A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

Background: Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle. Methods: Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change. Results: PSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2 + 2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower Km for UDP-glucose, in the presence and absence of G6P, when compared to wild type GS, and despite its phosphorylation. Conclusions: Elevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state. General significance: This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy

Successful treatment with azithromycin and rifampicin of penicillin and cephalosporin insensitive pneumococcal osteomyelitis in a child with HIV infection: a case report

Pneumococcal infection is common in children with HIV infection, but osteomyelits is unusual. The best treatment for bone and joint infection due to antibiotic resistant pneumococci is not known, especially in immunocompromised children

The implications of “pay-for-performance” reimbursement for Otolaryngology – Head and Neck Surgery

Objective: To introduce otolaryngologists to outcomes-linked reimbursement ( pay-for-performance ), identify clinical practice implications and recommend changes for successful transition from the traditional pay-for-effort reimbursement model. Study design: Policy review Results: Payers are actively linking reimbursement to quality. Since the Institute of Medicine issued its report on medical errors in 1999, there has been much public and private concern over patient safety. In an effort to base health care payment on quality, pay-for-performance programs reward or penalize hospitals and physicians for their ability to maintain standards of care established by payers and regulatory groups. More than 100 such programs are operational in the United States today. This reimbursement model relies on detailed documentation in specific patient care areas to facilitate evaluation of outcomes for purposes of determining reimbursement. Since performance criteria for reimbursement have not yet been proposed within Otolaryngology-Head and Neck Surgery, otolaryngologists must be involved to ensure the adoption of reasonable goals and development of reasonable systems for documentation. Conclusion: Pay-for-performance reimbursement is increasingly common in the current era of outcomes-based medicine. It will assume an even greater role over the next 3 years and will directly affect most otolaryngologists

Which circulating antioxidant vitamins are confounded by socioeconomic deprivation? The MIDSPAN family study

<p><b>Background:</b> Antioxidant vitamins are often described as having “independent” associations with risk of cancer, cardiovascular disease (CVD) and mortality. We aimed to compare to what extent a range of antioxidant vitamins and carotenoids are associated with adulthood and childhood markers of socioeconomic deprivation and to adverse lifestyle factors.</p> <p><b>Methods and Findings:</b> Socioeconomic and lifestyle measures were available in 1040 men and 1298 women from the MIDSPAN Family Study (30–59 years at baseline) together with circulating levels of vitamins A, C, E, and carotenoids (α-carotene, β-carotene, lutein and lycopene). Markers of socioeconomic deprivation in adulthood were consistently as strongly associated with lower vitamin C and carotenoid levels as markers of adverse lifestyle; the inverse association with overcrowding was particularly consistent (vitamin C and carotenoids range from 19.1% [95% CI 30.3–6.0] to 38.8% [49.9–25.3] lower among those in overcrowded residencies). These associations were consistent after adjusting for month, classical CVD risk factors, body mass index, physical activity, vitamin supplements, dietary fat and fibre intake. Similar, but weaker, associations were seen for childhood markers of deprivation. The association of vitamin A or E were strikingly different; several adult adverse lifestyle factors associated with higher levels of vitamin A and E, including high alcohol intake for vitamin A (9.5% [5.7–13.5]) and waist hip ratio for vitamin E (9.5% [4.8–14.4]), with the latter associations partially explained by classical risk factors, particularly cholesterol levels.</p> <p><b>Conclusions:</b> Plasma vitamin C and carotenoids have strong inverse associations with adulthood markers of social deprivation, whereas vitamin A and E appear positively related to specific adverse lifestyle factors. These findings should help researchers better contextualize blood antioxidant vitamin levels by illustrating the potential limitations associated with making causal inferences without consideration of social deprivation.</p&gt

aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization

Atypical protein kinase C (aPKC) is a key apical-basal polarity determinant and Par complex component. It is recruited by Par3/Baz (Bazooka in Drosophila) into epithelial apical domains through high-affinity interaction. Paradoxically, aPKC also phosphorylates Par3/Baz, provoking its relocalization to adherens junctions (AJs). We show that Par3 conserved region 3 (CR3) forms a tight inhibitory complex with a primed aPKC kinase domain, blocking substrate access. A CR3 motif flanking its PKC consensus site disrupts the aPKC kinase N lobe, separating P-loop/αB/αC contacts. A second CR3 motif provides a high-affinity anchor. Mutation of either motif switches CR3 to an efficient in vitro substrate by exposing its phospho-acceptor site. In vivo, mutation of either CR3 motif alters Par3/Baz localization from apical to AJs. Our results reveal how Par3/Baz CR3 can antagonize aPKC in stable apical Par complexes and suggests that modulation of CR3 inhibitory arms or opposing aPKC pockets would perturb the interaction, promoting Par3/Baz phosphorylation

