Common CCR 5 polymorphism in stroke: the CCR 5 delta32 polymorphism differentiates cardioembolism from other aetiologies of ischaemic cerebrovascular diseases.

Inflammation is involved in the development of atherosclerosis. The CC chemokine receptor 5 (CCR5) initiates chemotaxis and modulates the inflammation secondary to atherosclerosis and related vascular diseases. The CCR5 Delta32 polymorphism influences the expression of CCR5 on the cell surface. The purpose of this study was to examine the effect of the Delta32 polymorphism in ischaemic cerebrovascular disease (ICVD). The CCR5 Delta32 polymorphism was genotyped in 1462 individuals: 562 ischaemic stroke (IS), 97 transient ischaemic attack (TIA) and in 803 healthy controls. All 659 ICVD patients were categorized according to the Trial of Org 10172 in Acute Stroke Treatment aetiological classification. The investigated subtypes were large artery atherosclerosis (LAA), cardioembolism (CE), small artery occlusion (SAO) and cryptogenic disease (CRYPT). Genotyping was performed with the TaqMan polymerase chain reaction. The Delta32 allele was less frequent in CE patients compared with LAA (OR, 0.4; 95% CI, 0.24-0.79; P = 0.008), SAO (OR, 0.5; 95% CI, 0.29-0.84; P = 0.01), CRYPT (OR, 0.5; 95% CI, 0.28-0.82; P = 0.008) and controls (OR, 0.5; 95% CI, 0.36-0.82; P = 0.002). Multiple logistic regression analysis showed that the Delta32 allele is associated with a lower risk for cardioembolic ICVD (OR 0.5; 95% CI, 0.28-0.75; P = 0.002) when compared with ICVD of other causes. The Delta32 polymorphism of CCR5 may differentiate cardioembolism from the remaining causes of ICVD.

Genetic profile of ischemic cerebrovascular disease and carotid stenosis.

OBJECTIVES: Carotid artery stenosis (CS) is a major risk factor for ischemic cerebrovascular disease (ICVD) and is therefore of interest in genetic investigating. Here we report the distribution of 100 polymorphisms in 47 suspected susceptibility genes for ICVD and its risk factors. MATERIALS AND METHODS: Previously published markers in suspected susceptibility genes were genotyped in ICVD patients and controls (928/602). Genotyping was performed using multiplex polymerase chain reaction (PCR) and linear immobilized probe array assays. ICVD cases were subtyped according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) or subdivided into CS and non-CS patients by ultrasonography in a separate analysis. RESULTS: Three polymorphisms located in the lipoprotein lipase (LPL), angiotensinogen (AGT) and guanine nucleotide-binding protein beta-3 (GNB3) genes were significantly associated with ICVD after correction for age and gender. The strongest association was found for the protective LPL Ser447Term polymorphism. All the significant markers showed varying frequencies in different subphenotypes of ICVD. Factor VII, apolipoprotein E and two renin polymorphisms were differentially frequent in patients with evidence of CS compared with non-CS patients. CONCLUSIONS: We have found that some previously described susceptibility polymorphisms are weakly associated with ICVD and that subdivision of patients into CS and non-CS groups may help to identify new candidate polymorphisms.

Tolerability of NXY-059 at higher target concentrations in patients with acute stroke.

BACKGROUND AND PURPOSE: NXY-059 is a nitrone-based free radical-trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days. RESULTS: One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39; 420 mg/h, n=48; placebo, n=47). Mean age was 69 years (range, 34 to 92 years), and baseline National Institutes of Health Stroke Scale score was 8.5 (SD, 6.6). Serious adverse events occurred in 3, 17, and 13 patients, respectively, with deaths in 0, 4, and 3 patients and treatment discontinuations because of adverse events in 0, 1, and 3 patients. Good outcome, defined by modified Rankin Scale score of 0 or 1, was seen in 53%, 29% and 40%, respectively. No safety concern was identified in analysis of body temperature, blood pressure, or other laboratory parameters. The unbound plasma concentration at steady state was 260+/-79 micromol/L, exceeding the target of 200 micromol/L in the high-dose group. CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke at and above concentrations shown to be neuroprotective in an animal model when initiated 4 hours after onset of permanent focal ischemia.

