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Biomedical subjects

S Marshall

Publications and source records attributed to S Marshall.

At least 109 records · Page 6Linked to original sources
PubMed1991

Complete inhibition of glucose-induced desensitization of the glucose transport system by inhibitors of mRNA synthesis. Evidence for rapid turnover of glutamine:fructose-6-phosphate amidotransferase.

Glutamine:fructose-6-phosphate amidotransferase (GFAT) plays a key role in desensitizing the insulin-responsive glucose transport system (GTS), and recent studies have revealed that loss of GFAT activity accompanies desensitization. To gain insights into the mechanisms underlying loss of enzyme activity, we have used primary cultured adipocytes and two well established inhibitors of mRNA synthesis to estimate GFAT turnover. Both actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) caused a rapid and extensive loss in GFAT activity (greater than 70% loss, t1/2 of 45 min) indicating that GFAT has a relatively short half-life. Since induction of insulin resistance requires GFAT, we next examined the ability of mRNA inhibitors to block glucose-induced desensitization. When adipocytes were cultured for 18 h with 20 mM glucose, amino acids, and 25 ng/ml insulin, maximal insulin responsiveness of the GTS was reduced by greater than 70%. Both actinomycin D and DRB rapidly and completely prevented desensitization in a dose-dependent manner (ED50 of 16 nM and 15 microM, respectively). These findings are the predicted functional consequence of diminished GFAT activity. Evidence that actinomycin D acts selectively on GFAT without influencing other steps within the desensitization pathway was obtained using glucosamine, an agent that enters the hexosamine biosynthesis pathway at a point distal to the action of GFAT. Actinomycin D inhibited glucose-induced desensitization but failed to block glucosamine-induced desensitization. From these studies we conclude that 1) glucose-induced desensitization of the GTS can be completely prevented by actinomycin D and DRB, two potent and diverse inhibitors of mRNA synthesis; 2) the functional integrity of the desensitization pathway is maintained by a short-lived protein; and 3) the identity of this short-lived protein is most likely GFAT, the first and rate-limiting enzyme of the hexosamine biosynthesis pathway.

Animals↗
PubMed1991

Undiminished social class mortality differences in New Zealand men.

Social class mortality differences in New Zealand men aged 15-64 years have previously been examined for the period 1975-7. It was found that the lower social classes had mortality rates higher than the upper social classes with the mortality rate of the lowest class being approximately twice that of the highest class on a six category scale. The greatest relative social class differences were in men aged less than 35 years. The analysis has now been repeated for the period 1985-7. Mortality declined by 15% between 1975-7 and 1985-7, but the social class mortality differences were undiminished, and the mortality slope was actually slightly greater in the more recent time period. The primary significance of social class analyses is that they identify groups in the community which have an excess mortality that is potentially preventable. The findings of this study indicate that this potential has not been fully realised in New Zealand, since social class differences are undiminished despite the continuing decline in overall mortality.

Adolescent↗
PubMed1991

Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance.

