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Biomedical subjects

S Marshall

Publications and source records attributed to S Marshall.

At least 127 records · Page 7Linked to original sources
PubMed1991

The "natural history" of the transplanted lung: rates of pulmonary functional change in long-term survivors of heart-lung transplantation.

Long-term pulmonary function in HLT is well preserved with no evidence of functional decline as a result of transplant "aging," providing the allografts remain free of complications. Long-term survivors with OB appear to be able to maintain adequate oxygenation despite the marked alterations of pulmonary function. The ability to preserve gas exchange at reasonable levels of oxygenation may be the factors permitting extended survival with OB for mean periods of 36.0 months or greater. Preliminary studies suggest that a declining FEF50/FVC, at a time when pulmonary function is normal, may be an index of impending airway disease. Physiologically, from a long-term point of view, HLT remains a viable option for selected patients with end-stage cardiopulmonary disease.

Bronchiolitis Obliterans↗
PubMed1990

Glucose regulation of insulin receptor affinity in primary cultured adipocytes.

Treatment of primary cultured adipocytes with 20 mM glucose resulted in a progressive increase in specific 125I-insulin binding that began almost immediately (no lag period) and culminated in a 60% increase by 24 h. This effect was dose-dependent (glucose ED50 of 4.6 mM) and mediated by an increase in insulin receptor affinity. Moreover, it appears that glucose modulates insulin receptor affinity through de novo protein synthesis rather than through covalent modification of receptors, since cycloheximide selectively inhibited the glucose-induced increase in insulin binding capacity (ED50 of 360 ng/ml) and restored receptor affinity to control values. Importantly, insulin sensitivity of the glucose transport system was increased by glucose treatment (63%) to an extent comparable with the enhancement in receptor affinity, thus indicating a functional coupling between insulin binding and insulin action. When the long term effects of insulin were assessed (24 h), we found that insulin treatment reduced 125I-insulin binding by greater than 60% by down-regulating the number of cell surface receptors in a dose-dependent manner (insulin ED50 of 7.4 ng/ml). On the basis of these studies, we conclude that 1) insulin binding is subject to dual regulation (glucose controls insulin action by enhancing receptor affinity, whereas insulin controls the number of cell surface receptors); and 2) glucose appears to modulate insulin receptor affinity through the rapid biosynthesis of an affinity regulatory protein.

Adipose Tissue↗
PubMed1990

Follow up of New Zealand participants in British atmospheric nuclear weapons tests in the Pacific.

OBJECTIVE: To study the health of Royal New Zealand Navy personnel who participated in atmospheric nuclear weapons tests conducted by the United Kingdom at Malden Island and Christmas Island in 1957 and 1958. DESIGN: Blinded, controlled follow up of up to 30 years. SETTING: New Zealand. SUBJECTS: 528 Men known to have participated in the tests and a control group of 1504 men who were in the Royal New Zealand Navy during the same period but did not participate in the tests. MAIN OUTCOME MEASURES: Mortality and incidence of cancer. RESULTS: Follow up for the period 1957-87 was 94% complete in test participants and 91% complete in the controls. There were 70 deaths among test participants and 179 deaths among controls, yielding a relative risk of 1.08 (90% confidence interval 0.85 to 1.38, p = 0.29). The relative risk of death from causes other than cancer was 0.96 (0.71 to 1.29, p = 0.59) whereas the relative risk of death from cancer was 1.38 (0.90 to 2.10, p = 0.09) and of the incidence of cancer was 1.12 (0.78 to 1.60, p = 0.29). For cancers other than haematological malignancies the relative risk was 1.14 (0.69 to 1.83, p = 0.31) for mortality and 1.01 (0.67 to 1.50, p = 0.48) for incidence. There were seven deaths from haematological cancers among test participants (relative risk 3.25, 90% confidence interval 1.12 to 9.64, p = 0.02), including four leukaemias (5.58, 1.04 to 41.6, p = 0.03). The relative risk for incidence of haematological cancers was 1.94 (0.74 to 4.84, p = 0.10) and that for leukaemia was 5.51 (1.03 to 41.1, p = 0.03). There were no cases of multiple myeloma in the test participants during the follow up period, but the expected number was only 0.3. CONCLUSIONS: Although the numbers are small, the findings for leukaemia are similar to those for British participants in the nuclear weapons test programme. Some leukaemias, and possibly some other haematological cancers, may have resulted from participation in this programme. There is little evidence of an increased risk for non-haematological cancers, and there is no evidence of an increased risk for causes of death other than cancer.

