An option for measuring maternal mortality in developing countries: a survey using community informants.
The maternal mortality ratio (MMR) remains high in most developing countries. Local, recent estimates of MMR are needed to motivate policymakers and evaluate interventions. But, estimating MMR, in the absence of vital registration systems, is difficult. This paper describes an efficient approach using village informant networks to capture maternal death cases (Maternal Deaths from Informants/Maternal Death Follow on Review or MADE-IN/MADE-FOR) developed to address this gap, and examines its validity and efficiency. MADE-IN used two village informant networks - heads of neighbourhood units (RTs) and health volunteers (Kaders). Informants were invited to attend separate network meetings - through the village head (for the RT) and through health centre for the kaders. Attached to the letter was a form with written instructions requesting informants list deaths of women of reproductive age (WRA) in the village during the previous two years. At a 'listing meeting' the informants' understanding on the form was checked, informants could correct their forms, and then collectively agreed a consolidated list. MADE-FOR consisted of visits relatives of likely pregnancy related deaths (PRDs) identified from MADE-IN, to confirm the PRD status and gather information about the cause of death. Capture-recapture (CRC) analysis enabled estimation of coverage rates of the two networks, and of total PRDs. The RT network identified a higher proportion of PRDs than the kaders (estimated 0.85 vs. 0.71), but the latter was easier and cheaper to access. Assigned PRD status amongst identified WRA deaths was more accurate for the kader network, and seemingly for more recent deaths, and for deaths from rural areas. Assuming information on live births from an existing source to calculate the MMR, MADE-IN/MADE-FOR cost only $0.1 (US) per women-year risk of exposure, substantially cheaper than alternatives. This study shows that reliable local, recent estimates of MMR can be obtained relatively cheaply using two independent informant networks to identify cases. Neither network captured all PRDs, but capture-recapture analysis allowed self-calibration. However, it requires careful avoidance of false-positives, and matching of cases identified by both networks, which was achieved by the home visit.


Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial.
Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy. In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724. From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later. R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy. The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.


Assessment of an ultra-sensitive IFNγ immunoassay prototype for latent tuberculosis diagnosis.
Worldwide there are about 1.7 billion individuals with latent tuberculosis infection (LTBI) and only 5% to 15% will develop active tuberculosis (TB). It is recommended to treat only those most at risk of developing active TB to avoid problems of drug resistance. LTBI diagnosis involves reviewing the individual's medical history, physical examination, and biological tests. Interferon gamma release assays (IGRA) can yield "undeterminate" or "uncertain" results, which makes clinical management decisions difficult. We assessed an ultra-sensitive immunoassay prototype based on single molecule array (SiMoA) technology to evaluate its overall performance, and in particular, its performance for indeterminate and uncertain positive or negative samples, as classified by the results from the current ELISA technique used for IFNγ quantification. We analyzed samples from hospitalized or consulting patients and healthcare workers from three hospitals in Paris, previously classified as negative (n = 30), positive (n = 35), uncertain negative (n = 25), uncertain positive (n = 31), or indeterminate (n = 30). We observed that with the SiMoA assay 83.3% of the indeterminate samples became interpretable and could be classified as negative, whereas 74% of uncertain positive samples were classified as positive. Most uncertain negative samples (72%) were reclassified as uncertain positive (68%) or positive (4%). The results suggest that the ultra-sensitive SiMoA IFNγ assay could represent a useful tool for the identification of true positive and negative samples among those giving indeterminate or uncertain results with the TB IGRA assay currently used.


Variations by age in symptoms and dependency levels experienced by people in the last year of life, as reported by surviving family, friends and officials.
To explore the relationships between age, reported symptoms and dependency in the last year of life in those dying from cancer and in those dying from other causes. Secondary analysis of data from the Regional Study of Care for the Dying, a retrospective interview survey of deaths in 1990 in 20 nationally representative English health districts. There were 2061 cancer deaths and 1469 non-cancer deaths (sudden deaths were excluded). In cancer patients, the mean number of symptoms reported to have been experienced in the last year of life decreased with age (from 8.29 in those aged <65 to 7.79 in those aged 65 -74, 7.37 in those aged 75-84 and 7.42 in those aged 85 and older), while the number of symptoms reported to have lasted more than 6 months increased (2.93, 3.15, 3.24 and 3.52). In both cancer and non-cancer patients the proportion of symptoms reported to have been 'very distressing' decreased with age (cancer, 45, 43, 40 and 35%; non-cancer, 39, 38, 34 and 27%). In non-cancer patients the mean number of self-care tasks the deceased had needed help with increased substantially with age (2.23, 2.50, 3.04 and 3.95); in cancer patients the mean level was higher and there was no age gradient (3.89, 3.94, 3.83 and 4.1). The prevalence of dependency on most of the seven self-care tasks in cancer patients was comparable with or higher than that in the older and most restricted non-cancer patients. Younger cancer patients are more likely than older cancer patients to need help with relieving distressing symptoms. However, some elderly patients were reported to have had very distressing symptoms, and these patients should not be excluded from specialist palliative care services on the basis of their age. Cancer patients did not show increased dependency with age, indicating the importance of community health and social services being appropriate for and accessible by cancer patients of all ages.


Molecular epidemiology of human cancer: biomarkers of genotoxic exposure and susceptibility.
The new field of molecular epidemiology investigates the link between toxic exposure and an associated health effect by defining presumptive intermediate stages in the development of the disease based on known mechanisms. In the development of malignancy, these steps may involve exposure to known mutagens and carcinogens, internalization and potential metabolism of a chemical agent, characterization of the interaction of the agent at its site of action (usually DNA), characterization of induced preneoplastic changes, and, in certain instances, early detection of the cancer itself. These processes can be monitored through biomarkers specific to each of the steps in the progression toward disease using any of the host of applicable techniques now available. An overview of such techniques is presented, with emphasis on techniques offering insight into the malignant process. Evidence is presented suggesting that although there are many potential contributing mechanisms to carcinogenesis, mutagenesis remains the dominant driving force behind the process. Several methods of monitoring mutation have shown promise as predictors of cancer incidence. These methods might also be used as monitors of agents designed to intervene in the process to prevent the development of overt disease.


The views of the elderly on the impact that HIV and AIDS has on their lives in the Thulamela Municipality, Vhembe District, Limpopo province.
HIV and AIDS have a devastating impact on the lives of elderly people, particularly so because they are often expected to take care of their terminally ill children and assume the responsibility of looking after children orphaned by AIDS - in most cases with very little resources. The study sought to achieve to describe the views of elderly people regarding the impact of HIV and AIDS on their lives, to determine the challenges that elderly people living with HIV or AIDS (EPLWHA) face in their daily lives, and to gain a sense of the coping strategies they use to overcome the obstacles they face in relation to HIV and AIDS. Ethical issues, such as permission to conduct the study, informed consent, confidentiality and anonymity, withdrawal of participation and measure to ensure trustworthiness, were ensured. This was a qualitative, explorative, descriptive study. Participants were interviewed using an interview guide. Information provided by the participants was captured on a tape recorder and analysed using open coding, and thereafter collated into themes, categories and sub-themes. The study findings revealed that HIV and AIDS have serious negative impacts on the lives of elderly people, particularly those living in poverty. The following key areas in relation to EPLWHA were established: psychological or emotional health, as well as household and socio-economic burdens. Considering the role that elderly people play in the community in so far as HIV and AIDS are concerned, primary health promotion and social welfare programmes should be directed at educating all elderly people and their service providers on how to cope with the health and social problems related to HIV and AIDS.


Some chronobiological considerations related to physical exercise.
Variables associated with physical activity show circadian rhythms in resting subjects; these rhythms have both exogenous (due to the individual's lifestyle and environment) and endogenous (due to the "body clock") components. During exercise, many of the rhythms persist, even though some show decreasing amplitude with increasing severity of exercise. Whilst the value of physical fitness is not disputed (for elite athletes, for individuals who just want to be physically fit, or for patients undertaking physical rehabilitation regimens), there are certain times of the day when special care is needed. These times are soon after waking--when there is the possibility of an increased risk of cardiovascular morbidity and damage to the spine--and late in the day--when there is an increased risk of respiratory difficulties. Since physical exercise is inextricably linked with thermoregulation, there are special considerations to bear in mind when exercise takes place in cold or hot environments. Further, due to the effects of the body clock, exercise and activity during night work and after time-zone transitions presents problems peculiar to these circumstances. In addition, the menstrual cycle affects physical performance, and these circatrigintan rhythms interact with the circadian ones. Bearing in mind these factors, advice that is based upon knowledge of circadian and circatrigintan rhythms can be given to all those contemplating physical activity. Chronobiologically, there is advantage in undertaking physical activity programmes towards the middle of the waking day and not at times when a sleep or nap has just been taken.


