An airway epithelial iNOS-DUOX2-thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma.

Severe refractory asthma is associated with enhanced nitrative stress. To determine the mechanisms for high nitrative stress in human severe asthma (SA), 3-nitrotyrosine (3NT) was compared with Th1 and Th2 cytokine expression. In SA, high 3NT levels were associated with high interferon (IFN)-γ and low interleukin (IL)-13 expression, both of which have been reported to increase inducible nitric oxide synthase (iNOS) in human airway epithelial cells (HAECs). We found that IL-13 and IFN-γ synergistically enhanced iNOS, nitrite, and 3NT, corresponding with increased H(2)O(2). Catalase inhibited whereas superoxide dismutase enhanced 3NT formation, supporting a critical role for H(2)O(2), but not peroxynitrite, in 3NT generation. Dual oxidase-2 (DUOX2), central to H(2)O(2) formation, was also synergistically induced by IL-13 and IFN-γ. The catalysis of nitrite and H(2)O(2) to nitrogen dioxide radical (NO(2)(•)) requires an endogenous peroxidase in this epithelial cell system. Thyroid peroxidase (TPO) was identified by microarray analysis ex vivo as a gene distinguishing HAEC of SA from controls. IFN-γ induced TPO in HAEC and small interfering RNA knockdown decreased nitrated tyrosine residues. Ex vivo, DUOX2, TPO, and iNOS were higher in SA and correlated with 3NT. Thus, a novel iNOS-DUOX2-TPO-NO(2)(•) metabolome drives nitrative stress in HAEC and likely in SA.

The complex relationship between inflammation and lung function in severe asthma.

Asthma is a common respiratory disease affecting ∼300 million people worldwide. Airway inflammation is thought to contribute to asthma pathogenesis, but the direct relationship between inflammation and airway hyperresponsiveness (AHR) remains unclear. This study investigates the role of inflammation in a steroid-insensitive, severe allergic airway disease model and in severe asthmatics stratified by inflammatory profile. First, we used the T-helper (T(H))-17 cells adoptive transfer mouse model of asthma to induce pulmonary inflammation, which was lessened by tumor necrosis factor (TNF)-α neutralization or neutrophil depletion. Although decreased airspace inflammation following TNFα neutralization and neutrophil depletion rescued lung compliance, neither intervention improved AHR to methacholine, and tissue inflammation remained elevated when compared with control. Further, sputum samples were collected and analyzed from 41 severe asthmatics. In severe asthmatics with elevated levels of sputum neutrophils, but low levels of eosinophils, increased inflammatory markers did not correlate with worsened lung function. This subset of asthmatics also had significantly higher levels of T(H)17-related cytokines in their sputum compared with severe asthmatics with other inflammatory phenotypes. Overall, this work suggests that lung compliance may be linked with cellular inflammation in the airspace, whereas T-cell-driven AHR may be associated with tissue inflammation and other pulmonary factors.

Nitric oxide and related enzymes in asthma: relation to severity, enzyme function and inflammation.

BACKGROUND: Exhaled nitric oxide (FeNO) associates with asthma and eosinophilic inflammation. However, relationships between nitric oxide synthases, arginase, FeNO, asthma severity and inflammation remain poorly understood. OBJECTIVES: To determine the relationships of iNOS expression/activation and arginase 2 expression with asthma severity, FeNO, nitrotyrosine (NT) and eosinophilic inflammation. METHODS: Bronchial brushings and sputum were obtained from 25 normal controls, eight mild/no inhaled corticosteroids (ICS), 16 mild-moderate/with ICS and 35 severe asthmatics. The FeNO was measured the same day by ATS/ERS standards. The iNOS, arginase2 mRNA/protein and NT protein were measured in lysates from bronchial brushings by quantitative real-time PCR and Western blot. Induced sputum differentials were obtained. RESULTS: Severe asthma was associated with the highest levels of iNOS protein and mRNA, although the index of iNOS mRNA to arginase2 mRNA most strongly differentiated severe from milder asthma. When evaluating NO-related enzyme functionality, iNOS mRNA/protein expression both strongly predicted FeNO (r = 0.61, P < 0.0001 for both). Only iNOS protein predicted NT levels (r = 0.48, P = 0.003) with the strongest relationship in severe asthma (r = 0.61, P = 0.009). The iNOS protein, FeNO and NT, all correlated with sputum eosinophils, but the relationships were again strongest in severe asthma. Controlling for arginase 2 mRNA/protein did not impact any functional outcome. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that while iNOS expression from epithelial brushings is highest in severe asthma, factors controlling arginase2 mRNA expression significantly improve differentiation of severity. In contrast, functionality of the NO pathway as measured by FeNO, NT and eosinophilic inflammation, is strongly associated with iNOS expression alone, particularly in severe asthma.

