Distinctive field effects of smoking and lung cancer case-control status on bronchial basal cell growth and signaling.

RATIONAL: Basal cells (BCs) are bronchial progenitor/stem cells that can regenerate injured airway that, in smokers, may undergo malignant transformation. As a model for early stages of lung carcinogenesis, we set out to characterize cytologically normal BC outgrowths from never-smokers and ever-smokers without cancers (controls), as well as from the normal epithelial "field" of ever-smokers with anatomically remote cancers, including lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) (cases). METHODS: Primary BCs were cultured and expanded from endobronchial brushings taken remote from the site of clinical or visible lesions/tumors. Donor subgroups were tested for growth, morphology, and underlying molecular features by qRT-PCR, RNAseq, flow cytometry, immunofluorescence, and immunoblot. RESULTS: (a) the BC population includes epithelial cell adhesion molecule (EpCAM) positive and negative cell subsets; (b) smoking reduced overall BC proliferation corresponding with a 2.6-fold reduction in the EpCAMpos/ITGA6 pos/CD24pos stem cell fraction; (c) LUSC donor cells demonstrated up to 2.8-fold increase in dysmorphic BCs; and (d) cells procured from LUAD patients displayed increased proliferation and S-phase cell cycle fractions. These differences corresponded with: (i) disparate NOTCH1/NOTCH2 transcript expression and altered expression of potential downstream (ii) E-cadherin (CDH1), tumor protein-63 (TP63), secretoglobin family 1a member 1 (SCGB1A1), and Hairy/enhancer-of-split related with YRPW motif 1 (HEY1); and (iii) reduced EPCAM and increased NK2 homeobox-1 (NKX2-1) mRNA expression in LUAD donor BCs. CONCLUSIONS: These and other findings demonstrate impacts of donor age, smoking, and lung cancer case-control status on BC phenotypic and molecular traits and may suggest Notch signaling pathway deregulation during early human lung cancer pathogenesis.

Initial development and testing of an exhaled microRNA detection strategy for lung cancer case-control discrimination.

For detecting field carcinogenesis non-invasively, early technical development and case-control testing of exhaled breath condensate microRNAs was performed. In design, human lung tissue microRNA-seq discovery was reconciled with TCGA and published tumor-discriminant microRNAs, yielding a panel of 24 upregulated microRNAs. The airway origin of exhaled microRNAs was topographically "fingerprinted", using paired EBC, upper and lower airway donor sample sets. A clinic-based case-control study (166 NSCLC cases, 185 controls) was interrogated with the microRNA panel by qualitative RT-PCR. Data were analyzed by logistic regression (LR), and by random-forest (RF) models. Feasibility testing of exhaled microRNA detection, including optimized whole EBC extraction, and RT and qualitative PCR method evaluation, was performed. For sensitivity in this low template setting, intercalating dye-based URT-PCR was superior to fluorescent probe-based PCR (TaqMan). In application, adjusted logistic regression models identified exhaled miR-21, 33b, 212 as overall case-control discriminant. RF analysis of combined clinical + microRNA models showed modest added discrimination capacity (1.1-2.5%) beyond clinical models alone: all subjects 1.1% (p = 8.7e-04)); former smokers 2.5% (p = 3.6e-05); early stage 1.2% (p = 9.0e-03), yielding combined ROC AUC ranging from 0.74 to 0.83. We conclude that exhaled microRNAs are qualitatively measureable, reflect in part lower airway signatures; and when further refined/quantitated, can potentially help to improve lung cancer risk assessment.

Characterizing medical providers for jail inmates in New York State.

OBJECTIVES: People who are incarcerated exhibit high rates of disease, but data evaluating the delivery of medical services to inmates are sparse, particularly for jail settings. We sought to characterize the primary medical care providers for county jail inmates in New York State. METHODS: From 2007 through 2009, we collected data on types of medical care providers for jail inmates in all New York State counties. We obtained data from state monitoring programs and e-mail questionnaires sent to county departments of health. RESULTS: In counties outside New York City (n = 57), jail medical care was delivered by local providers in 40 counties (70%), correctional medical corporations in 8 counties (14%), and public providers in 9 counties (16%). In New York City, 90% of inmates received medical care from a correctional medical corporation. Larger, urban jails, with a greater proportion of Black and Hispanic inmates, tended to use public hospitals or correctional medical corporations as health care vendors. CONCLUSIONS: Jail medical services in New York State were heterogeneous and decentralized, provided mostly by local physician practices and correctional medical corporations. There was limited state oversight and coordination of county jail medical care.

Primary pulmonary hypertension and cor pulmonale.