In-vehicle carbon dioxide and adverse effects: An air filtration-based intervention study.
Drowsiness is considered a potential risk for traffic accidents. Exposure to high carbon dioxide (CO2) levels in vehicles may result in unpleasant feeling, fatigue, drowsiness or lethargy among drivers and passengers. However, little is known about whether reducing CO2 levels in vehicles by air filtration can relieve adverse effects among human subjects during driving. We recruited a panel of 84 healthy participants to drive a vehicle equipped with a CO2 filtration system for 1 h on a coastal road in a Northern Taiwan rural area. The operation modes of the CO2 filtration system, including fresh air from open windows without a CO2 filtration system (Control-mode), fresh air from an air conditioning (AC) system with closed windows and a false CO2 filtration system in operation (Off-mode) or a true CO2 filtration system in operation (On-mode), were examined. The repeated measurements of heart rate (HR), blood pressure (BP), CO2, total volatile organic compounds (TVOCs), particulate matter ≤2.5 μm in aerodynamic diameter (PM2.5) and a simple question about drowsiness were obtained for each participant in three different modes. We found that decreased HR, systolic BP (SBP) and diastolic BP (DBP) and increased drowsiness were associated with increased levels of in-vehicle CO2. The effects of in-vehicle CO2 on adverse effects were highest in the Off-mode during driving. In the On-mode, the participants showed slight decreases in HR, SBP and DBP and slight increases in drowsiness. We concluded that the utilization of a CO2 filtration system can reduce in-vehicle CO2 levels and modify the effect of in-vehicle CO2 on HR, BP and drowsiness among human subjects during driving.


India in search of right Universal Health Coverage (UHC) model: The risks of implementing UHC in the absence of political demand by the citizen.
Amid the global push for Universal Health Coverage (UHC), the agenda is being set for India's health care. In the absence of a constitutional mandate, a national policy and citizen-led political demand for UHC, there exist specific risks in rushing toward its implementation in India. As the debate of UHC continues, the health-care delivery system in India is at cross roads. UHC in India could take two different trajectories. The first one takes India toward becoming "Global Bazaar" of morbidity and ill health, founded on the pillars of a vibrant rapidly multiplying healthcare industry. The other path takes India on a course of preventing wasteful, expensive health-care expenditure by maintaining healthy populations. A poor professional blood donor cannot become rich by selling his or her own blood beyond medically permissible levels; similarly, India cannot become a developed economy by merely allowing exploitation of disease, illness, and morbidity of her citizen. It is the duty of the state and governments to protect individual citizen, population under consideration, as well as country's economy from wasteful and potentially harmful expenditure incurred to address ill health. In the economic sense, any sensible UHC implementation mechanism would seek to regulate wasteful preventable health-care expenditure for the purpose of future economic stability and growth of the country. Due diligence toward safeguarding "public health in public interest," during the process of UHC implementation, is the need of the hour.


Familial History of Autoimmune Disorders Among Patients With Pediatric Multiple Sclerosis.
The objective of this study was to determine whether family members of patients with pediatric multiple sclerosis (MS) have an increased prevalence of autoimmune conditions compared with controls. Data collected during a pediatric MS case-control study of risk factors included information about various autoimmune diseases in family members. The frequency of these disorders was compared between cases and controls. There was an increased rate of autoimmune diseases among family members of pediatric MS cases compared with controls with first-degree history of MS excluded (OR = 2.27, 95% CI 1.71-3.01, p < 0.001). There was an increased rate of MS among second-degree relatives of pediatric MS cases compared with controls (OR = 3.47, 95% CI 1.36-8.86, p = 0.009). The OR for MS was 2.64 when restricted to maternal relatives and 6.37 when restricted to paternal relatives. The increased rates of autoimmune disorders, including thyroid disorders and MS among families of patients with pediatric MS, suggest shared genetic factors among families with children diagnosed with pediatric MS.


Evaluation of intra-host variants of the entire hepatitis B virus genome.
Genetic analysis of hepatitis B virus (HBV) frequently involves study of intra-host variants, identification of which is commonly achieved using short regions of the HBV genome. However, the use of short sequences significantly limits evaluation of genetic relatedness among HBV strains. Although analysis of HBV complete genomes using genetic cloning has been developed, its application is highly labor intensive and practiced only infrequently. We describe here a novel approach to whole genome (WG) HBV quasispecies analysis based on end-point, limiting-dilution real-time PCR (EPLD-PCR) for amplification of single HBV genome variants, and their subsequent sequencing. EPLD-PCR was used to analyze WG quasispecies from serum samples of patients (n = 38) infected with HBV genotypes A, B, C, D, E and G. Phylogenetic analysis of the EPLD-isolated HBV-WG quasispecies showed the presence of mixed genotypes, recombinant variants and sub-populations of the virus. A critical observation was that HBV-WG consensus sequences obtained by direct sequencing of PCR fragments without EPLD are genetically close, but not always identical to the major HBV variants in the intra-host population, thus indicating that consensus sequences should be judiciously used in genetic analysis. Sequence-based studies of HBV WG quasispecies should afford a more accurate assessment of HBV evolution in various clinical and epidemiological settings.


Synthesis and turnover of polysomal mRNAs in sea urchin embryos.
The synthesis and turnover kinetics of polysomal mRNA have been measured in sea urchin embryos. Polysomes were isolated from stages ranging between mesenchyme blastula and late gastrula Strongylocentrotus purpuratus embryos which had been exposed to exogenous 3H-guanosine. The amount of radioactivity incorporated into messenger and ribosomal RNAs was determined separately as a function of time, and the precursor pool specific activity was measured in the same embryos. Synthesis and decay rate constants were extracted from the data by a least-squares procedure. Per embryo, the rate of mRNA synthesis was calculated to be about 0.13 pg min-1, while the rate of rRNA synthesis is about 0.022 pg min-1. The newly synthesized mRNA turns over with a half-time of 5.7 hr. The data support only a single decay rate for the mRNA, but small fractions of mRNA decaying at different rates cannot be excluded. Previous studies have shown that a minor fraction of the mRNA includes the least abundant, most highly diverse set of messages ("complex class" mRNAs). To determine whether mRNAs of the complex class are synthesized and degraded at similar rates, labeled mRNA was measured in hybrids formed in mRNA excess reactions with single copy DNA. These experiments showed that complex class mRNAs represent an approximately proportional amount of the new mRNA symthesis, and turn over at the same average rate as does the bulk of the mRNA. Most of the mRNAs in the embryo polysomes are newly synthesized, rather than maternal. This statement refers both to complex class mRNAs and to prevalent mRNAs. Considering the sequence homology between embryo and oocyte mRNAs shown earlier, these results indicate that many of the same structural genes active during oogenesis are being transcribed in embryos at these stages.


The effectiveness of nutrition education programmes on improving dietary intake in athletes: a systematic review.
Nutrition education programmes for athletes aim to enhance nutrition knowledge and more importantly support positive dietary change to enhance performance, health and well-being. This systematic review assessed changes in the dietary intakes of athletes in response to nutrition education programmes. A search was conducted which included studies providing quantitative dietary intake assessment of athletes of any calibre aged between 12 and 65 years in response to a nutrition education programme. Standardised differences (effect sizes) were calculated (when possible) for each dietary parameter. The search yielded 6285 papers with twenty-two studies (974 participants (71·9 % female)) eligible for inclusion. Studies described athletes competing at high school (n 3) through to college level or higher (n 19). Study designs were either single arm with an intervention-only group (twelve studies; n 241) or double arm including an intervention and control group (ten studies; n 689). No control groups received an alternative or 'sham' intervention. Face-to-face lectures (9/22) and individual nutrition counselling (6/22) were the most common education interventions. Non-weighed, 3-d diet records (10/22) were the most frequently utilised dietary assessment method. Although 14/22 studies (n 5 single and n 9 double) reported significant change in at least one nutrition parameter, dietary changes were inconsistent. Poor study quality and heterogeneity of methods prohibit firm conclusions regarding overall intervention success or superior types of educational modalities. Of note, carbohydrate intakes 'post-intervention' when assessed often failed to meet recommended guidelines (12/17 studies). Given the substantial investment made in nutrition education interventions with athletes, there is a need for well-designed and rigorous research to inform future best practice.


EphA2 Is a Clinically Relevant Target for Breast Cancer Bone Metastatic Disease.
EphA2 receptor tyrosine kinase (RTK) is highly expressed in breast tumor cells across multiple molecular subtypes and correlates with poor patient prognosis. In this study, the potential role of EphA2 in this clinically relevant phenomenon is investigated as metastasis of breast cancer to bone is a major cause of morbidity and mortality in patients. It was found that the EphA2 function in breast cancer cells promotes osteoclast activation and the development of osteolytic bone disease. Blocking EphA2 function molecularly and pharmacologically in breast tumors reduced the number and size of bone lesions and the degree of osteolytic disease in intratibial and intracardiac mouse models, which correlated with a significant decrease in the number of osteoclasts at the tumor-bone interface. EphA2 loss of function in tumor cells impaired osteoclast progenitor differentiation in coculture, which is mediated, at least in part, by reduced expression of IL-6. EPHA2 transcript levels are enriched in human breast cancer bone metastatic lesions relative to visceral metastatic sites; EphA2 protein expression was detected in breast tumor cells in bone metastases in patient samples, supporting the clinical relevance of the study's findings. These data provide a strong rationale for the development and application of molecularly targeted therapies against EphA2 for the treatment of breast cancer bone metastatic disease. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.


Genetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing.
Genetic alterations in kinases have been linked to multiple human pathologies. To explore the landscape of kinase genetic variation in gastric cancer (GC), we used targeted, paired-end deep sequencing to analyze 532 protein and phosphoinositide kinases in 14 GC cell lines. We identified 10,604 single-nucleotide variants (SNV) in kinase exons including greater than 300 novel nonsynonymous SNVs. Family-wise analysis of the nonsynonymous SNVs revealed a significant enrichment in mitogen-activated protein kinase (MAPK)-related genes (P < 0.01), suggesting a preferential involvement of this kinase family in GC. A potential antioncogenic role for MAP2K4, a gene exhibiting recurrent alterations in 2 lines, was functionally supported by siRNA knockdown and overexpression studies in wild-type and MAP2K4 variant lines. The deep sequencing data also revealed novel, large-scale structural rearrangement events involving kinases including gene fusions involving CDK12 and the ERBB2 receptor tyrosine kinase in MKN7 cells. Integrating SNVs and copy number alterations, we identified Hs746T as a cell line exhibiting both splice-site mutations and genomic amplification of MET, resulting in MET protein overexpression. When applied to primary GCs, we identified somatic mutations in 8 kinases, 4 of which were recurrently altered in both primary tumors and cell lines (MAP3K6, STK31, FER, and CDKL5). These results demonstrate that how targeted deep sequencing approaches can deliver unprecedented multilevel characterization of a medically and pharmacologically relevant gene family. The catalog of kinome genetic variants assembled here may broaden our knowledge on kinases and provide useful information on genetic alterations in GC.


Future climate change is predicted to shift long-term persistence zones in the cold-temperate kelp Laminaria hyperborea.
Global climate change is shifting species distributions worldwide. At rear edges (warmer, low latitude range margins), the consequences of small variations in environmental conditions can be magnified, producing large negative effects on species ranges. A major outcome of shifts in distributions that only recently received attention is the potential to reduce the levels of intra-specific diversity and consequently the global evolutionary and adaptive capacity of species to face novel disturbances. This is particularly important for low dispersal marine species, such as kelps, that generally retain high and unique genetic diversity at rear ranges resulting from long-term persistence, while ranges shifts during climatic glacial/interglacial cycles. Using ecological niche modelling, we (1) infer the major environmental forces shaping the distribution of a cold-temperate kelp, Laminaria hyperborea (Gunnerus) Foslie, and we (2) predict the effect of past climate changes in shaping regions of long-term persistence (i.e., climatic refugia), where this species might hypothetically harbour higher genetic diversity given the absence of bottlenecks and local extinctions over the long term. We further (3) assessed the consequences of future climate for the fate of L. hyperborea using different scenarios of greenhouse gas emissions (RCP 2.6 and RCP 8.5). Results show NW Iberia, SW Ireland and W English Channel, Faroe Islands and S Iceland, as regions where L. hyperborea may have persisted during past climate extremes until present day. All predictions for the future showed expansions to northern territories coupled with the significant loss of suitable habitats at low latitude range margins, where long-term persistence was inferred (e.g., NW Iberia). This pattern was particularly evident in the most agressive scenario of climate change (RCP 8.5), likely driving major biodiversity loss, changes in ecosystem functioning and the impoverishment of the global gene pool of L. hyperborea. Because no genetic baseline is currently available for this species, our results may represent a first step in informing conservation and mitigation strategies.


Stent expansion: a combination of delivery balloon underexpansion and acute stent recoil reduces predicted stent diameter irrespective of reference vessel size.
There is a strong inverse relationship between final vessel diameter and subsequent risk of treatment failure after coronary stent deployment. The aim of this study was to investigate the magnitude by which stent delivery balloon underexpansion and stent elastic recoil contributed to suboptimal final vessel geometry. A prospective angiographic study recruiting 499 lesions (385 patients) undergoing coronary stent implantation was performed. Quantitative coronary angiography (QCA) was used to measure the minimal lumen diameters of the delivery balloon during stent deployment (MLD1) and of the stented segment following balloon deflation (MLD2). The expected balloon diameter for the deployment pressure was determined from the manufacturer's reference chart. Delivery balloon deficit was measured by subtracting the MLD1 from the expected balloon size and stent recoil was calculated by subtracting MLD2 from MLD1. Delivery balloon deficit and stent recoil were examined as a function of reference vessel diameter (RVD) and balloon-vessel (BV) ratio. The final stent MLD was a mean 27.2% (SD = 7.2) less than the predicted diameter. The mean delivery balloon deficit was 0.65 mm (SD = 0.27) and the mean stent recoil was 0.28 mm (SD = 0.17). Percentage delivery balloon deficit and stent recoil were independent of RVD. Delivery balloon deficit increased with higher BV ratios. Stent recoil was independent of BV ratio and the use of predilatation. Failure to achieve predicted final stent diameter is a real problem with contribution from delivery balloon underexpansion and stent recoil. On average the final stent MLD is only 73% of the expected diameter, irrespective of vessel size.


Sample descriptors linked to metagenomic sequencing data from human and animal enteric samples from Vietnam.
There is still limited information on the diversity of viruses co-circulating in humans and animals. Here, we report data obtained from a large field collection of enteric samples taken from humans, pigs, rodents and other mammal hosts in Vietnam between 2012 and 2016. Each of 2100 stool or rectal swab samples was subjected to virally-enriched agnostic metagenomic sequencing; the short read sequence data are accessible from the European Nucleotide Archive (ENA). We link the sequence data to metadata on host type and demography and geographic location, distinguishing hospital patients, members of a cohort identified as a high risk of zoonotic infections (e.g. abattoir workers, rat traders) and animals. These data are suitable for further studies of virus diversity and virus discovery in humans and animals from Vietnam and to identify viruses found in multiple hosts that are potentially zoonotic.


Navigating uncharted territory: a qualitative study of the experience of transitioning to wheelchair use among older adults and their care providers.
An increasing number of older adults are procuring a wheelchair for mobility; however, the corresponding impact on related injuries, caregiver burden, and participation restriction is concerning. To inform the development of a wheelchair training program, we pursued a clearer understanding of the experience transitioning to wheelchair use for older adult users and their care provider. Six focus groups were conducted with older experienced wheelchair users (n = 10) and care providers (n = 4). Transcripts were analyzed using a Conventional Content approach; a coding framework enabled inductive theming and summary of the data. Three themes emerged from the user group: On My Own reflected both limited training and the necessity of venturing out, More Than Meets the Eye addressing barriers to use, and Interdependence between wheelchair users and the ambulatory community. Care provider responses fell into two themes: the All Encompassing impact of assumed responsibilities and Even the Best Laid Plans, where unpredictable and inaccessible environments sabotaged participation. The transition from ambulatory to wheelchair mobility can feel like uncharted territory. Balanced support and appropriate mentorship are fundamentally important and real-world encounters optimize independence and proficiency with skills. The impact on care providers is extensive, highlighting the importance of skills training.


Exact reconstruction of gene regulatory networks using compressive sensing.
We consider the problem of reconstructing a gene regulatory network structure from limited time series gene expression data, without any a priori knowledge of connectivity. We assume that the network is sparse, meaning the connectivity among genes is much less than full connectivity. We develop a method for network reconstruction based on compressive sensing, which takes advantage of the network's sparseness. For the case in which all genes are accessible for measurement, and there is no measurement noise, we show that our method can be used to exactly reconstruct the network. For the more general problem, in which hidden genes exist and all measurements are contaminated by noise, we show that our method leads to reliable reconstruction. In both cases, coherence of the model is used to assess the ability to reconstruct the network and to design new experiments. We demonstrate that it is possible to use the coherence distribution to guide biological experiment design effectively. By collecting a more informative dataset, the proposed method helps reduce the cost of experiments. For each problem, a set of numerical examples is presented. The method provides a guarantee on how well the inferred graph structure represents the underlying system, reveals deficiencies in the data and model, and suggests experimental directions to remedy the deficiencies.


Response Patterns to the Electric Stimulation of Epidural Catheters in Pregnant Women: A Randomized Controlled Trial of Uniport Versus Multiport Catheters.
The transcatheter electric stimulation test (Tsui test) can be performed at the bedside to confirm the correct placement of a wire-reinforced epidural catheter within the epidural space. The most commonly observed motor response with a uniport epidural catheter placed in the lumbar area is the unilateral contraction of the lower limbs. Wire-reinforced multiport catheters have recently been introduced into clinical practice; however, the characteristics of the Tsui test with such catheters are unknown. We designed a randomized controlled trial to test the hypothesis that the incidence of a bilateral response to the Tsui test would be higher with a multiport catheter, with all other characteristics of the test remaining unchanged. We recruited laboring women requesting epidural analgesia. The epidural catheter placement was performed in a standard fashion, assisted by ultrasound, aiming at the L3-L4 interspace. Patients were randomly allocated for the placement of either a 19-G uniport or a 19-G multiport wire-reinforced catheter. The Tsui test (frequency 2 Hz; pulse width 0.2 millisecond) was performed immediately after securing the catheter (baseline) and at 5 minutes after a test dose with 3 mL lidocaine 2%. The current output was increased from zero until motor activity was detected up to a maximum of 20 mA. Subsequently, an initial loading dose of 10 mL bupivacaine 0.125% and 50 μg fentanyl was administered. The sensory block level to ice was assessed bilaterally at 20 minutes after injection of the loading dose. The primary outcome was the motor response pattern to the electric stimulation of the epidural catheter, either unilateral or bilateral; secondary outcomes included minimal current intensity needed to elicit a motor response at baseline and 5 minutes after the test dose, sensory block level and incidence of symmetrical sensory block at 20 minutes after injection of the loading dose, pain scores before the test dose and at 20 minutes after the loading dose, and need for catheter replacement within 2 hours of completion of the loading dose. Sixty-three women were assessed for eligibility and 46 were randomly allocated equally to each group. Three patients were excluded, resulting in 21 subjects in the multiport group and 22 subjects in the uniport group. Patient characteristics in both groups were similar. The incidence of unilateral motor response to the Tsui test was 95.2% (20/21) and 95.5% (21/22) in the multiport and uniport groups, respectively (rate difference 0.22%; 95% confidence interval, for the difference -29.2 to 29.2%; P = 0.99). The minimal current intensity (mean ± SD) required to produce a motor response at baseline was 5.4 ± 3.5 mA and 5.4 ± 4.1 mA in the multiport and uniport groups, respectively (P = 0.98). The sensory block levels to ice on the left and right, as well as pain scores at 20 minutes, were similar in both groups. No epidural catheters were resited. The Tsui test produced a high percentage of unilateral motor response in women with both uniport and multiport wire-embedded catheters. A larger study is necessary to confirm that there is no clinically significant difference in the motor response patterns between the 2 catheter types.


