Central Nervous System-Infiltrating T Lymphocytes in Stroke Are Activated via Their TCR (T-Cell Receptor) but Lack CD25 Expression.

Background and Purpose: T lymphocytes contribute to secondary brain damage after stroke. It has not been fully investigated whether this contribution is caused by antigen-specific or antigen-nonspecific activation of T lymphocytes. Lymphocytes from Nur77GFP transgenic mice express a fluorescent protein upon activation via the TCR (T-cell receptor), allowing the differentiation of activation mode in a natural repertoire of immune cells and antigens. Methods: Middle cerebral artery occlusion or sham surgery was performed, and T-lymphocyte activation was analyzed by flow cytometry in the brain, spleen, and blood 16 hours, 2 days, 3 days, 4 days, and 7 days after surgery. Results: Ipsilateral hemispheric T-lymphocyte invasion peaked on day 4 poststroke. Here, we observed PD-1 (programmed cell death protein 1) expression on almost all invading T lymphocytes, while CD25 expression was low. CD25+, CD69+, or PD-1+ T lymphocytes predominantly displayed antigen-specific activation; the opposite was observed for T lymphocytes isolated from the blood. A mixed activation that favored antigen-specific activation was observed in the spleen. PD-1 was upregulated within the brain, whereas CD25 was not. Antigen-specific T lymphocytes home to the brain, while antigen-nonspecifically activated cells remain within the blood. Conclusions: Our data clearly demonstrate antigen-specific activation of T lymphocytes infiltrating ischemic brain lesions in stroke. The high expression of inhibitory PD-1 and low expression of CD25 on activated T lymphocytes in the brain most likely reflect immunosuppressive mechanisms.

A case of acute optic neuritis during pregnancy treated by membrane-based therapeutic plasma exchanges without systemic anticoagulation.

INTRODUCTION: In acute optic neuritis, high dose steroid therapy as first - line treatment is contraindicated in early pregnancy, therapeutic plasma exchanges (TPE) represent an alternative. We report a case of a pregnant woman with progressive, acute optic neuritis subjected to membrane-based therapeutic plasma exchange with extracorporal citrate-based anticoagulation. CASE PRESENTATION: A 35 year-old second-time pregnant woman (4th week of gravidity) of Caucasian ethnicity complained of visual impairment of the right eye. She was hospitalized for suspected optic neuritis. In the eye exam central and peripheral scotoma of the right side were found. T2 weighted Magnetic-Resonance Imaging revealed an isolated, prechiasmal lesion of the right optic nerve, and the patient had a delayed p100 latency of visually evoked potentials of the right eye. Cerebrospinal-fluid investigation was unrevealing. The diagnosis of right sided optic neuritis was established. Due to early pregnancy, steroids were contraindicated. Visual disturbances further deteriorated by day 2 in hospital. For therapy, 5 sessions of membrane-based therapeutic plasma exchange with albumin solution were performed. An extracorporal anticoagulation using citrate with calcium substitution was applied. After the second session, there was a subjective improvement of symptoms. At discharge on day 14, visual acuity was no longer impaired, sensitivity to bright light remained. In eye exam at 3.5 months after discharge, the patient ha d a complete recovery. Follow-up gynecological exams were unrevealing. CONCLUSION: This case of unilateral acute optic neuritis supports the view that membrane-based therpautic plasma exchange without systemic anticoagulation represents a safe intervention in pregnancy.

Evaluation of the COVID-19 pandemic using an algorithm based on the Bateman function: Prediction of disease progression using observational data for the city of Heidelberg, Germany
.

