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Biomedical subjects

R Wilkinson

Publications and source records attributed to R Wilkinson.

At least 109 records · Page 6Linked to original sources
PubMed1993

Erythrocyte sodium-lithium countertransport activity and total body insulin-mediated glucose disposal in normoalbuminuric normotensive type 1 (insulin-dependent) diabetic patients.

Insulin resistance in Type 1 (insulin-dependent) diabetes mellitus may be associated with raised erythrocyte sodium-lithium countertransport activity in patients with hypertension, or nephropathy, or both. However, in these circumstances it is difficult to separate the impact of hypertension, hyperlipidaemia and nephropathy on erythrocyte sodium-lithium countertransport from that of insulin resistance. We have therefore examined the relationship between insulin-mediated glucose disposal and erythrocyte sodium-lithium countertransport in 41 normotensive (mean blood pressure 120/74 mmHg), normoalbuminuric (mean albumin excretion 6.2 micrograms/min), normolipidaemic (mean serum cholesterol 4.3 mmol/l and mean serum triglycerides 1.0 mmol/l) Type 1 diabetic patients. Erythrocyte sodium-lithium countertransport was on average 0.31 mmol Li.h-1.l erythrocytes-1 (range 0.07-0.69). Nine patients had values above 0.40 mmol Li.h-1.l erythrocytes-1 (0.51 +/- 0.10 mmol Li.h-1.l erythrocytes-1). The patients with high erythrocyte sodium-lithium countertransport were matched for age, sex, BMI, HbA1 and duration of diabetes, with nine patients with normal erythrocyte sodium-lithium countertransport. Insulin-mediated glucose disposal was evaluated during the last hour of a euglycaemic clamp (insulin 0.015 U.kg-1.h-1; blood glucose clamped at 7.0 mmol/l). The free insulin levels were comparable between the patients with high and normal erythrocyte sodium-lithium countertransport (37.2 +/- 14.7 mU/l and 34.7 +/- 17.2 mU/l respectively). Insulin-mediated glucose disposal was on average 3.1 +/- 1.5 (range 0.8-6.8) mg.kg-1.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Sodium-lithium countertransport activity is not affected by short-term insulin exposure in vivo or in a physiologic medium in vitro.

This study examined the acute effects of physiologic concentrations of insulin in vitro and in vivo on sodium-lithium countertransport (SLC) kinetics in nondiabetic subjects. SLC was measured at eight different external sodium concentrations including the standard 150 mmol/L, allowing calculation of both maximal velocity (Vmax) and external sodium affinity (Km). Incubation with insulin (50 mU/L) in 110 MgCl2 but not in 150 mmol/L NaCl decreased standard SLC activity. The decrease was accounted for by a reduction in Vmax, whereas Km remained constant. There was no difference in standard SLC activity, Vmax, or Km when endogenous insulin concentrations were altered either by fasting or by a carbohydrate load. Similarly, standard SLC activity, Vmax, or Km were not significantly different before or at the completion of a euglycemic hyperinsulinemic clamp. These findings provide no support for an action of physiologic concentrations of insulin either in vitro or in vivo on the kinetics of the countertransporter measured in vitro in isotonic sodium-containing media.

Adult↗
PubMed1993

The effect of short-term low-dose cyclosporin on renal function and blood pressure in patients with psoriasis.

The effect of short-term (mean 2.4 months), low-dose (5 mg/kg) cyclosporin A (CyA) on renal function and blood pressure was studied in eight patients with psoriasis. Studies were undertaken before, during and after treatment. Glomerular filtration rate (GFR) post-treatment was significantly higher than pretreatment or during treatment (pre, 119 +/- 7; during, 113 +/- 9; post, 133 +/- 11 ml/min per 1.73 m2; pre vs. during, NS; during vs. post, P < 0.01; pre vs. post, P < 0.05); effective renal plasma flow (ERPF) was unchanged (pre, 515 +/- 38; during, 485 +/- 49; post, 560 +/- 45 ml/min per 1.73 m2). There was no change in the urinary excretion of either albumin or the enzymes N-acetyl-glucosaminidase, lactate dehydrogenase, alanine aminopeptidase and alkaline phosphatase. There was a decrease in exchangeable sodium which persisted post-treatment (pre, 56 +/- 3; during, 49 +/- 3; post, 49 +/- 3 mmol/kg LBM; pre vs. during, P = 0.07; during vs. post, NS; pre vs. post, P = 0.06). Blood pressure assessed as either a single reading, or the mean of a 24 h ambulatory recording, increased during treatment (single reading: pre, 113/73; during, 126/83; post, 114/70 mmHg; mean 24 h: pre, 114/71; during, 123/76; post, 120/72 mmHg). Thus, short-term use of CyA at a dose of 5 mg/kg for the treatment of psoriasis is associated with a significant increase in blood pressure, but only a transient mild reduction in GFR, which did not reach significance.

