Publications

OBJECTIVE

Inflammation is a potential mechanism to explain the accelerated atherosclerosis observed in HIV- and hepatitis C virus (HCV)-infected persons. We evaluated C-reactive protein (CRP) in HIV-infected and HIV/HCV-coinfected individuals in the era of effective antiretroviral (ARV) therapy.

DESIGN

Cross-sectional study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort and controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study.

METHODS

CRP levels were measured in 1135 HIV-infected participants from the FRAM cohort and 281 controls from the CARDIA study. The associations of HIV and HIV/HCV infection with CRP levels were estimated by multivariable linear regression.

RESULTS

Compared with controls, HIV monoinfection was associated with an 88% higher CRP level in men (P < 0.0001) but with no difference in women (5%; P = 0.80) in multivariate analysis. CRP levels were not associated with ARV therapy, HIV RNA level, or CD4 cell count. Compared with controls, HIV/HCV coinfection was associated with a 41% lower CRP level in women (P = 0.012) but with no difference in men (+4%; P = 0.90). Among HIV-infected participants, HCV coinfection was associated with 50% lower CRP levels after multivariable analysis (P < 0.0001) in men and women. Greater visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were strongly associated with CRP levels. Among HIV-infected participants, CRP levels were 17% (P < 0.001) and 21% (P = 0.002) higher per doubling of VAT and SAT; among controls, CRP levels were 34% (P < 0.001) and 61% (P = 0.009) higher, respectively.

CONCLUSIONS

In the absence of HCV coinfection, HIV infection is associated with higher CRP levels in men. HCV coinfection is associated with lower CRP levels in men and women.

Described as the body's largest organ, the skin is strategically located at the interface with the external environment where it has evolved to detect, integrate and respond to a diverse range of stressors. A flurry of recent findings has established the skin as an important peripheral (neuro)endocrine organ that is tightly networked to central stress axes. This capability is contributing to the maintenance of body homeostasis, and in this way could be harnessed for therapeutic strategies.

OBJECTIVE

Hepatic ischemia-reperfusion can be associated with acute lung injury. Alveolar epithelial type II cells (ATII) play an important role in maintaining lung homeostasis in acute lung injury.

DESIGN

To study potentially new mechanisms of hepatic ischemia-reperfusion-induced lung injury, we examined how liver ischemia-reperfusion altered the proteome of ATII.

SETTING

Laboratory investigation.

SUBJECTS

Spontaneously breathing male Zucker rats.

INTERVENTIONS

Rats were anesthetized with isoflurane. The vascular supply to the left and medial lobe of the liver was clamped for 75 mins and then reperfused. Sham-operated rats were used as controls. After 8 hrs, rats were killed.

MEASUREMENTS AND MAIN RESULTS

Bronchoalveolar lavage and differential cell counts were performed, and tumor necrosis factor-alpha and cytokine-induced neutrophil chemotactic factor-1 in plasma were determined by enzyme-linked immunosorbent assay. ATII were isolated, lysed, tryptically digested, and labeled using isobaric tags (iTRAQ). The samples were fractionated by cation exchange chromatography, separated by high-performance liquid-chromatography, and identified using electrospray tandem mass spectrometry. Spectra were interrogated and quantified using ProteinProspector. Quantitative proteomics provided quantitative data for 94 and 97 proteins in the two groups. Significant changes in ATII protein content included 30% to 40% increases in adenosine triphosphate synthases, adenosine triphosphate/adenosine diphosphate translocase, and catalase (all p < .001). Following liver ischemia-reperfusion, there was also a significant increase in the percentage of neutrophils in bronchoalveolar lavage (48% +/- 26%) compared with sham-operated controls (5% +/- 3%) (p < .01), and plasma tumor necrosis factor-alpha levels were also significantly increased.

CONCLUSIONS

The proteins identified by quantitative proteomics indicated significant changes in moderators of cell metabolism and host defense in ATII. These findings provide new insights into possible mechanisms responsible for hepatic ischemia-reperfusion-related acute lung injury and suggest that ATII cells in the lung sense and respond to hepatic injury.

OBJECTIVE

Glucocorticoid (GC) excess induces alterations in bone metabolism that weaken bone structure and increase fracture risk. The aim of this study was to identify genes associated with bone metabolism in GC-treated mice, by performing a microarray analysis.

METHODS

Long bones from mice exposed to GC excess were collected after 0, 7, 28, and 56 days of treatment, to measure bone microarchitecture and extract RNA for microarray analyses.

RESULTS

Bone loss in this animal model was confirmed by changes in bone turnover markers as well as bone architecture, as measured by microfocal computed tomography. GC excess induced an early up-regulation of genes involved in osteoclast activation, function, and adipogenesis, which peaked on day 7. The expression of genes associated with osteoclast cytoskeletal reorganization and genes associated with matrix degradation peaked on day 28. On day 28 and day 56, the expression of genes associated with osteoblast activation and maturation was decreased from baseline, while the expression of Wnt antagonists was increased. In addition, the expression of genes expressed in osteocytes associated with bone mineralization was significantly higher at the later time points, day 28 and day 56. Reverse transcription-polymerase chain reaction confirmed the results of microarray analysis in selected genes.

CONCLUSION

GC excess is associated with early activation of genes associated with osteoclastogenesis and adipogenesis and a later suppression of genes associated with osteogenesis and mineralization. Novel interventions with agents that modulate either Wnt signaling or mineralization may be effective in GC-induced osteoporosis.

STUDY DESIGN

The effect of N-acetylcysteine administration intravenously before hemilaminectomy surgery on neurologic outcome and 15F 2t isoprostane excretion in dogs was examined in a blinded, placebo-controlled trial.

