Cyanide resistant respiration and the alternative oxidase pathway : A from to mammals

In a large number of organisms covering all phyla, the mitochondrial respiratory chain harbors, in addition to the conventional elements, auxiliary proteins that confer adaptive metabolic plasticity. The alternative oxidase (AOX) represents one of the most studied auxiliary proteins, initially identified in plants. In contrast to the standard respiratory chain, the AOX mediates a thermogenic cyanide-resistant respiration; a phenomenon that has been of great interest for over 2 centuries in that energy is not conserved when electrons flow through it. Here we summarize centuries of studies starting from the early observations of thermogenicity in plants and the identification of cyanide resistant respiration, to the fascinating discovery of the AOX and its current applications in animals under normal and pathological conditions.Peer reviewe

Management of trypanosomiasis and leishmaniasis

<p>Background: The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from ideal but, for some, there has been significant recent progress. For HAT the only advances in treatment over the past two decades have been the introduction of an eflornithine/nifurtimox co-administration and a shorter regime of the old standard melarsoprol.</p> <p>Sources of data: PubMed.</p> <p>Areas of Agreement: There is a need for new safe, oral drugs for cost-effective treatment of patients and use in control programmes for all the trypanosomatid diseases.</p> <p>Areas of controversy: Cutaneous leishmaniasis is not on the agenda and treatments are lagging behind.</p> <p>Growing points: There are three compounds in development for the treatment of the CNS stage of HAT: fexinidazole, currently due to entry into phase II clinical studies, a benzoxaborole (SCYX-7158) in phase I trials and a diamidine derivative (CPD-0802), in advanced pre-clinical development. For Chagas disease, two anti-fungal triazoles are now in clinical trial. In addition, clinical studies with benznidazole, a drug previously recommended only for acute stage treatment, are close to completion to determine the effectiveness in the treatment of early chronic and indeterminate Chagas disease. For visceral leishmaniasis new formulations, therapeutic switching, in particular AmBisome, and the potential for combinations of established drugs have significantly improved the opportunities for the treatment in the Indian subcontinent, but not in East Africa.</p> <p>Areas timely for developing research: Improved diagnostic tools are needed to support treatment, for test of cure in clinical trials and for monitoring/surveillance of populations in control programmes.</p&gt

Baseline morning cortisol level as a predictor of pituitary-adrenal reserve: a comparison across three assays

The short ACTH stimulation test (250 μg) is the dynamic test most frequently used to assess adrenal function. It is possible that a single basal cortisol could be used to predict the dynamic response, but research has been hampered by the use of different assays and thresholds. OBJECTIVE: To propose a morning baseline cortisol criterion of three of the most commonly used modern cortisol immunoassays - Advia Centaur (Siemens), Architect (Abbott) and the Roche Modular System (Roche) - that could predict adrenal sufficiency. DESIGN: Observational, retrospective cross-sectional study at two centres. PATIENTS AND MEASUREMENTS: Retrospective analysis of the results of 1019 Short Synacthen tests (SSTs) with the Advia Centaur, 449 SSTs with the Architect and 2050 SSTs with the Roche Modular System assay. Serum cortisol levels were measured prior to injection of 250 μg Synacthen and after 30 min. Overall, we were able to collate data from a total of 3518 SSTs in 3571 patients. RESULTS: Using receiver-operator curve analysis, baseline cortisol levels for predicting passing the SST with 100% specificity were 358 nmol/l for Siemens, 336 nmol/l for Abbott and 506 nmol/l for Roche. Utilizing these criteria, 589, 158 and 578 SSTs, respectively, for Siemens, Abbott and Roche immunoassays could have been avoided. CONCLUSIONS: We have defined assay-specific morning cortisol levels that are able to predict the integrity of the hypothalamo-pituitary-adrenal axis. We propose that this represents a valid tool for the initial assessment of adrenal function and has the potential to obviate the need for dynamic testing in a significant number of patients

