Publications

OBJECTIVE

Both peripheral fat loss and central fat gain have been reported in HIV infection. Which changes are specific to HIV were determined by comparison with control subjects and the associations among different adipose tissue depots were determined.

METHODS

Cross-sectional analysis of HIV-positive and control men from the study of Fat Redistribution and Metabolic Change in HIV Infection. Lipoatrophy or lipohypertrophy was defined as concordance between participant report of change and examination. Regional adipose tissue volume was measured by magnetic resonance imaging (MRI).

RESULTS

HIV-positive men reported more fat loss than controls in all peripheral and most central depots. Peripheral lipoatrophy was more frequent in HIV-positive men than in controls (38.3% vs. 4.6%, P < 0.001), whereas central lipohypertrophy was less frequent (40.2% vs. 55.9%, P = 0.001). Among HIV-positive men, the presence of central lipohypertrophy was not positively associated with peripheral lipoatrophy (odds ratio = 0.71, CI: 0.47 to 1.06, P = 0.10). On MRI, HIV-positive men with clinical peripheral lipoatrophy had less subcutaneous adipose tissue (SAT) in peripheral and central sites and less visceral adipose tissue (VAT) than HIV-positive men without peripheral lipoatrophy. HIV-positive men both with and without lipoatrophy had less SAT than controls, with legs and lower trunk more affected than upper trunk. Use of the antiretroviral drugs stavudine or indinavir was associated with less leg SAT but did not appear to be associated with more VAT; nevirapine use was associated with less VAT.

CONCLUSION

Both peripheral and central subcutaneous lipoatrophy was found in HIV infection. Lipoatrophy in HIV-positive men is not associated with reciprocally increased VAT.

Mutations in the Melanocortin 4 receptor are implicated in 1-6% of early onset or severe adult obesity cases. Most of the patients carry heterozygous missense mutations. Arguments for the pathogenicity of these mutations are based on the frequency of rare functionally relevant non-synonymous mutations in severely obese children and adults versus non-obese controls, the segregation of mutations with obesity in the family of the probands (although with incomplete penetrance) and the relevant functional defects described for these mutations. We have developed new assays to study the functional characteristics of these obesity-associated MC4R mutations. Systematic and comparative functional study of over 50 different obesity-associated mutations suggests that multiple functional alterations contribute to their pathogenicity. These studies also lead to new insights into the structure-function relationship of MC4R, provide novel hypotheses for the genetic predisposition to common obesity in humans and allow the development of new molecular tools for studying the physiological role of GPCRs.

BACKGROUND

We examined the link between functioning and psychological status among persons with chronic obstructive pulmonary disease (COPD), using measures of both general functional status and performance of life activities.

METHODS

334 persons with COPD were interviewed by telephone. Functioning was assessed with two measures of difficulty with specific types of activities (self-care, recreational activities/hobbies) and a general measure of functional status (SF-12 Physical Component Score (PCS)).

RESULTS

About 16.2% of the sample had SF-12 Mental Component Score (MCS) scores indicative of psychological distress (MCS < 35). In separate regression models, difficulty with self-care and recreational activities was associated with an increased likelihood of distress (self-care: OR=2.9, 95%CI 1.3, 6.6; recreation: OR=7.5 [2.4, 23.7]), while PCS scores were not. In a model including all three predictors, difficulty with recreation was strongly associated with distress (OR=7.7 [2.1, 29.2]), difficulty with self-care was less strongly associated with distress (OR=2.1 [0.8, 5.5]), and PCS did not contribute significantly to the predictive ability of the model. However, low functioning as measured by the PCS was a significant risk factor for difficulty performing activities.

CONCLUSIONS

Measures of activity difficulty were independent predictors of psychological distress, while general physical function was not. Poor general physical function was a risk factor for activity difficulties, suggesting an indirect relationship between low PCS and psychological distress, with activity difficulties as the intermediate variable.

OBJECTIVE

To investigate breast cancer risk according to metabolizing genes polymorphisms in older women.

METHODS

A subset (43.8%) of 4248 older, white women from the Study of Osteoporotic Fractures (SOF) were genotyped for the catechol-O-methyltransferase (COMT) Val108Met polymorphism and the CYP1A1*2C locus. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between genotypes and breast cancer while controlling for potential confounders.

RESULTS

During a mean follow up of 12.4 years, 252 women (5.9%) developed breast cancer. The HR (95% CI) for breast cancer was 1.24 (0.87-1.75) for COMT(Val/Met) and 1.35 (0.93-1.97) for COMT(Met/Met). No interactions with lifestyle and reproductive factors were found. The HR associated with the CYP1A1*2C Val allele was 0.80 (0.46, 1.39) with little evidence for interactions with lifestyle or reproductive factors.

CONCLUSIONS

Among older white women, neither the COMT Val108/158Met polymorphism nor the CYP1A*2C Val allele plays a major role in breast cancer risk either alone or in combination with lifestyle and reproductive factors.

OBJECTIVES

ABCB1 (multidrug resistance 1 polypeptide, MDR1, Pgp) is a multispecific efflux transporter of drugs and xenobiotics. Among numerous polymorphisms in human ABCB1, the synonymous SNP 3435C > T has been associated with decreased mRNA and protein levels, via unknown mechanisms.

