Significant variation in mortality and functional outcome after acute ischaemic stroke between Western countries: data from the tinzaparin in acute ischaemic stroke trial (TAIST).

BACKGROUND: The medical care of patients with acute stroke varies considerably between countries. This could lead to measurable differences in mortality and functional outcome. OBJECTIVE: To compare case mix, clinical management, and functional outcome in stroke between 11 countries. METHODS: All 1484 patients from 11 countries who were enrolled into the tinzaparin in acute ischaemic stroke trial (TAIST) were included in this substudy. Information collected prospectively on demographics, risk factors, clinical features, measures of service quality (for example, admission to a stroke unit), and outcome were assessed. Outcomes were adjusted for treatment assignment, case mix, and service relative to the British Isles. RESULTS: Differences in case mix (mostly minor) and clinical service (many of prognostic relevance) were present between the countries. Significant differences in outcome were present between the countries. When assessed by geographical region, death or dependency were lower in North America (odds ratio (OR) adjusted for treatment group only = 0.52 (95% confidence interval, 0.39 to 0.71) and north west Europe (OR = 0.54 (0.37 to 0.78)) relative to the British Isles; similar reductions were found when adjustments were made for 11 case mix variables and five service quality measures. Similarly, case fatality rates were lower in North America (OR = 0.44 (0.30 to 0.66)) and Scandinavia (OR = 0.50 (0.33 to 0.74)) relative to the British Isles, whether crude or adjusted for case mix and service quality. CONCLUSIONS: Both functional outcome and case fatality vary considerably between countries, even when adjusted for prognostic case mix variables and measures of good stroke care. Differing health care systems and the management of patients with acute stroke may contribute to these findings.

Survival and recurrent strokes in patients with different subtypes of stroke: a fourteen-year follow-up study.

In this study, 339 patients (154 men, 185 women) with a median age of 74 years (range 23-97) admitted to the Stroke Unit, Department of Neurology in 1986, have been followed up for 14 years. The diagnoses were intracerebral hemorrhage (ICH; 30, 8.8%), cardioembolic cerebral infarction (CE, 71, 20.9%), lacunar infarction (LI; 47, 13.9%) and atherosclerotic cerebral infarction (ACI; 191, 56.3%). The cumulative probabilities of recurrent stroke rates at 1-, 5- and 10-year follow-ups were 13.5% (95% confidence interval, CI, 9.6-17.4), 38.7% (95% CI 32.6-44.8) and 53.9% (95% CI 46.7-61.1). According to Cox proportional hazard regression analysis, age, severity of stroke, previous stroke and systolic blood pressure are each of importance in predicting recurrent stroke. During the observation period, 290 patients (85.5%) died. The mortality rate of 24.5% during the first year was 4.5 times higher compared to the normal population of the same age and gender. Patients with LI had lower mortality rates compared to ICH by the log rank test (p = 0.0275); to CE (p = 0.000) and to ACI (p = 0.049). Thirty-nine percent of all vascular deaths after the first year were caused by recurrent strokes. Fatal index/recurrent stroke occurred statistically more frequently in the CE group versus the non-CE one (p = 0.005). Cox proportional hazard regression analysis indicated that age, severity of stroke, previous stroke, heart failure and fasting blood glucose exceeding 6 mmol/l or history of diabetes were each predictors of mortality. In conclusion, this study has shown the worse outcomes for all subtypes of stroke compared to the normal population and also clearly pointed out independent predictors of recurrent stroke or death at the time of diagnosis.

Sox18 expression in blood vessels and feather buds during chicken embryogenesis.

Sox18 encodes a transcription factor known to be important for the development of blood vessels and hair follicles in mice. In order to study the functional conservation of this gene through evolution, we have isolated and characterized Sox18 in chickens. cSox18 shows a high degree of sequence homology to both the mouse and human orthologues, particularly in the high mobility group DNA-binding domain and to a lesser extent in the transcriptional activation domain. A region of unusually high sequence conservation at the C-terminus may represent a further, previously unrecognized functional domain. Both the chicken and human proteins appear to be truncated at the N-terminus relative to mouse SOX18. In situ hybridization analyses showed expression in the developing vasculature and feather follicles, consistent with reported expression in the mouse embryo. In addition, cSox18 mRNA was observed in the retina and claw beds.

Transcriptional modulation of mouse mu-opioid receptor distal promoter activity by Sox18.

