Biomedical subjects
D Owens
Publications and source records attributed to D Owens.
Lack of evidence that feedback from lifestyle alters the amplitude of the circadian pacemaker in humans.
Two groups of healthy subjects were studied indoors, first while living normally for 8 days (control section) and then for 18 x 27 h "days" (experimental section). This schedule forces the endogenous (body clock-driven) and exogenous (lifestyle-driven) components of circadian rhythms to run independently. Rectal temperature and wrist movement were measured throughout and used as markers of the amplitude of the circadian rhythm, with the rectal temperature also "purified" by means of the activity record to give information about the endogenous oscillator. Results showed that, during the experimental days, there were changes in the amplitude of the overt temperature rhythm and in the relative amounts of out-of-bed and in-bed activity, both of which indicated an interaction between endogenous and exogenous components of the rhythm. However, the amplitude and the amount of overlap were not significantly different on the control days (when endogenous and exogenous components remained synchronized) and those experimental days when endogenous and exogenous components were only transiently synchronized; also, the amplitudes of purified temperature rhythms did not change significantly during the experimental days in spite of changes in the relationship between the endogenous and exogenous components. Neither result offers support for the view that the exogenous rhythm alters the amplitude of oscillation of the endogenous circadian oscillator in humans.
The effect of activity on the waking temperature rhythm in humans.
Nine healthy female subjects were studied when exposed to the natural light-dark cycle, but living for 17 "days" on a 27h day (9h sleep, 18h wake). Since the circadian endogenous oscillator cannot entrain to this imposed period, forced desynchronization between the sleep/activity cycle and the endogenous circadian temperature rhythm took place. This enabled the effects of activity on core temperature to be assessed at different endogenous circadian phases and at different stages of the sleep/activity cycle. Rectal temperature was measured at 6-minute intervals, and the activity of the nondominant wrist was summed at 1-minute intervals. Each waking span was divided into overlapping 3h sections, and each section was submitted to linear regression analysis between the rectal temperatures and the total activity in the previous 30 minutes. From this analysis were obtained the gradient (of the change in rectal temperature produced by a unit change in activity) and the intercept (the rectal temperature predicted when activity was zero). The gradients were subjected to a two-factor analysis of variance (ANOVA) (circadian phase/ time awake). There was no significant effect of time awake, but circadian phase was highly significant statistically. Post hoc tests (Newman-Keuls) indicated that gradients around the temperature peak were significantly less than those around its trough. The intercepts formed a sinusoid that, for the group, showed a mesor (+/-SE) of 36.97 (+/-0.12) and amplitude (95% confidence interval) of 0.22 degrees C (0.12 degrees C, 0.32 degrees C). We conclude that this is a further method for removing masking effects from circadian temperature rhythm data in order to assess its endogenous component, a method that can be used when subjects are able to live normally. We suggest also that the decreased effect of activity on temperature when the endogenous circadian rhythm and activity are at their peak will reduce the possibility of hyperthermia.
Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive.
To assess variations of coagulation factors in women, 123 women were included in a cross-sectional study of the effect of age, ethnic origin, blood group and menstrual cycle on surface induced coagulation time (activated partial thromboplastin time) and plasma levels of Factor VIII clotting assay, von Willebrand factor antigen, von Willebrand factor activity and factor XI. The effect of menstrual cycle was further assessed in a longitudinal study including 39 Caucasian women, 20 of whom were using combined oral contraceptives. Activated partial thromboplastin time was longer in women with blood groups B or O, and plasma levels of factor VIII clotting assay, von Willebrand factor antigen and von Willebrand factor activity were significantly higher in black women. Fibrinogen, von Willebrand factor antigen and von Willebrand factor activity concentrations showed strong cyclic variations with peak values in the luteal phase. This pattern was dampened for von Willebrand factor antigen and von Willebrand factor activity but completely disappeared for fibrinogen with the use of combined oral contraceptives. There was a cyclical pattern for factor VIII clotting assay in pill users, evidence of which was not evident in non-pill users. There were strong associations between the levels of von Willebrand factor antigen and von Willebrand factor activity and age, with levels rising by an average of 0.17 and 0.15 U/ml, respectively, for each 10 year increase in age. In conclusion, there are great inter- and intraindividual variations in coagulation markers in women due to different physiological conditions such as age, ethnicity, blood group and phases of the menstrual cycle. However, there were no significant associations between coagulation markers and weight, alcohol consumption or smoking status.
Pharmacokinetics of recombinant factor VIII (recombinate) using one-stage clotting and chromogenic factor VIII assay.
