Acidosis and Deafness in Patients with Recessive Mutations in FOXI1

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acidbase regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients

Mariana la vivandera :drama en cuatro actos y un prólogo

Representarse en Madrid el año 1851Copia digital. Madrid : Ministerio de Cultura. Dirección General del Libro, Archivos y Bibliotecas, 2010Pie de imprenta tomado del colofónSign.:1-3(4º)Texto a dos col.Colección de comedias representadas con éxito en los teatros de Madri

Indivo: a personally controlled health record for health information exchange and communication

<p>Abstract</p> <p>Background</p> <p>Personally controlled health records (PCHRs), a subset of personal health records (PHRs), enable a patient to assemble, maintain and manage a secure copy of his or her medical data. Indivo (formerly PING) is an open source, open standards PCHR with an open application programming interface (API).</p> <p>Results</p> <p>We describe how the PCHR platform can provide standard building blocks for networked PHR applications. Indivo allows the ready integration of diverse sources of medical data under a patient's control through the use of standards-based communication protocols and APIs for connecting PCHRs to existing and future health information systems.</p> <p>Conclusion</p> <p>The strict and transparent personal control model is designed to encourage widespread participation by patients, healthcare providers and institutions, thus creating the ecosystem for development of innovative, consumer-focused healthcare applications.</p

Sodium/myo-Inositol Transporters: Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology

Inositol stereoisomers, myo- and scyllo-inositol, are known to enter the brain and are significantly elevated following oral administration. Elevations in brain inositol levels occur across a concentration gradient as a result of active transport from the periphery. There are two sodium/myo-inositol transporters (SMIT1, SMIT2) that may be responsible for regulating brain inositol levels. The goals of this study were to determine the effects of aging and Alzheimer's disease (AD)-like amyloid pathology on transporter expression, to compare regional expression and to analyze substrate requirements of the inositol transporters. QPCR was used to examine expression of the two transporters in the cortex, hippocampus and cerebellum of TgCRND8 mice, a mouse model of amyloid pathology, in comparison to non-transgenic littermates. In addition, we examined the structural features of inositol required for active transport, utilizing a cell-based competitive uptake assay. Disease pathology did not alter transporter expression in the cortex or hippocampus (p>0.005), with only minimal effects of aging observed in the cerebellum (SMIT1: F2,26 = 12.62; p = 0.0002; SMIT2: F2,26 = 8.71; p = 0.0015). Overall, brain SMIT1 levels were higher than SMIT2, however, regional differences were observed. For SMIT1, at 4 and 6 months cerebellar SMIT1 levels were significantly higher than cortical and hippocampal levels (p<0.05). For SMIT2, at all three ages both cortical and cerebellar SMIT2 levels were significantly higher than hippocampal levels (p<0.05) and at 4 and 6 months of age, cerebellar SMIT2 levels were also significantly higher than cortical levels (p<0.05). Inositol transporter levels are stably expressed as a function of age, and expression is unaltered with disease pathology in the TgCRND8 mouse. Given the fact that scyllo-inositol is currently in clinical trials for the treatment of AD, the stable expression of inositol transporters regardless of disease pathology is an important finding

CD4+ T Cell-Derived IL-2 Signals during Early Priming Advances Primary CD8+ T Cell Responses

Stimulating naïve CD8+ T cells with specific antigens and costimulatory signals is insufficient to induce optimal clonal expansion and effector functions. In this study, we show that the activation and differentiation of CD8+ T cells require IL-2 provided by activated CD4+ T cells at the initial priming stage within 0–2.5 hours after stimulation. This critical IL-2 signal from CD4+ cells is mediated through the IL-2Rβγ of CD8+ cells, which is independent of IL-2Rα. The activation of IL-2 signaling advances the restriction point of the cell cycle, and thereby expedites the entry of antigen-stimulated CD8+ T-cell into the S phase. Besides promoting cell proliferation, IL-2 stimulation increases the amount of IFNγ and granzyme B produced by CD8+ T cells. Furthermore, IL-2 at priming enhances the ability of P14 effector cells generated by antigen activation to eradicate B16.gp33 tumors in vivo. Therefore, our studies demonstrate that a full CD8+ T-cell response is elicited by a critical temporal function of IL-2 released from CD4+ T cells, providing mechanistic insights into the regulation of CD8+ T cell activation and differentiation

Preliminary outcomes of a paediatric highly active antiretroviral therapy cohort from KwaZulu-Natal, South Africa

BACKGROUND: Few studies address the use of paediatric highly active antiretroviral therapy (HAART) in Africa. METHODS: We performed a retrospective cohort study to investigate preliminary outcomes of all children eligible for HAART at Sinikithemba HIV/AIDS clinic in KwaZulu-Natal, South Africa. Immunologic, virologic, clinical, mortality, primary caregiver, and psychosocial variables were collected and analyzed. RESULTS: From August 31, 2003 until October 31, 2005, 151 children initiated HAART. The median age at HAART initiation was 5.7 years (range 0.3–15.4). Median follow-up time of the cohort after HAART initiation was 8 months (IQR 3.5–13.5). The median change in CD4% from baseline (p < 0.001) was 10.2 (IQR 5.0–13.8) at 6 months (n = 90), and 16.2 (IQR 9.6–20.3) at 12 months (n = 59). Viral loads (VLs) were available for 100 children at 6 months of which 84% had HIV-1 RNA levels ≤ 50 copies/mL. At 12 months, 80.3% (n = 61) had undetectable VLs. Sixty-five out of 88 children (73.8%) reported a significant increase (p < 0.001) in weight after the first month. Eighty-nine percent of the cohort (n = 132) reported ≤ 2 missed doses during any given treatment month (> 95%adherence). Seventeen patients (11.3%) had a regimen change; two (1.3%) were due to antiretroviral toxicity. The Kaplan-Meier one year survival estimate was 90.9% (95%confidence interval (CI) 84.8–94.6). Thirteen children died during follow-up (8.6%), one changed service provider, and no children were lost to follow-up. All 13 deaths occurred in children with advanced HIV disease within 5 months of treatment initiation. In multivariate analysis of baseline variables against mortality using Cox proportional-hazards model, chronic gastroenteritis was associated with death [hazard ratio (HR), 12.34; 95%CI, 1.27–119.71) and an HIV-positive primary caregiver was found to be protective against mortality [HR, 0.12; 95%CI, 0.02–0.88). Age, orphanhood, baseline CD4%, and hemoglobin were not predicators of mortality in our cohort. Fifty-two percent of the cohort had at least one HIV-positive primary caregiver, and 38.4% had at least one primary caregiver also on HAART at Sinikithemba clinic. CONCLUSION: This report suggests that paediatric HAART can be effective despite the challenges of a resource-limited setting

