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Biomedical subjects

N Muirhead

Publications and source records attributed to N Muirhead.

At least 55 records · Page 3Linked to original sources
PubMed1992

Comparison of subcutaneous and intravenous recombinant human erythropoietin for anemia in hemodialysis patients with significant comorbid disease.

While recombinant human erythropoietin (rHuEPO) is an effective therapy for anemia in renal failure, most published studies concern benefits in relatively healthy hemodialysis patients. The present study compares intravenous and subcutaneous administration of rHuEPO in an unselected group of 128 hemodialysis patients who were randomized to receive rHuEPO in an initial dose of 150 U/kg/week in three divided doses by subcutaneous or intravenous injection. Following a 4-week placebo run-in period, patients received rHuEPO until their hemoglobin was stable between 105 and 125 g/l for 4 weeks and then followed for a further 24 weeks. Eighty-three patients completed the study, 45 in the subcutaneous and 38 in the intravenous group. There was no difference in mean hemoglobin at any stage between subcutaneous and intravenous patients. Mean rHuEPO dose at the time of stabilization was significantly lower in the subcutaneous group compared to the intravenous (205.9 +/- 135.4 vs. 274.1 +/- 142.4 U/kg/week; p = 0.019), mean time to hemoglobin target was 9.9 +/- 4.5 weeks for the subcutaneous group and 11.9 +/- 4.9 weeks for the intravenous group (p = 0.037). Time to stabilization was 14.9 +/- 4.7 weeks for the subcutaneous compared to 17.3 +/- 3.9 weeks for the intravenous group (p = 0.006). Diabetic patients had higher dose requirements for rHuEPO at all time points and required a longer time to reach stabilization than nondiabetics (18.6 +/- 4.6 vs. 15.6 +/- 4.3 weeks; p = 0.016). Quality of life estimated by a disease-specific Kidney Disease Questionnaire improved significantly during rHuEPO therapy in both groups. There was no significant change in dialysis prescription throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

A disease-specific questionnaire for assessing quality of life in patients on hemodialysis.

A disease-specific questionnaire was developed for patients receiving chronic hemodialysis by interviewing patients to determine which aspects of their quality of life were adversely affected by their disease. The final questionnaire contained 26 questions in five dimensions (physical symptoms, fatigue, depression, relationships with others, frustration). The questionnaire demonstrated construct validity when compared with the Sickness Impact Profile, time trade-off technique and an exercise stress test. It was reproducible in stable, placebo-treated patients (correlation coefficient 0.85-0.98 for the 5 dimensions). It was more responsive than other measures in detecting an improvement with erythropoietin therapy in a randomized, placebo-controlled trial. This questionnaire should be useful for the assessment of the effect of various interventions upon the quality of life of hemodialysis patients.

Anemia↗
PubMed1992

Erythropoietin for anaemia in haemodialysis patients: results of a maintenance study (the Canadian Erythropoietin Study Group).

Most published studies of recombinant human erythropoietin (rHuEpo) have been of limited duration and in small patient populations. The present study examines the long-term effects of rHuEpo in 98 haemodialysis patients treated for up to 18 months. All patients had completed a 6 month placebo-controlled study of rHuEpo. Patients previously on placebo (group 1; n = 31) received rHuEpo at an initial dose of 50 U/kg thrice weekly with subsequent dose adjustments to maintain haemoglobin (Hb) in the range 105-120 g/l. Patients previously on rHuEpo (group 2; n = 67) continued on their usual dose with adjustments made to maintain Hb at 105-120 g/l. Haematological parameters were measured every 2 weeks. Quality of life, assessed by a disease-specific kidney disease questionnaire (KDQ), was measured every 6 months. Mean Hb in group 1 increased from 74.2 +/- 11.4 g/l at baseline to 112.9 +/- 12.6 g/l after 12 months of rHuEpo therapy. After 12 weeks of rHuEpo therapy Hb in groups 1 and 2 was indistinguishable. Hb remained constant in both groups throughout the period of follow-up. Mean rHuEpo dose requirements were similar in both groups. At the end of the study the mean intravenous rHuEpo dose in group 1 patients was 176.6 +/- 154.4 and in group 2 patients was 210.0 +/- 144.0 U/kg per week. Access failure was increased during rHuEpo therapy in patients with synthetic grafts (46% versus 7% failures compared to fistulae; P less than 0.001). Group 1 patients receiving rHuEpo had a significant increase in diastolic but not systolic blood pressure despite a 32% increase in overall antihypertensive prescriptions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

The role of aluminium and parathyroid hormone in erythropoietin resistance in haemodialysis patients.

