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Biomedical subjects

J Cunningham

Publications and source records attributed to J Cunningham.

At least 109 records · Page 6Linked to original sources
PubMed1990

Fast (4-h) or slow (24-h) infusions of pamidronate disodium (aminohydroxypropylidene diphosphonate (APD)) as single shot treatment of hypercalcaemia.

Twenty-five patients with hypercalcaemia (ionised calcium, 1.57 +/- 0.04 mM; total calcium, 3.33 +/- 0.06 mM) due to malignancy were randomised to receive pamidronate (1 mg/kg body wt.) by infusion over 4 h (12 patients) or 24 h (13 patients). Forced saline diuresis was not utilised. Two patients died within 24 h and were not included in the analysis. Both groups combined (n = 23) showed a decrease in ionised calcium to 1.44 +/- 0.04 mM by 2 days (P less than 0.05 vs. day 0). By 4 days there had been a further fall to 1.27 +/- 0.05 mM (P less than 0.05 vs. day 2) and 7 days after treatment ionised calcium was 1.19 +/- 0.05 mM (P less than 0.05 vs. day 4). Total calcium declined from 3.33 +/- 0.06 to 2.65 +/- 0.11 mM over 7 days (P less than 0.001). Separate analyses of the two groups showed that the fast (4-h) infusion led to an earlier reduction in calcium than did the 24-h infusion (P less than 0.02), although after 7 days there was little difference between the two groups (4 h, 1.18 +/- 0.09 mM; 24 h, 1.23 +/- 0.06 mM, n.s.). Hypercalcaemic symptoms (analogue rating scale) improved between each of the time intervals 0, 4 and 7 days (P less than 0.05) and did not differ between the two groups. We recommend a single 4-h infusion of pamidronate (1 mg/kg) as primary treatment for malignancy-induced hypercalcaemia.

Calcium↗
PubMed1990

Immunoglobulin heavy chain switch region gene polymorphisms in glomerulonephritis.

Much evidence suggests that primary IgA nephropathy (IgAN) and idiopathic membranous nephropathy (MN) are immune complex mediated diseases. Moreover, genetic factors may play an important role in their pathogenesis. Recently, restriction fragment length polymorphisms (RFLPs) of the immunoglobulin heavy chain genes have been described which appear to associate with glomerulonephritis. We have studied RFLPs of the switch region of the IgM (S mu) and IgA1 (S alpha 1) heavy chain in MN and IgAN. DNA obtained from British Caucasoids with IgAN (N = 75), MN (N = 43), and normal controls (N = 73), was digested with the restriction enzyme Sac1, and studied using Southern blot techniques and hybridization with a 32P labelled DNA probe homologous to S mu. This probe detects RFLPs at the S mu and S alpha 1 loci. The genotypic and allelic frequencies of the S mu and S alpha 1 alleles in IgAN and MN was similar to normal controls. Caucasoid subjects with IgAN from Northern and Southern Europe (Finland and Italy, respectively) were also studied to determine whether an ethnic variation in genetic susceptibility to IgAN exists. The frequency of the S mu and S alpha 1 alleles was similar between the patient groups and their respective local healthy controls. These results do not support the recent findings of an association with RFLPs of the S mu and S alpha 1 loci in IgAN and MN, and suggest that the immunoglobulin heavy chain switch region genes are not important in conferring disease susceptibility to IgAN or MN.

Blotting, Southern↗
PubMed1990

Pharmacokinetics of once daily intra-peritoneal aztreonam and vancomycin in the treatment of CAPD peritonitis.

