Lipopolysaccharide (LPS), residing in the outer membrane of all gram-negative bacteria, is considered a major initiating factor of the gram-negative septic shock syndrome in humans. LPS forms a complex with the LPS binding protein (LBP) in plasma, and LPS-LBP complexes engage a specific receptor, CD14, on the surface of myeloid cells, leading to the production of potent proinflammatory cytokines. The major goal of this study was to test the importance of the CD14 pathway in vivo in a primate model that is similar to human septic shock. Primates were pretreated with one of two different inhibitory anti-CD14 mAbs, then challenged with intravenous endotoxin (375 g/kg/h) for 8 h. The anti-CD14 treatment regimens were successful in preventing profound hypotension, reducing plasma cytokine levels (TNF-␣ , IL-1 ␤ , IL-6, and IL-8), and inhibiting the alteration in lung epithelial permeability that occurred in animals treated with LPS and an isotype-matched control antibody. These results demonstrate for the first time the importance of the CD14 pathway in a primate model that is similar to human septic shock. Inhibition of the CD14 pathway represents a novel therapeutic approach to treating this life-threatening condition. ( J. Clin. Invest. 1996. 98:1533-1538.)

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Risk factors for the disease of chemical dependence, or addiction to alcohol and/or drugs, for physicians have not been clearly defined. Yet chemical dependence is believed to be a leading occupational hazard for physicians. This study compares the specialties of a population of physicians assessed for the presence of impairment (study group, N = 1000) with the distribution of specialties for all US physicians. Only 21 of the total were found to be free of impairment from chemical dependence or psychiatric disease, while 920 physicians (92.0%) had a primary diagnosis of chemical dependence, and 59 (5.9%) had a major psychiatric illness. Anesthesia and family and general practice were found to be overrepresented in the population under study, as compared with all US physicians. There were significant differences between the study group and all US physicians with respect to age, sex, and practice activity status. The authors urge these apparent high-risk specialties, as well as the medical profession itself, to develop control or prevention strategies that will reduce risk for chemical dependence through education, early identification, intervention, and treatment of those individuals with the disease.

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