Single MRI-Based Volumetric Assessment in Clinical Practice Is Associated With MS-Related Disability.

BACKGROUND: The added value of brain volume measurements in the clinical practice of multiple sclerosis (MS) has been questioned. PURPOSE: To investigate the contribution of volume measures obtained with magnetic resonance scans performed as part of regular care to predict measures of cognitive and physical MS disability in a real-world setting. STUDY TYPE: Retrospective. SUBJECTS: In all, 470 adults with diagnosed MS. FIELD STRENGTH/SEQUENCE: 3D fluid attenuation inversion recovery (FLAIR) and 3D T1 -weighted MR images at 3.0T MR. ASSESSMENT: Lesion and brain volume were measured by an automated method, MSmetrix, developed by icometrix. STATISTICAL TESTS: We used stepwise linear regression models to assess the added value of a single volumetric assessment in predicting Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Brain volumes categorized into quartiles were used as predictive variables in a time-to-event analysis and Cox proportional hazard regression with time to worsening from baseline as outcome measures. RESULTS: Brain and lesion volume in relapsing onset MS strongly contributed to the best models, with a substantial role for age in the EDSS model and a modest role for education in the SDMT model. Adding MR volumetric information increased the explained variance from 17% to 28% in the best model for EDSS and from 9% to 25% in the best model for SDMT. A significantly reduced hazard (P < 0.05) of SDMT worsening was found in the highest normalized brain volume quartiles (1375-1608 ml), compared with the lowest quartile (1201-1374 ml) in the total study population. DATA CONCLUSION: Our findings indicate that a single brain volumetric assessment contributes to the prediction of MS-related disability, with distinct patterns for EDSS as a measure of physical disability, and SDMT as a measure of cognitive disability. A threshold effect for the lowest brain volumes with regard to SDMT worsening over time was found. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1312-1321.

Fluoxetine in progressive multiple sclerosis: The FLUOX-PMS trial.

BACKGROUND: Preclinical studies suggest that fluoxetine has neuroprotective properties that might reduce axonal degeneration in multiple sclerosis (MS). OBJECTIVE: To determine whether fluoxetine slows accumulation of disability in progressive MS. METHODS: In a double-blind multicenter phase 2 trial, patients with primary or secondary progressive MS were randomized to fluoxetine 40 mg/day or placebo for a period of 108 weeks. Clinical assessments were performed every 12 weeks by trained study nurses who visited the patients at their home. The primary outcome was the time to a 12-week confirmed 20% increase in the Timed 25 Foot Walk or 9-Hole Peg test. Secondary outcomes included the Hauser ambulation index, cognitive tests, fatigue, and brain magnetic resonance imaging (MRI). RESULTS: In the efficacy analysis, 69 patients received fluoxetine and 68 patients received placebo. Using the log-rank test (p = 0.258) and Cox regression analysis (p = 0.253), we found no significant difference in the primary outcome between the two groups. Due to an unexpected slow rate of progression in the placebo group, there was insufficient statistical power to detect a potential benefit of fluoxetine. We found no differences between the two groups for secondary outcomes. CONCLUSION: The trial failed to demonstrate a neuroprotective effect of fluoxetine in patients with progressive MS.

Absence of system xc- on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System xc- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. METHODS: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT-/-) mice and irradiated mice reconstituted in xCT-/- bone marrow (BM), to their proper wild type (xCT+/+) controls. RESULTS: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT+/+ mice, xCT-/- mice were equally susceptible to EAE, whereas mice transplanted with xCT-/- BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. CONCLUSIONS: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc- on immune cells invading the CNS participates to EAE. Since a total loss of system xc- had no net beneficial effects, these results have important implications for targeting system xc- for treatment of MS.

Development and Pilot Testing of 24/7 In-Ambulance Telemedicine for Acute Stroke: Prehospital Stroke Study at the Universitair Ziekenhuis Brussel-Project.

