Publications

Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calcium-activated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.

Vitamin D and its analogs have been suggested to have palliative effects in the cardiovascular system. We have examined the effects of co-administration of the vitamin D receptor agonist, paricalcitol, on the hypertension, cardiac hypertrophy and interstitial fibrosis produced by chronic angiotensin II (AII) infusion. Administration of AII (800ng/kg/min) over a 14-day period resulted in increased blood pressure, myocyte hypertrophy, activation of the hypertrophic fetal gene program (atrial natriuretic peptide, B-type natriuretic peptide and alpha skeletal actin gene expression), increased expression of the pro-hypertrophic modulatory calcineurin inhibitor protein 1 (MCIP 1), and increased fibrosis with augmented procollagen 1 and 3 gene expression. In each case co-administration of paricalcitol (300ng/kg intraperitoneally every 48h) at least partially reversed the AII-dependent effect. These studies demonstrate that the liganded vitamin D receptor possesses potent anti-hypertrophic activity in this non-renin-dependent model of cardiac hypertrophy. The anti-hypertrophic activity appears to be at least partially intrinsic to the cardiac myocyte and may involve suppression of the MCIP 1 protein. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

The delivery of HIV risk assessment and behavioral counseling by clinicians in HIV clinical settings is one component in a comprehensive "positive prevention" strategy to help patients reduce their transmission risk behavior. Clinicians engage in behavioral prevention inconsistently, however, depending on whether patients are new to a practice or are established in regular care and on their attitudes and characteristics of their practices. We analyzed clinician reports of behavioral prevention delivered before and after participation in a large federal demonstration project of positive prevention interventions. The interventions that were part of this project were successful in increasing behavioral prevention among both new and returning patients. Prior to study interventions, clinicians reported counseling 69% of new patients and 52% of returning patients. In follow-up interviews 12 months after receiving training, clinicians reported delivering prevention messages to 5% more new patients and 9% of returning patients (both p<0.01). After 12 months, clinicians were more likely to engage in behavioral prevention if other providers in their sites were also involved. Clinicians agreeing that behavioral prevention was part of the clinic's mission were more likely to conduct it. The interventions were successful in mitigating the influence of provider attitudes precluding prevention delivery. Intervention strategies can help clinicians more consistently deliver behavioral prevention messages to their HIV-infected patients.