Contemporary medical television and crisis in the NHS

This article maps the terrain of contemporary UK medical television, paying particular attention to Call the Midwife as its centrepiece, and situating it in contextual relation to the current crisis in the NHS. It provides a historical overview of UK and US medical television, illustrating how medical television today has been shaped by noteworthy antecedents. It argues that crisis rhetoric surrounding healthcare leading up to the passing of the Health and Social Care Act 2012 has been accompanied by a renaissance in medical television. And that issues, strands and clusters have emerged in forms, registers and modes with noticeable regularity, especially around the value of affective labour, the cultural politics of nostalgia and the neoliberalisation of healthcare

L’impact d’un campus clinique régional en milieu urbain : les perceptions des parties prenantes de la collectivité

Background: Regional medical campuses (RMC) have shown promise in addressing physician shortages. RMCs have been positively evaluated in rural/remote communities, however, it is unclear whether this model will be as beneficial in underserved urban areas. This study evaluated the impact of a RMC on a midsized urban city (Windsor, Ontario). We compare our results with a similar study conducted in a remote community in British Columbia (BC). Methods: A broad array of community stakeholders representing different sectors were consulted using a semi-structured interview format replicated from the BC Northern Medical Program (NMP) study. Thematic analysis based on the resulting rich data was conducted within a grounded theory context. Results: Twenty-three participants (52% male) representing healthcare, education, business, community and government/politico sectors were consulted. Their views regarding the Windsor Regional Medical Campus (WRMC) aligned around several themes: improved healthcare, enhanced community reputation, stimulated economic/community development, expanded training opportunities and an engaged community regarding the WRMC. These results were compared to the main findings of the NMP study with both similarities (e.g. increased community pride) and differences (e.g. resource concerns) discussed. Conclusion: Community stakeholders provided strong support for the WRMC through their perceptions of its positive impact on this urban region. These findings are consistent with similar RMC studies in rural/remote areas. Those interested in developing a RMC might benefit from considering these findings.Contexte : Les campus cliniques régionaux (CCR) se sont révélés prometteurs pour remédier à la pénurie de médecins. Les CCR ont été évalués positivement dans les collectivités rurales/éloignées, mais il n’est pas certain que ce modèle soit aussi bénéfique dans les zones urbaines mal desservies. La présente étude évalue l’impact d’un CCR dans une ville de taille moyenne (Windsor, Ontario). Nous comparons nos résultats avec ceux d’une étude similaire menée dans une collectivité éloignée en Colombie-Britannique (BC). Méthode : Un large éventail de parties prenantes de la collectivité représentant différents secteurs a été consulté par le biais d’entrevues semi-structurées calquées sur celles de l’étude du BC Northern Medical Program (NMP). L’analyse thématique des riches données obtenues a été faite selon l’approche de la Grounded Theory (théorie ancrée). Résultats : Vingt-trois participants (52 % d’hommes) des secteurs de la santé, de l’éducation, des affaires, de la vie communautaire, du gouvernement ou encore du monde politique ont été consultés. Leurs opinions concernant le campus clinique régional de Windsor (WRMC) s’articulaient autour de plusieurs thèmes : l’amélioration des soins de santé, le renforcement de la réputation de la collectivité, la stimulation du développement économique et communautaire, l’élargissement des possibilités de formation et l’engagement de la communauté envers le WRMC. Les résultats ont été comparés aux principales conclusions de l’étude du NMP, en analysant aussi bien les similitudes (par exemple, fierté accrue de la collectivité) que les différences (par exemple, les préoccupations en matière de ressources). Conclusion : Percevant l’impact positif qu’a eu le WRMC dans la région urbaine, les acteurs de la collectivité témoignent d’un ferme appui à son égard. Ces résultats sont conformes aux études similaires portant sur des CCR dans les zones rurales/éloignées. Les résultats de l’étude seraient utiles à tous ceux qui souhaitant mettre sur pied un CCR

