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Biomedical subjects

M Brown

Publications and source records attributed to M Brown.

At least 433 records · Page 24Linked to original sources
PubMed1992

Skeletal muscle adaptations to endurance training in 60- to 70-yr-old men and women.

Previous studies of endurance exercise training in older men and women generally have found only minimal skeletal muscle adaptations to training. To evaluate the possibility that this may have been due to an inadequate training stimulus, we studied 23 healthy older (64 +/- 3 yr) men and women before and after they had trained by walking/jogging at 80% of maximal heart rate for 45 min/day 4 days/wk for 9-12 mo. This training program resulted in a 23% increase in maximal O2 consumption. Needle biopsy samples of the lateral gastrocnemius muscle were obtained before and after training and analyzed for selected histochemical and enzymatic characteristics. The percentage of type I muscle fibers did not change with training. The percentage of type IIb fibers, however, decreased from 19.1 +/- 9.1 to 15.1 +/- 8.1% (P less than 0.001), whereas the percentage of type IIa fibers increased from 22.1 +/- 7.7 to 29.6 +/- 9.1% (P less than 0.05). Training also induced increases in the cross-sectional area of both type I (12%; P less than 0.001) and type IIa fibers (10%; P less than 0.05). Capillary density increased from 257 +/- 43 capillaries/mm2 before training to 310 +/- 48 capillaries/mm2 after training (P less than 0.001) because of increases in the capillary-to-fiber ratio and in the number of capillaries in contact with each fiber. Lactate dehydrogenase activity decreased by 21% (P less than 0.001), whereas the activities of the mitochondrial enzymes succinate dehydrogenase, citrate synthase, and beta-hydroxyacyl-CoA dehydrogenase increased by 24-55% in response to training (P less than 0.001-0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1992

Bilateral atrial appendectomy abolishes increased plasma atrial natriuretic peptide release and blunts sodium and water excretion during volume loading in conscious dogs.

The atrial appendages contain most of the atrial natriuretic factor (ANF) in the mammalian heart, and atrial appendage mechanical function predicts ANF secretion during volume loading. To demonstrate the crucial role of the atrial appendages in ANF release, we first measured hemodynamics and changes in plasma ANF after injection of 1,000 ml i.v. normal saline in conscious dogs and again after bilateral atrial appendectomy; we next measured changes in renal function using infusions of atriopeptin 24 to achieve plasma levels corresponding to levels achieved during volume loading; and we lastly measured renal function during acute volume expansion and also after atrial appendectomy. Plasma ANF increased from 65 +/- 11 to 246 +/- 54 pg/ml after volume loading but did not increase after atrial appendectomy. Atrial appendectomy did not alter the tachycardia or hemodynamic effects of volume loading. Infusion of 10 ng/kg/min atriopeptin 24 increased plasma ANF from 50 +/- 9 to 234 +/- 54 pg/ml, increased urine output 34 +/- 10%, and increased sodium excretion 62 +/- 10% in dogs with intact atrial appendages. Renal function was compared in dogs before atrial appendectomy: 20, 40, and 60 minutes after volume loading, urine flow rate increased by 5.9 +/- 0.5, 6.9 +/- 0.4, and 4.4 +/- 0.8 ml/min, while sodium excretion increased by 717 +/- 60, 839 +/- 84, and 582 +/- 57 mueq/min. After atrial appendectomy urine flow rate increased 2.1 +/- 0.7, 2.7 +/- 0.7, and 2.0 +/- 0.6 ml/min, and sodium excretion increased only by 327 +/- 110, 324 +/- 77, and 340 +/- 92 mueq/min (p less than 0.01) during volume loading.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Central corticotropin-releasing hormone activates the sympathetic nervous system and reduces immune function: increased responsivity of the aged rat.

