Jack W. Snyder

Occupational fatality and persistent neurological sequelae after mass exposure to hydrogen sulfide

Exposure to hydrogen sulfide (H2S) has been associated with death as well as survival following coma with or without hypoxic brain damage. The release of H2S at a beachfront construction site led to the emergency evaluation and treatment of 37 people, with six admissions and one death. At least one victim, who underwent extensive therapy with hyperbaric oxygen, developed persistent neurological sequelae. Despite increased awareness of the potentially life-threatening consequences of exposure to H2S, significant poisoning continues to occur, even in workplaces where the hazards are well-known and can be avoided. Recommended therapy includes nitrites, hyperbaric oxygen, and supportive care, but documentation of efficacy is lacking. Because patients with chronic neurological sequelae after acute H2S exposure continue to be reported, we suggest that any survivor of H2S poisoning who presents in coma or who manifests objectively verifiable evidence of neurotoxicity on physical examination or lab testing should undergo baseline and annual neurological and neuropsychological testing for at least five years. This approach could standardize and enhance our knowledge of, and ability to detect, the subtle but permanent alterations of central nervous system function that follow H2S exposure.

l-Carnitine delays the killing of cultured hepatocytes by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The role of fatty acid metabolism in chemical-dependent cell injury is poorly understood. Addition of L-carnitine to the incubation medium of cultured hepatocytes delayed cell killing initiated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Protection by L-carnitine was stereospecific and observed as late as 1 h following addition of MPTP. D-Carnitine, but not iodoacetate, reversed the L-carnitine effect. Monoamine oxidase A and B activities, MPTP/N-methyl-4-phenyl-pyridinium levels, and MPTP-dependent loss of mitochondrial membrane potential measured by release of [3H]triphenylmethylphosphonium were not altered by addition of L-carnitine. Significant changes in MPTP-induced depletion of total cellular ATP did not occur with excess L-carnitine. Although the mechanism of cytoprotection exerted by L-carnitine remains unresolved, the data suggest that L-carnitine does not significantly alter: (i) mitochondrial-dependent bioactivation of MPTP; (ii) MPTP-dependent loss of mitochondrial membrane potential; or (iii) MPTP-mediated depletion of total cellular ATP content. We conclude that alterations of fatty acid metabolism may contribute to the toxic consequences of exposure to MPTP. Moreover, the lack of L-carnitine-mediated cytoprotection of monolayers incubated with 4-phenylpyridine or potassium cyanide suggests: (i) a link between fatty acid metabolism and mitochondrial membrane-mediated, bioactivation-dependent cell killing; and (ii) that inhibition of NADH dehydrogenase may not totally explain the mechanism of MPTP cytotoxicity.

Deciding to terminate treatment: a practical guide for physicians.

Providing house officers and practicing physicians with annotated, concise, practical guidelines for decisions to terminate treatment is the objective of this report. The study selection and data extraction focused on statutes, regulations, court decisions, medicolegal analyses, clinical studies, and position papers addressing termination-of-treatment issues. To foster a systematic approach, we developed a laminated, pocket-sized card containing a series of questions to be asked by any physician confronted with termination-of-treatment decisions. Systematic identification and deliberate assessment of (1) brain death; (2) the nature, extent, cause, prognosis, and reversibility of impairment; (3) the type of treatment to be withheld or withdrawn; (4) the futility of any proposed intervention; (5) the capacity of the patient for health care decision-making; (6) the evidence of patients wishes; (7) the proper roles of family members, surrogate decision makers, and other health professionals (eg, ethics committees); and (8) applicable policies, ethics, laws, and potential conflicts of interest will enhance efficiency and add value to the decision-making process at the end of life.

N-methyl-4-phenylpyridinium (MPP+) potentiates the killing of cultured hepatocytes by catecholamines

The role of catecholamines in the toxicity of MPTP (N-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) was explored. The killing of cultured hepatocytes by dopamine and 6-hydroxydopamine was enhanced following inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a manipulation known to sensitize such cells to an oxidative stress. The participation of activated oxygen species in the cell injury under such circumstances was shown by the ability of catalase and the ferric iron chelator deferoxamine to protect the hepatocytes. The toxicity of catecholamines was also potentiated by the mitochondrial site I (NADH dehydrogenase) inhibitor rotenone. MPP+ (N-methyl-4-phenyl-pyridinium), the putative toxic metabolite of MPTP is also a site I inhibitor. Incubation of hepatocytes with MPP+ similarly potentiated the toxicity of 6-hydroxydopamine, dopamine, and norepinephrine under conditions where MPP+ alone or catecholamines alone did not kill cells. Hepatocytes that had accumulated dopamine from the medium were killed by a subsequent exposure to MPP+ in the absence of a catecholamine in the medium. Hepatocytes that had not been pretreated with dopamine were not affected by the subsequent exposure to MPP+. These data indicated that catecholamines render hepatocytes more susceptible to the toxicity of MPP+ and suggest that the presence of catecholamines in specific neurons in the brain may be related to the selective neurotoxicity of MPTP.