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Biomedical subjects

C A Lang

Publications and source records attributed to C A Lang.

At least 19 recordsLinked to original sources
PubMed1992

Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney.

Glutathione (GSH) plays an essential role in the detoxification of acetaminophen (APAP) and the prevention of APAP-induced toxicity in the kidney. Our previous results demonstrated that a GSH deficiency is a general property of aging tissues, including the kidney, suggesting a hypothesis that senescent organisms are at greater risk to APAP-induced renal damage. To test this, C57BL/6NIA mice of different ages through the life span were injected with various doses of APAP, and the extent of GSH and cysteine (Cys) depletion and recovery were determined. At time intervals up to 24 hr, kidney cortex samples were obtained, processed and analyzed for glutathione status, namely GSH, glutathione disulfide (GSSG), Cys and cystine, using an HPLC method with dual electrochemical detection. In the uninjected controls, GSH and Cys concentrations decreased about 30% in the aging mouse, but the GSSG and cystine levels were unchanged during the life span. APAP administration depleted the kidney GSH and Cys contents in a dose- and time-dependent manner. Four hours after APAP administration, GSH levels of the young, growing (3- to 6-month) and the mature (12-month) mice decreased 34 and 58%, respectively, and recovered to near control values by 24 hr (95 and 98%). In contrast, the extent of depletion in old (31-month) mice was greater (64%) and the 24-hr recovery was less, returning only to 56%. Likewise, Cys levels of the young and mature mice decreased 49 and 65%, respectively, 4 hr following APAP, and increased to 99 and 85% by 24 hr. In contrast, in old mice, there was a 78% depletion after 4 hr followed by a recovery of only 65% by 24 hr. These results demonstrated clearly that in the aging mouse kidney, a GSH and Cys deficiency occurs that is accompanied by an impaired APAP detoxification capacity.

Acetaminophen↗
PubMed1992

Low blood glutathione levels in healthy aging adults.

The objective of this investigation was to test the hypothesis that blood glutathione levels are lower in aging human subjects as previously found in blood and tissues of standard rodent models of aging. Thus a study was conducted with 39 men and 130 women, 20 to 94 years old, who were selected by the criteria of being ambulatory, healthy, and free from diabetes mellitus, thyroid disease, anemias, and cancer. The reference group was comprised of the 20- to 39-year-old subjects, whose blood glutathione levels were 547 +/- 53.5 micrograms/10(10) erythrocytes (mean +/- SD) for 40 individuals and defined the reference range (95% confidence limits) of 440 to 654. Based on the 440 micrograms/10(10) erythrocyte cutoff, the incidence of low blood glutathione content in the older subjects increased significantly, particularly in the 60- to 79-year-old group. Their glutathione levels were 452 +/- 86.8 micrograms/10(10) erythrocytes, 17% lower than the reference group (p < 0.001). These findings demonstrate an increased incidence of low glutathione levels in apparently healthy elderly subjects, who thus may be at risk because of a decreased capacity to maintain many metabolic and detoxification reactions mediated by glutathione.

Adult↗
PubMed1991

Colonoscopic surveillance after polypectomy: considerations of cost effectiveness.

OBJECTIVE: To assess the cost effectiveness of the current recommendation that persons who have had an adenomatous colon polyp removed have periodic colonoscopic surveillance at fixed and regular intervals. DESIGN: Cost-effectiveness analysis using data from the medical literature in a simulation model to estimate the costs of and the risk for perforation associated with periodic colonoscopic surveillance for a 50-year-old man followed for 30 years. MAIN RESULTS: A program of colonoscopy every 3 years would incur cumulatively a 1.4% risk for colon perforation, a 0.11% risk for perforation-related death, and direct physician costs of $2071 for colonoscopy (discounted at 5%). If a 50-year-old man's cumulative remaining risk for death from cancer is 2.5% after the removal of a single small adenoma and if effectiveness of colonoscopic surveillance every 3 years is 100%, then one death from cancer could be prevented by doing 283 colonoscopies, incurring 0.6 perforations, 0.04 perforation-related deaths, and direct physician costs of $82,000. If surveillance were 50% effective and the cumulative remaining risk for death from cancer were 1.25%--a plausible scenario--1131 colonoscopies would be required to prevent one death from cancer, incurring 2.3 perforations, 0.17 perforation-related deaths, and physician costs of $331,000. CONCLUSIONS: The cost effectiveness of colonoscopic surveillance is very sensitive to estimates of the cumulative remaining risk for death from cancer after polypectomy as well as to surveillance efficacy. For persons whose remaining risk for death from cancer may be low, such as persons with a single small adenoma, recommendations for colonoscopic surveillance at fixed and regular intervals may be excessively costly.

