Hormesis: a highly generalizable and reproducible phenomenon with important implications for risk assessment.

From a comprehensive search of the literature, the hormesis phenomenon was found to occur over a wide range of chemicals, taxonomic groups, and endpoints. By use of computer searches and extensive cross-referencing, nearly 3000 potentially relevant articles were identified. Evidence of chemical and radiation hormesis was judged to have occurred in approximately 1000 of these by use of a priori criteria. These criteria included study design features (e.g., number of doses, dose range), dose-response relationship, statistical analysis, and reproducibility of results. Numerous biological endpoints were assessed, with growth responses the most prevalent, followed by metabolic effects, reproductive responses, longevity, and cancer. Hormetic responses were generally observed to be of limited magnitude with an average maximum stimulation of 30 to 60 percent over that of the controls. This maximum usually occurred 4- to 5-fold below the NOAEL for a particular endpoint. The present analysis suggests that hormesis is a reproducible and generalizable biological phenomenon and is a fundamental component of many, if not most, dose-response relationships. The relatively infrequent observation of hormesis in the literature is believed to be due primarily to experimental design considerations, especially with respect to the number and range of doses and endpoint selection. Because of regulatory considerations, most toxicologic studies have been carried out at high doses above the low-dose region where the hormesis phenomenon occurs.

High resolution computed tomography of the lung in lifelong non-smoking patients with rheumatoid arthritis.

OBJECTIVES: To define pulmonary involvement on high resolution computed tomography (HRCT) of the thorax in lifelong non-smoking rheumatoid arthritis patients and to relate the results to pulmonary function, bronchial reactivity, and a variety of clinical and serological factors. METHODS: Twenty lifelong non-smoking RA patients (mean age 59 years (range 44-72; 18 females) were studied. Detailed medical and drug histories were taken. Protease inhibitor phenotype (Pi) and HLA-DR4 status were assessed. Schirmer's tear tests were performed to detect keratoconjunctivitis sicca (KCS). Spirometry, flow volume loops, and gas transfer factor measurement were recorded. The degree of bronchial reactivity (PC20 FEV1) was measured by a methacholine inhalation test. Chest and hand radiographs and HRCT of the lung were performed in all patients. RESULTS: Thirteen patients were HLA-DR4 positive. Eighteen had the Pi MM and two the Pi MS phenotype. Eight patients had evidence of KCS on Schirmer's tear testing. Ten patients achieved PC20 FEV1 in the methacholine inhalation test. All the patients had normal chest radiographs and all showed evidence of erosive arthropathy on hand radiographs. Five patients (25%) showed basal bronchiectasis and one mild interstitial lung disease on HRCT. All five patients with bronchiectasis had the Pi MM phenotype, four had HLA-DR4, four had KCS and three achieved PC20 FEV1; these values were not significantly different (p > 0.05) from those in patients without bronchiectasis. CONCLUSION: Using the highly sensitive technique of HRCT, we found evidence to suggest that the incidence of bronchiectasis in lifelong non-smoking RA patients may be much higher than previously reported.

Association of HLA-DR4, protease inhibitor phenotypes and keratoconjunctivitis sicca with pulmonary abnormalities in rheumatoid arthritis.

One-hundred rheumatoid arthritis (RA) patients were assessed for the association of HLA-DR4, protease inhibitor (Pi) phenotype and keratoconjunctivitis sicca (KCS) with a variety of clinical features, airflow obstruction and bronchial reactivity. Spirometry, lung volume and gas transfer factor measurements were performed to detect airflow obstruction. Bronchial reactivity to inhaled methacholine was assessed by measuring the provocative dose of methacholine causing a 20% fall in FEV1 from the baseline (PD20). Sixty-two patients were HLA-DR4 positive, 87 had Pi MM and 13 MS phenotypes and 37 had positive Schirmer's tear tests. Patients with KCS had a significantly increased history of wheeze (11/37 vs 7/63, P = 0.03, relative risk (RR) 1.8 [95% CI 1.04, 3.1]), those with HLA-DR4 had a significantly decreased atopy on skin-prick testing [3/62 vs 7/38, were significantly higher in the Pi MS group compared to Pi MM group. There was no significant association of HLA-DR4, Pi phenotype and KCS with bronchial reactivity. We conclude that there is no overall significant association of HLA-DR4, Pi phenotype and KCS with airflow obstruction and bronchial reactivity in RA.