Recombinant human erythropoietin (rHuEpo) is an effective therapy for anaemia in most patients with end-stage renal disease (ESRD). However, there remain a minority of patients with ESRD who are resistant to the effects of rHuEpo. The present study examined the role of aluminium overload and hyperparathyroidism of the biological effects of rHuEpo. Twenty-two patients aged 26-74 (mean 53 +/- SD 15.5) received rHuEpo 50-200 U/kg per week for 16.5 +/- 8.0 months (range 3-27). Haemoglobin was maintained at 11.5-13.0 g/dl by appropriate dose adjustment. Iron supplements were provided to maintain serum ferritin greater than 200 ng/ml. The mean time to rHuEpo response (Hb greater than 2 g/dl over baseline) was 6.1 +/- 2.6 weeks. Mean pretreatment serum aluminium correlated with time to Hb response (r = 0.48; P less than 0.05) and pretreatment mean corpuscular volume (r = 0.43; P less than 0.05) but not with eventual rHuEpo maintenance dose. PTH did not correlate with either Hb response or eventual maintenance rHuEpo dose. In summary, elevated serum aluminium concentrations were associated with an initial resistance to the biological effects of rHuEpo but had no effect on long-term dose requirements. In contrast, no impact of PTH on either immediate or long-term rHuEpo dose was evident.

Adult↗
PubMed1991

The effect of human recombinant erythropoietin on iron absorption and hepatic iron in a rat model.

In order to ascertain whether recombinant human erythropoietin (EPO) therapy would result in further intestinal iron absorption in the setting of systemic iron loading, iron absorption was measured in iron-loaded rats receiving EPO therapy and a control group of iron-loaded rats. Parenteral iron dextran (100 mg) resulted in hepatic siderosis with predominantly a reticuloendothelial distribution. EPO was given by intraperitoneal injection (100 U/kg) for 10 days. Radioiron absorption was measured by total body counting. Iron absorption in EPO-treated rats was 4.8 +/- 2.0% (n = 12) and 4.5 +/- 2.2% (n = 10) in the control rats (p greater than 0.05). Mean hemoglobin in the EPO rats was 201 +/- 12.5 g/L and 140 +/- 18.2 g/L in the control rats (p less than 0.001). Mean hepatic iron concentration was 73 +/- 16 mumol/g in the control rats and 34 +/- 9.1 mumol/g in the EPO-treated rats (p less than 0.001). This study suggests that iron-loaded rats do not demonstrate an increase in intestinal iron absorption with EPO therapy despite a significant erythropoiesis. The reduction in hepatic iron concentration suggests that reticuloendothelial iron is accessible and mobilized to produce new red blood cells.

Animals↗
PubMed1987

cis-Diamminedichloroplatinum(II) selectively cross-links high mobility group proteins 1 and 2 to DNA in micrococcal nuclease accessible regions of chromatin.

The reaction of cis-diamminedichloroplatinum(II) with chicken erythrocyte nuclei produces covalent cross-linking of HMG proteins 1, 2 and E to DNA, in addition to cross-links amongst LMG proteins. This is supported by and consistent with the observations that all cross-links are chemically reversed by NaCN treatment, while only the cross-links involving the HMG proteins 1,2 and E are eliminated after a limited digestion with micrococcal nuclease. Having identified the subset of proteins selectively cross-linked to DNA by the bifunctional cis-(NH3)2PtCl2, a tentative model is proposed for the interactions between DNA and HMG proteins 1 and 2 in bulk chromatin. In addition, possible modes of action for this anti-neoplastic drug are suggested in light of these findings.