The pharmacokinetics of aztreonam and vancomycin were studied in six adult patients who developed peritonitis during Continuous Ambulatory Peritoneal Dialysis. Aztreonam 3 g was added to the first exchange in each 24 h period with vancomycin 500 mg on the first day and 250 mg on each subsequent day (provided the pre-dose serum vancomycin concentration was less than 10 mg/l) for a total of ten days. Aztreonam and vancomycin concentrations were measured in the serum and dialysate at 1, 2, 6, 12, 18 and 24 h after the initial dose and pre-dose on days 5 and 10. By the end of the ten day study all patients had recovered clinically and had a normal dialysate. For aztreonam, the mean peak serum concentration was 84.3 mg/l (range 59.6-102.8), the mean 24 h pre-dose serum concentration was 23.0 mg/l (range 8.6-39.2) and the mean 24 h pre-dose dialysate concentration was 15.5 mg/l (range 5.0-32.0). For vancomycin, the mean peak serum concentration was 10.2 mg/l (range 8.1-12.6), the mean 24 h pre-dose concentration was 5.5 mg/l (range 3.6-6.4), and the mean 24 h pre-dose dialysate concentration was 3.4 mg/l (range 2.4-4.6). In the treatment of CAPD peritonitis, once daily intra-peritoneal administration of aztreonam 3 g with vancomycin 500 mg initially and 250 mg on subsequent days (serum concentrations permitting) provides concentrations of antibiotic in both the serum and dialysate throughout the 24 h period in excess of the inhibitory concentrations of those organisms most frequently encountered in this condition.

Aztreonam↗
PubMed1990

Genetic mapping of a cloned sequence responsible for susceptibility to ecotropic murine leukemia viruses.

A mouse cDNA that confers susceptibility to ecotropic murine leukemia viruses following transfection into human EJ cells has been cloned and sequenced. We show that this sequence is likely to be Rec-1, the chromosome 5 locus originally defined by studies with somatic cell hybrids as responsible for virus susceptibility, and provide a specific chromosomal map position for this locus by analysis of an interspecies backcross. This locus maps in the distal region of chromosome 5 and is thus not within the cluster of retrovirus-related genes near the centromere.

Animals↗
PubMed1989

Disturbance of cerebral function by aluminium in haemodialysis patients without overt aluminium toxicity.

The psychomotor function of 27 long-term haemodialysis patients with apparently normal cerebral function, who had only mildly raised serum aluminium (mean 59 [SEM 9] micrograms/l), was measured by means of a computerised version of the symbol digit coding test. Compared with those of control subjects matched for age and the patients' estimated premorbid IQ, the patients' response times were significantly longer (2.51 [0.10] vs 1.88 [0.05] s). Abnormalities were also detected in five other computerised tests of psychomotor function. The mean activity of erythrocyte dihydropteridine reductase (DHPR), which is inhibited by aluminium, rose during 3 months' desferrioxamine treatment in most of the 15 patients so treated. Although there was no relation between baseline psychomotor function and either indices of cumulative aluminium exposure or erythrocyte DHPR activity, changes in DHPR induced by desferrioxamine correlated with changes in psychomotor performance (r = 0.62). The flash-stimulated visual evoked potential (measured in 10 patients) was delayed (133.4 [2.4] ms), although the pattern-stimulated visual evoked potential remained normal (101.8 [3.2] ms). The difference between the visual evoked potentials stimulated by flash and pattern was significantly greater in the patients than in the controls (31.6 [4.3] vs 19.4 [2.4] ms) and was significantly related to the symbol digit coding response times and to the oral aluminium intake. The results suggest that much more rigorous exclusion of aluminium from the dialysate and diet of dialysis patients is necessary.

Adult↗
PubMed1989

Pharmacological and metabolic interactions between ethanol and methyl n-butyl ketone, methyl isobutyl ketone, methyl ethyl ketone, or acetone in mice.

Methyl n-butyl ketone (MnBK), methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and acetone are widely used industrial solvents to which certain groups of workers are exposed. Pharmacological and metabolic interactions between these solvents and ethanol were explored in male CD-1 mice. The effects of these solvents on the duration of ethanol-induced loss of righting reflex and on ethanol elimination in mice were studied. The solvents were dissolved in corn oil and injected intraperitoneally 30 min before ethanol 4 g/kg ip. The four solvents prolonged significantly the duration of ethanol-induced loss of righting reflex when given in the following doses (mmol/kg): MnBK, 3.75 and 5; MIBK, 5; MEK, 5 and 10, acetone, 20 and 40. This prolongation was dose related and increased as the dose of the solvent was increased. The concentrations of ethanol in blood or brain on return of the righting reflex were similar in solvent-treated and control animals, with the exception of the group of mice treated with 40 mmol/kg acetone in which the ethanol concentrations were significantly lower than in control animals. The mean elimination rate of ethanol was markedly reduced in mice treated with MnBK 5 mmol/kg, MEK 15 mmol/kg, and acetone 40 mmol/kg. All four solvents reduced the activity of mouse liver alcohol dehydrogenase in vitro. It is concluded that enhancement of the ethanol-induced loss of righting reflex by these solvents in mice is well correlated to reduced elimination rate of ethanol.

