Glutathione conjugate mediated toxicities

Glutathione (gamma-glutamyl-L-cysteinylglycine: GSH) is present in high concentrations in most living cells and participates in a variety of vital cellular reactions. In particular, GSH protects cells from potentially toxic electrophiles formed via the metabolism of xenobiotics, and such reactions have long been associated with the process of detoxication (Baumann and Preusse, 1879; Jaffe, 1879). Compounds that form GSH conjugates are processed by gamma-glutamyl transpeptidase (gamma-GT) and dipeptidases to cysteine S-conjugates, which are usually excreted in urine as their corresponding mercapturic acids (S-substituted N-acetyl-L-cysteine conjugates). In addition, GSH peroxidase activity, whether catalyzed by the selenium-dependent GSH peroxidase or by the GSH S-transferases, serves to detoxify hydrogen peroxide and organic hydroperoxides. However, in recent years, evidence indicating that GSH conjugation plays an important role in the formation of toxic metabolites from a variety of chemicals has accumulated. Thus, several classes of compounds are converted, via conjugation with GSH, into either cytotoxic, genotoxic, or mutagenic metabolites. The purposes of the symposium on "Glutathione Conjugate Mediated Toxicities" presented at the 1990 Society of Toxicology Annual Meeting were to discuss recent findings in this rapidly moving field, to present ideas on the mechanisms and modulation of GSH conjugate-dependent toxicities, to present a consensus on the broader significance of this work, and to identify directions for future research. This paper summarizes these presentations. GSH conjugation reactions are involved in the bioactivation of several classes of xenobiotics, and four types of GSH-dependent bioactivation reactions can be identified: (1) directly toxic GSH conjugates may be formed from vicinal dihaloalkanes via formation of electrophilic sulfur mustards; (2) cysteine conjugate beta-lyase-dependent bioactivation is involved in the selective nephrotoxicity of haloalkenes; (3) GSH conjugates of hydroquinones and isothiocyanates may serve as transport and targeting metabolites; and (4) GSH-dependent reactions may be involved in the release of toxic agents from precursor organic thiocyanates and nitrosoguanidines (N-methyl-N'-nitro-N-nitroguanidine).     

Research review: a computer-based diagnostic model for individual case review

A previous study found that Iliad, a diagnostic expert system, detects diagnostic errors missed by peer review organization (PRO) review. That study used volunteer physicians from an institution as gold standard reviewers, however. The article discusses a second experiment employing Utah PRO (UPRO) review physicians as gold standards. Iliad was compared with the Unified Clinical Data Set used by the UPRO and was found to detect otherwise unsuspected diagnostic errors. The confirmation rate of Iliad flags was much higher in the earlier study, however. No agreement was found between institution and UPRO physicians, but there was agreement between a unique physician (who was both an institution and UPRO physician) and each of the two groups. Because Iliad screens for potential diagnostic errors to be confirmed or denied by gold standard physician review, the different types of physicians in the two experiments might have been the cause.     

Human complement regulatory proteins protect swine lungs from xenogeneic injury

BACKGROUND: Pulmonary xenotransplantation is not possible because of hyperacute lung injury, the pathogenesis of which is unknown. This study evaluates complement-dependent pathways of pulmonary injury during heterologous perfusion of swine lungs. METHODS: Lungs from unmodified swine and swine expressing human decay-accelerating factor and human CD59 (hDAF/hCD59 swine) were perfused with either human plasma or baboon blood. Pulmonary vascular resistance and static pulmonary compliance were measured serially, and swine lung tissue were examined by light microscopy. Complement activation was assessed by serial measurements of baboon plasma C3a-desArg concentrations. RESULTS: Perfusion of unmodified swine lungs with human plasma and baboon blood resulted in hyperacute lung injury within minutes of perfusion. However, function was preserved in swine lungs expressing human decay-accelerating factor and human CD59. In both study groups, xenogeneic perfusion with baboon blood resulted in at least a sevenfold increase in plasma C3a-desArg levels suggesting transient activation of complement. CONCLUSIONS: Lungs from swine expressing human decay-accelerating factor and human CD59 were resistant to injury during perfusion with human plasma and baboon blood, indicating that complement mediated some of the features of xenogeneic acute lung injury.     

Tarsal tunnel syndrome: a review of the literature

Tarsal tunnel syndrome is an uncommon clinical entity. This article will review the published reports on tarsal tunnel syndrome with respect to its anatomy, cause, pathophysiology, clinical presentation, diagnosis, treatment, and results of treatment in an attempt to improve understanding of this problem.     