Rapid, robust, and sustainable antibody responses to mRNA COVID-19 vaccine in convalescent COVID-19 individuals.
Longitudinal studies are needed to evaluate the SARS-CoV-2 mRNA vaccine antibody response under real-world conditions. This longitudinal study investigated the quantity and quality of SARS-CoV-2 antibody response in 846 specimens from 350 patients, comparing BNT162b2-vaccinated individuals (19 previously diagnosed with COVID-19, termed RecoVax; and 49 never diagnosed, termed NaiveVax) with 122 hospitalized unvaccinated (HospNoVax) and 160 outpatient unvaccinated (OutPtNoVax) COVID-19 patients. NaiveVax experienced delay in generating SARS-CoV-2 total antibodies (TAb) and surrogate neutralizing antibodies (SNAb) after the first vaccine dose (D1) but rapid increase in antibody levels after the second dose (D2). However, these never reached RecoVax's robust levels. In fact, NaiveVax TAb and SNAb levels decreased 4 weeks after D2. For the most part, RecoVax TAb persisted, after reaching maximal levels 2 weeks after D2, but SNAb decreased significantly about 6 months after D1. Although NaiveVax avidity lagged behind that of RecoVax for most of the follow-up periods, NaiveVax did reach similar avidity by about 6 months after D1. These data suggest that 1 vaccine dose elicits maximal antibody response in RecoVax and may be sufficient. Also, despite decreasing levels in TAb and SNAb over time, long-term avidity may be a measure worth evaluating and possibly correlating to vaccine efficacy.


D-serine regulation of NMDA receptor activity.
The N-Methyl-D-aspartate-type glutamate receptor (NMDAR) plays a key role in several important processes involving the nervous system, including brain development, synaptic plasticity, and learning. Unlike other neurotransmitter receptors, which are activated by individual neurotransmitters, activation of NMDARs requires the binding of a coagonist (D-serine or glycine) in addition to glutamate. Although previously considered an "unnatural" amino acid, D-serine is a key regulator of NMDAR activity and may be the main physiological ligand at the coagonist site. D-Serine is synthesized in the mammalian brain and is enriched in astrocytes, a class of glial cells that ensheath synapses in the brain. Astrocytes physiologically affect NMDAR neurotransmission by releasing D-serine, suggesting that D-serine acts as a gliotransmitter. However, recent findings indicate that D-serine signaling does not depend solely on glia, because D-serine and its biosynthetic enzyme are also present in substantial amounts in neurons. Here, we discuss these new findings, which begin to shed light on the relative roles of glia and neurons in D-serine signaling.


Signals required for programming effector and memory development by CD8+ T cells.
Stimulation of naïve CD8+ T cells with antigen and costimulation results in proliferation and weak clonal expansion, but the cells fail to develop effector functions and are tolerant long term. Initiation of the program leading to the strong expansion and development of effector functions and memory requires a third signal that can be provided by interleukin-12 (IL-12) or interferon-alpha (IFN-alpha). CD4+ T cells condition dendritic cells (DCs) to effectively present antigen to CD8+ T cells, and this conditioning involves, at least in part, CD40-dependent upregulation of the production of these signal 3 cytokines by the DCs. Upon being fully activated, the cytotoxic T lymphocytes develop activation-induced non-responsiveness (AINR), a form of split anergy characterized by an inability to produce IL-2 to support continued expansion. If antigen remains present, IL-2 provided by CD4+ T cells can reverse AINR to allow further expansion of the effector population and conversion to responsive memory cells following antigen clearance. If IL-2 or potentially other proliferative signals are not available, persistent antigen holds cells in the AINR state and prevents the development of a responsive memory population. Thus, in addition to antigen and costimulation, CD8+ T cells require cytokine signals at distinct stages of the response to be programmed for optimal generation of effector and memory populations.


Serotonin-Norepinephrine Reuptake Inhibitors and the Risk of AKI: A Cohort Study of Eight Administrative Databases and Meta-Analysis.
A safety signal regarding cases of AKI after exposure to serotonin-norepinephrine reuptake inhibitors (SNRIs) was identified by Health Canada. Therefore, this study assessed whether the use of SNRIs increases the risk of AKI compared with selective serotonin reuptake inhibitors (SSRIs) and examined the risk associated with each individual SNRI. Multiple retrospective population-based cohort studies were conducted within eight administrative databases from Canada, the United States, and the United Kingdom between January 1997 and March 2010. Within each cohort, a nested case-control analysis was performed to estimate incidence rate ratios (RRs) of AKI associated with SNRIs compared with SSRIs using conditional logistic regression, with adjustment for high-dimensional propensity scores. The overall effect across sites was estimated using meta-analytic methods. There were 38,974 cases of AKI matched to 384,034 controls. Current use of SNRIs was not associated with a higher risk of AKI compared with SSRIs (fixed-effect RR, 0.97; 95% confidence interval [95% CI], 0.94 to 1.01). Current use of venlafaxine and desvenlafaxine considered together was not associated with a higher risk of AKI (RR, 0.96; 95% CI, 0.92 to 1.00). For current use of duloxetine, there was significant heterogeneity among site-specific estimates such that a random-effects meta-analysis was performed showing a 16% higher risk, although this risk was not statistically significant (RR, 1.16; 95% CI, 0.96 to 1.40). This result is compatible with residual confounding, because there was a substantial imbalance in the prevalence of diabetes between users of duloxetine and users of others SNRIs or SSRIs. After further adjustment by including diabetes as a covariate in the model along with propensity scores, the fixed-effect RR was 1.02 (95% CI, 0.95 to 1.10). There is no evidence that use of SNRIs is associated with a higher risk of hospitalization for AKI compared with SSRIs.


Localized structures in nonlinear lattices with diffusive coupling and external driving
We study the stabilization of localized structures by discreteness in one-dimensional lattices of diffusively coupled nonlinear sites. We find that in an external driving field these structures may lose their stability by either relaxing to a homogeneous state or nucleating a pair of oppositely moving fronts. The corresponding bifurcation diagram demonstrates a cusp singularity. The obtained analytic results are in good quantitative agreement with numerical simulations.


Attitudes supporting violence and aggressive behavior among adolescents in Israel: the role of family and peers.
A secondary analysis of data obtained from a national representative sample of the adolescent population in Israel was conducted to explore the association between the quality of social relationships of adolescents and aggressive behavior. The quality of parent-adolescent relations and the quality of peer relations were not directly related to aggressive behavior. Adolescents who were close to their parents and their peers were less likely to report exposure to negative relations with other adolescents. Adolescents who reported being insulted held attitudes favoring the use of aggressive behavior, associated more with delinquent adolescents, and reported a high level of aggression toward others. Adolescents who did not share intimate communication with significant others tended to be more exposed to unpleasant behavior to associate with delinquent peers, and to adopt aggressive attitudes and behaviors. The results suggest that experiencing negative relations during adolescence might be a risk factor predicting aggressive conduct.


MAIRA- real-time taxonomic and functional analysis of long reads on a laptop.
Advances in mobile sequencing devices and laptop performance make metagenomic sequencing and analysis in the field a technologically feasible prospect. However, metagenomic analysis pipelines are usually designed to run on servers and in the cloud. MAIRA is a new standalone program for interactive taxonomic and functional analysis of long read metagenomic sequencing data on a laptop, without requiring external resources. The program performs fast, online, genus-level analysis, and on-demand, detailed taxonomic and functional analysis. It uses two levels of frame-shift-aware alignment of DNA reads against protein reference sequences, and then performs detailed analysis using a protein synteny graph. We envision this software being used by researchers in the field, when access to servers or cloud facilities is difficult, or by individuals that do not routinely access such facilities, such as medical researchers, crop scientists, or teachers.


Do anti-malarials in Africa meet quality standards? The market penetration of non quality-assured artemisinin combination therapy in eight African countries.
Quality of artemisinin-based combination therapy (ACT) is important for ensuring malaria parasite clearance and protecting the efficacy of artemisinin-based therapies. The extent to which non quality-assured ACT (non-QAACT), or those not granted global regulatory approval, are available and used to treat malaria in endemic countries is poorly documented. This paper uses national and sub-national medicine outlet surveys conducted in eight study countries (Benin, Kinshasa and Kantanga [Democratic Republic of the Congo, DRC], Kenya, Madagascar, Nigeria, Tanzania, Uganda and Zambia) between 2009 and 2015 to describe the non-QAACT market and to document trends in availability and distribution of non-QAACT in the public and private sector. In 2014/15, non-QAACT were most commonly available in Kinshasa (83%), followed by Katanga (53%), Nigeria (48%), Kenya (42%), and Uganda (33%). Non-QAACT accounted for 20% of the market share in the private sector in Kenya, followed by Benin and Uganda (19%), Nigeria (12%) and Zambia (8%); this figure was 27% in Katanga and 40% in Kinshasa. Public sector non-QAACT availability and distribution was much lower, with the exception of Zambia (availability, 85%; market share, 32%). Diverse generics and formulations were available, but non-QAACT were most commonly artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHA PPQ), in tablet formulation, imported, and distributed in urban areas at either pharmacies or drug stores. The number of unique manufacturers supplying non-QAACT to each country ranged from 9 in Uganda to 92 in Nigeria. Addressing the availability and distribution of non-QAACT will require effective private sector engagement and evidence-based strategies to address provider and consumer demand for these products. Given the variation in non-QAACT markets observed across the eight study countries, active efforts to limit registration, importation and distribution of non-QAACT must be tailored to the country context, and will involve addressing complex and challenging aspects of medicine registration, private sector pharmaceutical regulation, local manufacturing and drug importation. These efforts may be critical not only to patient health and safety, but also to effective malaria control and protection of artemisinin drug efficacy in the face of spreading resistance.