The COVID-19 pandemic has been evaluated using an algorithm based on the Bateman function in a modified SIR/SIZ-Model. Prediction of the number of persons carrying the live COVID-19 coronavirus (I) in a susceptible population (S) was achieved using two rate constants describing the rate of increase and decrease in the number of infectious persons on a daily basis. The model was verified using observational data for the city of Heidelberg, Germany. Three hypothetical scenarios, having their counterparts in practice were considered, namely Scenario A - No restrictions on the population; Scenario B - Assumption of a 10-fold higher number of infections than observed; Scenario C - Protective measures introduced only for elderly persons. It could be demonstrated using the model that the lockdown measures introduced prevented a major medical emergency and possibly a near catastrophe in the region. It was further demonstrated that the prospective application of the model can facilitate realtime decisions on pandemic management strategy for the population. This is achieved by curve-fitting for the rate constants, determinants for the number of infectious persons. The calculated maximum numbers of infected and infectious persons daily increased in proportion to the number of persons initially susceptible to the infection. After appearance of the first two infections in Heidelberg, the calculated maximum number of persons carrying live virus was 2,291 at Day 102 (Scenario B), 18,936 infectious persons at Day 139 (Scenario C) and 22,535 infectious at Day 142 (Scenario A). In Scenario A, high values would have persisted for 6 months during which a total of 124,301 persons would have been infected in Heidelberg. The model predicted that the virus would have disappeared within 1 year after being first detected. A disease catastrophe of this magnitude would not be expected provided the rate constant (α) for the rate of increase in the number of infectious persons remained lower than the rate constant (ß) for the fall in number of infectious persons.

Siponimod (BAF312) Treatment Reduces Brain Infiltration but Not Lesion Volume in Middle-Aged Mice in Experimental Stroke.

Background and Purpose- The contribution of neuroinflammation and, in particular, the infiltration of the brain by lymphocytes is increasingly recognized as a substantial pathophysiological mechanism after stroke. The interaction of lymphocytes with endothelial cells and platelets, termed thromboinflammation, fosters microvascular dysfunction and secondary infarct growth. Siponimod is an S1PR (sphingosine-1-phosphate receptor) modulator, which blocks the egress of lymphocytes from lymphoid organs and has demonstrated beneficial effects in multiple sclerosis treatment. We investigated the effect of treatment with siponimod on stroke outcome in a mouse model of cerebral ischemia. Methods- Transient middle cerebral artery occlusion was induced in middle-aged wild-type mice. Animals were either treated with siponimod (3 mg/kg; intraperitoneal) or vehicle for 6 days. Stroke outcome was assessed by magnetic resonance imaging (spleen volume: prestroke, day 3, and day 7; infarct volume: days 1, 3, and 7) and behavioral tests (prestroke, day 2, and day 6). Immune cells of the peripheral blood and brain-infiltrating cells ipsilateral and contralateral were analyzed by VETScan and by flow cytometry. Results- Siponimod significantly induced lymphopenia on day 7 after transient middle cerebral artery occlusion and reduced T-lymphocyte accumulation in the central nervous system. No effect was detected for lesion size. Conclusions- For siponimod administered at 3 mg/kg in transient middle cerebral artery occlusion mouse model, our findings do not provide preclinical evidence for the use of S1PR1/5 modulators as neuroprotectant in stroke therapy.

Iron Metabolism, Hepcidin, and Mortality (the Ludwigshafen Risk and Cardiovascular Health Study).

BACKGROUND: Anemia has been shown to be a risk factor for coronary artery disease (CAD) and mortality, whereas the role of iron metabolism remains controversial. METHODS: We analyzed iron metabolism and its associations with cardiovascular death and total mortality in patients undergoing coronary angiography with a median follow-up of 9.9 years. Hemoglobin and iron status were determined in 1480 patients with stable CAD and in 682 individuals in whom significant CAD had been excluded by angiography. RESULTS: Multivariate-adjusted hazard ratios (HRs) for total mortality in the lowest quartiles of iron, transferrin saturation, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were 1.22 (95% CI, 0.96-1.60), 1.23 (95% CI, 0.97-1.56), 1.27 (95% CI, 1.02-1.58), 1.26 (95% CI, 0.97-1.65), and 0.99 (95% CI, 0.79-1.24), respectively, compared to the second or third quartile, which served as reference (1.00) because of a J-shaped association. The corresponding HRs for total mortality in the highest quartiles were 1.44 (95% CI, 1.10-1.87), 1.37 (95% CI, 1.05-1.77), 1.17 (95% CI, 0.92-1.50), 1.76 (95% CI, 1.39-2.22), and 0.83 (95% CI, 0.63-1.09). HRs for cardiovascular death were similar. For hepcidin, the adjusted HRs for total mortality and cardiovascular deaths were 0.62 (95% CI, 0.49-0.78) and 0.70 (95% CI, 0.52-0.90) in the highest quartile compared to the lowest one. CONCLUSIONS: In stable patients undergoing angiography, serum iron, transferrin saturation, sTfR, and ferritin had J-shaped associations and hemoglobin only a marginal association with cardiovascular and total mortality. Hepcidin was continuously and inversely related to mortality.