Elevated expression of CCR5 by myeloid (CD11c+) blood dendritic cells in multiple sclerosis and acute optic neuritis.

Myeloid and plasmacytoid dendritic cells (DC) are present in cerebrospinal fluid (CSF) in non-inflammatory neurological diseases (NIND) and elevated in clinically definite multiple sclerosis (MS) and in early MS - acute monosymptomatic optic neuritis (ON). Here, we show that expression of CCR5, a chemokine receptor for regulated on activation, normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein (MIP)-1alpha/beta, is elevated on blood myeloid (CD11c+) DC in MS and ON compared to non-inflammatory controls. In contrast, expression of CXCR4, a receptor for stromal cell-derived factor (SDF)-1alpha, is similar in all groups. Blood myeloid DC from MS patients respond chemotactically to RANTES and MIP-1beta, which are expessed in MS lesions. In active MS and ON, expression of CCR5 by myeloid DC in blood correlates with numbers of these cells in CSF. Thus, elevation of CCR5 may contribute to recruitment of myeloid DC to CSF in MS and ON. Recruitment of plasmacytoid DC to CSF appears to be CCR5-independent.

Randomized controlled trial of rehabilitation at home after stroke: one-year follow-up of patient outcome, resource use and cost.

BACKGROUND AND PURPOSE: This study sought to evaluate early supported discharge and continued rehabilitation at home after stroke, at a minimum of 6 months after the intervention, in terms of patient outcome, resource use and health care cost. METHODS: Eighty-three patients, moderately impaired 5-7 days after acute stroke, were included in a randomized controlled trial, 42 being allocated to the intervention and 41 to routine rehabilitation. One-year follow-up of patient outcome included mortality, motor capacity, dysphasia, activities of daily living, social activities, perceived dysfunction, and self-reported falls. Resource use over 12 months included inpatient hospital care, outpatient health care, use of health-related services, informal care, and cost of health care. RESULTS: On univariate analysis there was no difference in patient outcome. Multivariate regression analysis showed that intervention had a significant effect on independence in activities of daily living. A significant difference in inpatient hospital care, initial and recurrent, was observed, with a mean of 18 (intervention) versus 33 days (control) (p = 0.002). Further significant differences were that the control group registered more outpatient visits to hospital occupational therapists (p = 0.02), private physical therapists (p = 0.03) and day-hospital attendance (p = <0.001), while the intervention group registered more visits to nurses in primary care (p = 0.03) and home rehabilitation (p = <0.001). Other differences in outcomes or resource utilization were nonsignificant. CONCLUSION: In Sweden, early supported discharge with continued rehabilitation at home proved no less beneficial as a rehabilitation service, and provided care and rehabilitation for 5 moderately disabled stroke patients over 12 months after stroke onset for the cost of 4 in routine rehabilitation.

IL-17 and IFN-gamma mRNA expression is increased in the brain and systemically after permanent middle cerebral artery occlusion in the rat.

Brain ischemia is characterized by local inflammation reflected by accumulation of inflammatory cells and a multitude of mediators. Among them, cytokines and chemokines may influence the inflammatory cascade that follows cerebral ischemia. Here we report on brain hemispheric and systemic increase of pro-inflammatory IL-17 and IFN-gamma, the anti-inflammatory cytokines IL-4 and IL-10, and the chemokines IP-10, IL-8 and MIP-2, 1 h to 6 days after permanent middle cerebral artery occlusion (pMCAO). IL-17 and IFN-gamma mRNA levels were elevated in the ischemic hemispheres of pMCAO-operated rats compared with corresponding hemispheres of sham-operated rats. Levels were slightly elevated at 1 h, and peaked at 6 days after pMCAO. IL-8 and MIP-2 levels in the ischemic hemispheres peaked at 24 h, whereas IP-10 showed a biphasic profile with two peaks at 6 h and 6 days after pMCAO. IL-4 peaked in the ischemic hemispheres at 6 h, when IL-10 levels were lower than in sham-operated rats, and IL-10 levels peaked at 2 days after pMCAO. Systemically, the numbers of IL-17 and IFN-gamma mRNA expressing blood mononuclear cells were elevated already at 1 h after pMCAO, preceding the changes in the ischemic hemispheres. Altered levels of IL-17 and IFN-gamma after pMCAO may affect outcome of brain ischemia.

Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke.

BACKGROUND AND PURPOSE: Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free radical trapping agent in development for acute stroke. NXY-059 has neuroprotective efficacy when given 5 hours after onset of transient focal ischemia in the rat. METHODS: This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study that evaluated the safety and tolerability of 2 NXY-059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days. RESULTS: One hundred fifty patients were recruited, of whom 147 received study treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (+/-SD) age was 68 (+/-10) years, and baseline National Institutes of Health Stroke Scale score was 7.9 (+/-6.2). Serious adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with primary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever were common but not related to treatment. The mean unbound steady state NXY-059 plasma concentrations were 25 and 45 micromol/L, respectively. Population pharmacokinetic analysis estimated clearance to be 4.6 L/h. CONCLUSIONS: NXY-059 was well tolerated in patients with an acute stroke. The testing of higher doses in future trials may be justified.

Two subsets of dendritic cells are present in human cerebrospinal fluid.

Little is known about the presence of dendritic cells in the human CNS. To investigate the occurrence of dendritic cells in the CSF, paired blood/CSF samples from patients with multiple sclerosis, acute optic neuritis, Lyme neuroborreliosis, other inflammatory neurological diseases and non-inflammatory neurological diseases were examined using flow cytometry. Almost all CSF samples contained myeloid (lin-CD11c+HLA-DR++CD123(dim)) and plasmacytoid (lin-CD11c-HLA-DR+CD123(high)) dendritic cells. In non-inflammatory neurological diseases, dendritic cells of either subset only constituted up to 1% of CSF mononuclear cells. Myeloid CSF dendritic cells were elevated in optic neuritis, neuroborreliosis and other inflammatory neurological disorders, while plasmacytoid dendritic cells were elevated in all neuroinflammatory conditions studied, with especially high numbers in neuroborreliosis. Numbers of CSF dendritic cells correlated with the common parameters of CNS inflammation. The myeloid dendritic cells in CSF expressed higher levels of HLA-DR, CD86, CD80 and CD40 than those in blood, whereas expression of these molecules by plasmacytoid dendritic cells was equal in blood and CSF. Both CSF and blood dendritic cells expressed the chemokine receptor CCR5. This is the first demonstration that dendritic cells are present in human CSF and that plasmacytoid dendritic cells are present in a non-lymphoid compartment. Myeloid and plasmacytoid dendritic cells in CSF may contribute to orchestration of the local immune responses.

A randomized controlled trial of rehabilitation at home after stroke in Southwest Stockholm: outcome at six months.

A 6-month follow-up of a single-blind, randomized, controlled trial in Southwest Stockholm was performed in order to evaluate the effect of early supported discharge and continued rehabilitation at home after stroke. Eighty-three stroke patients with moderate neurological impairments, continent, independent in feeding, and mental function within normal limits one week after onset were included in the study. The patients were allocated 1:1 to early supported discharge and continued rehabilitation at home by a specialized team, versus routine rehabilitation. Patient outcomes measured were motor capacity, dysphasia, activities of daily living, social activities, perceived dysfunction, mortality and reported falls. Data on length of stay in hospital; initial and recurrent during 6 months were compared. The 6-month follow-up of 78 patients showed no statistically significant differences in patient outcome. The results of multivariate logistic regression analysis suggest a positive effect of home rehabilitation on activities of daily living. At 3-6 months the frequency of significant improvements was higher in the intervention group. Death or dependency in activities of daily living was 24% in the intervention group compared with 44% in the control group. The mean initial hospitalization was 29 days in routine rehabilitation group versus 14 days in the home rehabilitation group. We conclude that for moderately disabled stroke patients with mental function within normal limits, early supported discharge and continued rehabilitation at home had no less a beneficial effect on patient outcome than routine rehabilitation, reduced initial hospitalization significantly and had no adverse effects on mortality and number of falls.