Cause of Death↗
PubMed1990

Analysing clinical decision analyses.

We present a critical review of aspects of clinical decision analysis which uses an application to screening for familial intracranial aneurysms. The analysis is reported together with methods for assessing decision trees. These methods appear to be powerful checks on the usually rather intuitive way in which decision trees are built. The problem of assessing the uncertainty in the results of a decision analysis is discussed in detail. In practice, sensitivity analysis covers nearly every calculation apart from the standard evaluation of the decision tree. Different forms of sensitivity analysis are distinguished and given appropriate names: influence analysis, threshold analysis, full Bayesian analysis, Bayesian influence analysis, attribute analysis, generalization analysis and scenario analysis. The biostatistical community may well contribute to the much needed methodological improvement in decision analysis and its different forms of sensitivity analysis, especially if prepared to look beyond the standard statistical techniques.

Adult↗
PubMed1990

Suitability of 2-deoxyglucose for measuring initial rates of glucose uptake in isolated adipocytes.

The suitability of [3H]-2-deoxyglucose from measuring initial rates of glucose uptake in isolated rat adipocytes was assessed using three approaches. Basal and insulin-stimulated rates of glucose uptake were directly compared in 2 sec and 5 min assays using [14C]-3-O-methylglucose, [3H]-2-deoxyglucose, and [3H]-D-glucose. Equilibrium kinetics of 2-deoxyglucose uptake were compared with those of 3-O-methylglucose through impairment of hexokinase activity by depleting cellular energy with 2,4-dinitrophenol. The equivalence of these glucose analogues in a dynamic system was assessed by measuring the lag time preceding insulin stimulation of glucose uptake, insulin activation rates, and the T 1/2 of insulin activation. Our results demonstrate that no fundamental difference exists in the initial transport of 3-O-methylglucose, 2-deoxyglucose, and D-glucose.

2,4-Dinitrophenol↗
PubMed1989

Role of amino acids in modulating glucose-induced desensitization of the glucose transport system.

Amino acids were found to play an integral role in modulating glucose-induced desensitization of the glucose transport system (GTS). When adipocytes were treated for 6 h in a defined buffer containing 25 ng/ml insulin, 20 mM glucose, plus the 15 amino acids found in Dulbecco's modified Eagle's medium, we observed marked desensitization of the GTS, manifested by a 60% decrease in maximal insulin responsiveness (MIR) and a 2.5-fold reduction in insulin sensitivity. In contrast, little or no desensitization was seen under similar conditions in the absence of amino acids. The ability of amino acids to co-regulate the GTS appears to be directly attributable to amino acids per se since desensitization was still observed in cycloheximide-treated cells. Moreover, the action of amino acids is specific to glucose-induced desensitization since amino acids were not required for dexamethasone-induced desensitization of the GTS. Of the 15 amino acids contained in Dulbecco's modified Eagle's medium, one group of 8 amino acids was fully effective in mediating loss of both MIR and insulin sensitivity, whereas the remaining 7 amino acids were ineffective. Interestingly, this second group selectively retained the ability to modulate loss of insulin sensitivity. Upon screening the individual amino acids, we found that L-glutamine (but not D-glutamine) was as effective as total amino acids in modulating loss of MIR, whereas glycine and threonine were only partially effective. Since isoleucine and serine enhanced both MIR and insulin sensitivity of the protein synthesis system without influencing the GTS, it appears that amino acids can influence several insulin effector systems with notable differences in rapidity of action, direction of regulation, and specificity of amino acids. From these studies we conclude: 1) desensitization of the GTS requires three components--glucose, insulin, and selective amino acids; 2) insulin resistance of the GTS can be induced through several mechanisms, but only glucose-induced desensitization requires amino acids; 3) glucose-induced desensitization is mediated primarily by metabolic events independent of de novo protein synthesis; and 4) glutamine is the primary amino acid modulating glucose-induced loss of MIR. Overall, these studies reveal that amino acids play an important role in modulating insulin action at the cellular level and provide new insights into the metabolic mechanisms mediating insulin resistance of the glucose transport system.