Intrathecal inflammation in young stroke.

OBJECTIVES: Correct identification of inflammatory etiologies of stroke is of outmost importance as they require treatment of the underlying disease. Aim of this study was to determine the prevalence of inflammatory changes in cerebrospinal fluid (CSF) observed in young cryptogenic stroke patients. MATERIALS AND METHODS: Of 6476 records of patients diagnosed with ischemic stroke, 278 had confirmed ischemia in brain imaging and received lumbar puncture. A total of 122 were classified as young stroke (≤55 years), and 156 were classified as older stroke patients; lumbar puncture in this cohort was indicated due to atypical clinical presentation. RESULTS: An infectious etiology was detected in 2.5% of young stroke patients (n = 3: vasculitis due to opportunistic infection, vasculitis due to neuroborreliosis, secondary vasospasm after viral meningitis) and in 1.9% (n = 3) in the older stroke cohort (vasculitis due to neurotuberculosis, septic embolic ischemia, vasculitis post-haemophilus influenza meningoencephalitis). Isolated vasculitis was evident in one patient of the older stroke cohort (0.6%). Non-specific alterations in CSF included increased cell count in 10% in young and in 9.3% in the older stroke cohort. Intrathecal Ig synthesis was present in 3.4% of the younger and in 4% of the older stroke cohort. CONCLUSIONS: The prevalence of an infectious etiology in young stroke is modest but slightly higher in comparison with older stroke patients. As brain imaging is not always sufficient for suspecting vasculitis, we recommend implementation of lumbar puncture in young cryptogenic stroke patients. If an infectious disease is present in ischemic stroke, it is of high therapeutic relevance.

Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease.

AIMS: The vascular effects of high-density lipoproteins (HDL) differ under certain clinical conditions. The composition of HDL is modified in patients with chronic kidney disease (CKD). As a consequence, uremic HDL induces endothelial dysfunction. We have previously shown that accumulation of symmetric dimethylarginine (SDMA) in HDL causes these adverse effects of HDL in CKD. The aim of the study is to determine the impact of the accumulation of SDMA on the association between HDL and mortality. METHODS AND RESULTS: Mortality, renal function, serum SDMA and HDL-cholesterol (HDL-C) were assessed in the LURIC study including 3310 subjects undergoing coronary angiography. All-cause mortality was 30.0% during median follow-up of 9.9 years. Serum SDMA levels significantly predicted all-cause and cardiovascular mortality, and were significantly correlated with SDMA accumulation in HDL. Notably, higher serum SDMA was independently associated with lower cholesterol efflux (P = 0.004) as a measure of HDL functionality. In subjects with low SDMA levels, higher HDL-C was associated with significantly lower mortality. In contrast, in subjects with high SDMA, HDL-C was associated with higher mortality. These findings were confirmed in 1424 participants of the MONICA/KORA S3 cohort. Of note, we derived an algorithm allowing for calculation of biologically effective HDL-C' based on measured HDL-C and SDMA. We corroborated these clinical findings with invitro evidence showing that SDMA accumulation abolishes the anti-inflammatory and regenerative properties of HDL. CONCLUSION: The data identify SDMA as a marker of HDL dysfunction. These findings highlight on the pivotal role of SDMA accumulation in HDL as a mediator of pre-mature cardiovascular disease in patients with CKD.

Ischaemic stroke and the recanalization drug tissue plasminogen activator interfere with antibacterial phagocyte function.