In a study designed to demonstrate the safety and pharmacokinetics of a recombinant factor VIII (Recombinate) manufactured in Andover, MA and Thousand Oaks, CA, two different methods of factor VIII assay (one-stage clotting and Chromogenic substrate) were compared in vivo. The study was performed in four centres in the UK: London, Oxford, Cardiff and Manchester. Two pharmacokinetic studies, at least one week apart, were performed in 30 patients with severe haemophilia A (VIII:C < 2 IU/dl). A dose of 50 IU/kg was administered with sampling pre-infusion, and +0.25, 0.5, 1, 3, 6, 9, 12 and 24 h post-infusion. The aggregate 60 pharmacokinetic study showed a half-life of 12.7 and 13.0 h (p = 0.28) and recovery of 127 and 161 IU/dl (p = 0.0001) using one-stage clotting or chromogenic substrate respectively. In a supplementary experiment, 20 post-infusion samples were re-assayed by 1-stage and chromogenic assay using two plasma (20th British plasma standard and an "in-house" pooled normal plasma) and two concentrate standards, derived from the same type, but different batch of infused concentrate (Recombinate) and pre-diluted in either individual pre-infusion sample or in pooled commercial haemophilic plasma. The use of the Recombinate concentrate standard overcame the significant difference in FVIII levels between 1-stage and chromogenic assay methods when a plasma standard was used (p <0.0001). It is concluded that where potency dosing designation is carried out by an assay system different to that used in the clinical situation, the use of the recombinant concentrate as a standard in post-infusion plasma samples is likely to give more reliable and reproducible results.
[Insulin secretion and repaglinide].
The natural history of type 2 diabetes involves a progressive pancreatic beta-cell dysfunction leading to quantitative, qualitative and/or temporal abnormalities in insulin secretion and insensitivity to insulin action which predominates in muscles. These abnormalities can be observed during early phases of glucose intolerance, but their determinism remains unclear. The high prevalence of type 2 diabetes, its increasing incidence among developed countries and the huge cost induced by diabetic complications explain why this disease is being viewed as a major public health issue. An earlier diagnosis by general practitioners and more intensive treatments are urged for patient and social beneficial outcome. In addition to non pharmacological (dietary, physical activity) approaches, several drugs were established as efficient therapies for type 2 diabetic patients: sulfonylureas acting by enhancing insulin secretion, metformin improving insulin resistance, or acarbose delaying carbohydrate intestinal absorption. These drugs have been used during the UKPDS trial; nevertheless, their effect was somehow limited, when considering long-term blood glucose control, risk for hypoglycemia, and/or prevention of macroangiopathy. The new generation of insulin secretion enhancers, including repaglinide, by allowing a reduction of total insulinemia, potentiating nutrient-induced insulin secretion, and minimizing risks for hypoglycemia, raises hope for a progress.
Joint working. Duel carriageway.
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Deliberate self harm: systematic review of efficacy of psychosocial and pharmacological treatments in preventing repetition.
OBJECTIVE: To identify and synthesise the findings from all randomised controlled trials that have examined the effectiveness of treatments of patients who have deliberately harmed themselves. DESIGN: Systematic review of randomised controlled trials of psychosocial and physical treatments. Studies categorised according to type of treatment. When there was more than one investigation in a particular category a summary odds ratio was estimated with the Mantel-Haenszel method. SETTING: Randomised trials available in electronic databases in 1996, in the Cochrane Controlled Trials Register in 1997, and from hand searching of journals to 1997. SUBJECTS: Patients who had deliberately harmed themselves shortly before entry into the trials with information on repetition of behaviour. The included trials comprised 2452 randomised participants with outcome data. MAIN OUTCOME MEASURE: Repetition of self harm. RESULTS: 20 trials reported repetition of self harm as an outcome variable, classified into 10 categories. Summary odds ratio (all for comparison with standard aftercare) indicated reduced repetition for problem solving therapy (0.73; 95% confidence interval 0.45 to 1.18) and for provision of an emergency contact card in addition to standard care (0.45; 0.19 to 1.07). The summary odds ratios were 0.83 (0.61 to 1.14) for trials of intensive aftercare plus outreach and 1.19 (0.53 to 2.67) for antidepressant treatment compared with placebo. Significantly reduced rates of further self harm were observed for depot flupenthixol versus placebo in multiple repeaters (0.09; 0.02 to 0.50) and for dialectical behaviour therapy versus standard aftercare (0.24; 0.06 to 0.93). CONCLUSION: There remains considerable uncertainty about which forms of psychosocial and physical treatments of patients who harm themselves are most effective. Further larger trials of treatments are needed.
