Search

Stress responses are essential for survival, but become detrimental to health and cognition with chronic activation. Chronic hypothalamic-pituitary-adrenal axis release of glucocorticoids induces hypothalamic-pituitary-adrenal axis dysfunction and neuronal loss, decreases learning and memory, and modifies glucocorticoid receptor/mineralocorticoid receptor expression. Elderly who report increased stress are nearly 3 times more likely to develop Alzheimer's disease, have decreased global cognition and faster cognitive decline than those reporting no stress. Patients with mild cognitive impairment are more sensitive to stress compared to healthy elderly and those with Alzheimer's disease. Stress may also transduce neurodegeneration via the gut microbiome. Coping styles determine hippocampal mineralocorticoid receptor expression in mice, indicating that coping modifies cortisol's effect on the brain. Identifying neuroprotective coping strategies that lessen the burden of stress may prevent or slow cognitive decline. Treatments and education designed to reduce stress should be recognized as neuroprotective.

We hypothesized that a prior history of a major depressive disorder would not compromise the efficacy of percutaneous transluminal coronary angioplasty (PTCA), a coronary revascularization procedure, in improving quality of life and health status when comparing patients with no previous history. To determine the utility of screening for risk for depression in heart patients scheduled for PTCA, 190 patients were administered a two-item depressive disorders screener prior to PTCA and the SF-36 and Seattle Angina Questionnaire prior to and 6 months post procedure. Results reveal that while those with no prior history of depression had statistically better quality of life and health status outcomes than those with a probable past depression, (P <.05), the clinically meaningful differences as determined by effect size scores showed that those susceptible to recurrent depression benefited from PTCA as well as, and on some measures better than those with no previous history. Prescreening patients at probable risk for a depression is not a valid or helpful enterprise if the purpose is to develop intervention strategies for improving outcome post PTCA. Screening out patients based on history of depression may in fact lead to an inequitable allocation of resources and have no major benefit in enhancing quality of life and improving health status.

Muconic acid (MA) is a urinary metabolite of benzene and has been used as a biomarker of exposure to benzene in humans exposed to levels as low as 1 ppm. We have modified a high-pressure liquid chromatography (HPLC) based assay for urinary MA (Ducos et al., 1990) by the use of a diode array detector. This modification increases the specificity of the HPLC-based assay by identifying false positives. In addition, we have developed a gas chromatography (GC) based assay that uses a flame ionization detector (GC-FID). Both assays identified and quantified MA in human urine at concentrations greater than 40-50 ng/ml. Assay precision was within 10% relative standard deviation for MA concentrations above 90 ng/ml using the HPLC assay and above 40 ng/ml using the GC-FID assay. Quantitative accuracy of the assays was evaluated by determining MA in human urine samples using both methods and also a gas chromatography-mass spectrometry (GC-MS) procedure. Numerical correlation among the three assays was good at MA concentrations above 100 ng/ml.

Perfusate from rat livers perfused with benzene (approximately 0.7-7 x 10(-4) M) or trans,trans-muconaldehyde (MUC) (10(-4) M) was extracted and analyzed by reverse-phase HPLC. Based on retention time and co-elution experiments, benzene was found to be metabolized to trans,trans-muconic acid, a urinary ring-opened metabolite of benzene and a major in vivo and in vitro metabolite of MUC. These data demonstrate that benzene ring-opening occurs in the liver. Following perfusion with MUC (a microsomal hematotoxic metabolite of benzene), trans,trans-muconic acid and three other MUC metabolites were detected in the perfusate extract, suggesting that these metabolites would be present in the circulation following metabolism of MUC.

trans,trans-Muconaldehyde (MUC), a six-carbon-diene-dialdehyde, is a microsomal, hematotoxic ring-opened metabolite of benzene. MUC is metabolized to a variety of compounds which are formed by oxidation and/or reduction of the aldehyde group(s). In the present studies, MUC and its metabolites were examined for mutagenic activity at the hypoxanthine guanine phosphoribosyltransferase (HGPRT) locus in Chinese hamster V79 cells. Mutagenicity was scored by counting 8-azaguanine-resistant colonies. Of the 6 compounds tested, MUC and its aldehydic metabolites 6-hydroxy-trans,trans-2,4-hexadienal and 6-oxo-trans,trans-hexadienoic acid were mutagenic in that order of potency. The other MUC metabolites tested (1,6-dihydroxy-trans, trans-2, 4-hexadiene, trans, trans-muconic acid, and 6-hydroxy-trans, trans-2,4-hexadienoic acid) had little or not activity in this system. The order of mutagenic activity of MUC and its aldehydic metabolites correlates with their reactivity towards glutathione, suggesting that alkylating potential is important in the genotoxicity of these compounds.