Cluster J Mycobacteriophages: Intron Splicing in Capsid and Tail Genes

Bacteriophages isolated on Mycobacterium smegmatis mc2155 represent many distinct genomes sharing little or no DNA sequence similarity. The genomes are architecturally mosaic and are replete with genes of unknown function. A new group of genomes sharing substantial nucleotide sequences constitute Cluster J. The six mycobacteriophages forming Cluster J are morphologically members of the Siphoviridae, but have unusually long genomes ranging from 106.3 to 117 kbp. Reconstruction of the capsid by cryo-electron microscopy of mycobacteriophage BAKA reveals an icosahedral structure with a triangulation number of 13. All six phages are temperate and homoimmune, and prophage establishment involves integration into a tRNA-Leu gene not previously identified as a mycobacterial attB site for phage integration. The Cluster J genomes provide two examples of intron splicing within the virion structural genes, one in a major capsid subunit gene, and one in a tail gene. These genomes also contain numerous free-standing HNH homing endonuclease, and comparative analysis reveals how these could contribute to genome mosaicism. The unusual Cluster J genomes provide new insights into phage genome architecture, gene function, capsid structure, gene mobility, intron splicing, and evolution. © 2013 Pope et al

Bronchoalveolar lavage cytological alveolar damage in patients with severe pneumonia

INTRODUCTION: Histological examination of lung specimens from patients with pneumonia shows the presence of desquamated pneumocytes and erythrophages. We hypothesized that these modifications should also be present in bronchoalveolar lavage fluid (BAL) from patients with hospital-acquired pneumonia. METHODS: We conducted a prospective study in mechanically ventilated patients with clinical suspicion of pneumonia. Patients were classified as having hospital-acquired pneumonia or not, in accordance with the quantitative microbiological cultures of respiratory tract specimens. A group of severe community-acquired pneumonias requiring mechanical ventilation during the same period was used for comparison. A specimen of BAL (20 ml) was taken for cytological analysis. A semiquantitative analysis of the dominant leukocyte population, the presence of erythrophages/siderophages and desquamated type II pneumocytes was performed. RESULTS: In patients with confirmed hospital-acquired pneumonia, we found that 13 out of 39 patients (33.3%) had erythrophages/siderophages in BAL, 18 (46.2%) had desquamated pneumocytes and 8 (20.5%) fulfilled both criteria. Among the patients with community-acquired pneumonia, 7 out of 15 (46.7%) had erythrophages/siderophages and 6 (40%) had desquamated pneumocytes on BAL cytology. Only four (26.7%) fulfilled both criteria. No patient without hospital-acquired pneumonia had erythrophages/siderophages and only 3 out of 18 (16.7%) had desquamated pneumocytes on BAL cytology. CONCLUSION: Cytological analysis of BAL from patients with pneumonia (either community-acquired or hospital-acquired) shows elements of cytological alveolar damage as hemorrhage and desquamated type II pneumocytes much more frequently than in BAL from patients without pneumonia. These elements had a high specificity for an infectious cause of pulmonary infiltrates but low specificity. These lesions could serve as an adjunct to diagnosis in patients suspected of having ventilator-associated pneumonia

Expression of the alternative oxidase mitigates beta-amyloid production and toxicity in model systems

Mitochondrial dysfunction has been widely associated with the pathology of Alzheimer's disease, but there is no consensus on whether it is a cause or consequence of disease, nor on the precise mechanism(s). We addressed these issues by testing the effects of expressing the alternative oxidase AOX from Ciona intestinalis, in different models of AD pathology. AOX can restore respiratory electron flow when the cytochrome segment of the mitochondrial respiratory chain is inhibited, supporting ATP synthesis, maintaining cellular redox homeostasis and mitigating excess superoxide production at respiratory complexes I and III. In human HEK293-derived cells, AOX expression decreased the production of beta-amyloid peptide resulting from antimycin inhibition of respiratory complex III. Because hydrogen peroxide was neither a direct product nor substrate of AOX, the ability of AOX to mimic antioxidants in this assay must be indirect. In addition, AOX expression was able to partially alleviate the short lifespan of Drosophila models neuronally expressing human beta-amyloid peptides, whilst abrogating the induction of markers of oxidative stress. Our findings support the idea of respiratory chain dysfunction and excess ROS production as both an early step and as a pathologically meaningful target in Alzheimer's disease pathogenesis, supporting the concept of a mitochondrial vicious cycle underlying the disease. (C) 2016 The Authors. Published by Elsevier Inc.Peer reviewe

Perioperative renal failure in pediatric heart transplant recipients: Outcome and risk factors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90192/1/j.1399-3046.2010.01445.x.pd