs using a luciferase reporter gene assay. In total, 5.2% of IFN-β-1a-treated patients (4/77) and 30.3% of IFN-β-1b-treated patients (46/152) were positive for Nabs. The frequency of NAbs was highest in patients treated for 13 to 24 months. Clinical relapse and contrast-enhancing lesions in the magnetic resonance imaging increased together with NAbs titers in this group. In conclusion, the prevalence of NAbs in Japanese MS patients is similar to that in Caucasian populations and is associated with an increase in disease activity. Therefore, routine NAbs testing is recommended also in Asian populations to ensure the early identification of patients who would benefit from a change in therapy.


Prediction of Thrombotic and Bleeding Events After Percutaneous Coronary Intervention: CREDO-Kyoto Thrombotic and Bleeding Risk Scores.
Prediction of thrombotic and bleeding risk is important to optimize antithrombotic therapy after percutaneous coronary intervention. We developed the prediction rules for thrombotic and bleeding events separately in Japanese patients. Derivation and validation cohorts consisted of 4778 patients from CREDO-Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) registry cohort 2 and 4669 patients from RESET (Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial) and NEXT (Nobori Biolimus-Eluting Versus Xience/Promus Everolimus-Eluting Stent Trial). Primary thrombotic and bleeding events were a composite of myocardial infarction, definite or probable stent thrombosis or ischemic stroke, and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate or severe bleeding. The prediction rule for thrombosis assigned 2 points for severe chronic kidney disease, atrial fibrillation, peripheral vascular disease, and anemia and 1 point for age ≥75 years, heart failure, diabetes mellitus, and chronic total occlusion. The prediction rule for bleeding assigned 2 points for thrombocytopenia, severe chronic kidney disease, peripheral vascular disease, and heart failure and 1 point for prior myocardial infarction, malignancy, and atrial fibrillation. In derivation and validation cohorts, area under the curve was 0.68 and 0.64, respectively, for thrombosis and 0.66 and 0.66, respectively, for bleeding. In the validation cohort, a high thrombosis risk score (≥4, n=682) was associated with higher 3-year incidence of thrombotic events than a score that was intermediate (2-3, n=1178) or low (0-1, n=2809) (7.6%, 3.7%, versus 2.4%, respectively; P<0.0001). A high bleeding risk score (≥3, n=666) was associated with higher incidence of bleeding than scores that were intermediate (1-2, n=1802) or low (0, n=2201) (8.8%, 4.1%, versus 2.3%, respectively; P<0.0001). Among 682 patients at high thrombotic risk, only 39 (5.7%) had low bleeding risk, whereas 401 (58.8%) had high bleeding risk with very high incidence of bleeding (11.6%). CREDO-Kyoto thrombotic and bleeding risk scores demonstrated modest accuracy in stratifying thrombotic and bleeding risks; however, a large proportion of patients at high thrombotic risk also had high bleeding risk.


Neutralizing monoclonal antibodies against hepatitis C virus E2 protein bind discontinuous epitopes and inhibit infection at a postattachment step.
The E2 glycoprotein of hepatitis C virus (HCV) mediates viral attachment and entry into target hepatocytes and elicits neutralizing antibodies in infected patients. To characterize the structural and functional basis of HCV neutralization, we generated a novel panel of 78 monoclonal antibodies (MAbs) against E2 proteins from genotype 1a and 2a HCV strains. Using high-throughput focus-forming reduction or luciferase-based neutralization assays with chimeric infectious HCV containing structural proteins from both genotypes, we defined eight MAbs that significantly inhibited infection of the homologous HCV strain in cell culture. Two of these bound E2 proteins from strains representative of HCV genotypes 1 to 6, and one of these MAbs, H77.39, neutralized infection of strains from five of these genotypes. The three most potent neutralizing MAbs in our panel, H77.16, H77.39, and J6.36, inhibited infection at an early postattachment step. Receptor binding studies demonstrated that H77.39 inhibited binding of soluble E2 protein to both CD81 and SR-B1, J6.36 blocked attachment to SR-B1 and modestly reduced binding to CD81, and H77.16 blocked attachment to SR-B1 only. Using yeast surface display, we localized epitopes for the neutralizing MAbs on the E2 protein. Two of the strongly inhibitory MAbs, H77.16 and J6.36, showed markedly reduced binding when amino acids within hypervariable region 1 (HVR1) and at sites ∼100 to 200 residues away were changed, suggesting binding to a discontinuous epitope. Collectively, these studies help to define the structural and functional complexity of antibodies against HCV E2 protein with neutralizing potential.


Intimate partner violence among HIV-serodiscordant couples in Durban, South Africa.
South Africa (SA) has a high prevalence rate of intimate partner violence (IPV) and HIV, both of which can be exacerbated further by HIV serodiscordancy in the couple dyad. Further exploration of the discordancy sidedness in known mediating factors, such as alcohol abuse risk and post-traumatic stress (PTS), is required. To investigate the extent of and gender differences in IPV, alcohol abuse risk and PTS symptoms among HIV-serodiscordant couples in Durban, SA, and to analyse these further with regard to female HIV serostatus. A cross-sectional analysis of data on 30 serodiscordant couples was conducted at the point of enrolment into a pilot study of an HIV risk reduction intervention. The statistical procedure for a dependent small sample was applied to examine gender differences in IPV, alcohol use and PTS symptoms among HIV-serodiscordant couples. The woman was HIV-positive in 18 (60.0%) of the 30 serodiscordant couples enrolled. Exposure to IPV differed significantly between men (28.6%) and women (89.3%) (proportional difference -0.61, 95% confidence interval (CI) -0.82 - -0.39). The Wilcoxon signed-rank test showed that PTS symptom scores differed significantly between men (median 22, interquartile range (IQR) 23) and women (median 44, IQR 28) (p=0.03). When the above analysis was stratified by female HIV serostatus, significant gender differences were found in IPV and PTS in the couples where the woman was HIV-positive. There were no significant gender differences for alcohol abuse risk. The findings demonstrated high levels of IPV in HIV-serodiscordant couples and a significant gender difference in mental health risk such as PTS in such relationships, particularly where the woman was HIV-positive. HIV intervention programmes should address gender-based violence and inequity among heterosexual couples.


Dynamic Notch signalling regulates neural stem cell state progression in the Drosophila optic lobe.
Neural stem cells generate all of the neurons and glial cells in the central nervous system, both during development and in the adult to maintain homeostasis. In the Drosophila optic lobe, neuroepithelial cells progress through two transient progenitor states, PI and PII, before transforming into neuroblasts. Here we analyse the role of Notch signalling in the transition from neuroepithelial cells to neuroblasts. We observed dynamic regulation of Notch signalling: strong activity in PI progenitors, low signalling in PII progenitors, and increased activity after neuroblast transformation. Ectopic expression of the Notch ligand Delta induced the formation of ectopic PI progenitors. Interestingly, we show that the E3 ubiquitin ligase, Neuralized, regulates Delta levels and Notch signalling activity at the transition zone. We demonstrate that the proneural transcription factor, Lethal of scute, is essential to induce expression of Neuralized and promote the transition from the PI progenitor to the PII progenitor state. Our results show dynamic regulation of Notch signalling activity in the transition from neuroepithelial cells to neuroblasts. We propose a model in which Lethal of scute activates Notch signalling in a non-cell autonomous manner by regulating the expression of Neuralized, thereby promoting the progression between different neural stem cell states.


The genetic basis of parental care evolution in monogamous mice.
Parental care is essential for the survival of mammals, yet the mechanisms underlying its evolution remain largely unknown. Here we show that two sister species of mice, Peromyscus polionotus and Peromyscus maniculatus, have large and heritable differences in parental behaviour. Using quantitative genetics, we identify 12 genomic regions that affect parental care, 8 of which have sex-specific effects, suggesting that parental care can evolve independently in males and females. Furthermore, some regions affect parental care broadly, whereas others affect specific behaviours, such as nest building. Of the genes linked to differences in nest-building behaviour, vasopressin is differentially expressed in the hypothalamus of the two species, with increased levels associated with less nest building. Using pharmacology in Peromyscus and chemogenetics in Mus, we show that vasopressin inhibits nest building but not other parental behaviours. Together, our results indicate that variation in an ancient neuropeptide contributes to interspecific differences in parental care.


The evolutionary demography of ecological change: linking trait variation and population growth.
Population dynamics and evolutionary change are linked by the fundamental biological processes of birth and death. This means that population growth may correlate with the strength of selection, whereas evolutionary change can leave an ecological signature. We decompose population growth in an age-structured population into contributions from variation in a quantitative trait. We report that the distribution of body sizes within a population of Soay sheep can markedly influence population dynamics, accounting for up to one-fifth of observed population growth. Our results suggest that there is substantial opportunity for evolutionary dynamics to leave an ecological signature and visa versa.