We studied the in vivo metabolism of benzene in mice to ring-opened compounds excreted in urine. Male CD-1 mice were treated intraperitoneally with benzene (110-440 mg/kg), [14C]benzene (220 mg/kg) or trans, trans-muconaldehyde (MUC; 4 mg/kg), a microsomal, hematotoxic metabolite of benzene. Urine, collected over 24 hr, was extracted and analyzed by HPLC with a diode-array detector and by scintillation counting. In addition to trans,trans-muconic acid, previously the only known ring-opened urinary benzene metabolite, a new metabolite, 6-hydroxy-trans,trans-2,4-hexadienoic acid, was detected in urine of mice treated with either benzene or MUC. We identified the new metabolite based on coelution of metabolites and UV spectral comparison with authentic standards in unmethylated and methylated urine extracts. Results presented here are consistent with the intermediacy of MUC in the in vivo metabolism of benzene to ring-opened metabolites.

(E,E)-Muconaldehyde (muconaldehyde) has been identified as a hematotoxic metabolite of benzene in vitro. It is metabolized in mouse liver cytosol to oxidized and reduced derivatives including the alpha, beta-unsaturated aldehydes (E,E)-6-oxohexadienoic acid and (E,E)-6-hydroxy-2,4-hexadienal. In this study we have synthesized the aldehydic metabolites of muconaldehyde. The reaction of glutathione with muconaldehyde and its aldehyde metabolites was investigated. Reactions were bimolecular and stoichiometric in aldehyde and glutathione in the initial phases. Second-order rate constants were determined, and the rates were in the order muconaldehyde > (E,E)-6-hydroxy-2,4-hexadienal > (E,E)-6-oxohexadienoic acid. Further investigation of the reaction of muconaldehyde with glutathione showed that the bimolecular reaction is reversible but the initial product decomposed irreversibly to two or more products, one of which had a red-shifted UV spectrum. Rate constants for these subsequent reactions were determined. The results are discussed in terms of the toxicity of muconaldehyde at tissues distal from the liver, where it is believed to be formed from the metabolism of benzene.

The metabolism of trans,trans-muconaldehyde (MUC), a hematotoxic agent which is a presumed in vivo metabolite of benzene, was studied in mouse liver cytosol. MUC was incubated for 30 min at 37 degrees C with mouse liver cytosol (from CD-1 mice) supplemented with NAD+ and the products were analyzed by reverse phase HPLC. Two products were detected in addition to the previously identified acid-aldehyde 6-oxo-trans,trans-2,4-hexadienoic acid (COOH-M-CHO) and the diacid trans,trans-muconic acid (COOH-M-COOH). Based on the molecular weight (112) obtained by thermo-spray LC-mass spectrometry and the absorbance maximum (269 nm), one of the products was identified as the aldehyde-alcohol 6-hydroxy-trans,trans-2,4-hexadienal (CHO-M-OH). The second product was identified as 6-hydroxy-trans,trans-2,4-hexadienoic acid (COOH-M-OH) by coelution with authentic standard, the fragmentation pattern obtained by electron impact mass spectrometry and the absorbance maximum (258 nm). Time course and concentration dependency studies indicate that COOH-M-OH and COOH-M-COOH are end products of MUC metabolism while CHO-M-OH, and COOH-M-CHO, the initially formed mono-reduction and mono-oxidation products, respectively, are the intermediates leading to these end products. The metabolite COOH-M-OH is formed mainly by oxidation of CHO-M-OH and to a much lesser extent by reduction of CHO-M-COOH, whereas COOH-M-COOH is formed solely by oxidation of COOH-M-CHO. The reduction of MUC to CHO-M-OH is reversible, whereas oxidation to COOH-M-CHO is not. The compound CHO-M-OH is not only oxidized to COOH-M-OH by oxidation of the aldehyde functional group, but is also converted back to MUC by oxidation of the alcohol functional group.