Acetone↗
PubMed1989

Posterior composites: evaluations without trials?

Clinical trials for the evaluation of restorative materials are time-consuming, expensive and often based on subjectively assessed criteria. By the conclusion of a clinical trial materials are often obsolete. A DHSS-commissioned programme at the Liverpool School of Dentistry is in progress where clinical and laboratory evaluations of materials are being carried out in parallel with a view to correlating the results. The structure and scope of the programme is discussed and the value of establishing short-term laboratory tests predictive of clinical performance is considered. Preliminary observations emerging from the programme are discussed.

Bicuspid↗
PubMed1989

Effect of direction and rate of change of calcium on parathyroid hormone secretion in uraemia.

We have studied the control of amino-terminal parathyroid hormone (PTH) secretion in haemodialysis patients in response to slow or fast calcium infusion and during acute hypocalcaemia. In nine patients, fast calcium infusion (0.4 mmol/kg bodyweight per hour) for 15 min increased ionised calcium and reduced PTH, with an initial t 1/2 of 12.8 min. After the infusion had ceased, calcium decreased steadily, and PTH increased, mean PTH reaching baseline values when calcium was still significantly greater than pre-infusion values. During slow calcium infusion for 2.5 h (0.1 mmol/kg bodyweight per hour), parathyroid suppression was evident at 15 min, when the calcium increment was only 0.03 mM. After 60 min, PTH did not decrease further despite progressive hypercalcaemia. Hypocalcaemic haemodialysis led to rapid increases in PTH. After 15 min, the mean calcium decrement was 0.09 mM (P less than 0.01) and the mean PTH increment was 283 pg/ml (P less than 0.01). The parathyroid response was maximal at 30 min, and did not increase subsequently, despite progressive hypocalcaemia for a further 90 min. During recovery from hypocalcaemia, PTH reduced and, despite comparable hypocalcaemia, PTH during periods of increasing calcium was always lower at a given calcium concentration than while calcium was decreasing. This influence of the direction of change of calcium was not seen during hypocalcaemia. The results showed that even in-advanced renal disease, the parathyroid glands are highly responsive to small initial increments (0.03 mM) and decrements (0.09 mM) in blood calcium, though less so to further perturbation of blood calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

One-shot high-dose pamidronate disodium (APD): effective, simple treatment for hypercalcaemia in haematological malignancy.

Fifteen patients with haematological malignancy and hypercalcaemia (mean +/- SEM calcium 3.44 +/- 0.14 mmol/l) received pamidronate (1 mg/kg) by infusion on 17 occasions (two patients were retreated 2 and 6 months after the first dose). After 4 days the plasma calcium had fallen to 2.84 +/- 0.14 mmol/l (P less than 0.001; n = 17), and in 10/17 episodes was less than 2.6 mmol/l. The mean fall was 0.61 mmol/l (95% confidence intervals 0.49-0.72 mmol/l). By 7 days a further decrease to 2.53 +/- 0.10 mmol/l had occurred, continuing to 2.38 +/- 0.11 mmol/l after 14 days. Plasma phosphate fell from 1.18 +/- 0.16 to 0.74 +/- 0.07 mmol/l at 7 days (P less than 0.001; n = 12). In 9 of the 17 episodes plasma creatinine initially exceeded 120 mumol/l (four of these greater than 300 mumol/l). This did not impair the response to pamidronate and there was no significant change in plasma creatinine following treatment. A single large dose of pamidronate was a simple, well-tolerated and very reliable treatment for hypercalcaemia complicating haematological malignancy, irrespective of renal function.

