Biomedical subjects
A Parfitt
Publications and source records attributed to A Parfitt.
Does meta-chlorophenylpiperazine (mCPP) activate human platelets?
mCPP (meta-chlorophenylpiperazine), an agonist at serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 receptors, has been used as a probe of serotonergic function. We assessed its effect on platelet activation by measuring median platelet volume (MPV), the Sonoclot (SCT) pattern and plasma and intraplatelet serotonin. (a) In vitro study: MPV was measured (n = 7) using a high-resolution channelyzer: Saline (median and range (5.23 fl; 5.10-6.18) vs. mCPP (5.36; 5.10-6.44) P = 0.03; ADP (5.42; 5.29-6.44) vs. ADP + mCPP (5.67; 5.42-6.63) P = 0.02; mCPP (5.36; 5.10-6.44) vs. ADP + mCPP (5.67; 5.42-6.63) P = 0.02. Therefore, mCPP increases the MPV and enhances the effect of ADP. (b) In vivo study: The SCT time to inflection (TI) and time to peak (TP) were measured following the oral administration of mCPP (0.5 mg/kg) or aspirin (300 mg) (n = 10). Ingestion of mCPP significantly shortened TI and TP indicating platelet activation. TI: 0 h (mean +/- SD: 10.2 +/- 2.0 min) vs. 6 h (9.3 +/- 1.5) P = 0.03; TP: 0 h (31.9 +/- 7.6) vs. 6 h (23.1 +/- 2.9) P = 0.01. Aspirin had no effect on TI or TP. There were no significant changes in plasma and intraplatelet 5-HT. It is concluded that mCPP activates human platelets via 5-HT receptors.
A regional approach to improving night time supervision of accident and emergency departments.
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An unusual case of patella dislocation.
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X-chromosome inactivation in monozygotic twins with systemic lupus erythematosus.
The hypothesis that a low concordance rate in monozygotic (MZ) twins with systemic lupus erythematosus (SLE) may be accounted for by differences in X-chromosome inactivation was examined. Five MZ twin pairs, four discordant and one concordant, were recruited, zygosity confirmed by DNA fingerprinting, and their pattern of X-chromosome inactivation in DNA samples prepared from peripheral blood and buccal cells were examined. X-chromosome inactivation was assessed by the methylation status of the CpG region near trinucleotide repeats in exon 1 of the androgen receptor gene on X-chromosome after digestion with the methylation-sensitive enzyme HpaII or HhaI and PCR amplification. X-chromosome inactivation patterns were found to be the same between affected and non-affected twins in all four discordant twin pairs, with random patterns in two pairs and skewed patterns in the others. The concordant twins demonstrated the same random patterns. X-chromosome inactivation was also examined from buccal smear DNA and shown to have the same pattern as that noted from peripheral blood DNA in one informative twin pair. Differences in X-chromosome inactivation patterns were not observed in these five MZ twin pairs. The results could not support the hypothesis that differences in X-chromosome inactivation is the mechanism accounting for the low concordance rate noted in MZ twins with SLE.
Family and twin studies in systemic lupus erythematosus.
We have estimated how much of the total genetic predisposition to SLE may be attributable to genes outside the HLA region by comparing figures for concordance of SLE in monozygotic twins with those for concordance in HLA identical siblings in Australia. None of six dizygotic co-twins of white Australian SLE probands was concordant for SLE. One of four (25%) monozygotic co-twins of white Australian SLE probands was concordant for SLE which when added to previously published figures for Caucasoid populations gives an overall concordance rate for SLE in monozygotic twins of 25%. None of 18 HLA identical, same sex siblings of SLE probands, had definite SLE by the study criteria (i.e. less than 6%). The comparison of these figures shows that most of the genetic predisposition to SLE is attributable to genes outside the HLA region.
A study of platelet activation during human cardiopulmonary bypass and the effect of S-nitrosoglutathione.