Aged↗
PubMed1991

Respirometric analysis of the biodegradation of organic contaminants in soil and water.

Client-funded bench-scale investigations concerning the likelihood of successfully applying biological remediation to hazardous wastes must be cost-effective, and they usually need only determine if biodegradation is likely to occur on site. To assess the potential for stimulating biodegradation, biochemical oxygen demand (BOD) was used to continuously monitor bacterial respiration during growth on mixed organic wastes from contaminated water and soil. Continuously collected oxygen-consumption data provided information on the overall metabolic activity of the resident bacterial population and permitted direct observation of the cessation of microbial respiratory activity and, thus, the termination of aerobic degradation. The correlation of biological oxygen utilization with biodegradation was confirmed using independent analytical methods. Continuous, long-term BOD analysis was applied to bench-scale studies to assess the biodegradation of mixed organic wastes from contaminated sites and industrial waste effluents. This information was used to make an initial determination regarding the need to further explore bioremediation as a potential remedial-action technology using on-site, pilot-scale testing.

Bacteria↗
PubMed1990

Small adenomas detected during fecal occult blood test screening for colorectal cancer. The impact of serendipity.

Yearly fecal occult blood testing (FOBT) has been recommended for men and women over age 50 years as part of a screening regimen intended to reduce colorectal cancer mortality. The primary targets of screening are early, surgically curable colon cancers and large adenomatous colon polyps; however, screening may sometimes reveal only small adenomas (ie, less than 1 cm in diameter). To assess the rates and mechanisms of FOBT detection of small adenomas, we performed quantitative analyses utilizing estimates of adenoma bleeding rates and FOBT sensitivity and specificity. The analysis suggests that the mechanisms of detection of small adenomas is often chance or serendipity. This occurs when an FOBT result is "falsely" positive because of diet or non-neoplastic gastrointestinal bleeding and leads to colonoscopic discovery of a nonbleeding small adenoma. Nevertheless, small adenomas remain undetected in most persons who have them, even if repeated yearly FOBT screening is done. The identification of persons with small adenomas should not be assumed to be an important beneficial outcome of FOBT screening, because the clinical significance of small adenomas is not clear, the mechanism of detection is serendipity, and only a minority of persons with small adenomas are identified. The current recommendations to perform periodic surveillance colonoscopy following removal of small adenomas detected during FOBT screening should be reexamined.

Adenocarcinoma↗
PubMed1990

Sample processing alters glutathione and cysteine values in blood.

The accurate assessment of glutathione status of blood is essential for its use as an index of health and aging. A major variable in glutathione analysis is sample processing, and identification of optimal standard conditions is needed. Thus our objective was to evaluate several methods to determine which one yields maximal levels of free and bound glutathione and cyst(e)ine in blood. Reduced glutathione (GSH), glutathione disulfide (GSSG), cysteine (Cys), and cystine were analyzed specifically by an HPLC-dual electrochemical method. The highest GSH levels were found in ultrafiltrates of hemolysates, which were 58% greater than those in acid extracts of whole blood, and accounted for 96% of the free and bound GSH in borohydride-reduced samples; GSSG was undetected. The next highest values were in acid extracts of hemolysates which were 13% greater than in extracts of whole blood; both extracts contained GSH and GSSG. Their GSSG contents expressed in GSH equivalents comprised 7-9% of GSH + GSSG. Cys levels were highest in ultrafiltrates which were 11-fold greater than in acid extracts of whole blood, accounting for 62% of the total cyst(e)ine pool. In summary, the results indicate that ultrafiltration of hemolysates is the blood processing method of choice to obtain maximal values of free and bound GSH and cyst(e)ine.