Light of domestic intensity produces phase shifts of the circadian oscillator in humans.
Twelve subjects have been studied in a chamber that isolated them from external noise and lighting. After several control days, one group (n = 6) was subjected to 18 x 27-h 'days' and the other to 11 x 30-h 'days'. Sleep was in the dark, and awake times were spent in normal domestic lighting (150-500 lux). Rectal temperature and wrist actimetry were measured throughout, and the phase of the circadian oscillator was inferred from that of the temperature data, purified to remove direct effects of activity. During the experimental 'days' the rhythms showed a mean period of 24.4 h. A detailed examination of the phase shifts from one day to the next showed that small advances and delays were superimposed upon this drift. Moreover, the mean size and direction of these shifts depended upon the time of exposure to lighting relative to the temperature minimum, as would be predicted from a phase-response curve.
Health action zones. Trouble zones?
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Frequency of inherited bleeding disorders in women with menorrhagia.
BACKGROUND: Although menorrhagia is a common gynaecological symptom, a specific cause is identified in less than 50% of affected women. We investigated the frequency of inherited bleeding disorders in women with menorrhagia. METHODS: Women referred for investigation of menorrhagia whose pelvis was normal on clinical examination and who had an estimated menstrual blood loss of more than 80 mL were studied. A detailed menstrual history and history about other bleeding symptoms was taken. The activated partial thromboplastin time, factor VIII activity, von-Willebrand-factor antigen and activity, and factor XI (FXI) were measured in all patients; further tests were done when results were at or outside the limits of the assays. FINDINGS: 150 women were screened. An inherited bleeding disorder was diagnosed in 26 (17%) patients: the disorders were von Willebrand's disease of mild (15) or moderate severity (three), mild FXI deficiency (four), mild von Willebrand's disease and FXI deficiency (one), combined von Willebrand's disease, FXI deficiency, and factor X deficiency (one), carriage of haemophilia-A gene (one), and platelet dysfunction (one). The frequency of von Willebrand's disease and FXI deficiency were 13% (95% CI 7.9-18.8%) and 4% (1.5-8.5%), respectively. Menorrhagia since menarche was noted in 11 (8.9%) of 123 women without a bleeding disorder compared with 13 (65%) of 20 women with von Willebrand's disease (p=0.001) and four (66.7%) of six women with FXI deficiency (p<0.001). INTERPRETATION: Inherited bleeding disorders are found in a substantial proportion of women with menorrhagia and a normal pelvis examination. We suggest that such patients should be investigated for these disorders-especially von Willebrand's disease-before invasive procedures are done.
Cellular cholesterol synthesis--the relationship to post-prandial glucose and insulin following weight loss.
Hyperinsulinaemia is a risk factor for atherosclerosis. We have previously demonstrated a relationship between hyperinsulinaemia and cellular cholesterol synthesis. In this paper we examine the separate relationship of glucose and insulin to cholesterol synthesis in three groups of obese patients. The first group was a group of non-insulin-dependent diabetic patients with a low post-prandial insulin response (n=8). The second group had non-insulin-dependent diabetes and a high insulin response (n=9). The third group were non-diabetic patients with a high post-prandial insulin (n=12). Six diabetic and seven non-diabetic patients who were hyperinsulinaemic on initial analysis, were re-examined following an 8% body weight reduction. Insulin resistance was defined as the ratio of area under curve for insulin/area under curve for glucose. Cellular cholesterol synthesis was measured in freshly isolated mononuclear leucocytes. Fasting cholesterol synthesis was similar in the three groups. In both diabetic and non-diabetic high insulin subjects cholesterol synthesis rose significantly after the meal (p < 0.05). Both hyperinsulinaemic groups showed a significantly greater change from baseline than did the non-hyperinsulinaemic group. There was a positive correlation between post-prandial cellular cholesterol synthesis and insulin resistance (p < 0.05). Following weight reduction patients were divided into two groups, those who did reduce insulin resistance (group 1) and those who did not reduce insulin resistance (group 2). The significant post-prandial increase in cholesterol synthesis was no longer seen in group 1 after weight loss whereas in group 2 after a similar weight loss the post-prandial cholesterol synthesis remained elevated. These results demonstrate that post-prandial hyperinsulinaemia is associated with increased cellular cholesterol synthesis. This increase in cholesterol synthesis is no longer seen in those patients in whom insulin resistance improved with weight reduction. This study suggests a mechanism for the association between insulin resistance and atherosclerosis.