Adult↗
PubMed1993

Increased human erythrocyte sodium-lithium countertransport in hyperlipidaemic patients may indicate increased membrane lipid fluidity.

Erythrocyte sodium-lithium countertransport (SLC) activity, membrane fluidity, plasma triglyceride and cholesterol were measured in hyperlipidaemic patients and normal subjects. Fluidity was assessed by the fluorescence anisotropy (inversely related to fluidity) of the probes 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1,4-trimethylammonium-3,5-hexatriene (TMA-DPH). In a second group of patients the maximum velocity (Vmax) and external sodium affinity constant (km) of SLC was also measured. In the first group of patients, SLC activity was increased compared with the controls (0.279 +/- 0.019 vs. 0.213 +/- 0.013, P = 0.006) as was membrane fluidity in the deep hydrophobic regions (DPH anisotropy 0.211 +/- 0.0007 vs. 0.215 +/- 0.0011, P = 0.007). There was a strong correlation between SLC and DPH anisotropy (Rs = -0.72, P = < 0.001) which was due to the correlation between Vmax and DPH anisotropy (Rs = -0.90, P = < 0.001). Increases in Vmax of SLC in hyperlipidaemic patients may be due to differences in lipid organisation in the deep hydrophobic regions of the membrane which may affect the turnover rate of the transporter.

Adult↗
PubMed1993

Increased red cell sodium lithium countertransport activity, total exchangeable sodium, and hormonal control of sodium balance in normoalbuminuric type 1 diabetes.

The relationship between erythrocyte sodium lithium countertransport activity (SLC), total exchangeable sodium (NaE), and hormonal control of renal function was examined in 40 normotensive, normoalbuminuric, non-neuropathic Type 1 diabetic subjects, of whom 8 had elevated SLC (> 0.40 mmol Li h-1l-1 rbc). Eleven health controls with normal SLC, who were of comparable age, body mass, and blood pressure were also studied. By contrast with healthy controls, SLC in Type 1 diabetes was not associated with plasma renin activity (PRA), aldosterone, systolic blood pressure or lean body mass. SLC was also unrelated to atrial natriuretic peptide (ANP) (Type 1 diabetes only) and NaE. NaE was not correlated with any other variables. The relationships between PRA and aldosterone in healthy controls were retained in Type 1 diabetes (R2 0.37 supine, p = 0.00001, and 0.27 ambulant, p = 0.0005), as were respective direct and inverse relations between vasopressin and ANP and both PRA (rs 0.54 to 0.57, rs -0.43 to -0.53), and aldosterone (rs 0.78 to 0.80, rs -0.71 to -0.80). Fasting free serum insulin and vasopressin were both inversely related to ANP (rs -0.91 and -0.71, respectively). In the absence of autonomic dysfunction, hypertension or early nephropathy in Type 1 diabetes, increased SLC or exchangeable sodium were unrelated to each other or with hormonal control of sodium balance, but the homeostatic factors controlling hormonal interaction appear to be maintained. The interaction between insulin and hormonal control of sodium and water balance may be modified by circulating free insulin concentrations.

Adolescent↗
PubMed1993

Erythrocyte sodium lithium countertransport in normal and hypertensive pregnancy: relation to haemodynamic changes.