Adult↗
PubMed1990

Rapid microwave-stimulated fixation of fine-needle aspiration biopsies for transmission electron microscopy.

A new technique is described in which fine-needle aspiration biopsies are processed for transmission electron microscopy within 2 hr. This rapid processing method includes exposure of the biopsy in a glutaraldehyde-formaldehyde mixture to microwaves for 25 sec in a domestic oven. The specimen is then routinely stained, processed through graded ethanol, and embedded in epoxy resin to produce excellent preservation of fine structural features.

Biopsy, Needle↗
PubMed1990

Fish oil fatty acids impair VLDL assembly and/or secretion by cultured rat hepatocytes.

We determined the effect of the two major fish oil fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on VLDL assembly and secretion by cultured rat hepatocytes. The incorporation of [3H]glycerol into total triglyceride (cell plus media) was stimulated eight-fold when hepatocytes were incubated for 2 h with 1 mM EPA, DHA, or oleic acid (OA), suggesting that fish oil fatty acids stimulate hepatic triglyceride synthesis to an extent similar to OA. In contrast, mass quantitation of secreted triglyceride showed impaired triglyceride secretion with EPA and DHA compared to OA. During a 42-h time course, cells stimulated with EPA and DHA progressively accumulated triglyceride compared to cells stimulated with OA. To determine whether fish oil fatty acids impair very low density lipoprotein (VLDL) secretion, cells were labeled with [35S]methionine and the secretion of de novo synthesized apoB was measured. Compared to OA, EPA and DHA significantly impaired the secretion of both molecular weight forms of apoB. The cellular content of apoB was not altered by any of the fatty acids. The concordant decrease in the secretion of both triglyceride and apoB suggests that fish oil fatty acids impair VLDL assembly and/or secretion.

Animals↗
PubMed1989

The effect of aging on glutathione and cysteine levels in different regions of the mouse brain.

A general glutathione (GSH) deficiency occurs in many tissues of the aging mouse. However, there is no information on GSH in the aging brain even though it has been involved in a number of neurobiologic reactions. To this end, C57BL/6 mice, 3-31 months old, representing the growth, maturation, and aging periods of the life-span were studied. Brain cortex, hippocampus, and stem samples were dissected, processed, and analyzed specifically for reduced and oxidized glutathione (GSH, GSSG) and cyst(e)ine using high performance liquid chromatography with dual electrochemical detection. The GSH content of each brain region varied in the order brain cortex greater than brain hippocampus greater than brainstem. However, the GSH profiles of all regions were the same through the life-span, namely, high values during growth dropping to a maturation plateau and then decreasing 30% during aging. In contrast to GSH, the order of cysteine levels was brain cortex less than brain hippocampus less than brainstem and no life-span changes occurred in any region. In addition, the brain GSSG and cystine contents of all regions were very low and did not change during the life-span. Thus, the GSH loss was not accountable by oxidation to GSSG or degradation to cyst(e)ine. Altogether these results demonstrated a GSH deficiency in brain tissues of aging mice like that found previously in other tissues. These findings suggest an increased susceptibility of the aging brain to oxidative damage.

Aging↗
PubMed1989

Blood glutathione: a biochemical index of life span enhancement in the diet restricted Lobund-Wistar rat.

These experimental results demonstrate that dietary restriction in both conventional and germfree rats results in enhanced longevity compared to fullfed animals. This increase in median survival age was due to a delay of 8 months in the onset of mortality in the restricted rats. Thereafter the aging rates of the short-lived subpopulations were the same for both groups. However, the aging rate of the long-lived restricted subpopulation was greater. The blood glutathione profiles demonstrated that a GSH deficiency of aging occurred in both the restricted and the long-lived groups. These data confirmed in the rat the findings observed previously in mosquito, mouse and man and verified the generality of the GSH and longevity relationship. Of special interest is that the blood glutathione levels were consistently higher at all ages of the restricted compared to fullfed rats and decreased more slowly during senescence. These findings indicate a direct relationship between enhanced GSH status and increased longevity due to dietary restriction. Further this suggests that glutathione may be a molecular mechanism for the diet restriction and longevity phenomenon.

Aging↗
PubMed1988

A decrease in cysteine levels causes the glutathione deficiency of aging in the mosquito.