Based on our previous finding that desensitization of the insulin-responsive glucose transport system (GTS) requires three components, glucose, insulin, and glutamine, we postulated that the routing of incoming glucose through the hexosamine biosynthesis pathway plays a key role in the development of insulin resistance in primary cultured adipocytes. Two approaches were used to test this hypothesis. First, we assessed whether glucose-induced desensitization of the GTS could be prevented by glutamine analogs that irreversibly inactivate glutamine-requiring enzymes, such as glutamine:fructose-6-phosphate amidotransferase (GFAT) the first and the rate-limiting enzyme in hexosamine biosynthesis. Both O-diazoacetyl-L-serine (azaserine) and 6-diazo-5-oxonorleucine inhibited desensitization in 18-h treated cells without affecting maximal insulin responsiveness in control cells. Moreover, close agreement was seen between the ability of azaserine to prevent desensitization of the GTS in intact adipocytes (70% inhibition, ED50 = 1.1 microM), its ability to inactivate GFAT in intact adipocytes (64% inhibition, ED50 = 1.0 microM) and its ability to inactivate GFAT activity in a cytosolic adipocyte preparation (ED50 = 1.3 microM). From these results we concluded that a glutamine amidotransferase is involved in the induction of insulin resistance. As a second approach, we determined whether glucosamine, an agent known to preferentially enter the hexosamine pathway at a point distal to enzymatic amidation by GFAT, could induce cellular insulin resistance. When adipocytes were exposed to various concentrations of glucosamine for 5 h, progressive desensitization of the GTS was observed (ED50 = 0.36 mM) that culminated in a 40-50% loss of insulin responsiveness. Moreover, we estimated that glucosamine is at least 40 times more potent than glucose in mediating desensitization, since glucosamine entered adipocytes at only one-quarter of the glucose uptake rate, yet induced desensitization at an extra-cellular dose 10 times lower than glucose. In addition, we found that glucosamine-induced desensitization did not require glutamine and was unaffected by azaserine treatment. Thus, we conclude that glucosamine enters the hexosamine-desensitization pathway at a point distal to GFAT amidation. Overall, these studies indicate that a unique metabolic pathway exists in adipocytes that mediates desensitization of the insulin-responsive GTS, and reveal that an early step in this pathway involves the conversion of fructose 6-phosphate to glucosamine 6-phosphate by the first and rate-limiting enzyme of the hexosamine pathway, glutamine:fructose-6-phosphate amidotransferase.

Animals↗
PubMed1991

Mania and seasonality in the southern hemisphere.

Admissions for mania over a 9-year period in New Zealand were analysed, including data from four separate regions spanning nine degrees in latitude. A spring/summer peak of admissions for mania was found. The four regions showed marked, unexpected variability in seasonality. Regression analyses were performed to test the association of admissions for mania, in the month of admission and the previous month, with mean daily temperature, day length, hours of bright sunshine and mean relative humidity plus the rate of change of each of these variables.

Bipolar Disorder↗
PubMed1991

Prostate irradiation does not affect the serum prostatic acid phosphatase level.

Twenty-nine consecutive patients with localized prostatic carcinoma were studied prospectively to assess the effect of radical pelvic irradiation on the serum prostatic acid phosphatase level (SPAPL). The doses of radiation given ranged from 64.00 to 66.00 Gy. SPAPLs were taken before, during and shortly after their treatment. No significant individual variations in SPAPLs were found. When patients with prostatic carcinoma show rises in serum prostatic acid phosphatase during or after pelvic irradiation, these are unlikely to be due to their treatment and occult pelvic nodal or bony disease should be considered.

Acid Phosphatase↗
PubMed1991

Stomach cancer in New Zealand: time trends, ethnic group differences and a cancer registry-based case-control study.

Stomach cancer trends in New Zealand were examined. Age-standardized mortality and incidence rates have declined over the past four decades, as in other countries. Rates have been consistently higher for men, and for Maori. A cancer registry-based case-control study of 1016 male stomach cancer cases and 19,042 male controls with other cancers was also conducted, to evaluate the relationships between stomach cancer and specific occupations. Adjustment was made for age, ethnicity, socioeconomic level, and smoking status. When 22 occupational groups were examined, adjusted odds ratios (ORs) and 95% confidence intervals (95% Cls) were elevated above unity for only one group: forestry workers (OR 1.83, 95% Cl 1.01-3.32). When two large, heterogeneous groups were broken down into 15 subgroups, adjusted ORs and 95% Cls elevated above unity were found for three sub-groups: grain millers and related workers; brewers, wine and beverage makers; and field crop workers. These findings may be because of the multiple comparisons and subgroup analyses undertaken. Men who had ever smoked cigarettes were found to have an increased stomach cancer risk compared to those who had never smoked (adjusted OR 1.36, 95% Cl 1.15-1.60).

Case-Control Studies↗
PubMed1991

Social class inequalities in the decline of coronary heart disease among New Zealand men, 1975-1977 to 1985-1987.