Increased IL-1beta, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study.

BACKGROUND AND PURPOSE: Ischemic brain injury secondary to arterial occlusion is characterized by acute local inflammation, which involves accumulation of polymorphonuclear neutrophils (PMN). Factors that influence the recruitment of PMN could represent new therapeutic targets in acute stroke. In this prospective study we evaluated numbers of peripheral blood mononuclear cells (PBMC) expressing mRNA for interleukin (IL)-1beta, IL-8, and IL-17 and macrophage inflammatory protein-1alpha (MIP-1alpha) after ischemic stroke. METHODS: Peripheral blood was obtained on days 1 to 3, 4 to 10, and 20 to 31 after onset of symptoms. In situ hybridization with radiolabeled synthetic oligonucleotide probes was adopted to measure cytokine mRNA expression in PBMC. Plasma and cerebrospinal fluid levels of IL-8 were measured by an enzyme-linked immunosorbent assay. RESULTS: Most patients with ischemic stroke had clearly elevated numbers of IL-1beta, IL-8, and IL-17 mRNA expressing PBMC 1 to 3 days after onset of symptoms compared with healthy individuals (P<0. 0001 for all comparisons). At follow-up after 20 to 31 days, numbers of IL-8 mRNA expressing PBMC were lower than during the acute stage (P<0.001), but only IL-1beta and IL-17 mRNA expression had returned to the level of the healthy individuals. Numbers of MIP-1alpha mRNA expressing PBMC did not differ between patients with ischemic stroke and healthy individuals at any time point. A correlation was observed between numbers of IL-1beta, IL-8, and IL-17 mRNA expressing PBMC and the degree of neurological impairment as measured by the Scandinavian Stroke Scale 1 to 3 days after onset of symptoms (r=0.5; P<0.01 for all correlations). CONCLUSIONS: A longitudinal study of patients with ischemic stroke revealed systemic increases of levels of IL-1beta, IL-8, and IL-17 that correlated with Scandinavian Stroke Scale scores. IL-8 levels were further increased in cerebrospinal fluid.

An angiotensin-converting enzyme gene polymorphism suggests a genetic distinction between ischaemic stroke and carotid stenosis.

BACKGROUND: Ischaemic cerebrovascular disease (ICVD) is a heterogeneous syndrome to which different genetic factors may contribute. We have investigated the distribution of alleles of the angiotensin-converting enzyme (ACE) gene, which has been suggested to be of possible importance in ischaemic stroke or cardiovascular disease, in groups of patients with ischaemic stroke and carotid artery stenosis (CS). MATERIALS AND METHODS: One hundred and thirty patients with ischaemic stroke and 68 patients with more than 50% stenosis of the internal carotid artery were investigated and compared with age- and sex-matched healthy control subjects. Alleles of an insertion/deletion polymorphism of the ACE gene were determined by one-stage polymerase chain reaction and visualized on agarose gels. RESULTS: There was a significant difference (P < 0.05) in the distribution of ACE alleles, homozygosity for the presumed susceptibility deletion allele being more common in patients with CS than in healthy control subjects. There was also a significant difference (P < 0.05) in patients with CS in comparison with matched ICVD patients without CS, both in allelic frequencies and in homozygosity for the deletion allele. CONCLUSIONS: Our results indicate that the ACE gene polymorphism may be a risk factor for the development of CS. The observed difference in ACE allele distribution may be seen as evidence for a genetic distinction between ICVD and CS, two clinically related conditions, which further supports the hypothesis that genetic factors are of importance for this group of diseases.

High levels of IL-10 secreting cells are present in blood in cerebrovascular diseases.

