Effects of the Long-Term Depletion of Reduced Glutathione in Mice Administered L-Buthionine-S,R-sulfoximine

Effects of the Long-Term Depletion of Reduced Glutathione inMice Administered L-Buthionine-S,R-sulfoximine. SUN, J. D.,RAGSDALE, S. S., BENSON, J. M., AND HENDERSON, R. F. (1985).Fundam. Appl. Toxicol.. 5,913-919. Previous methods to depletein vivo concentrations of reduced glutathione (GSH) have notbeen able to lower tissue GSH levels for extended periods, havebeen toxic, and can alter the metabolism of xenobiotics. A possiblealternative to lower in vivo concentrations of GSH may be theuse of buthionine-S,R-sulfoximine (BSO) in the drinking waterof laboratory animals to inhibit the biosynthesis of GSH. Ithas been previously reported that 20 mM BSO in the drinkingwater given to mice was able to lower GSH levels in a varietyof tissues after 15 days. In order to more fully characterizethe in vivo depletion of GSH in tissues by ingestion of BSOand determine if this method would be suitable in studies requiringdepressed levels of GSH for extended periods, we added differentamounts of this agent to the drinking water given to mice forvarious times up to 28 days. We found that ingested BSO at thehighest concentrtion used in drinking water (30 mM) was ableto maximally lower GSH concentrations in mouse lungs, lung lavagefluid, liver, kidneys, and blood to 59.0 ? 3.6%, 35.0 ? 5.1%,44.3 ? 1.5%, 69.5 ? 3.9%, and 70.0 ? 6.0% of control mice, respectively,for up to 28 days. These lowered concentrations of tissue GSHreturned to control levels after mice were returned to untreateddrinking water for 7 days. The potential toxicity of such treatmentswas also evaluated. Levels of alkaline phosphatase, lactatedehydrogenase, glucose-6-phosphate dehydrogenase, glutathioneperoxidase, and glutathione reductase in lungs and lung lavagefluid, and total and differential cell counts from lung lavagefluid were not different between control and BSO-treated mice.This showed that BSO treatment did not produce indications oflung injury as measured by these biochemical parameters. Serumaspartyl transferase and -glutamyl transpeptidase activitieswere unaffected by the BSO treatments, indicating normal liverfunctions. Lung and liver cytochrome P-450 concentrations werealso not different between controls and BSO-treated animals.Thus, BSO in the drinking water of mice was able to effectivelylower in vivo levels of GSH without eliciting aCUte toxic responses.     

The Fungicide Benomyl (Methyl 1 -(Butylcarbamoyl)-2-benzimidazolecarbamate) Causes Testicular Dysfunction by Inducing the Sloughing of Germ Cells and Occlusion of Efferent Ductules

The Fungicide Benomyl (Methyl 1-(Butylcarbamoyl)-2-benzimidazolecarbamate)Causes Testicular Dysfunction by Inducing the Sloughing of GermCells and Occlusion of Efferent Ductules. HESS, R. A., MOORE,B. J., FORRER, J., LINDER, R. E., ABUEL-ATTA, A. A. (1991).Fundam. Appl. Toxicol 17, 733–745. Adult male Sprague-Dawleyrats (100 days of age) were given single oral doses of the fungicidebenomyl (methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate)in dosages ranging from 25 to 800 mg/kg body weight. The testisand excurrent ducts were examined at 2 and 70 days posttreatmentto determine the chemical effects on spermatogenesis and theepididymis. Primary effects seen at 2 days postexposure weretesticular swelling and occlusions of the efferent ductules.Mean testis weight peaked with 400 mg/kg. Premature releaseof germ cells (sloughing), detected even with the lowest dosage(25 mg/kg), was the most sensitive short-term response to benomyl.Sloughing was found primarily in Stage VII of the spermatogeniccycle at the lower dosages, but at higher dosages sloughingextended into all stages except for Stages VIII-XI. Occlusionsof the efferent ductules of the testis were dose-dependent andcorrelated with testis weight. Sperm and sloughed germ cellswere compacted in the ductal lumen of occluded ductules, whichwere surrounded by two to four layers of polymorphonuclear leukocytesand other inflammatory cells. Although the caput epididymidiscontained sloughed germ cells and appeared swollen, evidenceof permanent occlusion was not found. The long-term (70 days)effects of benomyl were decreased testis weight (at 400 mg/kg),dose-dependent increases in seminiferous tubular atrophy, andincreases in the number of reproductive tracts containing occludedefferent ductules. Fibrosis, granulomas, and abnormal growthwere long-term consequences of occluded ductules, which werepresent 100% of the time in testes containing 26–100%seminiferous tubular atrophy. Only a few testes were found tobe completely regressed. Occlusion of efferent ductules anddisruption of the seminiferous epithelium by sloughing of germcells are overlapping dose-dependent mechanisms responsiblefor short- and long-term effects of benomyl on the rat testis.     