Coronary heart disease (CHD) is regarded as a disease of developed 'western' societies. Within developed societies, however, CHD is typically a disease of the less affluent socioeconomic classes. This has not always been the case. Forty years ago. CHD was reported to be more common among the upper social classes. In New Zealand, as in other developed countries, this original trend across social classes was reversed during the past 40 years. In 1975-1977, a gradient across social class was observed for both CHD and cerebrovascular disease mortality, with the lowest social classes experiencing the highest mortality. This study has now been repeated for the period 1985-1987. Employed males aged 15-64 years were categorized by the Elley-Irving scale into six social classes. The overall age-standardized mortality rate from CHD declined over the ten-year period, from 163.0 to 121.7 per 100,000 person-years. Over the same period, however, the social class gradient for coronary mortality actually increased. The overall age-standardized mortality rate from cerebrovascular disease also declined over the ten-year period, from 25.9 to 17.7 per 100,000 person-years. A social class gradient for cerebrovascular mortality was present in both periods. In contrast to coronary mortality, however, the social class gradient diminished slightly over the ten-year period.

Adolescent↗
PubMed1991

New insights into the metabolic regulation of insulin action and insulin resistance: role of glucose and amino acids.

In primary cultured adipocytes, metabolic substrates such as glucose and amino acids have profound effects on modulating insulin's stimulatory actions on glucose uptake and protein synthesis. Insights into how substrates modulate insulin action were recently obtained when we discovered that the routing of incoming glucose through the hexosamine biosynthesis pathway leads to a refractory state over a period of several hours in which the ability of insulin to stimulate glucose uptake is severely impaired--a state known as insulin resistance. Glutamine:fructose-6-phosphate amidotransferase was found to play a central role in the development of insulin resistance as this enzyme catalyzes the first and rate-limiting step in the formation of hexosamine products. Collectively, these results are consistent with the idea that the hexosamine biosynthesis pathway serves as a glucose sensor coupled to a negative feedback system that can limit the extent of glucose uptake in response to hyperglycemic and hyperinsulinemic conditions.

Adipose Tissue↗
PubMed1991

Noninvasive estimation of the instantaneous first derivative of left ventricular pressure using continuous-wave Doppler echocardiography.

BACKGROUND: The complete continuous-wave Doppler mitral regurgitant velocity curve should allow reconstruction of the ventriculoatrial (VA) pressure gradient from mitral valve closure to opening, including left ventricular (LV) isovolumic contraction, ejection, and isovolumic relaxation. Assuming that the left atrial pressure fluctuation is relatively minor in comparison with the corresponding LV pressure changes during systole, the first derivative of the Doppler-derived VA pressure gradient curve (Doppler dP/dt) might be used to estimate the LV dP/dt curve, previously measurable only at catheterization (catheter dP/dt). METHODS AND RESULTS: This hypothesis was examined in an in vivo mitral regurgitant model during 30 hemodynamic stages in eight dogs. Contractility and relaxation were altered by inotropic stimulation and hypothermia. The Doppler mitral regurgitant velocity spectrum was recorded along with simultaneously acquired micromanometer LV and left atrial pressures. The regurgitant velocity profiles were digitized and converted to VA pressure gradient curves using the simplified Bernoulli equation. The instantaneous dP/dt of the VA pressure gradient curve was then derived. The instantaneous Doppler-derived VA pressure gradients, instantaneous Doppler dP/dt, dP/dtmax, and -dP/dtmax were compared with corresponding catheter measurements. This method of estimating dP/dtmax from the instantaneous dP/dt curve was also compared with a previously proposed Doppler method of estimating dP/dtmax using the Doppler-derived mean rate of LV pressure rise over the time period between velocities of 1 and 3 m/sec on the ascending slope of the Doppler velocity spectrum. Both instantaneous Doppler-derived VA pressure gradients (r = 0.95, p less than 0.0001) and Doppler dP/dt (r = 0.92, p less than 0.0001) correlated well with corresponding measurements by catheter during systolic contraction and isovolumic relaxation (pooled data). The Doppler dP/dtmax (1,266 +/- 701 mm Hg/sec) also correlated well (r = 0.94) with the catheter dP/dtmax (1,200 +/- 573 mm Hg/sec). There was no difference between the two methods for measurement of dP/dtmax (p = NS). Although Doppler -dP/dtmax was slightly lower than the catheter measurement (961 +/- 511 versus 1,057 +/- 540 mm Hg/sec, p less than 0.01), the correlation between measurements by Doppler and catheter was excellent (r = 0.93, p less than 0.0001). The alternative method of mean isovolumic pressure rise (896 +/- 465 mm Hg/sec) underestimated the catheter dP/dtmax (1,200 +/- 573 mm Hg/sec) significantly (on average, 25%; p less than 0.001). CONCLUSIONS: The present study demonstrated an accurate and reliable noninvasive Doppler method for estimating instantaneous LV dP/dt, dP/dtmax, and -dP/dtmax.