Previously, we reported the presence of dual promoters, referred to as distal (DP) and proximal, with a negative regulatory element between them in the mouse mu-opioid receptor (mor) gene. Here we have identified a positive regulatory element influencing mor DP transcription, which contains multiple consensus binding motifs for Sox factors (sex-determining Sry-like high mobility group box-containing genes). In gel supershift assays, the Sox family member Sox18 bound directly to the multiple Sox consensus binding motifs of the mor DP enhancer. Overexpression of Sox18 cDNA increased luciferase activity regulated by the mor DP, and did so in a Sox18 concentration-dependent manner. In contrast, overexpression of another Sox member, Sox5, triggered no such trans-activation of mor DP-driven luciferase activity or DNA-protein binding activity. These results suggest that Sox18 directly and specifically stimulates mor gene expression, by trans-activating the mor DP enhancer.

Human pharmacokinetics of L-3,4-dihydroxyphenylalanine studied with microdialysis.

BACKGROUND: Intravenous and subcutaneous microdialysis was performed to compare the free concentrations and pharmacokinetics of L-3, 4-dihyroxyphenylalanine (L-dopa) in blood and tissue in healthy subjects and in patients with Parkinson disease. METHODS: Nine healthy volunteers and 10 patients with Parkinson disease, stage 1. 5-2 according to the Hoehn-Yahr rating scale, took part of the study. In the patient group subcutaneous microdialysis and ordinary blood sampling were performed, whereas in the control group intravenous microdialysis was also performed. Microdialysis samples were collected in fractions of 15 min. The first two fractions were collected for analysis of basal concentrations. A blood sample was also taken. The patients were then given one tablet of Madopar((R)) (100 mg of L-dopa and 25 mg of benserazide), and the microdialysis was continued for another 210 min. Blood samples were obtained at 30-min intervals. RESULTS: The serum samples gave a significantly higher mean area under the curve (AUC; 491 +/- 139 micromol. min/L) than that for intravenous dialysates (235 +/- 55.3 micromol. min/L), suggesting a protein binding of 50%. The L-dopa concentrations from the subcutaneous dialysates matched those from the intravenous dialysates, indicating rapid distribution of L-dopa to the tissues. CONCLUSIONS: Parkinsonian patients in early stages of the disease have a pharmacokinetic pattern of free L-dopa similar to that of healthy subjects. Comparison of AUCs from microdialysis with ordinary serum analysis revealed data indicating significant protein binding. Microdialysis is a suitable and easily applied tool in pharmacokinetic studies.

L-dopa pharmacokinetics studied with microdialysis in patients with Parkinson's disease and a history of malignant melanoma.

OBJECTIVES: The pharmacokinetics of free L-dopa in blood and tissue of five parkinsonian patients with malignant melanoma was studied with microdialysis. In one case the effect of L-dopa treatment on 5-S-cysteinyldopa and the melanoma was studied. Gastric emptying and its effects on free L-dopa in blood were also investigated in one of the patients. METHODS: Five patients were given 100 mg L-dopa with 25 mg benserazide. Blood and dialysates from the circulation and fatty tissue were collected for analysis. [13C]-Octanoic breath test was used for analyzing gastric half-emptying time. RESULTS: Four of the patients had similar pharmacokinetic patterns for L-dopa and a significant (P < 0.05) increase of serum 5-S-cysteinyldopa occurring 30 min after L-dopa intake. Delayed L-dopa peaks and slow gastric half-emptying time were found in 1 patient. A dose-dependent increase of 5-S-cysteinyldopa occurred but no melanoma metastases were seen during long-term L-dopa therapy. CONCLUSION: L-dopa therapy increases 5-S-cysteinyldopa levels but does not seem to cause progress of melanomas. Gastric emptying impacts L-dopa pharmacokinetics.

Tolcapone added to levodopa in stable parkinsonian patients: a double-blind placebo-controlled study. Tolcapone in Parkinson's Disease Study Group II (TIPS II).

The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose "wearing-off" phenomenon has been controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97 patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg three times daily (t.i.d.). Levodopa dosage was reduced by -35% on day 1 of study and subsequently retitrated as required. After 6 weeks, the tolcapone groups crossed over to receive the other dose for a further 3 weeks for exploratory purposes. Both tolcapone groups had greater reductions in levodopa dosage than the placebo group at week 6 (not statistically different). The 200-mg t.i.d. group showed greatest improvement in estimated mean scores for all efficacy parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d. The most frequently reported dopaminergic adverse events were nausea, cramps, dyskinesia, and dystonia. The most frequently reported unanticipated adverse event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to patients with moderately advanced Parkinson's disease with treated "wearing-off" phenomenon.

The evaluation of facial paralysis.

The clinician faces a major challenge in the evaluation of acute facial nerve paralysis. Not only must he or she differentiate the large proportion of patients with idiopathic palsy who will resolve spontaneously from that critical small group that will not, but must also diagnose correctly the other rather unusual to rare conditions that cause facial paralysis. This article reviews the differential diagnosis, initial clinical evaluation, natural history, and long-term follow up of patients with acute facial dysfunction.

Ligand for EPH-related kinase (LERK) 7 is the preferred high affinity ligand for the HEK receptor.

