Effect of metformin on outcome after acute ischemic stroke in patients with type 2 diabetes mellitus.

INTRODUCTION: Diabetes mellitus is a well-known risk factor for ischemic stroke and is associated with unfavorable outcome after stroke. Metformin is recommended as first-line treatment in these patients. Pre-stroke metformin use might have neuroprotective properties resulting in reduced stroke severity. However, results of the effects of pre-stroke metformin use on functional outcome are conflicting and has not been previously described in patients with type 2 diabetes mellitus regardless of stroke severity or revascularization treatment. In this study, we aimed to assess the association between metformin use and functional outcome in patients with type 2 diabetes mellitus and acute ischemic stroke. METHODS: We used data from patients with known type 2 diabetes mellitus who were admitted with acute ischemic stroke between 2017 and 2021 in the Isala Hospital Zwolle and Medisch Spectrum Twente (MST) Enschede, the Netherlands. The association between pre-stroke metformin use and favorable functional outcome at 3 months (defined as modified Rankin Scale (mRS) < 3) was expressed as Odds Ratios (ORs) with corresponding confidence intervals (CIs). Adjustments were made for age, sex, hyperglycemia on admission and revascularization treatment by means of multiple logistic regression. RESULTS: Nine hundred thirty seven patients were included of whom 592 patients (63%) used metformin. Six hundred seventy eight (74%) patients were hyperglycemic on admission. Median mRS was 3 (IQR 2-6) and 593 patients (63%) had a favorable outcome. Pre-stroke metformin use was associated with favorable outcome (aOR of 1.94 (95%- CI 1.45-2.59)). CONCLUSION: In this study, we showed that pre-stroke metformin use was associated with favorable outcome after acute ischemic stroke in patients with diabetes mellitus type 2.

Microscope objective for imaging atomic strontium with 0.63 micrometer resolution.

Imaging and manipulating individual atoms with submicrometer separation can be instrumental for quantum simulation of condensed matter Hamiltonians and quantum computation with neutral atoms. Here we present an open-source design of a microscope objective for atomic strontium, consisting solely of off-the-shelf lenses, that is diffraction-limited for 461 nm light. A prototype built with a simple stacking design is measured to have a resolution of 0.63(4) µm, which is in agreement with the predicted value. This performance, together with the near diffraction-limited performance for 532 nm light, makes this design useful for both quantum gas microscopes and optical tweezer experiments with strontium. Our microscope can easily be adapted to experiments with other atomic species such as erbium, ytterbium, and dysprosium, as with rubidium Rydberg atoms.

Comparison of outcome in stroke patients admitted during working hours vs. off-hours; a single-center cohort study.

INTRODUCTION: We aimed to disprove an in-hospital off-hour effect in stroke patients by adjusting for disease severity and poor prognostic findings on imaging. PATIENTS AND METHODS: Our study included 5378 patients from a single center prospective stroke registry of a large teaching hospital in the Netherlands, admitted between January 2003 and June 2015. Patients were categorized by admission time, off-hours (OH) or working hours (WH). The in-hospital mortality, 7-day mortality, unfavorable functional outcome (modified Rankin scale > 2) and discharge to home were analyzed. Results were adjusted for age, sex, stroke severity (NIHSS score) and unfavorable findings on imaging of the brain (midline shift and dense vessel sign). RESULTS: Overall, 2796 patients (52%) were admitted during OH, which had a higher NIHSS score [3 (IQR 2-8) vs. 3 (IQR 2-6): p < 0.01] and had more often a dense vessel sign at admission (7.9% vs. 5.4%: p < 0.01). There was no difference in mortality between the OH-group and WH-group (6.2% vs. 6.0%; p = 0.87). The adjusted hazard ratio of in-hospital mortality during OH was 0.87 (95% CI: 0.70-1.08). Analysis of 7-day mortality showed similar results. Unadjusted, the OH-group had an unfavorable outcome [OR: 1.14 (95% CI: 1.02-1.27)] and could less frequently be discharged to home [OR: 1.16 (95% CI: 1.04-1.29)], which was no longer present after adjustment. DISCUSSION AND CONCLUSIONS: The overall outcome of stroke patients admitted to a large Dutch teaching hospital is not influenced by time of admission. When studying OH effects, adjustment for disease severity and poor prognostic findings on imaging is crucial before drawing conclusions on staffing and material.

Detecting interictal discharges in first seizure patients: ambulatory EEG or EEG after sleep deprivation?