Bronchial reactivity and airflow obstruction in rheumatoid arthritis.

OBJECTIVES: To investigate the prevalence of airways obstruction and bronchial reactivity to inhaled methacholine in rheumatoid arthritis patients and unselected controls. The control population consisted of patients attending the rheumatology department for minor degenerative joint problems. METHODS: One hundred patients with rheumatoid arthritis (RA) [72 (72%) women, 28 (28%) men; mean (SD) age 58 (10) years] and fifty controls [30 (60%) women, 20 (40%) men; mean (SD) age 56 (9) years] were studied. Detailed medical, smoking and drug histories were taken; skin prick tests were performed to assess atopy and chest and hand radiographs were performed. Spirometry, flow volume loops and gas transfer factor measurement were performed to detect airflow obstruction and methacholine inhalation tests were carried out to assess bronchial reactivity. RESULTS: There was no significant difference between rheumatoid arthritis patients and the controls in age, sex, smoking status and atopy on skin prick testing (p < 0.05). A significantly higher number of patients with RA had a history of wheeze compared with the controls (18% v 4%, p < 0.05). FEV1, FVC, FEV1/FVC, FEF25-75%, FEF25%, FEF50% and FEF75% were all significantly lower in the rheumatoid arthritis group (p < 0.05). A significantly higher number of patients with RA compared with controls showed bronchial reactivity to inhaled methacholine [55 (55%) v 8 (16%), p < 0.05]. FEV1, FVC, FEV1/FVC, FEF25-75%, FEF25%, FEF50% and FEF75% were all significantly lower among the patients with RA achieving PD20 FEV1 to inhaled methacholine (p < 0.05). CONCLUSION: In unselected rheumatoid arthritis patients both airflow obstruction and bronchial reactivity are significantly increased compared with controls.

CRAHCA (Center for Research in Ambulatory Health Care Administration): member involvement leads to practical applications.

The research undertaken by CRAHCA results in many new techniques and ideas being adopted by medical practice managers. However, it is not merely a one-way street. In this article, six group practice managers respond to questions about how they have used and been involved with research activities the Center has developed.

A controlled study of stanozolol in primary Raynaud's phenomenon and systemic sclerosis.

A double blind, crossover study of fibrinolytic enhancement treatment using stanozolol has been performed in primary Raynaud's phenomenon and in systemic sclerosis. The outcome criteria included subjective evaluation, clinical examination, physiological measurements of peripheral blood flow, and fibrinolytic measurements. Nineteen patients entered and 11 completed the study of primary Raynaud's phenomenon. There was nonsignificant evidence of improvement in peripheral blood flow. Twenty four patients entered and 17 completed the study of systemic sclerosis. There was marked objective but not subjective evidence of improvement in the peripheral microcirculation during the stanozolol treatment period. There was also a nonsignificant improvement in dermal sclerosis. There were improvements in fibrinolytic activity during the stanozolol treatment period. There was no alteration in fibrinolytic reserve as measured by 1-desamino-8-D-arginine vasopressin stimulation, however. Although adverse events were common in both treatment periods, withdrawals predominantly occurred during the period of treatment with stanozolol and were principally due to anabolic problems. There does not seem to be any indication for the use of stanozolol in primary Raynaud's phenomenon. Fibrinolytic enhancement with stanozolol does appear useful in treating the microvascular features of systemic sclerosis.