The Antihypertensive and Metabolic Effects of Low and Conventional Dose Cyclopenthiazide in Type II Diabetics with Hypertension

The antihypertensive efficacy and metabolic effects of cyclopenthiazide125 µg were compared with cyclopenthiazide 500 µgin patients with non-insulin dependent diabetes and hypertensionin a double blind, randomized crossover study. After a 6-weekplacebo period 24 patients with non-insulin dependent diabetesmellitus, stabilized on diet or oral hypoglycaemic agents, whohad a mean diastolic blood pressure between 90 and 120 mmHgafter receiving placebo for 6 weeks were given 125 µgor 500 µg cyclopenthiazide for 12 weeks. Patients thenreceived placebo for a further 6-week period, following whichthey received the alternate treatment dosage for 12 weeks. Therewere no differences between doses in their antihypertensiveeffects. While 500 µg significantly reduced systolic anddiastolic blood pressures, only diastolic pressure was significantlyreduced by 125 µg from pre-treatment values. The higherdose of cyclopenthiazide had greater effects on measures ofdiabetic control than did the 125 µg dose and the risein blood glucose after 12 weeks' treatment with 500 µgwas significantly different from pre-treatment values. Cyclopenthiazide125 µg had significantly less effect on triglycerides,potassium and urate, than did 500 µg. Cyclopenthiazide500 µg resulted in a significant fall in serum potassiumfrom pre-treatment values. There were no intertreatment differencesin the other variables measured. Cyclopenthiazide 125 µgis as effective as 500 µg in reducing diastolic bloodpressure in mildly hypertensive non-insulin dependent diabeticpatients. The higher dose had more pronounced adverse effectson glucose control and serum concentrations of triglycerides,potassium and urate.     

Low-dose cyclopenthiazide in the treatment of hypertension: a one-year community-based study

After an 8-week placebo period, 73 patients whose diastolic blood pressures were between 90 and 110 mmHg were randomly assigned to receive 125 micrograms (low dose) or 500 micrograms of cyclopenthiazide (standard dose) for a period of one year. Blood pressure was measured in the patient's home by the same observer at two-weekly intervals during an 8-week placebo run-in period, every 4 weeks for a further 12 weeks and at 24, 36 and 52 weeks thereafter. Serum potassium, urate, glucose, glycosylated haemoglobin, total and HDL cholesterol, and apolipoproteins were measured at the end of the placebo period and at 4, 8, 24 and 52 weeks of active treatment. Twelve of the 73 patients had an inadequate antihypertensive response--five on the higher dose and seven on the lower dose. One patient receiving 500 micrograms was withdrawn because of adverse effects. In the remaining 60 patients, systolic and diastolic blood pressures were significantly reduced when compared with pretreatment values in both treatment groups throughout the one year period. The decreases in blood pressure were not significantly different from each other (p greater than 0.65). Three patients on 500 micrograms required potassium supplements. Maximum decreases in the serum potassium of 0.52 mmol/l (500 micrograms dose) and 0.14 mmol/l (125 micrograms dose) were observed at 24 weeks of treatment in the remaining 57 patients. The differences between the two doses at this time were statistically significant (p less than 0.05), as were the increases in serum urate observed at 4, 8 and 24 weeks (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The antihypertensive and metabolic effects of low and conventional dose cyclopenthiazide in type II diabetics with hypertension.

The antihypertensive efficacy and metabolic effects of cyclopenthiazide 125 micrograms were compared with cyclopenthiazide 500 micrograms in patients with non-insulin dependent diabetes and hypertension in a double blind, randomized crossover study. After a 6-week placebo period 24 patients with non-insulin dependent diabetes mellitus, stabilized on diet or oral hypoglycaemic agents, who had a mean diastolic blood pressure between 90 and 120 mmHg after receiving placebo for 6 weeks were given 125 micrograms or 500 micrograms cyclopenthiazide for 12 weeks. Patients then received placebo for a further 6-week period, following which they received the alternate treatment dosage for 12 weeks. There were no differences between doses in their antihypertensive effects. While 500 micrograms significantly reduced systolic and diastolic blood pressures, only diastolic pressure was significantly reduced by 125 micrograms from pre-treatment values. The higher dose of cyclopenthiazide had greater effects on measures of diabetic control than did the 125 micrograms dose and the rise in blood glucose after 12 weeks' treatment with 500 micrograms was significantly different from pre-treatment values. Cyclopenthiazide 125 micrograms had significantly less effect on triglycerides, potassium and urate, than did 500 micrograms. Cyclopenthiazide 500 micrograms resulted in a significant fall in serum potassium from pre-treatment values. There were no intertreatment differences in the other variables measured. Cyclopenthiazide 125 micrograms is as effective as 500 micrograms in reducing diastolic blood pressure in mildly hypertensive non-insulin dependent diabetic patients. The higher dose had more pronounced adverse effects on glucose control and serum concentrations of triglycerides, potassium and urate.     