BACKGROUND: In-ambulance telemedicine is a recently developed and a promising approach to improve emergency care. We implemented the first ever 24/7 in-ambulance telemedicine service for acute stroke. We report on our experiences with the development and pilot testing of the Prehospital Stroke Study at the Universitair Ziekenhuis Brussel (PreSSUB) to facilitate a wider spread of the knowledge regarding this technique. METHODS: Successful execution of the project involved the development and validation of a novel stroke scale, design and creation of specific hardware and software solutions, execution of field tests for mobile internet connectivity, design of new care processes and information flows, recurrent training of all professional caregivers involved in acute stroke management, extensive testing on healthy volunteers, organisation of a 24/7 teleconsultation service by trained stroke experts and 24/7 technical support, and resolution of several legal issues. RESULTS: In all, it took 41 months of research and development to confirm the safety, technical feasibility, reliability, and user acceptance of the PreSSUB approach. Stroke-specific key information can be collected safely and reliably before and during ambulance transportation and can adequately be communicated with the inhospital team awaiting the patient. CONCLUSION: This paper portrays the key steps required and the lessons learned for successful implementation of a 24/7 expert telemedicine service supporting patients with acute stroke during ambulance transportation to the hospital.

Admission hyperglycemia and outcome after intravenous thrombolysis: is there a difference among the stroke-subtypes?

BACKGROUND: The prognostic influence of hyperglycemia in acute stroke has been well established. While in cortical stroke there is a strong association between hyperglycemia and poor outcome, this relation is less clear in lacunar stroke. It has been suggested that this discrepancy is present among patients treated with intravenous tissue plasminogen activator (tPA), but confirmation is needed. METHODS: In two prospectively collected cohorts of patient treated with intravenous tPA for acute ischemic stroke, we investigated the effect of hyperglycemia (serum glucose level >8 mmol/L) on functional outcome in lacunar and non-lacunar stroke. Poor functional outcome was defined as modified Rankin Scale score ≥ 3 at 3 months. RESULTS: A total of 1012 patients was included of which 162 patients (16%) had lacunar stroke. The prevalence of hyperglycemia did not differ between stroke subtypes (22% vs 21%, p = 0.85). In multivariate analysis hyperglycemia was associated with poor functional outcome in non-lacunar stroke (OR 2.1, 95% CI 1.39-3.28, p = 0.001). In patients with lacunar stroke, we did not find an association (OR 1.8, 95% CI 0.62-4.08, p = 0.43). CONCLUSION: This study confirms a difference in prognostic influence of hyperglycemia between non-lacunar and lacunar ischemic stroke.

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.

Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.

The Effect of Age and Sex on Clinical Outcome after Intravenous Recombinant Tissue Plasminogen Activator Treatment in Patients with Acute Ischemic Stroke.

BACKGROUND: There are conflicting results regarding the effect of intravenous (IV) recombinant tissue plasminogen activator (rtPA) stroke treatment between men and women. Studies evaluating the impact of sex differences on functional outcome in relation to different age groups are nonexistent. AIM: The objective of the study is to examine the influence of sex differences in relation to age on the prognosis after IV rtPA treatment in acute stroke patients. METHODS: In this cohort study, 887 patients with acute ischemic stroke were treated with rtPA. Functional outcome after 3 months was determined with the modified Rankin Scale (mRS). Good outcome was defined as an mRS score of 2 or lower. Age was stratified in decades (41-50, 51-60, 61-70, 71-80, and >80 years). Multivariable analyses were performed with adjustment for age, sex, stroke severity (National Institutes of Health Stroke Scale [NIHSS]), and stroke subtype (Trial of Org 10172 in Acute Stroke Treatment). RESULTS: Fifty-five percent of the patients were men. The mean age was 67.4 (men) and 72.0 (women) years. Fifty-six percent of the men and 45% of the women had a favorable outcome (P = .001). After adjustment for NIHSS score and stroke subtype, the women had a better outcome in the age group 51-60 years compared with men (odds ratio [OR] .38, 95% confidence interval [CI] .15-.96). In the age group >80 years, men had a better outcome than women (OR 2.69, 95% CI 1.21-5.96). There were no significant differences in the other age groups. CONCLUSION: Men and women have different prognoses after IV rtPA treatment for acute ischemic stroke, which also depends on age. Women in middle age appear to have a better outcome than men, whereas at a more advanced age men appear to have a better outcome than women.

