Biomedical subjects
Publications and source records attributed to A Young.
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In summary, amylin, via its hormonal actions, may be relevant to the treatment of both forms of diabetes, and, paradoxically, via its amyloidogenic properties, may also be relevant to the pathogenesis of NIDDM. Amylin potently inhibits postprandial glucagon secretion. The absence of this action could contribute to the hyperglucagonemia and subsequently, excessive endogenous glucose production, fasting hyperglycemia, and propensity to ketosis seen in insulinopenic diabetes. Restoration of normal glucagon secretion by amylin replacement therapy could therefore be therapeutically important in treatment of insulin-dependent diabetes mellitus. Amylin potently inhibits gastric emptying. This action is consistent with a physiologic role of amylin to regulate carbohydrate absorption. Of peptides known to be secreted in response to ingested carbohydrate, only amylin and glucagon-like peptide-1 are reported to inhibit gastric emptying at near-physiologic concentrations, and could therefore participate in nutrient-mediated feedback control of carbohydrate release from the stomach. Amylin reduces food intake in rodents. This action, which synergizes with a similar action of CCK, could reflect a role as short-term peripheral satiety agent. Amylin alone or in combination with CCK may be useful in moderating caloric intake in obesity and other metabolic disorders. Although insulin has been extensively studied as a therapy and as a controller of nutrient storage and metabolism, the role of its beta-cell partner, amylin, has been largely unrecognized. In contrast to the nutrient disposal and storage role of insulin, amylin appears to more generally address the opposite side of the energy balance equation, the assimilation of nutrient.
Amylin is a 37 amino acid hormone, co-secreted with insulin from the pancreatic beta-cell in response to nutrient stimuli. Because the human amylin analog, pramlintide, is being tested in patients with diabetes mellitus, a known risk factor for nephropathy, we examined the role of the kidney on amylin and pramlintide metabolism and action in functionally nephrectomized rats. Nephrectomy markedly altered amylin metabolism: it increased incremental area under the plasma amylin concentration curve 3.6-fold (P<0.001) and increased the elimination half-life from 17+/-1 to 26+/-2 minutes (P < 0.01) after subcutaneous injection of 100 microg amylin. Nephrectomy decreased plasma amylin clearance from 20.3+/-1.1 to 7.9+/-0.4 mL/min (P < 0.0001). Thus, at these doses in the rat, the kidney is important for metabolizing amylin and pramlintide.
Amylin is a peptide secreted from the pancreatic beta-cell along with insulin in response to nutrient stimuli. Amylin has been reported to delay gastric emptying, inhibit glucagon secretion and gastric acid secretion, increase plasma lactate, plasma glucose and plasma renin activity, and decrease plasma calcium. Receptors for amylin have been found in the rat nucleus accumbens and the kidney. In the present experiments, amylin was administered to anesthetized rats by continuous intravenous infusions at varied rates. Amylin significantly increased urine flow at an infusion rate resulting in a plasma concentration of approximately 52 pM, and at a concentration of approximately 193 pM, it increased sodium excretion, glomerular filtration rate and renal plasma flow. Renal calcium and potassium excretion were significantly elevated at plasma amylin concentrations of approximately 52 pM and 193 pM, respectively. Higher concentrations of plasma amylin decreased plasma calcium and potassium and blunted urinary excretion of these electrolytes. Thus, of the renal responses tested, diuresis and natriuresis appeared to be the most sensitive to infused amylin. These renal effects occurred only at plasma concentrations above the normal range, but within the range of concentrations reported in insulin resistant rats.
Amylin is a 37-amino acid peptide co-secreted from the pancreatic beta-cell with insulin in response to nutrient stimuli. Plasma amylin concentrations in the rat are reported to vary widely. We have employed a recently-developed immunoenzymometric assay to quantify plasma amylin concentrations in fasted, fed and glucose-administered rats. Fasted amylin concentrations ranged between 1.02+/-0.09 and 1.63+/-0.15pM among three different common rat strains, and increased up to 7.70+/-0.80 pM after feeding. The differences among strains and between fasted and fed rats were all significant at P<0.01 or less. Intravenous glucose administration (5.2 mmol/kg) also significantly increased plasma amylin concentrations in fasted rats from 1.5+/-0.3pM to 3.4+/-0.5pM, and in fed rats from 4.6+/-1.1 pM to 9.1+/-1.7 pM. Plasma amylin/insulin molar ratios ranged between 2.3+/-0.2% and 3.6+/-0.5% (mean 3.0%), but did not differ among strains, or between the fasted vs fed state in any strain. In conclusion, a new sensitive immunoenzymometric assay revealed fasting plasma concentrations which are lower than previously reported, and which are significantly increased by stimulation with feeding or glucose administration.