Plasma potassium, serum magnesium and ventricular fibrillation: a prospective study

Low plasma potassium and magnesium concentrations have beenadvanced as risk factors for ventricular fibrillation (VF).For potassium, this assertion is based almost exclusively onretrospective data; for magnesium the evidence shows an associationwith ventricular arrhythmias but no direct association withVF. We studied the relationship between these electrolytes andVF prospectively. Plasma potassium and serum magnesium concentrations were measuredon admission to our coronary care unit. Drug therapy, time fromonset of symptoms, ECG, enzyme changes and clinical status wereall recorded. VF was confirmed by analysis of 24 h monitoringtapes. Mean plasma potassium in the 21 patients with VF who had measurementsprior to their arrhythmia was 3.49±0.54 mmol/l, lowerthan that of the 1165 patients without VF (mean K 3.88±0.57mmol/l, p<0.05). Plasma potassium concentrations in the 17patients with myocardial infarction and VF were lower (mean3.58 ± 0.41 mmol/l) than in those without VF (n = 417,mean 3.89 ± 0.61 mmol/l) (p < 0.05). Mean serum magnesiumin the 12 patients with VF, measured prior to their arrhythmia(all with myocardial infarction) was 0.80 ± 0.07 mmol/l,which was not different from the mean for patients without VF(n = 781, 0.82 ± 0.09 mmol/l) or from the mean of 0.81± 0.08 mmol/l for those with infarction but not VF (n= 331). Low plasma potassium concentrations are associated with increasedrisk of ventricular fibrillation, but low serum magnesium concentrationsare not.     

Failure of Dietary Protein and Phosphate Restriction to Retard the Rate of Progression of Chronic Renal Failure: A Prospective, Randomized, Controlled Trial