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.

OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. METHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. CONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis. METHOD: A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy. RESULTS: A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations. CONCLUSION: In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.

IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells.

BACKGROUND: Exhaled nitric oxide is increased in asthma, but the mechanisms controlling its production, including the effects of T-helper type 2 (Th2) cytokines, are poorly understood. In mouse and submerged human epithelial cells, Th2 cytokines inhibit expression of inducible nitric oxide synthase (iNOS). Arginases have been proposed to contribute to asthma pathogenesis by limiting the arginine substrate available to NOS enzymes, but expression of any of these enzymes has not been extensively studied in primary human cells. OBJECTIVES: We hypothesized that primary human airway epithelial cells in air-liquid interface (ALI) culture would increase iNOS expression and activity in response to IL-13, while decreasing arginase expression. METHODS: iNOS and arginase mRNA (real-time PCR) and protein expression (Western blot and immunofluorescence) as well as iNOS activity (nitrite levels) were measured in ALI epithelial cells cultured from bronchial brushings of normal and asthmatic subjects following IL-13 stimulation. RESULTS: IL-13 up-regulated iNOS mRNA primarily at a transcriptional level in epithelial cells. iNOS protein and activity also increased, arginase1 protein expression decreased while arginase 2 expression did not change. The changes in iNOS protein correlated strongly with changes in nitrites, and inclusion of arginase (1 or 2) did not substantially change the relationship. Interestingly, iNOS mRNA and protein were not correlated. CONCLUSIONS: These results contrast with many previous results to confirm that Th2 stimuli enhance iNOS expression and activity. While arginase 1 protein decreases in response to IL-13, neither arginase appears to substantially impact nitrite levels in this system.

Prospective prediction of spontaneous but not recurrent autoimmune diabetes in the non-obese diabetic mouse.

AIMS/HYPOTHESIS: Type 1 diabetes is a T cell-mediated autoimmune disease with a clinically silent prodrome, during which prediction and treatment of disease are theoretically possible. Using retrospective analysis, spontaneous disease in the non-obese diabetic (NOD) mouse has been correlated with islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8+ T cells in the peripheral blood. In this study, we determined prospectively whether IGRP-reactive T cells in peripheral blood could predict disease occurrence. Since recurrent autoimmunity is an important contributor to transplant failure, we also determined whether failure of islet grafts (syngeneic and allogeneic) could be predicted by the presence of circulating autoreactive T cells. MATERIALS AND METHODS: Peripheral blood samples were taken weekly from female NOD mice between the ages of 8 and 30 weeks and from NOD mice transplanted with NODscid islets. Peripheral blood cells and islet grafts were analysed for the presence of IGRP-reactive CD8+ T cells by flow cytometry. RESULTS: Prospective analysis of peripheral blood IGRP-reactive T cells in the prediabetic period predicted disease development with a sensitivity of 100% and a specificity of 60%, resulting in positive and negative predictive values of 85 and 100%, respectively. Significant proportions of IGRP-reactive T cells were found in the grafts, but not in peripheral blood of NOD mice undergoing syngeneic and allogeneic rejection. CONCLUSIONS/INTERPRETATION: The occurrence of spontaneous diabetes can be predicted prospectively by measuring peripheral blood autoreactive T cells. Rejection of syngeneic or allogeneic islets is associated with large populations of autoreactive CD8+ T cells within islets, suggesting that immunodominant autoreactive T cells during the prediabetic period are also responsible for autoimmune graft rejection.

Expression and activation of 15-lipoxygenase pathway in severe asthma: relationship to eosinophilic phenotype and collagen deposition.