OBJECTIVE

To determine the effect of N-acetylcysteine administration on urinary 15F 2t isoprostane excretion and neurologic outcome following hemilaminectomy for intervertebral disc disease.

SUMMARY OF BACKGROUND DATA

Oxidative stress is a mediator of secondary injury to the spinal cord following trauma. Acute intervertebral disc disease is associated with increased oxidative damage in dogs. N-acetylcysteine has preserved neurologic function following experimental spinal cord injury.

METHODS

Seventy dogs with naturally occurring acute intervertebral disc disease were administered either with saline placebo or N-acetylcysteine intravenously before hemilaminectomy surgery. Serial neurologic examinations were performed before and 1, 2, 7, 14, and 42 days following treatment. Urinary excretion of 15F 2t isoprostane excretion was determined before treatment and 1 hour after surgery.

RESULTS

Analysis of subjective data did not reveal any significant effect of N-acetylcysteine on neurologic outcome or rate of improvement of neurologic score in the 42 days following treatment. Urinary 15F 2t isoprostane excretion was not significantly different between treatment groups (P > 0.05).

CONCLUSION

N-acetylcysteine intravenously before hemilaminectomy has no effect on urinary 15F 2t isoprostane excretion or neurologic outcome. Treatment of dogs with the antioxidant N-acetylcysteine before hemilaminectomy, while not detrimental, does not affect neurologic outcome in the 42 days following surgery.

BACKGROUND

National asthma guidelines recommend that patients with persistent asthma regularly use an inhaled corticosteroid (ICS) in addition to as-needed albuterol, yet recent debates question whether this combination is equally efficacious in all ethnicities.

OBJECTIVE

To examine the effect of ICS use on bronchodilator responsiveness to albuterol in 3 different ethnic populations.

METHODS

A cross-sectional study of 106 Mexican Americans, 246 Puerto Ricans, and 163 African Americans with physician-diagnosed persistent asthma. Asthma severity, ethnicity, and medication use were evaluated using spirometry and questionnaires. Percentage change in forced expiratory volume in 1 second (FEV) was compared in patients who used ICSs vs those who used a short-acting beta2-agonist as their only asthma medication.

RESULTS

Inhaled corticosteroid use was associated with improvements in the percentage change in FEV1 after albuterol administration in Mexican Americans (21.7%, P = .01) and Puerto Ricans (18.5%, P = .02) but not in African Americans (3.0%, P = .73).

CONCLUSIONS

Inhaled corticosteroid use is associated with augmented bronchodilator responsiveness to albuterol in Mexican Americans and Puerto Ricans, but not in African Americans, with persistent asthma. This underscores the need for an improved understanding of ethnic-specific drug-drug interactions, particularly in those subgroups experiencing the highest burden of asthma morbidity and mortality in the United States.

Genetic association studies can be used to identify factors that may contribute to disparities in disease evident across different racial and ethnic populations. However, such studies may not account for potential confounding if study populations are genetically heterogeneous. Racial and ethnic classifications have been used as proxies for genetic relatedness. We investigated genetic admixture and developed a questionnaire to explore variables used in constructing racial identity in two cohorts: 50 African Americans and 40 Nigerians. Genetic ancestry was determined by genotyping 107 ancestry informative markers. Ancestry estimates calculated with maximum likelihood estimation were compared with population stratification detected with principal components analysis. Ancestry was approximately 95% west African, 4% European, and 1% Native American in the Nigerian cohort and 83% west African, 15% European, and 2% Native American in the African American cohort. Therefore, self-identification as African American agreed well with inferred west African ancestry. However, the cohorts differed significantly in mean percentage west African and European ancestries (P < 0.0001) and in the variance for individual ancestry (P < or = 0.01). Among African Americans, no set of questionnaire items effectively estimated degree of west African ancestry, and self-report of a high degree of African ancestry in a three-generation family tree did not accurately predict degree of African ancestry. Our findings suggest that self-reported race and ancestry can predict ancestral clusters but do not reveal the extent of admixture. Genetic classifications of ancestry may provide a more objective and accurate method of defining homogenous populations for the investigation of specific population-disease associations.

It is important to understand how knowledge of genomics can be translated from research into clinical practice and health policies. This review examines existing evidence on three key factors in the adoption of personalized medicine: utilization, preferences, and economic value, using two cancer examples: HER2/neu antigen testing and trastuzumab (Herceptin) treatment and genetic testing for Lynch syndrome. Our findings highlight areas in which additional research is required to build an evidence base addressing utilization of, preferences for, and the potential costs and benefits of personalized medicine. Major challenges include a lack of linked data, the need for relevant research frameworks and methodologies, and the clinical complexities of genomic-based diagnostics and treatment.

Most aging patients have multiple concurrent health problems. However, most current medical practice and research are largely based on a single disease model, failing to account for the simultaneous presence of multiple conditions. Clinical trials, practice guidelines, and pay-for-performance schemes may thus have limited applicability in older patients. We report on the 2005 American Geriatrics Society/National Institute on Aging conference on Comorbid Disease and Multiple Morbidity in an Aging Society. The two-day conference was designed to clarify concepts of multiple concurrent health conditions; explore implications for causation, health, function and systems of care; identify important gaps in knowledge; and propose useful next steps. While the conference did not attempt to standardize terminology, we here develop the concepts of comorbidity, multiple morbidity, condition clusters, physiological health, and overall health as they were used. The present report also summarizes sessions addressing the societal burden of comorbidity, and clinical research on particular diseases within the framework of comorbidity concepts. Next steps recommended include continuing clarification of terms and conceptual approaches, consideration of developing and improving measures, as well as developing new research directions.