OBJECTIVES: To determine the extent of muscle weakness in older female hip fracture patients compared with healthy older and young women; to determine the extent to which this weakness is caused by a decline of the force produced per unit area of muscle rather than by a decline in muscle bulk; and to investigate the mechanism of the decline in force per unit area. DESIGN: This was an open study of three groups of subjects, two age matched older groups and one young group. SETTING: University College London, Royal Free Hospital, and St. Thomas's Hospital, London. PARTICIPANTS: Twenty-nine older female hip fracture patients (mean age 85.6 +/- 0.9 SEM), 18 healthy older women (mean age 84.7 +/- 1.2 SEM), and 43 young women (mean age 28.9 +/- 1.2 SEM). MEASUREMENTS: Adductor pollicis muscle maximum voluntary force (MVF) during isometric and pliometric contractions and cross-sectional area (CSA), body weight, height, and demi-span. RESULTS: Isometric MVF was lowest in the hip fracture group. In both older groups, isometric MVF and CSA were lower than in the young women. Only part of this weakness in the older groups could be explained by the smaller CSAs. The isometric force per unit area (MVF/CSA) was also lower in both older groups, the hip fracture patients again having the lowest values. Analysis of variance showed a significant difference between groups. The age-related declines in pliometric force were much less than the declines in isometric force. This resulted in an increase in the pliometric/isometric force ratio both for the hip fracture patients and for the healthy older women compared with that for young women. CONCLUSION: In comparison with the results from young women, the adductor pollicis muscles of female hip fracture patients were even weaker than those of healthy older women when normalized for muscle size. This decline in isometric MVF/CSA accounted for at least half of the overall weakness in the hip fracture patients. Inasmuch as pliometric force is maintained in situations where weakness is caused by a decline in the force produced per muscle cross-bridge, this is the likely mechanism of the declines in isometric MVF/CSA observed in this study.
PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.
This article describes the long and arduous journey to the development of the Nursing Position Statement-Appropriate Care Provider for the Operating Room in Hamilton and Burlington, Ontario. From the first meeting to the final presentation of the Position Statement to management, it took over a year of intense review. The entire process was done in consultation with the College of Nurses of Ontario, Operating Room Management, educators and staff nurses.
In youth, most physiological functions have generous spare capacity. Even in health, however, increasing age is characterized by progressive erosion of these 'safety margins'. Examples include the decline of bone mass (towards a threshold for likelihood of fracture), of glomerular filtration rate (towards a threshold for susceptibility to clinical renal failure), of renal tubular function (towards a threshold for clinically important susceptibility to dehydration), of hepatic function (towards a threshold for accumulation following conventional 'young adult' doses of common medications), or of lower limb explosive power (towards thresholds for impaired functional mobility). Increasing age is also characterized by a rising prevalence of chronic pathologies, complicating attempts to determine the rate or the mechanism of the age-related decline in a physiological function. Nevertheless, it is clear that in many organs the loss of function is largely attributable to the loss of functioning cells, even in the absence of overt disease. This apparently fundamental aspect of ageing remains poorly understood.
