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BACKGROUND: PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. METHODS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. RESULTS: In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0-9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). CONCLUSIONS: Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002.

Interleukin-1beta (IL-1beta) is present in multiple sclerosis (MS) lesions. Interleukin-1 receptor antagonist (IL-1Ra) moderates the induction of experimental autoimmune encephalomyelitis (EAE). Here, we show that families that are characterized by high IL-1beta over IL-1Ra production ratio are at 2.2-fold (95% CI, 1.0-4.8; p=0.05) increased risk to have a patient relative with relapse-onset MS than families with a low ratio. It is also related to the reduction of volumetric magnetization transfer ratio (MTR) histogram height, a measure of parenchymal integrity (p=0.04). Those families who combine a high IL-1beta over IL-1Ra ratio with a high tumor necrosis factor (TNF) over IL-10 production ratio have a 6.2-fold (95% CI, 1.8-21; p=0.002) increased risk. Innate production of IL-1beta and IL-1Ra is not related to the outcome of primary progressive MS. Taq1 polymorphism in the IL-1beta gene and the variable number of tandem repeats (VNTR) polymorphism of 86-base pairs within the IL-1Ra gene cannot explain these findings.

Background and Purpose: Epidemiological studies have shown an increased risk of venous thrombosis in women taking third-generation oral contraceptives, ie, those containing the progestogens desogestrel or gestodene. This study assesses the risk of ischemic stroke with several types of oral contraceptives., Methods: A multicenter, population-based, case-control study was performed in 9 Dutch centers in women aged 18 to 49 years. Women with a first ischemic stroke were compared with control women without vascular diseases. The control subjects were recruited by random-digit dialing and were stratified by age, area of residence, and year of stroke. All patients and control subjects filled in a questionnaire about the use of oral contraceptives and risk factors for ischemic stroke. Odds ratios were adjusted for the stratification factors., Results: Two hundred three women with an ischemic stroke and 925 control women were included. The risk of stroke in women using any type of oral contraceptives versus none was 2.3 (95% CI 1.6 to 3.3). Current users of first-generation oral contraceptives had an odds ratio of 1.7 (95% CI 0.7 to 4.4). Low-dose second-generation oral contraceptives increased the risk of stroke 2.4 times (95% CI 1.6 to 3.7), and third-generation oral contraceptives increased the risk of stroke 2.0 times (95% CI 1.2 to 3.5). The risk of stroke in women using third-generation oral contraceptives was not different from that in women using second-generation oral contraceptives (odds ratio 1.0, 95% CI 0.6 to 1.8)., Conclusions: Third-generation oral contraceptives (containing desogestrel or gestodene) confer the same risk of first ischemic stroke as second-generation oral contraceptives (containing levonorgestrel).

Nitric oxide (NO) plays a pivotal role in the regulation of peripheral vascular tone. Its role in the regulation of cerebral vascular tone in humans remains to be elucidated. This study investigates the role of NO in hypoxia-induced cerebral vasodilatation in young healthy volunteers. The effect of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on the cerebral blood flow (CBF) was assessed during normoxia and during hypoxia (peripheral O(2) saturation 97 and 80%, respectively). Subjects were positioned in a magnetic resonance scanner, breathing normal air (normoxia) or a N(2)-O(2) mixture (hypoxia). The CBF was measured before and after administration of L-NMMA (3 mg/kg) by use of phase-contrast magnetic resonance imaging techniques. Administration of L-NMMA during normoxia did not affect CBF. Hypoxia increased CBF from 1,049 +/- 113 to 1,209 +/- 143 ml/min (P < 0.05). After L-NMMA administration, the augmented CBF returned to baseline (1,050 +/- 161 ml/min; P < 0.05). Similarly, cerebral vascular resistance declined during hypoxia and returned to baseline after administration of L-NMMA (P < 0.05 for both). Use of phase-contrast magnetic resonance imaging shows that hypoxia-induced cerebral vasodilatation in humans is mediated by NO.

The main causes of dementia at old age are Alzheimer's disease and vascular dementia. The clinical presentations of late-onset Alzheimer's disease and vascular dementia can barely be differentiated. This clinical observation is supported by pathological findings. Late-onset dementia should be considered a multifactorial disease, in which both vascular factors and amyloid dispositions contribute to cognitive decline.

