Molecular genetic approaches to mechanisms of senescence.
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Aging↗
Biomedical subjects
S Goldstein
Publications and source records attributed to S Goldstein.
Expression of alpha- and beta-human chorionic gonadotropin subunits in cultured human cells.
We surveyed several human cell lines for production of alpha- and beta-human chorionic gonadotropin (hCG) under a variety of conditions known to induce gene expression. alpha- and beta-hCG subunits were monitored in culture media by specific radioimmunoassays and were shown to be quite sensitive to serum refeeding and growth state of all cell types studied. The permanent line JEG-3 secreted both alpha- and beta-subunits whereas HeLa cells secreted only the alpha-subunit. Production of both subunits was augmented in these permanent cell lines, for each growth state, by pretreating cells with 5-azacytidine; in contrast, spontaneous beta-hCG production by normal human fibroblasts (four of six strains) was only rarely increased after 5-azacytidine treatment, and more often was suppressed by 30 to 40%. Three of five strains from inherited chromosomal breakage syndromes produced immunoassayable beta-hCG spontaneously, two of which increased secretion upon treatment with either UV or mitomycin C. Surprisingly, one normal cell strain of fetal origin was induced to secrete alpha-hCG, but not beta-hCG, after UV irradiation. JEG-3 and HeLa cells produced detectable cognate mRNA for alpha- or beta-hCG subunits or both by Northern and S1 nuclease protection analyses, whereas such transcripts from untransformed human fibroblasts were consistently below detectable levels. Quantitation of beta-hCG mRNA by RNA:RNA annealing kinetics indicates that even the fibroblast strain producing the highest secreted beta-hCG levels contained cognate mRNAs at only approximately 0.1 per cell. We conclude that hCG expression in human fibroblasts is strongly repressed at the transcriptional level, although a variety of conditions (growth state, serum refeeding, cell senescence, or DNA damage) can affect the level of "leaky" expression, at least in some responding fraction of cells.
Cell Division↗
The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988.
Digoxin intoxication has been reported to be a common adverse drug reaction with an in-hospital incidence of 6% to 23% and an associated mortality rate as high as 41%. A retrospective review was conducted to assess the accuracy of diagnosis, the morbidity and mortality of digoxin intoxication, and its incidence in hospitalized patients with heart failure. We reviewed the medical records of 219 patients discharged with the diagnosis of digoxin intoxication between 1980 and 1988. Patients were classified as follows: (1) Definite intoxication--patients with symptoms and/or arrhythmias suggestive of digoxin intoxication that resolved after discontinuation of digoxin; (2) possible intoxication--patients with symptoms and/or arrhythmias suggestive of digoxin intoxication in the absence of documented resolution after discontinuation of digoxin, or the presence of other clinical illnesses that could possibly account for those findings; (3) no intoxication--patients whose symptoms or ECG abnormalities were clearly explained by other associated clinical illnesses and persisted after withdrawal of digoxin. We identified only 43 patients (20%) with definite intoxication. The majority of patients discharged with the diagnosis of digoxin intoxication (133 or 60%) were classified as possibly digoxin intoxicated, and 43 patients (20%) had no clinical evidence to support this diagnosis. To estimate the incidence of digoxin intoxication, we also reviewed the medical records of 994 patients admitted in 1987 with heart failure. Of these, 563 were receiving digoxin and in 27 the diagnosis of digoxin intoxication was made by their clinicians. Our review showed that only four were definitely intoxicated (0.8%), and the diagnosis could not be excluded in another 16 (4%).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Nutrition and somatomedin. XXI. Insulin-like growth factor-I and somatomedin inhibitor in streptozotocin-diabetic rats: relation to ketogenesis and gluconeogenesis.