The Drive towards Sustainable Health Systems Needs an Alignment: Where are the Innovations in Health Systems Planning?
Clarifying the healthcare innovation agenda is critical in order to advance the impact of system innovations. As part of this agenda-setting it is important to address the four conditions within which innovations can enhance system sustainability: 1) the innovation agenda reflects and is aligned with healthcare objectives and policy; 2) planning methodologies for services, workforce and funding are aligned with healthcare objectives and policy; 3) innovations in services are accommodated in systems through innovations in policy, planning and funding; and 4) innovations are systematically monitored and evaluated. In order to illustrate these conditions, the authors present a case study of an evaluation of one Canadian Health Authority's efforts to transform healthcare delivery. This case study reveals that aligning innovations in policy, planning, funding and health services is critical to transforming health systems and that, in the absence of such alignment, sustainable health systems are difficult to achieve.


New approach to the ecotoxicological risk assessment of artificial outdoor sporting grounds.
Artificial surfaces for outdoor sporting grounds may pose environmental and health hazards that are difficult to assess due to their complex chemical composition. Ecotoxicity tests can indicate general hazardous impacts. We conducted growth inhibition (Pseudokirchneriella subcapitata) and acute toxicity tests (Daphnia magna) with leachates obtained from batch tests of granular infill material and column tests of complete sporting ground assemblies. Ethylene propylene diene monomer rubber (EPDM) leachate showed the highest effect on Daphnia magna (EC(50) < 0.4% leachate) and the leachate of scrap tires made of styrene butadiene rubber (SBR) had the highest effect on P. subcapitata (EC(10) = 4.2% leachate; EC(50) = 15.6% leachate). We found no correlations between ecotoxicity potential of leachates and zinc and PAH concentrations. Leachates obtained from column tests revealed lower ecotoxicological potential. Leachates of column tests of complete assemblies may be used for a reliable risk assessment of artificial sporting grounds.


Simultaneous determination of reactive oxygen and nitrogen species in mitochondrial compartments of apoptotic HepG2 cells and PC12 cells based on microchip electrophoresis-laser-induced fluorescence.
Determination of intracellular bioactive species will afford beneficial information related to cell metabolism, signal transduction, cell function, and disease treatment. In this study, the first application of a microchip electrophoresis-laser-induced fluorescence (MCE-LIF) method for concurrent determination of reactive oxygen species (ROS) and reactive nitrogen species (RNS), i.e., superoxide (O(2)(-•)) and nitric oxide (NO) in mitochondria, was developed using fluorescent probes 2-chloro-1,3-dibenzothiazolinecyclohexene (DBZTC) and 3-amino,4-aminomethyl-2',7'-difluorescein (DAF-FM), respectively. Potential interference of intracellular dehydroascorbic acid (DHA) and ascorbic acid (AA) for NO detection with DAF-FM was eliminated through oxidation of AA with the addition of ascorbate oxidase, followed by subsequent MCE separation. Fluorescent products of O(2)(-•) and NO, DBZTC oxide (DBO), and DAF-FM triazole (DAF-FMT) showed excellent baseline separation within 1 min with a running buffer of 40 mM Tris solution (pH 7.4) and a separating electric field of 500 V/cm. The levels of DBO and DAF-FMT in mitochondria isolated from normal HepG2 cells and PC12 cells were evaluated using this method. Furthermore, the changes of DBO and DAF-FMT levels in mitochondria isolated from apoptotic HepG2 cells and PC12 cells could also be detected. The current approach was proved to be simple, fast, reproducible, and efficient. Measurement of the two species with the method will be beneficial to understand ROS/RNS distinctive functions. In addition, it will provide new insights into the role that both species play in biological systems.


Skin lesions in European hibernating bats associated with Geomyces destructans, the etiologic agent of white-nose syndrome.
White-nose syndrome (WNS) has claimed the lives of millions of hibernating insectivorous bats in North America. Its etiologic agent, the psychrophilic fungus Geomyces destructans, causes skin lesions that are the hallmark of the disease. The fungal infection is characterized by a white powdery growth on muzzle, ears and wing membranes. While WNS may threaten some species of North American bats with regional extinction, infection in hibernating bats in Europe seems not to be associated with significant mortality. We performed histopathological investigations on biopsy samples of 11 hibernating European bats, originating from 4 different countries, colonized by G. destructans. One additional bat was euthanized to allow thorough examination of multiple strips of its wing membranes. Molecular analyses of touch imprints, swabs and skin samples confirmed that fungal structures were G. destructans. Additionally, archived field notes on hibernacula monitoring data in the Harz Mountains, Germany, over an 11-year period (2000-2011) revealed multiple capture-recapture events of 8 banded bats repeatedly displaying characteristic fungal colonization. Skin lesions of G. destructans-affected hibernating European bats are intriguingly similar to the epidermal lesions described in North American bats. Nevertheless, deep invasion of fungal hyphae into the dermal connective tissue with resulting ulceration like in North American bats was not observed in the biopsy samples of European bats; all lesions found were restricted to the layers of the epidermis and its adnexae. Two bats had mild epidermal cupping erosions as described for North American bats. The possible mechanisms for any difference in outcomes of G. destructans infection in European and North American bats still need to be elucidated.


New algorithm for tensor contractions on multi-core CPUs, GPUs, and accelerators enables CCSD and EOM-CCSD calculations with over 1000 basis functions on a single compute node.
A new hardware-agnostic contraction algorithm for tensors of arbitrary symmetry and sparsity is presented. The algorithm is implemented as a stand-alone open-source code libxm. This code is also integrated with general tensor library libtensor and with the Q-Chem quantum-chemistry package. An overview of the algorithm, its implementation, and benchmarks are presented. Similarly to other tensor software, the algorithm exploits efficient matrix multiplication libraries and assumes that tensors are stored in a block-tensor form. The distinguishing features of the algorithm are: (i) efficient repackaging of the individual blocks into large matrices and back, which affords efficient graphics processing unit (GPU)-enabled calculations without modifications of higher-level codes; (ii) fully asynchronous data transfer between disk storage and fast memory. The algorithm enables canonical all-electron coupled-cluster and equation-of-motion coupled-cluster calculations with single and double substitutions (CCSD and EOM-CCSD) with over 1000 basis functions on a single quad-GPU machine. We show that the algorithm exhibits predicted theoretical scaling for canonical CCSD calculations, O(N6 ), irrespective of the data size on disk. © 2017 Wiley Periodicals, Inc.


The SCN5A mutation A1180V is associated with electrocardiographic features of LQT3.
Mutations of the SCN5A gene are associated with several arrhythmic syndromes including the Brugada syndrome, conduction disease, long QT syndrome type 3 (LQT3), atrial fibrillation, and dilated cardiomyopathy. We report LQT3 associated with an A1180V cardiac sodium channel mutation, previously associated with cardiac conduction block, and dilated cardiomyopathy in three generations of a Chinese family. Clinical, electrocardiographic (ECG), and echocardiographic examination was followed by direct sequencing of SCN5A and HERG to screen genomic DNA from blood samples. The proband presented with multiple syncopes from the age of 7 years and was found to share a mutation with two other members of his family. Continuous ECG monitoring after presentation showed prolonged QTc and biphasic T waves, multiple episodes of ventricular tachycardia and torsades de pointes. The other two mutation carriers showed ECG features of LQT3 without clinical symptoms. Transthoracic echocardiography showed normal cardiac structure in all three mutation carriers. This study shows LQT3 features associated with an A1180V cardiac sodium channel mutation, expanding the spectrum of phenotypes resulting from this mutation in which biophysical study has shown a persistent late Na(+) current.


Economic impact of pertussis.
To assess the economic consequences of pertussis in Monroe County, New York (population, 713969), during a 6-year period (1989-1994). Cases of pertussis were identified retrospectively by passive reporting and diagnosis based on culture, positive results of direct fluorescent antibody testing, or Centers for Disease Control and Prevention clinical criteria (cough for > 14 days otherwise unexplained or for > 7 days with paroxysms or whoop epidemiologically linked to a laboratory-confirmed case). One hundred seven (50%) of 216 subjects with identified cases of pertussis completed questionnaires and had medical records reviewed to ascertain the costs of illness, including physician office visits, laboratory tests, medications, hospitalization, emergency department visits, additional child care, and lost days from school (children) or from work (parents or adult cases). Ninety-three (87%) of the pertussis case occurred in children. The average duration of illness before diagnosis was 21.3 days (range, 12-37 days). One hundred one patients (94%) saw a physician at least once; overall, the average number of visits per case was 3.2 (range, 1-15). Ninety-seven patients (91%) received at least 1 course of antibiotic therapy (average cost for all antibiotics, $95/case), and all took symptomatic treatment (average cost, $48/case). Fifteen patients (14%) required hospitalization; average cost per admission was $13425 (range, $1732-$69637). Thirty patients (28%) were seen in emergency departments; average cost was $202 (range, $69-$289). Additional child care costs ranged from $12 to $2688. For 50 families, 1 adult lost workdays because of illness or to provide child care for an average of 8.3 days (range, 1-45 days). For 4 families, 2 adults lost an average of 44 days from work (range, 10-120 days). The cumulative number of lost workdays was 758 in association with the 107 cases of pertussis. The average full recovery time from illness was 72.9 days (range, 25-115 days). Total direct and indirect cost for 107 cases of pertussis in Monroe County was $381052. The economic burden of pertussis is substantial and encourages broader use of vaccination to prevent disease.