SUMMARY Ninety-five patients (63 male, 32 female), age 45±2 years(mean±SEM) with chronic renal failure of varied aetiologywere randomized to receive either a conventional low proteindiet (0.6 g/kg/day protein, 800 mg phosphate; n=33), a low phosphatediet (providing approximately 1000 mg phosphate plus an orallyadministered phosphate binder, minimum protein intake 0.8 g/kg/day;n=30) or to control (minimum protein intake 0.8 g/kg/day, nophosphate restriction; n=32). Patients were reviewed for a minimumof 6 months before randomization and were withdrawn from thestudy if plasma creatinine exceeded 900 µmol/1, plasmaphosphate was > 2.0 mmol/1 or at the onset of uraemic symptoms. Following randomization patients were studied for an averageof 19±3 months. Mean plasma creatinine rose from 398±33to 600±50 µmol/1. Dietary protein intake was estimatedat 0.69±0.02 g/kg/day in the low protein group, 1.02±0.05in the low phosphate and 1.14±0.05 in the controls, phosphateintake was 815±43, 1000± 47, and 1315±57mg/day, respectively. Urinary urea excretion and protein catabolicrates were significantly reduced (p<0.01) only in those onprotein restriction, at 213±9 mmol/24 hours and 0.71g/kg/day, respectively. Phosphate excretion was significantlylower (p<0.05) in both the low protein group (17.9±0.8mmol/24 hours) and the low phosphate group (18.6±1.0mmol/24 hours) compared to controls. Changes in body weight,muscle mass and serum transferrin, albumin and immunoglobulinswere comparable between the groups. Mean blood pressure followingrandomization was 150/89±3/1 (low protein), 148/87±3/1(low phosphate) and 146/87±3/1 (controls). Progression of renal failure was analysed by rate of fall ofcreatinine clearance (ml/min/ 1.73 m²/month), by rate of deteriorationderived from reciprocal plasma creatinine against time plots(1/mmol/year) and to assess individual patient's response totreatment by two phase linear regression (‘breakpoint’)analysis of reciprocal plasma creatinine/time plots. Progressionwas analysed only in patients seen for at least 3 months followingrandomization. The rate of fall of creatinine clearance was not significantlydifferent between the groups (ANOVA): 0.56±0.08 ml/min/1.73m2/month (low protein, n=28), 0.44±0.07 (low phosphate,n=23) and 0.69±0.11 (control, n=27). In 50 patients (18low protein, 16 low phosphate and 16 control) whose rate ofprogression could be calculated before and after randomization,there was a fall in rate of progression averaging 0.18 ml/min/1.73m2/month in those on low protein diet and those on low phosphatediet, but a rise of 0.08 in the controls. These differenceswere, however, not statistically significant. Similar resultswere obtained when the rates of deterioration were calculatedfrom plasma creatinine. Significant individual improvements(p<0.01) in rates of progression by ‘breakpoint’analysis occurred in 17 patients: six on low protein, sevenon low phosphate and in four controls. Sixty-one (72 per cent)of the patients examined by this method showed no significantchange in the rate of progression while seven patients had acceleratedprogression. There was no difference in the requirement formaintenance dialysis facilities between groups. No significant benefit of protein and phosphate restrictionwas therefore demonstrated.     

Iron Overload, but not Treatment with Desferrioxamine Favours the Development of Septicemia in Patients on Maintenance Hemodialysis

During a 19-month period we determined the incidence of bacterialinfection among 39 patients treated with desferrioxamine whohad end-stage renal disease and were undergoing maintenancehemodialysis. Twenty-three received desferrioxamine becauseof aluminium-related bone disease, and 16 because of iron overload.A control group of 193 patients on maintenance hemodialysisbut without desferrioxamine was used. No difference was foundin the incidence of septicemia or of all bacterial infectionsbetween the patients with aluminium-related bone disease treatedwith desferrioxamine and the control patients (0.12 vs. 0.12septicemia per patient-therapy-year, p>0.05; 0.23 vs. 0.26bacterial infections per patient-therapy-year, p>0.05). Theincidence of septicemia in patients treated with desferrioxaminefor iron overload, however, was almost three times that in thecontrol patients (0.36 vs. 0.12 septicemia per patient-therapy-year,p<0.01). To assess the effect of iron overload itself, wedetermined the frequency of bacterial infection in patientson regular hemodialysis who have never received desferrioxamine.These were subdivided into three groups according to serum ferritinlevel which indicated normal or low iron stores (Group I: serumferritin 10-330 µg1/1, n=125), moderate (Group II: serumferritin 331-1000 µg/1, n=49) or more advanced iron overload(Group III: serum ferritin 1001-2000 µg/1, n=10). Comparedto patients with normal or low serum ferritin levels (GroupI), we found a significantly higher rate of bacterial infectionamong patients in Group II compared with Group I (0.18 vs. 0.34infections per patient-therapy-year, p<0.05) and Group IIIcompared with Group I (0.18 vs. 0.58 infections per patient-therapy-year,p<0.01). These results suggest that treatment with desferrioxaminedoes not favour the development of septicemia or bacterial infectionindependently of iron overload and that iron overload itselfmay predispose patients on regular hemodialysis to bacterialinfection.     

