The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury

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Health and disease as practical concepts: exploring function in context-specific definitions

Medicine, Health Care and Philosophy - Despite the longstanding debate on definitions of health and disease concepts, and the multitude of accounts that have been developed, no consensus has been...     

Validity of an automated telephonic system to assess COPD exacerbation rates

Current tools for recording chronic obstructive pulmonary disease (COPD) exacerbations are limited and often lack validity testing. We assessed the validity of an automated telephonic exacerbation assessment system (TEXAS) and compared its outcomes with existing tools. Over 12 months, 86 COPD patients (22.1% females; mean age 66.5 yrs; mean post-bronchodilator forced expiratory volume in 1 s 53.4% predicted) were called once every 2 weeks by TEXAS to record changes in respiratory symptoms, unscheduled healthcare utilisation and use of respiratory medication. The responses to TEXAS were validated against exacerbation-related information collected by observations made by trained research assistants during home visits. No care assistance was provided in any way. Diagnostic test characteristics were estimated using commonly used definitions of exacerbation. Detection rates, compliance and patient preference were assessed, and compared with paper diary cards and medical record review. A total of 1,824 successful calls were recorded, of which 292 were verified by home visits (median four calls per patient, interquartile range three to five calls per patient). Independent of the exacerbation definition used, validity was high, with sensitivities and specificities between 66% and 98%. Detection rates and compliance differed extensively between the different tools, but were highest with TEXAS. Patient preference did not differ. TEXAS is a valid tool to assess COPD exacerbation rates in prospective clinical studies. Using different tools to record exacerbations strongly affects exacerbation occurrence rates.     

Clinician vs mathematical statistical models: which is better at predicting an abnormal chest radiograph finding in injured patients?

Objective

The purpose of this study was to determine if statistical models for prediction of chest injuries would outperform the clinician's (MD) ability to identify injured patients at risk for a thoracic injury diagnosed by chest radiograph (CXR).

Design

A prospective observational study was done during a 12-month period.

Setting

The study was conducted in a level I trauma center.

Patients

Injured patients meeting trauma team activation criteria were enrolled to the study.

Interventions

Physical examination findings by a clinician were interpreted and CXR was performed.

Outcome measures

The accuracy of 2 mathematical models is compared against the accuracy of clinician's clinical judgment in predicting an injury by CXR. Two newly constructed multivariate models, binary logistic regression (LR) and classification and regression tree (CaRT) analysis, are compared to previously published data of clinician clinical assessment of probability of thoracic injury identified by CXR.

Results

Data for 757 patients were analyzed. Classification and regression tree analysis developed a stepwise decision tree to determine which signs/symptoms were indicative of an abnormal CXR finding.The sensitivity (CaRT, 36.6%; LR, 36.3%; MD, 58.7%), specificity (CaRT, 98.3%; LR, 98.2%; MD, 96.4%), and error rates (CaRT, 0.93; LR, 0.94; MD, 0.82) show that the mathematical decision aids are less sensitive and risk more misclassification compared to clinician judgment in predicting an injury by CXR.

Conclusion

Clinician judgment was superior to mathematical decision aids for predicting an abnormal CXR finding in injured patients with chest trauma.     

Phosphoproteomic Analysis Reveals Regulatory Mechanisms at the Kidney Filtration Barrier