Our previous results indicated that a glutathione (GSH) deficiency is a determinant of the aging process in many tissues and organisms. Correction of this deficiency in the aging mosquito by feeding the cysteine (Cys) precursor magnesium thiazolidine carboxylic acid (MgTc) suggested that the cause could be a lack of Cys. Adult mosquitoes (Aedes aegypti) were fed either a control diet or a diet supplemented with MgTC and then were analyzed for their Cys, cystine, GSH, and glutathione disulfide contents with our HPLC method. The life span profile of Cys levels paralleled that of GSH in the control group with high levels in the young that decreased during maturity and aging. Cystine and glutathione disulfide were undetectable. The causal relationship between the Cys and the GSH deficiencies was shown in the MgTC-supplemented group with an 83% increase in Cys and a 39% increase in GSH relative to control values. Further the conversion steps of MgTC to Cys and then to GSH were verified by use of buthionine sulfoximine. These results demonstrate that a Cys deficiency occurs in the aging mosquito and is the cause of the GSH deficiency.

Aedes↗
PubMed1987

The determination of glutathione, cyst(e)ine, and other thiols and disulfides in biological samples using high-performance liquid chromatography with dual electrochemical detection.

A determination of glutathione, cysteine, and their disulfides using HPLC and dual electrochemical detection (HPLC-DEC) was described previously but was not validated in biological tissues for these and other important thiols and disulfides (SH/SS). Thus, our objectives were to develop this method to quantify simultaneously reduced and oxidized glutathione, cysteine, cystine, and other SH/SS in various tissues, including human blood and plasma, rat liver and hippocampus, mosquito, and spinach leaf. Optimal conditions were determined for sample processing and analysis using metaphosphoric acid and HPLC-DEC. Authentic standards of 10 common SH/SS compounds were resolved and eluted within 15 min, and all standard curves were linear from 5 to 1600 pmol. Validation was based on the following: First, tissue sample sizes were proportional to peak areas over an eightfold range. Second, recovery of SH/SS added to samples before processing was 96-101%. Finally, the results were equivalent and correlated highly with values for total SH by 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) assay (r2 = 0.996) and for total glutathione by DTNB-GSSG reductase assay (r2 = 0.998). The life span of the Au/Hg electrode was limited to 200-500 samples based on the lineal range of standard curves. On the basis of these results, we believe that this method will fill a long-time need for the simultaneous determination of SH/SS in biological tissues.

Aedes↗
PubMed1987

Barrett's metaplasia and adenocarcinoma of the esophagus in scleroderma.

Gastroesophageal reflux is well documented in scleroderma, but the complications of Barrett's metaplasia and adenocarcinoma are not well described. The records of 75 patients with scleroderma seen over a four-year period at the Hospital of the University of Pennsylvania were retrospectively reviewed to determine the prevalence of Barrett's metaplasia and adenocarcinoma of the esophagus and to identify clinical, manometric, laboratory, or radiographic criteria that might predict the presence of these lesions. Twenty-four of these patients underwent endoscopy. In this group, the prevalence of Barrett's metaplasia was 37 percent (nine patients) and adenocarcinoma was also present in two of these patients. The patients with and without Barrett's metaplasia were similar in age (range, 22 to 64 compared with 28 to 79, respectively), sex (six of nine compared with 12 of 15 female, respectively), frequency of esophageal motility disorders, presence of proximal skin involvement, digital ulceration, and pulmonary involvement as measured by diffusion capacity. Barrett's metaplasia was diagnosed on the basis of double-contrast esophagographic results in only one of eight patients with Barrett's metaplasia so-studied. Patients with Barrett's metaplasia tended to have longer duration of heartburn (90 +/- 40 months compared with 11 +/- 35 months) and dysphagia (39 +/- 22 months compared with 7 +/- 3 months). Patients with Barrett's metaplasia also tended to have greater impairment of lower esophageal sphincter pressure either at end-expiration (4.0 +/- 2.1 compared with 6.1 +/- 1.8 mm Hg) or mid-respiration (13.0 +/- 3.0 compared with 16.9 +/- 2.5 mm Hg). Using chi-square analysis, however, none of these differences reached statistical significance. Discrimination did occur on the basis of the presence of the CREST (calcinosis, Raynaud's phenomenon, esophageal manifestations of scleroderma, sclerodactyly, and telangiectasis) variant (55 percent compared with 7 percent, p less than 0.01), a duration of dysphagia of more than five months (p less than 0.03), and mid-respiratory lower esophageal sphincter pressure of less than 10 mm Hg (p less than 0.05). It is suggested that: Barrett's metaplasia of the esophagus occurs in one third of patients with scleroderma; clinical, manometric, laboratory, and radiographic features are poor predictors of the presence of Barrett's metaplasia; patients with CREST syndrome, prolonged dysphagia, or a very low lower esophageal sphincter pressure may have an increased risk for the development of metaplasia; patients with scleroderma and Barrett's metaplasia have an increased risk of complications such as stricture or adenocarcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1987

