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Biomedical subjects

R Wilkinson

Publications and source records attributed to R Wilkinson.

At least 73 records · Page 4Linked to original sources
PubMed1996

Determinants of gingival overgrowth severity in organ transplant patients. An examination of the rôle of HLA phenotype.

The role of HLA phenotype as a risk factor for drug-induced gingival overgrowth was investigated in a cohort of 172 transplant recipients. Clinically significant overgrowth warranting surgical correction was observed in 72 patients (42%). Using stepwise regression modelling, 6 clinical parameters were identified as significant risk factors for the severity of gingival overgrowth. These were; age, sex, creatinine plasma level, duration of therapy, papilla bleeding index and concomitant medication with a calcium channel blocking drug. 3 HLA alleles were also identified as risk factors when adjusted for other clinically significant risk factors (HLA -DR2, A24, B37). However, when the p-values for the HLA variables were corrected to compensate for the use of multiple significance testing, only HLA-B37 remained statistically significant at the 5% level. Organ transplant patients are at risk of developing gingival overgrowth, with approximately 25% medicated with cyclosporin alone requiring corrective gingival surgery. This figure more than doubles in patients concomitantly medicated with a calcium blocking drug. The data at present available would suggest that the severity of gingival overgrowth is also significantly associated with the HLA-B37 phenotype.

Adolescent↗
PubMed1996

Renal reserve during human pregnancy.

Pregnancy in healthy women is associated with increments in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). We hypothesized that the hyperfiltration of normal pregnancy attenuates or exhausts renal reserve. In 21 healthy females studied serially in early and late pregnancy and then on average 15 wk postpartum, GFR and ERPF were determined by inulin and p-aminohippurate clearances, respectively, before and during either an amino acid infusion (Vamin 9; Kabi Pharmacia) (n = 14) or a control infusion of Hartman's solution (n = 7), both infused at 4 ml/min for 210 min. In early and late pregnancy, GFR increased significantly in response to amino acid infusion [from 137 +/- 29 to 162 +/- 35 ml/min (P < 0.001) and from 134 +/- 29 to 148 +/- 40 ml/min (P < 0.01), respectively], with the increments (18 and 10%, respectively) not significantly different from postpartum (non-pregnant) when GFR increased by 12% from 94 +/- 22 to 105 +/- 23 ml/min (P < 0.002). Amino acid infusion significantly increased ERPF from 874 +/- 188 to 980 +/- 215 ml/min in early pregnancy (P < 0.01), from 684 +/- 135 to 773 +/- 181 ml/min in late pregnancy (P < 0.01), and from 507 +/- 121 to 560 +/- 141 ml/min postpartum (P < 0.006), increments of 12, 13, and 10%, respectively. GFR did not change in response to control infusion. We conclude that, despite gestational increments in renal hemodynamics of > 40%, pregnancy does not attenuate the renal response to amino acid infusion.

Amino Acids↗
PubMed1996

Thiol group control of sodium-lithium countertransport kinetics in uraemia: evidence of a membrane abnormality affected by haemodialysis.

Uraemia affects erythrocyte metabolism and membrane function but no consistent effect on Na/Li countertransport (CT) has been reported. We report only small differences in Na/Li CT at 150 mmol/l Na over haemodialysis, but major differences in other properties of Na/Li CT. The Km for external sodium and Vmax both increased during haemodialysis but the Vmax/Km ratio, which was greater than normal, was not affected. The thiol reagent, N-ethylmaleimide (NEM), which causes a decrease in Km and Vmax in normal subjects, had no effect on Km in the predialysis erythrocytes. After haemodialysis, the sensitivity of Na/Li CT to NEM was improved. The changes in Na/Li CT kinetics were not related to changes in membrane lipid fluidity or plasma lipids. These observations suggest that uraemia affects a thiol group that controls Na/Li CT kinetics and that haemodialysis temporarily improves this aspect of membrane function.

Aged↗
PubMed1996

Increased susceptibility to membrane lipid peroxidation in renal failure.