BACKGROUND: Stroke induces immune alterations such as impaired oxidative burst and reduced release of neutrophil extracellular traps (NETs). We hypothesised that key enzymes of these defence mechanisms may be altered in ischaemic stroke. Therefore, we analysed the intra- and extracellular amounts of myeloperoxidase (MPO) and neutrophil elastase (NE) in patient sera and granulocytes and monocytes. Because the autonomous nervous system is thought to mediate stroke-induced immune alterations, we also studied the influence of stress hormones and acetylcholine on MPO and NE. Rapid recanalization by recombinant tissue plasminogen activator (r-tPA) is the only available treatment for ischaemic stroke besides thrombectomy, and its influence on antibacterial defence mechanisms of granulocytes and monocytes were addressed here. METHODS: Ex vivo: Intracellular and serum MPO and NE were measured on days 0, 1, 3 and 5 post-stroke by either flow cytometry or enzyme-linked immunosorbent assay (ELISA) and compared to controls. In vitro: Blood from healthy donors was incubated with catecholamines, dexamethasone and acetylcholine, and the percentage of NET-producing cells and the area covered by NETs were quantified immunohistochemically. Intra- and extracellular MPO and NE were quantified by flow cytometry or ELISA. Blood samples from healthy donors were incubated with r-tPA, and oxidative burst, phagocytosis, NETosis, cytokine release, MPO and NE were quantified by flow cytometry, ELISA and microscopy. RESULTS: MPO was reduced in granulocytes but increased in sera obtained from stroke patients compared to controls. NE was not altered intracellularly but was elevated in patient sera. The percentage of NET-producing neutrophils was decreased by stress hormones and increased by acetylcholine. Neither intracellular MPO nor NE was altered by hormone treatment; however, adrenaline and acetylcholine induced NE release. r-tPA led to reduced phagocytosis and oxidative burst in granulocytes and monocytes in vitro. NETosis, MPO release and cytokines were not altered, whereas NE release was enhanced by r-tPA. CONCLUSIONS: Intracellular reduction of MPO might be responsible for reduced NETosis in stroke patients. The impact of enhanced MPO and NE serum levels in stroke patients should be addressed in future studies. r-tPA impaired antibacterial defence function in vitro. Therefore, patients who undergo unsuccessful recanalization therapy might be at higher risk for infection, which should be analysed in future investigations. Immune alterations due to r-tPA effects in stroke patients should also be investigated.

Impairments in Walking Ability, Dexterity, and Cognitive Function in Multiple Sclerosis Are Associated with Different Regional Cerebellar Gray Matter Loss.

Both histological and neuroimaging studies highlight the role of the cerebellum in multiple sclerosis (MS). There is at least some evidence for associations of cerebellar gray matter (GM) loss with motor and cognitive ability. We therefore correlated motor and cognitive ability scores (the multiple sclerosis functional composite MSFC) with regional cerebellar GM volumes. We used voxel-based morphometry (VBM) to assess the regional GM volume loss in a cohort of 45 MS patients. For the regression analysis, we used the clinical subscores of the multiple sclerosis functional composite (25-ft walk test (T25FW), nine-hole peg test (9HPT), paced auditory serial addition task (PASAT)). Decreased GM in distinct cerebellar areas was associated with different subscores of the MSFC in Larsell's lobule VI with the T25FW (t = 5.16), in lobule IX with the 9HPT (t = 3.95), and in lobule IX with the PASAT (t = 4.81). Regional volume decrease in distinct cerebellar areas involved in motor and cognitive domains were associated with clinical impairment in these fields. Our data confirm the relationship between cerebellar GM volume loss and disability, extending the knowledge in the functional neuroanatomical perspective.

Prevalence and outcome of late-onset seizures due to autoimmune etiology: A prospective observational population-based cohort study.