A double-blind comparison of bisoprolol and atenolol in patients with essential hypertension

We compared the ß₁-selective adrenoceptor antagonistsbisoprolol and atenolol in a double-blind, randomized crossoverstudy. After 4 weeks placebo phase, 59 patients with essentialhypertension received either 10 mg bisoprolol or 50 mg atenololonce daily for 8 weeks, increased if necessary (target BP 150/90mmHg) to 20 and 100 mg, respectively, after 4 weeks. After asecondplacebo phase, crossover occurred to the alternative drug. Wemeasured resting systolicand diastolic blood pressures and heartrate at 24 h post-dose baseline and after 4 and 8 weeks treatment.Both drugssignificantly lowered systolic and diastolic bloodpressures and heart rate at 8 weeks compared to baseline (allp <0.05). Bisoprololreduced heart ratesignificantly morethan atenolol (p <0.01), but systolic and diastolic bloodpressure changes were not different between the two drugs. Therewas no difference in patient acceptability of the drugs as assessedby visual analogue scale. Despite theoreticaland circumstantialevidence to suggest superiority of bisoprolol over atenolol,no significant difference between the two was found except forgreater heart rate reduction with bisoprolol.     

Effect of a single test dose of lithium carbonate on sodium and potassium excretion in man.

1. The possible natriuretic and kaliuretic effects of a single dose of lithium, as used in lithium clearance studies, were investigated in 15 healthy subjects on fixed sodium (100 mmol/24 h) and potassium (70 mmol/24 h) intakes. Lithium carbonate (300 mg or 600 mg) or placebo tablets were administered, double-blind and in random order, midway through a 48 h urine collection (divided into six 8 h periods), at 23.00 hours. 2. During the three 24 h periods which preceded the administration of lithium or placebo (control days), rates of sodium and potassium excretion followed normal circadian patterns, but no differences in excretion rates between the 3 control days were observed. Placebo tablets did not affect excretion rates. 3. After the 300 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 17 mmol (P less than 0.05); almost all of the natriuretic effect occurred during the first two 8 h periods. No effect on potassium excretion was observed. 4. After the 600 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 48 mmol (P less than 0.001) and 24 h potassium excretion increased by approximately 19 mmol (P less than 0.01). These effects were confined to the first two 8 h periods and thus occurred before and during the usual lithium clearance period. 5. Plasma renin activity, measured in 10 subjects, increased after the 600 mg dose of lithium carbonate (P less than 0.005), but plasma concentrations of aldosterone and atrial natriuretic peptide were not significantly affected. Neither the 300 mg dose of lithium carbonate nor the placebo tablets affected hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinico-pathological Correlations and Long-term Follow-up of 253 United Kingdom Patients with IgA Nephropathy. A report from the MRC Glomerulonephritis Registry

The Medical Research Council's Glomerulonephritis Registry wasused to study clinicopathological correlations and renal survivalin patients with IgA nephropathy reported between 1978 and 1985.IgA nephropathy was the histological diagnosis in 9.3 per centof all renal biopsies reported to the registry during this period,and in 18.1 per cent of those with a primary glomerulonephritis.The 10-year cumulative renal survival rate accounting for censoreddata (Kaplan-Meier) was 83.3 per cent. Univariate analysis ofsurvival curves (log-rank test) found the following parametersto be significantly correlated with poor renal survival: serumcreatinine >120 µmol/l (p<0.001), hypertension(p<0.001), serum albumin <40 g/l (p<0.005), proteinuria>1 g (p<0.025), age >30 years (p<0.025), and focalmesangial proliferation (p<0.05). There was no significantdifference in renal survival between males and females. Multivariateanalysis (Cox's proportional hazards model) revealed that onlya serum creatinine of > 120 µmol/l and a serum albuminof <40 g/l were independently predictive of outcome. These findings indicate marked similarities between the UK experienceof IgA nephropathy and the published European experience. IgAnephropathy is not a benign condition in the UK and patientswith impaired renal function and/or those with a reduced serumalbumin are significiantly more likely to progress to end-stagerenal failure within 10 years.     