CRH acts within the brain to activate the sympathetic nervous system and reduce cellular immune function. To determine the effects of age on CRH-induced elevations of sympathetic activity and suppression of immunity, we examined the responses of plasma catecholamines, neuropeptide-Y (NPY), corticosterone, and splenic natural killer (NK) activity after microinjection of rat CRH (200 pmol) into the lateral ventricle of aged (24-month-old) Fischer 344 (F344) rats compared to those in young (4-month-old) F344 rats. Basal concentrations of plasma norepinephrine and NPY were higher in the aged than in the young animals. In addition, CRH produced a greater elevation of plasma levels of catecholamines and NPY, which persisted for a longer period of time in the aged rats compared to responses in the young animals. Splenic NK activity showed an age-related decrement at baseline, and CRH induced a further significant (P less than 0.01) reduction of lytic activity in the aged rats, but did not alter cytotoxicity in the young rats. Corticosterone basal levels and responses were similar in the aged and young rats. These results show an age-related increase in autonomic outflow and suppression of NK activity after central CRH administration. In aged animals, the central nervous system may have a role in abnormal regulation of sympathetic activity and suppression of natural cytotoxicity in vivo.

Aging↗
PubMed1992

The effects of human proinsulin on glucose turnover and intermediary metabolism in insulin-dependent-diabetes mellitus.

We have compared the action of human proinsulin and insulin on glucose turnover, intermediary carbohydrate, and lipid metabolism in insulin-dependent-diabetic (IDDM) subjects. Six, young, weight-matched (23 +/- 2 kg-2) IDDM subjects underwent separate hyperinsulinemic euglycemic clamps. Three, low dose, iv infusions of both insulin and proinsulin were used to construct dose response curves. The proinsulin infusions were chosen to give steady state levels approximately or equal to 20-fold higher on a molar basis than insulin, based on previous findings that proinsulin has only 5-10% the biological potency of insulin. Hepatic glucose production, measured using [6'6'2H2]glucose, was suppressed equally by proinsulin and insulin at the three dose levels; (I1) 2.8 +/- 0.7 (P1) 3.3 +/- 0.6, (I2) 2.3 +/- 0.9 (P2) 3.3 +/- 1.1, (I3) -2.0 +/- 1.7 (P3) -1.1 +/- 0.6 mumol/kg min-1. Percentage elevation of glucose disposal was significantly increased during the insulin infusions compared to proinsulin; (I1) 132 +/- 12 (P1) 78 +/- 4 p < 0.01; (I2) 157 +/- 18 (P2) 104 +/- 14; P < 0.05; (I3) 242 +/- 23 (P3) 159 +/- 24 p = 0.02. Dose response curve analysis demonstrated that proinsulin stimulated glucose disposal approximately or equal to 3.7% whereas suppression of HGP was congruent to 5.7% compared to insulin. Proinsulin had a significantly weaker effect than insulin, at the lowest infusion dose, in percent suppression of plasma nonesterified fatty acids (I1 34 +/- 4, P1 14 +/- 15%; P < 0.05), blood glycerol (I1 47 +/- 4, P1 30 +/- 3%; P < 0.01) and 3-hydroxybutyrate levels (I1 81 +/- 7, P1 42 +/- 17%; P < 0.05). Proinsulin caused significant net reductions in blood lactate levels compared to insulin at each infusion dose; (P1) -130 +/- 34, (I1) -32 +/- 30 mumol/L (P < 0.05) (P2) -139 +/- 76 (I2) +8 +/- 65 mumol/L (P < 0.05) (P3) 48 +/- 60 (I3) 230 +/- 64 mumol/L (P < 0.05). We conclude that in IDDM: 1) proinsulin has a preferential effect on the liver compared to muscle, in terms of glucose handling; 2) proinsulin may have a different effect on lactate metabolism compared to insulin; 3) proinsulin at the lowest dose resulted in an inability to suppress lipolysis and ketogenesis; 4) glucose turnover can be underestimated using [6'6'2H2]glucose.

Adult↗
PubMed1992

Antigenic expression of B-cell chronic lymphocytic leukemic cell lines.