The susceptibility of membrane lipids to peroxidation in renal failure was investigated. A fluorescent polyunsaturated fatty acid probe, cis-parinaric acid, showed that mononuclear leucocytes from both chronic renal failure and haemodialysis patients had increased susceptibility to membrane lipid peroxidation compared with normal controls. The effect of oxidant stress on the physical properties of the cell membrane was also investigated by measuring fluidity with the probes diphenylhexatriene and trimethylaminodiphenylhexatriene. Oxidant stress caused a significant increase in membrane fluidity of mononuclear leucocytes from normal controls, which was greater than that seen in renal failure. The effect of oxidant stress on the physical properties of the cell membrane was not simply determined by the susceptibility of the membrane lipids to peroxidation.

Cell Membrane↗
PubMed1996

A non-pharmacological approach to pain relief.

Effective pain management programmes must acknowledge the subjective nature of pain. Non-pharmacological pain management can be as effective, on occasions, as pharmacological pain management. Stress and anxiety evoke a similar physiological response to acute pain, highlighting the need for efficient cognitive management programmes.

Behavior Therapy↗
PubMed1996

Withdrawal of renal replacement therapy in Newcastle upon Tyne: 1964-1993.

BACKGROUND: Termination of renal replacement therapy (RRT) is common in North America and Australia but is considered to be rare in Europe. METHODS: In order to review the phenomenon of RRT termination in all patients treated in Newcastle upon Tyne between 1964 and 1993 a retrospective study of clinical case notes was undertaken. In all RRT patients sex, age at start of RRT, renal diagnosis and history of RRT were recorded. In addition, mortality data and marital and residential status were recorded in all patients who died, and Karnofsky index, bodyweight, complications, history of bereavement, place of death, overall survival, survival after withdrawal of treatment, other medical problems, higher mental function and surgical history in all patients stopping treatment. RESULTS: 1639 patients started RRT between 1964 and September 1993 inclusive. Eighty-eight patients were identified in whom death was a result of treatment being stopped (17% of all deaths). The first was in 1985. In these patients, age was greater (62 vs 47 years, P < 0.001) and diabetes was more prevalent (15 vs 7%, P < 0.03) than in the total RRT population. The Karnofsky index was 70 at the start and 33 at withdrawal of treatment (P < 0.001). The Karnofsky index at the start of RRT was weakly related to that at withdrawal and overall survival (r = 0.36 and 0.28 respectively, P < 0.01). The Karnofsky index at treatment withdrawal correlated with the following survival (r = 0.40, P < 0.001). The median survival of patients stopping treatment was significantly lower than in all RRT patients (16 vs 74 months, P < 0.001) and the majority survived less than 2 years. After dialysis withdrawal the median survival was 8 days, 15 patients survived 3 days or less and 19 more than 10 days. The majority (80%) received terminal care in hospital. At treatment withdrawal 11 patients were demented and 34 showed signs of early dementia. Seventy-eight patients (89%) stopped treatment as a consequence of multiple medical problems. The possibility of dialysis withdrawal was raised by physicians in 50.5%, the patient in 23.8% and the patients' relatives in 21.9% of cases. Four patients (3.8%) committed suicide. CONCLUSIONS: Death from dialysis termination is a relatively common cause of death in RRT patients in Newcastle upon Tyne. These patients are older with a higher prevalence of diabetes. In 89% of cases the decision to stop treatment was related to multiple medical problems with a recent deterioration. Physicians raised the issue of withdrawal in the majority of cases and most patients subsequently received terminal care in hospital.

Decision Making↗
PubMed1995

Localization of [125I]endothelin-1 in injured aorta of rabbits.

Endothelin-1 is a potent vasoconstrictor. This study was performed to determine whether arterial injury, induced by either hypercholesterolemia or mechanical disruption of the endothelium, is associated with increased localization of endothelin-1 in the artery. The blood clearance and tissue distribution of intravenously injected [125I]endothelin-1 was evaluated in 33 rabbits--control animals (n = 7), balloon de-endothelialized animals (n = 12), cholesterol-fed animals (n = 6) and animals that had both balloon de-endothelialization and high cholesterol diet (n = 8). The blood clearance half time was less than 10 min, with slightly slower clearance in the ballooned/cholesterol-fed animals. [125I]Endothelin-1 localized in the lung (approximately 12% injected dose (ID)/organ) and kidney (approximately 8%ID/organ). [125I]Endothelin-1 localization in the injured aorta increased from the baseline level of 0.06%kgID/g to its highest level within 5 min of balloon de-endothelialization (0.2%kgID/g) and decreased to 0.11%kgID/g within one week and remained essentially unchanged through 16 weeks. The area with increased binding of [125I]endothelin-1 corresponded to the zone of arterial injury stained with Evans blue. On the other hand, the binding in the aorta did not increase with the atherogenic diet. These findings suggest that endothelin-1 accumulates in injured vessels, attaining the highest levels immediately after mechanical injury.

