Intravenous prostacyclin (PGI2) infusion to 108 patients with ischaemic peripheral vascular disease: phase II-open study.

We recently reported the results of a double-blind trial of PGI2 in 108 patients with ischaemic peripheral vascular disease Stage II according to Fontaine. They were randomly allocated to receive an intravenous infusion of either PGI2 (6 ng/kg/min over 8 hours daily for 5 consecutive days) or placebo and classified as treatment responders or non-responders on the basis of changes in absolute and relative walking times. Patients treated with placebo and those who did not improve in this double blind trial entered an open trial in which they all received infusion of PGI2 (6 ng/kg/min over 8 hours daily for 5 consecutive days). The results of this open trial are reported here. Patients who had been allocated to PGI2 in the blind trial had significantly (p less than 0.01) longer walking times as compared to placebo-treated patients prior to receiving the second (PGI2) infusion. PGI2-infusion caused significant (p less than 0.01) prolongation of walking times in both groups up to the 2nd follow-up month. One month after infusion 52% (23 patients) of the initially placebo-treated patients and 31% (14 patients) of the initially PGI2-treated patients were scored as positive treatment responders (p less than 0.01).     

Intraluteal infusions of prostaglandins of the E, D, I, and A series prevent PGF2 alpha-induced, but not spontaneous, luteal regression in rhesus monkeys

A luteotropic role for prostaglandins (PGs) during the luteal phase of the menstrual cycle of rhesus monkeys was suggested by the observation that intraluteal infusion of a PG synthesis inhibitor caused premature luteolysis. This study was designed to identify PGs that promote luteal function in primates. First, the effects of various PGs on progesterone (P) production by macaque luteal cells were examined in vitro. Collagenase-dispersed luteal cells from midluteal phase of the menstrual cycle (Day 6-7 after the estimated surge of LH, n = 3) were incubated with 0-5,000 ng/ml PGE2, PGD, 6 beta PGI1 (a stable analogue of PGI2), PGA2, or PGF2 alpha alone or with hCG (100 ng/ml). PGE2, PGD2, and 6 beta PGI1 alone stimulated (p less than 0.05) P production to a similar extent (2- to 3-fold over basal) as hCG alone, whereas PGA2 and PGF2 alpha alone had no effect on P production. Stimulation (p less than 0.05) of P synthesis by PGE2, PGD2, and 6 beta PGI1 in combination with hCG was similar to that of hCG alone. Whereas PGA2 inhibited gonadotropin-induced P production (p less than 0.05), that in the presence of PGF2 alpha plus hCG tended (p = 0.05) to remain elevated. Second, the effects of various PGs on P production during chronic infusion into the CL were studied in vivo. Saline with or without 0.1% BSA (n = 12), PGE2 (300 ng/h; n = 4), PGD2 (300 ng/h; n = 4), 6 beta PGI1 (500 ng/h; n = 3), PGA2 (300 ng/h; n = 4), or PGF2 alpha (10 ng/h; n = 8) was infused via osmotic minipump beginning at midluteal phase (Days 5-8 after the estimated LH surge) until menses. In addition, the same dose of PGE, PGD, PGI, or PGA was infused in combination with PGF2 alpha (n = 3-4/group) for 7 days. P levels over 5 days preceding treatment were not different among groups. In 5 of 8 monkeys receiving PGF2 alpha alone, P declined to less than 0.5 ng/ml within 72 h after initiation of infusion and was lower (p less than 0.05) than controls. The length of the luteal phase in PGF2 alpha-infused monkeys was shortened (12.3 +/- 0.9 days; mean +/- SEM, n = 8; p less than 0.05) compared to controls (15.8 +/- 0.5). Intraluteal infusion of PGE, PGD, PGI, or PGA alone did not affect patterns of circulating P or luteal phase length.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of taprostene, a chemically stable prostacyclin analogue, in patients with ischaemic peripheral vascular disease: a placebo controlled double-blind trial