OBJECTIVE: To establish the changes in erythrocyte sodium lithium countertransport (SLC) with advancing normal pregnancy and to determine if these changes were different in pregnancy induced hypertension (PIH). The changes in both groups were assessed in relation to haemodynamic changes. DESIGN: SLC, mean arterial pressure (MAP), cardiac output (CO) and total peripheral vascular resistance (TPVR) were determined serially during normal pregnancy and cross-sectionally in PIH. Women were studied again 20 weeks after delivery where possible. SETTING: Routine antenatal clinic and antenatal ward of a regional reference centre. SUBJECTS: Fifty-one normal primigravid women were studied serially and 41 primigravid women with PIH were studied at time of diagnosis. RESULTS: During normal pregnancy SLC (mmol Li/h/l cells) increased from a nonpregnant value of 0.24 +/- 0.02 (mean +/- SEM) to 0.32 +/- 0.02 at 14 weeks, and 0.37 +/- 0.02 at 20 weeks gestation. This was maintained until 38 weeks (0.40 +/- 0.02). The increase until 20 weeks occurred at the time of greatest change in CO (5.10 +/- 0.18 to 6.79 +/- 0.20 l/min) and TPVR (1327 +/- 58 to 969 +/- 33 dyn/s/cm-5). The decrease in TPVR with a rise in SLC is opposite to the relation reported in essential hypertension so that a functional relation is unlikely. However, the changes within pregnancy were positively correlated (r = 0.43, P < 0.01). In hypertensive pregnancies TPVR was elevated compared with normotensive pregnancies (1543 +/- 100 vs 1090 +/- 37) but the SLC was not different from that found in normotensive pregnancies (0.43 +/- 0.02 vs 0.40 +/- 0.02). CONCLUSIONS: The changes in SLC activity suggest dynamic effects on erythrocyte membrane function during pregnancy. However, no differences could be found between normal and hypertensive pregnancy and SLC is unlikely to be of value as a marker of hypertensive risk during pregnancy.

Adult↗
PubMed1993

Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation.

The effect of correction of acidosis in chronic renal failure (CRF) was determined from the kinetics of infused L-[1-13C]leucine. Nine CRF patients were studied before (acid) and after two 4-wk treatment periods of sodium bicarbonate (NaHCO3) and sodium chloride (NaCl) (pH: acid 7.31 +/- 0.01, NaHCO3 7.38 +/- 0.01, NaCl 7.30 +/- 0.01). Leucine appearance from body protein (PD), leucine disappearance into body protein (PS) and leucine oxidation (O) decreased significantly with correction of acidosis (PD: acid 122.4 +/- 6.1, NaHCO3 88.3 +/- 6.9, NaCl 116.2 +/- 9.1 mumol.kg-1.h-1, acid vs. NaHCO3 P < 0.01, NaHCO3 vs. NaCl P < 0.01, acid vs. NaCl NS; PS: acid 109.4 +/- 5.6, NaHCO3 79.0 +/- 6.3, NaCl 101.3 +/- 7.7 mumol.kg-1.h-1, acid vs. NaHCO3 P < 0.01, NaHCO3 vs. NaCl P < 0.01, acid vs. NaCl NS; O: acid 13.0 +/- 1.2, NaHCO3 9.2 +/- 0.9, NaCl 15.0 +/- 1.9 mumol.kg-1.h-1, acid vs. NaHCO3 P < 0.05, NaHCO3 vs. NaCl P < 0.01, acid vs. NaCl NS). There were no significant changes in plasma amino acid concentrations. These results confirm that correction of acidosis in chronic renal failure removes a potential catabolic factor.

Acidosis↗
PubMed1993

Adequacy of dialysis and nutritional status in CAPD.