Reduced information processing speed as primum movens for cognitive decline in MS.

BACKGROUND: Cognitive impairment affects half of the multiple sclerosis (MS) patient population and is an important contributor to patients' daily activities. Most cognitive impairment studies in MS are, however, cross-sectional or/and focused on the early disease stages. OBJECTIVE: We aim to assess the time course of decline of different cognitive domains. METHODS: We collected neuropsychological data on 514 MS patients to construct Kaplan-Meier survival curves of the tests included in the Neuropsychological Screening Battery for MS (NSBMS) and the Symbol Digit Modalities Test (SDMT). Cox-proportional hazard models were constructed to examine the influence of MS onset type, age at onset, gender, depression and level of education on the time course, expressed as age or disease. RESULTS: Survival curves of tests focusing on information processing speed (IPS) declined significantly faster than tests with less specific demands of IPS. Median age for pathological decline was 56.2 years (95% CI: 54.4-58.2) on the SDMT and 63.9 years (95% CI: 60-66.9) on the CLTR, a memory task. CONCLUSION: In conclusion, IPS is the cognitive domain not only most widely affected by MS but it is also the first cognitive deficit to emerge in MS.

ß2-adrenergic agonists modulate TNF-α induced astrocytic inflammatory gene expression and brain inflammatory cell populations.

BACKGROUND: The NF-κB signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic ß2-adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic ß2-adrenergic receptors and the TNF-α induced inflammatory gene program. METHODS: Proinflammatory conditions were generated by the administration of TNF-α. Genes that are susceptible to astrocytic crosstalk between ß2-adrenergic receptors (stimulated by clenbuterol) and TNF-α were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes in vitro were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes. In vivo expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF-α in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-α administration. RESULTS: Parallel transcriptional patterns in vivo and in vitro confirmed the relevance of astrocytic ß2-adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of ß2-adrenergic receptor agonists and TNF-α on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-α co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance. CONCLUSIONS: Our results show that astrocytic ß2-adrenergic receptors are potent regulators of astrocytic TNF-α-activated genes in vitro and in vivo, and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic ß2-adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses.

Prehospital stroke care: limitations of current interventions and focus on new developments.

BACKGROUND: The global burden of stroke is immense, both in medical and economic terms. With the aging population and the ongoing industrialization of the third world, stroke prevalence is expected to increase and will have a major effect on national health expenditures. Currently, the medical treatment for acute ischemic stroke is limited to intravenous recombinant tissue plasminogen activator (IV r-tPA), but its time dependency leads to low utilization rates in routine clinical practice. Prehospital delay contributes significantly to delayed or missed treatment opportunities in acute stroke. State-of-the-art acute stroke care, starting in the prehospital phase, could thereby reduce the disease burden and its enormous financial costs. SUMMARY: The first part of this review focuses on current education measures for the general public, the emergency medical services (EMS) dispatchers and paramedics. Although much has been expected of these measures to improve stroke care, no major effects on prehospital delay or missed treatment opportunities have been demonstrated over the years. Most interventional studies showed little or no effect on the onset-to-door time, IV r-tPA utilization rates or outcome, except for prenotification of the receiving hospital by the EMS. No data are currently available on the cost-effectiveness of these commonly used measures. In the second part, we discuss new developments for the improvement of prehospital stroke diagnosis and treatment which could open new perspectives in the nearby future. These include the implementation of prehospital telestroke and the deployment of mobile stroke units. These approaches may improve patient care and could serve as a platform for prehospital clinical trials. Other opportunities include the implementation of noninvasive diagnostics (like transcranial ultrasound and blood-borne biomarkers) and the reevaluation of neuroprotective strategies in the prehospital phase. Key Messages: Timely initiation of treatment can effectively reduce the medical and economic burden of stroke and should begin with optimal prehospital stroke care. For this, prehospital telemedicine is a particularly attractive approach because it is a scalable solution that has the potential to rapidly optimize acute stroke care at limited cost.