Cardiac surgery is complicated by the occurrence of post-operative bleeding due to platelet dysfunction. This is largely caused by platelet activation and consumption during cardiopulmonary bypass. Patients undergoing cardiac surgery requiring cardiopulmonary bypass were studied to determine whether early platelet changes due to bypass could be inhibited using the platelet-selective nitric oxide donor S-nitrosoglutathione (GSNO). Flow cytometry was used to measure platelet surface expression of P-selectin (an alpha-granule protein) and glycoproteins (GP) IIb/IIIa and Ib (mediators of aggregation and adhesion) before and 5 and 10 min after commencing cardiopulmonary bypass, in 6 controls and 6 patients receiving GSNO 50 microg/min. Platelet P-selectin expression increased during bypass both in controls and patients receiving GSNO. Glycoproteins IIb/IIIa and Ib fell during bypass in control and GSNO-treated patients. There was no difference between control and GSNO-treated groups. Thus no significant platelet inhibition by S-nitrosoglutathione was demonstrated under these conditions.
Acupuncture as an antiemetic treatment.
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Surgical treatment of anaemia in malignant melanoma.
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On the effect of garlic on plasma lipids and lipoproteins in mild hypercholesterolaemia.
The ingestion of garlic has been reported to have many cardiovascular effects, including a reduction in plasma cholesterol concentration and the susceptibility of LDL to oxidation. A double-blind, placebo-controlled, randomised crossover study was conducted in subjects with mild to moderate hypercholesterolaemia who were subject to strict dietary supervision and assessment. After a baseline dietary period of 28 days, subjects took Kwai garlic powder tablets 300 mg three times daily or matching placebo for 12 weeks, followed by 28 days washout, followed by a 12 weeks crossover on the alternative preparation. In the analysis hypercholesterolaemia was defined as those subjects in the range 5.5-8.05 mmol/l. Three subjects were withdrawn, one allocated to garlic and complaining of garlic body odour, one using placebo having intercurrent health problems, and one with a baseline cholesterol below 5.5 mmol/l, yielding analysable results in 28 subjects. Comparing the period on garlic with that on placebo, there were no significant differences in plasma cholesterol, LDL cholesterol, HDL cholesterol, plasma triglycerides, lipoprotein(a) concentrations, or blood pressure. Mean LDL cholesterol concentration was 4.64 +/- 0.52 mmol/l on garlic and 4.60 +/- 0.59 mmol/l on placebo. There was no demonstrable effect of garlic on oxidisability of LDL, on the ratio of plasma lathosterol/cholesterol (a measure of cholesterol synthesis), nor on LDL receptor expression in lymphocytes. This study found no demonstrable effect of garlic ingestion on lipids and lipoproteins.
Coronary risk factors 6-12 months after coronary artery bypass grafting. Comparison of surveys in 1986, 1990 and 1994.
OBJECTIVE: To assess coronary risk factors and management 6-12 months after coronary artery bypass grafting. DESIGN: Patient survey by questionnaire after discharge from hospital in 1994 and comparison with similar surveys from 1990 and 1986. SETTING AND PATIENTS: One hundred and ninety-four patients undergoing coronary artery bypass grafting at one hospital campus between 1 March 1993 and 31 August 1993. Replies to questionnaires were received from 175 patients (90%); we had clinical and biochemical data for 166-175 patients (86%-90%). RESULTS: The proportion with hypercholesterolaemia (serum cholesterol levels > or = 6.5 mmol/L) declined from 60% in 1986 to 9% in 1994. Those with diastolic hypertension (> or = 95 mmHg) declined from 23% to 3%. The proportion of current smokers remained low at 6%. The proportion overweight had increased from 32% in 1986 to 47% in 1994. The proportion taking lipid-regulating drugs increased from 2% in 1986 to 37% in 1994. CONCLUSION: Coronary risk factors after coronary artery bypass grafting appear to be better managed in 1994 than in earlier years, but there may still be a need for improvement in lipid disorders and weight.
Treatment of arrow wounds by nineteenth century USA Army surgeons.
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Single-cell [Ca2+]i analysis and biochemical characterization of pinealocytes immobilized with novel attachment peptide preparation.