Urea kinetic modelling (UKM) was used to assess adequacy of dialysis in 50 CAPD patients. Nutritional status was assessed from the measurement of visceral protein status (total protein, albumin, transferrin, immunoglobulins, complement), somatic protein status (anthropometry), and dietary intake (1 week weighed dietary inventory and normalized protein catabolic rate (NPCR) from UKM). Morbidity was assessed from the peritonitis and admission history. Mean Kt/V (corrected to x3 weekly dialysis) was 0.66 +/- 0.02. Dietary protein intake estimated from the NPCR (1.08 +/- 0.03 g kg-1 day-1) correlated well (r = 0.72, P < 0.001) with that estimated from the dietary inventory (1.10 +/- 0.04 g kg-1 day-1). There was a strong correlation between Kt/V and NPCR corrected for actual weight (r = 0.65, P < 0.001), but when NPCR was corrected for IBW this correlation was weaker (r = 0.35, P < 0.05). Patients were divided by Kt/V into two groups (> 0.65, n = 22 and < 0.65, n = 28). There were no significant differences in the indices of visceral protein status between the two groups. Weight, height, BMI, fat free mass and arm muscle area were significantly greater in the group Kt/V < 0.65. Residual renal function (creatinine clearance) was higher in the group Kt/V > 0.65 (3.8 +/- 0.7 versus 1.9 +/- 0.5 1/24 h, P < 0.05) and plasma creatinine less (913 +/- 51 versus 1265 +/- 51 mumol/l, P < 0.001). Hb, potassium, bicarbonate, phosphate, alkaline phosphatase, PTH, and blood pressure were not different. Neither was there any difference between the two groups in any of the indices of morbidity.

Adult↗
PubMed1993

Metaiodobenzylguanidine: evaluation of its potential as a tracer for monitoring doxorubicin cardiomyopathy.

We evaluated alterations in cardiac adrenergic neuron activity and progression of left ventricular dysfunction in comparison with the severity of structural changes using a rat model of adriamycin cardiomyopathy. Rats were treated with adriamycin (2 mg/kg s.c. once a week) for 6, 7, 8 and 9 wk. Accumulation of 125I-metaiodobenzylguanidine (MIBG) 4 hr after intravenous administration was determined and left ventricular ejection fraction (LVEF) was calculated from gated blood-pool images. H & E and Masson-Trichrome stained specimens of the myocardium were examined by light microscopy. Histopathologic examination demonstrated dose-dependent myocyte damage, although there were no differences between the 8-wk and 9-wk groups. LVEF did not differ between controls and the 6-wk group (81.3% +/- 5.5% versus 82.1% +/- 4.8%, p = ns). LVEF began to decrease slightly in the 7-wk group (75.0% +/- 5.7%, p < 0.05) and showed a remarkable decrease in the 8-wk group (53.7% +/- 2.6%, p < 0.001). In the 9-wk group, LVEF diminished to 47.9% +/- 3.1% (p < 0.001), accompanied by massive pleural effusions and ascites. MIBG accumulation in the heart (%ID/heart) significantly and progressively diminished; 1.42% +/- 0.15% in the 6-wk group, 1.06% +/- 0.16% in the 7-wk group, 0.77% +/- 0.13% in the 8-wk group and 0.34% +/- 0.11% in the 9-wk group, respectively p < 0.001, compared to controls (1.99% +/- 0.30%). These results demonstrate that MIBG accumulation in the heart showed a greater and more linear dose-dependent decrease than LVEF. Furthermore, MIBG uptake was significantly reduced in the 6-wk group where only mild myocyte damage (isolated vacuolation or myofibrillar loss) was observed. Thus, MIBG may be a sensitive biochemical marker of adriamycin cardiomyopathy.

3-Iodobenzylguanidine↗
PubMed1993

Distribution of deoxyglucose and technetium-99m-glucarate in the acutely ischemic myocardium.

The regional myocardial distribution of 99mTc-glucarate was compared to 3H-deoxyglucose in 22 rabbits with left circumflex marginal artery occlusion. In 12 rabbits, tissue radioactivity measurements were compared to the results of triphenyl tetrazolium chloride staining and light microscopy. In 10 additional rabbits, the myocardial sodium space (24NaCl), an indicator of tissue edema induced by injury, was compared to the distribution of deoxyglucose and glucarate. Technetium-99m-glucarate accumulated in injured myocardium within 6 hr after coronary ligation and myocardial concentration was greatest in the most severely injured zones (TTC unstained). Hydrogen-3-deoxyglucose behaved as a marker of ischemia but concentrated in tissue with injury ranging from mild ischemia (TTC stained) to transmural infarction (TTC unstained). Both 99mTc-glucarate and 3H-deoxyglucose concentrated in acute, severely injured myocardial tissue. These studies suggest that 99mTc-glucarate is a useful tracer for evaluating myocardial injury. In addition, it appears that 99mTc-glucarate and 3H-deoxyglucose demarcate different points in the spectrum of myocardial injury.

