Publications

BACKGROUND AND METHODS

HIV-infected patients receiving antiretroviral therapy often develop changes in body fat distribution; the dominant change is reduction in sc adipose tissue (SAT). Because adipose tissue makes important hormones involved in whole-body energy metabolism, including leptin and adiponectin, we examined plasma concentrations and their relationship to regional adiposity measured by magnetic resonance imaging in 1143 HIV-infected persons (803 men and 340 women) and 286 controls (151 men and 135 women) in a cross-sectional analysis of the FRAM study.

RESULTS

Total and regional adiposity correlated positively with leptin levels in HIV-infected subjects and controls (P < 0.0001). In controls, total and regional adiposity correlated negatively with adiponectin. In HIV-infected subjects, adiponectin was not significantly correlated with total adiposity, but the normal negative correlation with visceral adipose tissue and upper trunk SAT was maintained. However, leg SAT was positively associated with adiponectin in HIV-infected subjects. Within the lower decile of leg SAT for controls, HIV-infected subjects had paradoxically lower adiponectin concentrations compared with controls (men: HIV 4.1 microg/ml vs. control 7.5 microg/ml, P = 0.009; women: HIV 7.8 microg/ml vs. control 11.6 microg/ml, P = 0.037). Even after controlling for leg SAT, exposure to stavudine was associated with lower adiponectin, predominantly in those with lipoatrophy.

CONCLUSION

The normal relationships between adiponectin levels and total and leg adiposity are lost in HIV-infected subjects, possibly due to changes in adipocyte function associated with HIV lipodystrophy, whereas the inverse association of adiponectin and visceral adipose tissue is maintained. In contrast, the relationship between adiposity and leptin levels appears similar to controls and unaffected by HIV lipodystrophy.

Genetic variation in ABCB1, encoding P-glycoprotein (P-gp), is a potential cause of interindividual variation in drug response. Numerous studies have focused on the effects of coding region variants on P-gp expression and function, whereas few noncoding region variants have been investigated. The 3'-untranslated region (UTR) regulates mRNA levels or stability via RNA-protein interactions with mRNA degradation machinery. mRNA stability is a key regulatory step controlling ABCB1 mRNA expression that ultimately affects P-gp levels and function. We hypothesized that ABCB1 3'-UTR polymorphisms alter mRNA stability by disrupting RNA-protein interactions. An ethnically diverse panel of DNA samples was sequenced to identify 3'-UTR polymorphisms and determine allele frequencies. The three most common variants, along with reference ABCB1, were stably expressed in cells in order to measure mRNA half-life. The calculated half-life for ABCB1 reference in HEK293 cells was 9.4 +/- 1.3 h and was similar to that estimated for the 3'-UTR variants. Endogenous ABCB1 mRNA decay was similar in lymphoblastoid cell lines carrying 3'-UTR variant and reference alleles. Although the examined ABCB1 3'-UTR variants have no effect on ABCB1 mRNA stability, these data represent one of the first attempts to determine the influence of genetic variation in UTRs on ABCB1 mRNA levels.

Post transplantation constrictive bronchiolitis (PTCB) is the most common pulmonary complication among long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT). It is a late manifestation of GVHD. Its treatment with high-dose systemic corticosteroids and other immunosuppressive regimens is associated with multiple side effects. Topical corticosteroids are used for the treatment of other manifestations of GVHD to minimize these side effects. We conducted a retrospective analysis of a series of adult patients to evaluate the efficacy of high-dose inhaled corticosteroids in the treatment of PTCB. Seventeen patients with new-onset airflow obstruction were diagnosed with PTCB. Their forced expiratory volume in 1 s (FEV1) declined from a median of 84% (range, 56-119) before HSCT to 53% (26-82) after HSCT. All patients received inhaled fluticasone propionate 500-940 microg two times daily. Symptoms of airway obstruction improved and FEV1 stabilized 3-6 months after treatment. We conclude that high-dose inhaled corticosteroids may be effective in the treatment of PTCB and propose a plausible mechanism of its action. A prospective evaluation of its efficacy is warranted.

BACKGROUND

Evidence suggests that fatigue may be a greater problem for cancer survivors than people without cancer. The present study sought to determine whether fatigue was greater in women who had completed treatment for early-stage breast cancer relative to a demographically matched comparison group of women with no cancer history.

METHODS

As part of a larger study, women with stage 0-II breast cancer were recruited before the start of chemotherapy and radiotherapy (n = 100) or radiotherapy only (n = 121). Fatigue was assessed at the end of treatment and 2, 4, and 6 months later. An age- and geographically matched sample of women with no history of cancer was recruited and assessed for comparison purposes.

RESULTS

Relative to comparison subjects, breast cancer survivors reported more days of fatigue in the past week at all 4 study assessments (P < .05). These differences appeared to be clinically meaningful in that a greater percentage of patients than nonpatients earned scores in the abnormal range on this measure at each assessment (P < .05). Additional analyses indicated that differences in fatigue between patients and comparison subjects were attributable primarily to heightened fatigue in women who received both chemotherapy and radiotherapy.

CONCLUSIONS

Findings suggest that fatigue is a greater problem for breast cancer survivors in the 6 months after completion of chemotherapy than for women with no cancer history. Future research should include longer-term follow-up to determine the persistence of fatigue in this population of survivors.

The Center for Disease Control and Prevention (CDC) recommends screening and surveillance of dialysis patients for hepatitis C virus (HCV), but there are limited data on the real life performance of confirmatory tests. We performed a cost-identification analysis of CDC recommendations using a large database of dialysis subjects. Screening and surveillance were performed according to CDC guidelines: enzyme immunoassay (EIA) testing upon entry then biannual surveillance. All positive EIA tests were confirmed by either polymerase chain reaction (PCR) or radioimmunoblot assay (RIBA). A total of 12,563 patients were tested from 1997 to 2004. By EIA, the prevalence of HCV was 8.4% and annual incidence was 0.96%. The prevalence after confirmation by RIBA and PCR was 5.8% and 4.8%, respectively. The annual incidence of hepatitis C confirmed by RIBA and PCR was 0.13% and 0.084%, respectively. Using Medicare reimbursement, the cost to screen and confirm one case of hepatitis C by RIBA was $372 versus $503 by PCR. However, the cost to identify an incident infection increased to $30,594 by RIBA and $48,622 by PCR. In the sensitivity analysis, the cost of identifying incident HCV infection dropped by 50% when the surveillance interval was extended to 1 year or when seroconversion rates for EIA occurred at 2%. Due to high surveillance cost, further studies are necessary to determine optimal intervals and settings.