Selection of hepatitis C virus resistant to ribavirin.
Given the side effects associated with intravenous injections of interferon, an interferon-free regimen for the treatment of HCV infections is highly desirable. Recently published clinical studies show that interferon-free combination therapies containing ribavirin are efficacious, suggesting that an interferon-free therapy could be adopted in the near future. Therefore, understanding HCV resistance to ribavirin could be of major importance. In an approach to understand the effect of ribavirin on HCV replication and HCV resistance, we have selected a ribavirin resistant mutant of HCV in vitro. We serially passed the J6/JFH1 strain of HCV in Huh7D cells (a Huh7 cell derivative more permissive to HCV replication) in the presence of different concentrations of ribavirin. Virus replication was assessed by detection of HCV antigens by immunfluorscence of infected cells and titration of recovered virus present in the supernatant. cDNAs from virus RNA grown in 0 or 250 uM concentrations of ribavirin were synthesized by RT-PCR, and sequenced. A concentration of 125 uM of ribavirin did not have a dramatic effect on HCV replication, while 500 uM of ribavirin lead to viral extinction. Concentrations of 250 uM of ribavirin dramatically reduced virus replication which was sustained over six passages. At passage seven viral resurgence began and over two passages the level of virus reached that of the wild type virus grown without ribavirin. Virus recovered from these cultures were more resistant to 250 uM ribavirin than wild type virus, and showed no difference in replication relative to wild type virus when grown in the absence of ribavirin. The ribavirin resistant virus accumulated multiple synonymous and non-synonymous mutations that are presently being analyzed for their relationship to ribavirin resistance. It is possible to select a ribavirin resistant mutant of HCV that can replicate to levels similar to wild type virus grown without ribavirin. Analysis of the mutations responsible for the ribavirin resistance may aid in understanding the mechanism of action of ribavirin.


Characteristics of mammography facility locations and stage of breast cancer at diagnosis in Chicago.
In the United States, despite substantial investment in public health initiatives to promote early detection of breast cancer through screening mammography, the proportion of female breast cancers that have advanced beyond the localized stage by the time of diagnosis remains high. Our objective in this exploratory study was to investigate whether stage of breast cancer at diagnosis among Chicago residents is associated with characteristics of the neighborhoods in which proximate mammography facilities are located. Those characteristics may influence likelihood of utilizing the service routinely and partly explain differences in stage at diagnosis. We used a retrospective cohort design and combined 3 years of data from the Illinois State Cancer Registry (ISCR) with information on locations of mammography facilities, public transportation service, crime, and area demographic and economic characteristics. Using a Geographic Information System (GIS), we identified the five facilities located nearest to each case's residence. Estimates of the association between characteristics of mammography facility locations and breast cancer stage at diagnosis were obtained using the partial proportional odds regression model. We found that the number of homicides in areas in which the nearest mammography facilities were located was associated with increased odds of later stage diagnosis. This effect was independent of age, race, and residential area education and income. We found no effect on stage of distance, public transportation service, or measures of neighborhood social similarity. The "spatial dynamics" of health may involve geographies beyond the immediate neighborhood. The results of our study suggest that areas in which the nearest mammography facilities are located may be one such geography. We hope that this study will spark research interest in the impact of health service locations on utilization.


Ultraviolet B Exposure Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Expanding CD4+Foxp3+ Regulatory T Cells.
Pathogenic immune responses are known to play an important role in abdominal aortic aneurysm (AAA) development. Ultraviolet B (UVB) irradiation has been demonstrated to have therapeutic potential not only for cutaneous diseases but also for systemic inflammatory diseases in mice by suppressing immunoinflammatory responses. We investigated the effect of UVB irradiation on experimental AAA. We used an angiotensin II-induced AAA model in apolipoprotein E-deficient mice fed a high-cholesterol diet. Mice aged 10 weeks were irradiated with 5 kJ/m2 UVB once weekly for 6 weeks (UVB-irradiated, n=38; nonirradiated, n=42) and were euthanized for evaluation of AAA formation at 16 weeks. Overall, 93% of angiotensin II-infused mice developed AAA, with 60% mortality possibly because of aneurysm rupture. UVB irradiation significantly decreased the incidence (66%) and mortality (29%) of AAA (P=0.004 and P=0.006, respectively). UVB-irradiated mice had significantly smaller diameter AAA (P=0.008) and fewer inflammatory cells in the aortic aneurysm tissue than nonirradiated mice, along with systemic expansion of CD4+Foxp3+ regulatory T cells and decreased effector CD4+CD44highCD62Llow T cells in para-aortic lymph nodes. Genetic depletion of regulatory T cells abrogated these beneficial effects of UVB treatment, demonstrating a critical role of regulatory T cells. Our data suggest that UVB-dependent expansion of regulatory T cells has beneficial effects on experimental AAA and may provide a novel strategy for the treatment of AAA.


Elemental composition of human semen is associated with motility and genomic sperm defects among older men.
Older men tend to have poorer semen quality and are generally at higher risks for infertility and abnormal reproductive outcomes. We employed proton-induced X-ray emission (PIXE, 3 MeV proton beam) to investigate the concentrations of zinc, copper, calcium, sulfur, chlorine, potassium, titanium, iron and nickel in washed sperm and seminal plasma from non-smoking groups of 10 older men (65-80 years old) and 10 younger men (22-28 years old) who were concurrently assayed for sperm function and genomicly defective sperm. The older group showed elevated zinc, copper and calcium in sperm and elevated sulfur in seminal plasma compared with the younger men. The older group also showed reduced motility as well as increased sperm DNA fragmentation, achondroplasia mutations, DNA strand breaks and chromosomal aberrations. Sperm calcium and copper were positively associated with sperm DNA fragmentation (P < 0.03). Seminal sulfur was positively associated with sperm DNA fragmentation and chromosomal aberrations (P < 0.04), and negatively associated with sperm motility (P < 0.05). Sperm calcium was negatively associated with sperm motility, independent of male age (P = 0.01). We identified major differences in elemental concentrations between sperm and seminal plasma and that higher sperm copper, sulfur and calcium are quantitatively associated with poorer semen quality and increased frequencies of genomic sperm defects.


Infection of L6E9 myoblasts with Trypanosoma cruzi alters adenylate cyclase activity and guanine nucleotide binding proteins.
We studied the consequences of infection of L6E9 myoblasts with T. cruzi on the adenylate cyclase complex to test the hypothesis that infection alters the functional properties of the guanine nucleotide regulatory proteins, Ns and Ni. Stimulating activities of adenylate cyclase due to isoproterenol, isoproterenol plus Gpp(NH)p, or forskolin (activities mediated by Ns) are not altered by infection. However, inhibitory activities mediated by Ni [Gpp(NH)p, acetylcholine, and adenosine inhibition of forskolin-dependent adenylate cyclase activity] are compromised by infection. The reduction in adenosine's inhibition of forskolin-dependent adenylate cyclase activity is seen throughout the effective concentration range of adenosine. Pertussis toxin does not change basal or stimulated adenylate cyclase activity in infected cells compared with normal uninfected cells, nor does it alter the inhibiting action of adenosine. To evaluate the coupling proteins (Ns and Ni) involved in the stimulation and inhibition of adenylate cyclase more directly, cholera- and pertussis-toxin-dependent ADP ribosylation studies were performed. The incorporation of [32P]ADP ribose in the presence (specific) or absence (nonspecific) of the toxins was markedly decreased in membranes prepared from infected cells. However, in membranes prepared from infected or uninfected cells previously treated with pertussis toxin, there was a significant reduction in specific pertussis-toxin dependent ADP ribosylation. The infection-associated diminution in toxin-dependent ADP ribosylation complements the impaired inhibition of adenylate cyclase data. Collectively, the data further substantiate an infection-associated alteration in the adenylate cyclase complex, probably at the level of the guanine nucleotide binding proteins.