Unassisted assessment of stroke severity using telemedicine.

BACKGROUND AND PURPOSE: Quantification of stroke severity through telemedicine consultation is challenging and relies on professional support at the patient's bedside. We aimed to develop a novel scale for assessing stroke severity through telemedicine without assistance from a third party (Unassisted TeleStroke Scale [UTSS]). METHODS: Stroke severity was assessed in 45 patients with suspicion of acute stroke by bedside examination using the National Institutes of Health Stroke Scale (NIHSS) and by teleconsultation using the UTSS. Scale reliability was evaluated by intrarater and interrater variability, internal consistency, and rater agreement. Concurrent and predictive validity were tested by relating the UTSS with the NIHSS and long-term outcome (modified Rankin Scale and mortality at 6 months). Clinimetric analysis of the UTSS was obtained via the Rasch model. RESULTS: The mean examination time for the UTSS was 3.1 minutes (SD, 1.1) versus 8.5 minutes for the NIHSS (SD, 2.6; P<0.001). Both UTSS and NIHSS showed excellent intrarater variability (r=0.97 and 0.98; P<0.001) and interrater variability (r=0.96 and 0.98; P<0.001), as well as excellent internal consistency and rater agreement. The UTSS correlated strongly with the NIHSS and was identified as an independent predictor of stroke outcome in logistic regression analysis. Rasch analysis indicated that the UTSS represents a unidimensional scale of stroke severity. CONCLUSIONS: The UTSS is a rapid, reliable, and valid tool for unassisted assessment of stroke severity through telemedicine.

Prehospital unassisted assessment of stroke severity using telemedicine: a feasibility study.

BACKGROUND AND PURPOSE: We evaluated the feasibility and the reliability of remote stroke severity quantification in the prehospital setting using the Unassisted TeleStroke Scale (UTSS) via a telestroke ambulance system and a fourth-generation mobile network. METHODS: The technical feasibility and the reliability of the UTSS were studied in healthy volunteers mimicking 41 stroke syndromes during ambulance transportation. RESULTS: Except for 1 issue, high-quality telestroke assessment was feasible in all scenarios. The mean examination time for the UTSS was 3.1 minutes (SD, 0.4). The UTSS showed excellent intrarater and interrater variability (ρ=0.98 and 0.97; P<0.001), as well as excellent internal consistency and rater agreement. Adequate concurrent validity can be derived from the strong correlation between the UTSS and the National Institutes of Health Stroke Scale (ρ=0.90; P<0.001). CONCLUSIONS: Remote assessment of stroke severity in fast-moving ambulances using a system dedicated to prehospital telemedicine, 4G technology, and the UTSS is feasible and reliable.

Cerebral white matter blood flow and energy metabolism in multiple sclerosis.

BACKGROUND: Cerebral blood flow (CBF) is reduced in normal-appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but the underlying mechanism is unknown. OBJECTIVE: The objective of this article is to assess the relationship between reduced NAWM CBF and both axonal mitochondrial metabolism and astrocytic phosphocreatine (PCr) metabolism. METHODS: Ten healthy controls and 25 MS subjects were studied with 3 Tesla magnetic resonance imaging. CBF was measured using pseudo-continuous arterial spin labeling. N-acetylaspartate/creatine (NAA/Cr) ratios (axonal mitochondrial metabolism) were obtained using (1)H-MR spectroscopy and PCr/ß-ATP ratios using (31)P-MR spectroscopy. In centrum semiovale NAWM, we assessed correlations between CBF and both NAA/Cr and PCr/ß-ATP ratios. RESULTS: Subjects with MS had a widespread reduction in CBF of NAWM (centrum semiovale, periventricular, frontal and occipital), and gray matter (frontoparietal cortex and thalamus). Compared to controls, NAA/Cr in NAWM of the centrum semiovale of MS subjects was decreased, whereas PCr/ß-ATP was increased. We found no correlations between CBF and PCr/ß-ATP. CBF and NAA/Cr correlated in controls (p = 0.02), but not in MS subjects (p = 0.68). CONCLUSIONS: Our results suggest that in MS patients there is no relationship between reduced CBF in NAWM and impaired axonal mitochondrial metabolism or astrocytic PCr metabolism.