BACKGROUND: Although 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), a product of 15-lipoxygenase (15-LO), may be involved in mild to moderate asthma, little is known about its potential roles in severe asthma. OBJECTIVES: This study was performed to evaluate 15(S)-HETE levels in bronchoalveolar lavage fluid (BALF) from severe asthmatics with and without airway eosinophils and from the control groups. In addition, 15-LO protein expression was examined in endobronchial biopsy, while its expression and activation were evaluated in BAL cells. RESULTS: While 15(S)-HETE levels in BALF were significantly higher in all severe asthmatics than normal subjects, severe asthmatics with airway eosinophils had the highest levels compared with mild, moderate asthmatics and normal subjects. 15(S)-HETE levels were associated with tissue eosinophil numbers, sub-basement membrane thickness and BALF tissue inhibitor of metalloproteinase-1 levels, and were accompanied by increased 15-LO expression in bronchial epithelium. In addition, activation of 15-LO was suggested by the increased proportion of 15-LO in the cytoplasmic membrane of alveolar macrophages from severe asthmatics. CONCLUSION: The data suggest that severe asthmatics with persistent airway eosinophils manifest high levels of 15(S)-HETE in BALF, which may be associated with airway fibrosis. It is likely that 15-LO expression and activation by airway cells explain the increased 15(S)-HETE levels.

Expansion of the antigenic repertoire of a single T cell receptor upon T cell activation.

Activated T cells and their naive precursors display different functional avidities for peptide/MHC, but are thought to have identical antigenic repertoires. We show that, following activation with a cognate mimotope (NRP), diabetogenic CD8(+) T cells expressing a single TCR (8.3) respond vigorously to numerous peptide analogs of NRP that were unable to elicit any responses from naive 8.3-CD8(+) T cells, even at high concentrations. The NRP-reactive, in vivo activated CD8(+) cells arising in pancreatic islets of nonobese diabetic mice are similarly promiscuous for peptide/MHC, and paradoxically this promiscuity expands as the aviditiy of the T cell population for NRP/MHC increases with age. Thus, activation and avidity maturation of T lymphocyte populations can lead to dramatic expansions in the range of peptides that elicit functional T cell responses.

Persistent wheezing in very young children is associated with lower respiratory inflammation.

Despite advances in understanding the pathophysiology of asthma, morbidity and mortality in pediatrics continue to rise. Little is known about the initiation and chronicity of inflammation resulting in asthma in this young population. We evaluated 20 "wheezing" children (WC) (median age 14.9 mo) with a minimum of two episodes of wheezing or prolonged wheezing > or = 2 mo in a 6-mo period with bronchoscopy and bronchoalveolar lavage (BAL). Comparisons were made with six normal controls (NC) (median age 23.3 mo) undergoing general anesthesia for elective surgery. BAL fluid cell counts and differentials were determined. The eicosanoids, leukotriene (LT) B(4), LTE(4), prostaglandin (PG)E(2), and 15-hydroxyeicosatetraenoic acid (HETE) and the mast cell mediators, beta-tryptase and PGD(2), were evaluated by enzyme immunoassay (EIA). WC had significant elevations in total BAL cells/ml (p = 0.01), as well as, lymphocytes (LYMPH, p = 0.007), macrophages/monocytes (M&M, p = 0.02), polymorphonuclear cells (PMN, p = 0.02), epithelial cells (EPI, p = 0.03), and eosinophils (EOS, p = 0.04) compared with NC. Levels of PGE(2) (p = 0.0005), 15-HETE (p = 0.002), LTE(4) (p = 0.04), and LTB(4) (p = 0.05) were also increased in WC compared with NC, whereas PGD(2) and beta-tryptase were not. This study confirms that inflammation is present in the airways of very young WC and may differ from patterns seen in adults with asthma.

Peripheral blood and airway tissue expression of transforming growth factor beta by neutrophils in asthmatic subjects and normal control subjects.