A flow cytometric analysis of five B cell chronic lymphocytic leukemic (B-CLL) cell lines was undertaken using 129 unknown reagents from the blind panel (BP) and 72 reagents from the known CD panel obtained from the Fourth International Leucocyte Differentiation Conference and Workshop, B cell section (Vienna, 1989). The five cell lines examined were: SeD (PNAS 75, 5706, 1978), B-CLL-LCL (BLOOD 71, 9, 1988), JVM-HH and JVM-2(INT J CAN 38, 531, 1986), and WR#1 (TH and BD). The reagents were #1-129 (blinded panel) and reagents 1-44 and 53-84 (CD panel with CD23 reagents missing). Positivity was defined as greater than 30% of the cells having a three fold increase or more in mean channel fluorescence. Fourty-three reagents of the blinded panel were negative by these criteria while all remaining reagents were positive on all five lines. SeD showed the lowest reactivity; B-CLL-LCL and JVM-2 showed the most reactivity; JVM-HH and WR#1 were intermediate. The known CD panel confirmed the reactivity of the blinded panel. An average immunophenotype was constructed and compared to published normal EBV lymphoblastoid cell lines and several differences were noted. There was an absence or significant decrease in the expression of CD19, CD21, CD22 and CD37 while there was an increased expression of CD38, CD54, CD74 and CD76. The heterogeneity observed between the B-CLL lines may in part be due to polymorphisms but is more likely to represent the underlying heterogeneity seen in common and familial B-CLL.2+öff

Antigens, CD↗
PubMed1992

A class of their own.

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Administrative Personnel↗
PubMed1992

Healthcare reform.

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Financing, Organized↗
PubMed1992

PRAD1 (cyclin D1): a parathyroid neoplasia gene on 11q13.

Hyperparathyroidism is a central component of multiple endocrine neoplasia type 1 (MEN 1), and both sporadic and familial forms of parathyroid disease may share certain pathogenetic features. We recently identified a gene that is clonally rearranged with the PTH locus in a subset of sporadic parathyroid adenomas. This candidate oncogene, PRAD1 (previously D11S287), appears to contribute to parathyroid tumorigenesis in a fashion analogous to activation of C-MYC or BCL-2 by rearrangement with tissue-specific enhancers of the immunoglobulin genes in B-lymphoid neoplasia. The PRAD1 gene maps to 11q13 and has been linked to the BCL-1 breakpoint locus, although not to the most tightly linked MEN 1 markers, by pulsed field gel electrophoresis. PRAD1 may, in fact, be the long-sought BCL-1 lymphoma oncogene. PRAD1 encodes a novel type of cyclin protein and thus may normally function in controlling the cell cycle, perhaps through direct interaction with cdc2 or a related kinase. PRAD1's possible primary, or more likely secondary, involvement in the pathogenesis of MEN 1-related tumors is unknown and under investigation.

Amino Acid Sequence↗
PubMed1991

ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study.