There is accumulating evidence that statins reduce stroke risk, even though total cholesterol is not a risk factor for stroke. The explanation for this discrepancy is subject to discussion. It should be realised that the beneficial effects of statins on stroke risk have only been demonstrated in a select population, i.e. middle-aged men with ischaemic heart disease. Several clinical trials are underway to examine the effects of statins on stroke risk in more characteristic groups of patients who are at increased risk of developing stroke. The results of these studies should be awaited before statins are recommended for the prevention of stroke. Recently it has been reported that statins lower the risk of developing dementia. These conclusions were drawn from two cross-sectional studies. Because of the nature of the studies, only an association between the use of statins and a lower risk of developing dementia was shown, and not a causal relationship. Experimentally-controlled studies have to be designed to investigate the effect of statins on dementia.

Background: Inflammation plays a pivotal role in amyloid plaque progression thereby contributing to Alzheimer's disease-related neurodegeneration. We hypothesized that patients with Alzheimer's disease have an innate pro-inflammatory phenotype, as compared to control subjects without dementia., Methods: Patients with a diagnosis of probable Alzheimer's disease (n=12) and control subjects without signs of dementia (n=18) were enrolled. Whole blood samples were stimulated ex vivo with endotoxin under standard conditions. Cytokine levels were assessed by ELISA and compared by Mann-Whitneyll-test after log transformation., Results: Patients with Alzheimer's disease had seven- to ten-fold higher IL-1beta production relative to the amount of IL-10 both at the low (p=0.006) and high concentration of endotoxin (p=0.007). Subjects who display a pro-inflammatory phenotype as defined by a high IL-1beta/IL-10 ratio had 13.0-fold higher odds (95% CI: 2.1-82) to have dementia., Conclusion: The data support the hypothesis that a pro-inflammatory phenotype contributes to the development of Alzheimer's disease.

Objective: To determine whether volumetric magnetization transfer imaging (MTI) histogram analysis can detect abnormalities in patients with active neuropsychiatric systemic lupus erythematosus (NPSLE) and to compare the MTI findings in patients with active NPSLE, chronic NPSLE, and multiple sclerosis (MS), as well as in normal control subjects., Methods: Eight female and 1 male patient with active nonthromboembolic NPSLE (mean +/- SD age 39 +/- 9 years), 10 female patients with chronic NPSLE (age 33 +/- 11 years), 10 female patients with SLE and no history of NPSLE (non-NPSLE; age 34 +/- 11 years), 10 female patients with inactive MS (age 41 +/- 6 years), and 10 healthy control subjects (age 33 +/- 11 years) underwent MTL. Using the MTI scans, histograms were composed from which we derived a variety of parameters that quantitatively reflect the uniformity of the brain parenchyma as well as the ratio of cerebrospinal fluid to intracranial volume, which reflects atrophy., Results: The magnetization transfer ratio (MTR) histograms in the non-NPSLE group and the healthy control group were similar, whereas those in the chronic NPSLE and MS groups were flatter. There was also flattening of the histograms in the active NPSLE group, but with a shift toward higher MTRs., Conclusion: Our results indicate that volumetric MTI analysis detects cerebral changes in the active phase of NPSLE. The abnormalities in the brain parenchyma of patients with chronic NPSLE produced MTI values that were the same as those in patients with inactive MS. MTI values in the active phase of NPSLE differed from those in the chronic phase, which might reflect the presence of inflammation. These preliminary results suggest that MTI might provide evidence for the presence of active NPSLE. MTI might also prove to be a valuable technique for monitoring treatment trials.

Both Alzheimer's disease and vascular dementia are featured by inflammatory responses and it is known that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk and severity of these diseases. To study the effect of NSAIDs on PGE2 levels and pro- and anti-inflammatory cytokine levels in the whole blood assay, blood samples from 23 elderly persons aged 85 years were stimulated with thrombin or LPS as primary stimulus. Indomethacin was added in concentrations ranging from 0.4 to 16 microg/ml and acetylsalicylic acid was added to in concentrations ranging from 0.5 to 8.0 microg/ml. Indomethacin abrogated thrombin- and LPS-induced PGE2 production at all concentrations tested. In addition, indomethacin reduced the production of thrombin-induced IL-6 and IL-10 (p<0.05) at physiological concentrations. Indomethacin reduced the production of LPS-induced IL-6, IL-1 beta and IL-10 (p<0.05) at the highest indomethacin concentration tested. Similar results were obtained upon incubation with acetylsalicylic acid. It is concluded that indomethacin may reduce the thrombin-induced inflammatory reaction by decreasing IL-6 through inhibition of PGE2 synthesis. This IL-6 reduction may be relevant for the ability of indomethacin to reduce the risk of Alzheimer's disease. However, the decrease in IL-10 production due to indomethacin suggests a more inflammatory state.

