Publications

We sought to evaluate the association of urine calcium excretion (UCaE), which reflects systemic calcium absorption, with cardiovascular (CV) events and mortality in outpatients with prevalent coronary heart disease (CHD). Calcium supplementation is associated with vascular calcification and adverse CV outcomes in patients with end-stage renal disease. Recent studies have raised concern that this phenomenon may also extend to the general population. However, previous studies have assessed oral calcium intake, which correlates poorly with systemic calcium absorption. We measured UCaE from 24-hour urine collections provided by 903 outpatients who were recruited from 2000 to 2002. We used Cox proportional hazard models to evaluate the association of baseline UCaE with a primary end point of any CV event (myocardial infarction [MI], heart failure, stroke, or CV mortality). During a mean follow-up of 6 ± 3 years, 287 subjects (32%) had a CV event. After multivariate adjustment for demographics, traditional CV risk factors, and kidney function, there was no association between UCaE and the primary end point of any CV event (per 10-mg/day greater UCaE, hazard ratio 1.00, 95% confidence interval 0.98 to 1.02). Evaluation of individual CV outcomes revealed a lower rate of MI with higher UCaE (hazard ratio 0.97, 95% confidence interval 0.94 to 1.00). In conclusion, greater UCaE is not associated with higher overall CV event rates or mortality in outpatients with stable CHD. On the contrary, greater UCaE is associated with a modestly lower rate of MI. These findings suggest that greater systemic calcium absorption does not confer CV harm in outpatients with prevalent CHD.

Lichen sclerosus is a commonly misdiagnosed disease that is characterized by thinned, hypopigmented, crinkled skin that often forms a figure-eight shape around the vaginal and anal openings. We present a case of advanced lichen sclerosus in a 53-year-old female patient prescribed a nonsteroidal aromatase inhibitor after the excision of a breast cancer tumor. We present a diagnostic approach to lichen sclerosus by recognizing its common figure-eight pattern, and we review the known causes and treatment of lichen sclerosus. Research has shown that lichen sclerosus is more common in low estrogen states, and thus it is logical that aromatase inhibitors could increase a patient's risk for developing this disease. We therefore propose that all patients prescribed aromatase inhibitors undergo regular vulvo-vaginal exams to rule out lichen sclerosus and other hypoestrogen-related vulvo-vaginal problems.

BACKGROUND

Despite strong evidence for the effectiveness of anti-retroviral therapy for improving the health of women living with HIV and for the prevention of mother-to-child transmission (PMTCT), HIV persists as a major maternal and child health problem in sub-Saharan Africa. In most settings antenatal care (ANC) services and HIV treatment services are offered in separate clinics. Integrating these services may result in better uptake of services, reduction of the time to treatment initiation, better adherence, and reduction of stigma.

METHODOLOGY/PRINCIPAL FINDINGS

A prospective cluster randomized controlled trial design was used to evaluate the effects of integrating HIV treatment into ANC clinics at government health facilities in rural Kenya. Twelve facilities were randomized to provide either fully integrated services (ANC, PMTCT, and HIV treatment services all delivered in the ANC clinic) or non-integrated services (ANC clinics provided ANC and basic PMTCT services and referred clients to a separate HIV clinic for HIV treatment). During June 2009- March 2011, 1,172 HIV-positive pregnant women were enrolled in the study. The main study outcomes are rates of maternal enrollment in HIV care and treatment, infant HIV testing uptake, and HIV-free infant survival. Baseline results revealed that the intervention and control cohorts were similar with respect to socio-demographics, male partner HIV testing, sero-discordance of the couple, obstetric history, baseline CD4 count, and WHO Stage. Challenges faced while conducting this trial at low-resource rural health facilities included frequent staff turnover, stock-outs of essential supplies, transportation challenges, and changes in national guidelines.

CONCLUSIONS/SIGNIFICANCE

This is the first randomized trial of ANC and HIV service integration to be conducted in rural Africa. It is expected that the study will provide critical evidence regarding the implementation and effectiveness of this service delivery strategy, with important implications for programs striving to eliminate vertical transmission of HIV and improve maternal health.

TRIAL REGISTRATION

ClinicalTrials.gov NCT00931216 http://clinicaltrials.gov/ct2/show/NCT00931216.

RATIONALE

Changes in airway epithelial cell differentiation, driven in part by IL-13, are important in asthma. Micro-RNAs (miRNAs) regulate cell differentiation in many systems and could contribute to epithelial abnormalities in asthma.

OBJECTIVES

To determine whether airway epithelial miRNA expression is altered in asthma and identify IL-13-regulated miRNAs.

METHODS

We used miRNA microarrays to analyze bronchial epithelial brushings from 16 steroid-naive subjects with asthma before and after inhaled corticosteroids, 19 steroid-using subjects with asthma, and 12 healthy control subjects, and the effects of IL-13 and corticosteroids on cultured bronchial epithelial cells. We used quantitative polymerase chain reaction to confirm selected microarray results.

MEASUREMENTS AND MAIN RESULTS

Most (12 of 16) steroid-naive subjects with asthma had a markedly abnormal pattern of bronchial epithelial miRNA expression by microarray analysis. Compared with control subjects, 217 miRNAs were differentially expressed in steroid-naive subjects with asthma and 200 in steroid-using subjects with asthma (false discovery rate < 0.05). Treatment with inhaled corticosteroids had modest effects on miRNA expression in steroid-naive asthma, inducing a statistically significant (false discovery rate < 0.05) change for only nine miRNAs. qPCR analysis confirmed differential expression of 22 miRNAs that were highly differentially expressed by microarrays. IL-13 stimulation recapitulated changes in many differentially expressed miRNAs, including four members of the miR-34/449 family, and these changes in miR-34/449 family members were resistant to corticosteroids.

CONCLUSIONS

Dramatic alterations of airway epithelial cell miRNA levels are a common feature of asthma. These alterations are only modestly corrected by inhaled corticosteroids. IL-13 effects may account for some of these alterations, including repression of miR-34/449 family members that have established roles in airway epithelial cell differentiation. Clinical trial registered with www.clinicaltrials.gov (NCT 00595153).

In humans, up to 75% of newly generated B cells and about 30% of mature B cells show some degree of autoreactivity. Yet, how B cells establish and maintain tolerance in the face of autoantigen exposure during and after development is not certain. Studies of model B-cell antigen receptor (BCR) transgenic systems have highlighted the critical role of functional unresponsiveness or ‘anergy’. Unlike T cells, evidence suggests that receptor editing and anergy, rather than deletion, account for much of B-cell tolerance. However, it remains unclear whether the mature diverse B-cell repertoire of mice contains anergic autoreactive B cells, and if so, whether antigen was encountered during or after their development. By taking advantage of a reporter mouse in which BCR signalling rapidly and robustly induces green fluorescent protein expression under the control of the Nur77 regulatory region, antigen-dependent and antigen-independent BCR signalling events in vivo during B-cell maturation were visualized. Here we show that B cells encounter antigen during development in the spleen, and that this antigen exposure, in turn, tunes the responsiveness of BCR signalling in B cells at least partly by downmodulating expression of surface IgM but not IgD BCRs, and by modifying basal calcium levels. By contrast, no analogous process occurs in naive mature T cells. Our data demonstrate not only that autoreactive B cells persist in the mature repertoire, but that functional unresponsiveness or anergy exists in the mature B-cell repertoire along a continuum, a fact that has long been suspected, but never yet shown. These results have important implications for understanding how tolerance in T and B cells is differently imposed, and how these processes might go awry in disease.