Primary pulmonary hypertension and cor pulmonale represent forms of precapillary pulmonary hypertension due to intrinsic lung disease. In the case of primary pulmonary hypertension, this is due to disease of the pulmonary vasculature while cor pulmonale is related to diseases of the pulmonary vasculature, airways, or interstitium. Patients present with signs and symptoms of right ventricular dysfunction and low cardiac output including dyspnea, chest pain and peripheral edema. Therapy is directed at the underlying disease and may include supplemental oxygen for diseases causing chronic hypoxemia and anticoagulation for thrombotic disease. Vasodilator therapy has variable efficacy for pulmonary vascular disorders. Postacyclin by continuous infusion has been a major advance in the therapy of primary pulmonary hypertension and has prolonged survival and delayed the need for lung transplantation. Bosentan, an endothelin receptor blocking agent is the first oral medication approved for the therapy of pulmonary hypertension.

Low bone mass and high bone turnover in postmenopausal human immunodeficiency virus-infected women.

CONTEXT: Low bone mineral density (BMD) is commonly reported in young men and women with HIV infection, and fracture rates may be higher. With effective antiretroviral therapy (ART), the HIV population is aging. However, little is known about the skeletal status of postmenopausal women. OBJECTIVE: We aimed to assess the effects of HIV infection and ART on BMD and bone turnover in postmenopausal minority women. DESIGN, SETTING, AND PATIENTS: A prospective cohort study was performed in 92 HIV+ and 95 HIV- postmenopausal Hispanic and African-American women. MAIN OUTCOME MEASURES: We measured BMD by dual-energy x-ray absorptiometry, fracture prevalence, serum levels of inflammatory cytokines (TNFalpha, IL-6), bone turnover markers, calciotropic hormones, and estrone. RESULTS: HIV+ women were younger (56 +/- 1 vs. 60 +/- 1 yr; P < 0.01) and had lower BMI (28 +/- 1 vs. 30 +/- 1 kg/m(2); P < 0.01) and estrone levels. Prevalence of T scores below -1.0 was greater in HIV+ women at the spine (78 vs. 64%; P < 0.05), total hip (45 vs. 29%; P < 0.05), and femoral neck (64 vs. 46%; P < 0.05), and Z scores adjusted for BMI were lower in HIV+ women at the same sites. Serum TNFalpha, N-telopeptide, and C-telopeptide were significantly higher in HIV+ than HIV- women, particularly those receiving ART. HIV+ status was independently and negatively associated with spine and hip BMD after adjustment for age, ethnicity, BMI, and alcohol. CONCLUSION: The lower BMD, higher prevalence of low BMD, and higher levels of bone turnover markers detected in HIV+ postmenopausal minority women could place them at high risk for future fractures.

Bone mass and mineral metabolism in HIV+ postmenopausal women.

The objective of this cross-sectional study was to estimate the prevalence of and risk factors for osteoporosis in HIV+ postmenopausal women. Bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) and biochemical indices of mineral metabolism were measured in 31 Hispanic and African American HIV+ postmenopausal women. BMD was compared with 186 historical controls, matched for age, ethnicity and postmenopausal status. Mean BMD was significantly lower at the lumbar spine and total hip in the HIV+ group, as compared with controls. Prevalence of osteoporosis was higher in the HIV+ group than controls at the lumbar spine (42% vs 23%, p =0.03) and total hip (10% vs 1%, p =0.003). Among HIV+ women, time since menopause and weight were significant predictors of BMD, while duration or class of antiretroviral therapy (ART), AIDS diagnosis, nadir CD4, steroid use, and vitamin D deficiency were not. Prevalence of osteoporosis is substantially higher in HIV+ Hispanic and African-American postmenopausal women than in controls. Established osteoporosis risk factors were more important in predicting BMD than factors associated with HIV infection and ART. Long-term management of the growing female HIV population should include the evaluation for and management of osteoporosis.

Antitussive effect of the leukotriene receptor antagonist zafirlukast in subjects with cough-variant asthma.

Cough-variant asthma (CVA) occurs in a subgroup of asthmatics whose sole or predominant respiratory symptom is cough. Although bronchodilators are often sufficient to treat CVA, refractory cough may require therapy with inhaled or systemic corticosteroids. In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of a 14-day course of the leukotriene receptor antagonist zafirlukast on subjective cough score and cough-reflex sensitivity to inhaled capsaicin in eight subjects with CVA refractory to inhaled beta agonists, and in five subjects refractory to inhaled corticosteroids. Seven of eight subjects experienced significant subjective and objective improvement in cough after treatment with zafirlukast. Mean (+/- SEM) cough score improved from 7.75 +/- 0.56 to 3.25 +/- 0.84 (p = 0.0006). Cough sensitivity to capsaicin was suppressed by zafirlukast in all subjects. Patients with CVA may represent a distinct subgroup of asthmatics whose afferent cough receptors within the respiratory epithelium are hypersensitive relative to those of patients with the typical form of asthma. Zafirlukast appears to be particularly effective in treating CVA by inhibiting the sensitivity of these receptors. Leukotriene receptor antagonists may offer an alternative to corticosteroids for the treatment of CVA refractory to inhaled bronchodilators.