Search PubMed⌕ Search

Biomedical subjects

J W Snyder

Publications and source records attributed to J W Snyder.

At least 37 records · Page 2Linked to original sources
PubMed1993

Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition.

Cyclosporin A (CyA) and L-carnitine (LC) prevented the killing of cultured hepatocytes by anoxia and rotenone but not by cyanide. Neither CyA nor LC affected the rate or extent of the loss of the mitochondrial membrane potential or the rate or extent of the depletion of ATP. Atractyloside blocked the ability of both CyA and LC to protect, and D-carnitine antagonized the effect of LC but not that of CyA. Cell killing by cyanide was prevented when the phospholipase A2 inhibitor butacaine was added together with CyA. Butacaine by itself had no effect on cell killing. In a swelling assay with isolated rat liver mitochondria having a low calcium content, phenylarsine oxide or palmitoyl-CoA induced the inner membrane permeability transition when electron transport was inhibited by rotenone or cyanide. CyA prevented the permeability transition with rotenone but not with cyanide, and atractyloside reversed the effect of CyA. LC prevented the permeability transition occurring with palmitoyl-CoA plus rotenone but not with palmitoyl-CoA plus cyanide. Atractyloside and D-carnitine antagonized the protective effect of LC. Inhibition of the cyanide-dependent permeability transition in isolated liver mitochondria required the presence of both CyA and butacaine. These data document the close correlation between the effect of CyA and LC on the response of cultured hepatocytes to inhibition of mitochondrial electron transport and their ability to prevent the permeability transition in isolated mitochondria. It is concluded that the ability of CyA and LC to protect cultured hepatocytes is a consequence of their ability to prevent the mitochondrial permeability transition, indicating that this event is likely to be causally linked to the genesis of irreversible injury. Thus, cell death with anoxia or inhibitors of electron transport is related to a mitochondrial alteration by a mechanism that is independent of the maintenance of a membrane potential or cellular stores of ATP.

4-Aminobenzoic Acid↗
PubMed1993

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.

1-Methyl-4-phenylpyridinium↗
PubMed1993

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 patient's 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.

Brain Death↗
PubMed1993

ATP synthase activity is required for fructose to protect cultured hepatocytes from the toxicity of cyanide.

The contributions of the loss of the mitochondrial membrane potential (MMP) and a depletion of ATP to the genesis of lethal injury were evaluated in the killing of cultured hepatocytes by cyanide (CN). The glycolytic production of ATP from fructose (Fru) maintained the MMP and prevented the killing by CN. Inhibition of the mitochondrial ATP synthase by 0.1 micrograms/ml oligomycin (Oligo) reduced ATP stores at the same rate and to the same extent as did 1 mM CN. With Oligo there was no loss of the MMP, and the hepatocytes maintained viability over the 6 h during which CN killed all of the cells. Oligo had no effect on the rate of killing by CN. However, Oligo reversed the protective effect of Fru on CN-induced killing, a result that correlated with the loss of MMP but not with the depletion of ATP. Neither Fru nor Oligo affected the intracellular acidosis achieved with CN alone. Fru also prevented toxicity of the uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), a result that correlated with the preservation of MMP. Oligo potentiated the toxicity of CCCP. It is concluded that a functioning mitochondrial ATP synthase is required for the production of ATP from Fru to prevent the killing of hepatocytes by CN. The extent of killing correlated closely with changes in the MMP but not with changes in the content of ATP.

Adenosine Triphosphate↗
PubMed1993

Successful donation and transplantation of multiple organs from a victim of cyanide poisoning.

Demand for viable human organs for transplantation continues to exceed the supply. To expand supply, the criteria for identification and management of suitable donors must continue to evolve. Poisoned patients are often excluded as potential organ donors due to perceived risks of transmittable agents and/or physiologically compromised organs. In this report, a patient succumbed after an intentional ingestion of cyanide and multiple pharmaceuticals. Donor organ viability was determined by lack of significant injury beyond the central nervous system. Following standard procurement procedures, the heart, liver, corneas, 16 skin grafts and 16 bone grafts were deemed suitable and successfully transplanted. All organ recipients were doing well eight months post transplantation. The focus of procurement personnel should be on tissue injury and not on the mere presence of clinical effect of a toxic agent. With the paucity of organs available, poison centers need to be cognizant of this dilemma when faced with a toxicologically compromised potential organ donor.

Adult↗
PubMed1993

Microtubule antagonists activate programmed cell death (apoptosis) in cultured rat hepatocytes.

