35 research outputs found

    Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression

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    The Brn-3a and Brn-3b transcription factor have opposite and antagonistic effects in neuroblastoma cells since Brn-3a is associated with differentiation whilst Brn-3b enhances proliferation in these cells. In this study, we demonstrate that like Brn-3a, Brn-3b physically interacts with p53. However, whereas Brn-3a repressed p53 mediated Bax expression but cooperated with p53 to increase p21(cip1/waf1), this study demonstrated that co-expression of Brn-3b with p53 increases trans-activation of Bax promoter but not p21(cip1/waf1). Consequently co-expression of Brn-3b with p53 resulted in enhanced apoptosis, which is in contrast to the increased survival and differentiation, when Brn-3a is co-expressed with p53. For Brn-3b to cooperate with p53 on the Bax promoter, it requires binding sites that flank p53 sites on this promoter. Furthermore, neurons from Brn-3b knock-out (KO) mice were resistant to apoptosis and this correlated with reduced Bax expression upon induction of p53 in neurons lacking Brn-3b compared with controls. Thus, the ability of Brn-3b to interact with p53 and modulate Bax expression may demonstrate an important mechanism that helps to determine the fate of cells when p53 is induced

    Using Complex, Multi-Sectoral Data in a Needs Assessment to Inform Future Strategies in Childhood Asthma Management

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    The purpose of this needs assessment was to study the current state of asthma management in high-risk children in Houston, Texas to inform a theory-based approach to improving asthma management. The mixed-method assessment included multi-sectoral survey, quantitative, and geospatial data that address a range of social and community factors in family, community, home, and medical contexts. Houston Emergency Medical Services (EMS) provided ambulance-treated asthma data mapped by geographic area to identify where childhood asthma management was weakest. Texas Children’s Health Plan (TCHP) provided medication compliance rates and counts of children by zip code that TCHP considered high-risk according to claims data. Houston Independent School District (HISD) provided school nurse survey results from schools with high-rates of ambulance-treated asthma attacks regarding local barriers to asthma management. Elementary schools with children at highest risk were identified by overlaying the EMS data, TCHP data, and HISD school zone boundaries. Survey results from the high-rate schools indicate the priority challenges to childhood asthma management, including lack of resources, lack of communication, lack of knowledge of triggers, and inadequate time for quality care from providers. By weaving together EMS, TCHP, and HISD data, the needs assessment informed a socio-ecological view of gaps in high-risk childhood asthma management and control, specifically where and what to target. An assessment approach with multi-sectoral data, geospatial mapping, nurse input, current systems of care, education, and funding helped focus planning on a practical approach to asthma control solutions for high-risk children

    Risk factors and outcomes of acute kidney injury in South African critically ill adults: a prospective cohort study

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    Abstract Background There is a marked paucity of data concerning AKI in Sub-Saharan Africa, where there is a substantial burden of trauma and HIV. Methods Prospective data was collected on all patients admitted to a multi-disciplinary ICU in South Africa during 2017. Development of AKI (before or during ICU admission) was recorded and renal recovery 90 days after ICU discharge was determined. Results Of 849 admissions, the mean age was 42.5 years and mean SAPS 3 score was 48.1. Comorbidities included hypertension (30.5%), HIV (32.6%), diabetes (13.3%), CKD (7.8%) and active tuberculosis (6.2%). The most common reason for admission was trauma (26%). AKI developed in 497 (58.5%). Male gender, illness severity, length of stay, vasopressor drugs and sepsis were independently associated with AKI. AKI was associated with a higher in-hospital mortality rate of 31.8% vs 7.23% in those without AKI. Age, active tuberculosis, higher SAPS 3 score, mechanical ventilation, vasopressor support and sepsis were associated with an increased adjusted odds ratio for death. HIV was not independently associated with AKI or hospital mortality. CKD developed in 14 of 110 (12.7%) patients with stage 3 AKI; none were dialysis-dependent. Conclusions In this large prospective multidisciplinary ICU cohort of younger patients, AKI was common, often associated with trauma in addition to traditional risk factors and was associated with good functional renal recovery at 90 days in most survivors. Although the HIV prevalence was high and associated with higher mortality, this was related to the severity of illness and not to HIV status per se

    Increasing access to institutional deliveries using demand and supply side incentives: early results from a quasi-experimental study