Talking about sexuality: desire, virility, and intimacy in the context of prostate cancer associations.
Prostate cancer and its outcomes are a real threat for health and well-being for men living in the Western world. The number of men with a diagnosis of prostate cancer, before the age of 65 years, has increased in recent decades. The aim of this study was to explore how some of these Swedish men experienced and talked about their sexuality. Four focus group discussions were performed in the context of associations for prostate cancer. Using qualitative content analysis, it was identified how the diagnosis was a threat to their male identity; the men's vulnerability as a group in society was made explicit. Their sexuality was diminished by their illness experiences. These experiences were difficult to share and talk about with others and therefore connected with silence and sorrow. As a result of this, the informants often played a passive role when or if they discussed issues related to sexuality with someone in the health care organizations. The possibility of voluntarily joining a cancer association was probably highly beneficial for these men. During the sessions, several men expressed the opinion that "it is always great to talk."


Dentin permeability of carious primary teeth.
Many in vitro studies have used dentine permeability to evaluate the efficacy of various restorative and preventative procedures. The easiest way to evaluate dentine permeability is to calculate its hydraulic conductance (Lp) using fluid filtration methods. Research has examined electronic hydraulic conductance measurement methods that give more precise and reliable results for the permeability of dentine than the classical method. To our knowledge, no study has examined the dentine permeability of carious primary teeth. This in vitro study determined the dentine permeability of carious primary molars precisely with a new electronic hydraulic conductance measurement system and compared them with healthy primary molars. The study examined 60 carious and noncarious primary second molars with no restorations, fractures, or cracks at different root resorption stages. The results showed that the dentine permeability increased with the severity of caries in primary teeth. The dentine permeability of carious primary teeth was higher than that of noncarious primary teeth. Therefore, treatment of primary teeth should be performed more quickly.


Socioeconomic variations in nicotine dependence, self-efficacy, and intention to quit across four countries: findings from the International Tobacco Control (ITC) Four Country Survey.
To examine the effect of socioeconomic status (SES) on nicotine dependence, self-efficacy, and intention to quit. Data were from the first wave (2002) of the International Tobacco Control (ITC) Four Country Survey (ITC-4), a panel study of over 2000 adult smokers from each of four countries: the United States, Canada, the United Kingdom, and Australia. Data were collected via telephone interviews. Nicotine dependence, intention to quit, and self-efficacy to quit smoking were the main outcome measures used in this study. Lower levels of education were associated with higher nicotine dependence. The effect of lower income on higher heaviness of smoking index (HIS) scores was significant in Canada, the UK, and Australia. Respondents with low education had 35% larger odds of low self-efficacy than those with high education. Respondents with low education had 40% larger odds of having no intention to quit than those with high education. Respondents with low income had 23% larger odds of having no intention to quit than those with high income. Country was not a moderator of the association of SES with self-efficacy and intention to quit. To the extent that lower SES smokers are more addicted, they are likely to need more intensive support if they are to be successful in their attempts to quit. Given their lower incomes, this places a special responsibility on government to provide or subsidise such services. This should include access to the widest possible range of effective pharmacotherapies complemented with evidence based counselling and support.


Incidence and severity of acute cellular rejection in recipients undergoing adult living donor or deceased donor liver transplantation.
Living donor liver transplantation (LDLT) may have better immunological outcomes compared to deceased donor liver transplantation (DDLT). The aim of this study was to analyze the incidence of acute cellular rejection (ACR) after LDLT and DDLT. Data from the adult-to-adult living donor liver transplantation (A2ALL) retrospective cohort study on 593 liver transplants done between May 1998 and March 2004 were studied (380 LDLT; 213 DDLT). Median LDLT and DDLT follow-up was 778 and 713 days, respectively. Rates of clinically treated and biopsy-proven ACR were compared. There were 174 (46%) LDLT and 80 (38%) DDLT recipients with >/=1 clinically treated episodes of ACR, whereas 103 (27%) LDLT and 58 (27%) DDLT recipients had >/=1 biopsy-proven ACR episode. A higher proportion of LDLT recipients had clinically treated ACR (p = 0.052), but this difference was largely attributable to one center. There were similar proportions of biopsy-proven rejection (p = 0.97) and graft loss due to rejection (p = 0.16). Longer cold ischemia time was associated with a higher rate of ACR in both groups despite much shorter median cold ischemia time in LDLT. These data do not show an immunological advantage for LDLT, and therefore do not support the application of unique posttransplant immunosuppression protocols for LDLT recipients.


Medical residency: factors relating to "difficulty in helping" in the resident physician-patient relationship.
Previous studies have attempted to understand what leads physicians to label patients as 'difficult'. Understanding this process is particularly important for resident physicians, who are developing attitudes that may have long-term impact on their interactions with patients. The aim of this study was to distinguish between patients' self-rated emotional state (anxiety and depression) and residents' perceptions of that state as a predictor of patients being considered difficult. Cross-sectional survey conducted in the hospital of Universidade Federal de São Paulo (Unifesp). The residents completed a sociodemographic questionnaire and rated their patients using the Hospital Anxiety and Depression Scale (HADS) and Difficulty in Helping the Patient Questionnaire (DTH). The patients completed HADS independently and were rated using the Karnofsky Performance Status scale. On average, the residents rated the patients as presenting little difficulty. The residents' ratings of difficulty presented an association with their ratings for patient depression (r = 0.35, P = 0.03) and anxiety (r = 0.46, P = 0.02), but not with patients' self-ratings for depression and anxiety. Residents from distant cities were more likely to rate patients as difficult to help than were residents from the city of the hospital (mean score of 1.93 versus 1.07; P = 0.04). Understanding what leads residents to label patients as having depression and anxiety problems may be a productive approach towards reducing perceived difficulty. Residents from distant cities may be more likely to find their patients difficult.


Anthropogenic noise impairs foraging for cryptic prey via cross-sensory interference.
Anthropogenic noise levels are globally rising with profound impacts on ecosystems and the species that live in them. Masking or distraction by noise can interfere with relevant sounds and thereby impact ecological interactions between individuals of the same or different species. Predator-prey dynamics are particularly likely to be influenced by rising noise levels, with important population- and community-level consequences, as species may differentially adapt to noise disturbance. Acoustic noise can, however, also impair the use of visual information by animals through the process of cross-sensory interference, possibly impacting species interactions that have so far been largely ignored by noise impact studies. Here, we assessed how noise affected the performance of great tit (Parus major) foraging on cryptic prey. Birds trained individually to search for paper moths differing in the level of camouflage with the test background were tested in the presence and absence of noise. We found that noise significantly increased approach and attack latencies, but that the effect depended on the level of crypsis. Noise increased latencies for cryptic prey targets, but not for conspicuous and colour-matched prey targets. Our results show that noise can interfere with the processing of visual information, particularly in difficult tasks such as separating objects from a similar looking background. These results have important ecological and evolutionary implications as they demonstrate how globally rising anthropogenic noise levels can influence the arms race between predators and prey across sensory domains.


Importance of characteristics and modalities of physical activity and exercise in the management of cardiovascular health in individuals with cardiovascular disease (Part III).
The beneficial effect of exercise training and exercise-based cardiac rehabilitation on symptom-free exercise capacity,cardiovascular and skeletal muscle function, quality of life, general healthy lifestyle, and reduction of depressive symptoms and psychosocial stress is nowadays well recognized. However, it remains largely obscure, which characteristics of physical activity (PA) and exercise training--frequency, intensity, time (duration), type (mode), and volume (dose: intensity x duration) of exercise--are the most effective. The present paper, therefore, will deal with these exercise characteristics in the management of individuals with cardiovascular disease, i.e. coronary artery disease and chronic heart failure patients, but also in patients with congenital or valvular heart disease. Based on the current literature, and if sufficient evidence is available, recommendations from the European Association on Cardiovascular Prevention and Rehabilitation are formulated regarding frequency, intensity, time and type of PA, and safety aspects during exercise inpatients with cardiovascular disease. This paper is the third in a series of three papers, all devoted to the same theme: the importance of the exercise characteristics in the management of cardiovascular health. Part I is directed to the general population and Part II to individuals with cardiovascular risk factors. In general, PA recommendations and exercise training programmes for patients with coronary artery disease or chronic heart failure need to be tailored to the individual's exercise capacity and risk profile, with the aim to reach and maintain the individually highest fitness level possible and to perform endurance exercise training 30–60 min daily (3–5 days per week) in combination with resistance training 2–3 times a week. Because of the frequently reported dose–response relationship between training effect and exercise intensity, one should seek sufficiently high training intensities, although more scientific evidence on effect sizes and safety is warranted. At present, there is insufficient data to give more specific recommendations on type, dosage, and intensity of exercise in some other cardiovascular diseases, such as congenital heart disease, valve disease, cardiomyopathies, channelopathies, and patients with implanted devices.