Headache associated with cough: a review.

Headache only triggered by coughing is a rather uncommon condition. The aim of the present review is to present an overview of the diagnosis, clinical characteristics, pathophysiology and treatment of both primary and symptomatic cough headache and discuss other relevant headache disorders affected by coughing. The diagnosis of primary cough headache is made when headache is brought on and occurs only in association with coughing, straining or a Valsalva manoeuvre and in the absence of any abnormalities on neuro-imaging. In case an underlying pathology is identified as a cause of the headache, the diagnosis of symptomatic cough headache is made. The vast majority of these patients present with a Chiari malformation type I. Other frequently reported causes include miscellaneous posterior fossa pathology, carotid or vertebrobasilar disease and cerebral aneurysms. Consequently, diagnostic neuroimaging is key in the diagnosis of cough-related headache and guides treatment. Besides primary and symptomatic cough headache, several other both primary and secondary headache disorders exist where coughing acts as a trigger or aggravator of headache symptomatology.

Gut microbiome composition is associated with long-term disability worsening in multiple sclerosis.

Predicting the long-term outcome of multiple sclerosis (MS) remains an important challenge to this day. As the gut microbiota is emerging as a potential player in MS, we investigated in this study whether gut microbial composition at baseline is related to long-term disability worsening in a longitudinal cohort of 111 MS patients. Fecal samples and extensive host metadata were collected at baseline and 3 months post-baseline, with additional repeated neurological measurements performed over (median) 4.4 y. Worsening (with EDSS-Plus) occurred in 39/95 patients (outcome undetermined for 16 individuals). The inflammation-associated, dysbiotic Bacteroides 2 enterotype (Bact2) was detected at baseline in 43.6% of worsened patients, while only 16.1% of non-worsened patients harbored Bact2. This association was independent of identified confounders, and Bact2 was more strongly associated with EDSS-Plus than neurofilament light chain (NfL) plasma levels. Furthermore, using fecal sampling performed 3 months post-baseline, we observed Bact2 to be relatively stable, suggesting its potential use as a prognostic biomarker in MS clinical practice.

Exaggerated postural blood pressure rise is related to a favorable outcome in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: The effects of early upright positioning in the acute phase of ischemic stroke on both blood pressure and functional outcome have not been previously examined. METHODS: Prospective investigation of mean arterial pressure, heart rate, and peripheral oxygen saturation in the supine, sitting, and (if achievable) active standing position 1, 2, and 3 days after an acute stroke was performed. Also investigated was the presence of a significant postural blood pressure rise and fall using orthostatic definitions and the relation to functional outcome after 3 months. RESULTS: One hundred sixty-seven patients were included (mean age, 68.5±15.2 years; median National Institutes of Health Stroke Scale, 7). Approximately 60% of the patients were able to stand. On average the mean arterial pressure increased when patients moved from the supine to sitting (Day 1: Δ 3.9 mm Hg; P<0.001) and from sitting to an active standing position (Day 1: Δ 4.6 mm Hg; P<0.001). Changes were most pronounced within the first 24 hours after a stroke. Blood pressure decreased significantly (fall) on standing in 13% of patients and increased significantly (rise) in 20% of the patients. The latter was independently associated with a favorable outcome (P=0.003). Moving to the standing position was accompanied by an increase of heart rate. No difference in oxygen saturation was observed in the various positions over the period of investigation. CONCLUSIONS: We found that a significant blood pressure rise during early upright positioning in patients with acute stroke was independently associated with a favorable outcome. No contraindication to early mobilization was found in this study.

Spontaneously hypertensive rats display reduced microglial activation in response to ischemic stroke and lipopolysaccharide.

