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LE Magazine May 2001


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Stroke/Cardiovascular Disease

Incidence of silent stroke in the United States.

Background: Recent estimates of stroke incidence in the US range from 715,000 to 750,000 annually. These estimates, however, do not reflect silent infarcts and hemorrhages. Since population-based studies have found that prevalence of silent stroke is 10 to 20 times that of symptomatic, estimates of stroke incidence based solely on symptomatic events may substantially underestimate the annual burden of stroke. Silent strokes contribute to vascular dementia, gait impairment and other major adverse patient outcomes. Methods: Incidence of silent infarcts for different age strata were derived from two US population-based studies of the prevalence of silent infarct-like lesions on MRI, Atherosclerosis Risk In Communities and Cardiovascular Health Study. Prevalence observations in these studies and age-specific death rates from the US Census Bureau were inputted to calculate silent infarct incidence (method of Leske et al). Similarly, incidence rates of silent hemorrhage at differing ages were extrapolated from population-based prevalence observations employing MR GRE imaging in the Austrian Stroke Prevention Study. Age-specific incidence rates were projected onto age cohorts in the 1998 US population to calculate annual burden of silent stroke. Results: Derived incidence rates per 100,000 of silent infarct ranged from 6400 in the age 50 to 59 strata to 16400 at ages 75 to 79. Extrapolated incidence rates of silent hemorrhage ranged from 230 in the age 30 to 39 strata to 7360 at ages > 80. Incidence rates of both subclinical infarcts and hemorrhage increased exponentially with age. Overall estimated annual US occurrence of silent infarct was 9,039,000, and of silent hemorrhage 2,130,000. Conclusion: In 1998, nearly 12 million strokes occurred in the United States, of which 750,000 were symptomatic and over 11 million were subclinical. Among the silent strokes, 81% were infarcts and 19% hemorrhages. These findings demonstrate that the annual burden of stroke is substantially higher than suggested by estimates based solely on clinically manifest events, and suggest that greater research and clinical resources should be allocated to stroke prevention and treatment.

Stroke. 2000;32:363-b

Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.

BACKGROUND: C-reactive protein (CRP) predicts risk of myocardial infarction (MI) and stroke among apparently healthy men, but in women, virtually no data are available. METHODS AND RESULTS: CRP was measured in baseline blood samples from 122 apparently healthy participants in the Women's Health Study who subsequently suffered a first cardiovascular event and from 244 age-and smoking-matched control subjects who remained free of cardiovascular disease during a three year follow-up period. Women who developed cardiovascular events had higher baseline CRP levels than control subjects (P=0.0001), such that those with the highest levels at baseline had a five-fold increase in risk of any vascular event (RR=4.8; 95% CI, 2.3 to 10.1; P=0.0001) and a seven-fold increase in risk of MI or stroke (RR=7.3; 95% CI, 2.7 to 19.9; P=0.0001). Risk estimates were independent of other risk factors, and prediction models that included CRP provided a better method to predict risk than models that excluded CRP (all P values <0.01). In stratified analyses, CRP was a predictor among subgroups of women with low as well as high risk as defined by other cardiovascular risk factors. CONCLUSIONS: In these prospective data among women, CRP is a strong independent risk factor for cardiovascular disease that adds to the predictive value of risk models based on usual factors alone.

Circulation 1998 Aug 25;98(8):731-3

Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke.

BACKGROUND AND PURPOSE: The prognostic influences of fibrinogen and C-reactive protein (CRP) levels and their relations in ischemic stroke have not been well described. The aim of this study was to investigate and compare the one year prognostic influences of fibrinogen and CRP levels on outcome in ischemic stroke. METHODS: Fibrinogen and CRP were determined within 24 hours after stroke and related to one year outcome in 128 patients with first-ever ischemic stroke. The Kaplan-Meier technique was applied in survival analysis. Multiple logistic regression analysis was used to evaluate the associations between risk factors and outcome. RESULTS: The probabilities of death or new vascular event were 21.1%, 27.9%, and 51.7% (P:=0.0172, chi(2) for trend), respectively, in patients stratified by tertiles of fibrinogen (<3.78, 3.78 to 6.17, and >6.17 g/L). The probabilities of a primary end point were 12.1%, 29.7%, and 54.8% (P:=0.0004), respectively, after stratification of patient data by tertiles of CRP level (<5, 5 to 33, and >33 mg/L). In multiple logistic regression analysis, higher CRP levels (odds ratio, 2.39; 95% CI, 1.28 to 4.49; P:=0.0066) and stroke severity on the Canadian Neurological Stroke Scale (odds ratio, 2.37; 95% CI, 1.01 to 5.58; P:=0.0472) were independently associated with death or new vascular event. CONCLUSIONS: Increased levels of CRP are associated with a worse outcome in patients with ischemic stroke. The increased risk associated with elevated CRP levels is independent of the prognostic influence of fibrinogen.