High resolution analysis of the human transcriptome: detection of extensive alternative splicing independent of transcriptional activity.
Commercially available microarrays have been used in many settings to generate expression profiles for a variety of applications, including target selection for disease detection, classification, profiling for pharmacogenomic response to therapeutics, and potential disease staging. However, many commercially available microarray platforms fail to capture transcript diversity produced by alternative splicing, a major mechanism for driving proteomic diversity through transcript heterogeneity. The human Genome-Wide SpliceArray(TM) (GWSA), a novel microarray platform, utilizes an existing probe design concept to monitor such transcript diversity on a genome scale. The human GWSA allows the detection of alternatively spliced events within the human genome through the use of exon body and exon junction probes to provide a direct measure of each transcript, through simple calculations derived from expression data. This report focuses on the performance and validation of the array when measured against standards recently published by the Microarray Quality Control (MAQC) Project. The array was shown to be highly quantitative, and displayed greater than 85% correlation with the HG-U133 Plus 2.0 array at the gene level while providing more extensive coverage of each gene. Almost 60% of splice events among genes demonstrating differential expression of greater than 3 fold also contained extensive splicing alterations. Importantly, almost 10% of splice events within the gene set displaying constant overall expression values had evidence of transcript diversity. Two examples illustrate the types of events identified: LIM domain 7 showed no differential expression at the gene level, but demonstrated deregulation of an exon skip event, while erythrocyte membrane protein band 4.1 -like 3 was differentially expressed and also displayed deregulation of a skipped exon isoform. Significant changes were detected independent of transcriptional activity, indicating that the controls for transcript generation and transcription are distinct, and require novel tools in order to detect changes in specific transcript quantity. Our results demonstrate that the SpliceArray(TM) design will provide researchers with a robust platform to detect and quantify specific changes not only in overall gene expression, but also at the individual transcript level.


Relative effectiveness of dominant versus non-dominant hand position for rescuer's side of approach during chest compressions between right-handed and left-handed novice rescuers.
The major components affecting high quality cardiopulmonary resuscitation (CPR) have been defined as the ability of the rescuer, hand position, position of the rescuer and victim, depth and rate of chest compressions, and fatigue. Until now, there have been no studies on dominant versus non-dominant hand position and the rescuer's side of approach. This study was designed to evaluate the effectiveness of hand position and approach side on the quality of CPR between right-handed (RH) and left-handed (LH) novice rescuers. 44 health science university students with no previous experience of basic life support (BLS) volunteered for the study. We divided volunteers into two groups by handedness. Adult BLS was performed on a manikin for 2 min in each session. The sequences were randomly performed on the manikin's left side of approach (Lap) with the rescuer's left hand in contact with the sternum (Lst), Lap/Rst, Rap/Lst and Rap/Rst. We compared the quality of chest compressions between the RH and LH groups according to predetermined positions. A significant decrease in mean compression depth between the two groups was only observed when rescuers performed in the Rap/Lst scenario, regardless of hand dominance. The frequency of correct hand placement also significantly decreased in the Lap/Rst position for the LH group. The performance of novice rescuers during chest compressions is influenced by the position of the dominant hand and the rescuer's side of approach. In CPR training and real world situations, a novice rescuer, regardless of handedness, should consider hand positions for contacting the sternum identical to the side of approach after approaching from the nearest and most accessible side, for optimal CPR performance.


Paediatric oral pathology in a Chilean population: a 15-year review.
There is only limited information available in Chile regarding the frequency of biopsied oral lesions in paediatric patients. To determine the frequency of histologically diagnosed lesions in oral pathology specimens from paediatric patients in a Chilean population over a 15-year period. Oral and maxillofacial biopsy records of patients aged 16 years or under were retrieved by visual inspection from the archives of public and private Oral Pathology Health Services in Valdivia, Chile, during the period 1995-2010. Records that contained anatomical site and histopathological diagnoses of the specimen were included. The study population was divided into three age groups according to dentition stage. Oral lesions were classified as inflammatory/reactive, cystic, or tumour/tumour-like. A total of 542 biopsy specimens from children were found. These represented 20.6% of all oral biopsies. The average age was 11.1 years, with female predilection. The most common category of oral lesions was inflammatory/reactive (75.8%), followed by tumour/tumour-like (16.8%) and cystic (7.4%) lesions. The mucocele was the most commonly found lesion, followed by pyogenic granuloma and irritation fibroma, which taken together accounted for 63.8% of all paediatric oral biopsies. The most common localisation for lesions was the lower lip (50.3%). The vast majority of oral lesions found were predominantly inflammatory/reactive and benign types, although malignant lesions can present themselves in children.


Annoyance, perception, and physiological effects of wind turbine infrasound.
Even though some individuals subjectively associate various symptoms with infrasound, there are very few systematic studies on the contribution of infrasound to the perception, annoyance, and physiological reactions elicited by wind turbine sound. In this study, sound samples were selected among long-term measurement data from wind power plant and residential areas, both indoors and outdoors, and used in laboratory experiments. In the experiments, the detectability and annoyance of both inaudible and audible characteristics of wind turbine noise were determined, as well as autonomic nervous system responses: heart rate, heart rate variability, and skin conductance response. The participants were divided into two groups based on whether they reported experiencing wind turbine infrasound related symptoms or not. The participants did not detect infrasonic contents of wind turbine noise. The presence of infrasound had no influence on the reported annoyance nor the measured autonomic nervous system responses. No differences were observed between the two groups. These findings suggest that the levels of infrasound in the current study did not affect perception and annoyance or autonomic nervous system responses, even though the experimental conditions corresponded acoustically to real wind power plant areas.


Efficient nuclear localization and immortalizing ability, two functions dependent on the adenovirus type 5 (Ad5) E1A second exon, are necessary for cotransformation with Ad5 E1B but not with T24ras.
Expression of adenovirus type 5 E1A 12S is sufficient to immortalize primary baby rat kidney cells, but another viral or cellular oncogene, such as E1B or T24ras, is necessary for complete transformation. The regions of 12S sufficient for T24ras cotransformation have been well characterized and are located in the first exon. The second exon is dispensable for ras cotransformation, although it contains a region which appears to modulate the transforming phenotype. The same 12S first exon regions important in ras transformation are also necessary for E1B transformation. Analysis of an extensive series of second exon deletion and amino acid point mutations demonstrated that mutations affecting either the efficient nuclear localization and/or the immortalizing ability of the 12S protein also prevented cooperation with E1B. In general, the entire C-terminal half of 12S, including the nuclear localization signal, was necessary for efficient cotransformation with E1B. In addition to the differences between T24ras and E1B regarding 12S regions necessary for cotransformation, the characteristics of E1B-cotransformed foci differed from those of T24ras. The E1B foci took longer to appear and had a much slower growth rate. No hypertransformed foci were produced with E1B cotransfections, and established E1A-E1B lines exhibited minimal growth in soft agar compared with that of E1A-T24ras lines.


Acoustic micro-vortexing of fluids, particles and cells in disposable microfluidic chips.
We demonstrate an acoustic platform for micro-vortexing in disposable polymer microfluidic chips with small-volume (20 μl) reaction chambers. The described method is demonstrated for a variety of standard vortexing functions, including mixing of fluids, re-suspension of a pellet of magnetic beads collected by a magnet placed on the chip, and lysis of cells for DNA extraction. The device is based on a modified Langevin-type ultrasonic transducer with an exponential horn for efficient coupling into the microfluidic chip, which is actuated by a low-cost fixed-frequency electronic driver board. The transducer is optimized by numerical modelling, and different demonstrated vortexing functions are realized by actuating the transducer for varying times; from fractions of a second for fluid mixing, to half a minute for cell lysis and DNA extraction. The platform can be operated during 1 min below physiological temperatures with the help of a PC fan, a Peltier element and an aluminum heat sink acting as the chip holder. As a proof of principle for sample preparation applications, we demonstrate on-chip cell lysis and DNA extraction within 25 s. The method is of interest for automating and chip-integrating sample preparation procedures in various biological assays.


Pro- or anti-inflammatory role of apolipoprotein A-1 in high-density lipoproteins?
Apolipoprotein A-1 (apoA-1) is the principal protein fraction of high-density lipoprotein (HDL), conferring to the latter many of its pleiotropic atheroprotective functions. After its effect on cholesterol efflux, the second most studied feature of apoA-1 is its anti-inflammatory property. In addition, it interferes with lipid peroxidation and innate immune receptors. These anti-inflammatory effects are due to various properties, in particular the ability to inhibit the transendothelial migration of immune cells by reducing integrin expression, to inhibit monocyte activation and cytokine production induced by T-cell contact, to inhibit lipid peroxidation and to interfere with innate immune receptors. Recent studies have demonstrated that during chronic systemic inflammation HDL could lose some of its atheroprotective functions and become dysfunctional or even proinflammatory. Recent evidence suggests that specific post-translational modifications of apoA-1 transform this genuine anti-inflammatory molecule into a proinflammatory one. The structural changes include chlorination, nitration and carbamylation of amino acids by myeloperoxidase, oxidation by reactive carbonyls, as well as glycation. Humoral autoimmunity to apoA-1 and HDL has been reported in populations at high cardiovascular risk and constitutes another emerging mechanism contributing to the loss of functions of apoA-1 and HDL. The fact that in recent trials cholesteryl ester transfer protein inhibitors (torcerapib and dalcetrapib) have unfortunately failed to prevent cardiovascular disease despite increasing cholesterol efflux in vitro and HDL levels in vivo, further highlights the clinical importance of understanding the mechanisms driving apoA-1 and HDL towards pro- or anti-inflammatory molecules. These findings should not affect current dyslipidaemia management guidelines.