N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is a water-soluble, folate-based thymidylate synthase (TS) inhibitor designed to be a less toxic and more potent analogue of the clinically tested N10-propargyl-5,8-dideazafolic acid. Inhibition of isolated L1210 TS by ICI D1694 is mixed noncompetitive (although tending toward competitive), with a Ki of 62 nM (Kies = 960 nM). The synthetic gamma-polyglutamates are up to 2 orders of magnitude more potent as inhibitors of TS; e.g., the tetraglutamate (glu4) has a Ki of 1.0 nM (Kies = 15 nM). Although inhibitory activity of ICI D1694 toward rat liver dihydrofolate reductase was similar to that of TS (Ki = 92 nM; competitive inhibition) the polyglutamate derivatives did not show enhanced activity. ICI D1694 was also a very potent inhibitor of L1210 cell growth (50% inhibitory activity = 8 nM). L1210 growth inhibition was not observed in the presence of thymidine, consistent with TS being the locus of action. Folinic acid antagonized L1210 growth inhibition in a competitive fashion such that the highest folinic acid concentration used (25 microM) increased the 50% inhibitory activity 6000-fold. When given as a 4-h delayed "rescue", folinic acid was much less effective in antagonizing growth inhibition. These observations are consistent with folinic acid competing with ICI D1694 for uptake into the cell and/or intracellular polyglutamation. The L1210:1565 cell line, which has greatly impaired reduced-folate/methotrexate transport and thus is resistant to methotrexate, was significantly cross-resistant to ICI D1694 (121-fold), suggesting that ICI D1694 is dependent on this uptake mechanism for good cytotoxic potency in L1210 cells. L1210 cells that were incubated for 4 h with 0.1 microM 3H-ICI D1694 accumulated approximately 1.5 microM intracellular 3H, and the high performance liquid chromatography analysis of the cell extracts demonstrated that 96% of the 3H was associated with the ICI D1694 polyglutamate fractions (principally glu4). Upon resuspension in drug-free medium for 24 h, approximately 75% of the cellular 3H was retained, this being the higher polyglutamate pool (glu4-6). In mice, after a single bolus injection of 10 mg/kg of ICI D1694, TS was inhibited greater than 80% for 24 h in ascitic L1210:NCI cells (as measured by the rate of 3H release from [5-3H]deoxyuridine). ICI D1694 cured the L1210:ICR ascitic tumor in mice at 0.4 mg/kg daily for 5 days (maximum tolerated dose, approximately 50 mg/kg).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Effects of diltiazem on long-term outcome after acute myocardial infarction in patients with and without a history of systemic hypertension. The Multicenter Diltiazem Postinfarction Trial Research Group.

The effect of diltiazem on long-term outcome in patients with acute myocardial infarction with and without a history of systemic hypertension was investigated in 2,466 patients using the Multicenter Diltiazem Postinfarction Trial data-base. The baseline variables were comparable in the diltiazem and placebo-treated patients within the groups with and without hypertension. The initial 60-mg dose of diltiazem was associated with a significant (p less than 0.001) but modest (3%) reduction in blood pressure and heart rate in both groups with and without hypertension. Univariate and multivariate analyses revealed a meaningful overall reduction in first recurrent cardiac events (cardiac death or nonfatal reinfarction, whichever occurred first) and cardiac death in patients with hypertension treated with diltiazem compared with results in those treated with placebo. Similar effects were not observed in patients without a history of hypertension. When first recurrent cardiac events were used as the end point, the diltiazem:placebo hazard ratio (95% confidence limits) was 0.77 (0.58, 1.01) for the total hypertension group, and 0.67 (0.47, 0.96) and 1.32 (0.83, 2.10) for patients with hypertension with and without pulmonary congestion during the acute infarction, respectively. Similar results were observed using cardiac death as the end point. Beta blockers had a negligible effect on the hypertension-diltiazem relation. These findings suggest that diltiazem may exert a long-term beneficial effect in most patients with hypertension who do not have pulmonary congestion during an acute infarction, and a detrimental effect in the minority who have pulmonary congestion.

Adult↗
PubMed1991

Structural analysis of the interaction between the human immunodeficiency virus Rev protein and the Rev response element.

The specific interaction between a defined structural element of the human immunodeficiency virus mRNA (RRE, the Rev response element) and the virus-encoded protein Rev has been implicated in the regulation of the export of unspliced or singly spliced mRNA from the nucleus to the cytoplasm. Rev protein was expressed and purified from insect cells using the baculovirus expression system. Chemical and RNase probes were used to analyze the structure of the RRE and the regions involved in Rev binding. Increased reactivity to single-strand-specific probes of nucleotides in two helical domains indicates that Rev binding induces conformational changes in the RRE. Binding of Rev to the RRE primarily protects helical segments and adjacent nucleotides in domain II. A Rev unit binding site is proposed that consists of a six-base-pair helical segment and three adjacent nucleotides. The data also suggest that multiple Rev proteins bind to repeated structural elements of the RRE.

Animals↗