IL-6 Plasma Levels Correlate With Cerebral Perfusion Deficits and Infarct Sizes in Stroke Patients Without Associated Infections

Introduction: We aimed to investigate several blood-based biomarkers related to inflammation, immunity, and stress response in a cohort of patients without stroke-associated infections regarding their predictive abilities for functional outcome and explore whether they correlate with MRI markers, such as infarct size or location. Methods: We combined the clinical and radiological data of patients participating in two observational acute stroke cohorts: the PREDICT and 1000Plus studies. The following blood-based biomarkers were measured in these patients: monocytic HLA-DR, IL-6, IL-8, IL-10, LBP, MRproANP, MRproADM, CTproET, Copeptin, and PCT. Multiparametric stroke MRI was performed including T2*, DWI, FLAIR, TOF-MRA, and perfusion imaging. Standard descriptive sum statistics were used to describe the sample. Associations were analyzed using Fischer's exact test, independent samples t-test and Spearmans correlation, where appropriate. Results: Demographics and stroke characteristics were as follows: 94 patients without infections, mean age 68 years (SD 10.5), 32.2% of subjects were female, median NIHSS score at admission 3 (IQR 2-5), median mRS 3 months after stroke 1 (IQR 0-2), mean volume of DWI lesion at admission 5.7 ml (SD 12.8), mean FLAIR final infarct volume 10 ml (SD 14.9), cortical affection in 61% of infarctions. Acute DWI lesion volume on admission MRI was moderately correlated to admission/maximum IL-6 as well as maximum LBP. Extent of perfusion deficit and mismatch were moderately correlated to admission/maximum IL-6 levels. Final lesion volume on FLAIR was moderately correlated to admission IL-6 levels. Conclusion: We found IL-6 to be associated with several parameters from acute stroke MRI (acute DWI lesion, perfusion deficit, final infarct size, and affection of cortex) in a cohort of patients not influenced by infections

Hemmung des GM2-Gangliosid Metabolismus in, aus humanen Monozyten generierten, Dendritischen Zellen