Thirty patients with ischaemic peripheral vascular disease and intermittent claudication were randomly allocated to receive either placebo or taprostene, a chemically stable prostacyclin analogue, intravenously at a rate of 25 ng/kg/min for 6 hours daily on 5 consecutive days. Taprostene produced a significant (p less than 0.05) increase in absolute walking time compared to placebo on one day after infusion and at 1, 4 and 8 weeks (14% vs 2.8%) later. Taprostene also produced a significant (p less than 0.05) increase in the pain-free walking time compared to placebo in the follow-up period (8 weeks after infusion: 23% vs 3.8%). During the infusion period systolic and diastolic blood pressure decreased (p less than 0.05) and heart rate was accelerated (p less than 0.05) in the taprostene treated group whereas no change was monitored in the placebo group. The ankle/brachial Doppler index was unaffected by taprostene. The platelet half-life was significantly (p less than 0.05) prolonged following taprostene-infusion (72.6 +/- 9.35 vs 77.9 +/- 7.44 hours). However, no change on platelet half-life was found in the placebo group (p less than 0.05). Various measures of platelet function parameters followed in vitro (ADP-induced aggregation, platelet sensitivity to PGI2, PGE1, PGD1 and taprostene, concentrations of platelet factor 4 and beta-thromboglobulin) showed no change with taprostene. Measures of circulating platelet aggregates and endothelial cells count showed no changes during the 2 months follow-up period too. It is assumed that taprostene may be of clinical benefit in patients with ischaemic peripheral vascular disease. However, future investigations have to be carried out to assess the optimal dose regime.     

Plasma theophylline concentrations,six minute walking distances,and breathlessness in patients with chronic airflow obstruction.

Twenty patients with chronic bronchitis were given incremental dosages of a new slow release preparation of theophylline and observed for its effect on lung function and exercise tolerance. Measurements were made subjectively by using visual analogue scales and objectively using six minute walking distances and spirometry. The study was placebo controlled and had a double blind randomised design. In the dosages used (200, 400, 600, and 800 mg) theophylline produced no significant improvement in forced expiratory volume in one second or forced vital capacity, and there was no overall improvement in peak expiratory flow rate. Similarly, neither effort tolerance nor degree of breathlessness appeared to be influenced by the drug, even when unacceptably high dosages were used. By contrast, placebo yielded a 7% increase in the six minute walking distance. From these results it seems difficult to justify the routine, indiscriminate use of theophylline for chronic bronchitis.     

A double blind placebo controlled trial of intravenous prostacyclin (PGI2) in 108 patients with ischaemic peripheral vascular disease

108 patients with ischemic peripheral vascular disease were randomly allocated to receive infusion of either PGI2 (6 ng/kg/min over 8 hours daily for 5 consecutive days) or placebo in a double-blind manner. All patients had Stage II disease (Fontaine classification). One month after infusion the absolute and relative walking times were significantly (p less than 0.05) longer in the PGI2- than in the placebo-treated group. Patients were further classified as treatment responders or non-responders on the basis of increase of absolute and relative walking times. After one month 44% (24 out of 54) of the PGI2- and 15% (8 out of 54) of the placebo-treated patients were positive treatment-responders (p less than 0.01).     

Controlled trial of azathioprine in chronic ulcerative colitis.

A double-blind controlled trial of azathioprine in a dose of 2-2.5 mg/kg body weight over six months was conducted among 44 patients with active chronic ulcerative colitis. Three patients treated with placebo did not complete the trial because their disease became so severe that colectomy was performed. Among patients who completed the trial the mean dose of prednisolone necessary to control the disease decreased in those treated with azathioprine and those treated with placebo; the reduction was greater among those who took azathioprine (p less than 0.001). Activity of the disease apparently improved in both treatment groups but a significant (p less than 0.001) trend was observed only in those patients treated with azathioprine. No serious side effects from azathioprine occurred during the trial but seven of 24 patients had to stop the drug because of nausea. Azathioprine may have a role in the treatment of a few patients wih troublesome chronic colitis for whom conventional drug treatment is ineffectual, or for whom continuous systemic corticosteroid treatment is needed to control symptoms, and for whom surgical treatment is inappropriate.     

The prostacyclin analogue beraprost sodium prevents development of arterial stiffness in elderly patients with cerebral infarction

Prostacyclin (PGI(2)) inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. Arterial stiffness assessed by pulse wave velocity (PWV) predicts mortality in various cardiovascular diseases. To study the preventive effects of a prostacyclin analogue, beraprost sodium, on arterial PWV values in elderly patients with cerebral infarction. Forty-four patients with a history of cerebral infarction received beraprost sodium (120 microg/day p.o.) or no beraprost sodium (control) for 3 months. Arterial PWV and ankle brachial indices (ABI) were determined prior to starting the medication and after 3 months of medication. Initially, there were no differences in age, blood pressure, and body mass index. Further, PWV or ABI did not differ between the beraprost sodium group (n = 22) and the control group (n = 22). After 3 months, PWV in beraprost sodium group was significantly reduced (-123 +/- 282) when compared with the control group (147 +/- 274)(P = 0.006). ABI was not significantly different when comparing the two groups at 3 months. Long-term administration of beraprost sodium prevents the decline in arterial biomechanics in elderly patients with cerebral infarction.     