Animals↗
PubMed1986

Increased sensitivity of adenylate cyclase activity in the striatum of the rat to calmodulin and GppNHp after chronic treatment with haloperidol.

Chronic treatment of rats with haloperidol causes behavioral supersensitivity to dopaminergic agonists and an increase in the sensitivity of adenylate cyclase activity in the striatum to stimulation by dopamine. In this study the authors examined whether chronic treatment with haloperidol could elicit a change in sensitivity of adenylate cyclase in the striatum of the rat for guanyl nucleotides and the endogenous Ca2+-binding protein, calmodulin. These agents increase the activation of adenylate cyclase activity by dopamine but act beyond the level of the dopamine receptor. Male, Sprague-Dawley rats were injected subcutaneously with either 0.6 mg/kg haloperidol or vehicle for 14 days. Four days after the last injection, the animals were sacrificed and the activity of adenylate cyclase was measured in a EGTA-washed particulate preparation of the striatum. There was an increase in the activation of adenylate cyclase activity by calmodulin and GppNHp but not by guanosine triphosphate (GTP) in particulate fractions of the striatum from rats treated with haloperidol as compared to controls. The sensitivity of adenylate cyclase to calmodulin was increased 5-fold in particulate fractions from rats treated with haloperidol as opposed to vehicle-treated rats. The lack of change in activation by GTP was not due to an altered activity of GTPase in rats treated with haloperidol. In animals treated for 14 days but not withdrawn from haloperidol there was no statistically significant increase in the sensitivity of adenylate cyclase to calmodulin. There was no change in activation of the enzyme by GppNHp or GTP as compared to control. The activation of adenylate cyclase by calmodulin was not affected when haloperidol was added in vitro to the assay or after the acute injection of rats with haloperidol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1986

Removal of aluminum during hemodialysis: effect of different dialyzer membranes.

Aluminum toxicity is now widely recognized as a major cause of morbidity in patients on maintenance hemodialysis. Desferrioxamine (DFO) chelation therapy has been suggested as a method of AI removal in such patients, though the most appropriate treatment schedule is yet to be established. In the present study, AI removal following DFO infusion was evaluated using two different dialyzer membranes to test the hypothesis that polyacrilonitrile (PAN) membranes permit better AI clearance. All patients studied had significantly elevated plasma AI concentrations (1.22 to 9.45 mumol/L; normal less than 0.56 mumol/L). Plasma AI did not correlate with estimated total AI intake. During hemodialysis with a cuprophane membrane, AI clearance ranged from 33.5 to 42.1 mL/min. Total AI removal was 192.2 +/- 90.4 mumol during cuprophane dialysis. During hemodialysis with a PAN membrane, AI clearance ranged from 35.7 to 54 mL/min. Total AI removal was 154.2 to 93.9 mumol during PAN dialysis. The differences in AI clearance and total AI removal were not statistically significant. It is concluded that use of a PAN membrane does not significantly enhance DFO-AI clearance.

Acrylic Resins↗
PubMed1986

Zinc metabolism in patients on maintenance hemodialysis.

Recent studies have focused attention on the possible role of zinc depletion in the pathogenesis of uremic symptoms such as dysgeusia and impotence. The present studies were undertaken to evaluate the prevalence of zinc deficiency and abnormalities of zinc metabolism in patients with end-stage renal disease. A total of 43 stable chronic hemodialysis patients were screened for evidence of zinc deficiency by measurement of fasting predialysis leukocyte and plasma zinc. The results were compared with those from 30 healthy volunteers. Seventeen of these 43 patients had 65Zn absorption measured, and in 9 the rate of disappearance of 65Zn from the body was also measured. The results were compared with those obtained in 20 healthy controls. The nutritional status of these 17 patients was estimated by global nutritional assessment and calculation of the Quetelet index while 9 of 17 had dietary zinc intake calculated from a diet history. The mean plasma zinc level was lower in the hemodialysis patients (11.7 +/- 2.3 mumol/l vs. 13.3 +/- 2.9 mumol/l in controls; p less than 0.05). The mean leukocyte zinc level was 0.81 +/- 0.27 mumol/g dry weight in dialysis patients and 0.81 +/- 0.22 mumol/g in controls (p greater than 0.2). The mean 65Zn absorption in the patients was 49 +/- 14% and in controls 53 +/- 12% (p greater than 0.2). Mean turnover of body 65Zn was 0.47 +/- 0.11%/day in patients and 0.43 +/- 0.18%/day in controls (p greater than 0.1). The mean 65Zn half-life was 154 +/- 29 days in patients and 187 +/- 75 days in controls (p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1985