Seitdem man Ende der 80er Jahre mit der Verwendung von dendritischen Zellen in der immuntherapeutischen Behandlung von Krebs begann, wurden in klinischen Studien bereits einige Fortschritte, die zu einer verbesserten Prognose von Patienten beitrugen, erzielt. Jedoch sind DC-basierte Antitumorvakzinierungen bislang nur Chemotherapie-begleitend einsetzbar, da den induzierten Immunantworten eine ausreichende Aggressivität zur Auslöschung jeglicher Tumorzelle fehlt. Durch ihre Zelltyp-spezifische und Differenzierungsgrad-abhängige endogene Expression auf eukaryotischen Zellen und durch ihre extrinsische immunsupprimierende Wirkungsweise, wenn sie in charakteristischen Sekretionsprofilen von Tumorzellen abgegeben werden, wurde gezeigt, dass Ganglioside wichtige Modulatoren von Immunantworten sind. Durch die Beobachtung, dass eine GM2- bzw. GM2A-Expression in Monozyten fehlt, aber kontinuierlich während der Differenzierung zu unreifen MDCs steigt um dann in LPS-gereiften MDCs wieder verringert zu sein, lässt sich schlussfolgern, dass dieses Gangliosid eine essentielle Rolle hinsichtlich Überleben und Funktion in DCs haben könnte. In Anlehnung an die durch GM2-Akkumulation charakterisierten neurodegenerativen und letztendlich fatalen GM2-Gangliosidosen, Tay-Sachs (HexA), Sandhoff (HexA/HexB) und AB Variant (GM2A), wurden während dieser Arbeit beide am GM2-Metabolismus beteiligten Komponenten herunterreguliert; zum einen durch Anwendung von PUGNAc – ein chemischer Inhibitor der HexA – und zum anderen durch Elektrotransfektion mit einer GM2A-spezifischen siRNA. Während sich für die Hemmung des GM2-Aktivatorproteins keine phänotypischen und funktionellen Veränderungen nachweisen ließen – was wahrscheinlich auf einer verbliebenen Restaktivität durch eine nicht vollständige Hemmung des GM2A basiert – , konnten für die PUGNAc-bedingte Hemmung der HexA sowohl morphologische als auch funktionelle Beeinträchtigungen, deren Vehemenz in Korrelation zur angewandten Inhibitorkonzentration stand, nachgewiesen werden. Je höher die angewandte Inhibitorkonzentration war, desto drastischer war das Ausmaß der Beeinträchtigungen. Es konnte ein PUGNAc-bedingter Verlust der Phagozytoseaktivität unreifer MDCs, eine reduzierte Migrationsfähigkeit und allostimulatorische Kapazität in LPS-gereiften MDCs einhergehend mit einer Herunterregulierung der Expression bestimmter CD-Moleküle und einer stark verminderte Produktion proinflammatorischer Zytokine und Chemokine nachgewiesen werden. Aufgrund des funktionellen Einflusses und der deutlich gewordenen regulatorischen Importanz hinsichtlich der Immunogenität von MDCs stellt das GM2-Gangliosid und die, zu seinem Metabolismus unabdingbaren Komponenten, potente Faktoren zur Modifikation und Optimierung der DC-Immunogenität zu Zwecken der Tumorvakzinierung dar.Inhibition of the GM2 ganglioside metabolism in human monocyte derived dendritic cells Since the late 80’s when usage of dendritic cells in immunotherapeutic treatment of cancer began, some progress within clinical trials could be achieved, contributing to improved prognosis of patients. However, DC-based anti-tumor vaccinations are so far only chemotherapy concomitantly used, since the induced immune responses lack sufficient aggressiveness to remove all tumor cells. By their cell type-specific and differentiation-dependent endogenous expression on eukaryotic cells and their extrinsic immunosuppressive action, when submitted in characteristic secretion-profiles by tumor cells it could be shown that gangliosides are important modulators of immune responses. By the observation that the expression of GM2 (and GM2A resp.) is lacking in monocytes, but increases continuously during differentiation to MDCs to then again decrease in LPS-matured MDCs, the conclusion that there might be an essential role of this ganglioside towards DC-survival and function could be assumed. Relating to by GM2-accumulation characterized neurodegenerative and ultimately fatal GM2-gangliosidosis, Tay-Sachs (HexA), Sandhoff (HexA / HexB) and AB Variant (GM2a), both components involved in the GM2-metabolism were down-regulated during this work; on the one hand by the application of PUGNAc - a chemical inhibitor of HexA - and on the other hand by electrotransfection with a GM2A-specific siRNA. While no phenotypic and functional changes could be detected for the inhibition of the GM2-activator protein - which is probably based on a residual activity due to an incomplete inhibition of GM2A - for the PUGNAc-induced inhibition of HexA both morphological and functional impairments, with a vehemence correlating to the applied inhibitor concentrations, could be demonstrated. The higher the inhibitor concentration applied, the more drastic was the extent of deterioration. A PUGNAc-induced loss of phagocytic activity of immature MDCs, a reduced migratory ability and allostimulatory capacity in LPS-matured MDCs, accompanied by a down-regulated expression of certain CD-molecules and a greatly reduced production of proinflammatory cytokines and chemokines, was demonstrated. Due to the functional influence and the regulatory importancy regarding the immunogenicity of MDCs the GM2 ganglioside and the indispensable components to its metabolism, are potent factors for the modification and optimization of DC immunogenicity for tumor vaccination purposes

risk factors and impact on quality of life

Objectives Emerging evidence suggests that fatigue in myasthenia gravis (MG) is a relevant problem that negatively impacts activities of daily living (ADL). The relationship between fatigue and quality of life (QoL) has never been systematically explored in MG patients. The study aimed to assess the prevalence of fatigue and its relation to ADL and QoL as well as to identify factors associated with fatigue in MG. Material and Methods This was a cross- sectional observational study in patients with confirmed diagnosis of MG independent of disease severity. Prevalence of fatigue was assessed using the Chalder Fatigue Scale (CFQ). Impact of fatigue on ADL and QoL was assessed by the MG activities of daily living profile (MG-ADL) and the MG-specific quality-of-life instrument (MG-QoL), respectively. Association of fatigue with sociodemographics, clinical characteristics of MG, and comorbidities including mood and anxiety disorders as well as sleep disorders was investigated using multivariable logistic regression analyses. Results Overall, 200 MG patients were included. The observed rate of fatigue was 56.1%, of those 70.4% fulfilled the criteria of chronic fatigue (CF) with a duration of ≥6 months. Relevant fatigue was strongly associated to ADL and QoL. Factors associated with relevant fatigue were disease severity and depressive state. Furthermore, positive muscle-specific tyrosine kinase (MuSK) antibody status showed a strong association with relevant fatigue. Conclusions MG patients have a high prevalence of fatigue which negatively impacts ADL and QoL. MG-specific clinical characteristics are related to fatigue and might help to identify MG patients at risk for fatigue