Diabetes is associated with a fall in serum insulin-like growth factor-I (IGF-1) and a rise in somatomedin inhibitor, a circulating factor(s) of approximately 30,000 MW that is released by the liver and can antagonize both somatomedin and insulin action. Levels of inhibitor correlate with levels of glucose, beta-hydroxybutyrate, and weight loss. To study pathways that could underlie the fall in IGF-1 and rise in inhibitor, the effects of metabolic inhibitors on circulating metabolic fuels, serum IGF-1, and serum somatomedin inhibitor activity were studied. Rats given streptozotocin exhibited weight loss of 14% +/- 0.1%, glucose 457 +/- 26 mg/dL, and beta-hydroxybutyrate (BOHB) 6.3 +/- 0.5 mmol/L. Somatomedin inhibitor was separated from IGF-1 by size exclusion HPLC at pH 3; IGF-1 was measured by RIA, and somatomedin inhibitor by cartilage bioassay. Diabetic animals exhibited a fall in IGF-1 to 76% of normal (P less than .02) and a rise in inhibitor to 270% of normal (P less than .01). 3-Mercaptopicolinic (3-MPA) acid, an inhibitor of gluconeogenesis, lowered glucose to 68 +/- 2 mg/dL and BOHB to 0.96 +/- 0.09 mmol/L (both P less than .01 v diabetic), but levels of inhibitor did not fall. Nicotinic acid, an inhibitor of lipolysis, did not affect glucose but reduced BOHB to 0.42 +/- 0.02 mmol/L; somatomedin inhibitor fell 19% below diabetic levels (NS) but remained above normal (P less than .01). In contrast, inhibition of fatty acid oxidation with methyl-2-tetradecylglycidate reduced glucose to 191 +/- 18 mg/dL but lowered BOHB to normal, 0.16 +/- 0.02 mmol/L, accompanied by normalization of somatomedin inhibitor levels (152% +/- 33% of normal, NS). Below 1.0 mmol/L BOHB, somatomedin inhibitor and BOHB were strongly correlated (r = .67, P less than .001); no comparable relation was found with glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Ethics in cardiovascular medicine. Task Force IV: Scientific responsibility and integrity in medical research.
Ethical standards are a set of affirmative responsibilities to which the investigator must subscribe; behavior that is incompatible with these responsibilities should be presumed unethical, whether or not it is explicitly proscribed. This Task Force sought to present these standards as principles or guidelines. In undertaking research an investigator must accept that publicly funded or supported research is intended to yield public benefit; personal gain should be only incidental to and not at the expense of the public benefit. The responsibilities of the investigator are summarized as follows: Design of Research To develop a research design that effectively and efficiently addresses the scientific question while minimizing the likelihood of incorrect or misleading results. To protect the rights and welfare of human subjects, assure the humane use of laboratory animals and protect the safety of laboratory workers and the environment. Conduct of Research To ensure that accepted laboratory and research practices are followed and that all data are accurately collected and properly recorded; the investigator must participate in the review of original data. To carry out research in accordance with that approved by the institutional review board and ensure that fully informed consent is obtained, that the welfare of human subjects is protected and that animal welfare and laboratory safety procedures are carried out. To provide effective ongoing supervision of research trainees and technicians. In multidisciplinary collaborative research, to have at least an overview familiarity with the work outside his or her areas of expertise. In fixed protocol, multicenter collaborative research the investigator must be satisfied with the adequacy of the collaborative activities.(ABSTRACT TRUNCATED AT 250 WORDS)
Biomedical Research↗
Enhancement of the rate of the beta-elimination of phosphate from radicals derived from glycerol-2-phosphate by Cu(I)-phenanthroline. A pulse radiolysis study.
Hydroxyl radicals abstract hydrogen atoms from glycerol-2-phosphate with a specific rate constant of (7.0 +/- 1.5) x 10(8) M-1s-1 forming the beta-phospho radical as the major product. At physiological pH this radical undergoes a beta-phosphate elimination with a rate constant less than or equal to 1 x 10(3) s-1. The beta-phospho radical reacts with Cu(I)-phenanthroline to produce an unstable transient with a metal-carbon sigma-bond which has an absorbance similar to that of the cuprous phenanthroline complex in the visible region. This intermediate decomposes via a beta-elimination of phosphate with a rate constant of (1.0 +/- 1.5) x 10(4) s-1, which was independent of the acidity in the pH range 4-9.
DNA Damage↗
Clonal variation in gene methylation: c-H-ras and alpha-hCG regions vary independently in human fibroblast lineages.
The stability of DNA methylation has been followed in clonal lineages of human diploid fibroblasts, for the gene regions encoding the c-H-ras proto-oncogene and the alpha subunit of human chorionic gonadotropin (alpha-hCG). Although methylation losses predominated, both de novo gains and losses of cytosine methylation were observed in subclones and sub-subclones, at frequencies which differed between individual clonal lineages, and between the 2 gene regions compared. Methylation of these loci varied independently among clones; e.g., a lineage which showed frequent methylation loss in the c-H-ras gene region remained highly methylated for alpha-hCG, and vice versa. Thus, the fidelity with which DNA methylation is inherited in specific endogenous gene regions must be governed by a clone-specific property affecting local chromatin structure, but apparently not by gene expression per se. Late in the replicative life-span of diploid fibroblasts, as cell replication slowed, restriction patterns for methylation-sensitive enzymes became simpler and more discrete, while those for other enzymes did not change. This is interpreted as a consequence of 'clonal succession', in which the fastest-replicating or longest-lived clones/subclones eventually predominate in a cell population; it could also reflect a decreased rate or a non-random selection of methylation changes in late-passage cells.