Effects of an analogue of thyrotrophin-releasing hormone, RX77368, on infarct size and cerebral blood flow in focal cerebral ischaemia in the rat

Effects of a stable analogue of thyrotrophin-releasing hormone, RX77368, on cerebral blood flow and infarct size have been studied in an acute model of cerebral ischaemia in the rat. Two hours after electrocoagulation of the left middle cerebral artery (MCA), the mean area of ischaemia (+/- SEM), determined histochemically, was 11.5 +/- 2.2% of a single hemisphere and blood flow, determined using radiolabelled microspheres, was reduced by 40% in the left forebrain (p less than 0.001 compared with sham-operated animals). Administration of RX77368 (50 micrograms/kg, intracerebroventricularly) within 10 min of arterial occlusion caused a significant (p less than 0.01) reduction in mean lesion size to 3.7 +/- 1.8% and stimulation of blood flow to the left ischaemic forebrain (60% above saline treated). Peripheral administration of RX77368 (1 mg/kg intraperitoneally) also significantly stimulated blood flow to the ischaemic forebrain and caused an apparent decrease in frequency of large infarcted areas of brain tissue, although mean lesion size was not significantly affected. These findings indicate that RX77368 ameliorates tissue damage in acute focal cerebral ischaemia. Such effects may be related to stimulation of cerebral blood flow.     

大动脉粥样硬化性脑梗死合并SCH患者甲状腺激素与血脂、BDNF及Hcy的关系研究

摘要 目的：探讨大动脉粥样硬化性脑梗死合并亚临床甲状腺功能减退(SCH)患者甲状腺激素与血脂、脑源性神经营养因子(BDNF)以及血清同型半胱氨酸(Hcy)的关系。方法：选取2017年8月~2019年8月期间本院收治的单纯大动脉粥样硬化性脑梗死患者278例纳入脑梗死组,大动脉粥样硬化性脑梗死合并SCH患者122例纳入合并组,另选同期在我院进行体检的健康受试者40例为对照组。检测并对比三组受试者的甲状腺激素、血脂指标、BDNF、Hcy水平,并对大动脉粥样硬化性脑梗死合并SCH患者甲状腺激素与血脂、BDNF、Hcy的相关性进行分析。结果：脑梗死组、合并组患者的促甲状腺激素(TSH)水平均高于对照组,且合并组高于脑梗死组(P<0.05)。脑梗死组、合并组患者的甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL-C)水平均高于对照组,且合并组高于脑梗死组(P<0.05)。脑梗死组、合并组BDNF水平低于对照组,Hcy水平高于对照组,且合并组BDNF水平低于脑梗死组,Hcy水平高于脑梗死组 (P<0.05)。经Pearson相关性分析,大动脉粥样硬化性脑梗死合并SCH患者的TSH水平与TG、TC、LDL-C、Hcy呈正相关性,与BDNF呈负相关性(P<0.05)。结论：脑梗死合并SCH患者甲状腺激素水平与患者的血脂水平、BDNF、Hcy有一定的相关性,初步推测SCH通过影响机体的脂质代谢、升高Hcy水平、降低BDNF水平等途径,加重患者的脑梗死程度。     

Olsalazine in active ulcerative colitis.

Olsalazine (azodisalicylate) is a new drug in which two molecules of 5-aminosalicylic acid are linked by an azo bond. Its role in the treatment of mildly active, distal ulcerative colitis was investigated. Sixty patients were randomly allocated to receive olsalazine 1 g or a placebo as a retention enema nightly for two weeks. Clinical improvement was seen in 19 (66%) and sigmoidoscopic improvement in 17 (59%) of the 29 patients receiving olsalazine compared with 12 (43%) and 11 (39%), respectively, of the 28 in the control group. These differences were not significant. In a second trial 40 patients were randomised to receive oral olsalazine 2 g daily or a placebo capsule for two weeks. Significant clinical and sigmoidoscopic improvement was seen in the patients receiving oral olsalazine compared with the patients receiving placebo capsules. Oral olsalazine may be valuable in the treatment of mildly active ulcerative colitis. Its role in maintaining remission is yet to be determined.     

Randomised controlled trial of nicotine chewing-gum.