Ischemic stroke is associated with altered systemic immune responses both early after the onset and in the recovery phase. Interleukin (IL)-10, a Th2 related cytokine, has multiple effects on different cell types, including T and B lymphocytes, monocytes, neutrophils and mast cells. IL-4 is another Th2 cytokine that inhibits the synthesis of pro-inflammatory cytokines by Th1 clones. We used enzyme-linked immunospot assays to detect and enumerate blood mononuclear cells (MNC) secreting IL-10 and IL-4 spontaneously as well as after stimulation with myelin basic protein (MBP), considered to be an autoantigen of possible pathogenic importance in, for example, multiple sclerosis, to evaluate the involvement of anti-inflammatory cytokines in ischemic stroke. All patients with ischemic stroke and cerebral hemorrhage had strongly elevated numbers of IL-10 secreting blood MNC compared with healthy individuals. Numbers of MBP-reactive IL-10 secreting blood MNC were also elevated in a proportion of the patients with stroke and hemorrhage. Levels of IL-4 secreting blood MNC did not differ in ischemic stroke versus healthy individuals. The anti-inflammatory IL-10 could play a pivotal role in ischemic stroke as well as cerebral hemorrhage.

A methylenetetrahydrofolate reductase gene polymorphism in ischaemic stroke and in carotid artery stenosis.

METHODS: A biallelic polymorphism of the methylenetretrahydrofolate reductase (MTHFR) gene, reported to influence the plasma level of homocysteine (Hcy), was investigated for a possible role in influencing the risk of ischaemic cerebrovascular disease (ICVD) and occlusive atherosclerosis in 126 patients with ischaemic stroke and 70 patients with internal carotid artery (ICA) stenosis. RESULTS: Only minor differences were observed between different groups of patients and control subjects. Although 47% of ICA stenosis patients had increased plasma Hcy, the MTHFR genotype did not correlate with levels of either Hcy, folic acid or vitamin B12. In addition, the MTHFR genotype did not affect Hcy levels, even in the presence of low blood folate. CONCLUSION: We conclude that this common MTHFR gene polymorphism does not exert a significant influence on the risk of developing ICVD or ICA stenosis, and does not cause the increased level of Hcy observed in ICA stenosis.

A randomized controlled trial of rehabilitation at home after stroke in southwest Stockholm.

BACKGROUND AND PURPOSE: This study describes the methodology, patient outcome, and use of hospital and rehabilitation services at 3 months of a population-based randomized controlled trial. The purpose was to evaluate rehabilitation at home after early supported discharge from the Department of Neurology, Huddinge Hospital, for moderately disabled stroke patients in southwest Stockholm. METHODS: The patients were eligible if they were continent, independent in feeding, had mental function within normal limits, and had impaired motor function and/or aphasia 1 week after stroke. Patients were randomized either to early supported discharge with continuity of rehabilitation at home for 3 to 4 months or to routine rehabilitation service in a hospital, day care, and/or outpatient care. The home rehabilitation team consisted of two physical therapists, two occupational therapists, and one speech therapist; one of the therapists was assigned as case manager for the patient. The rehabilitation program at home emphasized a task- and context-oriented approach. The activities were chosen on the basis of the patient's personal interests. Spouses were offered education and individual counseling. A total of 81 patients were followed up for a minimum of 3 months. Patient outcome was assessed by the Frenchay Social Activity Index, Extended Katz Index, Barthel Index, Lindmark Motor Capacity Assessment, Nine-Hole Peg Test, walking speed over 10 m, reported falls, and subjective dysfunction according to the Sickness Impact Profile. Patient use of hospital and home rehabilitation service and patient satisfaction with care were studied. RESULTS: Overall there were no statistical significant differences in outcome. Multivariate logistic regression analysis suggested a systematic positive effect for the home rehabilitation group in social activity, activities of daily living, motor capacity, manual dexterity, and walking. A considerable difference in resource use during such a 3-month period was seen. A 52% reduction in hospitalization was observed: from 29 days in the routine rehabilitation group to 14 days in the home rehabilitation group. Patient satisfaction was in favor of the latter group. CONCLUSIONS: Early supported discharge with continuity of home rehabilitation services for the majority of moderately disabled stroke patients during the first 3-month period after acute stroke is not less beneficial than routine rehabilitation and can be a rehabilitation service of choice if follow-up at 6 and 12 months confirms the suggested effectiveness and considerable reduction in use of health care.