Left ventircular performance and graft patency were studied postoperatively at 2 weeks in 19 patients, and at 9 months in 15 patients. At early follow-up, left ventricular ejection fraction and mean rate of circumferential shortening were unchanged for the group as a whole, but were slightly improved in patients who had had a moderately abnormal preoperative ejection fraction of 0.30 to 0.60. At late follow-up, 10 of 14 patients had occluded at least one graft or the proximal segment of the grafted coronary artery and had an associated decrease in ventricular function. The risk of graft occlusion was greater if the preoperative ejection fraction was decreased; seven of 10 patients with a preoperative EF of less than 0.60 suffered one or more graft occlusions, but only three of 16 patients with a preoperative EF greater than 0.60 had a postoperative graft occlusion (p is less than 0.05). The results suggest that bypass graft surgery is not generally indicated as a measure to improve ventricular function in patients with ischemic heart disease.

6 alpha-chloroepoxides have been tested for in vitro activity in a variety of systems. The epoxides were cis- and trans-1-chloropropene oxide, cis- and trans-1,3-dichloropropene oxide, trichloroethylene oxide and tetrachloroethylene oxide. The epoxides were assayed for mutagenicity in the absence of metabolic activation in S. typhimurium TA1535 and E. coli WP2 uvrA and for preferential inhibition of growth of DNA-repair-deficient E. coli. All 6 epoxides possessed DNA-modifying activity as evidenced by their ability to preferentially inhibit DNA polymerase-deficient E. coli. All of the test chemicals except trichloroethylene oxide were mutagenic for S. typhimurium and all except trichloroethylene oxide and tetrachloroethylene oxide were mutagenic for E. coli Wp2 uvrA. Cis- and trans-1,3-dichloropropene oxide were the most potent mutagens and DNA modifiers. For all cases, the cis isomers were more active than the corresponding trans isomers. alpha-Chloroepoxides are considered likely to be the active intermediates of the carcinogenic parent halo-olefins. These mutagenicity studies are considered relevant in assessing the carcinogenicity of the parent hydrocarbons.

The authors examine the relationship between psychosocial factors and factors and survival of patients with chronic renal failure, while considering simultaneously the influence of parameters of physiologic functioning. Psychosocial and physiologic variables selected for discriminant analysis were extracted from data on 285 home-dialysis patients in Ontario, Canada. This analytical procedure defined which variables best discriminated between the survivor and nonsurvivor groups. The findings suggest that demographic and psychosocial factors may be more important than physiologic variables in determination of survival on home dialysis. The severity and type of depression is of particular importance to outcome.

Angiographic studies demonstrating alterations in left ventricular contraction have been cited as evidence that isolated mitral valve prolapse (MVP) may be associated with a cardiomyopathy. We studied 17 patients with isolated MVP undergoing cardiac catheterization who had chest pain, palpitations, and/or a murmur of mitral regurgitation. Eleven of 13 patients (85%) with no or mild (Grade 1+) mitral regurgitation had normal left ventricular hemodynamic measurements, while three of four patients (75%) with moderate or marked (Grades 2+-4+) regurgitation had abnormal left ventricular hemodynamic measurements. An increased mean rate of circumferential fiber shortening (greater than 1.9 circumferences/sec) was observed in nine of 13 patients (70%). Systolic ventricular wall motion was analyzed from left ventriculograms by methods which quantitate percent shortening of ventricular areas, transverse chords, and radial axes. Marked variations in the number and location of alterations in ventricular contraction were obtained by the different methods used to analyze the ventriculograms, with segments of hypokinesis being detected in from 0-14 patients studied, depending upon the method used. Localization of alterations in contraction predominantly in the basal and mid-segments of the left ventricular and the association of hemodynamic abnormalities with mitral regurgitation suggest that changes in ventricular contraction are primarily related to an alteration of mitral valve function in this condition.