BACKGROUND: Airway remodeling may play an important role in asthma pathophysiology. Transforming growth factor beta (TGF-beta) has a critical role in the remodeling process. Although cellular sources for TGF-beta have been previously investigated in asthma airways, the expression, release, or both of TGF-beta from asthmatic airways and blood neutrophils has not been reported. OBJECTIVE: The current study evaluated the TGF-beta protein and messenger (m)RNA expression by airway and peripheral blood neutrophils in asthmatic and normal subjects. METHODS: TGF-beta protein expression by airway and peripheral blood neutrophils was detected by using immunocytochemistry. TGF-beta protein levels in blood neutrophil supernatant were measured by using an enzyme immunoassay. TGF-beta mRNA expression was evaluated by using reverse transcription-PCR. RESULTS: Higher numbers of TGF-beta(+) cells and neutrophils were found in airway tissue of asthmatic (n = 15) compared with normal subjects (n = 10). Although neutrophils in both asthmatic and normal airway tissue expressed TGF-beta protein and the percentage of neutrophils expressing TGF-beta was similar between the two groups, the total number of TGF-beta(+) neutrophils was higher in the asthmatic subjects (P =.01). Peripheral blood neutrophils from asthmatic (n = 5) and normal subjects (n = 7) also expressed TGF-beta protein and mRNA. Blood neutrophils from asthmatic subjects spontaneously released significantly higher levels of TGF-beta than those from normal subjects (P =.007). CONCLUSION: These data suggest that airway and blood neutrophils from both asthmatic and normal subjects can express and release TGF-beta. Higher levels of TGF-beta expression-release from asthmatic neutrophils indicate that neutrophils may be involved in the airway remodeling process of asthmatic subjects.

Methodological issues in workplace substance abuse prevention research.

Substance abuse among working adults represents billions of dollars in preventable health care costs and industry financial loss. Therefore, it is imperative to develop and test effective substance abuse prevention programs for the workplace. However, applied workplace substance abuse prevention research is fraught with numerous methodological challenges. This article highlights a number of these challenges, which include (1) reaching a broad audience with prevention messages, (2) handling the concerns of the employer, (3) collecting substance use data in the workplace, (4) accessing and using records-based data, and (5) linking survey and records-based data. Using examples from the authors' ongoing research assessing a workplace health promotion and substance abuse prevention program, funded by the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Prevention, the authors address these challenges.

Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?

In neonatal rodents, the beta-cell mass undergoes a phase of remodeling that includes a wave of apoptosis. Using both mathematical modeling and histochemical detection methods, we have demonstrated that beta-cell apoptosis is significantly increased in neonates as compared with adult rats, peaking at approximately 2 weeks of age. Other tissues, including the kidney and nervous system, also exhibit neonatal waves of apoptosis, suggesting that this is a normal developmental phenomenon. We have demonstrated that increased neonatal beta-cell apoptosis is also present in animal models of autoimmune diabetes, including both the BB rat and NOD mouse. Traditionally, apoptosis has been considered a process that does not induce an immune response. However, recent studies indicate that apoptotic cells can do the following: 1) display autoreactive antigen in their surface blebs; 2) preferentially activate dendritic cells capable of priming tissue-specific cytotoxic T-cells; and 3) induce the formation of autoantibodies. These findings suggest that in some circumstances physiological apoptosis may, in fact, initiate autoimmunity. Initiation of beta-cell-directed autoimmunity in murine models appears to be fixed at approximately 15 days of age, even when diabetes onset is dramatically accelerated. Taken together, these observations have led us to hypothesize that the neonatal wave of beta-cell apoptosis is a trigger for beta-cell-directed autoimmunity.

A confrontational naming task produces congruent increases and decreases in PET and fMRI.

This work uses the well-established (by PET) confrontation naming task to compare PET and fMRI in a cognitive activation experiment. The signal changes from this task are much less than the changes caused by visual or motor activation tasks used in previous comparisons. ANOVA methods adjusted for multiple comparisons were used to determine significant changes in signal between confrontation naming and figure size discrimination tasks. All 17 significantly increased regions (confrontation naming signal greater) seen on one modality were increased on both modalities. Ten of 13 regions that were significantly decreased on one modality were decreased on the other. Three mismatched regions showed a significant decrease on one modality and a nonsignificant increase on the other. This study could not detect a consistent difference in activation site location between PET and fMRI.

Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.