OBJECTIVE: The increasing incidence of new-onset seizures with age is well known. Often, the etiology cannot be clarified. In the present study, patients with unprovoked late-onset seizures and without known neoplasm, who might have had paraneoplastic encephalitis, were investigated for a potentially underlying autoimmunity. METHODS: Sixty-six consecutive patients (36 women; aged ≥55 years) after having at least one seizure or seizures for ≤6 months were prospectively identified over a period of 4.75 years. All patients were tested for serum and cerebrospinal fluid (CSF) antibodies (Abs) to both neural cell-surface and intracellular antigens. Forty-five (68%) underwent brain magnetic resonance imaging (MRI). Follow-up in Ab-positive cases was ≥6 months. RESULTS: Two patients had high titers of anti-CASPR2 (contactin-associated protein-like 2) Abs in serum and CSF and fulfilled the diagnostic criteria of definite limbic encephalitis. Another two patients had bilateral encephalitic temporal MRI abnormalities. They also satisfied the criteria of definite limbic encephalitis, even though they had no Abs in serum or CSF. All four were in the age range of 55-70 years. They received immunotherapy and/or antiepileptic drug treatment and became seizure-free. SIGNIFICANCE: Our findings suggest that autoimmunity should be considered an important etiology in patients with late-onset seizures. Testing for neural antibodies and brain MRI may be worthwhile in this patient group.

Reduced Numbers and Impaired Function of Regulatory T Cells in Peripheral Blood of Ischemic Stroke Patients.

BACKGROUND AND PURPOSE: Regulatory T cells (Tregs) have been suggested to modulate stroke-induced immune responses. However, analyses of Tregs in patients and in experimental stroke have yielded contradictory findings. We performed the current study to assess the regulation and function of Tregs in peripheral blood of stroke patients. Age dependent expression of CD39 on Tregs was quantified in mice and men. METHODS: Total FoxP3(+) Tregs and CD39(+)FoxP3(+) Tregs were quantified by flow cytometry in controls and stroke patients on admission and on days 1, 3, 5, and 7 thereafter. Treg function was assessed by quantifying the inhibition of activation-induced expression of CD69 and CD154 on T effector cells (Teffs). RESULTS: Total Tregs accounted for 5.0% of CD4(+) T cells in controls and <2.8% in stroke patients on admission. They remained below control values until day 7. CD39(+) Tregs were most strongly reduced in stroke patients. On day 3 the Treg-mediated inhibition of CD154 upregulation on CD4(+) Teff was impaired in stroke patients. CD39 expression on Treg increased with age in peripheral blood of mice and men. CONCLUSION: We demonstrate a loss of active FoxP3(+)CD39(+) Tregs from stroke patient's peripheral blood. The suppressive Treg function of remaining Tregs is impaired after stroke.

Galectin-3, Renal Function, and Clinical Outcomes: Results from the LURIC and 4D Studies.

Galectin-3 has been linked to incident renal disease, experimental renal fibrosis, and nephropathy. However, the association among galectin-3, renal function, and adverse outcomes has not been described. We studied this association in two large cohorts of patients over a broad range of renal function. We measured galectin-3 concentrations in baseline samples from the German Diabetes mellitus Dialysis (4D) study (1168 dialysis patients with type 2 diabetes mellitus) and the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (2579 patients with coronary angiograms). Patients were stratified into three groups: eGFR of ≥90 ml/min per 1.73 m(2), 60-89 ml/min per 1.73 m(2), and <60 ml/min per 1.73 m(2). We correlated galectin-3 concentrations with demographic, clinical, and biochemical parameters. The association of galectin-3 with clinical end points was assessed by Cox proportional hazards regression within 10 years (LURIC) or 4 years (4D) of follow-up. Mean±SD galectin-3 concentrations were 12.8±4.0 ng/ml (eGFR≥90 ml/min per 1.73 m(2)), 15.6±5.4 ng/ml (eGFR 60-89 ml/min per 1.73 m(2)), 23.1±9.9 ng/ml (eGFR<60 ml/min per 1.73 m(2)), and 54.1±19.6 ng/ml (dialysis patients of the 4D study). Galectin-3 concentration was significantly associated with clinical end points in participants with impaired kidney function, but not in participants with normal kidney function. Per SD increase in log-transformed galectin-3 concentration, the risks of all-cause mortality, cardiovascular mortality, and fatal infection increased significantly. In dialysis patients, galectin-3 was associated with the combined end point of cardiovascular events. In conclusion, galectin-3 concentrations increased with progressive renal impairment and independently associated with cardiovascular end points, infections, and all-cause death in patients with impaired renal function.

Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk.