Ischemic stroke is associated with a systemic increase of blood mononuclear cells expressing interleukin-8 mRNA.

BACKGROUND AND PURPOSE: Ischemic brain injury secondary to an arterial occlusion is characterized by acute local inflammation. Blood polymorphonuclear leukocytes (PMNL), primarily neutrophils, adhere to endothelial cells and rapidly invade the injured brain after the arterial occlusion. This neutrophilic invasion might correlate with the production of certain chemoattractants by blood mononuclear cells (MNC). We evaluated mRNA expression of the CXC chemokine interleukin (IL)-8, and the CC chemokines monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta in blood MNC from patients with ischemic stroke. METHODS: Peripheral blood was obtained at 8 AM on days 1 to 7 (mean, day 3) after onset of symptoms. In situ hybridization with radiolabeled synthetic oligonucleotide probes for the chemokines was adopted to measure chemokine mRNA expression in MNC. An enzyme-linked immunosorbent assay for IL-8 was used to measure IL-8 levels in plasma. RESULTS: Most patients with ischemic stroke had high numbers of IL-8 mRNA expressing blood MNC, regardless of the time interval between onset of clinical symptoms and examination. There was a marked difference between patients with ischemic stroke and healthy subjects (median, 6228 versus 885 positive cells per 10(5) MNC; P<.0001). IL-8 levels in plasma correlated positively to IL-8 mRNA expression in examined patients (n=7) with ischemic stroke (r=.78, P<.05). In contrast, mRNA expression for the CC chemokines showed no significant difference between patients with ischemic stroke and healthy control subjects. CONCLUSIONS: This study demonstrated a systemic increase of IL-8 mRNA expressing MNC and IL-8 levels in plasma from patients with ischemic stroke, suggesting that IL-8 could be involved in recruiting blood PMNL to the sites of cerebral ischemia.

Lipoprotein lipase gene polymorphisms in ischaemic stroke and carotid stenosis.

Ischaemic stroke is pathogenetically heterogeneous, but there is strong evidence that genetic as well as environment factors contribute to the risk of the individual. Here we report the similar distribution of polymorphic markers of the lipoprotein lipase (LPL) gene in 128 patients with ischaemic stroke, 56 patients with carotid artery stenosis and 95 healthy control subjects, in spite of a significant influence of the Asn291-->Ser mutation on serum levels of triglycerides. We conclude that these LPL polymorphisms do not contribute greatly to the overall risk of ischaemic stroke in the general population.

Cell death in human atherosclerotic plaques involves both oncosis and apoptosis.

The aim of the present study was to analyze the frequency and mechanism of cell-death in atherosclerotic plaques with a recent history (< 6 months) of rupture. Atherosclerotic plaques were obtained from patients with symptomatic ipsilateral carotid stenosis > 70% diameter reduction undergoing carotid endarterectomy. In situ tailing and nick translation of fragmented DNA, agarose gel electrophoresis of plaque DNA and electron microscopy were used to identify cell death by apoptosis (programmed cell death) and oncosis. The mean number of cells containing fragmented DNA in the plaques was 12.7 +/- 3.5% (n = 15). Focal accumulations of cells with DNA fragmentation occurred in the fibrous cap, at sites of rupture, close to lipid deposits and necrosis and was always accompanied by the presence of inflammatory cells. Electrophoretic separation of DNA isolated from part of plaques, where the presence of DNA fragmentation had previously been demonstrated by in situ DNA nick translation, resulted in multiple ladders of 180-200 base pairs characteristic of apoptosis. Electron microscopic analysis revealed presence of cells with morphological signs of degeneration in a frequency even higher than that found by in situ nick translation. Some of these cells had a characteristic apoptotic appearance with condensed chromatin and cytoplasm, but the large majority of the cells had an ultrastructure typical for cells undergoing cell death by oncosis with membrane disruption and swollen, disintegrating organelles. Thus, although apoptosis clearly takes place in atherosclerotic plaques, oncosis appears to be a much more common mechanism for cell death.