Double blind Randomized Study of Prolonged Higher-dose Oral Amoxycillin in Purulent Bronchiectasis

Thirty-eight patients with bronchiectasis and daily expectorationof purulent sputum despite conventional antibiotic courses wererandomly allocated to receive a sachet of amoxycillin (3g) ormatched placebo twice daily for 32 weeks in a double-blind study.Nine patients (four amoxycillin, five placebo) were withdrawnfrom the study treatment; the response of the two patients (bothon amoxycillin) withdrawn within the first six weeks was notassessed. The pretreatment characteristics of the two groupswere similar. Independent assessment of overall response basedon patients' diary cards showed that a higher proportion improvedin the amoxycillin group (11 of 17) than in the placebo group(four of 19; p= 0·02). Patients in the amoxycillin groupspent significantly less time confined to bed and away fromwork during treatment. The frequency of exacerbations duringthe study treatment phase was similar in the two groups butthey were less severe than before study treatment in the amoxycillingroup. There was a greater reduction in purulent sputum volumebetween exacerbations during the study treatment in the amoxycillingroup to 20 per cent of pretreatment volume than in the placebogroup (88 per cent of pretreatment volume, p= 0·008),although the concentrations of Haemophilus spp. in sputum betweenexacerbations was similar in the two groups. Adverse effectsexperienced were minor except in one patient (amoxycillin) withdrawnafter developing a rash and in six patients (three amoxycillin,three placebo) who had diarrhoea lasting more than one weeknecessitating withdrawal of two patients (one amoxycillin, oneplacebo) from study treatment. Sputum and stool cultures collectedregularly during the study showed no important changes in thebacterial flora in either group. Prolonged higher-dose antibiotictherapy in these patients with severe purulent bronchiectasissignificantly reduced the host (patient) inflammatory responseto colonizing microorganisms and reduced morbidity.     

The Relationship Between Long-term Glycaemic Control and Diabetic Nephropathy

Urine albumin excretion was studied by two widely accepted methodsin 210 patients with insulin-dependent diabetes mellitus andrelated to the mean of serial glycosylated haemoglobin (HbA₁)measurements made every 3 months during the previous 6 years.Microalbuminuria (albumin excretion rate > 20 µg/min)was present in 9.5 per cent of patients when defined by a 24-hourcollection and 8.1 per cent of patients when defined by a timedovernight urine sample. Those with microalbuminuria, as estimatedfrom a timed overnight urine sample, had a longer duration ofdiabetes but otherwise did not differ in age, duration of diabetesor arterial blood pressure from patients whose albumin excretionrate was 20 µg/min or less irrespective of the methodof urine collection. The mean and the most recent HbA₁ levelsdiffered significantly between the normal and the microalbuminuriagroups when defined by the 24-hour albumin excretion rate (p<0.001,p<0.01), but no significant difference between these groupswas found when albumin excretion rates were calculated fromthe timed overnight urine sample. Albumin excretion rate, examinedin relation to mean HbA₁, increased significantly with worseningglycaemic control whether measured over 24 hours or overnight(p<0.05, p< 0.01). These findings support an associationbetween glycaemic control and microalbuminuria, but the correlationis weak, dependent on the method of urine collection and isjust as good for a relatively short-term as for a long-termmeasure of average blood glucose.     

The Effect of External Pituitary Irradiation on Elevated Serum Prolactin Levels in Patients with Pituitary Macroadenomas