Six epoxides of structurally related chloroalkenes were examined for their carcinogenicity by chronic testing in female ICR/Ha Swiss mice, 30/group. Repeated skin application three times weekly or s.c. injection once weekly were used for the life spans of the mice. The epoxides were: cis-1-chloropropene oxide, trans-1-chloropropene oxide, cis-1,3-dichloropropene oxide, trans-1,3-dichloropropene oxide, trichloroethylene oxide (TCEO), and tetrachloroethylene oxide (PCEO). In mouse skin, cis-1-chloropropene oxide, trans-1-chloropropene oxide, cis-1-,3-dichloropropene oxide, and trans-1,3-dichloropropene oxide induced statistically significant incidences of squamous carcinomas of the skin; TCEO did not cause any skin tumors; and PCEO resulted in three mice with benign skin tumors and one with a squamous carcinoma of the skin. Repeated s.c. injection of the four propene oxides induced statistically significant incidences of local tumors, mostly fibrosarcomas. This was not the case with TCEO and PCEO. The data are consistent with the carcinogenicity findings on the parent chloropropenes and suggest that the epoxides function as their activated carcinogenic intermediates. The essentially negative findings with TCEO and PCEO suggest further studies on the carcinogenicity of trichloroethylene and tetrachloroethylene.

The present study was performed to evaluate scintigraphic imaging with technetium 99m-labeled glucoheptonate and serum enzyme levels of creatine phosphokinase isoenzyme (MB-CPK) in the early diagnosis of perioperative acute myocardial infarction associated with saphenous vein bypass graft operations. Myocardial imaging was done in 27 patients (50% of whom were considered high-risk) before operation and again 5 hours after operation. Four of these patients (15%) had both electrocardiographic and serum MB-CPK evidence of acute myocardial infarction, and all 4 had developed positive postoperative scintigrams. Four other patients had only elevated serum MB-CPK, and scintigrams became positive after operation in 3 of them. In addition, serum MB-CPK 6 hours after operation was 83 +/- 21 mIU/ml (mean +/- standard error of the mean) in patients with positive postoperative scans compared with 24 +/- 5 mIU/ml in those patients with negative postoperative scintigrams (p less than 0.001). Myocardial imaging with 99mTc-glucoheptonate in the perioperative period is rapid, safe, and atraumatic. Furthermore, our results suggest that it is a sensitive method for the early diagnosis of perioperative acute myocardial infarction, and, when imaging is combined with serum MB-CPK isoenzyme analysis, the reliability of the diagnosis of acute myocardial infarction is enhanced even further. Only 1 of the patients who showed perioperative myocardial damage had acute hemodynamic compromise or obvious impairment of recovery in the immediate postoperative period, and the 30-day mortality of the total group was 4% (1 of 27).

An important part of health behavior variability is a supportive environment. This paper examines the concept and discusses its application to a general and geriatric home dialysis population. Social environment is analyzed along three interrelated dimensions: social support, social integration, and social network. The authors conclude that a multimethod approach for assessing environmental support is preferred over a single-item index. Furthermore, a supportive interpersonal environment is important for patients and family, both as a preventive agent and as a protective buffer against the impact of ESRD related stress.

For nearly 20 years, disulfiram implanted subcutaneously, has been used in alcoholics who have failed to respond to other treatment. Significantly positive results have been reported in a large number of cases. Despite this extensive use, many questions remain as to how these effects are exerted. As the reaction to alcohol following disulfiram implantation occurs less frequently and in lower intensity than following oral ingestion, psychological mechanisms probably play a vital role. Based in part on out own recent series of cases, the following explanations are offered regarding the possible mechanisms of action: (1) high motivation to stop drinking is manifested by agreeing to the precedure and reinforced by the procedure; (2) palpable presence of hte drug in the site of implantation; (3) generally sufficient reactivity of the agent to indicate activity to the patient;(4) in obsessional patients there is a removal of the fear of resumption of drinking for an extended period of time. For the more sociopathic patients the implant appears to provide a more structured ego boundary to allow the patient to change.