We investigated the mechanism of lethal injury following the disruption of microtubules in cultured hepatocytes treated with vinblastine (VBL) or colchicine (COL). These agents kill hepatocytes by a process readily distinguished from two well-known pathways that lead to a loss of viability, namely, oxidative stress and inhibition of mitochondrial electron transport. Cell killing with VBL and COL was accompanied by fragmentation of DNA. Both the loss of viability and the fragmentation of DNA were prevented by the inhibition of protein synthesis within 6 hours following exposure to VBL or COL. Cell death and the fragmentation of DNA were also prevented when Ca2+ was removed from the culture medium. By contrast, the inhibition of protein kinase C prevented cell killing by VBL or COL, but did not alter the extent of DNA fragmentation. The requirements here for protein synthesis, extracellular Ca2+, and protein kinase C activity define a model of apoptosis, or programmed cell death, that seems to involve mechanisms that can be dissociated from the fragmentation of DNA.

Animals↗
PubMed1992

Protection by cyclosporin A of cultured hepatocytes from the toxic consequences of the loss of mitochondrial energization produced by 1-methyl-4-phenylpyridinium.

Cyclosporin A prevented the killing of cultured rat hepatocytes by 1-methyl-4-phenylpyridinium (MPP+). However, in the presence of both cyclosporin and atractyloside, there was no protection. Cyclosporin had no effect on the depletion of ATP or the loss of mitochondrial energization by MPP+. Cyclosporin, however, did prevent the increase in the molecular order of hepatocyte membranes produced by MPP+. These data suggest that mitochondrial de-energization produced by MPP+ is accompanied by a "permeability transition" analogous to that which occurs in vitro in the presence of calcium. By preventing this transition, cyclosporin protects the cells. By antagonizing this action of cyclosporin, atractyloside restores the cell killing. The mitochondrial transition is causally linked to cell killing by a mechanism that increases the molecular order of the hepatocyte plasma membrane.

1-Methyl-4-phenylpyridinium↗
PubMed1991

An in vitro study of the potency and stability of fortified ophthalmic antibiotic preparations.

We studied the potency of fortified ophthalmic antibiotic preparations of cefazolin sodium (50 mg/ml) and tobramycin sulfate (15 mg/ml), as measured by the minimum inhibitory concentration, against Streptococcus pneumoniae and Pseudomonas aeruginosa, respectively. We also examined absorbance spectra, pH, and the effect of storage temperature on these fortified solutions to determine their stability over a four-week period. Cefazolin and tobramycin maintained a constant potency throughout the experiment. There was no difference in potency if the fortified solutions were stored at 4 C or 24 C. Cefazolin stored at 24 C exhibited changes in both its absorbance spectra and pH after seven days. Cefazolin stored at 4 C and tobramycin stored at 24 C and 4 C remained stable throughout the four-week period.

Anti-Bacterial Agents↗
PubMed1990

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.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Mechanisms of toxic cell injury.

The biochemical mechanisms by which xenobiotic agents initiate cell injury involve networks of interactions at a variety of molecular and structural targets. The author highlights current concepts in six major areas of investigation: covalent binding, oxidative stress, alterations of glutathione and protein thiols, peroxidation and hydrolysis of phospholipids, mitochondrial deenergization, and alterations of intracellular calcium homeostasis.

Calcium↗
PubMed1987

The role of lipid peroxidation in the chemical-dependent activation of hepatic phospholipase C in vitro.

This study assessed the role of lipid peroxidation in the chemical-dependent activation of hepatic phospholipase C in vitro. Hepatocellular membranes (1000 X g) were incubated with sn-[1,3-14C] glycerol-3-P, ATP, CoA, palmitate, Ca2+, NaF and dithiothreitol to form membrane-bound, labeled phosphatidic acid. Membrane-associated phosphatidate was incubated (10-45 min) with 2 mM Fe2+SO4 or 5mM CCl4 in the presence or absence of various antioxidants. Membranes exposed to Fe2+SO4 displayed an antioxidant-sensitive, 20-fold increase in malonic dialdehyde (MDA) formation without measurable increase in phospholipase C activity. In contrast, membranes exposed to 5 mM CCl4 displayed an antioxidant-insensitive, 2-3-fold increase in phospholipase C activity without significant increase in MDA production. These results suggest that under these incubation conditions in vitro, the CCl4-dependent activation of hepatic phospholipase C is not regulated by nor dependent upon the peroxidation of membrane phospholipids.

Animals↗
PubMed1986

Acute manic psychosis following the dermal application of N,N-diethyl-m-toluamide (DEET) in an adult.

Extensive animal testing and 30 years of human experience have established the general safety of DEET when applied episodically to skin or bedclothes. Local and systemic toxic and allergic reactions to DEET have been observed in man. Three weeks prior to admission, for the purpose of self-medication, a 30 year old man began daily applications of the insect repellant, DEET followed by a 1-2 hour period in a light-bulb heated box. Sedation and incoherence were noted for short periods following each application session. Aggressiveness and psychotic ideation led to hospital admission where he displayed psychomotor hyperactivity, rapid and pressured speech, tangentiality, flight of ideas, and grandiose delusions. Treatment was begun with haloperidol. Clinical improvement was complete within 6 days, atypical for classic endogenous mania. Drug and metabolites were identified in the urine more than 2 weeks after the last drug application.

Administration, Topical↗