The response of serum prolactin to external radiotherapy wasstudied in 58 patients (32 women) with pituitary tumours, agedbetween 16 and 75 years. Forty-four patients underwent pituitarysurgery before radiotherapy. Six Patients were irradiated witha regimen of 20 Gy in eight fractions over 10–11 daysand the remainder received 35–42.5 Gy in 15 fractionsover 20–22 days. Following radiotherapy, 44 patients receivedadditional treatment with dopaminergic agonists. Prolactin levelsranged from 1078 to 491000 mU/I (median 11750 mU/I) before radiotherapyand all but three patients showed a fall in serum prolactin(measured 4 weeks after stopping bromocriptine in those on dopamineagonist therapy) during observation over periods of up to 154months. All patients had evidence of pituitary fossa erosionor expansion at presentation and large tumours (Hardy-VezinaGrade 3–4) were more common in male patients (²=10.08,p<0.01). The rate of fall of serum prolaetin levels was greaterin patients with true prolactin-secreting tumours when comparedwith those who had stalk or hypothalamic damage (p< 0.005).The rate of decline of serum prolactin was also significantlyrelated to the pre-radiotherapy value (p=0.519, p<0.01).A serum prolactin level. <500 mU/I was achieved in 31 outof 44 patients treated with radiotherapy and dopaminergic agonistbut only nine remained normoprolactinaemic when medication wasdiscontinued for 4 weeks or more. The serum prolactin levelfell permanently to <500 mU/I in two of 14 patients treatedwith radiotherapy only. Actuarial analysis of data from allpatients indicated a 50 per cent probability that prolactinwould be reduced to <500 mU/I by 10 years; this increasedto 58 per cent for patients with smaller tumours (Hardy-Vezinagrade 2). Fourteen of 19 women of premenopausal age were amenorrhoeicbefore radiotherapy, but despite bromocriptine, menstruationwas restored in only five. A separate group of nine patientswith primary suprasellar, non-prolactin-secreting tumours andelevated prolactin levels was also studied. Prolactin concentrationsranged between 1016 and >4600 mU/I intially and were reducedby radiotherapy at a rate indistinguishable from that of patientswith pituitary adenomas associated with disconnection hyperprolactinaemia.None achieved permanent reduction of serum prolactin to <500mU/I. External radiotherapy is effective in reducing serum prolactinlevels in patients with pituitary macroadenomas, particularlywhere the hyperprolactinaemia is due to true tumour hypersecretion,but normal levels may take over 10 years to achieve. Radiation-inducedhypothalamic damage probably contributes to the hyperprolactinaemiapersisting after therapy and together with tumour-associatedor radiation-induced hypopituitarism accounts for the poor prospectsfor fertility in female patients.     

LONG-TERM POTASSIUM SUPPLEMENTATION LOWERS BLOOD PRESSURE IN ELDERLY HYPERTENSIVE SUBJECTS

Following a randomised cross-over trial of the effect of a four-week 60 mmol/day potassium supplement versus placebo on blood pressure (BP), eight of the original 18 hypertensive subjects continued with a 48 mmol daily potassium supplement for four months. For these eight subjects 24-h potassium excretion during placebo, one month of 60 mmol and four months of 48 mmol daily potassium supplementation phases was 56 ± 23, 102 ± 28 and 90 ± 35 mmol/24 hours, respectively, and mean 24-h BP following each phase was 160 ± 16/89 + 11, 147 ± 13/83 ± 12 and 145 ± 14/81 ± 9 mmHg respectively, a significant fall in mean 24-h SBP between four months of potassium supplement and placebo period of 15 ± 13 mmHg (95% CI: 4, 26 mmHg, p=0.02), although the fall in 24-h DBP was not significant (8 ± 11 mmHg, 95% CI: 0, 17 mmHg, p=0.08). Modest increases in dietary potassium intake could have significant effects on lowering BP in the large proportion of elderly subjects with hypertension.     

'Healthy living' and sulphonylurea theraphy have different effects on glucose tolerance and risk factors for vascular disease in subject with impaired glucose tolerance

This study was undertaken to determine whether impaired glucosetolerance and associated risk factors for cardiovascular diseasecan be improved with ‘healthy living’ by diet andexercise or with sulphonylurea therapy. Patients were recruitedby screening subjects with either a family history of type IIdiabetes, previous gestational diabetes, or a previously raisedplasma glucose (5.6–6.6 mmol/l). Impaired glucose tolerancewas defined as hyperglycaemia on two separate tests, an achievedglucose level after a glucose infusion test above the 90th percentileof an age-matched normal population (> 9.3 mmol/l) or a fastingplasma glucose above the 95th percentile (> 5.6 mmol/l).Thirty-seven subjects with impaired glucose tolerance were enteredinto a randomized, prospective study for 6 months with allocationsto healthy living or double blind to sulphonylurea (gliclazide40 mg twice daily) or placebo tablets. The study took placein an outpatient setting, with three times weekly exercise sessionsat a Sports Centre. After 6 months the placebo group showedno change in plasma glucose, cholesterol and blood pressure.The subjects receiving gliclazide showed improved glucose levels(mean fasting plasma glucose levels fell from 5.8 to 5.1 mmol/l,p<0.05) but no significant change in plasma cholesterol orblood pressure. The healthy living group, after exclusion offour non-compliant subjects, showed no change in glucose levels,but a decreased systolic blood pressure (fall in mean from 124to 116 mmHg, p<0.05) and plasma cholesterol levels (fallin mean from 5.2 to 4.5 mmol/l, p0.01) with an increase in HDL:LDLratio (rise in mean from 0.39 to 0.46, p<0.05). Subjectswith impaired glucose tolerance may benefit in different waysfrom gliclazide and healthy living. The metabolic responsesto each therapy may help to decrease the risk of developingdiabetes and cardiovascular disease.     