PURPOSE: Uncertainty about recurrence after a first unprovoked seizure is a significant psychological burden for patients, and motivates the need for diagnostic tools with high sensitivity and specificity to assess recurrence risk. As the sensitivity of a routine EEG after a first unprovoked seizure is limited, patients often require further diagnostics. Here, we study if ambulatory EEG (aEEG) has similar diagnostic accuracy as sleep deprived EEG (sdEEG). METHODS: In this retrospective cohort, we included patients with an unprovoked first seizure and a normal routine EEG who subsequently underwent an sdEEG or aEEG. All EEGs were reviewed for the presence of interictal epileptiform discharges (IEDs). We calculated specificity and sensitivity of sdEEG and aEEG, using the clinical diagnosis of epilepsy as golden standard. All patients had a follow-up of one year. RESULTS: We included 104 patients. Sensitivities for sdEEG and aEEG were 45% (specificity 91%) and 63% (specificity 95%), respectively. Independent risk factor for recurrent seizure were IEDs on the additional EEG, with a relative risk of 1.5 of having a recurrent seizure within a year. CONCLUSION: Diagnostic accuracies of sdEEG and aEEG are similar and depending on patients' and clinicians' preference both can be considered in patients with a first seizure and a normal routine EEG to determine recurrence risk.

Levels of heparin-releasable TFPI are increased in first-ever lacunar stroke patients.

OBJECTIVES: New insights in the pathophysiology of lacunar stroke (LS) suggest that it is caused by increased permeability of the blood-brain barrier due to endothelial activation. Because endothelial cells are the major production and storage site of tissue factor pathway inhibitor (TFPI), this protein can be used as marker of endothelial activation. In this observational study we measured the different pools of TFPI, as a marker of endothelial function, in first-ever lacunar stroke patients. METHODS: We determined antigen levels of total and free full-length (FL) TFPI using ELISA in 149 patients and 42 controls. Heparin-releasable free FL TFPI was determined in a random subset of 17 patients and 15 controls. By brain MRI, we classified LS patients as having isolated lacunar infarct (ILA) or silent ischemic lesions (SILs). RESULTS: Plasma levels of total TFPI were highest in patients with SILs compared with those with ILA, but this association disappeared after correction for age and levels of low-density lipoprotein cholesterol. However, levels of heparin-releasable free FL TFPI were higher in patients than in controls. CONCLUSIONS: Although ambient plasma levels of total TFPI were not different in subtypes of LS, the increased levels of heparin-releasable TFPI in patients suggest a role of endothelial activation in the pathogenesis of LS.

Disappearing hyperdense middle cerebral artery sign is associated with striatocapsular infarcts on follow-up CT in ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND: A striatocapsular infarct (SCI) is a subcortical infarct in the territory of the lenticulostriate arteries, most likely due to transient occlusion of the main stem of the middle cerebral artery (MCA). Presence of the hyperdense middle cerebral artery sign (HMCAS) is a reliable marker of occlusion of the MCA. We hypothesized that SCIs are related to HMCAS at baseline, which subsequently disappears (HMCAS-D) on follow-up CT in stroke patients treated with intravenous rtPA. METHODS: Baseline and 24-hour follow-up CTs were evaluated for HMCAS in acute ischemic stroke patients treated with intravenous rtPA and follow-up scans were also reviewed for the presence of isolated cortical (CIn), SCI, cortical and striatocapsular (CI-SCI) or lacunar infarct. We determined the incidence of SCI and the association between SCI and HMCAS on baseline and follow-up CT. RESULTS: Of the 247 patients, 43 had an SCI (17.4%; 95% CI: 13.1-22.5). The presence of HMCAS at baseline was related to the occurrence of infarction with involvement of the striatocapsular region (SCI or CI-SCI) on follow-up CT (OR: 11.6; 95% CI: 5.9-22.8). HMCAS-D on follow-up scans was significantly related to SCI on follow-up CT compared to CI-SCI (OR: 4.9; 95% CI: 3.7-6.1). CONCLUSIONS: Occurrence of SCI and CI-SCI is associated with the presence of HMCAS on CT before thrombolysis, whereas HMCAS-D on follow-up CT is strongly related to the occurrence of SCI. Our findings support the causative role of transient occlusion of the MCA main stem in the pathogenesis of SCI.