AIMS: High-density lipoproteins (HDLs) are considered as anti-atherogenic. Recent experimental findings suggest that their biological properties can be modified in certain clinical conditions by accumulation of serum amyloid A (SAA). The effect of SAA on the association between HDL-cholesterol (HDL-C) and cardiovascular outcome remains unknown. METHODS AND RESULTS: We examined the association of SAA and HDL-C with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, which included 3310 patients undergoing coronary angiography. To validate our findings, we analysed 1255 participants of the German Diabetes and Dialysis study (4D) and 4027 participants of the Cooperative Health Research in the Region of Augsburg (KORA) S4 study. In LURIC, SAA concentrations predicted all-cause and cardiovascular mortality. In patients with low SAA, higher HDL-C was associated with lower all-cause and cardiovascular mortality. In contrast, in patients with high SAA, higher HDL-C was associated with increased all-cause and cardiovascular mortality, indicating that SAA indeed modifies the beneficial properties of HDL. We complemented these clinical observations by in vitro experiments, in which SAA impaired vascular functions of HDL. We further derived a formula for the simple calculation of the amount of biologically 'effective' HDL-C based on measured HDL-C and SAA from the LURIC study. In 4D and KORA S4 studies, we found that measured HDL-C was not associated with clinical outcomes, whereas calculated 'effective' HDL-C significantly predicted better outcome. CONCLUSION: The acute-phase protein SAA modifies the biological effects of HDL-C in several clinical conditions. The concomitant measurement of SAA is a simple, useful, and clinically applicable surrogate for the vascular functionality of HDL.

Stroke alters respiratory burst in neutrophils and monocytes.

BACKGROUND AND PURPOSE: Stroke-induced immune alterations predispose patients to infections. Although the relationship between stroke and the adaptive immune system has been investigated in detail, to date it is unknown whether the innate immune system, which forms the first line of antibacterial defense, is also impaired in patients with stroke. Therefore, we investigated whether chemotaxis, phagocytosis, oxidative burst, degranulation of defensins, and NETosis in monocytes and in neutrophil granulocytes are altered in patients with stroke compared with controls. METHODS: Sixty-three patients having acute ischemic stroke were recruited within 12 hours of symptom onset; blood was sampled on admission and on days 1, 3, 5, and 7. Thirty-seven age-matched controls were also recruited. Cell migration, phagocytosis, and oxidative burst of phagocytes were determined in vitro. Human neutrophil peptides 1 to 3 and serum metanephrine levels were measured by enzyme-linked immunosorbent assay, and NETosis was quantified by immunohistochemistry. RESULTS: The key mechanisms required for bacterial killing, oxidative burst, and NETosis were significantly reduced in samples taken from patients with stroke compared with controls, whereas migration, phagocytic function, and defensin production remained unimpaired in monocytes and granulocytes from patients with stroke. CONCLUSIONS: Stroke-induced immune alterations include impairment of the first-line defense performed by specialized phagocytes against bacteria. The hypothesis that these changes enhance susceptibility to acquired infections is supported by our observation that on admission oxidative burst in monocytes was more impaired in patients with stroke with subsequent stroke-associated infections.

Diagnosis of late presenting subarachnoid hemorrhage: comparison of methods for cerebrospinal fluid ferritin.

BACKGROUND: The majority of subarachnoid hemorrhage (SAH) is diagnosed using imaging techniques. The sensitivity of computed tomography scans decreases with increasing time after the bleeding event which can lead to false negative CT scans. Spectrophotometry and microscopic investigations of the cerebrospinal fluid (Csf) can provide additional diagnostic support, but may not be available for emergency diagnoses. Csf-Ferritin has been suggested as an alternative additional marker for SAH that present late and has a potency to be measured in a routine laboratory. METHODS: A routine Ferritin chemiluminescent assay (Dimension Vista) was compared with a branded and CE-marked Csf-Ferritin nephelometric assay (BN ProSpec) using surplus routine patient samples. We calculated imprecision at pertinent concentrations, compared patient samples, and established reference intervals. RESULTS: The standard deviation was about a third for the Dimension Vista assay compared to that of the BN ProSpec assay at the three tested concentrations. The correlation showed a systematic difference between the methods but the correlation was high (r = 0.955). Accordingly, the reference intervals were higher for the BN ProSPec (2.7-16.8 µg/L) than for the Dimension Vista (2.0-12.6 µg/L). CONCLUSION: The precision of the Dimension Vista measurements was considerably better than that of the BN ProSpec. The Dimension Vista results correlated well with those of the comparative method, yielding slightly lower values. This is reflected in the reference intervals. These findings permit the use of the routinely available Ferritin assay of the Dimension Vista for measuring Csf-Ferritin and complementing the late diagnosis of SAH outside office hours of specialized Csf laboratories.