Acute Disease↗
PubMed1993

Serial course of left ventricular function, perfusion and fatty acid uptake in the cardiomyopathic hamster.

To determine the relationship of metabolic and perfusion changes to alterations in ventricular function in the course of cardiomyopathy, we performed serial measurements of ejection fraction, myocardial perfusion, fatty acid uptake of 3-methyl-p[123I]-phenyl-pentadecanoic acid ([123I]3MPDA) and myocardial histology in Syrian hamsters genetically predisposed to the development of congestive cardiomyopathy (Bio T0-2) (n = 30) and normal age-matched control animals (Bio F1B) (n = 13). To obtain high-resolution information about the myocardium at the time of onset of the first noticeable decrease in ventricular function, a multitracer autoradiographic study using 99mTc-pyrophosphate, 201Tl and [14C]3MPDA was obtained at 90 days of age. Baseline ejection fraction recorded at 60 days averaged 60.3%; by 90 days, it decreased to 54.3% (p < 0.05), falling to 41.3% at 180 days (p < 0.01) and declining to 30% at the end of the study. A progressive increase in the extent of myocytolysis, fibrosis and calcification was seen in the histologic studies as the animals aged. The ratio of fatty acid-to-thallium uptake dropped from 0.51 +/- 0.09 to 0.45 +/- 0.11 (p < 0.01), which is in parallel with the reduction in ejection fraction. The thallium lung-to-heart ratio increased from 0.51 at 90 days to 0.59 at 270 days (p < 0.05), which corresponds to the worsening of cardiac function. The macroautoradiographic studies demonstrated slight uptake of pyrophosphate in the myopathic hamster hearts and minimal changes in the regional distribution of fatty acid compared to that of perfusion. We conclude that the decrease in ventricular function parallels the severity of myocytolysis and fibrosis. Although decreased fatty acid uptake was apparent at an early stage, the extent of the change is modest and is difficult to detect from external images.

Animals↗
PubMed1993

Myocardial substrate utilization and left ventricular function in adriamycin cardiomyopathy.

We evaluated alterations of substrate utilization in a rat model of adriamycin cardiomyopathy with deteriorating left ventricular function. Rats were treated with adriamycin (2 mg/kg), once a week for 6, 8, 9 and 10 wk. Fluorine-18-F-deoxyglucose (18F-FDG) and 125I-beta-methyl-branched fatty acid (125I-BMIPP) were used as tracers of glucose and fatty acid metabolism and 99mTc-hexakis (2-methoxyisobutyl-isonitrile) (99mTc-MIBI) was used as a myocardial blood flow tracer. Left ventricular ejection fraction (LVEF) calculated from gated blood pool images was used as an indicator of cardiac function. LVEF was normal in the 6-wk group (78.0% +/- 4.8%), abruptly decreased in the 8-wk group (43.1% +/- 10.1%) and further deteriorated in the 9-wk group (27.6% +/- 13.4%). Accumulation of 18F-FDG (%kgID/g) in the hearts of adriamycin treated animals progressively decreased compared to controls (2.19% +/- 0.38%); 1.47% +/- 0.42% (p < 0.01) at 6 wk, 1.22% +/- 0.27% (p < 0.001) at 8 wk, 0.69% +/- 0.56% (p < 0.001) at 9 wk and 0.50% +/- 0.08% (p < 0.001) at 10 wk. This decrease occurred earlier than the deterioration in LVEF. Myocardial accumulation of 125I-BMIPP decreased in the advanced stages of adriamycin cardiomyopathy and was well correlated with the decrease in 18F-FDG accumulation. However, the decrease was less profound than for 18F-FDG; 53.7% +/- 9.8% versus 31.6% +/- 25.4% of control at 9 wk (p = NS), 49.5% +/- 15.3% versus 22.6% +/- 3.5% of control at 10 wk (p < 0.05). Accumulation of 99mTc-MIBI did not differ between controls and the adriamycin treated groups. There were no differences in blood glucose levels between controls and adriamycin treatment groups. Both glucose and fatty acid utilization are decreased in adriamycin-induced cardiomyopathy and these critical impairments in energy metabolism are associated with heart failure. Impaired myocardial glucose utilization measured with 18F-FDG may be a particularly sensitive marker of adriamycin cardiomyopathy.