Current trends in opportunistic infections in children living with HIV/AIDS in a tertiary care hospital in Northern India.
A prospective cohort study was undertaken from November 2010 to March 2012 at Kalawati Saran Children's Hospital (KSCH), Lady Hardinge Medical College (LHMC), New Delhi. The study included all HIV positive children aged between 0-15 years that were registered in the anti-retroviral therapy (ART) centre during the study period. HIV +ve children enrolled at the ART centre were started on ART on the basis of CD4counts (National/NACO guidelines). Various samples were collected from the patients depending on their presenting complaints as per the standard protocols. These included stool, sputum, gastric aspirate, urine, blood, pus and CSF. All the samples were processed in the microbiology laboratory as per the standard techniques. Majority of children presented to the hospital with respiratory system involvement. Fever with cough was the presenting symptom in around half of all the children suggesting involvement of upper and/or lower respiratory tract. Diarrhea and protein energy malnutrition (PEM) were the next most common findings. Clinical presentations more suggestive of HIV (e.g. generalized lymphadenopathy, mucocutaneous lesions, oral thrush etc.) were less commonly the presenting complaints. OIs are still a major health hazard in children living with HIV/AIDS. The pattern of OIs encountered in a developing country like ours is different from the pattern observed in western countries. Tuberculosis is still a major problem as well as other bacterial infections. Fungal and parasitic infections are also a common health hazard. ART is a major pillar for combat against this dreadful disease. As suggested by our study, timely initiation of ART leads to an increase in CD4+ counts which is imperative in protection against OIs in HIV infected patients. Hence, routine monitoring of CD4+ counts and timely initiation and continuation of ART should be a major event in the life of a child infected with HIV.


Fast double-phase retrieval in Fresnel domain using modified Gerchberg-Saxton algorithm for lensless optical security systems.
A novel fast double-phase retrieval algorithm for lensless optical security systems based on the Fresnel domain is presented in this paper. Two phase-only masks are efficiently determined by using a modified Gerchberg-Saxton algorithm, in which two cascaded Fresnel transforms are replaced by one Fourier transform with compensations to reduce the consumed computations. Simulation results show that the proposed algorithm substantially speeds up the iterative process, while keeping the reconstructed image highly correlated with the original one.


Cost-effectiveness of SHINE: A Telephone Translation of the Diabetes Prevention Program.
The Support, Health Information, Nutrition, and Exercise (SHINE) trial recently showed that a telephone adaptation of the Diabetes Prevention Program (DPP) lifestyle intervention was effective in reducing weight among patients with metabolic syndrome. The aim of this study is to determine whether a conference call (CC) adaptation was cost effective relative to an individual call (IC) adaptation of the DPP lifestyle intervention in the primary care setting. We performed a stochastic cost-effectiveness analysis alongside a clinical trial comparing two telephone adaptations of the DPP lifestyle intervention. The primary outcomes were incremental cost-effectiveness ratios estimated for weight loss, body mass index (BMI), waist circumference, and quality-adjusted life years (QALYs). Costs were estimated from the perspective of society and included direct medical costs, indirect costs, and intervention costs. After one year, participants receiving the CC intervention accumulated fewer costs ($2,831 vs. $2,933) than the IC group, lost more weight (6.2 kg vs. 5.1 kg), had greater reduction in BMI (2.1 vs. 1.9), and had greater reduction in waist circumference (6.5 cm vs. 5.9 cm). However, participants in the CC group had fewer QALYs than those in the IC group (0.635 vs. 0.646). The incremental cost-effectiveness ratio for CC vs. IC was $9,250/QALY, with a 48% probability of being cost-effective at a willingness-to-pay of $100,000/QALY. CC delivery of the DPP was cost effective relative to IC delivery in the first year in terms of cost per clinical measure (weight lost, BMI, and waist circumference) but not in terms of cost per QALY, most likely because of the short time horizon.


Autoradiographic distribution and receptor binding profile of [125I]Bolton Hunter-rat amylin binding sites in the rat brain.
Amylin is a recently isolated peptide from amyloid plaques in noninsulin-dependent diabetic patients and showed high sequence homology with calcitonin gene-related peptide. We investigated the distribution and the binding profile of [125I]Bolton Hunter-rat amylin ([125I]BH-rat amylin) binding sites in the rat brain, as well as the affinity of rat amylin for [125I]hCGRP alpha binding sites in the brain, atrium (CGRP1 receptor-enriched tissue) and vas deferens (CGRP2 receptor-enriched tissue). High amounts of high affinity [125I]BH-rat amylin binding sites were observed in the nucleus accumbens, various hypothalamic nuclei, amygdaloid body, dorsal raphe, tegmental and parabrachial nuclei and the locus ceruleus. Interestingly, both rat amylin and salmon calcitonin revealed low nanomolar affinities (2-19 nM) for [125I] BH-rat amylin binding sites in the various brain areas, whereas human calcitonin gene-related peptide-alpha (hCGRP alpha) showed lower affinities ranging between 13 to 150 nM. Moreover, the affinity of rat amylin was much lower than that of hCGRP alpha for [125I]hCGRP alpha binding in the brain, atrium and vas deferens, except for very few areas such as the nucleus accumbens and ventral striatum. Similarly, rat amylin was much weaker (100- to 400-fold) than hCGRP alpha to induce a biological effect in the atrium and vas deferens. These results thus suggest the existence of unique [125I]BH-rat amylin binding sites in the rat brain as well as limited cross-reactivity between rat amylin and [125I]hCGRP alpha receptors present in the brain, atrium and vas deferens.


Importance of Cross-Sector Interactions When Projecting Forest Carbon across Alternative Socioeconomic Futures.
In recent decades, the carbon sink provided by the U.S. forest sector has offset a sizable portion of domestic greenhouse gas (GHG) emissions. In the future, the magnitude of this sink has important implications not only for projected U.S. net GHG emissions under a reference case but also for the cost of achieving a given mitigation target. The larger the contribution of the forest sector towards reducing net GHG emissions, the less mitigation is needed from other sectors. Conversely, if the forest sector begins to contribute a smaller sink, or even becomes a net source, mitigation requirements from other sectors may need to become more stringent and costlier to achieve economy wide emissions targets. There is acknowledged uncertainty in estimates of the carbon sink provided by the U.S. forest sector, attributable to large ranges in the projections of, among other things, future economic conditions, population growth, policy implementation, and technological advancement. We examined these drivers in the context of an economic model of the agricultural and forestry sectors, to demonstrate the importance of cross-sector interactions on projections of emissions and carbon sequestration. Using this model, we compared detailed scenarios that differ in their assumptions of demand for agriculture and forestry products, trade, rates of (sub)urbanization, and limits on timber harvest on protected lands. We found that a scenario assuming higher demand and more trade for forest products resulted in increased forest growth and larger net GHG sequestration, while a scenario featuring higher agricultural demand, ceteris paribus led to forest land conversion and increased anthropogenic emissions. Importantly, when high demand scenarios are implemented conjunctively, agricultural sector emissions under a high income-growth world with increased livestock-product demand are fully displaced by substantial GHG sequestration from the forest sector with increased forest product demand. This finding highlights the potential limitations of single-sector modeling approaches that ignore important interaction effects between sectors.


The endosome fusion regulator early-endosomal autoantigen 1 (EEA1) is a dimer.
EEA1, an early-endosomal protein originally identified as an autoantigen, is essential for endocytic membrane fusion. It interacts with early endosomes via binding to the membrane lipid phosphatidylinositol 3-phosphate (PtdIns3P) and the active form of the small GTPase Rab5. Most of the EEA1 sequence contains heptad repeats characteristic of proteins involved in coiled-coil protein-protein interactions. Here we have investigated the ability of EEA1 to self-interact. Crosslinking of cytosolic and recombinant EEA1 resulted in the disappearance of the 180-kDa monomer in SDS/PAGE and the strong appearance of a approximately 350-kDa crosslinked product. Glycerol gradient centrifugation experiments indicated that native EEA1 had the same hydrodynamic properties as the approximately 350-kDa crosslinked complex. Two-hybrid analysis indicated that N- and C-terminal fragments of EEA1 can interact with themselves, but not with each other, suggesting that EEA1 forms parallel coiled-coil dimers. The ability of the C-terminus of EEA1 to dimerize correlates with its ability to bind to Rab5 and early endosomes, whereas its binding to PtdIns3P is independent of dimerization. These data enable us to propose a model for the quaternary structure of EEA1.