Animals↗
PubMed1995

Modification of erythrocyte Na+/Li+ countertransport kinetics by two types of thiol group.

Erythrocyte Na+/Li+ countertransport activity is decreased by reagents that react with thiol groups. An understanding of the role of these groups in control of Na+/Li+ countertransport may help to explain its association with disease states. The effect of thiol reactive agents on the kinetic parameters of Na+/Li+ countertransport has not previously been described. In choline medium, N-ethylmaleimide (NEM) and iodoacetamide (IAamide) cause a rapid decrease of about 40% in Km for external sodium (Km(So)) that is complete in 10 s with a much smaller change in Vmax and an increase in the Vmax/Km ratio. In Na medium, NEM and IAamide both cause a rapid decrease in Km(So) and Vmax. With NEM the partial reduction in Vmax is complete in 100s although the NEM is sufficient to reduce Vmax up to 15 min. With IAamide the decrease in Vmax is initially slower but it continues apparently towards complete inhibition. These results indicate at least two types of thiol group controlling Na+/Li+ countertransport kinetics. The type 1 thiol reaction is Na independent and causes an increase in the apparent rate constant for Na association with the unloaded carrier so that Vmax/Km rises and Km(So) decreases. The type 2 thiol reaction is facilitated by Na at the outside ion-binding site and causes a decrease in Vmax, possibly by total blockage of carriers with IAamide but by a different mechanism with NEM such as reduced turnover rate.

Antiporters↗
PubMed1995

Cell membrane dynamics and insulin resistance in non-insulin-dependent diabetes mellitus.

Insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) could be related to changes in cell membrane properties. We measured insulin sensitivity and mononuclear leucocyte membrane fluidity by fluorescence polarisation in fifteen NIDDM patients and twenty-one normal subjects. Core-region anisotropy was significantly lower in leucocytes from diabetic subjects (mean 0.164 vs 0.174, p < 0.001). Insulin sensitivity was positively correlated with such anisotropy before and after acute in-vitro insulin treatment. There was no difference in superficial membrane anisotropy. This study suggests that altered membrane dynamics in NIDDM may contribute to insulin resistance.

Cell Membrane↗
PubMed1995

Calcification and fatigue failure in a polyurethane heart value.

The prosthetic heart valves were fabricated from a polyurethane containing a 4,4'-diphenylmethane diisocyanate hard segment, chain-extended with butanediol and with a polyether soft segment. The rate of calcification of these polyurethane heart valves was much slower in a dynamic in vitro test system than similar bioprosthetic heart valves. The calcified deposits were located exclusively at regions of material failure. Fourier transform infrared (FTIR) spectroscopy indicated the involvement of the polyether soft segments of the polymer directly in the calcification process. Calcification of polymer fractions also suggested that small molecular weight extractable components are accelerating factors in the calcification process.

Animals↗
PubMed1995

Liposomal amphotericin B (AmBisome) in the treatment of complicated kala-azar under field conditions.

An open trial of liposomal amphotericin B (AmBisome [L-AmB]; Vestar, San Dimas, CA) for treatment of complicated visceral leishmaniasis was performed in Sudan. Forty-nine patients were treated, and there were six deaths (12% mortality); these were not attributed to therapy. Thirty-seven patients were selected for the trial because of (1) relapse after treatment with a combination of pentavalent antimony (Sbv) and aminosidine, (2) incomplete parasitological response to Sbv and aminosidine, or (3) severe illness. Drug regimen 1 (3 doses of 3-5 mg/kg, on days 0, 3, and 10) cured 8 (50%) of 16 patients; regimen 2 (6 doses of 3-5 mg/kg, on days 0, 3, 6, 8, 10, and 13) cured 14 (88%) of 16. For four of 10 partial responders, "rescue" therapy with L-AmB alone (3 mg/kg daily for 10 days) resulted in cure. Twelve less-unwell patients received regimen 3 (4 doses of 4-5 mg/kg, on days 0, 2, 5, and 7); seven of 11 patients evaluated (64%) were cured. The optimal regimen of L-AmB in these circumstances is administration of 4 mg/kg on days 0, 3, 6, 8, 10, and 13.