Single-cell image analysis of rat pinealocytes has been difficult because they do not attach readily to coated or uncoated surfaces and typically adhere in clusters to fibroblast-like cells. In the present report, a new method for the rapid attachment of rat pinealocytes is described. Cells were prepared using papain digestion and density centrifugation and then were placed on coverslips or slides coated with PepTite-2000, a preparation containing the attachment peptide sequence Arg-Gly-Asp. Cells immobilized with this preparation responded to norepinephrine treatment with an increase in cyclic AMP and melatonin production. Single-cell analysis of Fura-2-loaded cells revealed that norepinephrine increased [Ca2+]i. This development makes it possible to conduct routine single-cell image analysis and other studies of freshly isolated rat pinealocytes.
Treatment of primary hypercholesterolaemia with pravastatin: efficacy and safety over three years.
OBJECTIVE: To assess the efficacy, safety and tolerability of pravastatin over three years of treatment. DESIGN: An open, multicentre randomised study. SETTING: Subjects receiving tertiary care at three hospital lipid clinics. PATIENTS: Subjects with primary hypercholesterolaemia (type IIa) or combined hyperlipidaemia (type IIb), already stabilised on a cholesterol-lowering diet, with low density lipoprotein (LDL) cholesterol levels of greater than 4.7 mmol/L and triglyceride levels of less than 4.5 mmol/L. Sixty-one subjects were randomly assigned to the treatment groups: 60 completed 12 weeks and 46 completed 30-36 months of treatment. INTERVENTIONS: Subjects were randomly assigned to receive either pravastatin 20 mg/day, pravastatin 40 mg/day or cholestyramine 16 g/day for a period of 12 weeks. Subsequently, dose titration of pravastatin up to 40 mg/day was permitted, if required, and all groups received supplementary therapy with other lipid-lowering drugs. MAIN OUTCOME MEASURES: Lipids, lipoproteins, haematological and biochemical safety parameters were measured at regular intervals. Adverse events were monitored. RESULTS: There were significant reductions in total and LDL cholesterol levels with all treatments over 12 weeks (P < 0.001). The mean reductions (+/- SD) in LDL cholesterol were 26% +/- 14% in the group taking pravastatin 20 mg/day (n = 21), 30% +/- 8% in the group taking pravastatin 40 mg/day (n = 21) and 34% +/- 13% in the group taking resin (n = 18). The percentage changes in LDL cholesterol were independent of age, baseline cholesterol level or lipid phenotype. High density lipoprotein (HDL) cholesterol levels were significantly increased, by 8%-18% with all treatments (P < 0.001). Triglyceride levels were reduced by high-dose pravastatin only (7% +/- 29%), but were found to increase with resin (45% +/- 63%). During long-term treatment over 36 months, still greater reductions in total and LDL cholesterol were found in patients taking pravastatin (n = 35), but not in those taking resin (n = 11). There was an apparent decrease in effect beyond 18 months in both groups, possibly related to reduced compliance with diet or cholestyramine intake. Eight subjects allocated to pravastatin and seven allocated to resin withdrew (one and two subjects respectively because of drug-induced adverse events). Adverse events during 12 weeks' monotherapy with pravastatin included central nervous system (CNS) symptoms (12%), gastrointestinal (GIT) symptoms (7%) and an acute hepatitic reaction (one subject). Of those in the resin therapy group, 22% developed GIT symptoms. Myalgia occurred in three subjects using a combination of pravastatin and clofibrate, but this resolved fully upon clofibrate withdrawal. CONCLUSIONS: Pravastatin was found to be a relatively effective, safe and well tolerated lipid-lowering drug. Still greater LDL reduction was achieved with pravastatin combination therapy and this was essentially maintained over three years.
Successful management of primary hypercholesterolaemia with simvastatin and low-dose colestipol.