Diseases of the kidney filtration barrier are a leading cause of ESRD. Most disorders affect the podocytes, polarized cells with a limited capacity for self-renewal that require tightly controlled signaling to maintain their integrity, viability, and function. Here, we provide an atlas of in vivo phosphorylated, glomerulus-expressed proteins, including podocyte-specific gene products, identified in an unbiased tandem mass spectrometry–based approach. We discovered 2449 phosphorylated proteins corresponding to 4079 identified high-confidence phosphorylated residues and performed a systematic bioinformatics analysis of this dataset. We discovered 146 phosphorylation sites on proteins abundantly expressed in podocytes. The prohibitin homology domain of the slit diaphragm protein podocin contained one such site, threonine 234 (T234), located within a phosphorylation motif that is mutated in human genetic forms of proteinuria. The T234 site resides at the interface of podocin dimers. Free energy calculation through molecular dynamic simulations revealed a role for T234 in regulating podocin dimerization. We show that phosphorylation critically regulates formation of high molecular weight complexes and that this may represent a general principle for the assembly of proteins containing prohibitin homology domains.The kidney filter consists of three layers: fenestrated endothelial cells, the glomerular basement membrane, and podocytes.¹ Damage to any of these compartments becomes clinically evident as proteinuria and the development of kidney disease.² Of particular importance for the regulation of podocyte biology through signaling is the slit diaphragm, a specialized intercellular junction that bridges the 40-nm gap in between foot processes of neighboring podocytes. It also serves as a signaling platform regulating podocyte function. Mutations in genes encoding for components of the slit diaphragm, such as nephrin,³ podocin,⁴ CD2AP,⁵ and TRPC6,^6,7 are important causes of genetic forms of proteinuria. Alteration of these proteins results in defective signaling causing podocyte dysfunction, progressive glomerulosclerosis, and kidney failure. The slit diaphragm protein complex is a lipid-multiprotein supercomplex.⁸ Of central importance to the integrity and function of the protein complex is the prohibitin homology (PHB) domain protein podocin,⁹ which forms multimeric complexes and is required to control signal transduction through associated transmembrane proteins.^10,11Signaling processes governing podocyte function, integrity, and survival largely depend on signaling processes involving phosphorylation.^12,13 Comprehensive analyses of the signaling events in podocytes in vivo have been hampered by the fact that interference with these signaling cascades by genetic deletion often results in massively disrupted and dysfunctional podocytes. One of the primary aims of this study was to use phosphoproteomics to analyze thousands of phosphorylation sites in native murine glomeruli within single samples. Within this study, we show that this approach allows the introduction of new concepts into signaling processes at the kidney filtration barrier.     

Chronic respiratory conditions in a cohort of metropolitan fire-fighters: associations with occupational exposure and quality of life

Objectives

To assess the prevalence of chronic respiratory conditions in metropolitan fire-fighters and to study associations between occupational exposure, use of respiratory protection and health-related quality of life (HRQoL) in fire-fighters with and without chronic respiratory conditions.

Methods

Cross-sectional cohort analysis: Respiratory symptoms, medical conditions, occupational tasks and exposures and consistency of using respiratory protection were inquired by questionnaire. The SF12^®V2 Health Survey was used to measure physical (PCS-12) and mental (MCS-12) HRQoL. Fire-fighters were categorised in subgroups: asthma; COPD/emphysema/chronic bronchitis; no chronic respiratory conditions; and as being ‘not involved’ or ‘involved’ in fire-fighting tasks, the latter further categorised as ‘consistent’ or ‘inconsistent’ use of respiratory protection. PCS-12 and MCS-12 scores were compared between subgroups and categories using linear regression.

Results

Five hundred and seventy fire-fighters were analysed, 24 (4 %) fulfilled the criteria for asthma, 39 (7 %) for COPD/emphysema/chronic bronchitis. Fire-fighters with asthma were older than those in the other two subgroups and had been employed in the fire service longer. Respiratory subgroups did not differ in their involvement in fire-fighting tasks. Ninety-one percent of fire-fighters reported relevant occupational exposure in the past year. Mean PCS-12 scores for fire-fighters with no chronic respiratory conditions, asthma and COPD/emphysema/bronchitis were 52.0 (SD 6.9), 47.0 (8.5) and 48.1 (9.4). For PCS-12 (but not for MCS-12), interaction between having a chronic respiratory condition and inconsistent use of respiratory protection during fire knockdown was observed (p < 0.001).

Conclusions

Ten percent of metropolitan fire-fighters reported underlying chronic respiratory conditions. Presence of such a condition in combination with suboptimal protection from inhaled exposures may lead to poorer physical HRQoL.     

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain–containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein–coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.