Adolescent↗
PubMed1995

Abnormal effect of thiol groups on erythrocyte Na/Li countertransport kinetics in adult polycystic kidney disease.

BACKGROUND: Evidence suggests that in adult polycystic kidney disease (APCKD) there is abnormal membrane organisation that involves cytoskeletal proteins and affects ion-transport proteins. The possibility of detecting a membrane organisation defect in erythrocytes from APCKD patients was investigated. METHODS: Na/Li countertransport (CT) kinetics were measured in erythrocytes from APCKD patients compared with normal controls. The modulation of Na/Li CT kinetics by key membrane thiol groups and by dissociation of spectrin by heating was studied. RESULTS: In erythrocytes from APCKD compared to normal subjects the Km of Na/Li CT was lower (64 SEM 3v 90 SEM 3 mmol Na/l, P < 0.001) and Vmax/Km was higher (6.8 SEM 0.6v 5.3 SEM 0.4 (x 19(-3)), P < 0.05). In erythrocytes from normal subjects, after N-ethylmaleimide (NEM) treatment in choline medium, Km of Na/Li CT was reduced and Vmax/Km increased (59 SEM 5, 8.2 SEM 0.4 (x 10(-3)), P < 0.001) but there was no effect on these kinetic parameters in erythrocytes from APCKD. The effect of heating was similar to that of NEM in choline medium. In normal controls after NEM treatment in sodium medium both Km and Vmax were reduced whereas in APCKD Vmax was reduced but Km was unchanged. CONCLUSIONS: In APCKD the effect of a key membrane thiol group on Na association with Na/Li CT was absent and the effect of spectrin dissociation was similarily abnormal. A second thiol group effect on the Vmax of Na/Li CT was normal. The results are consistent with a thiol-protein linked to the spectrin cytoskeleton that modulates Na/Li CT and is abnormal in APCKD.

Adolescent↗
PubMed1995

Sulphydryl group control of sodium-lithium countertransport kinetics: a membrane protein control abnormality in essential hypertension.

Erythrocyte sodium-lithium countertransport (SLC) is an obligatorily coupled equimolar exchange of intracellular sodium or lithium with extracellular sodium or lithium. SLC is partially inhibited by N-ethylmaleimide (NEM) but only when a transported ion (sodium of lithium) is present in the extracellular medium. In essential hypertensive patients with a strong family history of hypertension the Km of SLC for extracellular sodium was lower and Vmax tended to be higher than in normal controls, but the ratio Vmax/Km gave a much clearer distinction between the two groups. After NEM treatment, the remaining SLC activity in normal individuals had a lower Vmax and Km for sodium but Vmax/Km was not affected. In essential hypertensives the remaining SLC activity after NEM again had lowered Vmax and Km but in these patients the Vmax/Km was much lower than in untreated erythrocytes and was then the same as in normal controls. On the assumption that NEM reacts with a -SH group on a membrane protein that regulates SLC, and that the ratio Vmax/Km reflects a rate constant for binding extracellular sodium to the unloaded carrier, the results suggest that (a) essential hypertensives have an increased rate of sodium binding to the transporter and (b) this is due to abnormal behaviour of a membrane -SH group.

Adolescent↗
PubMed1995

Haemolytic disease of the newborn due to anti-M.

A patient with haemolytic disease of the newborn (HDN) due to anti-M which required exchange transfusion is described. Anti-M antibodies are usually assumed to be naturally occurring and to consist of immunoglobulin M (IgM); many however have an immunoglobin G (IgG) component. In view of this and the described occurrence of HDN, recommendations are made regarding the management of a pregnancy in which anti-M antibodies are detected.