BACKGROUND: For successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed. Two important criteria are testing of therapeutic interventions in conscious animals and the presence of a co-morbidity factor. We chose to work with hypertensive rats since hypertension is an important modifiable risk factor for stroke and influences the clinical outcome. We aimed to compare the susceptibility to ischemia in hypertensive rats with those in normotensive controls in a rat model for induction of ischemic stroke in conscious animals. METHODS: The vasoconstrictor endothelin-1 was stereotactically applied in the vicinity of the middle cerebral artery of control Wistar Kyoto rats (WKYRs) and spontaneously hypertensive rats (SHRs) to induce a transient decrease in striatal blood flow, which was measured by the laser Doppler technique. Infarct size was assessed histologically by cresyl violet staining. Sensory-motor functions were measured at several time points using the neurological deficit score. Activation of microglia and astrocytes in the striatum and cortex was investigated by immunohistochemistry using antibodies against CD68/Iba-1 and glial fibrillary acidic protein. RESULTS AND CONCLUSIONS: The SHRs showed significantly larger infarct volumes and more pronounced sensory-motor deficits, compared to the WKYRs at 24 h after the insult. However, both differences disappeared between 24 and 72 h. In SHRs, microglia were less susceptible to activation by lipopolysaccharide and there was a reduced microglial activation after induction of ischemic stroke. These quantitative and qualitative differences may be relevant for studying the efficacy of new treatments for stroke in accordance to the Stroke Therapy Academic Industry Round Table criteria.

Thrombolytic therapy for ischaemic stroke in patients using warfarin: a systematic review and meta-analysis.

BACKGROUND: It is uncertain whether thrombolytic therapy is safe in patients with acute ischaemic stroke who are treated with warfarin and have a subtherapeutic international normalised ratio (INR) at stroke onset. METHODS: The authors performed a systematic review of the literature and included studies that assessed the relation between prior warfarin use with subtherapeutic INR and outcome after intravenous or intra-arterial thrombolytic therapy in acute ischaemic stroke. Outcome measures were symptomatic intracranial haemorrhage (SICH), modified Rankin scale score 0-2 and mortality. Second, the authors performed a meta-analysis of the included studies. RESULTS: Seven studies with 3631 patients were included. 240 (6.6%) patients used warfarin before stroke onset. The risk of SICH was increased in the warfarin group (OR 2.6; 95% CI 1.1 to 5.9. p=0.02). There was no significant difference, however, in functional outcome (OR 0.9; 95% CI 0.6 to 1.2, p=0.32) or death from all causes (OR 1.2; 95% CI 0.9 to 1.8). DISCUSSION: The risk of SICH after thrombolytic therapy is increased in patients using warfarin with subtherapeutic INR levels. The authors found no evidence of an increase in death from all causes or worsening of functional outcome in warfarin treated patients.

Intra-arterial blood pressure reading in intensive care unit patients in the lateral position.

BACKGROUND: Routine lateral turning of patients has become an accepted standard of care to prevent complications of immobility. The haemodynamic and oxygenation effects for patients in both lateral positions (45°) are still a matter of debate. We aimed to study the effect of these positions on blood pressure, heart rate and oxygenation in a general intensive care population. DESIGN: Observational study. METHOD: Twenty stable intensive care unit patients had intra-arterial blood pressure recordings in the supine and lateral positions with the correction of hydrostatic height compared with a fixed reference point (phlebostatic level). A multilevel model was used to analyse the data. RESULTS: Mean arterial pressure readings in the lateral positions were, on average, 5 mmHg higher than in the supine position (p < 0.001). There were no significant differences between mean arterial pressure recordings in the left and right lateral position (p = 1.0). No important differences in oxygenation and heart rate were observed. After correction for covariates, the effects persisted. CONCLUSION: Our study demonstrated an increase, albeit small, in blood pressure in the lateral positions. No major differences between the left and right lateral position were found. No important differences in oxygenation and heart rate were observed. RELEVANCE TO CLINICAL PRACTICE: Turning haemodynamically stable patients in the intensive care unit has no important effects on blood pressure measurements when continuous hydrostatic height correction is applied.