Lipoprotein(a) as a determinant of the severity of angiographically defined carotid atherosclerosis

We measured fasting serum lipids, lipoproteins, apolipoproteinsand lipoprotein(a) [Lp(a)] in 49 Caucasian patients with transientischaemic attacks undergoing carotid angiography. The severityof extracranial cerebrovascular disease was assessed visuallyby a highly reproducible grading system that focused on theinternal carotid artery and carotid bifurcation. Compared witha healthy reference group, patients had significantly higherserum concentrations of: total cholesterol (mean ± SD),6.2 ± 1.6 vs. 5.6 + 1.0 mmol/l, p = 0.02; apolipoproteinB, 1.4 ±0.5 vs. 1.2±0.3g/l, p = 0.03; triglyceride[geometric mean(95% Cl)], 2.02(1.75–2.32) vs. 1.66(0.67–4.06)mmol/l, p = 0.03; and Lp(a), 0.33(0.26–0.42) vs. 0.17(0.40–0.76)g/l, p <0.001. Regression analysis showed that of the lipoprotein-relatedvariables, only Lp(a) was significantly related to the severityof carotid artery disease (p = 0.04) in the patients; this associationremained significant after adjusting for age, sex, blood pressure,and a history of stroke. Serum Lp(a) concentration was significantlyhigher in patients with carotid artery disease severity scoreabove the median value of the sample population compared withthose below the median: 0.45 vs. 0.24 g/l (95% Cl for difference0.35–0.88), p = 0.01. Elevated serum Lp(a) is a significantdeterminant of the extent of carotid atherosclerosis and maybe useful in identifying patients most at risk of stroke.     

Serum urea concentration and the risk of hepatotoxicity after paracetamol overdose

Background: Glutathione depletion increases the incidence oftoxicity after paracetamol overdose. Risk factors for toxicity,including chronic ethanol excess and malnutrition, are associatedwith low serum urea concentrations. Therefore, we hypothesizedthat low serum urea concentration might itself be predictiveof hepatotoxicity in patients that present to hospital afterparacetamol overdose. Methods: The present study prospectively collected data from1085 patients attending the Emergency Department after paracetamoloverdose. Hepatotoxicity was predefined by prothrombin timeratio >1.3 or alanine transaminase 1000 U/l. Serum urea concentrationswere considered in a stepwise multiple regression analysis thatincluded paracetamol dose, co-ingestion of ethanol and otherdrugs, serum concentration, N-acetylcysteine, interval to treatment,vomiting and serum creatinine. Results: Median (IQR) serum urea concentrations were 3.3 mmol/l(2.7–4.2 mmol/l) in those without risk factors, comparedwith 3.0 mmol/l (2.4–3.9 mmol/l) in those with chronicexcess ethanol intake (P < 0.001 by Mann Whitney test) and2.5 mmol/l (1.9–2.8 mmol/l) in patients with other riskfactors (P < 0.001). Multivariate analysis found that serumurea concentrations were not independently associated with hepatotoxicity. Conclusions: Low serum urea concentration is not an independentrisk factor for hepatotoxicity after paracetamol overdose.     