Adult↗
PubMed1995

Quantitation of slow drug release from an implantable and degradable gentamicin conjugate by in vivo magnetic resonance imaging.

A biodegradable model hydrogel containing a covalently bound aminoglycoside in which drug release can be monitored by magnetic resonance imaging (MRI) in vivo was developed. The hydrogel consists of the bishydroxysuccinimide ester of polyethylene glycol disuccinate cross-linked albumin, to which gentamicin and Gd-diethylenetriaminepentaacetic acid are covalently attached in stochiometric quantities. MRI allowed us to depict the three-dimensional structure of implanted gels, to accurately calculate their volumes, and thus to calculate the concentration of hydrogel-bound gentamicin. The correlation coefficient for the concentration of released gentamicin and the hydrogel volume was 0.965. Free and hydrogel-released gentamicin conjugates had similar antibiotic efficacies when tested in microbiological agar diffusion assays. In vivo, hydrogel-released gentamicin had a longer half-life in plasma than unaltered gentamicin (5.6 versus 0.7 h), presumably because of residual bound polyethylene glycol residues. Hydrogel implants into rats resulted in a prolonged (7 to 10 days) release of gentamicin and a decreased 24-h mortality in mice infected with a lethal dose of Pseudomonas aeruginosa. The results indicate the feasibility of imaging and quantitating therapeutic drug concentrations in vivo by MRI.

Animals↗
PubMed1995

Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with CRF.

To test the hypothesis that acidosis contributes to the insulin resistance of chronic renal failure (CRF) and impairs the action of insulin to decrease protein degradation, eight CRF patients were studied using the combined L-[1-13C]leucine-euglycemic clamp technique before (acid) and after (NaHCO3) 4 wk treatment with NaHCO3 (pH: acid 7.29 +/- 0.01 vs. NaHCO3 7.36 +/- 0.01, P < 0.001). Protein degradation (PD) was estimated sequentially from the kinetics of a primed continuous infusion of L-[1-13C]leucine in the basal state and during a hyperinsulinemic euglycemic clamp. Insulin sensitivity was measured during the clamp. The correction of acidosis significantly increased the glucose infusion rate necessary to maintain euglycemia (acid 6.44 +/- 0.89 vs. bicarbonate 7.38 +/- 0.90 mg.kg-1.min-1, P < 0.01) and significantly decreased PD in the basal state (acid 126.4 +/- 8.1 vs. bicarbonate 100.1 +/- 6.9 mumol.kg-1.h-1, P < 0.001). Hyperinsulinemia decreased PD in both studies (acid basal 126.4 +/- 8.1 vs. clamp 96.5 +/- 7.7, P < 0.001; bicarbonate basal 100.1 +/- 6.9 vs. clamp 88.2 +/- 5.5 mumol.kg-1.h-1, P = 0.06), its effect being unaltered by acidosis, with a reduction of 24% before and 12% after the correction of acidosis. In conclusion, acidosis contributes to the insulin resistance of CRF but does not affect the action of insulin on PD.

Acidosis↗
PubMed1995

Sodium-lithium countertransport kinetics in IgA nephropathy: relation to plasma lipids and renal impairment.

We have investigated the activity and kinetics of sodium-lithium countertransport (SLC) in patients with IgA nephropathy and their relationship to plasma lipids. Standard SLC activity, the Michaelis constant (Km) and maximum velocity (Vmax) were measured in patients who had IgA nephropathy with either normal serum creatinine (IgA-NRF), or raised serum creatinine (IgA-IRF), and normal subjects (NC). The standard SLC activity was raised in hypertensive patients with IgA-NRF due to a raised Vmax in association with hyperlipidaemia. The Km was significantly lower and Vmax also tended to be lower in IgA-IRF. Km and Vmax were not different in IgA-NRF compared with the NC. There was no difference in the mean standard SLC activity between all three groups. The low Km and low Vmax resulted in a normal standard SLC activity being observed in IgA-IRF which is similar to the situation we have observed in a proportion of diabetic patients with nephropathy. The low Km in patients with IgA nephropathy may be due to inheritance associated with familial essential hypertension or to an acquired change of the kinetics related to a change in the environment of the plasma membrane during the development of renal impairment.

Adult↗