Multiple sclerosis (MS) typically presents with a relapsing-remitting onset. This can be distinguished from primary progressive MS. Typical MS is characterized by a profound inflammatory reaction in which anti-inflammatory cytokine interleukin-10 (IL-10) and pro-inflammatory cytokine tumor necrosis factor (TNF) may play a pivotal role. We tested the hypothesis that patients with MS have a distinct innate cytokine production that contributes to the susceptibility for and outcome of MS. The innate cytokine production of patients was estimated as the average production of cytokines in lipopolysaccharide -stimulated whole-blood cultures of 2 to 5 first-degree healthy family members. A total of 126 family members of 50 patients with typical MS, 61 family members of 25 patients with primary progressive MS, and 129 control subjects of 54 families were enrolled in this study. We found that members of families with low IL-10 and high TNF production had a fourfold increased risk of developing typical MS compared with members of families with high IL-10 and low TNF production. Patients with MS were eightfold more likely to develop typical MS than primary progressive MS when they belonged to families with low IL-10 and high TNF production. The presence of human leukocyte antigen-DR2 was associated with MS but not with TNF production. This study shows that typical MS is associated with an innate pro-inflammatory cytokine profile in contrast to primary progressive MS.

Stroke is a heterogeneous disorder, with the definition including both haemorrhagic and ischaemic stroke. Although these subtypes of stroke have different underlying pathophysiological mechanisms, atherosclerosis plays a pivotal role in both. Most risk factors for cardiovascular disease are also risk factors for stroke. Patients with a history of cardiovascular events are at an increased risk of stroke. Although hypercholesterolaemia is the most characteristic risk factor for atherosclerotic diseases, recent data suggest that the correlation between cholesterol levels and either ischaemic or haemorrhagic stroke is weak. However, the interpretation of these results is hampered by the inconsistent use of classifications of the various subtypes of stroke in studies. Pooled data on the effect of HMG-CoA reductase inhibitors show a 30% risk reduction in strokes. These beneficial effects are obtained from studies in middle aged patients with ischaemic heart disease, the interpretation being that the effects of HMG-CoA reductase inhibitors on stroke are mediated via (i) cholesterol-lowering effects on the coronary vasculature or (ii) cholesterol-independent effects of these agents. The results cannot be extrapolated to the elderly, among whom stroke most frequently occurs.

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomized, double-blind, placebo-controlled trial designed to test the hypothesis that treatment with pravastatin will diminish risk of subsequent major vascular events in a cohort of men and women (70 to 82 years old) with preexisting vascular disease or significant risk of developing this condition. Five thousand eight hundred four men and women in addition to receiving advice on diet and smoking, have been randomized equally to treatment with 40 mg pravastatin/day or matching placebo in 3 centers (Cork, Ireland, Glasgow, Scotland, and Leiden, The Netherlands). Following an average 3.5-year intervention period, a primary assessment will be made of the influence of this therapy on major vascular events (a combination of coronary heart disease, death, nonfatal myocardial infarction, and fatal and nonfatal stroke). A number of additional analyses will also be conducted on the individual components of the primary end point, on men, on women, and on subjects with and without previous evidence of vascular disease. Finally, an assessment will be made of the effects of treatment on cognitive function, disability, hospitalization or institutionalization, vascular mortality, and all-cause mortality.

This article reviews the neurophysiological abnormalities described in Huntington's disease. Among the typical features of choreic movements are variable and random patterns of electromyographic (EMG) activity, including cocontraction of agonist and antagonist muscles. Studies of premotor potentials show that choreic movements are not preceded by a Bereitschaftspotential, therefore demonstrating that choreic movement is involuntary. Early cortical median-nerve somatosensory-evoked potentials have reduced amplitudes and the reduction correlates with reduced glucose consumption in the caudate nucleus. Long-latency stretch reflexes evoked in the small hand muscles are depressed. These findings may reflect failed thalamocortical relay of sensory information. In Huntington's disease, the R2 response of the blink reflex has prolonged latencies, diminished amplitudes, and greater habituation than normal. These abnormalities correlate with the severity of chorea in the face. Patients with Huntington's disease perform simple voluntary movements more slowly than normal subjects and with an abnormal triphasic EMG pattern. Bradykinesia is also present during their performance of simultaneous and sequential movements. Eye movements show abnormalities similar to those seen in arm movements. In Huntington's disease, arm movement execution is associated with reduced PET activation of cortical frontal areas. Studies using transcranial magnetic stimulation show that patients with Huntington's disease have normal corticospinal conduction but some patients have a prolonged cortical silent period. Bradykinesia results from degeneration of the basal ganglia output to the supplementary motor areas concerned with the initiation and maintenance of sequential movements. The coexisting hyperkinetic and hypokinetic movement disorders in patients with Huntington's disease probably reflect the involvement of direct and indirect pathways in the basal ganglia-thalamus-cortical motor circuit.