METHODS

To search for cis-acting polymorphism affecting transcription or mRNA processing, we used 3435C > T as a marker single nucleotide polymorphism (SNP), for measuring differences in allelic mRNA expression. Ratios of allelic abundance in genomic DNA and mRNA (after conversion to cDNA) were measured quantitatively with a primer extension assay, in human liver samples.

RESULTS

mRNA expression of the 3435C allele was significantly higher than that of the 3435T allele (3435C/3435T ratios ranging from 1.06-1.61). Cotransfection of equal amounts of ABCB1 expression plasmids containing 3435C or 3435T also revealed higher 3435C mRNA expression. Increasing 3435C/3435T ratios after cessation of transcription indicated that the 3435C > T substitution decreases mRNA stability. 3435C > T is in strong linkage disequilibrium with two other coding SNPs (1236C > T and 2677G > T) forming two abundant haplotypes (ABCB1*1 and ABCB1*13). Transfection of all possible combinations of these three SNPs demonstrated that only 3435T is associated with lower mRNA levels. Calculations of mRNA folding, using Mfold, suggested an effect on mRNA secondary structure.

CONCLUSIONS

the abundant 3435C > T SNP appears to be a main factor in allelic variation of ABCB1 mRNA expression in the liver, by changing mRNA stability.

Since the first minimally invasive colon resection 15 years ago, laparoscopic colectomy has been implemented as techniques have evolved. Like the laparoscopic approach for other operations, minimally invasive colectomy has potential benefits of improved short-term outcomes. Questions have been raised, however, regarding its use for colorectal cancer resection. Until recently, it was unclear whether minimally invasive surgery for colonic malignancies would achieve adequate oncologic resection. This review provides an overview of laparoscopic colectomy and techniques and examines recent data from randomized, controlled trials that report the short- and long-term outcomes after laparoscopic colectomy for cancer.

Various reports have demonstrated the importance of small airway inflammation in the development of airflow limitation and progression of COPD. This hypothesis proposes that the pathogenesis of COPD mirrors a chronic inhalational dust-induced disease. The putative inorganic dust in cigarette smoke is aluminum silicate or kaolinite, a common component of clay soils. Kaolinite has been recovered in the alveolar macrophages of smokers and has been reported as a constituent of tobacco products. The origin of kaolinite in tobacco products remains unknown, and possible potential sources are proposed. On inhalation, kaolinite deposition in the distal lung may promote macrophage accumulation within the terminal airways leading to a respiratory bronchiolitis. In the susceptible smoker, important genetic, environmental, immunologic, and mechanical factors interact and modulate this small airway inflammation, ultimately leading to the pathologic lesion of emphysema. Further studies into the effects of kaolinite on macrophage function and the subsequent development of respiratory bronchiolitis could lead to prevention of COPD at its precursor lesion.

BACKGROUND

To date, no management approach has proven to be efficacious for the treatment of idiopathic pulmonary fibrosis (IPF). Consequently, therapeutic options remain controversial and confusing for many clinicians. We sought to formally review available evidence on treatment options for IPF and to have a diverse panel of physicians rate the "appropriateness," "inappropriateness," or "uncertainty" of some of the available therapeutic options.

METHODS

The RAND/UCLA Appropriateness Method was used to review and rate multiple clinical scenarios for the treatment of IPF. The panel was composed of nine physicians from geographically diverse areas who received a systematic review on the risks and benefits of commonly used treatments for IPF as background.

RESULTS

A total of 324 clinical scenarios were rated: 25% as appropriate; 39%, uncertain; and 36%, inappropriate. The panel disagreed about 12% of the therapy indications in the final ratings, falling from 26% in the first-round ratings.

CONCLUSIONS

Key themes emerged from the consensus process. Lacking evidence for a definitive therapy, it was considered most appropriate to enroll eligible patients in clinical trials and refer eligible patients for transplant evaluation. For patients without access to clinical trials, the committee was not unanimous regarding treatment recommendations. It was considered inappropriate for patients with a confident diagnosis of IPF to be treated with corticosteroids as the sole agent: corticosteroids should be used in conjunction with azathioprine. With progressive disease despite such combination use, there was agreement for the use of interferon gamma-1b in patients unwilling or unable to participate in available clinical trials.

In this study, we asked if a naturally occurring HIV-1 variant exists that circumvents CypA dependence in human cells. To address this issue, we sought viruses for CypA independence using Debio-025, a cyclosporine A (CsA) analog that disrupts CypA-capsid interaction. Surprisingly, viral variants from the Main group replicate even in the presence of the drug. Sequencing analyses revealed that these viruses encode capsid substitutions within the CypA-binding site (V86P/H87Q/I91V/M96I). When we introduced these substitutions into viruses that normally rely on CypA for replication, these mutants no longer depended on CypA, suggesting that naturally occurring capsid substitutions obviate the need for CypA. This is the first demonstration that isolates from the Main group naturally develop CypA-independent strategies to replicate in human cells. Surprisingly, we found that these capsid substitutions render HIV-1 capable of infecting Owl monkey (OMK) cells that highly restrict HIV-1. OMK cell resistance to HIV-1 is mediated via TRIM-Cyp, which arose from a retrotransposition of CypA into the TRIM5 alpha gene. Interestingly, saturation experiments suggest that the Pro86/Gln87/Val91/Ile96 capsid core is "invisible" to TRIM-Cyp. This study demonstrates that specific capsid substitutions can release HIV-1 from both CypA dependence in human cells and TRIM-Cyp restriction in monkey cells.