Uncoupling protein (UCP1) is a transmembrane proton transporter present in the mitochondria of brown adipose tissue (BAT), a specialized tissue which functions in temperature homeostasis and energy balance (Nicholls, D. G., and Locke, R. M. (1984) Physiol. Rev. 64, 2-40; Lowell, D. D., and Flier, J. S. (1997) Annu. Rev. Med.). UCP1 mediates the thermogenesis that is characteristic of BAT by uncoupling mitochondrial oxidation of substrates from ATP synthesis. Recently, two proteins related to UCP1 have been identified and designated UCP2 (Fleury, C., et al. (1997) Nature Genetics 15, 269-272) or UCP homolog (UCPH) (Gimeno, R. E., et al. (1997) Diabetes 46, 900-906) and UCP3 (Boss, O., et al. (1997) FEBS Lett. 408, 39-42; Vidal-Puig, A., et al. (1997) Biochem. Biophys. Res. Commun. 235, 79-82). We investigated the regulation in rats of UCP3, which is expressed primarily in skeletal muscle and BAT. Expression of rat UCP3 mRNA in BAT was upregulated by in vivo treatment with triiodothyronine (T3) and by exposure to cold, suggesting that UCP3 is active in thermogenesis and energy expenditure. In skeletal muscle, UCP3 mRNA was also upregulated by T3 but, surprisingly, not by cold exposure. A hypothesis is proposed to account for this differential regulation.
Peutz-Jeghers syndrome (PJS) was recently mapped in a single report to the telomeric region of chromosome 19p (A. Hemminki et al., Nat. Genet., 15: 87-90, 1997). Our studies confirm this location and provide further localization of the PJS locus. In the five families examined, there were no recombinants with the marker D19S886. The multipoint log odds score at D19S886 is 7.52, and we found no evidence for genetic heterogeneity. We also found that all carriers expressed the PJS phenotype and no noncarriers displayed PJS sequellae, indicating complete penetrance with no sporadic cases.
The pancreatic hormone amylin is co-secreted with insulin by beta-cells in response to nutrient intake. Studies performed in experimental animals have provided evidence that amylin may have several effects associated with carbohydrate metabolism. Amylin is a potent inhibitor of gastric emptying. This effect appears to require an intact vagus nerve and it is over-ridden by hypoglycaemia. These observations, coupled with the identification of putative amylin receptors in the area postrema of the hindbrain (a region implicated in the regulation of gastric motility) suggest that the effects of amylin on gastric emptying are mediated, at least in part, by the central nervous system. There is also evidence that amylin acts to inhibit food intake, an action which is distinct from its effects on gastric emptying. In addition, amylin has been shown to inhibit amino acid-stimulated glucagon secretion, suggesting that it may reduce endogenous glucose production in the postprandial period.
We compared several strategies for identifying and estimating effects from a genetic locus in the etiology of a complex trait. For our analyses we used data from simulated trait 1 and chromosome 5. Results from analysis of the first 20 replicates showed that a components of variance test provided considerably better power for identifying linkage than tests that consider pair differences. We also compared the power from constructing tests with a single marker, an approximate method using five markers jointly, or a multipoint analysis using all 25 markers on chromosome 5 jointly. Results from this analysis showed substantially better power when all markers were jointly used in the analysis. Results from considering all replicates showed that all methods of estimation provided maximal test statistics at the correct marker position, but the components of variance procedure provided more power to detect the correct position than other methods.
OBJECTIVE: To determine whether circulating concentrations of defined cell adhesion molecules, which are thought to reflect endothelial expression, are increased in insulin-dependent diabetic women during pregnancy. METHODS: Pregnant diabetic women demonstrating good glycemic control and without major complications before pregnancy were studied at 8-12 (n = 15), 18 (n = 15), 28 (n = 16), 32 (n = 16), and 36 (n = 16) weeks' gestation. A subgroup of ten diabetic women was sampled longitudinally through all five gestational ages. The diabetic women were compared with healthy nondiabetic women sampled cross sectionally at 12 (n = 20), 28 (n = 19), and 36 (n = 19) weeks' gestation. Nonpregnant diabetic (n = 22) and nonpregnant nondiabetic women (n = 28) also were studied. Plasma concentrations of the cell adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular endothelial cell adhesion molecule-1 (VCAM-1) were measured by enzyme-linked immunosorbent assay. RESULTS: Significantly higher median (range) concentrations of E-selectin (63.0 [20.2-107.0] ng/mL) and ICAM-1 (281.5 [171.6-778.4] ng/mL) but not VCAM-1 (459.7 [301.0-909.7] ng/mL) were found in nonpregnant diabetic women compared with nonpregnant nondiabetic women (43.5 [18.1-93.2], 243.6 [174.4-329.2], and 476.0 [253.8-929.4] ng/mL, respectively). During pregnancy these significant differences between diabetic and control groups were lost. The median (range) concentration of E-selectin (50.0 [21.2-96.3] ng/mL) was significantly lower in pregnant compared with nonpregnant diabetic women. The plasma concentrations of E-selectin and ICAM-1 did not change significantly with gestation in either diabetic or nondiabetic pregnant groups. Vascular endothelial cell adhesion molecule-1 concentration changed significantly with gestation in the diabetic pregnant group only. CONCLUSION: Circulating concentrations of defined vascular cell adhesion molecules are not increased abnormally in diabetic women with good glycemic control during otherwise uncomplicated pregnancy.