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    <p>Abstract</p> <p>Background</p> <p>Geographical inaccessibility, lack of transport, and financial burdens are some of the demand side constraints to maternal health services in Uganda, while supply side problems include poor quality services related to unmotivated health workers and inadequate supplies. Most public health interventions in Uganda have addressed only selected supply side issues, and universities have focused their efforts on providing maternal services at tertiary hospitals. To demonstrate how reforms at Makerere University College of Health Sciences (MakCHS) can lead to making systemic changes that can improve maternal health services, a demand and supply side strategy was developed by working with local communities and national stakeholders.</p> <p>Methods</p> <p>This quasi-experimental trial is conducted in two districts in Eastern Uganda. The supply side component includes health worker refresher training and additions of minimal drugs and supplies, whereas the demand side component involves vouchers given to pregnant women for motorcycle transport and the payment to service providers for antenatal, delivery, and postnatal care. The trial is ongoing, but early analysis from routine health information systems on the number of services used is presented.</p> <p>Results</p> <p>Motorcyclists in the community organized themselves to accept vouchers in exchange for transport for antenatal care, deliveries and postnatal care, and have become actively involved in ensuring that women obtain care. Increases in antenatal, delivery, and postnatal care were demonstrated, with the number of safe deliveries in the intervention area immediately jumping from <200 deliveries/month to over 500 deliveries/month in the intervention arm. Voucher revenues have been used to obtain needed supplies to improve quality and to pay health workers, ensuring their availability at a time when workloads are increasing.</p> <p>Conclusions</p> <p>Transport and service vouchers appear to be a viable strategy for rapidly increasing maternal care. MakCHS can design strategies together with stakeholders using a learning-by-doing approach to take advantage of community resources.</p

    A smartphone-based test for the assessment of attention deficits in delirium: A case-control diagnostic test accuracy study in older hospitalised patients.

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    BACKGROUND: Delirium is a common and serious acute neuropsychiatric syndrome which is often missed in routine clinical care. Inattention is the core cognitive feature. Diagnostic test accuracy (including cut-points) of a smartphone Delirium App (DelApp) for assessing attention deficits was assessed in older hospital inpatients. METHODS: This was a case-control study of hospitalised patients aged ≥65 years with delirium (with or without pre-existing cognitive impairment), who were compared to patients with dementia without delirium, and patients without cognitive impairment. Reference standard delirium assessment, which included a neuropsychological test battery, was based on Diagnostic and Statistical Manual of Mental Disorders-5 criteria. A separate blinded assessor administered the DelApp arousal assessment (score 0-4) and attention task (0-6) yielding an overall score of 0 to 10 (lower scores indicate poorer performance). Analyses included receiver operating characteristic curves and sensitivity and specificity. Optimal cut-points for delirium detection were determined using Youden's index. RESULTS: A total of 187 patients were recruited, mean age 83.8 (range 67-98) years, 152 (81%) women; n = 61 with delirium; n = 61 with dementia without delirium; and n = 65 without cognitive impairment. Patients with delirium performed poorly on the DelApp (median score = 4/10; inter-quartile range 3.0, 5.5) compared to patients with dementia (9.0; 5.5, 10.0) and those without cognitive impairment (10.0; 10.0, 10.0). Area under the curve for detecting delirium was 0.89 (95% Confidence Interval 0.84, 0.94). At an optimal cut-point of ≤8, sensitivity was 91.7% (84.7%, 98.7%) and specificity 74.2% (66.5%, 81.9%) for discriminating delirium from the other groups. Specificity was 68.3% (56.6%, 80.1%) for discriminating delirium from dementia (cut-point ≤6). CONCLUSION: Patients with delirium (with or without pre-existing cognitive impairment) perform poorly on the DelApp compared to patients with dementia and those without cognitive impairment. A cut-point of ≤8/10 is suggested as having optimal sensitivity and specificity. The DelApp is a promising tool for assessment of attention deficits associated with delirium in older hospitalised adults, many of whom have prior cognitive impairment, and should be further validated in representative patient cohorts

    Unlocking community capabilities for improving maternal and newborn health: participatory action research to improve birth preparedness, health facility access, and newborn care in rural Uganda

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    Background: Community capacities and resources must be harnessed to complement supply side initiatives addressing high maternal and neonatal mortality rates in Uganda. This paper reflects on gains, challenges and lessons learnt from working with communities to improve maternal and newborn health in rural Uganda. Methods: A participatory action research project was supported from 2012 to 2015 in three eastern districts. This project involved working with households, saving groups, sub county and district leaders, transporters and village health teams in diagnosing causes of maternal and neonatal mortality and morbidity, developing action plans to address these issues, taking action and learning from action in a cyclical manner. This paper draws from project experience and documentation, as well as thematic analysis of 20 interviews with community and district stakeholders and 12 focus group discussions with women who had recently delivered and men whose wives had recently delivered. Results: Women and men reported increased awareness about birth preparedness, improved newborn care practices and more male involvement in maternal and newborn health. However, additional direct communication strategies were required to reach more men beyond the minority who attended community dialogues and home visits. Saving groups and other saving modalities were strengthened, with money saved used to meet transport costs, purchase other items needed for birth and other routine household needs. However saving groups required significant support to improve income generation, management and trust among members. Linkages between savings groups and transport providers improved women’s access to health facilities at reduced cost. Although village health teams were a key resource for providing information, their efforts were constrained by low levels of education, inadequate financial compensation and transportation challenges. Ensuring that the village health teams and savings groups functioned required regular supervision, review meetings and payment for supervisors to visit. Conclusions: This participatory program, which focused on building the capacity of community stakeholders, was able to improve local awareness of maternal and newborn health practices and instigate local action to improve access to healthcare. Collaborative problem solving among diverse stakeholders, continuous support and a participatory approach that allowed flexibility were essential project characteristics that enabled overcoming of challenges faced