Animals↗
PubMed1993

Effect of renal function on the pharmacokinetics and pharmacodynamics of trandolapril.

1. The pharmacokinetics and pharmacodynamics of a single dose of trandolapril, an angiotensin converting enzyme (ACE) inhibitor with an active metabolite, trandolaprilat, which is in part further metabolised prior to renal elimination, were evaluated in 31 subjects with a wide range of renal function (creatinine clearance 4-112 ml min-1 1.73 m-2). 2. The pharmacokinetics of trandolapril were unaffected by differences in renal function. 3. In contrast, there was a close correlation between the renal clearance (0-96 h) of trandolaprilat and creatinine clearance (r = 0.95, P = 0.0001). The maximum plasma concentration of trandolaprilat, and the area under the concentration curve (0-96 h) correlated inversely with creatinine clearance (r = -0.59, P < 0.001; and r = -0.61, P < 0.001 respectively). 4. Significant changes in plasma trandolaprilat concentrations were seen only in patients with creatinine clearances of 30 ml min-1 1.73 m-2 or less, suggesting that a dose reduction in trandolapril might be advisable in severe renal impairment. 5. However, the majority of parameters of ACE inhibition were unrelated to creatinine clearance, although area under the curve for ACE inhibition (0-336 h) showed a weak negative correlation (r = -0.49, P < 0.01). Similarly, weighted mean changes in blood pressure were not influenced by renal function. 6. Therefore, while the pharmacokinetic parameters of trandolaprilat correlated with creatinine clearance, pharmacodynamic measurements (ACE inhibition and blood pressure changes) in general showed no such relationship, indicating that dose adjustment of ACE inhibitors in renal impairment should be based on pharmacokinetic results only in conjunction with pharmacodynamic data.

Adult↗
PubMed1992

Serum triglyceride and insulin levels are associated with erythrocyte sodium-lithium counter-transport activity in normoglycaemic individuals.

The relationship between erythrocyte sodium-lithium counter-transport activity, serum insulin, lipids and demographic factors was examined in 93 normoglycaemic predominantly normotensive individuals with mild fasting hypercholesterolaemia (greater than 5.2 mmol/l). The major significant univariate correlates of sodium-lithium counter-transport activity were fasting serum triglycerides, HDL cholesterol, the ratio of fasting glucose: insulin, apo A1, alcohol consumption and apo B. Stepwise multiple regression analysis revealed 24% of the variability in sodium-lithium counter-transport activity could be accounted for by independent contributions of fasting serum triglycerides, alcohol consumption, the fasting glucose/insulin ratio and apo A1 and ANOVA confirmed a significant relationship with fasting insulin measures that was independent of serum triglycerides (P less than 0.05). The relationship between erythrocyte sodium-lithium counter-transport activity and concentrations of serum triglycerides, HDL components, insulin and additionally alcohol consumption, could reflect the influence of those variables on erythrocyte structure and function.

Alcohol Drinking↗
PubMed1992

Isolation of koala lymphoid cells and their in vitro responses to mitogens.

Baseline parameters have been established for the successful in vitro culture of mononuclear cells from the peripheral blood (PMC) of koalas. To minimise stress-related influences and allow repeated testing of cells from the same animals, most studies were performed using blood samples from captive koalas which had become accustomed to regular handling. Ficoll-Paque density gradient fractionation of whole blood was required to prepare cell suspensions which responded well to the T-lymphocyte mitogens phytohaemagglutinin, concanavalin A and pokeweed mitogen. In contrast, very low or negligible proliferative responses were induced by the B-lymphocyte mitogens lipopolysaccharide, jacalin and protein A, even when purified PMC were cultured with a wide range of concentrations of these molecules. Using the standard approaches established with T-lymphocytes of eutherian animals, it was shown that concanavalin A-stimulated PMC produced an interleukin 2-like growth factor. The significance of these findings is discussed in the context of current knowledge and understanding of similar studies carried out using the lymphoid cells of eutherian and other metatherian animals.

Animals↗