A randomised, double-blind comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of mild-to-moderate hypertension.
OBJECTIVE: To compare the anti-hypertensive efficacy, safety, and tolerability of irbesartan with those of the full dose range of enalapril in patients with mild-to-moderate hypertension. DESIGN AND METHODS: A total of 200 patients were randomised to irbesartan 75 mg or enalapril 10 mg (once daily). Doses were doubled at Weeks 4 and/or 8 if seated diastolic blood pressure (DBP) was > or = 90 mm Hg. Trough blood pressure was measured after completion of a 4- to 5-week placebo lead-in period and again after 2, 4, 8, and 12 weeks of treatment. MAIN OUTCOME MEASURES: Efficacy was evaluated by determining the change from baseline in trough seated blood pressure and the proportion of patients normalised (seated DBP <90 mm Hg) at Week 12. Safety and tolerability were assessed by adverse events reported by physicians, by patients in response to a specific-symptoms questionnaire, by open-ended questioning of patients by physicians, and by clinical laboratory evaluations. RESULTS: Both treatments significantly lowered blood pressure with no significant difference in efficacy between treatment groups. At Week 12, the percentage of patients titrated to either enalapril 40 mg or irbesartan 300 mg was 24% and 28%, respectively. The frequency of overall adverse events was similar in both groups. The incidence of cough in the enalapril and irbesartan groups was 17% and 10%, respectively. In contrast to other AII receptor antagonists, there was no change in uric acid concentrations with irbesartan. CONCLUSIONS: Irbesartan was as effective as the full dose range of enalapril. Irbesartan also demonstrated an excellent tolerability profile.
Antibodies to oxidized lipoproteins and their relationship to myocardial infarction.
The inflammatory process and autoimmunity in the form of antibodies to oxidized LDL are important factors in the formation of the atherosclerotic plaque. We examined the time relationship of oxidized lipoprotein antibodies to the acute oxidative stress of myocardial infarction (MI). We also examined the relationship of C-reactive protein, an index of inflammation, and therefore of free radical production, to oxidized low-density lipoprotein (LDL) antibodies. We examined five groups of patients in a cross-sectional study: group 1, within 48 h of MI; group 2, two days to 1 week; group 3, 1-4 weeks; group 4, 1-3 months; and group 5, 3-6 months post MI. Nine patients with high antibody levels were re-examined 12 months after their first assessment. Malondialdehyde (MDA)-LDL and MDA-HDL antibodies were determined by an ELISA method. The highest MDA-LDL antibodies were found within 48 h of MI, but there was no significant difference in MDA-HDL antibodies between the groups. When 9/10 patients with LDL antibodies greater than the mean of 2.7 were re-examined 1 year later, there was a significant decrease in the mean antibody levels (5.2 +/- 1.7 vs. 3.2 +/- 0.6, p < 0.02). There was no correlation between antibodies to MDA-LDL and antibodies to MDA-HDL. There was a positive correlation between serum HDL cholesterol and antibodies to MDA-LDL (r = 0.4, p < 0.02) and a positive correlation between serum triglycerides and MDA-HDL antibodies (r = 0.39, p < 0.02). Acute MI appears to be associated with significantly higher C-reactive protein and antibodies to MDA-LDL, suggesting a possible acceleration of the atherosclerotic process immediately prior to MI.
Effects of the endogenous clock and sleep time on melatonin, insulin, glucose and lipid metabolism.
This study was undertaken to determine whether the internal clock contributes to the hormone and metabolic responses following food, in an experiment designed to dissociate internal clock effects from other factors. Nine female subjects participated. They lived indoors for 31 days with normal time cues, including the natural light: darkness cycle. For 7 days they retired to bed from 0000 h to 0800 h. They then underwent a 26-h 'constant routine' (CR) starting at 0800 h, being seated awake in dim light with hourly 88 Kcal drinks. They then lived on an imposed 27-h day (18 h of wakefulness, 9 h allowed for sleep), for a total of 27 days. A second 26-h CR, starting at 2200 h, was completed. During each CR salivary melatonin and plasma glucose, triacylglycerol (TAG), non-essential fatty acids (NEFA), insulin, gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured hourly. Melatonin and body temperature data indicated no shift in the endogenous clock during the 27-h imposed schedule. Postprandial NEFA, GIP and GLP-1 showed no consistent effects. Glucose, TAG and insulin increased during the night in the first CR. There was a significant effect of both the endogenous clock and sleep for glucose and TAG, but not for insulin. These findings may be relevant to the known increased risk of cardiovascular disease amongst shift workers.