Metabolic syndrome relates to lacunar stroke without white matter lesions: a study in first-ever lacunar stroke patients.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of three or more of the following risk factors: obesity, elevated blood pressure, elevated triglyceride level, elevated glucose level, and low high-density lipoprotein level. Lacunar infarcts (LS) account for 25% of all ischemic strokes and are small, deeply located brain infarcts. Two different subtypes exist, which are distinguished by the presence of concomitant white matter lesions (WML) on brain imaging. We determined the prevalence of MetS in LS and the association between MetS with LS subtypes in a series of first-ever LS patients. METHODS: We included 92 patients with a first-ever LS, and 92 patients with a first-ever atheroslerotic cortical stroke (CS) matched for age and sex. LS subtypes were defined according to presence of concomitant WML. We defined MetS retrospectively according to previously defined standards. RESULTS: 35.9% of LS patients and 45.7% of CS patients had MetS (OR 0.67; 95% CI 0.37-1.20). MetS was more prevalent in LS without WML than in LS with WML (44.4 and 23.7%, respectively; OR 2.98; 95% CI 1.04-8.47). Similarly, MetS related more to CS compared to LS with WML (OR 2.56; 95% CI 1.03-6.37). CONCLUSION: MetS relates more strongly to LS without WML and to CS, than to LS with WML. Our results suggest a different underlying mechanism between LS without WML and CS, and lacunar stroke with WML.

Haptoglobin phenotype may alter endothelial progenitor cell cluster formation in cerebral small vessel disease.

Cerebral small vessel disease results in silent ischemic lesions (SIL) among which is leukoaraiosis. In this process, endothelial damage is probably involved. Endothelial progenitor cells (EPC), are involved in endothelial repair. By restoring the damaged endothelium, EPC could mitigate SIL and cerebral small vessel disease. Haptoglobin 1-1, one of three phenotypes of haptoglobin, relates to SIL and may therefore attenuate the endothelial repair by EPC. Our aim was to quantify EPC number and function and to assess haptoglobin phenotype and its effect on EPC function in patients with a high prevalence of SIL: lacunar stroke patients. We assessed EPC In 42 lacunar stroke patients and 18 controls by flow cytometry and culture with fetal calf serum, patient and control serum. We determined haptoglobin phenotype and cultured EPC with the three different haptoglobin phenotypes. We found that EPC cluster counts were lower in patients (96.9 clusters/well +/- 83.4 (mean +/- SD)), especially in those with SIL (85.0 +/- 64.3), than in controls (174.4 +/- 112.2). Cluster formation was inhibited by patient serum, especially by SIL patient serum, but not by control serum. Patients with haptoglobin 1-1 had less clusters in culture, and when haptoglobin 1-1 was added to EPC cultures, cluster numbers were lower than with the other haptoglobin phenotypes. We conclude that lacunar stroke patients, especially those with SIL, have impaired EPC cluster formation, which may point at decreased endothelial repair potential. The haptoglobin 1-1 phenotype is likely a causative factor in this impairment.

Virchow-Robin spaces relate to cerebral small vessel disease severity.

BACKGROUND AND PURPOSE: Virchow-Robin spaces (VRs) are perivascular spaces surrounding the deep perforating brain arteries. VRs dilatation is pathologic, and it could be a manifestation of cerebral small vessel disease. In the present study we assessed the relation between VRs and silent ischemic lesions in a cohort of patients with cerebral small vessel disease. METHODS: We divided dilated VRs on MRI (1.5 Tesla) into three semi-quantitative categories in 165 first ever lacunar stroke patients. We counted asymptomatic lacunar infarcts and graded white matter lesions, and compared the prevalence of vascular risk factors in different categories of VRs. We also determined independent predictors of silent ischemic lesions. RESULTS: VRs at basal ganglia level related to age, hypertension, asymptomatic lacunar infarcts, and white matter lesions. VRs at basal ganglia level predicted silent ischemic lesions (odds ratio 10.58 per higher VRs category; 95 %- confidence interval 3.40 - 32.92). CONCLUSION: Dilated VRs in the basal ganglia relate to the severity of cerebral small vessel disease and might be a manifestation of the same small vessel abnormality that causes silent ischemic lesions. This adds a role for VRs as a potential marker for small vessel disease.

A clinical overview of Tilarin.