Adult↗
PubMed1989

High-dose calcium carbonate with stepwise reduction in dialysate calcium concentration: effective phosphate control and aluminium avoidance in haemodialysis patients.

To reduce potentially toxic aluminium exposure, the phosphate binding agent aluminium hydroxide was replaced by high-dose oral calcium carbonate in 15 haemodialysis patients. Stepwise reduction in dialysate calcium concentration (from 1.75 to 1.35 mmol/l and then to 1.05 mmol/l) was made when necessitated by hypercalcaemia. After 6 months, the mean daily dose of calcium carbonate was 62 mmol (range 25-150 mmol). This dose maintained good control of plasma phosphate (baseline, 1.34 +/- 0.32 mmol/l (mean +/- SD); 12 weeks, 1.30 +/- 0.22 mmol/l; 24 weeks, 1.51 +/- 0.31 mmol/l). Calcium x phosphate product did not rise significantly (baseline, 3.41; 12 weeks, 3.44; 24 weeks, 4.02). Apart from a transient early increase, ionised calcium did not change significantly (baseline, 1.23 +/- 0.10 mmol/l; 12 weeks, 1.24 +/- 0.10 mmol/l). Intact (1-84) parathyroid hormone concentration decreased from 241 pg/ml to 116 pg/ml (median values, P less than 0.05) after 12 weeks. This simple and well-tolerated regimen almost completely eliminated oral aluminium exposure, effectively controlled plasma phosphate and calcium concentrations, and reduced hyperparathyroidism.

Administration, Oral↗
PubMed1989

Seizures in haemodialysis patients treated with recombinant human erythropoietin.

Administration of recombinant erythropoietin (r-HuEPO) is an effective treatment for the anaemia of chronic renal failure, but in some patients it has been accompanied by elevated blood pressure. This study focuses on seven patients with end-stage renal failure, managed on haemodialysis, who developed probable hypertensive encephalopathy with seizures during treatment with r-HuEPO. All made a full recovery. The events were not clearly related to the haemoglobin concentrations achieved, and four patients have subsequently been restarted on r-HuEPO therapy at a reduced dose, resulting in a slower increase in haemoglobin with no recurrence of episodes of severe hypertension. Close attention needs to be paid to blood pressure in patients commencing erythropoietin therapy, and it seems prudent to aim for a gradual increase in haemoglobin concentration to allow the circulation to adapt to changes in oxygen delivery and haematocrit.

Adult↗
PubMed1989

Hypophosphatemia complicating bronchodilator therapy for acute severe asthma.

Hypophosphatemia has been recently highlighted as a reversible cause of respiratory muscle hypocontractility and reduced tissue oxygen extraction in patients with chronic obstructive lung disease and asthma. To define the prevalence and mechanism of hypophosphatemia under these circumstances, we studied phosphate homeostasis in 22 patients with chronic asthma, who had been hospitalized for emergency bronchodilator therapy. Serum phosphate concentration was normal in all patients on presentation, and fell after the initiation of bronchodilator therapy. Twelve patients (54%) developed hypophosphatemia (serum phosphate, less than 0.8 mmol/L). Urinary phosphate level fell in parallel. A negative correlation was observed between serum phosphate and serum theophylline concentrations, and a positive correlation between serum and urinary phosphate concentrations. No correlation was found between serum phosphate and serum albumin or urea concentration. These data indicate that hypophosphatemia is a common metabolic abnormality during the emergency treatment of asthma. The underlying mechanism appears to be drug-induced phosphate flux from the extra-cellular to the intracellular space. We suggest that the serum phosphate level be monitored in patients undergoing emergency treatment of bronchospasm, particularly if a prolonged period of bronchodilator therapy is required or if respiratory muscle fatigue supervenes.

Adolescent↗
PubMed1988

Isolation and identification of seven metabolites of 25-hydroxydihydrotachysterol3 formed in the isolated perfused rat kidney: a model for the study of side-chain metabolism of vitamin D.