Development and evaluation of a new composite Laserskin graft

BACKGROUND: Tremendous effort has been made to improve the graft take rate of cultured epidermal autograph. The purpose of this study is to develop and evaluate a new composite Laserskin graft (CLSG) as a human skin substitute for wound resurfacing. METHODS: The seeding efficacy of cultured keratinocytes on plain Laserskin was compared with the 3T3 cell-seeded Laserskin and allogenic fibroblast-populated Laserskin. Three different types of CLSG, 2 cm in diameter each, were prepared and tested in rats. Type A CLSG consisted of proliferative allogenic rat fibroblasts on both sides of the Laserskin with autologous keratinocytes also on the upper side. Fibroblasts and keratinocytes were seeded only on the upper side of the Laserskin in type B CLSG. Keratinocytes alone were seeded on plain Laserskin in type C CLSG. Type B CLSG consisting of autologous keratinocytes and autologous dermal fibroblasts was tested on five selected wounds (5x5 cm each) of a patient with full-thickness burn. In another burn patient, type B CLSG consisting of autologous keratinocytes and allogenic dermal fibroblasts was grafted onto three wounds (5x5 cm each). RESULTS: The seeding efficacy of human keratinocytes on plain Laserskin increased from 75% to 95% when proliferative allogenic fibroblasts were grown as a feeder layer on the Laserskin. The seeding efficacy of rat keratinocytes increased from 36% to 88% in the presence of a proliferative allogenic fibroblast feeder layer, whereas human/rat keratinocytes had respective seeding efficacy of 98%/91% on Laserskin preseeded with mitomycin C-treated 3T3 cells. Skin biopsies of grafted type A CLSG on day 14 after grafting showed complete epithelialization without severe inflammation in 16 of 20 (80%) grafted surgical wounds in rats. There were eight (40%) and seven (35%) "takes" of the CLSG in types B and C, respectively. The infection rate in type B CLSG was two (10%). There was one (5%) infection in types A and C. The respective take rates on the two patients grafted with type B CLSG were 60% and 100%. CONCLUSION: The animal experiment and the preliminary clinical data showed that the CSLGs consisting of autologous keratinocytes and of autologous/allogenic fibroblasts are good human skin substitutes in terms of durability, biocompatibility, high seeding efficacy for keratinocytes, high graft take rate, and low infection rate.     

Hip fracture in Hong Kong over the last decade--a comparison with the UK.

BACKGROUND: Hip fracture is a major public health problem in Asia and the UK. The objectives of this study were to describe the trends of hip fracture in Hong Kong over the last decade, and to compare the incidence in Hong Kong with that from the Wessex Health Region of the UK in 1995. METHODS: The number of hip fractures was calculated using hospital discharge records for all public hospitals in Hong Kong in 1991 and 1995. Age-specific incidence rates were then calculated using the mid-year census population for the two years. These rates were presented with previously reported age-specific rates for Hong Kong in 1966 and 1985. These age-specific rates for Hong Kong in 1995 were compared with rates for the Wessex Health Region of the UK. The total number of hip fracture expected in 2010 was calculated by applying the age-specific rates of 1995 to the projected population for 2010. RESULTS: In 1995, a total of 1138 men and 2782 women in Hong Kong fractured their hip. The age-specific rates had remained static from 1985 to 1995, after substantial rise from 1966 to 1985. In 1995, the rates of hip fracture rates were 11/1000 in women and 5/1000 in men who were 70 years and older. These rates were almost identical to those observed in the Wessex Health Region of the UK. CONCLUSION: The age-specific incidence rates of hip fracture had not risen in Hong Kong in the last decade. The incidence of hip fracture in Hong Kong was similar to that in the UK in 1995. The total number of patients with hip fracture in Hong Kong will increase substantially in the future, as a result of the ageing of the population.     

Lorazepam for chronic catatonia: a randomized, double-blind, placebo-controlled cross-over study

Acute catatonic syndromes occurring in the context of various medical and neuropsychiatric conditions, including schizophrenia, have been shown to respond well to benzodiazepines (BZD). However, there have been no studies specifically designed to address the BZD treatment response of persistent catatonic states. Eighteen patients with clinically stable chronic schizophrenia, who also displayed enduring catatonic features, underwent a 12-week long, random assignment, double-blind, placebo-controlled cross-over trial with lorazepam (6 mg/day). A comprehensive assessment, including the subjects’ clinical and motor (catatonic as well as drug-induced movement disorders) condition, was performed at baseline and four weekly intervals thereafter. Pre-existing medication was kept constant throughout the study. Lorazepam had no effect on the subjects’catatonic signs and symptoms, suggesting that acute and chronic catatonic syndromes associated with schizophrenic illness might have a different neurobiological basis. Received: 25 May 1998/Final version: 22 September 1998