HEK is a member of the EPH-like receptor tyrosine kinase family, which appear to have roles in development and oncogenesis. Recently, we purified a soluble HEK ligand which is also a ligand (AL1) for the HEK-related receptor EHK1. Promiscuity appears to be a characteristic feature of interactions between the EPH-like receptors and their ligands, termed ligands for EPH-related kinases (LERKs). This prompted us to analyze the interactions between the HEK exodomain and fusion proteins comprising candidate LERKs and the Fc portion of human IgG1 (Fc) or a FLAGTM-peptide tag by surface plasmon resonance, size exclusion high performance liquid chromatography, sedimentation equilibrium, and transphosphorylation. Our results indicate that AL1/LERK7 is the preferred high-affinity ligand for HEK, forming a stable 1:1 complex with a dissociation constant of 12 nM. As expected the apparent affinities of bivalent fusion proteins of LERKs and the Fc portion of human IgG1 had significantly reduced dissociation rates compared with their monovalent, FLAGTM-tagged derivatives. High-avidity binding of monovalent ligands can be achieved by antibody-mediated cross-linking of monovalent ligands and with LERK7 results in specific phosphorylation of the receptor. By extrapolation, our findings indicate that some of the reported LERK-receptor interactions are a consequence of the use of bivalent ligand or receptor constructs and may be functionally irrelevant.

Human beta-trace in normal and pathological CNS tissues, genital organs and body fluids.

The function of BTP is still unknown. In CNS, the high amount of BTP in the white CNS matter and the glial cells as well as in genital organs of the stroma of epididymis suggest that BTP has a supportive function. Slight evidence of a synthesis in patients with MS and slightly increased CSF values in stroke patients may suggest that BTP is involved in repair mechanism of damaged brain tissue, or may be related from destroyed brain tissue. In samples of CSF, determination of BTP could be of value as differentiating glial cell tumors from tumors of other kinds, as well as the recently suggested diagnostic value of the Creutzfeldt-Jakob disease (20). However, also other functions of BTP has been suggested. (21, 22).

Transgenic mice carrying the dominant rhodopsin mutation P347S: evidence for defective vectorial transport of rhodopsin to the outer segments.

To explore the pathogenic mechanism of dominant mutations affecting the carboxyl terminus of rhodopsin that cause retinitis pigmentosa, we generated five lines of transgenic mice carrying the proline-347 to serine (P347S) mutation. The severity of photoreceptor degeneration correlated with the levels of transgene expression in these lines. Visual function as measured by the electroretinogram was approximately normal at an early age when there was little histologic evidence of photoreceptor degeneration, but it deteriorated as photoreceptors degenerated. Immunocytochemical staining showed the mutant rhodopsin predominantly in the outer segments prior to histologically evident degeneration, a finding supported by quantitation of signal intensities in different regions of the photoreceptor cells by confocal microscopy. A distinct histopathologic abnormality was the accumulation of submicrometer-sized vesicles extracellularly near the junction between inner and outer segments. The extracellular vesicles were bound by a single membrane that apparently contained rhodopsin as revealed by ultrastructural immunocytochemical staining with anti-rhodopsin antibodies. The outer segments, although shortened, contained well-packed discs. Proliferation of the endoplasmic reticulum as reported in Drosophila expressing dominant rhodopsin mutations was not observed. The accumulation of rhodopsinladen vesicles likely represents aberrant transport of rhodopsin from the inner segments to the nascent disc membranes of the outer segments. It is possible that photoreceptor degeneration occurs because of a failure to renew outer segments at a normal rate, thereby leading to a progressive shortening of outer segments, or because of the loss of cellular contents to the extracellular space, or because of both.

Age-standardized incidence and prevalence of Parkinson's disease in a Swedish community.

Parkinson's disease (PD) shows a geographical variation. All prescriptions for anti-parkinsonian drugs were recorded for a half-year in a region with low L-dopa consumption. Hospital and outpatient records were studied and physicians were asked to supply details of PD patients in the region, with 147,777 inhabitants. The crude prevalence was 115 PD per 100,000 inhabitants, based on 170 cases. In contrast to other studies we report an age-standardized prevalence, which was 76 per 100,000, using the European Standard Population as reference. The corresponding approximate incidences were 11.0 (crude) and 7.9 (age-standardized) per 100,000 person-years. Male preponderance appeared in all age groups. Mean age at onset was 65.6 years, the highest figure reported. Variation between studies for age at onset, differences in prevalence, and male preponderance suggest environmental risk factors to be of importance for PD.

Embryonic stem cells express multiple Eph-subfamily receptor tyrosine kinases.