OBJECTIVE: To examine whether a small dose of bile acid sequestrant used in combination with a hydroxymethylglutaryl coenzyme A reductase inhibitor is more effective in reducing serum and low-density lipoprotein (LDL) cholesterol levels than inhibitor used alone. DESIGN: A randomised, double-blind study. SETTING: Subjects receiving tertiary care at a hospital lipid clinic. PATIENTS: Subjects with severe primary hypercholesterolaemia (types IIa and IIb), already stabilised on a cholesterol-lowering diet, with serum cholesterol levels of 7.0 mmol/L or more and triglyceride levels of 6.0 mmol/L or less. Sixty-four subjects were randomly assigned to the treatment groups; three withdrew before any outcome observations; 61 completed the trial and their results were analysed. INTERVENTIONS: Subjects were randomly assigned to receive either colestipol placebo or colestipol 5 g or 10 g each morning in fixed dosage for 18 weeks. They simultaneously received incremental doses of simvastatin: placebo for six weeks, then 20 mg/night for six weeks, then 40 mg/night for a final six weeks. MAIN OUTCOME MEASURES: Lipids, lipoproteins, and haematological and biochemical safety parameters were measured at the end of each treatment period. Adverse events were monitored. RESULTS: Respective maximum reductions (95% confidence intervals) in serum cholesterol, LDL cholesterol and apolipoprotein B (apo-B) values in subjects taking combination therapy were 41% (38%-45%), 50% (46%-53%) and 43% (39%-46%), compared with lesser reductions of 32% (26%-37%), 38% (31%-45%) and 37% (32%-41%) in those taking simvastatin monotherapy. The percentage changes in LDL cholesterol with combination therapy were independent of baseline cholesterol level or lipid phenotype. Combination therapy reduced serum triglyceride levels by up to 24% (15%-32%) and increased high-density lipoprotein (HDL) cholesterol levels by up to 9% (3%-15%). Three subjects withdrew within a few weeks because of severe gastrointestinal side effects related to colestipol; 19 experienced milder gastrointestinal side effects, 15 were taking combination therapy. CONCLUSIONS: A combination of low-dose colestipol and simvastatin was found to be more effective in reducing serum and LDL cholesterol than simvastatin used alone. Such combination therapy offers the possibility of improved cholesterol lowering without the need for full dosage of either drug.
Coronary risk factors six to twelve months after coronary artery bypass surgery. 1986 compared with 1990.
A 1986 study found that coronary risk factors were receiving insufficient attention in patients who had recently undergone coronary artery bypass grafting. This issue was readdressed in a like group of 100 patients from the same surgical unit three and a half years later, in 1990, to ascertain whether risk factor management had improved over the period. An increased proportion of patients in 1990 were undergoing active management of hypertension and hyperlipidaemia. Only 25% of patients in 1990 manifested hypercholesterolaemia (cholesterol levels greater than or equal to 6.5 mmol/L) compared with 60% in 1986. Five per cent of patients in 1990 manifested diastolic hypertension (diastolic pressure greater than or equal to 95 mmHg) compared with 23% in 1986. Such patients appear better managed in 1990 than they were in 1986.
Effects of an ethyl ester preparation of fish oils (Himega) on lipids and lipoproteins in hyperlipidaemia.
Clinical trials were conducted to assess the utility of HimegaR in the management of hyperlipidaemia. Himega is an ethyl ester concentrate from fish oil containing at least 50% n-3 fatty acid and minimal cholesterol. In Study 1, 13 subjects with primary hypertriglyceridaemia consumed Himega or a triglyceride-based fish oil in a randomised, double-blind crossover study for 12 weeks. Nine subjects took 2 g/day of n-3 fatty acid but four subjects with marked hypertriglyceridaemia took 4 g/day. Plasma triglycerides were reduced by approximately 50% with either product. There was a very similar effect on all lipid and lipoprotein parameters, including an 18% increase in LDL cholesterol and 23% increase in serum apolipoprotein B. In Study 2, nine subjects with primary hypercholesterolaemia took 2 g/day of n-3 fatty acid (Himega) or placebo (olive oil) in a randomised, double-blind crossover study for nine weeks. Plasma cholesterol was reduced by 6%, without significant change in LDL cholesterol. Fish oils in the form of ethyl esters or triglyceride are assimilated to a similar degree and lead to equivalent triglyceride-lowering in hypertriglyceridaemia, while simultaneously increasing LDL particle numbers. Himega does not reduce LDL levels in hypercholesteraemia, despite being a product with minimal cholesterol content.