Adipose Tissue↗
PubMed1989

Recovery of maximal insulin responsiveness and insulin sensitivity after induction of insulin resistance in primary cultured adipocytes.

Treatment of primary cultured adipocytes with 50 ng/ml insulin and 20 mM glucose for 0-6 h resulted in a loss of maximal insulin responsiveness (MIR) which was immediate (no lag period), rapid (t1/2 of 3 h), linear, and extensive (80% of that seen at 24 h), whereas loss of insulin sensitivity from 0-24 h was slow (t1/2 = 8 h), extensive (insulin ED50 of 0.3 and 1.45 ng/ml at 2 and 24 h, respectively), and was preceded by an initial 2-h lag. Recovery of MIR and insulin sensitivity was assessed by inducing desensitization for various times from 2-24 h, removing insulin and glucose, and then measuring MIR and insulin sensitivity over a subsequent 1-6-h period. After 2 h, recovery of MIR in desensitized cells was rapid (251 pmol of glucose/3 min/h), whereas after 24 h, recovery was much slower (35 pmol/3 min/h). In contrast, the opposite trend was seen for recovery of insulin sensitivity: at early times recovery of insulin sensitivity was slow (0.05 ng/ml/h) but was rapid after 24 h (0.12 ng/ml/h). Thus, it appears that MIR and insulin sensitivity can be independently regulated since recovery rates for MIR and insulin sensitivity diverged with the progression of insulin resistance. When the effects of insulin and glucose on recovery were examined, we found that insulin alone was unable to block recovery of MIR or insulin sensitivity. Glucose alone, however, was effective in preventing recovery of insulin sensitivity but not recovery of MIR. In the presence of 20 mM glucose, low doses of insulin (treatment EC50 = 0.22-0.46 ng/ml) effectively prevented recovery of both MIR and insulin sensitivity. De novo protein synthesis apparently is not involved in the development of insulin resistance or the reversal of desensitization since inhibition of protein synthesis by cycloheximide had no effect on the loss of MIR and insulin sensitivity or recovery.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗
PubMed1989

A young woman with abdominal pain.

Patients rarely present with solely a physical problem. While psychological overlay and social factors expand the differential diagnosis and modify management, physical dangers should not be forgotten. Disruption of the family unit isolates individuals and requires extra consideration from the caring practitioner, as in the case of Sarah Leigh.

Abdominal Pain↗
PubMed1989

Kinetics of insulin action on protein synthesis in isolated adipocytes. Ability of glucose to selectively desensitize the glucose transport system without altering insulin stimulation of protein synthesis.

When adipocytes were exposed to [3H]leucine for times ranging from 5 to 180 s, leucine was found to enter cells rapidly and equilibrate with the cell interior within 5 s. After an additional 15-30 s [3H]leucine was incorporated into nascent protein, and the rate of incorporation was linear for up to 6 h in both control and insulin-treated cells. Since treatment of adipocytes with 10 ng/ml insulin enhanced the rate of leucine incorporation 2-3-fold with minimal or no effect on the rate of protein degradation or leucine uptake, we conclude that the predominant effect of insulin is on enhancement of protein synthesis. To assess the time required for insulin to stimulate protein synthesis, we preincubated cells with 10 ng/ml of insulin for various times from 2 to 30 min and then measured [3H]leucine incorporation into protein during a 4-min assay. These results revealed that the insulin stimulation of protein synthesis is rapid (t 1/2 of 4.4 min), but 9-fold slower than insulin activation of glucose transport (t 1/2 less than 0.5 min under identical conditions). In contrast to the rapidity of insulin activation, we found that deactivation proceeded at much slower rates (t 1/2 of 32 and 21 min for protein synthesis and glucose transport, respectively). Desensitization of the glucose transport system has previously been shown to occur after adipocytes are exposed to high glucose and insulin. To examine the specificity of desensitization, we treated cells for 6 h with 20 mM glucose and 25 ng/ml insulin and then examined insulin sensitivity and maximal insulin responsiveness of both the glucose transport and protein synthesis systems. After treatment, the glucose transport was markedly insulin-resistant (60% loss in maximal insulin responsiveness and a marked loss in insulin sensitivity), whereas the protein synthesis system exhibited neither diminished insulin responsiveness nor loss of insulin sensitivity. In fact, insulin sensitivity actually increased, as indicated by the finding that less insulin was required to stimulate protein synthesis (insulin ED50 values of 0.25 and 18 ng/ml at 0 and 6 h of treatment). From these studies we conclude that desensitization of the glucose transport system by glucose and insulin treatment appears to be specific for this particular effector system and does not reflect a state of generalized cellular insulin resistance.

