Publications

BACKGROUND

Despite improvements in survival with human immunodeficiency virus (HIV) infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated with the development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals and compare ESRD risk by estimated glomerular filtration rate (eGFR) and proteinuria levels.

STUDY DESIGN

Retrospective cohort study.

SETTING & PARTICIPANTS

22,156 HIV-infected veterans without pre-existing ESRD receiving health care in the Veterans' Affairs medical system between 1996 and 2004.

PREDICTORS

Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin <3.5 mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and eGFR were identified using the Veterans' Affairs electronic record system.

OUTCOMES

ESRD was ascertained by the US Renal Data System.

RESULTS

366 cases of ESRD occurred, corresponding to 3 cases/1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5-2.4), diabetes (HR, 1.7; 95% CI, 1.3-2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7-2.7) were associated independently with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/μL (HR, 1.5; 95% CI, 1.2-2.0), HIV viral load ≥30,000 copies/mL (HR, 2.0; 95% CI, 1.5-2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5-2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8-2.5). Compared with persons without chronic kidney disease, defined as eGFR >60 mL/min/1.73 m(2) and no proteinuria, lower eGFR and higher proteinuria categories were associated jointly with exponentially higher ESRD rates, ranging from 6.6 events/1,000 person-years for persons with urine protein excretion of 30-100 mg/dL and eGFR >60 mL/min/1.73 m(2) to 193 events/1,000 person-years for persons with urine protein excretion ≥300 mg/dL and eGFR <30 mL/min/1.73 m(2).

LIMITATIONS

Results may not be generalizable to female and nonveteran populations.

CONCLUSIONS

In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for chronic kidney disease staging is most effective for stratifying the risk of ESRD.

The alveolar epithelium serves as a barrier to the entry of potential respiratory pathogens. Alveolar Type II (TII) cells have immunomodulatory functions, but whether Type I (TI) cells, which comprise approximately 95% of the alveolar epithelium, also play a role in immunity is unknown. Because the renin-angiotensin system (RAS) is emerging as an important mediator of inflammation, and angiotensin-converting enzyme 2 (ACE2), an element of the RAS, has been implicated in lung injury, we hypothesize that TI cells can produce cytokines in response to LPS stimulation, and that this inflammation can be modulated by the RAS. Alveolar TI cells were isolated from adult Sprague-Dawley rat lungs that had been injured with an intratracheal instillation of LPS. PCR was performed to determine whether TI cells expressed transcripts for TNF-α, IL-6, or IL-1β at baseline and after lung injury. Immunocytochemical and protein analysis detected angiotensin II (Ang II) and ACE2, as well as angiotensin Type 1 receptor (AT1R) and Type 2 receptor (AT2R), in TI cells. To separate cell-specific responses, primary TI cells were isolated, cultured, and exposed to LPS, Ang II, or specific inhibitors of AT1R or AT2R. Cytokine production was assayed by ELISA. LPS stimulated the production of all cytokines, whereas ACE2 and losartan, an AT1R inhibitor, blocked elements of the LPS-induced cytokine response. Primary TI cells produce cytokines when treated with LPS, contain important components of the RAS, and can modulate LPS-induced cytokine production via the RAS, suggesting a role for TI cells in the innate immune response of the lung.

Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.

The function of populations of nociceptors in muscle pain syndromes remain poorly understood. We compared the contribution of two major classes, isolectin B4-positive (IB4(+)) and IB4-negative (IB4(-)) nociceptors, in acute and chronic inflammatory and ergonomic muscle pain. Baseline mechanical nociceptive threshold was assessed in the gastrocnemius muscle of rats treated with IB4-saporin, which selectively destroys IB4(+) nociceptors. Rats were then submitted to models of acute inflammatory (intramuscular carrageenan)- or ergonomic intervention (eccentric exercise or vibration)-induced muscle pain, and each of the three models also evaluated for the transition from acute to chronic pain, manifest as prolongation of prostaglandin E2 (PGE(2))-induced hyperalgesia, after recovery from the hyperalgesia induced by acute inflammation or ergonomic interventions. IB4-saporin treatment did not affect baseline mechanical nociceptive threshold. However, compared to controls, IB4-saporin treated rats exhibited shorter duration mechanical hyperalgesia in all three models and attenuated peak hyperalgesia in the ergonomic pain models. And, IB4-saporin treatment completely prevented prolongation of PGE(2)-induced mechanical hyperalgesia. Thus, IB4(+) and IB4(-) neurons contribute to acute muscle hyperalgesia induced by diverse insults. However, only IB4+ nociceptors participate in the long term consequence of acute hyperalgesia.

Calsequestrin is the most abundant Ca-binding protein of the specialized endoplasmic reticulum found in muscle, the sarcoplasmic reticulum (SR). Calsequestrin binds Ca with high capacity and low affinity and importantly contributes to the mobilization of Ca during each contraction both in skeletal and cardiac muscle. Surprisingly, mutations in the gene encoding the cardiac isoform of calsequestrin (Casq2) have been associated with an inherited form of ventricular arrhythmia triggered by emotional or physical stress termed catecholaminergic polymorphic ventricular tachycardia (CPVT). Despite normal cardiac contractility and normal resting ECG, CPVT patients present with a high risk of sudden death at a young age. Here, we review recent new insights regarding the role of calsequestrin in genetic and acquired arrhythmia disorders. Mouse models of CPVT have shed light on the pathophysiological mechanism underlying CPVT. Casq2 is not only a Ca-storing protein as initially hypothesized, but it has a far more complex function in Ca handling and regulating SR Ca release channels. The functional importance of Casq2 interactions with other SR proteins and the importance of alterations in Casq2 trafficking are also being investigated. Reports of altered Casq2 trafficking in animal models of acquired heart diseases such as heart failure suggest that Casq2 may contribute to arrhythmia risk beyond genetic forms of Casq2 dysfunction.

BACKGROUND

Electronic health record (EHR) adoption is a national priority in the USA, and well-designed EHRs have the potential to improve quality and safety. However, physicians are reluctant to implement EHRs due to financial constraints, usability concerns, and apprehension about unintended consequences, including the introduction of medical errors related to EHR use. The goal of this study was to characterize and describe physicians' attitudes towards three consequences of EHR implementation: (1) the potential for EHRs to introduce new errors; (2) improvements in healthcare quality; and (3) changes in overall physician satisfaction.

METHODS

Using data from a 2007 statewide survey of Massachusetts physicians, we conducted multivariate regression analysis to examine relationships between practice characteristics, perceptions of EHR-related errors, perceptions of healthcare quality, and overall physician satisfaction.

RESULTS

30% of physicians agreed that EHRs create new opportunities for error, but only 2% believed their EHR has created more errors than it prevented. With respect to perceptions of quality, there was no significant association between perceptions of EHR-associated errors and perceptions of EHR-associated changes in healthcare quality. Finally, physicians who believed that EHRs created new opportunities for error were less likely be satisfied with their practice situation (adjusted OR 0.49, p=0.001).

CONCLUSIONS

Almost one third of physicians perceived that EHRs create new opportunities for error. This perception was associated with lower levels of physician satisfaction.