FINDING MEANING IN A CHILD'S VIOLENT DEATH: A FIVE-YEAR PROSPECTIVE ANALYSIS OF PARENTS' PERSONAL NARRATIVES AND EMPIRICAL DATA

Finding meaning in the death of a loved one is thought to be extremely traumatic when the circumstances surrounding the death is perceived to be due to negligence, is intentional, and when the deceased suffered extreme pain and bodily harm immediately prior to death. We addressed this assumption by obtaining personal narratives and empirical data from 138 parents 4, 12, 24, and 60 months after an adolescent's or young adult child's death by accident, suicide, or homicide. Using the Janoff-Bulman and Frantz's(1997) framework ofmeaning-as-comprehensibility and meaning-as-significance, the purposes were to identify the time course to find meaning, present parents' personal narratives describing finding meaning in their experiences, identify predictors of finding meaning, and compare parents who found meaning versus those who did not on five health and adjustment outcomes. The results showed that by 12 months postdeath, only 12% of the study sample had found meaning in a child's death. By 60 months postdeath, 57% of the parents had found meaning but 43% had not. Significant predictors of finding meaning 5 years postdeath were the use of religious coping and support group attendance. Parents who attended abereavement support group were 4 times more likely to find meaning than parents who did not attend. Parents who found meaning in the deaths of their children reported significantly lower scores on mental distress, higher marital satisfaction, and better physical health than parents who were unable to find meaning. Recommendations for future research are made.     

Morphology of the Cardiac Conduction System in Patientswith Electrophysiologically Proven Dual Atrioventricular Nodal Pathways

Conduction System in Dual AV Nodal Pathways. Introduction: Although the electrophysiologic criteria for dual atrioventricular nodal pathways are well established, the anatomical substrate is still unclear.
Methods and Results: We examined the hearts from 10 patients who had been studied electrophysiologically prior to cardiac transplantation. All 10 patients were male, aged 22 to 60years. Nine of the 10 patients had dual atrioventricular nodal pathways according to acceptedcriteria. Histologic studies of the atrioventricular conduction system showed normal structureof the atrioventricular node in all 10 hearts, with minor variations within the node in 3 cases, within the penetrating bundle in 3 cases, and within the nonbranching bundle in 3 cases. Theatrial approaches to the atrioventricular node were generally scanty in 6 hearts. The solitarycase that was shown electrophysiologically to lack dual pathways had no obvious difference inthe structure of the nodal area other than sparsity of transitional cells. We were unable tolocate any extranodal atrial tracts as described by other investigators.
Conclusion: The anatomical substrate for conduction over dual pathways may he too subtleto be detected by gross morphologic studies. Since dual pathways were unmasked in allpatients but one during electrophysiologic studies, it may be that the potential for these pathways is ubiquitous.     

Pharyngeal diverticula

A series of 73 hypopharyngeal (Zenker's) diverticula is reported and the choice of treatment and technique of excision are discussed. The problems of excision include operation on an infected site with limited access but few patients are unfit for the procedure. Preoperatively the sac should be packed and the oesophagus stented. The side of approach is unimportant as the condition is essentially midline. Cricopharyngeal myotomy appears to reduce the recurrence rate, possibly by improving coordination of pharyngeal contraction and upper oesophageal relaxation. The use of electrocoagulation is not recommended as 20% of patients require repeated general anaesthesia and the procedure fails in 13%. For all but the smallest pouches, excision is the treatment of choice.     

STUDIES OF STAPHYLOCOCCAL TOXINS IN RELATION TO TOXIC EPIDERMAL NECROLYSIS (THE SCALDED SKIN SYNDROME)

Summary.— A diffusible product which causes extensive epidermal splitting in new-born mice, has been obtained from phage group II staphylococci in a highly purified form. It is free of staphylococcal α-toxin, δ-toxin and hyaluronidase and has a molecular weight of approximately 33,000. Criteria of purity are presented and the possible role of this factor in experimental T.E.N. is discussed.