Objectives: To define the cumulative risk of central nervous system (CNS) relapse in systemic non-Hodgkin lymphoma (NHL); to assess the risk factors of age, sex, malignancy grade, stage, localization, and response to initial therapy; and to evaluate the effect of CNS prophylaxis., Patients and Methods: An unselected group of 532 patients with systemic NHL. A retrospective analysis., Results: Eleven patients presented with systemic as well as CNS localization, whereas in 55 patients, CNS relapse occurred later. The cumulative risk of CNS relapse at 4 years for all 532 patients was 19%. High-grade NHL carried a 39% risk of CNS relapse, with the vast majority of relapses occurring in the first 14 months after the initial diagnosis. The cumulative risk in patients with intermediate-grade NHL was considerable (22%) and dispersed throughout a much longer period (6 years). Patients with low-grade NHL still carried a 7% risk of CNS relapse; in all these patients, low malignancy grade was transformed into a higher malignancy grade at that time. In a multivariate analysis, high- and intermediate-grade NHL and advanced stage were independent risk factors for CNS relapse. There was not any strong evidence for a beneficial role of CNS prophylaxis in patients with intermediate- and high-grade NHL, but a retrospective analysis cannot be conclusive with regard to the effect of therapy. Systemic relapse occurred rapidly after CNS relapse, resulting in a median survival time after CNS relapse of only 2 months., Conclusions: Patients with high- and intermediate-grade NHL carry a considerable risk of CNS relapse. Advanced stage is an additional independent risk factor. The role of CNS prophylaxis seems to be disappointing, but a retrospective analysis cannot be conclusive. Prognosis after CNS relapse is poor.

In assessing the optimal intensity of anticoagulant therapy, the International Normalized Ratio (INR) at admission is used as a basis for INR-specific incidence rates. In 47 patients suffering a haemorrhagic stroke we tested the assumption that the INR at admission is an acceptable measure for the INR that preceded the haemorrhage. We found high D-dimer levels in 70% of the patients, which indicated activated coagulation and fibrinolysis. This was not of such an extent that it could also be measured with other routine coagulation tests, with the possible exception of two patients. We found normal INRs in 33 non-anticoagulated patients, and only a mildly prolonged INR of 1.9 in one patient, which was most probably caused by a vitamin K deficiency. We concluded that the INR at admission can be used in studies to assess the optimal level of anticoagulation.

TNF-alpha production in whole blood cultures upon stimulation with LPS was determined in 179 individuals from 61 families in order to characterise the magnitude of inherited differences in TNF-alpha production. The three families characterised by highest TNF production showed 7.1 +/- 0.3 ng TNF/ml upon culture with 10 ng LPS and 10.2 +/- 0.2 ng TNF/ml upon culture with 1000 ng LPS. in contrast to the three families characterised by the lowest TNF production that showed a production of 1.6 +/- 0.1 ng TNF upon culture with 10 ng and 2.5 +/- 0.2 ng/ml upon culture with 1000 ng LPS/ml. This difference could not be attributed to the promoter polymorphisms -308 G to A. -238 G to A or -376 G to A, although the -238 GA donors produced 2.1 +/- 0.9 ng TNF upon culture with 10 ng endotoxin compared to 3.2 +/- 2.2 ng TNF for the -238 GG donors. In line with these results the frequency of the -238 GG genotype was increased in hospitalized MS patients in a nursing home (100% 238GG, n = 57) compared to MS patients in an outpatient's clinic (94% 238GG, n = 98) or Dutch controls (90% 238GG, n = 180). These results suggest that the -238 GG genotype is differently distributed in hospitalized MS patients in a nursing home.