Adipose Tissue↗
PubMed1989

Amino acid regulation of insulin action in isolated adipocytes. Selective ability of amino acids to enhance both insulin sensitivity and maximal insulin responsiveness of the protein synthesis system.

UNLABELLED: Using the number and concentration of amino acids in Dulbecco's modified Eagle's medium as reference (DMEM = 100%), we found that a maximally effective concentration of insulin (10 ng/ml) stimulated protein synthesis by 125% over basal rate in the presence of 50% amino acids (EC50 = 19%), but by only 48% in amino acid-free buffer. Moreover, time course experiments revealed that amino acid regulation of insulin action was very rapid (t1/2 of 9.5 min) and readily reversible (less than 30 min). This effect was specific in that basal rates of protein synthesis were unaltered by amino acids. A second effect of amino acids was to markedly enhance insulin sensitivity of the protein synthesis system in a dose-dependent manner. Thus, the half-maximally effective concentrations of insulin required to stimulate protein synthesis fell from 0.43 to 0.25 to 0.15 ng/ml in the presence of 0, 50, and 150% amino acids. Neither insulin sensitivity nor maximal insulin responsiveness of the glucose transport system was altered by amino acids, nor did amino acids affect the insulin binding capacity of cells. When we divided the 14 amino acids found in DMEM into two groups, we found that one group of 7 amino acids had little or no effect on insulin sensitivity or responsiveness, whereas the other group was fully active (a 157% increase in insulin responsiveness, ED50 of 0.21 ng/ml versus a 68% increase, ED50 of 0.51 ng/ml, with no amino acids). Isoleucine and serine together increased both insulin sensitivity and responsiveness to 60-70% of that seen with the full complement of amino acids. IN CONCLUSION: 1) amino acids modulate insulin action by enhancing maximal insulin responsiveness and insulin sensitivity of the protein synthesis system, and the regulatory site of amino acid action appears to be distal to the common signal pathway, within the insulin action-protein synthesis cascade, and 2) the effects of amino acids are specific, in that basal rates of protein synthesis are unaffected, only certain amino acids influence insulin action, and amino acids fail to alter insulin binding or the insulin-responsive glucose transport system. These studies, together with those in the companion paper, demonstrate that the pleiotropic actions of insulin on enhancing glucose uptake and protein synthesis are mediated through divergent pathways that can be independently regulated.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗
PubMed1989

Bone mineral content, serum vitamin D metabolite concentrations, and ultraviolet B light exposure in infants fed human milk with and without vitamin D2 supplements.

OBJECTIVE: To monitor ultraviolet B light exposure in human milk-fed infants both with and without supplemental vitamin D2, and to measure longitudinally the bone mineral content, growth, and serum concentrations of calcium, phosphorus, 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D, and parathyroid hormone. DESIGN: Longitudinal, randomized, double-blind, placebo-controlled study of 6 months' duration. SETTING: Patients from private pediatric practice, Madison, Wisconsin. PATIENTS: Sequential sampling of 46 human milk-fed white infants; 24 received 400 IU/day of vitamin D2, and 22 received placebo. An additional 12 patients were followed who received standard infant formula. Eighty-three percent of patients completed a full 6 months of the study. MEASUREMENTS AND RESULTS: Ultraviolet B light exposure and measurements of growth did not differ between groups. At 6 months, the human milk groups did not differ significantly in bone mineral content or serum concentrations of parathyroid hormone or 1,25-dihydroxyvitamin D, although total 25-hydroxyvitamin D values were significantly less in the unsupplemented human milk group (23.53 +/- 9.94 vs 36.96 +/- 11.86 ng/ml; p less than 0.01). However, 25-hydroxyvitamin D3 serum concentrations were significantly higher in the unsupplemented human milk-fed group compared with the supplemented group (21.77 +/- 9.73 vs 11.74 +/- 10.27 ng/ml, p less than 0.01) by 6 months of age. CONCLUSION: Unsupplemented, human milk-fed infants had no evidence of vitamin D deficiency during the first 6 months of life.

25-Hydroxyvitamin D 2↗