Reduction of AEDs in postsurgical patients who attain remission.
Little evidence guides practice regarding the reduction of antiepileptic drugs (AEDs) in individuals who achieve significant periods of remission after resective surgery. In a prospective study of 396 individuals who underwent resective surgery for intractable seizures, the impact of reducing AEDs on relapse and predictors of relapse were examined. Of 301 study subjects who attained a 1-year seizure remission after surgery, 129 reduced from two to one or from one to no AEDs after achieving remission, and 162 did not reduce drugs. Ten patients who stopped all AEDs before attaining remission were excluded from analysis. In all, 114 (39%) patients relapsed: 73 (45%) of 162 in the nonreduction group and 41 (32%) of 129 in the reduction group (p = 0.02). Patients who reduced drugs were more likely to have remitted immediately after hospital discharge (p<0.0001). After adjustment for this factor, little or no apparent impact of drug reduction on the rate of relapse was noted [rate ratio (RR), 1.1; 95% CI, 0.72-1.71; p=0.64 for reducing from two to one AED, and RR, 0.85; 95% CI, 0.50-1.45; p=0.56 for reducing from one to no AEDs]. Within the 129 patients who reduced AEDs, only delayed remission after hospital discharge was significantly associated with an increased rate of relapse (RR, 2.26; 95% CI, 1.15- 4.48; p=0.02). Continued auras had a marginally significant association with relapse (RR, 2.06; p=0.07) Although many relapses in this cohort of postsurgical patients who achieved remission occurred in the context of reducing or completely eliminating AEDs, the risk was no higher than in those who continued AEDs. Randomized studies are needed to test the impact of drug reduction in seizure-free postsurgical patients.


How Wnt signaling affects bone repair by mesenchymal stem cells from the bone marrow.
Human mesenchymal stem cells (hMSCs) from bone marrow are a source of osteoblast progenitors in vivo, and under appropriate conditions they differentiate into osteoblasts ex vivo. The cells provide a convenient cell culture model for the study of osteogenic tissue repair in an experimentally accessible system. Recent advances in the field of skeletal development and osteogenesis have demonstrated that signaling through the canonical wingless (Wnt) pathway is critical for the differentiation of progenitor cell lines into osteoblasts. Inhibition of such signals can predispose hMSCs to cell cycle entry and prevent osteogenesis. Our investigation of the role of Wnt signaling in osteogenesis by hMSCs ex vivo has demonstrated that osteogenesis proceeds in response to bone morphogenic protein 2 stimulation and is sustained by Wnt signaling. In the presence of Dkk-1, an inhibitor of Wnt signaling, the cascade is disrupted, resulting in inhibition of osteogenesis. Peptide mapping studies have provided peptide Dkk-1 agonists and the opportunity for the production of blocking antibodies. Anti-Dkk-1 strategies are clinically relevant since high serum levels of Dkk-1 are thought to contribute to osteolytic lesion formation in multiple myeloma and possibly some forms of osteosarcoma. Specific inhibitors of glycogen synthetase kinase 3beta (GSK3beta), which mimic Wnt signaling, may also have a therapeutic benefit by enhancing in vitro osteogenesis despite the presence of Dkk-1. Antibodies that block Dkk-1 and GSK3beta inhibitors may provide novel opportunities for the enhancement of bone repair in a variety of human diseases such as multiple myeloma and osteosarcoma.


Polycarbonate membrane impression cytology: evidence for fluorescein staining in normal and dry eye corneas.
Corneal impression cytology is usually performed with mixed cellulose ester membranes and a limited array of stains. A method using polycarbonate membrane air-dried preparations led to the discovery of fluorescein staining in cells from patients with and without dry eye disease and a membrane-induced defect that was not due to cell removal. Impressions after fluorescein installation were performed using polycarbonate and mixed cellulose ester membranes with rapid staining protocols for Diff-Quick as well as haematoxylin and eosin stains. Prior to staining the air-dried material was examined for fluorescence. Epithelia of both normal and dry eye corneas retained fluorescence from clinical instillation of fluorescein. Corneal defects created by the polycarbonate membrane could not be explained by membrane-induced cell removal. After rapid staining, polycarbonate membranes revealed less background, dissolved easily prior to coverslip application, but showed lower cellular yield compared with the mixed cellulose membranes. Polycarbonate membrane impression cytology enables immediate assessment with rapid stains. Topically applied fluorescein penetrates corneal epithelial cells in both normal and dry eye patients. Cells fluoresce on the cytology membranes. The impression-induced defect on the cornea is not due to cell stripping and may represent removal of mucins.


Tangeretin inhibits the proliferation of human breast cancer cells via CYP1A1/CYP1B1 enzyme induction and CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin.
Tangeretin is a polymethoxylated flavone with multifaceted anticancer activity. In the present study, the metabolism of tangeretin was evaluated in the CYP1 expressing human breast cancer cell lines MCF7 and MDA-MB-468 and in the normal breast cell line MCF10A. Tangeretin was converted to 4' OH tangeretin by recombinant CYP1 enzymes and by CYP1 enzymes expressed in MCF7 and MDA-MB-468 cells. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Tangeretin exhibited submicromolar IC50 (0.25 ± 0.15 μM) in MDA-MB-468 cells, whereas it was less active in MCF7 cells (39.3 ± 1.5 μM) and completely inactive in MCF10A cells (>100 μM). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 70-fold increase was noted in the IC50 (18 ± 1.6 μM) of tangeretin. In the presence of the CYP1 inhibitor acacetin, the conversion of tangeretin to 4' OH tangeretin was significantly reduced in MDA-MB-468 cells (2.55 ± 0.19 μM vs. 6.33 ± 0.12 μM). The mechanism of antiproliferative action involved cell cycle arrest at the G1 phase for MCF7 and MDA-MB-468 cells. Tangeretin was further shown to induce CYP1 enzyme activity and CYP1A1/CYP1B1 protein expression in MCF7 and MDA-MB-468 cells. These results suggest that tangeretin inhibits the proliferation of breast cancer cells via CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin.


SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway.
SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson's disease (PD). Our previous study demonstrates that SIRT3 had a neuroprotective effect on a rotenone-induced PD cell model, however, the exact mechanism is unknown. In this study, we investigated the underlying mechanism. We established a SIRT3 stable overexpression cell line using lentivirus infection in SH-SY5Y cells. Then, a PD cell model was established using rotenone. Our data demonstrate that overexpression of SIRT3 increased the level of the autophagy markers LC3 II and Beclin 1. After addition of the autophagy inhibitor 3-MA, the protective effect of SIRT3 diminished: the cell viability decreased, while the apoptosis rate increased; α-synuclein accumulation enhanced; ROS production increased; antioxidants levels, including SOD and GSH, decreased; and MMP collapsed. These results reveal that SIRT3 has neuroprotective effects on a PD cell model by up-regulating autophagy. Furthermore, SIRT3 overexpression also promoted LKB1 phosphorylation, followed by activation of AMPK and decreased phosphorylation of mTOR. These results suggest that the LKB1-AMPK-mTOR pathway has a role in induction of autophagy. Together, our findings indicate a novel mechanism by which SIRT3 protects a rotenone-induced PD cell model through the regulation of autophagy, which, in part, is mediated by activation of the LKB1-AMPK-mTOR pathway.


Predicting response to opiate antagonists and placebo in the treatment of pathological gambling.
Although opiate antagonists have shown promise in the treatment of pathological gambling (PG), individual responses vary. No studies have systematically examined predictors of medication treatment outcome in PG. Understanding clinical variables related to treatment outcome should help generate treatment algorithms for PG. We sought to identify clinical variables associated with treatment outcome in PG subjects receiving opiate antagonists. Two hundred eighty-four subjects [137 (48.2%) women] with DSM-IV PG were treated in one of two double-blind placebo-controlled trials (16 weeks of nalmefene or 18 weeks of naltrexone). Gambling severity was assessed with the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) with positive response defined as > or =35% reduction in PG-YBOCS score for at least 1 month by study endpoint. Depression, anxiety, and psychosocial functioning were included in stepwise logistic regression analyses designed to identify clinical factors independently associated with treatment response. The clinical variable most strongly associated with a positive response to an opiate antagonist was a positive family history of alcoholism (p = 0.006). Among individuals receiving higher doses of opiate antagonists (i.e., nalmefene 50 or 100 mg/day or naltrexone 100 or 150 mg/day), intensity of gambling urges (PG-YBOCS urge subscale) was associated with a positive response on a trend level (p = 0.036). Among individuals receiving placebo, younger age was associated, on a trend level, with positive treatment outcome (p = 0.012). A family history of alcoholism appears to predict response to an opiate antagonist in PG. Future research is needed to identify specific factors (e.g., genetic) mediating favorable responses.