IL-6 Plasma Levels Correlate With Cerebral Perfusion Deficits and Infarct Sizes in Stroke Patients Without Associated Infections

Introduction: We aimed to investigate several blood-based biomarkers related to inflammation, immunity, and stress response in a cohort of patients without stroke-associated infections regarding their predictive abilities for functional outcome and explore whether they correlate with MRI markers, such as infarct size or location.Methods: We combined the clinical and radiological data of patients participating in two observational acute stroke cohorts: the PREDICT and 1000Plus studies. The following blood-based biomarkers were measured in these patients: monocytic HLA-DR, IL-6, IL-8, IL-10, LBP, MRproANP, MRproADM, CTproET, Copeptin, and PCT. Multiparametric stroke MRI was performed including T2*, DWI, FLAIR, TOF-MRA, and perfusion imaging. Standard descriptive sum statistics were used to describe the sample. Associations were analyzed using Fischer's exact test, independent samples t-test and Spearmans correlation, where appropriate.Results: Demographics and stroke characteristics were as follows: 94 patients without infections, mean age 68 years (SD 10.5), 32.2% of subjects were female, median NIHSS score at admission 3 (IQR 2–5), median mRS 3 months after stroke 1 (IQR 0–2), mean volume of DWI lesion at admission 5.7 ml (SD 12.8), mean FLAIR final infarct volume 10 ml (SD 14.9), cortical affection in 61% of infarctions. Acute DWI lesion volume on admission MRI was moderately correlated to admission/maximum IL-6 as well as maximum LBP. Extent of perfusion deficit and mismatch were moderately correlated to admission/maximum IL-6 levels. Final lesion volume on FLAIR was moderately correlated to admission IL-6 levels.Conclusion: We found IL-6 to be associated with several parameters from acute stroke MRI (acute DWI lesion, perfusion deficit, final infarct size, and affection of cortex) in a cohort of patients not influenced by infections.Clinical Trial Registration:www.ClinicalTrials.gov, identifiers NCT01079728 and NCT0071553

Machine learning from wristband sensor data for wearable, noninvasive seizure forecasting

Objective: Seizure forecasting may provide patients with timely warnings to adapt their daily activities and help clinicians deliver more objective, personalized treatments. Although recent work has convincingly demonstrated that seizure risk assessment is in principle possible, these early approaches relied largely on complex, often invasive setups including intracranial electrocorticography, implanted devices, and multichannel electroencephalography, and required patient-specific adaptation or learning to perform optimally, all of which limit translation to broad clinical application. To facilitate broader adaptation of seizure forecasting in clinical practice, noninvasive, easily applicable techniques that reliably assess seizure risk without much prior tuning are crucial. Wristbands that continuously record physiological parameters, including electrodermal activity, body temperature, blood volume pulse, and actigraphy, may afford monitoring of autonomous nervous system function and movement relevant for such a task, hence minimizing potential complications associated with invasive monitoring and avoiding stigma associated with bulky external monitoring devices on the head. Methods: Here, we applied deep learning on multimodal wristband sensor data from 69 patients with epilepsy (total duration > 2311 hours, 452 seizures) to assess its capability to forecast seizures in a statistically significant way. Results: Using a leave-one-subject-out cross-validation approach, we identified better-than-chance predictability in 43% of the patients. Time-matched seizure surrogate data analyses indicated forecasting not to be driven simply by time of day or vigilance state. Prediction performance peaked when all sensor modalities were used, and did not differ between generalized and focal seizure types, but generally increased with the size of the training dataset, indicating potential further improvement with larger datasets in the future. Significance: Collectively, these results show that statistically significant seizure risk assessments are feasible from easy-to-use, noninvasive wearable devices without the need of patient-specific training or parameter optimization

Myasthenia gravis - a retrospective analysis of e-mail inquiries made to a patient organisation and specialized center to uncover unmet needs from patients and caregivers