Tuberculosis in alpaca (Lama pacos) on a farm in Ireland. 1. A clinical report

This case report describes tuberculosis (TB) due to infection with Mycobacterium bovis (M. bovis) in alpaca (Lama pacos) on a farm in Ireland. Two severely debilitated alpaca were presented to the University Veterinary Hospital, University College Dublin in November 2004. Bloods were taken, and haematology and biochemistry results were indicative of chronic infection. Radiological examination showed evidence of diffuse granulomatous pneumonia suggestive of tuberculosis. On necropsy there were granulomatous lesions present throughout many body organs including lung, liver, kidney, intestine as well on peritoneum and mesentery. Culture of acid-fast bacilli from lesions led to a diagnosis of tuberculosis due to M. bovis. The use of intradermal skin testing proved inefficient and unreliable for ante mortem diagnosis of tuberculosis in alpaca. Infection due to M. bovis should be considered among the differential diagnoses of debilitating diseases in alpaca, particularly those farmed in areas known to be traditional black spots for tuberculosis in cattle

Absence of influenza vaccination among high-risk older adults in Taiwan

<p>Abstract</p> <p>Background</p> <p>Older adults, who often have more than one chronic disease, are at greater risk of influenza and its complications. However, because they often see physicians for other more pressing complaints, their physicians, focusing on one condition, may forget to suggest preventive measures for other diseases such as influenza. This study investigates what major factors affect an older adult with more than one chronic condition missing a vaccination opportunity.</p> <p>Methods</p> <p>Retrospectively reviewing a nationally representative random sample of medical claims from Taiwan's National Health Insurance Research Database during the period 2004 - 2006, we first identified patients sixty-five years or older who had visited physicians. Each patient was assigned a proxy for health status, the Charlson Comorbidity Index (CCI) score. An older claimant was defined has having "absence of a vaccination" when he or she had visited a physician during an influenza season but did not receive an influenza vaccination. Multivariate logistic regression was performed to estimate how likely it would be for older adults with various CCI scores to miss a vaccination.</p> <p>Results</p> <p>Out of 200,000 randomly selected claims, 20,923 older adults were included in our final analysis. We found older adults with higher CCIs to be more likely to have an absence of vaccination (<it>p </it>< 0.01). Our multivariate logistic regression results revealed CCI to be the greatest predictor of absence of vaccination, after controlling for individual factors and medical setting. Older adults with CCI scores three or higher were nearly five times more likely to miss a vaccination than those with a CCI of zero [OR: 4.93 (95%CI, 4.47-5.42)]. Those with CCIs of one and two were 2.53 and 3.92 times more likely to miss vaccination than those with a CCI of zero [OR 2.53 (95%CI, 2.26-2.84) and OR 3.92 (95%CI, 3.51-4.38), respectively].</p> <p>Conclusions</p> <p>The greater the number of certain comorbid conditions, the greater the likelihood a flu vaccination will be missed. Physicians would be well advised to not let the presenting problems of older patients distract from other possible health problems that might also need attention, in this case influenza vaccinations.</p

Insulin utilizes the PI 3-kinase pathway to inhibit SP-A gene expression in lung epithelial cells

BACKGROUND: It has been proposed that high insulin levels may cause delayed lung development in the fetuses of diabetic mothers. A key event in lung development is the production of adequate amounts of pulmonary surfactant. Insulin inhibits the expression of surfactant protein A (SP-A), the major surfactant-associated protein, in lung epithelial cells. In the present study, we investigated the signal transduction pathways involved in insulin inhibition of SP-A gene expression. METHODS: H441 cells, a human lung adenocarcinoma cell line, or human fetal lung explants were incubated with or without insulin. Transcription run-on assays were used to determine SP-A gene transcription rates. Northern blot analysis was used to examine the effect of various signal transduction inhibitors on SP-A gene expression. Immunoblot analysis was used to evaluate the levels and phosphorylation states of signal transduction protein kinases. RESULTS: Insulin decreased SP-A gene transcription in human lung epithelial cells within 1 hour. Insulin did not affect p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and the insulin inhibition of SP-A mRNA levels was not affected by PD98059, an inhibitor of the p44/42 MAPK pathway. In contrast, insulin increased p70 S6 kinase Thr389 phosphorylation within 15 minutes. Wortmannin or LY294002, both inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), or rapamycin, an inhibitor of the activation of p70 S6 kinase, a downstream effector in the PI 3-kinase pathway, abolished or attenuated the insulin-induced inhibition of SP-A mRNA levels. CONCLUSION: Insulin inhibition of SP-A gene expression in lung epithelial cells probably occurs via the rapamycin-sensitive PI 3-kinase signaling pathway