The role of leukotriene receptor signaling in inflammation and cancer.
Leukotrienes (LTs) and prostaglandins (PGs) are metabolites of arachidonic acid that play major roles in various inflammatory conditions. The release of these mediators, by cells recruited to or present at the site of inflammation, modulate/influence the magnitude of the inflammatory response. A better understanding of eicosanoids and how their receptors trigger intracellular signaling during inflammatory conditions is helping to elucidate the well-known connection between chronic inflammatory disease and neoplastic transformation. In the current review, we summarize the role of LTs and PGs in chronic inflammation and, in particular, we focus on recent insights into the role of CysLT1 receptor signaling pathway. In addition, we delineate how continuous CysLT1 receptor activation and signaling can increase cell survival and proliferation as important early steps toward oncogenicity.


Bioprinted Multi-Cell Type Lung Model for the Study of Viral Inhibitors.
Influenza A virus (IAV) continuously causes epidemics and claims numerous lives every year. The available treatment options are insufficient and the limited pertinence of animal models for human IAV infections is hampering the development of new therapeutics. Bioprinted tissue models support studying pathogenic mechanisms and pathogen-host interactions in a human micro tissue environment. Here, we describe a human lung model, which consisted of a bioprinted base of primary human lung fibroblasts together with monocytic THP-1 cells, on top of which alveolar epithelial A549 cells were printed. Cells were embedded in a hydrogel consisting of alginate, gelatin and collagen. These constructs were kept in long-term culture for 35 days and their viability, expression of specific cell markers and general rheological parameters were analyzed. When the models were challenged with a combination of the bacterial toxins LPS and ATP, a release of the proinflammatory cytokines IL-1β and IL-8 was observed, confirming that the model can generate an immune response. In virus inhibition assays with the bioprinted lung model, the replication of a seasonal IAV strain was restricted by treatment with an antiviral agent in a dose-dependent manner. The printed lung construct provides an alveolar model to investigate pulmonary pathogenic biology and to support development of new therapeutics not only for IAV, but also for other viruses.


Lithium-ion storage performances of sunflower-like and nano-sized hollow SnO2 spheres by spray pyrolysis and the nanoscale Kirkendall effect.
Nanostructured metal selenides with a variety of morphologies are crucial for fabricating porous, hollow metal-oxide nanomaterials by nanoscale Kirkendall diffusion. Herein, SnSe-SnO2 composite powders and SnSe nanospheres were synthesized via one-pot spray pyrolysis by optimizing the concentration of the Se precursor in the spray solution; these were then used to fabricate sunflower-like SnO2 and hollow SnO2 nanospheres, respectively, via nanoscale Kirkendall diffusion. Post-treatment of the SnSe-decorated SnO2 under air produced sunflower-like SnO2, in which ray and disk florets consisting of hollow nanoplates and dense nanospheres, respectively, were present. The mean diameter of the homogeneous hollow SnO2 nanospheres was 150 nm. The hollow morphology shortens the diffusion length, increasing the contact area between the electrolyte and voids and buffering large volume changes during repeated cycling. As anode materials for lithium-ion batteries, the hollow SnO2 nanospheres showed excellent cycling and rate performances. The discharge capacity of the hollow SnO2 nanospheres, after 500 cycles from 0.001 V to 3.0 V, was 1043 mA h g-1, at a current density of 3.0 A g-1. The hollow SnO2 nanospheres showed a high reversible capacity of 638 mA h g-1, even at current density as high as 10 A g-1.


Relationship between psychosocial factors and onset of multiple sclerosis.
The aim of this study was to investigate the influence of psychosocial variables on patients with multiple sclerosis (MS) and the relationship between these variables and the onset of MS. The current evidence indicates that many types of psychosocial factors are involved in the development and relapse of MS, and it has been suggested that they could serve as predictors as well. So far, little has been reported on the effect of psychosocial factors on MS and the relationship between psychosocial factors and the onset of MS. Forty-one patients, 15 males and 26 females, average age 37.44 +/- 12.24 years (mean +/- SD), were evaluated by the Life Event Scale, Eysenck Personality Questionnaire, Social Support Revaluate Scale and Symptom Check List 90 and compared with 41 equivalent healthy control subjects, 15 males and 26 females, average age 36.38 +/- 12.84 years (mean +/- SD). Disease, demographic, psychosocial and lifestyle factors were measured at baseline. Patients with MS were first diagnosed by 3 neurologists according to the Poser (1983) MS diagnostic criteria. Significant differences were found between the MS and the control group in their negative emotions and symptoms such as depression, anxiety, obsession, phobia, tense interpersonal relationship and somatization disorder. Significant differences were found between the two groups in the total number of negative life events, their family problems and the utilization of social support. The scores for various negative emotions in the MS group correlated positively with those for neuroticisms in personality type, and negatively with those for introverted and extroverted personality. Many kinds of negative emotions in the MS group correlated positively with the total number of life events, negative life events and family problems. Many kinds of negative emotions in the MS group correlated negatively with the utilization of social support. The psychosocial factors are closely associated with MS onset and may play important roles in the development of the disease.


Nepticulidae (Lepidoptera) of East Asia (2). Study of a collection sample deposited at the Russian Academy of Sciences, with descriptions of new species and a checklist.
Over the few couple of decades, the Nepticulidae of East Asia have been the subject of continuing investigation. Male genitalia of the nepticulid species described from Primorskiy Kray (the Russian Far East) were re-examined in the preceding paper in this journal. The present paper continues our study on the diversity and systematics of the Nepticulidae of East Asia based on a sample of specimens collected in 1974-1990 at various sites of the southern part of Primorskiy Kray and treats 35 species: two new taxa (Ectoedemia ortiva sp. nov. and E. species 219) and 33 other species. Seventeen of them are briefly discussed and illustrated with photographs of male genitalia. Two new synonyms are proposed, and three new distribution records are provided. We also provide an updated checklist of the Nepticulidae of East Asia, which comprises 105 species; 67 species occur in the Russian Far East and 53 in Japan (20 of which occur both in Japan and Russia). Species with Euro-East Asiatic distribution currently comprise 11% of the Japanese fauna and 16% of the continental fauna of the Russian Far East, Primorskiy Kray.


Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells.
Recently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs) that have a stem-like genomic signature and express a number of stem cell genes including Oct3/4 and Nanog and are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation. Differentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of both Stat3 and Sox1. Using this method we can begin to understand which genes are epigenetically regulated in the invasive population compared to the bulk tumor cells. These aggressive sub-populations of cells may be linked to the cancer stem cell hypothesis, making their patterns of epigenetic regulation very attractive for biomarker analysis.


CXCL10 is required to maintain T-cell populations and to control parasite replication during chronic ocular toxoplasmosis.
Toxoplasma gondii is a major cause of ocular disease, which can lead to permanent vision loss in humans. T cells are critically involved in parasite control, but little is known about the molecules that promote T-cell trafficking and migration in the retina. Thus, the aim of this study was to image and dissect the T-cell response during chronic toxoplasmic retinochoroiditis. C57BL/6 mice were infected with the Me49 strain of T. gondii, and T cells that infiltrated the eye were analyzed by flow cytometry and imaged using multiphoton microscopy. IFN-γ, CXCL9, CXCL10, and CXCR3 mRNA levels were measured by real-time PCR. To investigate the role of CXCL10, mice were treated with anti-CXCL10 antibodies, and histopathology and immunohistochemistry were performed to monitor changes in pathology, cellular infiltration, and parasite burden in the eye. Infection with T. gondii leads to the infiltration of highly activated motile T cells into the eye. These cells express CXCR3 and are capable of producing IFN-γ and TNF-α, and CD8+ T cells express granzyme B. The expression of CXCL9 and CXCL10 in the retina was significantly upregulated during chronic infection. Treatment of chronically infected mice with anti-CXCL10 antibodies led to decreases in the numbers of CD3+, CD4+, and CD8+ T cells and the amount of IFN-γ mRNA expression in the retina and an increase in replicating parasites and ocular pathology. The maintenance of the T-cell response and the control of T. gondii in the eye during chronic infection is dependent on CXCL10.


Readmissions after colorectal surgery cannot be predicted.
Readmission after discharge from the hospital is an undesirable outcome. In an attempt to prevent unplanned readmissions after abdominal or perineal colon resection, we proposed to identify risk factors associated with return to the hospital. Study participants consisted of 249 patients who were operated on from July 1, 1996, to March 30, 1998. All patients who were readmitted within 90 days of discharge from the hospital after surgery were evaluated for the study. A retrospective review of charts was performed to assess whether readmission within 90 days was a direct consequence of the recent operation (unplanned related readmission). These patients were compared with a control group consisting of patients who were never readmitted or who were readmitted with an unrelated problem. Of the 249 patients, 59 (24 percent) were readmitted within 90 days of discharge from the hospital. Twenty-two (9 percent) were unplanned related readmissions. Ten patients were readmitted with unrelated emergencies, and 27 patients were readmitted electively. In the unplanned related group, there was no correlation between age, gender, admission diagnosis, activity status, or postoperative length of stay and the likelihood of readmission. Patients with multiple chronic medical problems or those who developed postoperative complications did not have a higher readmission rate. Patients with ulcerative colitis or those who underwent abdominoperineal resection or total/subtotal colectomy had a higher incidence of readmissions, although the difference was not significant. The mean interval between discharge from the hospital and readmission with a related complication was 19 days. Small-bowel obstruction was the most common reason for readmission, and all cases resolved with conservative management. Mean length of stay during all readmissions was 8 days. The incidence of unplanned related readmissions 90 days after abdominal or perineal colon resection is 9 percent, and these readmissions could not be predicted from the postoperative course. Because 82 percent of unplanned readmissions occurred within 30 days, this time frame is suitable for computerized comparative analysis.