Correction of a glutathione deficiency in the aging mosquito increases its longevity.

The decrease of tissue glutathione (GSH) concentrations in different senescent organisms gave rise to our hypothesis that a glutathione deficiency is a biochemical cause of the aging process. A rigorous test of this notion would be the correction of the deficiency and concomitant increase in life span. To this end, adult mosquitoes were fed magnesium thiazolidine-4-carboxylic acid, and their GSH levels and life spans were determined. The GSH levels increased 50-100% (P less than 0.005) regardless of the age when feeding was initiated or whether the feeding period extended over 2 days or the entire life span. Also the median life spans increased 30-38% over control values (P less than 0.005). The responses were specific for the thiazolidine carboxylate moiety, because MgCl2 had no effect. These findings confirm the GSH deficiency hypothesis and demonstrate a specific biochemical mechanism of aging that can be nutritionally modified.

Aedes↗
PubMed1986

Magnesium deficiency inhibits biosynthesis of blood glutathione and tumor growth in the rat.

Previously we found that blood glutathione (GSH) levels increase in response to tumor growth in the rat and that this increase is not prevented with zinc deficiency. We also found that zinc deficiency which inhibited tumor growth did not prevent this increase in blood GSH. Therefore, the objectives of this study were to determine the effects of another nutritional modification, namely magnesium deficiency, on blood GSH status and on tumor growth. Magnesium was selected because it is an obligatory cofactor in GSH synthesis and in all biosynthetic reactions involving ATP. To this end, magnesium- and zinc-deficient rats with and without tumors were compared to pair-fed control rats with and without tumors. After 32 days of depletion, the rats were killed, and blood samples were analyzed for nonprotein sulfhydryls (SH) and specifically for GSH. The key finding was that in magnesium-deficient rats with or without tumors, blood GSH levels were low and SH levels were normal indicating a decrease in GSH biosynthesis. In contrast, zinc deficiency affected SH and GSH in parallel. Thus, these two deficiencies must act by different mechanisms. The zinc data verified our earlier results obtained with a different tumor type and rat strain, for blood GSH levels increased in tumor-bearing rats fed control diets, and zinc deficiency did not prevent this increase. Depletion of magnesium or zinc was equally effective in inhibiting tumor growth. These results provide in vivo evidence of a magnesium requirement for GSH biosynthesis in rat erythrocytes. Further, the results suggest that magnesium deficiency may inhibit tumor growth by limiting GSH synthesis from SH precursors.

Animals↗
PubMed1986

Dietary nordihydroguaiaretic acid increases the life span of the mosquito.

Our previous findings indicated that a major characteristic of aging organisms is a decrease in reducing capacity. Our objectives were to correct this impairment by administration of nordihydroguaiaretic acid (NDGA), a potent reducing agent, and to determine the effect on adult longevity of the mosquito. NDGA supplements were included in the axenic larval medium or adult diet of mosquitoes of different ages. The mean adult life spans of both sexes increased 42-64% over controls (P less than 0.025), and the most effective doses were 0.001% for females and 0.005% for males. This NDGA effect was dependent on the age when feeding was initiated, since only biosynthetically active larvae and young adults were responsive. Also the effect was not due to dietary restriction. These results confirm the life span-enhancement effect of NDGA using defined conditions and establish the importance of redox status in the aging process.

Aedes↗