The nature of the relationship between candidates and their examiners is explored, and suggestions made as to how candidates might comfort themselves during the oral examinations. In addition, the authors describe some of the organizing principles for responding to questions during the question and answer portion of the examination.

This paper summarizes a number of considerations in the areas of technique, structure, diagnosis and formulation for candidates attempting to qualify in the psychiatry oral examination.

Rate-corrected left ventricular ejection time was measured from the aortic pressure tracings of 171 catheterised patients with aortic valve area less than or equal to 1.2 cm2. In 50 patients with pure aortic stenosis, left ventricular ejection time in increased with decreasing valve area and was significantly higher (468 +/- 5 ms, mean +/- SEM) than in 13 normal subjects (435 +/- 5 ms). Additional aortic regurgitation in 72 patients further increased the left ventricular ejection time to 484 +/- 4 ms. Significant mitral stenosis (mitral valve are less than or equal to 1.2 cm2) in 6 patients with aortic stenosis and 33 patients with aortic stenosis and regurgitation reduced the left ventricular ejection time to normal. Similarly, severe mitral regurgitation in 3 patients with aortic stenosis and regurgitation reduced left ventricular ejection time to normal, though slight or moderate mitral regurgitation in 4 of these patients did not. These data show that the prolonged left ventricular ejection time in aortic valve disease may be restored to normal in the presence of coexisting significant mitral disease.

The authors wished to study some of the internal psychological dynamics of achievement in a nonpatient identified high school population. Questionnaires were administered to the Grade 13 students and their parents in a large high school. A number of students whose achievement and educational plans were not congruous with their general background were selected for interview. The findings suggest that a wide variety of ages and developmental stages can be discerned as critical points in the development of a student's attitude toward higher education. These students have many values in common, and their values appear related to a positive or negative identification with parental values. The students themselves show a wide range of personality integration. They relate in a special way to a wide variety of teachers' personalities.

1,2-Dibromoethane (DBE) and two of its potential metabolites, bromoethanol (BE) and bromoacetaldehyde (BA), were tested for carcinogenicity in male and female B6C3F1 mice using 30 animals of each sex per group. The carcinogen DBE was included in this assay as a positive control. The compounds were administered in distilled drinking water using equimolar concentrations, 4 mmol, of the chemicals. The dose chosen was based on subchronic bioassays of three months' duration. The chronic tests were continued for approximately 450 days in the case of DBE and approximately 560 days for both BE and BA. DBE induced squamous carcinomas of the forestomach in 22 females and 26 males and squamous papillomas of the esophagus in 3 females. BE induced squamous papillomas of the forestomach only in 10 females and 9 males. BA did not induce a significant incidence of tumors of the forestomach. Significant tumor incidences at other sites were not observed in any groups including the distilled water control group. Based on these findings, it is unlikely that BE or BA are activated carcinogenic intermediates of DBE.

Recent advances in understanding of the pathophysiology of myocardial necrosis indicate the need for a noninvasive method that will allow detection and quantification of infarcts in the first few hours after the onset of infarction. Myocardial infarct scintigraphy using technetium-99m glucoheptonate is capable of detecting infarction in dogs and man within 4 to 6 hours of onset. Studies were performed in 45 dogs with acute myocardial infarction: 28 with with an anterior infarct, 5 with an inferior infarct, 6 with an anterior infarct studied after infusion of mannitol and 6 with ligation of the left anterior descending coronary coronary artery and reperfusion of the ischemic area. The dogs were given 20 m Ci of technetium-99m glucoheptonate 1 hour after coronary occlusion, subjected to imaging 5 to 9 hours later and then killed. The experiments revealed that (1) scintigraphic infarct size correlated with infarct weight for anterior (r = 0.85) and inferior (r = 0.88) infarcts; (2) technetium-99m glucoheptonate also concentrated in a rim of myocardium around the infarct that probably represented the ischemic zone; and (3) technetium-99m glucoheptonate uptake by infarcted myocardium could be greatly increased with mannitol and reperfusion.

Fiscal matters were analyzed in four specialized programmes of the Department of Psychiatry at the Toronto Western Hospital in order to plan for service and academic activities. The resultant analysis allowed for the establishment of criteria for growth and the evaluation of clinical service performance and goals.