Objective: Determination of the efficacy of hydroquinine treatment of the restless legs syndrome., Design: Double blind cross-over trial., Setting: University Hospital Leiden., Patients and Methods: Selection through an announcement in the press and followed by structured interview. Inclusion criteria according to the international classification of sleep disorders. Exclusion criteria defined by medication risks. Patients used either hydroquinine (200 mg in the evening and 200 mg before going to bed) or placebo in the second and fourth of four periods of two weeks duration. Severity of complaints was assessed using a daily questionnaire and a Suggested Immobilization Test (SIT) twice weekly, in which they noted the severity of complaints as experienced during a 15-minute period of immobilization., Results: The study was completed by 59 out of 68 patients. Analysis of variance showed no significant differences between the two groups of patients (those starting with placebo and those starting with hydroquinine) for any of the questions of the daily questionnaire or of the SIT. McNemar's test showed no significant differences between the proportions of patients who wished to continue the use of either placebo or hydroquinine., Conclusion: This study showed no significant differences between the efficacy of placebo or hydroquinine in the restless legs syndrome.

The variability inherent in nerve conduction velocity (NCV) studies suggests that multiple measurements may yield more information than a single measurement. To test this hypothesis, three motor nerve conduction velocities (NCVs) of the peroneal nerve were measured: to the extensor digitorum brevis muscle over the fibular head and in the lower leg, and to the tibialis anterior muscle over the fibular head. Three groups were studied: controls, polyneuropathy cases and peroneal pressure neuropathy cases. Over the fibular head, NCVs recorded from the tibialis anterior were consistently higher than those from the extensor digitorum brevis, and showed a higher number of abnormalities. Differences between NCVs, their Z-scores and Mahalanobis distances were compared to study the influence of variance differences and covariances. The best compromise between true and false positives was found to be a comparison between NCVs over the fibular head recorded from the tibialis anterior and the leg segment recorded from the extensor digitorum muscle. Z-scores are more useful than Mahalanobis distances in this respect.

Baclofen and oxazepam enhance extinction of conflict behaviour in the Geller-Seifter test while baclofen and diazepam release punished behaviour in Vogel's conflict test. In order to investigate the possibility that the effect of the selective GABA-B receptor agonist baclofen is mediated indirectly via the GABA-A/benzodiazepine receptor complex, the effect of pretreatment of rats with baclofen on [3H]-diazepam binding to washed and unwashed cortical and cerebellar membranes of rats has been studied. Baclofen pretreatment increased Bmax in washed cerebellar membranes when bicuculline was present in the incubation mixture. No effect was seen in cortical membranes. The present results render it unlikely that the effect of baclofen on extinction of conflict behaviour and punished drinking is mediated via the GABA-A/benzodiazepine receptor complex.

In view of recent reports on lower brainstem dysfunction in Huntington's chorea, we studied respiration during sleep in 12 patients with Huntington's chorea (HC) and in controls. There were no statistically significant differences between patients and controls with respect to apnea periods, respiratory frequency and time elapsed between minimal and maximal value of the respiratory curve. No statistically significant differences in respiratory variability were observed between patients and controls. In the present study, no indication was found for dysfunction of lower brainstem structures involved in respiration in HC.

Somatosensory evoked potentials were measured in 21 patients with Huntington's chorea and 12 controls. Central brain conduction time was normal. Early cortical component amplitudes were reduced in the patient group, latencies were normal. These abnormalities probably can be attributed to cortical dysfunction in Huntington's chorea. No indication of brain-stem dysfunction was found.

Saccadic eye movements, fixation and smooth pursuit were studied in 28 children with Gilles de la Tourette syndrome and found to be normal. A link has been postulated between Gilles de la Tourette syndrome and other movement disorders. The results obtained in the present series do not support this hypothesis.

The disability outcome related to the presenting signs and symptoms was studied retrospectively in 193 patients with definite multiple sclerosis (MS). Patients whose first sign was motor weakness were found to be more severely disabled, at all stages throughout the course of the disease, than patients with other presenting signs or symptoms. Patients whose disease manifested initially with sensory disturbances or paraesthesiae proved to be less seriously disabled than other patients at all stages of the disease. A similar tendency was found in patients presenting with optic neuritis (ON) for the first 20 years of the disease; after that, their disability was comparable to that of patients with other presenting complaints. The difference during the first 20 years of the disease is mainly due to the asymptomatic period after initial manifestation of optic neuritis.