Localization of sterol 27-hydroxylase immuno-reactivity in human atherosclerotic plaques.

It has recently been shown that extrahepatic cells can eliminate intracellular cholesterol by enzymatic conversion into 27-hydroxy-cholesterol and 3 beta-hydroxy-5-cholestenoic acid. Using immunohistochemical methods, we studied the presence of the enzyme responsible for these conversions, sterol 27-hydroxylase, in human carotid atherosclerotic plaques. All plaques examined were found to contain sterol 27-hydroxylase immuno-reactive cells. While some endothelial cells stained for sterol 27-hydroxylase, the majority of the immunoreactive cells co-localized with macrophages. Accumulation of sterol 27-hydroxylase-positive cells were often observed in macrophage-rich core regions of complicated lesions. High concentrations of 27-hydroxycholesterol were found in plaques, while the concentration in non-atherosclerotic human vessels was lower by two orders of magnitude. The rabbit, which is particularly sensitive to dietary cholesterol and easily develops fatty streaks, had low plasma levels of 27-hydroxycholesterol, 3 ng/ml compared to 150 ng/ml in humans. The concentration of 27-hydroxycholesterol in the atherosclerotic rabbit vessels was also lower compared to human atherosclerotic plaques. The results are consistent with our hypothesis that sterol 27-hydroxylase may be utilized by human macrophages as a defence towards a high cholesterol load. This mechanism may be less important in some other species.

Intervention design for rehabilitation at home after stroke. A pilot feasibility study.

This study aimed at identifying the characteristics and feasibility of rehabilitation at home for acute stroke patients in south-west Stockholm. A population-based systematic sample of 16 patients, fulfilling defined criteria, was selected from approximately 1/3 of the stroke patients having been in hospital for one week or more at a neurology department, and offered early discharge in combination with home-based rehabilitation as an alternative to sustained rehabilitation in hospital. Fifteen patients, mean age 68.2 years, male/female ratio 9/6, independent in feeding and continent one week after acute stroke, participated in the study. The most important components of the home-based rehabilitation programme were that: 1) one therapist was selected as case-manager using the other therapists on a consultant basis; 2) the training sessions consisted of different task-specific activities, based on the patients' personal interest; 3) education and individual counselling were offered to all spouses; and 4) adherence to structured training between therapy sessions was promoted. The length of such programmes varied from 4 to 19 weeks after discharge and the mean number of home visits was 11. Reported time for training between therapy sessions for 14 patients was mean 1.2 hours per day. The patients' lifestyle activities, personal and instrumental ADL, and motor capacity at 3, 6 and 12 months after stroke, assessed by validated and reliable methods, followed patterns similar to those reported for other stroke patients. The mean time in hospital for patients in the study was 14 days; for patients with similar ADL capacity but not included in the study it was 27 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Parkinson's disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood.

The etiology of Parkinson's disease is mainly unknown. Immune abnormalities have been described, but the cause of such abnormalities has not been resolved. We examined by two-colour flow cytometry HLA-DR antigen expression on monocytes from cerebrospinal fluid (CSF) and blood and, moreover, lymphocyte subpopulations (CD4+ CD45RO+, CD4+ CD45RA+, CD8+ CD11b+high) in peripheral blood from patients with Parkinson's disease compared with age-matched patients with other neurological diseases (OND) and tension headache. We found higher HLA-DR expression on CSF monocytes compared with blood monocytes. This difference was restricted to Parkinson's disease patients. T helper cell analysis revealed a decreased percentage of CD45RA+ "naive" and an increased percentage of CD45RO+ "memory" T cell subset from CD4+ T cells in peripheral blood of patients with Parkinson's disease compared with patients with tension headache. The proportions of CD8+ CD11b+high "suppressor" T cells remained unchanged, among the three patient groups compared. A selective loss of CD4+ CD45RA+ cells, previously observed in diseases like multiple sclerosis and Down's syndrome as compared with healthy controls suggests a common immunological abnormality in neurological disorders.