Metabolic Studies in Kidney Stone Disease

Patients with kidney stones (n=59) and healthy controls (n=31)collected a 24-hour urine sample and later underwent a 6-hour‘fast and load’ test in which an oral calcium loadwas taken after 2 hours. In the 24-hour urine sample, mean calciumexcretion was higher in patients than controls, while mean urate,oxalate and citrate levels were similar. The patients had higherlevels of fasting plasma calcium, serum calcitriol and fastingurinary calcium, and lower levels of plasma phosphate than didthe controls. Following the calcium load, plasma and urinarycalcium increased similarly in both groups. Serum parathyroidhormone (PTH) levels were similar in both groups and decreasedsimilarly following the calcium load. Multiple linear regression, relating the presence or absenceof stone formation to all variable, found the only variablessignificantly related to stone formation to be plasma levelsof calcium (p<0.001) and phosphate (p=0.001) and fastingurinary area (p<0.001), and 24-hour urinary calcium excretion(p<0.05). Urinary oxalate and citrate were not related tostone formation. The data do not support the hypothesis thatprimary stimulation by calcitriol produces a normal fastingplasma calcium level, with an exaggerated increase after anoral calcium load. The findings instead suggest an abnormalityof parathyroid cell ‘set point’, such that PTH secretioncontinues until the plasma calcium level is a little higherand the phosphate a little lower than in controls.     

Safety and efficacy of increasing wintertime vitamin D and calcium intake by milk fortification

We studied the safety and efficacy of milk fortified with vitaminD₃ and calcium. Over the winter, we conducted a double-blind,placebo-controlled trial of fortified milk (12µg vitaminD₃ and 1525 mg calcium per litre) compared to unfortified milk(0.3µg vitamin D₃ and 1270 mg calcium per litre) in 102adults (aged 17–54 years). Serum 25-hydroxyvitamin D [25(OH)D],ionized calcium, and creatinine were measured at baseline andafter intervention. Fortification reduced the seasonal declinein serum 25(OH)D concentrations by >50%. In the fortifiedgroup, serum 25(OH)D decreased by 15nmol/l from 77±35nmol/l to 62±26 nmol/l (p<0.001). In the control group,serum 25(OH)D fell by 31 nmol/l from 85±39 nmol/l to54±25 nmol/l (p<0.001). We suggest that milk enrichedwith vitamin D be provided in high-latitude European countriesto diminish the wintertime fall in serum 25(OH)D.     

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects

Blood was taken at the first antenatal clinic from 56049 pregnantwomen. Neural tube defect (NTD) pregnancies (81) were comparedto controls (247) for plasma vitamin B₁₂ (B₁₂) (ng/l), plasmafolate (µg/1), and red cell folate (RCF) (µg/l).Median values were significantly different and were, respectively,243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269and 338 (p < 0.001). There was a significant correlationbetween plasma B₁₂ and RCF in cases (r = 0.31, p = 0.004) butnot in controls (r = 0.02, p = 0.725). In cases only, multipleregression showed that both plasma B₁₂ and plasma folate influencedthe maternal RCF (multiple r = 0.68, p < 0.001). Plasma folateand plasma B₁₂ were independent risk factors for NTDs, suggestingthat the enzyme methionine synthase is involved directly orindirectly in the aetiology. The levels of folate and B₁₂ whereincreased risk occurred were not those usually associated withdeficiency, calling for a re-evaluation of their recommendeddaily allowances. Whether the aetiology is purely nutritionalor a metabolic defect, this study suggests that considerationshould be given to including B₁₂ as well as folic acid in anyprogramme of supplementation or food fortification to preventNTDs.     

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects

Blood was taken at the first antenatal clinic from 56049 pregnantwomen. Neural tube defect (NTD) pregnancies (81) were comparedto controls (247) for plasma vitamin B₁₂ (B₁₂) (ng/l), plasmafolate (µg/1), and red cell folate (RCF) (µg/l).Median values were significantly different and were, respectively,243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269and 338 (p < 0.001). There was a significant correlationbetween plasma B₁₂ and RCF in cases (r = 0.31, p = 0.004) butnot in controls (r = 0.02, p = 0.725). In cases only, multipleregression showed that both plasma B₁₂ and plasma folate influencedthe maternal RCF (multiple r = 0.68, p < 0.001). Plasma folateand plasma B₁₂ were independent risk factors for NTDs, suggestingthat the enzyme methionine synthase is involved directly orindirectly in the aetiology. The levels of folate and B₁₂ whereincreased risk occurred were not those usually associated withdeficiency, calling for a re-evaluation of their recommendeddaily allowances. Whether the aetiology is purely nutritionalor a metabolic defect, this study suggests that considerationshould be given to including B₁₂ as well as folic acid in anyprogramme of supplementation or food fortification to preventNTDs.