Animals↗
PubMed1991

Lack of evidence for beta-2 receptor selectivity: a study of metaproterenol, fenoterol, isoproterenol, and epinephrine in patients with asthma.

In order to investigate the pharmacodynamic selectivity of a number of beta-receptor agonists currently used in asthma, we compared the pulmonary and extrapulmonary effects of repeated inhalations of epinephrine, fenoterol, isoproterenol, and metaproterenol in 12 patients with asthma in a randomized double-blind crossover study. The drugs were administered from metered-dose inhalers at 15-min intervals for five doses (total dose, 10 puffs of each compound). Measurements of heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval, plasma potassium, and FEV1 were made 5 min after each dose and 30 min after the final dose. Fenoterol and metaproterenol had significantly greater inotropic, electrocardiographic, chronotropic, and hypokalemic effects than did both isoproterenol and epinephrine. There was no difference in the bronchodilating effect of metaproterenol, fenoterol, or isoproterenol although these agents caused a significantly greater increase in FEV1 than did epinephrine. The concept of increasing beta-2 selectivity for metaproterenol and fenoterol compared with isoproterenol are not supported in the clinical setting.

Adrenergic beta-Agonists↗
PubMed1991

The influence of growth hormone and thyroxine on iodothyronine deiodinase activity in the liver, kidney and brown adipose tissue in hypophysectomized rats.

The effects of GH and T4 substitution on peripheral iodothyronine deiodinase activity in the liver, kidney and brown adipose tissue of hypophysectomized rats were investigated. Animals were treated with GH (140 micrograms hGH/day), T4 (3 micrograms/day), GH plus T4 (same doses), or saline. Rats were killed 0, 4, 7 or 11 days after treatment was started. Non-hypophysectomized, age-matched rats were killed after 0 and 11 days and served as controls. GH plus T4 restored body weight gain to normal, whereas GH alone and T4 alone did not. Tissue deiodinase activity and T3 concentrations were severely depressed in the hypophysectomized rats compared with non-hypophysectomized controls (to less than 10%). GH substitution in hypophysectomized rats led to a slight but significant elevation in tissue iodothyronine deiodinase activity in the liver and kidney, without concomitant increases in T3. Deiodinase activity in brown adipose tissue did not differ from that in saline-treated controls. T4 administration normalized deiodinase activity and tissue T3 content in all the evaluated tissues. GH plus T4 resulted in a lesser increase in deiodinase activity than T4 alone in the liver and kidney (p less than 0.01 at day 11), whereas no significant difference was observed in brown adipose tissue. In conclusion, GH stimulates iodothyronine deiodinase activity of the liver and kidney in hypophysectomized rats. Moreover, when GH is administered together with T4, the T4-stimulated enzyme activity in the liver and kidney is downregulated, suggesting that GH attenuates (or modulates) the T4 effect on this specific enzyme activity.

Adipose Tissue, Brown↗
PubMed1991

Plasma membrane phospholipid translocation in the mouse peritoneal macrophage: differential response to stimulation of eicosanoid production.