Bronchoalveolar lavage in the diagnosis of lipoid pneumonia.
Lipoid pneumonia (LP) is an uncommon entity with the characteristic radiographic features and histologic findings of alveoli filled with vacuolated, lipid-laden histiocytes. We questioned whether bronchoalveolar lavage (BAL) could be useful in the confirmation of LP. We examined lipid stains (oil-red O) in BAL specimens from 18 cases, representing a variety of pulmonary disease states, and compared them with an index case of confirmed LP. The index case of LP had a history of chronic intranasal use of mentholated petrolatum with subsequent x-ray findings of progressive air bronchograms. Positive histochemical confirmation (oil-red O) performed on frozen sections of transbronchial lung biopsy was obtained. Eleven of the non-LP cases had no intracellular staining of BAL macrophages with oil-red O stain, whereas the index case of LP exhibited markedly positive intracytoplasmic staining of macrophages for lipid. The remaining seven cases showed minimal to mild lipid staining with only one other case having moderate staining. This study demonstrates that BAL macrophages from patients with a variety of pulmonary states and without suspected LP do not demonstrate significant staining for intracellular lipids, in contrast with the expected strong positivity of LP. Lipid staining of BAL specimens, although not entirely specific, may be a preferred method for confirming the diagnosis of LP, thereby avoiding more invasive procedures.


Fetal fibronectin as a predictor of spontaneous preterm birth: a European perspective.
Preterm birth (PTB) is estimated to account for 6-10% of all births worldwide with 13 million PTBs occurring annually and 1 million resulting in death. The diagnosis of spontaneous preterm labor and accurate prediction of preterm delivery is notoriously difficult. Identification of effective risk assessment markers can potentially improve outcomes by enabling targeted therapy while allowing efficient use of resources and avoiding unnecessary interventions. Advances in perinatal medicine have not reduced PTB and effective measures that improve outcome are yet to be established. However, considerable progress has been made in the development of accurate methods (fetal fibronectin and cervical length assessment) to predict PTB in both symptomatic and asymptomatic high-risk women. The excellent negative predictive value of fFN has the ability to facilitate decision-making regarding admission, in utero transfer, administration of antenatal corticosteroids and/or tocolysis and has been shown to be cost-effective. This review describes the European perspective on the use of fFN and describes ongoing European clinical studies, which are appropriately designed with meaningful endpoints, which will undoubtedly facilitate a better understanding of test accuracy and cost-effectiveness within different populations.


Renormalized basal metabolic rate describes the human aging process and longevity.
The question of why we age and finally die has been a central subject in the life, medical, and health sciences. Many aging theories have proposed biomarkers that are related to aging. However, they do not have sufficient power to predict the aging process and longevity. We here propose a new biomarker of human aging based on the mass-specific basal metabolic rate (msBMR). It is well known by the Harris-Benedict equation that the msBMR declines with age but varies among individual persons. We tried to renormalize the msBMR by primarily incorporating the body mass index into this equation. The renormalized msBMR (RmsBMR) which was derived in one cohort of American men (n = 25,425) was identified as one of the best biomarkers of aging, because it could well reproduce the observed respective American, Italian, and Japanese data on the mortality rate and survival curve. A recently observed plateau of the mortality rate in centenarians corresponded to the lowest value (threshold) of the RmsBMR, which stands for the final stage of human life. A universal decline of the RmsBMR with age was associated with the mitochondrial number decay, which was caused by a slight fluctuation of the dynamic fusion/fission system. This decay form was observed by the measurement in mice. Finally, the present approach explained the reason why the BMR in mammals is regulated by the empirical algometric scaling law.


Neocortical post-traumatic epileptogenesis is associated with loss of GABAergic neurons.
The subtle mechanisms of post-traumatic epileptogenesis remain unknown, although the incidence of chronic epilepsy after penetrating cortical wounds is high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immuno-histochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantification of the labeled neurons was performed in control animals and at 2, 4, and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals, the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, potentially explaining the increased propensity to seizures in chronic undercut cortex.


Wearable Large-Scale Perovskite Solar-Power Source via Nanocellular Scaffold.
Dramatic advances in perovskite solar cells (PSCs) and the blossoming of wearable electronics have triggered tremendous demands for flexible solar-power sources. However, the fracturing of functional crystalline films and transmittance wastage from flexible substrates are critical challenges to approaching the high-performance PSCs with flexural endurance. In this work, a nanocellular scaffold is introduced to architect a mechanics buffer layer and optics resonant cavity. The nanocellular scaffold releases mechanical stresses during flexural experiences and significantly improves the crystalline quality of the perovskite films. The nanocellular optics resonant cavity optimizes light harvesting and charge transportation of devices. More importantly, these flexible PSCs, which demonstrate excellent performance and mechanical stability, are practically fabricated in modules as a wearable solar-power source. A power conversion efficiency of 12.32% for a flexible large-scale device (polyethylene terephthalate substrate, indium tin oxide-free, 1.01 cm2 ) is achieved. This ingenious flexible structure will enable a new approach for development of wearable electronics.


High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy.
Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged >6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD.


Exacerbation of cigarette smoke-induced pulmonary inflammation by Staphylococcus aureus enterotoxin B in mice.
Cigarette smoke (CS) is a major risk factor for the development of COPD. CS exposure is associated with an increased risk of bacterial colonization and respiratory tract infection, because of suppressed antibacterial activities of the immune system and delayed clearance of microbial agents from the lungs. Colonization with Staphylococcus aureus results in release of virulent enterotoxins, with superantigen activity which causes T cell activation. To study the effect of Staphylococcus aureus enterotoxin B (SEB) on CS-induced inflammation, in a mouse model of COPD. C57/Bl6 mice were exposed to CS or air for 4 weeks (5 cigarettes/exposure, 4x/day, 5 days/week). Endonasal SEB (10 μg/ml) or saline was concomitantly applied starting from week 3, on alternate days. 24 h after the last CS and SEB exposure, mice were sacrificed and bronchoalveolar lavage (BAL) fluid and lung tissue were collected. Combined exposure to CS and SEB resulted in a raised number of lymphocytes and neutrophils in BAL, as well as increased numbers of CD8+ T lymphocytes and granulocytes in lung tissue, compared to sole CS or SEB exposure. Moreover, concomitant CS/SEB exposure induced both IL-13 mRNA expression in lungs and goblet cell hyperplasia in the airway wall. In addition, combined CS/SEB exposure stimulated the formation of dense, organized aggregates of B- and T- lymphocytes in lungs, as well as significant higher CXCL-13 (protein, mRNA) and CCL19 (mRNA) levels in lungs. Combined CS and SEB exposure aggravates CS-induced inflammation in mice, suggesting that Staphylococcus aureus could influence the pathogenesis of COPD.


As(V)/Cr(VI) pollution control in soils, hemp waste, and other by-products: competitive sorption trials.
We study As(V)/Cr(VI) competitive sorption on a forest soil, a vineyard soil, pyritic material, mussel shell, pine bark, oak ash, and hemp waste, adding variable As(V) and Cr(VI) concentrations or displacing each pollutant with the same concentration of the other. When using variable concentrations, As(V) showed more affinity than Cr(VI) for sorption sites on most materials (sorption up to >84 % on oak ash and pyritic material). The only exception was pine bark, with clearly higher Cr(VI) sorption (>90 %) for any Cr(VI)/As(V) concentration added. Regarding the displacement experiments, when As(V) was added and reached sorption equilibrium, the subsequent addition of equal Cr(VI) concentration did not cause relevant As displacement from oak ash and pyritic material, indicating strong As bindings, and/or low competitive effects. When Cr(VI) was added and reached sorption equilibrium, the subsequent addition of equal As(V) concentration caused Cr(VI) displacement from all materials except pine bark, indicating weak Cr bindings. In view of these results, oak ash and the pyritic material could be used to remove As(V) in concentrations as high as 6 mmol L(-1), even in the presence of a wide range of Cr(VI) concentrations, whereas pine bark could be used to remove Cr(VI) concentrations as high as 6 mmol L(-1). The other materials assayed (including hemp waste, studied for the first time as As(V) and Cr(VI) bio-sorbent) cannot be considered appropriate to remove As(V) and/or Cr(VI) from polluted media.


Morganella psychrotolerans sp. nov., a histamine-producing bacterium isolated from various seafoods.
Mesophilic Morganella morganii (n=6) and psychrotolerant M. morganii-like isolates from various seafoods (n=13), as well as clinical M. morganii isolates (n=3), were characterized by using a polyphasic approach including multi-locus sequencing. Based on the phylogenetic analysis, the 22 strains were divided into two distinct groups comprising mesophilic and psychrotolerant isolates, respectively. This classification was supported by DNA-DNA hybridization studies, whereby a psychrotolerant isolate (strain U2/3(T)) showed 41.0 and 17.8 % relatedness to the type strains of the mesophilic species Morganella morganii subsp. morganii (strain LMG 7874(T)) and Morganella morganii subsp. sibonii (strain DSM 14850(T)), respectively. Analysis of the 16S rRNA gene sequences showed a similarity of 98.6 % between mesophilic and psychrotolerant isolates. However, fragments of seven protein-encoding housekeeping genes (atpD, dnaN, gyrB, hdc, infB, rpoB and tuf) all showed less than 90.9 % sequence similarity between the two groups. The psychrotolerant isolates grew at 0-2 degrees C and also differed from the mesophilic M. morganii isolates with respect to growth at 37 degrees C and in 8.5 % (w/v) NaCl and fermentation of d-galactose. The psychrotolerant strains appear to represent a novel species, for which the name Morganella psychrotolerans sp. nov. is proposed. The type strain is U2/3(T) (=LMG 23374(T)=DSM 17886(T)).