Stroke, IL-1ra, IL1RN, infection and outcome.

BACKGROUND: Infection is a common phenomenon following stroke, and adversely affects outcome. Previous studies suggest that interleukin-1 receptor antagonist (IL-1ra) and single nucleotide polymorphisms (SNPs) in the IL1RN gene might influence the risk of post-stroke infection and outcome. In this study, we addressed the effects of the rs4251961 SNP in IL1RN on infection risk and outcome. METHODS: Subjects with acute ischemic stroke were enrolled within 72 h of symptom onset and followed up to 1 year. Plasma IL-1ra was measured at multiple time points and outcome assessed at 1, 3, 6, and 12 months. Active surveillance for infection occurred while subjects were hospitalized. Subjects were genotyped for the IL1RN rs4251961 polymorphism. RESULTS: In the population of 113 subjects for this study, those with the minor C allele of rs4251961 polymorphism in IL1RN were more likely to be Caucasian, hypertensive, and to be afflicted with coronary heart disease. Higher plasma IL-1ra was associated with an increased risk of infection (other than pneumonia), and the minor C allele of rs4251961 was independently associated with a decreased risk of infection (other than pneumonia). Initial plasma IL-1ra was not predictive of long-term outcome, but patients with the minor C allele of rs4251961 were more likely to experience good (modified Rankin Score <2) long-term outcome. CONCLUSIONS: These data indicate that IL-1ra and IL1RN may influence the risk of infection after stroke, but this influence seems limited to infections other than pneumonia. Further studies are needed to better understand the complexities of immune regulation on infection and outcome after stroke.

Diagnostic performance of rapid antigen testing for SARS-CoV-2: the COVid-19 AntiGen (COVAG) extension study.

Background: This study is the extension of the COVAG study. We compared two RATs, the Panbio COVID-19 Ag Rapid Test (Abbott) and the SD Biosensor Q SARS-CoV-2 Rapid Antigen Test (Roche), against RT-PCR on the foil of new variants. Methods: We included 888 all-comers at a diagnostic center between October 20, 2021, and March 18, 2022. RT-PCR-positive samples with a Ct value ≤32 were examined for SARS-CoV-2 variants. Findings: The sensitivity of the Abbott-RAT and Roche-RAT were 65 and 67%, respectively. For both RATs, lower Ct values were significantly correlated with higher sensitivity. For samples with Ct values ≤25, the sensitivities of the Roche-RAT and of the Abbott-RAT were 96 and 95%, for Ct values 25-30 both were 19%, and for Ct values ≥30 they were 6 and 2%, respectively. The RATs had substantially higher sensitivities in symptomatic than asymptomatic participants (76, 77%, vs. 29, 31%, for Abbott-RAT, Roche-RAT, respectively) and in participants referred to testing by their primary care physician (84, 85%) compared to participants who sought testing due to referral by the health department (55, 58%) or a warning by the Corona-Warn-App (49, 49%). In persons with self-reported previous COVID-19 sensitivities were markedly lower than in patients without previous COVID-19: 27% vs. 75% for Roche-RAT and 27% vs. 73% for Abbott-RAT. We did not find significant correlation between vaccination status and sensitivity. The Omicron variant was detected with a sensitivity of 94 and 92%, the delta variant with a sensitivity of 80 and 80% for Abbott-RAT and Roche-RAT, respectively. This difference is attributable to the lower Ct values of the Omicron samples compared to the Delta samples. When adjusted for the Ct value, a multivariate logistic regression did not show a significant difference between Omicron and Delta. In terms of sensitivity, we found no significant difference between the wild-type and the Omicron and Delta variants, but a significantly lower sensitivity to the alpha variant compared to the other variants.The specificities were > 99% overall.

