bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice

bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice. HIV-associated nephropathy is characterized by extensive tubulointerstitial disease with epithelial cell injury, microcystic proliferation, and tubular regeneration with glomerulosclerosis. To explore the role of bFGF as a mediator of HIV-induced interstitial disease, we utilized an HIV transgenic mouse model that manifests clinical and histological features observed in patients. In transgenic mice, simultaneous renal epithelial cell proliferation and injury were detected in vivo. In areas of microcystic proliferation, immunoreactive bFGF colocalized with extracellular matrix. Kidneys from transgenic mice had increased bFGF low affinity binding sites, particularly in the renal interstitium. In vitro, transgenic renal tubular epithelial cells proliferated more rapidly and generated tubular structures spontaneously, in marked contrast to nontransgenic renal cells where these pathologic features could be mimicked by exogenous bFGF. These studies suggest that renal bFGF and its receptors play an important role in the pathogenesis of HIV-associated nephropathy

Evaluation of a clinical decision support strategy to increase seasonal influenza vaccination among hospitalized children before inpatient discharge

Importance: Hospitalized children are at increased risk of influenza-related complications, yet influenza vaccine coverage remains low among this group. Evidence-based strategies about vaccination of vulnerable children during all health care visits are especially important during the COVID-19 pandemic. Objective: To design and evaluate a clinical decision support (CDS) strategy to increase the proportion of eligible hospitalized children who receive a seasonal influenza vaccine prior to inpatient discharge. Design, Setting, and Participants: This quality improvement study was conducted among children eligible for the seasonal influenza vaccine who were hospitalized in a tertiary pediatric health system providing care to more than half a million patients annually in 3 hospitals. The study used a sequential crossover design from control to intervention and compared hospitalizations in the intervention group (2019-2020 season with the use of an intervention order set) with concurrent controls (2019-2020 season without use of an intervention order set) and historical controls (2018-2019 season with use of an order set that underwent intervention during the 2019-2020 season). Interventions: A CDS intervention was developed through a user-centered design process, including (1) placing a default influenza vaccine order into admission order sets for eligible patients, (2) a script to offer the vaccine using a presumptive strategy, and (3) just-in-time education for clinicians addressing vaccine eligibility in the influenza order group with links to further reference material. The intervention was rolled out in a stepwise fashion during the 2019-2020 influenza season. Main Outcomes and Measures: Proportion of eligible hospitalizations in which 1 or more influenza vaccines were administered prior to discharge. Results: Among 17 740 hospitalizations (9295 boys [52%]), the mean (SD) age was 8.0 (6.0) years, and the patients were predominantly Black (n = 8943 [50%]) or White (n = 7559 [43%]) and mostly had public insurance (n = 11 274 [64%]). There were 10 997 hospitalizations eligible for the influenza vaccine in the 2019-2020 season. Of these, 5449 (50%) were in the intervention group, and 5548 (50%) were concurrent controls. There were 6743 eligible hospitalizations in 2018-2019 that served as historical controls. Vaccine administration rates were 31% (n = 1676) in the intervention group, 19% (n = 1051) in concurrent controls, and 14% (n = 912) in historical controls (P \u3c .001). In adjusted analyses, the odds of receiving the influenza vaccine were 3.25 (95% CI, 2.94-3.59) times higher in the intervention group and 1.28 (95% CI, 1.15-1.42) times higher in concurrent controls than in historical controls. Conclusions and Relevance: This quality improvement study suggests that user-centered CDS may be associated with significantly improved influenza vaccination rates among hospitalized children. Stepwise implementation of CDS interventions was a practical method that was used to increase quality improvement rigor through comparison with historical and concurrent controls

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.

Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB

Internet-based medical education: a realist review of what works, for whom and in what circumstances