In view of the pathological placental features of pre-eclampsia and intrauterine growth restriction (IUGR), and the angiogenic effects of vascular endothelial growth factor (VEGF), the aim of this study was to determine the expression of VEGF in placentae from normal pregnancies and to compare the results with placentae from pregnancies complicated by pre-eclampsia and intrauterine growth restriction (IUGR). ELISA was used to measure circulating VEGF immunoreactivity in umbilical vein serum samples and immunohistochemistry was used to determine tissue expression of the protein. Since VEGF is known to be upregulated by hypoxia, the expression pattern of VEGF would provide further clues to the oxygen status in the placentae at the time of sampling, presently a subject under great debate. The geometric mean concentration of VEGF immunoreactivity in umbilical vein serum of normal pregnant women was 112.46 pg/ml, in women with pre-eclampsia 50.23 pg/ml and in IUGR alone 175.35 pg/ml. These values were not statistically different from each other. Immunolocalization of VEGF in normal term villous placenta was observed in the syncytiotrophoblast with less intense staining in stromal cells. No qualitative differences in localization of staining between the groups (normal pregnancies, pre-eclampsia, pre-eclampsia plus IUGR, and IUGR) was found. Intensity of staining in stromal cells was also similar in the groups studied. However, intensity of VEGF immunostaining in syncytiotrophoblast was significantly reduced in the three pathological groups (P < 0.02) compared with the control group. These results suggest that reduced VEGF may be responsible, at least in part, for the impaired vascular development which occurs in these conditions. Our results are therefore not consistent with villous placental hypoxia at the time of sample collection.
Tryptophan is the precursor of the neurotransmitter 5-hydroxytryptamine (5-HT), known to be involved in sleep and fatigue. In the blood, tryptophan binds to albumin, and that which does not, free tryptophan, competes with branched chain amino acids (BCAA) for entry into the brain. The plasma concentrations of albumin, free tryptophan, total tryptophan, and BCAA were measured before and after major surgery in nine elderly and nine coronary artery bypass graft (CABG) patients. In both the elderly and the CABG patients plasma free tryptophan concentrations were increased after surgery, compared with baseline levels; the plasma free tryptophan/BCAA concentration ratio was also increased significantly after surgery. Plasma albumin concentrations were decreased significantly after surgery in both the elderly and the CABG patients. Plasma BCAA concentrations were not affected by surgery in either group. The effect of exercising to exhaustion on 5-HT and tryptophan were investigated in Nagase analbuminemic rats (NAR). The intrasynaptosomal concentration of tryptophan, 5-hydroxy-tryptophan, and 5-HT was increased by fatigue after exercise. In addition, running time to exhaustion was shortened in NAR. These data suggest that free tryptophan uptake and 5-HT synthesis were enhanced in the nerve terminal. A decrease in plasma albumin may account for the increase in plasma-free tryptophan levels. An increase in plasma free tryptophan, resulting in an enhanced plasma concentration ratio of free tryptophan/BCAA, may lead to a higher 5-HT concentration in some parts of the brain and, consequently, to central fatigue. It is suggested that provision of BCAA as a dietary supplement may counteract the increase in plasma free tryptophan and thus improve the status of some patients after major surgery.
This chapter will describe the reasons why prognostic factors that predict aggressive disease are helpful and what the problems are in interpreting studies in this field. A summary of cohort studies on prognosis of patients with early rheumatoid arthritis are presented. This is done separately for studies predicting radiographic damage, functional outcome and mortality. The overall conclusions of these studies and the value they have for the clinician are demonstrated.