Stability of amphotericin B 0.05 and 0.5 mg/mL in 20% fat emulsion.
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Autoantibodies to oxidized low density lipoprotein: the relationship to low density lipoprotein fatty acid composition in diabetes.
Autoantibodies to oxidized low density lipoprotein have been shown to be an independent predictor of the progression of carotid atherosclerosis. This study examines the relationship between low density lipoprotein fatty acid composition and autoantibodies to both malondialdehyde-modified and copper-oxidized low density lipoprotein in non-diabetic patients with (n = 17), and without (n = 18), definite evidence of previous myocardial infarction. The third group were non-insulin-dependent diabetic patients with no evidence of atherosclerosis (n = 15) and the fourth group were patients with non-insulin-dependent diabetes (n = 17) who had definite evidence of previous myocardial infarction. Fatty acids were measured by gas-liquid chromatography. Antibodies to malondialdehyde-modified low density lipoprotein and copper-oxidized low density lipoprotein were determined by an ELISA method. Autoantibodies to copper-oxidized low density lipoprotein were significantly higher in the non-diabetic patients with heart disease when compared to any other group (p < 0.05). Autoantibodies to malondialdehyde-modified low density lipoprotein were significantly higher in the non-diabetic subjects with heart disease and in both diabetic groups compared to non-diabetic subjects without coronary heart disease (p < 0.05). Linoleic acid (%) in low density lipoprotein did not differ between groups groups but arachidonic acid (%) was significantly lower in both diabetic and non-diabetic patients with coronary heart disease (p < 0.05). The diabetic patients with low antibodies had 39.6 +/- 2.2% polyunsaturated fatty acids in their low density lipoprotein while diabetic patients with high antibodies had 46.7 +/- 1.2% polyunsaturates in their low density lipoprotein (p < 0.01). This study confirms the association between antibodies to oxidized low density lipoprotein and coronary heart disease and shows raised low density lipoprotein antibody levels in diabetic patients with and without demonstrable atherosclerosis. In the diabetic patients, those with high antibody levels had high polyunsaturated fatty acid levels in their LDL suggesting a possible role for dietary intervention.
The role of dietary cholesterol in the regulation of postprandial apolipoprotein B48 levels in diabetes.
The atherogenicity of intestinally derived postprandial lipoproteins has been confirmed in a number of recent studies. We have shown abnormalities in postprandial lipoprotein metabolism in diabetic patients, a group with an increased susceptibility to atherosclerosis. This study examined the relationship between dietary cholesterol and the postprandial, intestinally derived, apolipoprotein B48 and apolipoprotein B100 from the liver. We compared 10 non-insulin-dependent (Type 2, NIDDM) diabetic patients and 10 age-matched non-diabetic control subjects. Fasting blood was taken and subjects were fed a cholesterol-free, high fat meal. Blood samples were repeated at 2 h, 4 h, 6 h, and 8 h postprandial. The following week fasting blood was collected and subjects were given the same meal with 1 g of added cholesterol. Blood was collected at the same time points. Chylomicrons and very low density lipoprotein were isolated by sequential ultracentrifugation and their lipoprotein composition determined. Apolipoproteins B48 and B100 were separated by gradient gel electrophoresis and quantified by densitometric scanning using a low density lipoprotein apolipoprotein B100 standard. Post prandial chylomicron cholesterol and triglyceride increased after the high cholesterol meal in both groups (p < 0.001). The postprandial chylomicron apolipoprotein B48 response of both diabetic and control subjects to the cholesterol meal was less than to the cholesterol-free meal (p < 0.001). Fasting very low density lipoprotein apolipoprotein B48 was higher in diabetic patients compared to control subjects and their postprandial increase following the cholesterol-free meal was significantly greater (p < 0.001). There was a 10-fold increase in the incremental postprandial VLDL apolipoprotein B48 area under the curve after the cholesterol-rich meal in the diabetic patients compared to a 3-fold increase in control subjects. The postprandial very low density lipoprotein apolipoprotein B100 was similar in the two groups with both meals. The study demonstrates a very significant increase in the amount of intestinally derived small apolipoprotein B48-associated particles in the very low density lipoprotein fraction following a cholesterol-rich meal in diabetic patients. Synthesis rather than clearance may be the major cause of the increase in these atherogenic postprandial particles.