Combining Free Text and Structured Electronic Medical Record Entries to Detect Acute Respiratory Infections

The electronic medical record (EMR) contains a rich source of information that could be harnessed for epidemic surveillance. We asked if structured EMR data could be coupled with computerized processing of free-text clinical entries to enhance detection of acute respiratory infections (ARI).A manual review of EMR records related to 15,377 outpatient visits uncovered 280 reference cases of ARI. We used logistic regression with backward elimination to determine which among candidate structured EMR parameters (diagnostic codes, vital signs and orders for tests, imaging and medications) contributed to the detection of those reference cases. We also developed a computerized free-text search to identify clinical notes documenting at least two non-negated ARI symptoms. We then used heuristics to build case-detection algorithms that best combined the retained structured EMR parameters with the results of the text analysis.An adjusted grouping of diagnostic codes identified reference ARI patients with a sensitivity of 79%, a specificity of 96% and a positive predictive value (PPV) of 32%. Of the 21 additional structured clinical parameters considered, two contributed significantly to ARI detection: new prescriptions for cough remedies and elevations in body temperature to at least 38°C. Together with the diagnostic codes, these parameters increased detection sensitivity to 87%, but specificity and PPV declined to 95% and 25%, respectively. Adding text analysis increased sensitivity to 99%, but PPV dropped further to 14%. Algorithms that required satisfying both a query of structured EMR parameters as well as text analysis disclosed PPVs of 52-68% and retained sensitivities of 69-73%.Structured EMR parameters and free-text analyses can be combined into algorithms that can detect ARI cases with new levels of sensitivity or precision. These results highlight potential paths by which repurposed EMR information could facilitate the discovery of epidemics before they cause mass casualties

Organizational readiness to change assessment (ORCA): Development of an instrument based on the Promoting Action on Research in Health Services (PARIHS) framework

<p>Abstract</p> <p>Background</p> <p>The Promoting Action on Research Implementation in Health Services, or PARIHS, framework is a theoretical framework widely promoted as a guide to implement evidence-based clinical practices. However, it has as yet no pool of validated measurement instruments that operationalize the constructs defined in the framework. The present article introduces an Organizational Readiness to Change Assessment instrument (ORCA), organized according to the core elements and sub-elements of the PARIHS framework, and reports on initial validation.</p> <p>Methods</p> <p>We conducted scale reliability and factor analyses on cross-sectional, secondary data from three quality improvement projects (n = 80) conducted in the Veterans Health Administration. In each project, identical 77-item ORCA instruments were administered to one or more staff from each facility involved in quality improvement projects. Items were organized into 19 subscales and three primary scales corresponding to the core elements of the PARIHS framework: (1) Strength and extent of evidence for the clinical practice changes represented by the QI program, assessed with four subscales, (2) Quality of the organizational context for the QI program, assessed with six subscales, and (3) Capacity for internal facilitation of the QI program, assessed with nine subscales.</p> <p>Results</p> <p>Cronbach's alpha for scale reliability were 0.74, 0.85 and 0.95 for the evidence, context and facilitation scales, respectively. The evidence scale and its three constituent subscales failed to meet the conventional threshold of 0.80 for reliability, and three individual items were eliminated from evidence subscales following reliability testing. In exploratory factor analysis, three factors were retained. Seven of the nine facilitation subscales loaded onto the first factor; five of the six context subscales loaded onto the second factor; and the three evidence subscales loaded on the third factor. Two subscales failed to load significantly on any factor. One measured resources in general (from the context scale), and one clinical champion role (from the facilitation scale).</p> <p>Conclusion</p> <p>We find general support for the reliability and factor structure of the ORCA. However, there was poor reliability among measures of evidence, and factor analysis results for measures of general resources and clinical champion role did not conform to the PARIHS framework. Additional validation is needed, including criterion validation.</p

Radiocarbon dating and cultural dynamics across Mongolia’s early pastoral transition

All necessary permits were obtained for the described study, which complied with all relevant regulations. Collaboration contract between the Max Planck Institute for the Science of Human HIstory and the National University of Mongolia began on the 10th November, 2016. Export number 10/413 (7b/52) was received on the 2nd Feb, 2017 (#A0109258, MN DE 7 643). This research was supported by the Max Planck Institute for the Science of Human History. Special thanks to Dr. Katerina Douka and the Oxford Radiocarbon Accelerator Laboratory for conducting 14C analysis, and to all of the original excavators and authors who published the radiocarbon dates cited in this study.Peer reviewedPublisher PD