Inhibition of a low Km GTPase activity in rat striatum by calmodulin.

In rat striatum, the activation of adenylate cyclase by the endogenous Ca2+-binding protein, calmodulin, is additive with that of GTP but is not additive with that of the nonhydrolyzable GTP analog, guanosine-5'-(beta, gamma-imido)triphosphate (GppNHp). One possible mechanism for this difference could be an effect of calmodulin on GTPase activity which has been demonstrated to "turn-off" adenylate cyclase activity. We examined the effects of Ca2+ and calmodulin on GTPase activity in EGTA-washed rat striatal particulate fractions depleted of Ca2+ and calmodulin. Calmodulin inhibited GTP hydrolysis at concentrations of 10(-9)-10(-6) M but had no effect on the hydrolysis of 10(-5) and 10(-6) M GTP, suggesting that calmodulin inhibited a low Km GTPase activity. The inhibition of GTPase activity by calmodulin was Ca2+-dependent and was maximal at 0.12 microM free Ca2+. Maximal inhibition by calmodulin was 40% in the presence of 10(-7) M GTP. The IC50 for calmodulin was 100 nM. In five tissues tested, calmodulin inhibited GTP hydrolysis only in those tissues where it could also activate adenylate cyclase. Calmodulin could affect the activation of adenylate cyclase by GTP in the presence of 3,4-dihydroxyphenylethylamine (DA, dopamine). Calmodulin decreased by nearly 10-fold the concentration of GTP required to provide maximal stimulation of adenylate cyclase activity by DA in the striatal membranes. The characteristics of the effect of calmodulin on GTPase activity with respect to Ca2+ and calmodulin dependence and tissue specificity parallel those of the activation of adenylate cyclase by calmodulin, suggesting that the two activities are closely related.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1985

IgA nephropathy is not a rare disease in the United Kingdom.

A retrospective analysis of all renal biopsies performed in the Grampian Region of Scotland during 1977-1980 revealed that IgA nephropathy was the most frequently encountered glomerular lesion. The commonest indications for renal biopsy were the presence of asymptomatic urinary abnormalities (90/184; 48.9%) especially asymptomatic haematuria (42/184; 22.8%). A histological diagnosis was made in 36 of the 42 patients presenting with asymptomatic haematuria (85.7%); 16 of the 26 cases of IgA nephropathy presented in this way. Overall, IgA nephropathy was detected in 14.1% of all biopsies and accounted for 21.8% of primary glomerular diseases. This study indicates that IgA nephropathy is apparently more common in Grampian than elsewhere in the United Kingdom. However, it is suggested that this does not represent a true variation in the prevalence of the condition; IgA nephropathy is probably a common cause of haematuria in the United Kingdom.

Adolescent↗
PubMed1985

Ultrafiltration studies in vitro of serum aluminum in dialysis patients after deferoxamine chelation therapy.

Using gel filtration chromatography, we evaluated aluminum bound to albumin, transferrin, and other plasma proteins in the serum of patients on maintenance hemodialysis. The proportion of dialyzable aluminum, as determined by selective membrane ultrafiltration and flameless atomic absorption spectrometry, increased by more than fourfold on treatment with the metal chelator, deferoxamine. This ultrafiltration technique may prove useful for monitoring the proportion of aluminum mobilized during such therapy.

Aluminum↗