Stroke 2001 Jan;32(1):133-8

Dilatation of common carotid artery is strongly associated with cerebral ischemic stroke with or without the presence of carotid atherosclerosis.

Background: Dilatation of common carotid artery (CCA) was related to age, sex and body height in population studies. It was also considered a compensatory mechanism to carotid atherosclerotic stenosis. The present study examined the risk of CCA dilatation associated with ischemic stroke (IS) and its relations to carotid atherosclerosis, hypertension, hyperglycemia, fibrinogen, cholesterol, HDL-cholesterol (HDL-C), smoking and alcohol consumption. Methods: A case-control study was carried on 251 first-ever IS patients (age 40) excluding previous history of myocardial infarction and cancer and 242 non-stroke outpatients. Intraluminal diameter of middle portion of CCA, and plaque thickness in CCA, bulb, internal and external carotid arteries were measured. Information on hypertension and diabetes status and data of life-styles such as smoking and alcohol consumption were collected. Levels of fibrinogen, factor VIIIc, cholesterol, HDL-C and glucose were obtained. Results: CCA dilatation was a strong factor for IS (OR=4.13, P=0.0001). It was also associated with hypertension, hyperglycemia, smoking, alcohol consumption, low HDL-C, and high levels of fibrinogen, factor VIIIc, cholesterol and plaque score. The association remained significant with or without each of the following conditions: hypertension (p=0.0001, p=0.0007), hyperglycemia (p=0.0446, p=0.0001), elevated fibrinogen (p=0.0104, p=0.0001) or factor VIIIc (p=0.2458, p=0.0001), hypercholesterolemia (p=0.0238, p=0.0001), decreased HDL-C (p=0.0012, p=0.0001) and presence of plaque score (p=0.0263, p=0.0003). Adjusting above risk factors, odds ratios of elevated diameter could associated with IS, before (OR=2.21, P=0.0066) and after (OR=6.63, p=0.0055) excluding subjects with plaque. Conclusion: Dilatation of CCA is a strong risk factor for IS. The fact the association remained significant without ultrasonic evidence of carotid plaque indicates that IS in Chinese involved a mechanism of active vasculopathy, not just a passive compensatory process to extracranial atherosclerosis.

Stroke. 2000;32:365-d

Predictors of progression in lacunar stroke.

Objective: To identify predictors of deterioration in patients with lacunar syndromes. Methods: We prospectively evaluated 46 consecutive patients (12 women, 34 men; age 64.5 ± 13.7 yrs. [ mean ± SD ] ) with acute lacunar stroke by daily clinical neurological examination including NIHSS and follow-up using the Barthel Index after three months. In addition, we determined parameters of inflammation ( C-reactive protein, leukocytes, body temperature), coagulation (d-dimers, fibrinogen, PTT, vWF ), glutamate, as well as blood glucose and blood pressure. Progressive neurological deficit was defined as worsening of the NIHSS by one point in one singular item. Results: Eleven patients (23.9 % ) showed a clinical progression of stroke symptoms, 35 patients remained stable or improved. The NIHSS on admission was similar in both groups (4.2 ±2.7 vs. 3.8 ±2.2), but significantly higher in progressive patients on day two (5.4 ±3.5 vs. 2.6 ±2.0; p=0.02) and at discharge (3.7 ±3.3 vs. 1.6 ±1.7; p=0.046). Nine of the 11 progressive patients showed deterioration in the first 24 hours after admission. Barthel Index after 90 days was significantly lower in the progressive patients (87 ±18 vs. 95 ±19; p=0.005). Clinical progression was significantly associated with elevated body temperature (p=0.031 ), fibrinogen ( p=0.048 ) and a higher leucocyte count ( p=0.017 ) on admission. Mean blood glucose and blood pressure were also higher in progressive patients, but this difference did not reach the level of significance. There was no significant correlation for the other coagulation parameters, glutamate level on admission, risk factors, age and gender. Conclusions: In lacunar stroke there is a high rate (= 23.9 % ) of neurological worsening, and the long-term prognosis of progressive patients is worse compared to non-progressive patients. Progression usually occurs within 24 hours and may be related to an acute-phase response.

Stroke. 2000;32:347-c


Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment.