Severe stroke induces long-lasting alterations of high-mobility group box 1.

BACKGROUND AND PURPOSE: The signals that initiate the poststroke inflammatory response are unknown. High-mobility group box (HMGB) 1 protein is a nuclear protein that is passively released from necrotic tissue and is able to activate leukocytes, which in turn secrete HMGB1. HMGB1 is also able to activate antigen-presenting cells and therefore stands at the crossroads of innate and adaptive immunity. METHODS: Plasma HMGB1 concentrations were determined at multiple time points after ischemic stroke (N=110) and correlated to stroke severity and biomarkers of inflammation. The relationships between HMGB1, stroke outcome, and autoimmune responses to brain antigens were also assessed. RESULTS: Stroke resulted in an increase in HMGB1 that persisted for 30 days. Plasma HMGB1 was correlated with the number of circulating leukocytes but was not predictive of either stroke outcome or the development of autoimmune responses to brain antigens. Patients with a Th1(+) response to myelin basic protein at 90 days after stroke, however, had higher plasma HMGB1. CONCLUSIONS: HMGB1 appears to be involved in the postischemic inflammatory response, but it remains unclear whether HMGB1 initiates this response or merely reflects activation of leukocytes by another signal.

Platelet Reactivity and Cardiovascular Mortality Risk in the LURIC Study.

BACKGROUND: The clinical and prognostic implications of platelet reactivity (PR) testing in a P2Y12-inhibitor naïve population are poorly understood. OBJECTIVES: This explorative study aims to assess the role of PR and explore factors that may modify elevated mortality risk in patients with altered PR. METHODS: Platelet ADP-induced CD62P and CD63 expression were measured by flow-cytometry in 1520 patients who were referred for coronary angiography in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). RESULTS: High- and Low-platelet reactivity to ADP were strong predictors of cardiovascular and all-cause mortality and risk equivalent to the presence of coronary artery disease. (High platelet reactivity 1.4 [95% CI 1.1-1.9]; Low platelet reactivity: 1.4 [95% CI 1.0-2.0]). Relative weight analysis indicated glucose control (HbA1c), renal function ([eGFR]), inflammation (high-sensitive C-reactive protein [hsCRP]) and antiplatelet therapy by Aspirin as consistent mortality risk modifiers in patients with Low- and High-platelet reactivity. Pre-specified stratification of patients by risk modifiers HbA1c (<7.0%), eGFR (>60 mL/min/1.73 m2) and CRP (<3 mg/L) was associated with a lower mortality risk, however irrespective of platelet reactivity. Aspirin treatment was associated with reduced mortality in patients with high platelet reactivity only (p for interaction: 0.02 for CV-death [<0.01 for all-cause mortality]. CONCLUSIONS: Cardiovascular mortality risk in patients with High- and Low platelet reactivity is equivalent to the presence of coronary artery disease. Targeted glucose control, improved kidney function and lower inflammation are associated with reduced mortality risk, however independent of platelet reactivity. In contrast, only in patients with High-platelet reactivity was Aspirin treatment associated with lower mortality.

Modulation of cytokine release from peripheral blood mononuclear cells from multiple sclerosis patients by coenzyme A and soraphen A.

By applying the acetyl-CoA-carboxylase inhibitors soraphen A (SorA) and coenzyme A (CoA) ex vivo, we aimed to reduce proinflammatory cytokine release by PBMCs and increase anti-inflammatory cytokine levels, thereby demonstrating a possible application of those pathways in future multiple sclerosis (MS) therapy. In a prospective exploratory monocentric study, we analysed cytokine production by PBMCs treated with SorA (10 or 50 nM) and CoA (600 µM). Thirty-one MS patients were compared to 18 healthy age-matched controls. We demonstrated the immunomodulatory potential of SorA and CoA in targeting the immune function of MS patients, with an overall reduction of cytokines except of IL-2, IL-6 and IL-10.