    Communities, birth attendants and health facilities: a continuum of emergency maternal and newborn care (the global network's EmONC trial)

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    <p>Abstract</p> <p>Background</p> <p>Maternal and newborn mortality rates remain unacceptably high, especially where the majority of births occur in home settings or in facilities with inadequate resources. The introduction of emergency obstetric and newborn care services has been proposed by several organizations in order to improve pregnancy outcomes. However, the effectiveness of emergency obstetric and neonatal care services has never been proven. Also unproven is the effectiveness of community mobilization and community birth attendant training to improve pregnancy outcomes.</p> <p><b>Methods/Design</b></p> <p>We have developed a cluster-randomized controlled trial to evaluate the impact of a comprehensive intervention of community mobilization, birth attendant training and improvement of quality of care in health facilities on perinatal mortality in low and middle-income countries where the majority of births take place in homes or first level care facilities. This trial will take place in 106 clusters (300-500 deliveries per year each) across 7 sites of the Global Network for Women's and Children's Health Research in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. The trial intervention has three key elements, community mobilization, home-based life saving skills for communities and birth attendants, and training of providers at obstetric facilities to improve quality of care. The primary outcome of the trial is perinatal mortality. Secondary outcomes include rates of stillbirth, 7-day neonatal mortality, maternal death or severe morbidity (including obstetric fistula, eclampsia and obstetrical sepsis) and 28-day neonatal mortality.</p> <p>Discussion</p> <p>In this trial, we are evaluating a combination of interventions including community mobilization and facility training in an attempt to improve pregnancy outcomes. If successful, the results of this trial will provide important information for policy makers and clinicians as they attempt to improve delivery services for pregnant women and newborns in low-income countries.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT01073488</p

    Complete Genome Sequence of the Complex Carbohydrate-Degrading Marine Bacterium, Saccharophagus degradans Strain 2-40T

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    The marine bacterium Saccharophagus degradans strain 2-40 (Sde 2-40) is emerging as a vanguard of a recently discovered group of marine and estuarine bacteria that recycles complex polysaccharides. We report its complete genome sequence, analysis of which identifies an unusually large number of enzymes that degrade >10 complex polysaccharides. Not only is this an extraordinary range of catabolic capability, many of the enzymes exhibit unusual architecture including novel combinations of catalytic and substrate-binding modules. We hypothesize that many of these features are adaptations that facilitate depolymerization of complex polysaccharides in the marine environment. This is the first sequenced genome of a marine bacterium that can degrade plant cell walls, an important component of the carbon cycle that is not well-characterized in the marine environment

    Elevation in Body Temperature to Fever Range Enhances and Prolongs Subsequent Responsiveness of Macrophages to Endotoxin Challenge

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    Macrophages are often considered the sentries in innate immunity, sounding early immunological alarms, a function which speeds the response to infection. Compared to the large volume of studies on regulation of macrophage function by pathogens or cytokines, relatively little attention has been devoted to the role of physical parameters such as temperature. Given that temperature is elevated during fever, a long-recognized cardinal feature of inflammation, it is possible that macrophage function is responsive to thermal signals. To explore this idea, we used LPS to model an aseptic endotoxin-induced inflammatory response in BALB/c mice and found that raising mouse body temperature by mild external heat treatment significantly enhances subsequent LPS-induced release of TNF-α into the peritoneal fluid. It also reprograms macrophages, resulting in sustained subsequent responsiveness to LPS, i.e., this treatment reduces “endotoxin tolerance” in vitro and in vivo. At the molecular level, elevating body temperature of mice results in a increase in LPS-induced downstream signaling including enhanced phosphorylation of IKK and IκB, NF-κB nuclear translocation and binding to the TNF-α promoter in macrophages upon secondary stimulation. Mild heat treatment also induces expression of HSP70 and use of HSP70 inhibitors (KNK437 or Pifithrin-µ) largely abrogates the ability of the thermal treatment to enhance TNF-α, suggesting that the induction of HSP70 is important for mediation of thermal effects on macrophage function. Collectively, these results support the idea that there has been integration between the evolution of body temperature regulation and macrophage function that could help to explain the known survival benefits of fever in organisms following infection
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