http://creativecommons.org/licenses/by/2.0

The NIDDK Central Repository at 8 years—Ambition, Revision, Use and Impact

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository makes data and biospecimens from NIDDK-funded research available to the broader scientific community. It thereby facilitates: the testing of new hypotheses without new data or biospecimen collection; pooling data across several studies to increase statistical power; and informative genetic analyses using the Repository’s well-curated phenotypic data. This article describes the initial database plan for the Repository and its revision using a simpler model. Among the lessons learned were the trade-offs between the complexity of a database design and the costs in time and money of implementation; the importance of integrating consent documents into the basic design; the crucial need for linkage files that associate biospecimen IDs with the masked subject IDs used in deposited data sets; and the importance of standardized procedures to test the integrity data sets prior to distribution. The Repository is currently tracking 111 ongoing NIDDK-funded studies many of which include genotype data, and it houses over 5 million biospecimens of more than 25 types including serum, plasma, stool, urine, DNA, red blood cells, buffy coat and tissue. Repository resources have supported a range of biochemical, clinical, statistical and genetic research (188 external requests for clinical data and 31 for biospecimens have been approved or are pending). Genetic research has included GWAS, validation studies, development of methods to improve statistical power of GWAS and testing of new statistical methods for genetic research. We anticipate that the future impact of the Repository’s resources on biomedical research will be enhanced by (i) cross-listing of Repository biospecimens in additional searchable databases and biobank catalogs; (ii) ongoing deployment of new applications for querying the contents of the Repository; and (iii) increased harmonization of procedures, data collection strategies, questionnaires etc. across both research studies and within the vocabularies used by different repositories

Developing a community based psychosocial intervention with older people and third sector workers for anxiety and depression: a qualitative study

Background: One-in-five people in the UK experience anxiety and/or depression in later life. However, anxiety and depression remain poorly detected in older people, particularly in those with chronic physical ill health. In the UK, a stepped care approach, to manage common mental health problems, is advocated which includes service provision from non-statutory organisations (including third/voluntary sector). However, evidence to support such provision, including the most effective interventions, is limited. The qualitative study reported here constitutes the first phase of a feasibility study which aims to assess whether third sector workers can deliver a psychosocial intervention to older people with anxiety and/or depression. The aim of this qualitative study is to explore the views of older people and third sector workers about anxiety and depression among older people in order to refine an intervention to be delivered by third sector workers. Methods: Semi-structured interviews with participants recruited through purposive sampling from third sector groups in North Staffordshire. Interviews were digitally recorded with consent, transcribed and analysed using principles of constant comparison. Results: Nineteen older people and 9 third sector workers were interviewed. Key themes included: multiple forms of loss, mental health as a personal burden to bear, having courage and providing/receiving encouragement, self- worth and the value of group activities, and tensions in existing service provision, including barriers and gaps. Conclusions: The experience of loss was seen as central to feelings of anxiety and depression among community- dwelling older people. This study contributes to the evidence pointing to the scale and severity of mental health needs for some older people which can arise from multiple forms of loss, and which present a significant challenge to health, social care and third sector services. The findings informed development of a psychosocial intervention and training for third sector workers to deliver the intervention

The experience of health in an unequal society

The Politics of Food and Healt

Multigene phylogeny of the Mustelidae: Resolving relationships, tempo and biogeographic history of a mammalian adaptive radiation

<p>Abstract</p> <p>Background</p> <p>Adaptive radiation, the evolution of ecological and phenotypic diversity from a common ancestor, is a central concept in evolutionary biology and characterizes the evolutionary histories of many groups of organisms. One such group is the Mustelidae, the most species-rich family within the mammalian order Carnivora, encompassing 59 species classified into 22 genera. Extant mustelids display extensive ecomorphological diversity, with different lineages having evolved into an array of adaptive zones, from fossorial badgers to semi-aquatic otters. Mustelids are also widely distributed, with multiple genera found on different continents. As with other groups that have undergone adaptive radiation, resolving the phylogenetic history of mustelids presents a number of challenges because ecomorphological convergence may potentially confound morphologically based phylogenetic inferences, and because adaptive radiations often include one or more periods of rapid cladogenesis that require a large amount of data to resolve.</p> <p>Results</p> <p>We constructed a nearly complete generic-level phylogeny of the Mustelidae using a data matrix comprising 22 gene segments (~12,000 base pairs) analyzed with maximum parsimony, maximum likelihood and Bayesian inference methods. We show that mustelids are consistently resolved with high nodal support into four major clades and three monotypic lineages. Using Bayesian dating techniques, we provide evidence that mustelids underwent two bursts of diversification that coincide with major paleoenvironmental and biotic changes that occurred during the Neogene and correspond with similar bursts of cladogenesis in other vertebrate groups. Biogeographical analyses indicate that most of the extant diversity of mustelids originated in Eurasia and mustelids have colonized Africa, North America and South America on multiple occasions.</p> <p>Conclusion</p> <p>Combined with information from the fossil record, our phylogenetic and dating analyses suggest that mustelid diversification may have been spurred by a combination of faunal turnover events and diversification at lower trophic levels, ultimately caused by climatically driven environmental changes. Our biogeographic analyses show Eurasia as the center of origin of mustelid diversity and that mustelids in Africa, North America and South America have been assembled over time largely via dispersal, which has important implications for understanding the ecology of mustelid communities.</p