The in vivo metabolism of dihydrotachysterol3, an analogue of vitamin D3 and a potent calcemic factor, has been studied in the rat. This in vivo metabolism is compared to the in vitro metabolism of 25-hydroxydihydrotachysterol3 in the perfused rat kidney. Using mass spectrometry and ultraviolet spectroscopy, we have identified seven novel metabolites derived from 25-hydroxydihydrotachysterol3. The seven compounds represent intermediates on two renal pathways (24-oxidation and 26,23-lactone formation) also observed for 25-hydroxyvitamin D3. No evidence was found for the renal synthesis of a 1-hydroxylated metabolite of 25-hydroxydihydrotachysterol3 analogous to the hormone 1,25-dihydroxyvitamin D3. Two of the compounds formed in vitro, 24,25-dihydroxydihydrotachysterol3 and 25-hydroxydihydrotachysterol 26,23-lactone, were also formed in vivo. In vivo studies also revealed the formation of two other unidentified metabolites which are presumed to be formed nonrenally and may be calcemic factors. This work shows that dihydrotachysterol3 metabolism is complex and probably utilizes the same side-chain enzymes as vitamin D3. In addition, our work also confirms that intermediates postulated to lie on pathways to 26,23-lactone in the vitamin D3 series are also formed for the side chain in dihydrotachysterol3.

Animals↗
PubMed1988

Aluminium chelation therapy in dialysis patients: evidence for inhibition of haemoglobin synthesis by low levels of aluminium.

To investigate the possibility that aluminium may exacerbate anaemia in dialysis patients with only modest aluminium accumulation, 15 patients whose exposure to aluminium had been low were treated for three months with the aluminium chelating agent desferrioxamine, 30 mg/kg intravenously at the end of each dialysis session. Serum aluminium concentrations before treatment were 5-125 micrograms/ml. After one month of desferrioxamine, serum aluminium (including the chelate) had risen from 54.6 (SEM 11.2) to 167.0 (27.5) micrograms/l; and after three months haemoglobin had risen from 8.46 (0.70) to 10.43 (0.80) g/l. Mean cell volume and mean cell haemoglobin concentration also increased significantly. The maximum rise in haemoglobin correlated with the patients' aluminium burden as estimated by the mean serum aluminium concentration after one month of desferrioxamine therapy (r = 0.85). The greatest response to desferrioxamine occurred in patients with a baseline serum aluminium of 15-75 micrograms/l (mean increase in haemoglobin 38%). The results indicate that even the modest aluminium accumulation found in most dialysis patients has a pronounced inhibitory effect on haemoglobin synthesis. The possible toxic effect of aluminium should be considered in all anaemic dialysis patients.

Adult↗
PubMed1988

Use of mass spectrometry in the identification of in vivo and in vitro metabolites of dihydrotachysterol3 in the rat.

The metabolism of dihydrotachysterol3 (DHT3), a vitamin D analogue, has been investigated in vivo in the rat after intraperitoneal injection, and the metabolism of the 25-hydroxylated metabolite of DHT3 was studied in vitro in the isolated perfused rat kidney. A large number of metabolites have been obtained and some have been identified. The rat plasma or kidney perfusate were extracted and the metabolites separated by high-performance liquid chromatography (HPLC) in straight- and reverse-phase systems and using cyano columns. Metabolites were identified, using a photodiode array assembly which monitored the HPLC eluate, by the characteristic ultraviolet spectrum of DHT compounds. Tentative structures were assigned to some of the metabolites obtained on the basis of their mobility in the various HPLC systems used in comparison to that of known metabolites of vitamin D. Gas chromatography/mass spectrometry (GC/MS) and direct probe mass spectrometry have been used to confirm the identity of seven metabolites formed in vitro, of which only two have been definitely shown also to be formed in vivo. GC/MS was carried out after derivatization forming trimethylsilyl ethers, n-butyl boronate cyclic esters, and N-O-methyl oximes before and after oxidation with sodium periodate and/or reduction with sodium borohydride. Molecular ions of these compounds are usually of low abundance and characteristic mass fragments at m/z 273, 255 and 121 are always seen with metabolites of DHT.

Animals↗