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.     

INITIAL DEVELOPMENT OF A NEW CULTURE-SPECIFIC SCREEN FOR EMOTIONAL DISTRESS IN OLDERCARIBBEAN PEOPLE

Previous research and our own observations suggested that older Caribbean people might use terms for emotional distress that differed from those found in standard screening instruments. Using a combination of qualitative approaches derived from the ‘new cross-cultural psychiatry’, we have developed a new 13-item culture-specific screen containing items which both overlap and differ from those found in, for example, the Geriatric Depression Scale. Further research is in progress to test the validity of this screen in a large community sample.     

Polymerization Depths of Contemporary Light-Curing Units Using Microhardness

Purpose: This research investigated composite depths of cure using a variety of light‐curing units and exposure protocols. Materials and Methods: Composite (Herculite XRV, shade A2, Kerr, Orange, California) was exposed in opaque compules to conventional quartz tungsten halogen (QTH) units, soft‐start units, high‐intensity QTH and plasma arc (PAC) curing lights, and one argon laser. Cured compules were sonicated to remove uncured composite and were sectioned and polished along the long axis to expose cured composite. Knoop hardness was measured 0.5 mm from the irradiated, top surface and then at 1.0 mm and in 1.0‐mm increments until reliable readings could no longer be obtained. Hardness values were compared by analysis of variance at similar depths within a specific curing‐light classification, using the hardness of the standard 40‐second conventional QTH exposure as comparison (Dunnett's t‐test). Depth of cure was defined as the deepest hardness value found equivalent to that at 0.5‐mm depth for a specific curing light and scenario. Results: Conventional QTH lights provided similar hardness profiles. At 2‐mm depth, use of a different unit or curing tip made no difference in hardness compared with the standard. At this depth, soft‐start (pulse‐delay and step‐cure) methods yielded hardness similar to that of the standard. High‐intensity QTH lights provided similar hardness at 2‐mm depth in 10 seconds to that of the standard 40‐second exposure. Plasma arc exposure for less than 10 seconds produced inferior hardness compared with the standard. A 10‐second PAC and a 5‐second laser exposure gave hardness at 2‐mm depth equivalent to that of the 40‐second standard. Depth of cure for almost all curing scenarios was not greater than 2 mm. CLINICAL SIGNIFICANCE Similar‐type conventional QTH lights with different tip diameter (8 and 12 mm) provide similar composite cure characteristics. Soft‐start techniques provide similar cure profiles to those achieved with conventional QTH technique when used according to manufacturer's recommendations. High‐intensity QTH units and the argon laser can reduce exposure time while providing composite with similar hardness to that of conventional QTH curing. Plasma arc exposure should be at least of 10 seconds duration to provide hardness equivalent to that achieved with conventional 40‐second QTH exposure. Even with consideration of high‐intensity curing units, composite increments should still be no greater than 2 mm to provide homogeneous hardness.     

The HIT Expert Probability (HEP) Score: a novel pre‐test probability model for heparin‐induced thrombocytopenia based on broad expert opinion

Summary. Background: The diagnosis of heparin‐induced thrombocytopenia (HIT) is challenging. Over‐diagnosis and over‐treatment are common. Objectives: To develop a pre‐test clinical scoring model for HIT based on broad expert opinion that may be useful in guiding clinical decisions regarding therapy. Patients/methods: A pre‐test model, the HIT Expert Probability (HEP) Score, was constructed based on the opinions of 26 HIT experts. Fifty patients referred to a reference laboratory for HIT testing comprised the validation cohort. Two hematology trainees scored each patient using the HEP Score and a previously published clinical scoring system (4 T’s). A panel of three independent experts adjudicated the 50 patients and rendered a diagnosis of HIT likely or unlikely. All subjects underwent HIT laboratory testing with a polyspecific HIT ELISA and serotonin release assay (SRA). Results: The HEP Score exhibited significantly greater interobserver agreement [intraclass correlation coefficient: 0.88 (95% CI 0.80–0.93) vs. 0.71 (0.54–0.83)], correlation with the results of HIT laboratory testing and concordance with the diagnosis of the expert panel (area under receiver‐operating curve: 0.91 vs. 0.74, P = 0.017) than the 4 T’s. The model was 100% sensitive and 60% specific for determining the presence of HIT as defined by the expert panel and would have allowed for a 41% reduction in the number of patients receiving a direct thrombin inhibitor (DTI). Conclusion: The HEP Score is the first pre‐test clinical scoring model for HIT based on broad expert opinion, exhibited favorable operating characteristics and may permit clinicians to confidently reduce use of alternative anticoagulants. Prospective multicenter validation is warranted.     

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.     

ICD Data Storage: Value in Arrhythmia Management

Sophisticated diagnos tic information is provided by the latest generation of implantable defibriliators. The success of therapy and the type of therapy successful in terminating ventricular arrhythmias is provided by interrogating the ICD device. In addition, R to R interval information can be retrieved. In selected devices, either locai bipolar electrograms from the rate sensing leads or wide bipolar electrograms from the energy delivering leads provide visual confirmation of the presence of ventricular tachyarrhythmic events loading to ther apy. The value and limilations of this sophisticated diagnostic information in providing insight into the electrical events triggering therapy and the events triggering ventricular arrhythmias are discussed.