Tilarin is a nasal spray containing 1% nedocromil sodium, a non-toxic pyranoquinoline dicarboxylate compound with potent antiallergic antiinflammatory properties. As a first-line topical treatment for seasonal allergic rhinitis (SAR) the pharmacokinetics of nedocromil sodium nasal formulation are such that it rivals sodium cromoglycate for safety. Less than 8% of the total dose of nedocromil sodium is systemically absorbed from the nasal mucosa, and this is reversibly bound to plasma proteins and is cleared rapidly from the circulation. Nedocromil sodium is eliminated unmetabolised in the urine and faeces, with an elimination half-life of 5.3 +/- 0.9 minutes. No significant adverse effects have been reported following intranasal administration of 1% nedocromil sodium four times daily, to a total of 964 patients with allergic rhinitis during clinical trials. Laboratory studies have shown that nedocromil sodium has a more wide-ranging pharmacological antiinflammatory profile than sodium cromoglycate and this is manifest in its clinical efficacy in allergic asthma and rhinoconjunctivitis. Analysis of pooled data from a series of double-blind, placebo-controlled group comparative studies in SAR patients demonstrated that, despite a significantly lower use of rescue antihistamines than with placebo treatment (31% reduction; p = 0.005), four times daily dosage with nedocromil sodium 1% nasal spray significantly reduced daily symptoms of rhinitis (p < 0.001) and was considered effective by the majority of patients (p < 0.001). Specific examples of the therapeutic efficacy of nedocromil sodium compared with placebo in patients with grass or ragweed pollen SAR can be found in the literature. One ragweed study (1) included four times daily sodium cromoglycate 4% nasal spray as an active comparator and showed a consistent, if non-significant, trend in favour of nedocromil sodium 1%, which was the more effective drug in comparison to placebo. An Italian paediatric study (2) compared nedocromil sodium 1% nasal spray with placebo in 149 children of whom 72% were under twelve years of age. After one week, the clinicians observed a significant reduction (p = 0.03) in sneezing with nedocromil sodium and after four weeks, patient (p < 0.01) and clinican (p < 0.001) opinions favoured the active treatment. Overall, the clinical profile of topical nedocromil sodium in SAR demonstrates fast relief of existing symptoms, sustained efficacy with four times daily use during peak pollen challenge, and a reduced need for concomitant symptomatic therapies. Nedocromil sodium 1% nasal spray is well tolerated, with minimal side-effects, and is acceptable to a wide age-range of patients.

Inhibition of the late asthmatic response by nedocromil sodium administered more than two hours after allergen challenge.

Fourteen adult patients with bronchial asthma who were known late responders to bronchial allergen challenge were entered into a double-blind crossover study to compare the protective effects of nedocromil sodium (3 x 4 mg) and placebo aerosols on the late asthmatic response (LAR). After screening for development of an LAR (fall in forced expiratory volume in 1 second [FEV1] > or = 20% at at least 3 consecutive time points, 4 to 10 hours after challenge), patients were randomized to test treatment on 2 study days, with an interval of at least 3 days. Nine of the patients had a dual late response, which is a combination of an immediate and a late response, and five other patients had an isolated late response only. On each study day the concentration of allergen that previously elicited a response was inhaled for 10 minutes. FEV1 was recorded every 10 or 15 minutes for up to 1 hour after challenge, and then at hourly intervals for 12 hours and every second hour on the next 2 days. Test treatments were administered in three doses at 30-minute intervals, with the first dose given 90 minutes before the expected onset of the LAR for each patient. Compared with placebo, nedocromil sodium significantly inhibited the LAR (p < 0.05) at each time point measured from 6 to 10 hours after challenge and reduced the maximum fall in FEV1 by 21.0% overall (p = 0.003).

Nedocromil sodium 2% ophthalmic solution (Tilavist(TM)) A new topical treatment for ocular allergic inflammation.

Nedocromil sodium, a non-toxic pyranoquinoline dicarboxylate, was developed as a novel topical treatment for allergic inflammatory lung diseases. With a broader pharmacological potential than the chromone compound sodium cromoglycate, nedocromil sodium has more potent antiinflammatory effects whilst maintaining a good safety profile due to rapid excretion, unmetabolized. Having the ability to stabilize both mucosal (MC(T)) and connective tissue (MC(TC)) mast cells and directly to inhibit activated cells such as eosinophils, which are involved in continuing allergic inflammation in the eye as well as in the airways, nedocromil sodium appears ideally suited to the treatment of allergic conjunctivitis. Preliminary therapeutic trials have confirmed efficacy and the lack of side-effects of the 2% eye drop formulation of nedocromil sodium, and its comparative potency which permits twice-daily administration for seasonal ocular symptoms, with the safe option of increasing to four times daily use for more severe, chronic allergic inflammatory conditions. With many patients already symptomatic at the start of trial treatment, nedocromil sodium eye drops have also proved to have a rapid onset of action providing relief of symptoms in 24 hours in the majority of cases, and often within one hour of the first dose.