The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogenous. It was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil (-)] had nearly absent eosinophils (< 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil (+). Eosinophil (+) severe asthmatics had associated increases (p < 0.05) in lymphocytes (CD3+, CD4+, CD8+), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil (+) severe asthmatics than eosinophil (-) severe asthmatics and correlated with eosinophil numbers (r = 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV(1) was marginally lower in eosinophil (-) asthmatics (p = 0.05) with no difference in bronchodilator response. The eosinophil (+) group (with a thicker SBM) had more intubations than the eosinophil (-) group (p = 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.

Visualizing the firestorms in the brain: an inside look at the clinical and physiological connections between drugs and violence using brain SPECT imaging.

The connection between drugs and violence has been well documented. Understanding the intricacies of this connection is essential to finding effective interventions. Much has been written about the psychosocial causes of these problems, but there have been few studies exploring the biophysiological interface between drug effects, violent behavior and brain metabolism. Over the past eight years, The Amen Clinic has been extensively involved in the clinical use of brain SPECT imaging to evaluate complicated neuropsychiatric problems, especially related to the issues of both violence and substance abuse. From this work several clinical patterns, as well as brain SPECT imaging patterns, have been recognized that may help further our understanding of these problems. In this article, following a brief review of the literature on drugs, violence and the brain, five clinical examples are explored; the authors show how these support the clinical utility of incorporating SPECT imaging into psychiatric assessment of drug abuse and violence. Finally, a model is proposed to help explain the complex interaction between the brain, violence and drug abuse.

Myocardial suppression in vivo by spin locking with composite pulses.

Improved myocardium-blood contrast by myocardial suppression resulting from T1 rho-weighting in contrast-enhanced, gradient-echo, bright-blood cine images, acquired at 1.5T, is shown. In the standard images, blood has twice the intensity of muscle. In similar T1 rho-weighted images, it has 3-4 times the intensity of muscle. A composite spin-lock pulse before each observation pulse provides T1 rho-weighting. A typical pulse was: 90y-135x-360x-135x-90(-y) with element durations: 0.84, 1.26, 8.12, 1.26, and 0.84 ms. The tolerance of this composite pulse to shimmering and frequency errors allows spin locking with comparatively weak RF and therefore low specific absorption rate (SAR). Initial clinical evaluation on patients with poor ventricular function demonstrates both a qualitative and quantitative improvement in delineation of myocardial borders.

Theophylline: potential antiinflammatory effects in nocturnal asthma.

BACKGROUND: Recent information suggests that one of the therapeutic properties of theophylline is an antiinflammatory effect. OBJECTIVE: We evaluated this potential effect of theophylline in eight patients with nocturnal asthma. METHODS: The study design was a randomized, double-blind, placebo-controlled crossover of 2-week treatment periods, separated by a 1-week washout period. Spirometry and bronchoscopy were performed. RESULTS: Theophylline, compared with placebo, significantly improved the overnight decrement in lung function. The higher the nocturnal theophylline level, the greater the improvement in lung function. Theophylline also significantly decreased the percentage of neutrophils in the 4:00 AM bronchoalveolar lavage fluid and stimulated leukotriene B4 levels from macrophages obtained at 4:00 AM. The greater change in neutrophils correlated with increasing serum theophylline concentration. Also, the change in leukotriene B4 production was significantly correlated with the theophylline-induced decrement in lavage granulocytes (neutrophils and eosinophils). CONCLUSION: This study suggests that one action of theophylline is to alter inflammatory cell number and function in nocturnal asthma and that it may do this through an leukotriene B4-mediated mechanism.

Preventing alcohol use problems among blue-collar workers: a field test of the Working People program.

A program designed to prevent alcohol misuse among working adults was developed and presented in four sessions to employees of a medium-sized printing company. The Working People program, based on a social-learning model, was field-tested with 108 employees in the context of a quasi-experimental design. Members of the Program Group (n = 38) and two Comparison Groups (n = 26 and 44) were assessed before and after the program on a questionnaire containing measures of alcohol consumption, attitudes and intentions regarding alcohol use, problem consequences of alcohol use, and health beliefs. Program effects were demonstrated on alcohol consumption, motivation to reduce consumption, and problem consequences of drinking. No effects were found on health beliefs or self-efficacy to reduce drinking. Although the findings are qualified by the self-selected nature of the samples, the results suggest that alcohol consumption can be reduced among adults who participate in this type of worksite program.