"Vitamin D" as a profile marker for cardiovascular diseases.
A growing body of research indicates that there exists a correlation between Vit D deficiency and cardiovascular diseases (CVD). In addition to being genetically determined, it is strongly influenced by lifestyle factors. In this study, Vit D and its interrelated factors have been studied as profile marker for identifying the risk of CVD in patients. The present study includes comparison of a total 200 adults CVD patients with the healthy patients as control, by measuring their serum lipid levels and Vit D concentrations with other CVD risk factors. The average serum Vit D in CVD patients and controls are found to be 22.55±6.2 ng/ml and 37.62±3.2 ng/ml respectively, showing that 63% of CVD patients and 35% of controls are Vit D deficient. Serum lipids levels were considered as marker for patients having CVD which include high levels of total cholesterol, triglycerides, and low-density lipoprotein-cholesterol while low levels of high-density lipoproteins-cholesterol levels. Other risk factors like hypertension, lifestyle, smoking, dietary factors and nutritional status shows significantly correlation for CVD patients compared to controls. Literature supports the relationship between lipid profile and Vit D level by using this as a profile marker for CVD patients. Our study also suggests the same that vitamin D can be used as profile marker for cardiovascular diseases.


Origin of DNA-Induced Circular Dichroism in a Minor-Groove Binder.
Induced circular dichroism (ICD) of DNA-binding ligands is well known to be strongly influenced by the specific mode of binding, but the relative importance of the possible mechanisms has remained undetermined. With a combination of molecular dynamics simulations, CD response calculations, and experiments on an AT-sequence, we show that the ICD of minor-groove-bound 4',6-diamidino-2-phenylindole (DAPI) originates from an intricate interplay between the chiral imprint of DNA, off-resonant excitonic coupling to nucleobases, charge-transfer, and resonant excitonic coupling between DAPIs. The significant contributions from charge-transfer and the chiral imprint to the ICD demonstrate the inadequacy of a standard Frenkel exciton theory of the DAPI-DNA interactions.


Standard guidelines of care: Keloids and hypertrophic scars.
Keloids and hypertrophic scars (HTS) are the result of overgrowth of fibrous tissue, following healing of a cutaneous injury, and cause morbidity. There are several treatment modalities which are useful for the management of keloids, though no single modality is completely effective. The most commonly used modalities are pressure, silicone gel sheet, intralesional steroids, 5-fluorouracil (5 FU), cryotherapy, surgical excision, and lasers. They may be used either singly or, as is done more commonly, in combinations. Any qualified dermatologist who has attained postgraduate qualification in dermatology can treat keloids and HTS. Some procedures, such as cryosurgery and surgical excision, may require additional training in dermatologic surgery. Most modalities for keloids, including intralesional injections and mechanical therapies such as pressure and silicone gel based products, can be given/prescribed on OPD basis. Surgical excision requires a minor operation theater with the facility to handle emergencies. It is important to counsel the patient about the nature of the problem. One should realize that keloid will only improve and not disappear completely. Patients should be informed about the high recurrence rates. Different modalities carry risk of adverse effects and complications and the treating physician needs to be aware of these and patients should be informed about them.


Advances in keratinocyte delivery in burn wound care.
This review gives an updated overview on keratinocyte transplantation in burn wounds concentrating on application methods and future therapeutic cell delivery options with a special interest in hydrogels and spray devices for cell delivery. To achieve faster re-epithelialisation of burn wounds, the original autologous keratinocyte culture and transplantation technique was introduced over 3 decades ago. Application types of keratinocytes transplantation have improved from cell sheets to single-cell solutions delivered with a spray system. However, further enhancement of cell culture, cell viability and function in vivo, cell carrier and cell delivery systems remain themes of interest. Hydrogels such as chitosan, alginate, fibrin and collagen are frequently used in burn wound care and have advantageous characteristics as cell carriers. Future approaches of keratinocyte transplantation involve spray devices, but optimisation of application technique and carrier type is necessary.


CDP-glycerol:poly(glycerophosphate) glycerophosphotransferase, which is involved in the synthesis of the major wall teichoic acid in Bacillus subtilis 168, is encoded by tagF (rodC).
Assays of CDP-glycerol:poly(glycerophosphate) glycerophosphotransferase (CGPTase) (EC 188.8.131.52) in membranes isolated from Bacillus subtilis 168 wild type and 11 strains bearing conditional lethal thermosensitive mutations in tagB, tagD, or tagF revealed that CGPTase deficiency was associated only with mutant tagF alleles. In vitro, thermosensitivity of CGPTase strongly suggests that the structural gene for this enzyme is tagF. We discuss apparent discrepancies between biochemical evidence favoring a membrane location for TagF and a previous report that suggested a cytoplasmic location based on sequence analysis.


Rowachol--a possible treatment for cholesterol gallstones.
It has been claimed that Rowachol, a proprietary choleretic, is occasionally successful in the treatment of gallstones. In gallstone patients we have examined its effect on the lipid composition of (1) samples of fasting gall bladder bile obtained at the time of cholecystectomy, and (2) T-tube bile on the tenth post-operative day. In a dose of two capsules, three times a day for only 48 hours, Rowachol significantly lowered the cholesterol solubility of both gall bladder (P less than 0.001) and T-tube bile (P less than 0.05). Rowachol in a dose of one capsule three times a day for 48 hours did not alter bile composition, while four capsules four times a day for a similar period caused a significant (P less than 0.05) deterioration in biliary lipid composition. The possible mechanisms of action of Rowachol and their therapeutic implications are discussed.


"Proactive" in many ways: Developmental evidence for a dynamic pluralistic approach to prediction.
The anticipation of the forthcoming behaviour of social interaction partners is a useful ability supporting interaction and communication between social partners. Associations and prediction based on the production system (in line with views that listeners use the production system covertly to anticipate what the other person might be likely to say) are two potential factors, which have been proposed to be involved in anticipatory language processing. We examined the influence of both factors on the degree to which listeners predict upcoming linguistic input. Are listeners more likely to predict book as an appropriate continuation of the sentence "The boy reads a", based on the strength of the association between the words read and book (strong association) and read and letter (weak association)? Do more proficient producers predict more? What is the interplay of these two influences on prediction? The results suggest that associations influence language-mediated anticipatory eye gaze in two-year-olds and adults only when two thematically appropriate target objects compete for overt attention but not when these objects are presented separately. Furthermore, children's prediction abilities are strongly related to their language production skills when appropriate target objects are presented separately but not when presented together. Both influences on prediction in language processing thus appear to be context dependent. We conclude that multiple factors simultaneously influence listeners' anticipation of upcoming linguistic input and that only such a dynamic approach to prediction can capture listeners' prowess at predictive language processing.


Weighted change-point method for detecting differential gene expression in breast cancer microarray data.
In previous work, we proposed a method for detecting differential gene expression based on change-point of expression profile. This non-parametric change-point method gave promising result in both simulation study and public dataset experiment. However, the performance is still limited by the less sensitiveness to the right bound and the statistical significance of the statistics has not been fully explored. To overcome the insensitiveness to the right bound we modified the original method by adding a weight function to the D(n) statistic. Simulation study showed that the weighted change-point statistics method is significantly better than the original NPCPS in terms of ROC, false positive rate, as well as change-point estimate. The mean absolute error of the estimated change-point by weighted change-point method was 0.03, reduced by more than 50% comparing with the original 0.06, and the mean FPR was reduced by more than 55%. Experiment on microarray Dataset I resulted in 3974 differentially expressed genes out of total 5293 genes; experiment on microarray Dataset II resulted in 9983 differentially expressed genes among total 12576 genes. In summary, the method proposed here is an effective modification to the previous method especially when only a small subset of cancer samples has DGE.


Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel.
Pyrethroid insecticides are widely used as one of the most effective control measures in the global fight against agricultural arthropod pests and mosquito-borne diseases, including malaria and dengue. They exert toxic effects by altering the function of voltage-gated sodium channels, which are essential for proper electrical signaling in the nervous system. A major threat to the sustained use of pyrethroids for vector control is the emergence of mosquito resistance to pyrethroids worldwide. Here, we report the successful expression of a sodium channel, AaNav1-1, from Aedes aegypti in Xenopus oocytes, and the functional examination of nine sodium channel mutations that are associated with pyrethroid resistance in various Ae. aegypti and Anopheles gambiae populations around the world. Our analysis shows that five of the nine mutations reduce AaNav1-1 sensitivity to pyrethroids. Computer modeling and further mutational analysis revealed a surprising finding: Although two of the five confirmed mutations map to a previously proposed pyrethroid-receptor site in the house fly sodium channel, the other three mutations are mapped to a second receptor site. Discovery of this second putative receptor site provides a dual-receptor paradigm that could explain much of the molecular mechanisms of pyrethroid action and resistance as well as the high selectivity of pyrethroids on insect vs. mammalian sodium channels. Results from this study could impact future prediction and monitoring of pyrethroid resistance in mosquitoes and other arthropod pests and disease vectors.