Cell Survival↗
Transition metal ions and oxygen radicals.
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Free Radicals↗
Cholesterol embolization: clinical findings and implications.
The clinical characteristics of 13 patients with cholesterol embolization are described. Embolization occurred spontaneously in 2 patients and after a vascular procedure in 11. Acute but vague symptoms were reported by 11 of the 13 patients; skin findings of purple toes or livedo reticularis and renal dysfunction were present in 12 patients, 5 of whom required dialysis. Blood pressure elevation occurred in all 13 patients, eosinophilia in 9 of 10 and elevated sediment rate in 5 of 6. Death occurred within 6 months in three patients. Two distinct patterns were observed: mild (five patients) and severe (eight patients). Compared with the severe pattern, patients with mild cholesterol embolization had early symptoms less frequently (two of five versus eight of eight), less severe renal insufficiency (serum creatinine 1.7 versus 7.4 mg/100 ml), less of an increase in blood pressure (22 versus 34 mm Hg) and later development of skin lesions (14 versus 6 weeks). Baseline blood pressure and development of eosinophilia were comparable in both groups. The presentation of cholesterol embolization is often subtle and may go unrecognized, particularly in its mild form. As vascular interventions increase in elderly atherosclerotic and hypertensive patients, so too will the incidence of this disorder.
Aged↗
Aerobics enhances cardiovascular fitness and agility in preschoolers.
Investigated effects of aerobic exercise on a sample of 24 preschoolers. Thirty minutes of aerobic exercises were provided daily for a period of 8 weeks for a group of 12 children while the remaining 12 children engaged in freeplay on the school playground. The children were given pretests and posttests on the following measures: a submaximal exercise test on a pediatric bicycle (baseline and three workloads), an agility test, a health knowledge test, a self-esteem scale, and an observational measure of their gross-motor activity. Despite comparability on pretests, significant group X repeated measures effects suggested that the aerobic exercise group showed decreases in heart rate at all three workloads as well as increases in agility and self-esteem following the exercise program. These findings suggest that cardiovascular fitness, agility, and self-esteem can be facilitated in preschoolers by an aerobic exercise program.
Arousal↗
Regulation and action of insulin-like growth factors at the cellular level.
Present understanding of IGF-1 as a growth factor mediating integration of nutritional-hormonal interactions indicates that IGF-1 acts in both an endocrine mode on distant targets and an autocrine-paracrine mode on local targets. In the liver, the combined presence of GH, insulin, and critical metabolic fuels such as essential amino acids results in increased levels of IGF-1 messenger RNA, increased production of a high-MW IGF-1 precursor, and increased release of IGF-1 into the circulation, permitting action on distant target tissues bearing specific receptors for IGF-1. The net effect is distant amplification of anabolic hormone action via IGF-1 acting in an endocrine mode. In extrahepatic tissues, both 'general' anabolic hormones (insulin and GH) as well as 'specific' hormones (e.g. gonadotropins) acting on a wide variety of targets (including fibroblasts and chondrocytes as well as granulosa and Leydig cells) promote both local secretion of IGF-1 and an increase in IGF-1 receptors. Local actions of IGF-1 then result in a secondary increase in both hormone receptors and hormone responses. The net effect is local amplification of hormone action via IGF-1 acting as a growth factor in an autocrine-paracrine mode.
Animals↗
Werner syndrome: a molecular genetic hypothesis.
On the basis of clinical and experimental observations, we postulate that the primary genetic abnormality in Werner syndrome (WS) is mutation in a gene encoding a trans-acting factor that normally represses a second genetic locus or its product, an inhibitor of DNA synthesis elaborated when cells reach the end of their replicative life span. The result is early derepression of this second locus, leading to reduced initiation of DNA synthesis and premature replicative senescence. This hypothesis and its corollaries provide a heuristic model for decisive experiments.
DNA↗
PR interval behavior during exercise: implications for physiological pacemakers.