Defected and Functionalized Germanene-based Nanosensors under Sulfur Comprising Gas Exposure.
Efficient sensing of sulfur containing toxic gases like H2S and SO2 is of the utmost importance due to the adverse effects of these noxious gases. Absence of an efficient 2D-based nanosensor capable of anchoring H2S and SO2 with feasible binding and an apparent variation in electronic properties upon the exposure of gas molecules has motivated us to explore the promise of a germanene nanosheet (Ge-NS) for this purpose. In the present study, we have performed a comprehensive computational investigation by means of DFT-based first-principles calculations to envisage the structural, electronic, and gas sensing properties of pristine, defected, and metal substituted Ge-NSs. Our initial screening has revealed that although interaction of SO2 with pristine Ge-NSs is within the desirable range, H2S binding however falls below the required values to guarantee an effective sensing. To improve the binding characteristics, we have considered the interactions between H2S and SO2 with defected and metal substituted Ge-NS. The systematic removals of Ge atoms from a reasonably large super cell lead to monovacancy, divacancies, and trivacancies in Ge-NS. Similarly, different transition metals like As, Co, Cu, Fe, Ga, Ge, Ni, and Zn have been substituted into the monolayer to realize substituted Ge-NS. Our van der Waals corrected DFT calculations have concluded that the vacancy and substitution defects not only improve the binding characteristics but also enhance the sensing propensity of both H2S and SO2. The total and projected density of states show significant variations in electronic properties of pristine and defected Ge-NSs before and after the exposure to the gases, which are essential in constituting a signal to be detected by the external circuit of the sensor. We strongly believe that our present work would not only advance the knowledge towards the application of Ge-NS-based sensing but also provide motivation for the synthesis of such efficient nanosensor for H2S and SO2 based on Ge monolayer.


Intermittent hypoxia conditioning prevents endothelial dysfunction and improves nitric oxide storage in spontaneously hypertensive rats.
Although intermittent hypoxia is often associated with hypertension, experimental and clinical studies have demonstrated definite antihypertensive effects of some intermittent hypoxia conditioning (IHC) regimens. Mechanisms of this antihypertensive response are unknown. Endothelial dysfunction related to disturbed synthesis and/or reduced availability of nitric oxide (NO) has been linked to hypertension. Thus, experiments were conducted to determine if IHC can improve endothelium-dependent relaxation and formation of releasable vascular NO stores of young (4-8-week-old) spontaneously hypertensive rats (SHR). Rats were subjected to either IHC (9.5-10% O(2), 5-10 min, 5-8 times per day, 20 d) or to sham conditioning. Endothelium-dependent relaxation to acetylcholine was measured in norepinephrine-precontracted, isolated aortic rings, and the size of NO stores was evaluated by percent relaxation to N-acetylcysteine (NAC), which releases stored NO. The capacity of aortic rings for NO storage was evaluated by the relaxation to NAC after prior incubation with an NO donor. IHC significantly suppressed the development of hypertension in young SHR. Endothelial function decreased from 54.7 ± 4.6% to 28.1 ± 6.4% relaxation to acetylcholine after 20 d of sham IHC, whereas endothelial function was sustained (60.3 ± 6.0% relaxation) in IHC rats. IHC also induced formation of available NO stores and enhanced the capacity of aortic rings to store NO. Therefore, the antihypertensive effect of IHC in young SHR is associated with prevention of endothelial dysfunction and with increased accumulation of NO stores in vascular walls.


Avoiding transcription factor competition at promoter level increases the chances of obtaining oscillation.
The ultimate goal of synthetic biology is the conception and construction of genetic circuits that are reliable with respect to their designed function (e.g. oscillators, switches). This task remains still to be attained due to the inherent synergy of the biological building blocks and to an insufficient feedback between experiments and mathematical models. Nevertheless, the progress in these directions has been substantial. It has been emphasized in the literature that the architecture of a genetic oscillator must include positive (activating) and negative (inhibiting) genetic interactions in order to yield robust oscillations. Our results point out that the oscillatory capacity is not only affected by the interaction polarity but by how it is implemented at promoter level. For a chosen oscillator architecture, we show by means of numerical simulations that the existence or lack of competition between activator and inhibitor at promoter level affects the probability of producing oscillations and also leaves characteristic fingerprints on the associated period/amplitude features. In comparison with non-competitive binding at promoters, competition drastically reduces the region of the parameters space characterized by oscillatory solutions. Moreover, while competition leads to pulse-like oscillations with long-tail distribution in period and amplitude for various parameters or noisy conditions, the non-competitive scenario shows a characteristic frequency and confined amplitude values. Our study also situates the competition mechanism in the context of existing genetic oscillators, with emphasis on the Atkinson oscillator.


Diurnal variation of serum and urine biomarkers in patients with radiographic knee osteoarthritis.
To evaluate diurnal variation of biomarkers in subjects with osteoarthritis (OA) of the knee. Twenty subjects with radiographic knee OA were admitted to the General Clinical Research Center of Duke University for an overnight stay to undergo serial blood and urine sampling. Biomarkers measured included serum hyaluronan (HA), cartilage oligomeric matrix protein (COMP), keratan sulfate (KS-5D4), aggrecan neoepitope (CS846), high-sensitivity C-reactive protein (hsCRP), osteocalcin, transforming growth factor beta1 (TGFbeta1), and type II collagen (CII)-related epitopes (neoepitope from cleavage of CII [C2C], carboxy-terminus of three-quarter peptide from cleavage of CI and CII [C1,2C], and type II procollagen carboxy-propeptide [CPII] in serum, and C-terminal telopeptides of CII [CTX-II] and C2C in urine). Levels of serum HA, COMP, KS-5D4, and TGFbeta1 increased significantly from T0 (before arising from bed) to T1 (1 hour after arising). More diurnal variation in HA was observed in patients with higher daily mean HA concentrations. CPII increased significantly from T0 to T2 (4 hours after arising). Urinary concentrations of CTX-II were also found to vary with morning activity, decreasing significantly from T0 to T2. Urinary C2C concentrations increased significantly from T0 until T3 (early evening). No diurnal variations in CS846, hsCRP, osteocalcin, serum C2C, or C1,2C were observed. Six biomarkers (serum C2C, C1,2C, COMP, KS-5D4, TGFbeta1, and urinary CTX-II) were associated with radiographic knee OA (expressed as the sum of Kellgren/Lawrence radiographic severity grades), with the strongest correlations observed with measurements obtained at later time points (either T2 or T3). Our study results suggest that serum and urine sampling for HA, COMP, KS-5D4, TGFbeta1, CPII, urinary CTX-II, and urinary C2C should be standardized in future OA clinical trials. Serum and urine sampling at late midday time points may be the optimal approach for OA studies, although this result should be validated in a larger cohort.


MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages.
The inflammatory responses of monocytes/macrophages and the stimulation of lipid uptake into these cells by oxidized low density lipoprotein (oxLDL) are critical to the initiation and development of atherosclerosis. Increasing evidence has demonstrated that many microRNAs play important roles in the cell proliferation, apoptosis, and differentiation that accompany inflammatory responses. However, whether microRNAs are associated with monocyte/macrophage inflammatory responses or oxLDL stimulation is not yet known. The aim of the present study is to investigate microRNAs in monocytes/macrophages and their potential role in oxLDL-stimulation of lipid uptake and other atherosclerotic responses. Microarrays were used to analyse the global expression of microRNAs in oxLDL-stimulated human primary peripheral blood monocytes. Expression profiles of the microRNAs were verified using TaqMan real-time PCR. Five microRNAs (microRNA-125a-5p, microRNA-9, microRNA-146a, microRNA-146b-5p, and microRNA-155) were aberrantly expressed after oxLDL treatment of human primary monocytes. Bioinformatics analysis suggested that microRNA-125a-5p is related to a protein similar to ORP9 (oxysterol binding protein-like 9) and this was confirmed by a luciferase reporter assay. MicroRNA-125a-5p was found to mediate lipid uptake and to decrease the secretion of some inflammatory cytokines (interleukin-2, interleukin-6, tumour necrosis factor-alpha, transforming growth factor-beta) in oxLDL-stimulated monocyte-derived macrophages. MicroRNA-125a-5p may partly provide post-transcriptional regulation of the proinflammatory response, lipid uptake, and expression of ORP9 in oxLDL-stimulated monocyte/macrophages.


[The Swedish stroke register indicates differences in stroke care. Unconscious discrimination might explain some of the differences].
In this article, results from a series of studies on the relationships between socioeconomic factors and stroke processes (stroke unit care, acute reperfusion treatment, secondary prevention with oral anticoagulants and statins) and outcomes (long-term survival, return to work and risk of suicide and suicide attempts) are summarized. The overall pattern is that acute and secondary prevention interventions and prognosis are better in patients with a high compared with a low level of education, better in people with high than low income, better in people who are cohabitant than single. As to country of birth, a more complex pattern has emerged. Unmeasured confounding may possibly explain part of the difference, but the socioeconomic gradients remain after adjustment for multiple potential confounders, leaving the possibility that there is an element of unconscious discrimination in stroke care.