The effectiveness of 2 mg nicotine chewing-gum as an aid to stopping smoking was compared with a placebo containing 1 mg nicotine, but unbuffered, in a double-blind randomised trial. Of 58 subjects given the active gum, 27 (47%) were not smoking at one-year follow-up compared with 12 (21%) of the 58 subjects treated with placebo (p less than 0.025). By the most stringent criterion of outcome, 18 (31%) subjects in the active treatment group and eight (14%) in the placebo group had not smoked at all from the start of treatment to follow-up at one year (p less than 0.05). Subjects receiving the active gum experienced less severe withdrawal symptoms and rated their gum as more helpful than did the placebo group. Minor side effects were common but only gastric symptoms were more frequent with the active gum. Subjects receiving active gum used it for longer than those receiving placebo but most stopped using it within six months and only four (7%) developed longer-term dependence. The number of gums used daily correlated significantly with pretreatment blood nicotine concentrations in the active treatment group and with pretreatment cigarette consumption in the placebo group. A lower pretreatment blood nicotine value was the best predictor of success at one year (p less than 0.001) but there was no significant relation to cigarette consumption, sex, and social class. The results clearly confirm the usefulness of nicotine chewing-gum as an aid to stopping smoking and imply a definite role for nicotine in cigarette dependence and withdrawal. Successful use of the gum requires careful attention to subjects'' expectations and clear instructions on how to use it.     

Nifedipine in hypertensive emergencies.

The effects and safety of using oral nifedipine 10-20 mg as acute antihypertensive treatment were studied in a single-blind placebo-controlled study of 25 consecutive patients with very high blood pressure requiring emergency reduction. In addition the effect of this treatment on cerebral blood flow was investigated using xenon-133 in 10 patients randomly allocated to receive oral nifedipine or intravenous clonidine. Whereas placebo did not alter the blood pressure, oral nifedipine significantly reduced the systolic and diastolic blood pressures in all 25 patients (from 221 +/- 22/126 +/- 14 mm Hg to 152 +/- 20/89 +/- 12 mm Hg after 30 minutes, p less than 0.001). Heart rate increased from 74 +/- 11 to 84 +/- 11 beats/minute (p less than 0.01); this effect was inversely related to age (r = -0.65, p less than 0.01). The falls in systolic and diastolic blood pressures were closely related to the blood pressures before treatment ) r = 0.67, p less than 0.001 for systolic, and r = -0.58, p less than 0.01 for diastolic values). No serious unwanted effects were observed. Measurement of cerebral blood flow after nifedipine showed an increase in flow in four out of five patients. Clonidine, by contrast, reduced cerebral blood flow in all patients by up to 28%. Nifedipine is a simple, effective, and safe alternative drug for managing hypertensive emergencies, especially when continuous monitoring of the patient cannot be guaranteed.     

TULIP study: Trail of Lurasidone in bipolar disorder in Pakistan

BackgroundThis study examined usefulness and efficiency of Lurasidone in appraisal with the placebo as for the treatment of Bipolar Disorders.MethodsSeven treatment centers in Pakistan were selected for the purpose of starting a six week-long control trial (randomized and double-blind placebo). 76 subjects, already diagnosed with Bipolar I or II based on DSM 5 diagnosis, were selected after randomization. Patients were allocated in one of the two groups. Primary efficacy of the drug was measured using Young Mania Rating Scale. Positive response of the drug was defined as 50% reduction in symptoms from the baseline/13 point less than the baseline score on Young Mania Rating Scale. Efficacy and safety of the drug was assessed using variety of markers such as administering extra-pyramidal symptoms rating scale, adverse side effects reported, electrocardiograms, body weight, vital signs changes, and laboratory investigations.ResultsPatients treated with Lurasidone showed enhanced improvement in their overall health and symptoms manifestation in comparison to patients who were given placebo. Lurasidone treated patients showed a better response to the drug (66%), in comparison with the placebo treated patients (42%).LimitationsStudy was conducted on small scale due to complexity.ConclusionPatients treated with Lurasidone showed reduction in bipolar symptoms and tolerate the drug well.     