Eph and its homologues form the largest subfamily of receptor tyrosine kinases. Normal expression patterns of this subfamily indicate roles in differentiation and development, whereas their overexpression has been linked to oncogenesis. This study investigated the potential role of Eph-related molecules during very early embryonic development by examining their expression in embryonic stem (ES) cells and embryoid bodies differentiated from ES cells in vitro. By use of a strategy based on reverse transcriptase-mediated PCR, nine clones containing Eph-subfamily sequence were isolated from ES cells. Of these, eight were almost identical to one of four previously identified molecules (Sek, Nuk, Eck, and Mek4). However, one clone contained sequence from a novel Eph-subfamily member, which was termed embryonic stem-cell kinase or Esk. Northern analysis showed expression of Esk in ES cells, embryoid bodies, day 12 mouse embryos, and some tissues of the adult animal. Levels of expression were similar in ES cells and embryoid bodies. By comparison, Mek4 showed no significant transcription in the ES cell cultures by Northern analysis, whereas Eck displayed stronger signals in ES cells than in the embryoid bodies. These results suggest that Eph-subfamily molecules may play roles during the earliest phases of embryogenesis. Furthermore, the relative importance of different members of this subfamily appears to change as development proceeds.

Assessment of rehabilitation technologies in stroke. Outcomes and costs.

Initial functional ability (Barthel Index, mean 57) was found to be an important predictor of functional ability 1 year after stroke (mean 80) and for costs during the period. On average the total cost for a stroke patient was about SEK 200,000; the main expense, accommodation, averaged about SEK 140,000, while assistive devices amounted to SEK 2,600. Those who use assistive devices, although having achieved a high functional ability, perceive and rate their life situation (Nottingham Health Profile) considerably more impaired than those without assistive devices.

High level of anticardiolipin antibodies is an unusual finding in an unselected stroke population.

Anticardiolipin antibodies (ACA) were analysed in 502 consecutive patients admitted to our stroke unit Elevated ACA levels ≥11 units) were found in 20 of 396 patients (5%) with ischemic stroke and TIA, in none of 42 patients with cerebral haematomas and in five of 64 patients (8%) with other diagnoses than stroke. There were no statistically significant differences in occurrence of ACA in these groups. Markedly elevated ACA levels (> 20 units) were found in nine of the 396 patients (2%) with TIA/ischemic stroke. The frequency of ACA was higher in the age group 40-50 years (15%) than in the age group 50-90 years (3.6-6.0%). Re-examination in 18 of the 20 patients with ischemic stroke and elevated ACA levels after 26-395 days (mean 100 days) showed that in 10 patients ACA levels were lower (difference ≥ 6 units = 2 SD), compared to the initial value, whereas eight patients had unchanged ACA levels. The occurrence of previous deep venous thrombosis was significantly more common in patients with elevated ACA levels, otherwise there were no differences concerning earlier stroke, risk factor analysis or other laboratory parameters between patients with and without elevated ACA levels. In conclusion, we found elevated ACA levels in patients with ischemic stroke at a rather low prevalence as compared to most previous studies. The clinical relevance of ACA is uncertain, especially in patients with multiple risk factors. We recommend screening for ACA only in stroke patients < 50 years of age, or when the antiphospholipid syndrome is suspected.

[Binswanger disease. A blood pressure-related dementia]. / Binswangers sjukdom. En blodtrycks-relaterad demens.

Interest in Binswanger's disease has increased during the past decade, owing to the possibility of detecting white matter changes with computerised and magnetic resonance tomography. This paper consists in a summary of clinical symptoms and signs and possible diagnostic criteria, discussion of differential diagnosis, and the presentation of two own cases. Both patients manifested mild dementia and gait disturbance, and one had frequent drop attacks. Severe supra- and infra-tentorial white matter changes were present in both cases. It is important to consider a possible diagnosis of Binswanger's disease, as treatment of the appropriate risk factors may prevent or delay the development of dementia.

Work-related, noise-induced hearing loss: evaluation including evoked potential audiometry.

This article reviews the evaluation of 246 workers (492 ears) who underwent otologic and audiologic testing as part of a worker's compensation claim for work-related, noise-induced hearing loss. Tinnitus was present in 58% of the patients, but was rarely a major symptom. Other otologic symptoms or a history of ear disease were virtually nonexistent. Standard audiometry showed a downsloping, high-frequency sensorineural hearing loss in 85% of the ears tested, with only 37% having a characteristic "noise notch" at 4000 or 6000 hertz. Asymmetric hearing loss was not uncommon, with 48 patients (20%) undergoing magnetic resonance scanning, all of whom showed no central lesion responsible for the loss. Proven malingering was surprisingly uncommon (9%). In this study, evoked response audiometry was a valuable adjunct to confirm behavioral thresholds in the evaluation of possible work-related, noise-induced hearing loss. The middle latency response was more effective than the auditory brainstem response as a result of the high-frequency steepness of the audiometric curve.