Publications

OBJECTIVE

To examine the long-term effects of individual antiretroviral drugs on body composition among 416 persons initiating antiretroviral therapy (ART).

METHODS

In a substudy of a clinical trial of persons initiating ART, changes in body composition attributable to individual ART were examined. ARTs assessed were as follows: indinavir, ritonavir, nelfinavir, efavirenz, nevirapine, stavudine (d4T), zidovudine (ZDV), lamivudine (3TC), didanosine, and abacavir. Skinfolds and circumferences were measured at baseline and every 4 months. Mid arm, mid thigh, and waist subcutaneous tissue areas and nonsubcutaneous tissue areas were calculated. Rates of change per year of exposure to each individual ART drug were determined using multivariate longitudinal regression.

RESULTS

d4T and ZDV use was associated with losses in subcutaneous tissue area and skinfold thickness. 3TC use was associated with gains in all subcutaneous tissue areas and skinfold thickness, whereas abacavir use was associated with an increase in waist subcutaneous tissue area. Indinavir was associated with gains in waist subcutaneous tissue area, whereas indinavir, efavirenz, and nevirapine were associated with increases in upper back skinfolds. d4T use was also associated with increases in all nonsubcutaneous tissue areas; 3TC use was associated with the greatest increase in waist nonsubcutaneous tissue area.

CONCLUSION

In this prospective nonrandomized evaluation, the nucleoside reverse transcriptase inhibitors d4T and ZDV were associated with decreases in subcutaneous tissue areas, whereas 3TC use was associated with increased subcutaneous tissue areas and waist nonsubcutaneous tissue area.

Chronic prostatitis is a common disease of unclear etiology and has no specific treatment. Mice deficient in the expression of the autoimmune regulator (Aire) gene, which are defective in thymic expression of self antigens and central tolerance, develop spontaneous prostatitis. In this study, we found that Aire-deficient mice developed spontaneous B and T cell immune responses to a prostate autoantigen, seminal vesicle secretory protein 2 (SVS2), which we believe to be novel. We show that thymic expression of this self antigen was Aire dependent. Moreover, prostatitis was induced in WT mice through immunization with SVS2, demonstrating that immunity to SVS2 was sufficient to induce prostatitis. The clinical relevance of this antigen was highlighted by our observation that patients with chronic prostatitis possessed specific autoantibodies against the human SVS2-like seminal vesicle protein semenogelin. These results provide direct evidence that spontaneous chronic prostatitis is an autoimmune disease and is regulated by both central and peripheral tolerance. Moreover, SVS2 and semenogelin are among the relevant autoantigens in mice and humans, respectively.

Olfaction and nasal trigeminal chemoreception together convey an impression of the physical and chemical qualities of inspired air. "Nasal pungency" refers to the nasal trigeminal impact of inhaled air pollutants as well as spicy foods and selected medicaments. Such diverse sensations as cooling, numbness, tingling, itching, burning, and stinging are all conveyed by the trigeminal system yet are successfully differentiated in psychophysical testing, with or without concomitant olfactory information. Here we briefly review the neurobiological and psychophysical evidence for qualitative specificity in the nasal trigeminal system.

OBJECTIVE

To examine occupational risk for Chronic Obstructive Pulmonary Disease (COPD).

METHODS

We randomly recruited 233 subjects aged 55 to 75 reporting a physician's diagnosis of COPD, emphysema, or chronic bronchitis. Interviews assessed cigarette smoking and longest held job, identifying exposure to vapors, gas, dust, or fumes (VGDF). Lung function was assessed in n = 138. Comparison data were derived from a sample of referents without COPD.

RESULTS

VGDF was reported in 123 (53%) of 233 cases versus 577 (34%) of 1709 referents. VGDF was associated with COPD (Odds Ratio [OR] 2.5; 95% CI = 1.9 to 3.4); the population attributable fraction was 32%. In the lung function subset, the FEV1/FVC was <70% in 79 (57%); 35 (44%) reported VGDF associated with an OR = 1.6 (95% CI = 0.99 to 2.6) and population attributable fraction 17%.

CONCLUSIONS

These data support an important role for occupational exposures in COPD.

Patients with systemic lupus erythematosus (SLE) confront an increased risk of developing osteoporosis and fragility fractures. Traditional risk factors, such as smoking, advanced age, physical inactivity, and low weight, are partly responsible, but a number of lupus-specific risk factors may also play an important role. Chronic, systemic inflammation in patients with SLE has been proposed as a possible mechanism for osteoporosis development. Other potential risk factors include vitamin D deficiency due to sun avoidance, premature gonadal failure, and the chronic use of medications known to increase osteoporosis risk. Increased awareness of this potentially preventable condition is warranted, as early detection and treatment help optimize bone health and improve long-term outcomes in patients with SLE. This article presents recent epidemiologic data related to bone health in SLE and discusses preventative and therapeutic strategies.

OBJECTIVE

A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients.

METHODS

Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene-gene interactions were tested by using multiple linear regression analyses.

RESULTS

No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene-gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol.

CONCLUSION

Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.

OBJECTIVE

The goal of this study was to determine the effect of a genetic variant in the organic cation transporter 2 (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the antidiabetic drug, metformin.

METHODS

The uptake of metformin was performed in stably transfected HEK-293 cells expressing the empty vector (MOCK), the reference OCT2-808G, and the variant OCT2-808T. Healthy individuals with known OCT2 genotypes [14 homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, *3D)] were recruited to this study. Metformin concentrations in plasma and urine were measured by liquid chromatography-tandem mass spectrometry method. Creatinine levels were also measured in plasma and urine. Pharmacokinetic parameters were evaluated for both the groups.

RESULTS

We observed that in HEK-293 stably transfected cells, OCT2-808T had a greater capacity to transport metformin than did the reference OCT2. Metformin pharmacokinetics was characterized in 23 healthy volunteers of Caucasian and African-American ancestries. We observed that the renal clearance (CL(R)) and the net secretion (SrCL(R)) of metformin were significantly different between the volunteers heterozygous for the variant allele (808G/T), and the volunteers homozygous for the reference allele (808G/G) (P<0.005). Multivariate analysis revealed that OCT2 genotype was a significant predictor of CL(R) and SrCL(R) of metformin (P<0.01).

CONCLUSION

We conclude that genetic variation in OCT2 plays an important role in the CL(R) and SrCL(R) of metformin in healthy volunteers.

BACKGROUND

The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways.

PURPOSE

The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older.

METHODS

A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures.

RESULTS

The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response.

CONCLUSIONS

The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.