Beneficial effect of beraprost sodium plus telmisartan in the prevention of arterial stiffness development in elderly patients with hypertension and cerebral infarction

Beraprost sodium (BPS, an analogue of prostacyclin) and telmisartan (TS, an angiotensin receptor blocker) have been reported to have a preventive effect on arterial stiffness in patients with cardiovascular diseases. The purpose of this study was to estimate the effects of a combined therapy using BPS and TS on arterial pulse wave velocity (PWV) values in elderly patients with hypertension and cerebral infarction. Over a 3-month period, 80 subjects with hypertension and histories of cerebral infarction received BPS only (120 microg/day p.o.), TS only (40 mg/day p.o.), both BPS and TS, or no medication at all (control). Arterial PWV and ankle brachial indices (ABI) were determined prior to and after 3 months of drug administration. During the follow-up, there were no significant changes in any of the parameters monitored with the exception of a significant decrease in systolic blood pressure in the BPS only, TS only, and BPS plus TS groups when compared to controls. The difference values for PWV in the control group, BPS only group, TS only group, and BPS plus TS group were +232.5, -114.6, -151.5, and -248.1 cm/s, respectively. The reduction values were significantly more pronounced in the BPS plus TS group than in the BPS only (P=0.037) and the TS only (P=0.022) groups. When BPS is combined with TS, an overall additive effect is seen in the improvement of PWV in Japanese patients with hypertension and cerebral infarction. This combination therapy is more beneficial than the corresponding monotherapies.     

Beneficial actions of prostacyclin in traumatic shock.

Prostacyclin (PGI2) infused at a rate of 350 ng/kg/min significantly increased survival time in rats subjected to Noble-Collip drug trauma from 2.7 +/- 0.3 to 4.6 +/- 0.2 h (p less than 0.01) compared with traumatized rats given only the vehicle (Tris buffer). Moreover, PGI2 treated rats exhibited significantly lower circulating cathepsin D and myocardial depressant factor (MDF) activities, indicative of lower lysosomal disruption and lower toxic factor formation. PGI2 induced vasodilation in rats as well as these other protective effects.     

Characterization of prostaglandin (PG)-binding sites expressed on human basophils. Evidence for a prostaglandin E1, I2, and a D2 receptor.

Recent data suggest that prostaglandins (PGs) are involved in the regulation of basophil activation. The aim of this study was to characterize the basophil PG-binding sites by means of radioreceptor assays using 3H-labeled PGs. Scatchard analysis for pure (greater than 95%) chronic myeloid leukemia (CML) basophils revealed two classes of PGE1-binding sites differing in their affinity for the natural ligand (Bmax1 = 217 +/- 65 fmol/10(8) cells; Kd1 = 0.5 +/- 0.2 nM; Bmax2 = 2462 +/- 381 fmol/10(8) cells; Kd2 = 47 +/- 20 nM; IC50 = PGE1 less than PGI2 less than PGD2 less than PGE2 less than PGF2 alpha) as well as two classes of PGI2 (iloprost)-binding sites (Bmax1 = 324 +/- 145 fmol/10(8) cells; Kd1 = 0.5 +/- 0.3 nM; Bmax2 = 2541 +/- 381; Kd2 = 27 +/- 6 nM; IC50 = PGI2 less than PGE1 less than PGD2 less than PGE2 less than PGF2 alpha. In addition, CML basophils exhibited a single class of PGD2-binding sites (Bmax = 378 +/- 98 fmol/10(8) cells; Kd = 13 +/- 4 nM; IC50: PGD2 less than PGI2 less than PGE1 less than PGE2 less than PGF2 alpha). In contrast, we were unable to detect specific saturable PGE2-binding sites. Primary and immortalized (KU812) CML basophils revealed an identical pattern of PG receptor expression. Basophils (KU812) expressed significantly (p less than 0.001) lower number of PGE1 (PGI2)-binding sites (Bmax1: 9% (20%) of control; Bmax2: 36% (50%) of control) when cultured with recombinant interleukin 3 (rhIL-3), a basophil-activating cytokine, whereas rhIL-2 had no effect on PG receptor expression. Functional significance of binding of PGs to basophils was provided by the demonstration of a dose-dependent increase in cellular cAMP upon agonist activation, with PGE1 (ED50 = 1.7 +/- 1.1 nM) and PGI2 (ED50 = 2.8 +/- 2.3 nM) being the most potent compounds. These findings suggest that human basophils express specific receptors for PGE1, PGI2 as well as for PGD2.     