The relationship between heart rate response and the dynamic changes in the PR interval was assessed in 631 patients undergoing routine cardiac exercise tests for a variety of clinical indications. Patients were stratified into four subsets: nonmedicated normals (n = 437), patients on beta-antagonist agents (n = 118), those on antiarrhythmic agents alone (n = 61) and those with a clinical diagnosis of advanced (New York Heart Association [NYHA] Class III or IV) congestive heart failure. All patients were in stable sinus rhythm throughout the test. PR intervals were measured at rest, at mid-exercise and at peak exercise. Mean PR intervals shortened to a statistically significant degree in most subgroups. This effect was predominantly observed in the earlier stages of exercise. In patients with advanced heart failure, there was no statistically significant shortening of exercise PR intervals later in exercise, demonstrating a parallel with their relatively blunted heart rate response. These changes in exercise PR intervals suggest that implanted pacemaker algorithms may be constructed to maximize hemodynamic benefit in patients requiring physiological pacemakers.
Adolescent↗
Toward a new understanding of the mechanism and prevention of sudden death in coronary heart disease.
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Anti-Arrhythmia Agents↗
Hepatic drug metabolism is increased in poorly controlled insulin-dependent diabetes mellitus.
In addition to increased glycosylation of hemoglobin, abnormalities of other heme proteins such as cytochrome P-450 might also occur in patients with insulin-dependent diabetes mellitus. Antipyrine is a useful marker drug for cytochrome P-450 dependent hepatic drug metabolism. Antipyrine kinetics and urinary excretion of antipyrine metabolites were measured in 14 patients with insulin-dependent diabetes mellitus in poor metabolic control. Improvement in diabetic control in 9 patients, as measured by more normal HbA1 values, led to normalization of plasma antipyrine half-time (t1/2) and metabolism: the mean antipyrine t1/2 slowed from 4.7 +/- 0.2 (SEM) initially to 7.8 +/- 0.3 h in these 9 patients and was thus nearly identical to that of normal subjects 8.6 +/- 1.0. Antipyrine plasma clearance improved in the 9 diabetic patients whose diabetic control improved. The apparent volume of distribution was normal on both occasions in the diabetic patients. These findings provide a new argument for tight metabolic control in patients with insulin-dependent diabetes mellitus.
Adolescent↗
A reinvestigation of the reaction of desferrioxamine with superoxide radicals. A pulse radiolysis study.
The reaction of desferrioxamine with superoxide has been studied using the pulse radiolysis technique. The decay of O2- was not accelerated in the presence of up to 4 x 10(-4) M desferrioxamine at physiological pH. The rate constant was found to be lower than 2 x 10(4) M-1s-1. In acid solutions the rate constant of the reaction between desferrioxamine and HO'2 was found to be lower than 10(5) M-1s-1. The reaction was not studied in alkaline solutions due to the high absorbance of desferrioxamine in the U.V. region. The pK of desferrioxamine was determined to be 9.2 +/- 0.05.
Deferoxamine↗
Reye's syndrome: a case control study of medication use and associated viruses in Australia.
The records of 49 cases of Reye's syndrome at three pediatric hospitals in Australia are compared with 94 controls. The diagnosis of Reye's syndrome was confirmed pathologically in 42 of 49 cases (86%). Aspirin or salicylate ingestion occurred in only 4 (8%), and paracetamol (acetaminophen) ingestion in 12 (24%) (P greater than 0.05 by chi-square analysis). Of the controls, 3 (3%) had taken aspirin and 39 (41%) had taken paracetamol. Associated viruses included paramyxoviruses, picornaviruses, reoviruses, adenoviruses, and occasional varicella-zoster (herpesvirus). No influenza A or B viruses were recovered from any patient. This case control study of Reye's syndrome in Australia confirmed a lack of association between aspirin ingestion and the development of Reye's syndrome.
Age Factors↗
Population movement in Zhejiang province, China: the impact of government policies.
"China's urbanization policies include strict control of permanent migration to large cities, but encourage the growth of small cities and towns. Concurrently, temporary migration is widely permitted as a way to stimulate commerce. Data for Zhejiang province indicate that permanent mobility is largely directed toward urban places, that towns gain more than cities and that rural areas experience migration losses. Permanent migrants to urban places are selective of the better educated. Temporary migration is also urban directed but greater in volume than permanent migration, and places considerable strain on urban infrastructure. Government policies are a key to understanding the migration streams and migrant characteristics. The considerable net movement into cities suggests that strict control of city growth is more difficult to achieve than envisaged by policymakers." This is a revised version of a paper originally presented at the 1989 Annual Meeting of the Population Association of America (see Population Index, Vol. 55, No. 3, Fall 1989, p. 386).
Asia↗