The objective of the present study was to assess the toxicology of melatonin (10 mg), administered for 28 days to 40 volunteers randomly assigned to groups receiving either melatonin (N = 30) or placebo (N = 10) in a double-blind fashion. The following measurements were performed: polysomnography (PSG), laboratory examinations, including complete blood count, urinalysis, sodium, potassium and calcium levels, total protein levels, albumin, blood glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), urea, creatinine, uric acid, glutamic-oxalacetic transaminase (GOT), glutamic-pyruvate transaminase (GPT), bilirubin, alkaline phosphatase, gama-glutamic transaminase (GGT), T3, T4, TSH, LH/FSH, cortisol and melatonin serum concentrations. In addition, the Epworth Somnolence Scale (ESS) and a sleep diary (SD) were also applied to the volunteers one week before each PSG. In addition, the volunteers were asked about possible side effects (SE) that appeared during the treatment. The study was carried out according to the following timetable: Visit 0, filling out the term of consent and inclusion criteria; Visit 1, PSG, laboratory examinations, ESS, SD, melatonin serum concentrations; Visit 2, SD, melatonin serum concentrations, SE; Visit 3, melatonin serum concentrations, PSG, ESS, SE; Visit 4, laboratory examinations, SE, melatonin serum concentrations, SD; and Visit 5, PSG, ESS, SE. Analysis of the PSG showed a statistically significant reduction of stage 1 of sleep in the melatonin group. No other differences between the placebo and melatonin groups were obtained. In the present study we did not observe, according to the parameters analyzed, any toxicological effect that might compromise the use of melatonin at a dose of 10 mg for the period of time utilized in this study.

J Pineal Res 2000 Nov;29(4):193-200

Effect of sustained nocturnal transbuccal melatonin administration on sleep and temperature in elderly insomniacs.

Previous research has suggested a role for the pineal hormone melatonin in the control of the body's sleep-wake and thermoregulatory systems. In the elderly population, there have been reports of decreased nighttime secretion of melatonin and suggestions that this may, in turn, be responsible for the increased incidence of sleep disorders reported by this age group. On this basis, it has been suggested that augmented nocturnal melatonin levels may improve sleep quality in age-related sleep disorders. Following screening assessments, 12 elderly (> 55 years) subjects with sleep maintenance insomnia were treated with either 0.5 mg transbuccal melatonin or a placebo for two sessions of four consecutive nights, at least three days apart. Subjects self-selected lights-out times, and sleep was assessed using standard polysomnographic (PSG) measures. Body temperature was measured continually from 2100 to 0700 hour, and sleep quality was assessed from PSG variables measured. Nightly urine samples were assayed for the melatonin metabolite 6-sulfatoxy-melatonin (aMT.6S). Compared to the placebo, transbuccal melatonin administration significantly increased mean nocturnal aMT.6S excretion (mean +/- SEM: 194.2 +/- 16.5 vs. 42.5 +/- 7.7 nmol). In addition, there was a significant reduction in core body temperature relative to the placebo condition (p < .05). However, sustained transbuccal melatonin treatment had no positive significant effect on any PSG measure of sleep quality. The results from the present study suggest that sustained nocturnal administration of melatonin, in the low pharmacological range, might be of limited clinical benefit in this subject population.

J Biol Rhythms 1998 Dec;13(6):532-8

Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag.

To compare the impact of various dosage forms of melatonin and placebo on jet lag symptoms, 320 volunteers who had flights over 6 to 8 time zones were recruited for a double-blind, randomized, placebo-controlled study. The volunteers received either melatonin 0.5-mg fast-release (FR) formulation, melatonin 5-mg FR formulation, melatonin 2-mg controlled-release (CR) formulation, or placebo. The study medication was taken once daily at bedtime during four days after an eastward flight. The volunteers completed the Profile of Mood States (POMS), sleep log, and symptoms questionnaires once daily and the Karolinska Sleepiness Scale (KSS) three times daily prior to departure and during the 4 days of medication intake postflight. A total of 234 (73.1%) participants were compliant and completed the study. The FR melatonin formulations were more effective than the slow-release formulation. The 5-mg FR formulation significantly improved the self-rated sleep quality (p < .05), shortened sleep latency (p < .05), and reduced fatigue and daytime sleepiness (p < .05) after intercontinental flight. The lower physiological dose of 0.5 mg was almost as effective as the pharmacological dose of 5.0 mg. Only the hypnotic properties of melatonin, sleep quality and sleep latency, were significantly greater with the 5.0-mg dose.

Chronobiol Int 1998 Nov;15(6):655-66

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