The metabolism and translocation of exogenously introduced plasma membrane phosphatidylcholine (PC) having the fluorescent fatty acid analog aminocaproyl NBD (N-nitrobenzo-2-oxa-1,3 diazole) (NBD-PC), in the sn2 position was studied in cultured murine peritoneal macrophages using biochemical and morphological techniques. Following labeling of the cell plasma membrane at 2 degrees C by vesicle lipid exchange, macrophages were warmed in the presence or absence of pharmacological stimuli of eicosanoid production and release. Fluorescence microscopy indicated that the phospholipid was translocated to an internal cellular pool upon stimulation with zymosan. In contrast, the membrane PC analog was primarily metabolized and released after being found diffusely associated with the cytoplasm in macrophages stimulated with the calcium ionophore A23187. Evidence obtained by double labeling zymosan-treated macrophages with NBD-PC and a monoclonal antibody directed against a lysosomal membrane protein demonstrated that the fluorescent lipid is internalized in association with the zymosan particles and both are found in lysosomes. The results suggest that multiple pathways exist in peritoneal macrophages which target plasma membrane PC into different cellular compartments for hydrolysis and conversion to eicosanoid products and release from cells.

4-Chloro-7-nitrobenzofurazan↗
PubMed1991

Differential protein phosphorylation in human gastric adenocarcinomas.

A qualitative analysis of endogenous protein phosphorylation in microsomal fractions from surgical specimens of human gastric cancer, benign gastric ulcers and normal gastric tissues is presented. Fractions were incubated in the presence of (gamma-32P)ATP to measure the transfer of (gamma-32P) to natural substrates mediated by endogenous protein kinases. Phosphoproteins were characterized through PAGE-SDS and detected by autoradiography. KOH at high temperature was used to select for tyrosine-phosphorylated polypeptides on dried gels. We report a notorious enhancement in overall protein phosphorylation in gastric cancer samples over benign ulcers and normal controls as well. Moreover, a highly basic-low molecular weight phosphoprotein is found through 2-D protein gel analysis and a 50 kDa protein is detected only in the presence of Mg2+ after KOH treatment. These two proteins might become putative molecular markers to detect this type of neoplasia.

Adenocarcinoma↗
PubMed1991

Vitamin K status of lactating mothers, human milk, and breast-feeding infants.

Hemorrhagic disease of the newborn is a disease of breast-feeding newborns. There is little information on longitudinal breast milk concentrations of phylloquinone (vitamin K1) or the effects of maternal phylloquinone supplements on breast milk. In study part 1, 11 lactating mothers, who received 20 mg of phylloquinone orally, had rises in plasma (less than 1 to 64.2 +/- 31.5 ng/mL by 6 hours) and breast milk concentrations (from 1.11 +/- 0.82 to 130 +/- 188 ng/mL by 12 hours). In part 2, 23 lactating mothers and their infants were observed longitudinally along with a formula-fed control group of infants (n = 11). Mean breast milk concentrations of phylloquinone at 1, 6, 12, and 26 weeks were 0.64 +/- 0.43, 0.86 +/- 0.52, 1.14 +/- 0.72, and 0.87 +/- 0.50 ng/mL, respectively, in the infants fed human milk. Maternal phylloquinone intakes (72-hour dietary recalls) exceeded the recommended daily allowance of 1 microgram/kg per day. Infant phylloquinone intakes did not achieve the recommended daily allowance of 1 microgram/kg per day in any infant. Plasma phylloquinone concentrations in the infants fed human milk remained extremely low (mean less than 0.25 ng/mL) throughout the first 6 months of life compared with the formula-fed infants (4.39 to 5.99 ng/mL). In this small sample, no infant demonstrated overt vitamin K deficiency. Despite very low plasma phylloquinone concentrations, vitamin K supplements (other than in the immediate newborn period) cannot be recommended for exclusively breast-fed infants based on these data.

Bottle Feeding↗