Leptin OB3 peptide suppresses leptin-induced signaling and progression in ovarian cancer cells.
Obesity and its comorbidities constitute a serious health burden worldwide. Leptin plays an important role in diet control; however, it has a stimulatory potential on cancer cell proliferation. The OB3 peptide, a synthetic peptide, was shown to be more active than leptin in regulating metabolism but with no mitogenic effects in cancer cells. In this study, we investigated the proliferative effects, gene expressions and signaling pathways modulated by leptin and OB3 in human ovarian cancer cells. In addition, an animal study was performed. Leptin, but not OB3, induced the proliferation of ovarian cancer cells. Interestingly, OB3 blocked the leptin-induced proliferative effect when it was co-applied with leptin. Both leptin and OB3 activated the phosphatidylinositol-3-kinase (PI3K) signal transduction pathway. In addition, leptin stimulated the phosphorylation of signal transducer and activator of transcription-3 (STAT3) Tyr-705 as well as estrogen receptor (ER)α, and the expression of ERα-responsive genes. Interestingly, all leptin-induced signal activation and gene expressions were blocked by the co-incubation with OB3 and the inhibition of extracellular signal-regulated kinase (ERK)1/2. Coincidently, leptin, but not OB3, increased circulating levels of follicle-stimulating hormone (FSH) which is known to play important roles in the initiation and proliferation of ovarian cancer cells. In summary, our findings suggest that the OB3 peptide may prevent leptin-induced ovarian cancer initiation and progression by disrupting leptin-induced proliferative signals via STAT3 phosphorylation and ERα activation. Therefore, the OB3 peptide is a potential anticancer agent that might be employed to prevent leptin-induced cancers in obese people.


Excited states and quantum confinement in room temperature few nanometre scale silicon single electron transistors.
Single nanometre scale quantum dots (QDs) have significant potential for many 'beyond CMOS' nanoelectronics and quantum computation applications. The fabrication and measurement of few nanometre silicon point-contact QD single-electron transistors are reported, which both operate at room temperature (RT) and are fabricated using standard processes. By combining thin silicon-on-insulator wafers, specific device geometry, and controlled oxidation, <10 nm nanoscale point-contact channels are defined. In this limit of the point-contact approach, ultra-small, few nanometre scale QDs are formed, enabling RT measurement of the full QD characteristics, including excited states to be made. A remarkably large QD electron addition energy ∼0.8 eV, and a quantum confinement energy ∼0.3 eV, are observed, implying a QD only ∼1.6 nm in size. In measurements of 19 RT devices, the extracted QD radius lies within a narrow band, from 0.8 to 2.35 nm, emphasising the single-nanometre scale of the QDs. These results demonstrate that with careful control, 'beyond CMOS' RT QD transistors can be produced using current 'conventional' semiconductor device fabrication techniques.


Vitamin C and the common cold.
The effect of vitamin C on the common cold has been the subject of several studies. These studies do not support a considerable decrease in the incidence of the common cold with supplemental vitamin C. However, vitamin C has consistently decreased the duration of cold episodes and the severity of symptoms. The benefits that have been observed in different studies show a large variation and, therefore, the clinical significance may not be clearly inferred from them. The biochemical explanation for the benefits may be based on the antioxidant property of vitamin C. In an infection, phagocytic leucocytes become activated and they produce oxidizing compounds which are released from the cell. By reacting with these oxidants, vitamin C may decrease the inflammatory effects caused by them. Scurvy, which is caused by a deficiency in vitamin C, is mostly attributed to the decreased synthesis of collagen. However, vitamin C also participates in several other reactions, such as the destruction of oxidizing substances. The common cold studies indicate that the amounts of vitamin C which safely protect from scurvy may still be too low to provide an efficient rate for other reactions, possibly antioxidant in nature, in infected people.


Structural insights into T2-cluster-containing chalcogenides with vertex-, edge- and face-sharing connection modes of NaQ6 ligands: Na3ZnMIIIQ4 (MIII = In, Ga; Q = S, Se).
A series of quaternary chalcogenides, Na3ZnMIIIQ4 (MIII = In, Ga; Q = S, Se), were successfully synthesized for the first time through a high temperature solid-state reaction method. All of them exhibit similar structures and crystallize in the I41/acd space group of the tetragonal system. In their structures, typical super-tetrahedron (T2-type) clusters composed of four vertex-sharing (Zn/MIII)S4 tetrahedra are discovered and these T2-clusters further link together to form interesting wavelike chains. Adjacent T2 clusters present a torsion angle of 24.6° with each other when viewed along the c-axis, which has rarely been found among all the reported T2-containing chalcogenides. Moreover, we have systematically investigated the connection modes of NaSn (n = 4-6) in all the known Na-contained quaternary sulfides, and the result shows that the connection modes (corner-, edge-, and face-sharing) of NaS6 ligands in the title sulfides are also rarely (only 3%) found. Besides, the optical properties including diffuse-reflection and Raman spectra are systematically characterized. Theoretical calculations based on the first principles theory were also used to analyze their structure-performance relationships.


Friendship in high-functioning children with autism spectrum disorder: mixed and non-mixed dyads.
Friendships containing a child with autism and a friend with typical development ("mixed" friendships, n = 26) and those of children with autism and a friend with a disability ("non-mixed," n = 16) were contrasted with friendships of typically developing subjects and their friends (n = 31). Measures included dyadic interaction samples, and interview and questionnaire data from subjects, friends, and parents. Mixed friendship interactions resembled typical friendships. Participants in mixed friendships were more responsive to one another, had stronger receptive language skills, exhibited greater positive social orientation and cohesion, and demonstrated more complex coordinated play than in the non-mixed dyads. Exposure to typical peers appears to have significant effects on friendship behaviors.


Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells.
CD4+ regulatory T cells (Tregs) maintain immunological self-tolerance and immune homeostasis by suppressing aberrant or excessive immune responses. The core genetic program of Tregs and their ability to suppress pathologic immune responses depends on the transcription factor Foxp3. Despite progress in understanding mechanisms of Foxp3-dependent gene activation, the molecular mechanism of Foxp3-dependent gene repression remains largely unknown. We identified Eos, a zinc-finger transcription factor of the Ikaros family, as a critical mediator of Foxp3-dependent gene silencing in Tregs. Eos interacts directly with Foxp3 and induces chromatin modifications that result in gene silencing in Tregs. Silencing of Eos in Tregs abrogates their ability to suppress immune responses and endows them with partial effector function, thus demonstrating the critical role that Eos plays in Treg programming.


Remodeling leads to distinctly more intimal hyperplasia in coronary than in infrainguinal vein grafts.
Flow patterns and shear forces in native coronary arteries are more protective against neointimal hyperplasia than those in femoral arteries. Yet, the caliber mismatch with their target arteries makes coronary artery bypass grafts more likely to encounter intimal hyperplasia than their infrainguinal counterparts due to the resultant slow flow velocity and decreased wall stress. To allow a site-specific, flow-related comparison of remodeling behavior, saphenous vein bypass grafts were simultaneously implanted in femoral and coronary positions. Saphenous vein grafts were concomitantly implanted as coronary and femoral bypass grafts using a senescent nonhuman primate model. Duplex ultrasound-based blood flow velocity profiles and vein graft and target artery dimensions were correlated with dimensional and histomorphologic graft remodeling in large, senescent Chacma baboons (n = 8; 28.1 ± 4.9 kg) during a 24-week period. At implantation, the cross-sectional quotient (Q(c)) between target arteries and vein grafts was 0.62 ± 0.10 for femoral grafts vs 0.17 ± 0.06 for coronary grafts, resulting in a dimensional graft-to-artery mismatch 3.6 times higher (P < .0001) in coronary grafts. Together with different velocity profiles, these site-specific dimensional discrepancies resulted in a 57.9% ± 19.4% lower maximum flow velocity (P = .0048), 48.1% ± 23.6% lower maximal cycling wall shear stress (P = .012), and 62.2% ± 21.2% lower mean velocity (P = .007) in coronary grafts. After 24 weeks, the luminal diameter of all coronary grafts had contracted by 63%, from an inner diameter of 4.49 ± 0.60 to 1.68 ± 0.63 mm (P < .0001; subintimal diameter: -41.5%; P = .002), whereas 57% of the femoral interposition grafts had dilated by 31%, from 4.21 ± 0.25 to 5.53 ± 1.30 mm (P = .020). Neointimal tissue was 2.3 times thicker in coronary than in femoral grafts (561 ± 73 vs 240 ± 149 μm; P = .001). Overall, the luminal area of coronary grafts was an average of 4.1 times smaller than that of femoral grafts. Although coronary and infrainguinal bypass surgery uses saphenous veins as conduits, they undergo significantly different remodeling processes in these two anatomic positions.