Acute and chronic effects of oral enprostil, a synthetic dehydroprostaglandin E2, on uterine contractility

In acute experiments eleven nonpregnant women received a single oral dose of enprostil (prostaglandin E2 analogue) 35-140 mcg. Uterine activity was measured by a microtransducer-tipped Millar catheter. A single, oral dose of enprostil caused a long-lasting contracture response of the uterus. 3 h after enprostil, uterine resting pressure (RP) was still high. In chronic experiments, eleven women with regular menstrual cycles received 35 mcg or 70 mcg BID enprostil and placebo in a crossover, double-blind fashion from cycle day 10 +/- 3 for four weeks, then had a washout period of four weeks followed by another four-week treatment period. An increase of uterine RP after enprostil was dose-dependent. After two weeks of twice-daily administration of enprostil, the baseline RP was lower than after placebo (p less than 0.01) and the increase in RP after the morning enprostil less than that seen on the first day. In eight patients studied, the mean values of plasma progesterone were normal, both during placebo--and enprostil--treated cycles.     

Effects of pseudoephedrine and triprolidine,alone and in combination,on symptoms of the common cold.

A total of 466 healthy adults from four different regions of England entered a double-blind, randomised trial to test the effectiveness of an antihistamine (triprolidine) and a decongestant (pseudoephedrine), alone or in combination, in relieving symptoms of the common cold. During the study 199 subjects reported a total of 243 colds. Subjects recorded the severity of 12 symptoms during treatment and noted separately the severity of a further seven symptoms that represented unwanted effects of treatment or served as an index of suggestibility. They were then asked about their overall improvement in symptoms during treatment and whether they thought they had taken placebo. Sneezing, nasal obstruction, and overall response to treatment were significantly improved (p <0.01) with psuedoephedrine or pseudoephedrine and triprolidine compared with placebo.     

Campylobacter pyloridis and associated gastritis: investigator blind,placebo controlled trial of bismuth salicylate and erythromycin ethylsuccinate.

An investigator blind trial was performed comparing bismuth salicylate, erythromycin ethylsuccinate, and placebo in the treatment of Campylobacter pyloridis associated gastritis in patients without peptic ulceration. Fifty patients fulfilled the study criteria. There was a strong correlation between the presence of C pyloridis and histologically confirmed gastritis. Clearance of organisms led to improvement of the gastritis. C pyloridis was cleared from 15 patients; of these, 13 had gastritis initially, which resolved in 12. Conversely, gastritis resolved in only four of 32 patients not cleared of organisms (p less than 0.0001). There was significantly greater improvement in endoscopic appearances in the patients cleared of C pyloridis compared with those whose infection persisted (p less than 0.001). In the three treatment groups organisms were cleared from 14 of 18 patients receiving the locally active bismuth salicylate, only one of 15 patients receiving erythromycin ethylsuccinate, and none of 17 patients taking placebo. These findings suggest that the ideal antimicrobial for the successful eradication of C pyloridis associated gastritis should be locally active, stable at low pH, and should penetrate gastric mucus. The resolution of gastritis and improvement in endoscopic appearances associated with clearance of C pyloridis support the view that these organisms may play a part in this condition.     

Diurnal variation in incidence of stroke: Oxfordshire community stroke project.

OBJECTIVE--To determine whether diurnal variation occurs in the onset of stroke. DESIGN--Community based study over four years. SETTING--Oxfordshire, United Kingdom. SUBJECTS--105,000 people, of whom 675 had a first ever stroke. 545 had a cerebral infarction, 66 had primary intracerebral haemorrhage, 33 had subarachnoid haemorrhage, and in 31 the type of stroke was not known. MAIN OUTCOME MEASURES--Time of stroke and degree of activity at onset. RESULTS--In the 578 patients for whom it was known whether onset occurred while asleep or awake, the proportion with onset during sleep was 25% (135/545) for cerebral infarction, 17% (11/66) for primary intracerebral haemorrhage, and 0% (0/33) for subarachnoid haemorrhage. This difference persisted if patients in whom it was not known whether they were asleep or awake at onset were classed as asleep. For all stroke types together there was a significant (chi 2 = 218.7, p less than 0.001) diurnal variation with a morning peak between 0800 and 1000, which persisted even after allowing for strokes first noted on waking by redistributing the hour of onset through the preceding eight hours (chi 2 = 47, p less than 0.001). A significant diurnal variation was also found in the onset of cerebral infarction (peak 0800-1000, chi 2 = 208.4, p less than 0.001). Fewer patients had other forms of stroke and the diurnal variations for primary intracerebral haemorrhage (peak 1000-1200) and subarachnoid haemorrhage (peaks 0800-1000 and 1800-2000) were not significant. There seemed to be a second smaller peak for all types of stroke. CONCLUSIONS--All types of stroke are most likely to occur after waking in the morning. The cause of the circadian variation requires further study.