Background and aims: Myasthenia Gravis requires expert treatment from specialized neurologists. In Germany, this treatment is mainly provided by 18 Integrated Myasthenia Centers (iMZ) accredited by the German Myasthenia Gravis Association (DMG). The DMG is a large and well-organized patient organisation that is regarded as a trusted source for disease-specific information. The aim of this study was to analyse the type of requests that each of these institutions receives in order to identify any potential unmet needs regarding the availability of advice for patients and caregivers. This data can then be used in further research to tailor modern digital communication tools to the specific needs of MG patients. Methods: Counselling requests sent via e-mail to both institutions were extracted for defined examination periods and divided into a period 'before COVID-19 pandemic' (01.07.2019-31.12.2019) and 'during COVID-19 pandemic' (01.07.2020-31.12.2020). Requests were then analysed using four main categories: medical requests, organisational issues, COVID-19 and social legislation inquiries. Results: One thousand seven hundred eleven requests for advice were addressed to DMG and iMZ Charite. Most inquiries directed to the DMG (47%; n = 750) were related to medical issues, most frequently to side effects of medications (n = 325; 20%) and questions about treatment (n = 263; 16%), followed by inquiries regarding organisational issues (26%; n = 412). About half of the inquiries (n = 69; 58%) to the iMZ Charite were related to medical issues and almost one in three inquiries concerned organisational issues (n = 37; 30%). About one in ten inquiries concerned socio-legal matters (iMZ: n = 7; 6% and DMG: n = 177; 11%). During the pandemic, COVID-19 related issues accounted for 8% (n = 6) of inquiries at iMZ, and 16% (n = 253) at DMG. Conclusions: MG sufferers have a high demand for timely advice. In the current setting, they address their requests to both iMZs and the DMG via e-mail. Our findings confirm that the DMG is highly trusted by patients and caregivers and is used to obtain second opinions. A relevant proportion of requests to the iMZ could be answered more effectively through standardized responses or improved process management. The implementation of modern digital solutions, including telemedicine, for communication between patient and specialist should be evaluated in further research

Procalcitonin-Guided Antibiotic Therapy after Stroke

Background: Pneumonia is among the most common acute complications after stroke and is associated with poor long-term outcome. Biomarkers may help identifying stroke patients at high risk for developing stroke-associated pneumonia (SAP) and to guide early treatment. Aims: This trial investigated whether procalcitonin (PCT) ultrasensitive (PCTus)-guided antibiotic treatment of SAP can improve functional outcome after stroke. Methods: In this international, multicenter, randomized, controlled clinical trial with blinded assessment of outcomes, patients with severe ischemic stroke in the middle cerebral artery territory were randomly assigned within 40 h after symptom onset to PCTus-based antibiotic therapy guidance in addition to stroke unit care or standard stroke unit care alone. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale (mRS) and dichotomized as acceptable (≤4) or unacceptable (≥5). Secondary endpoints included usage of antibiotics, infection rates, days of fever, and mortality. The trial was registered with http://ClinicalTrials.gov (Identifier NCT01264549). Results: In the intention-to-treat-analysis based on 227 patients (112 in PCT and 115 in control group), 197 patients completed the 3-month follow-up. Adherence to PCT guidance was 65%. PCT-guided therapy did not improve functional outcome as measured by mRS (odds ratio 0.79; 95% confidence interval 0.45–1.35, p = 0.47). Pneumonia rate and mortality were similar in both groups. Days with fever tended to be lower (p = 0.055), whereas total number of days treated with antibiotics were higher (p = 0.004) in PCT compared to control group. A post hoc analysis including all PCT values in the intention-to-treat population demonstrated a significant increase on the first day of infection in patients with pneumonia and sepsis compared to patients with urinary tract infections or without infections (p < 0.0001). Conclusion: PCTus-guided antibiotic therapy did not improve functional outcome at 3 months after severe ischemic stroke. PCT is a promising biomarker for early detection of pneumonia and sepsis in acute stroke patients

Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus

Background: Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear. Case presentation: We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRV beta 2(+) T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4(+)CD8(+) population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4(+)CD8(+)T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology. Conclusions: This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research

a pilot study

Muscular weakness in myasthenia gravis (MG) is commonly assessed using Quantitative Myasthenia Gravis Score (QMG). More objective and quantitative measures may complement the use of clinical scales and might detect subclinical affection of muscles. We hypothesized that muscular weakness in patients with MG can be quantified with the non-invasive Quantitative Motor (Q-Motor) test for Grip Force Assessment (QGFA) and Involuntary Movement Assessment (QIMA) and that pathological findings correlate with disease severity as measured by QMG. Methods This was a cross-sectional pilot study investigating patients with confirmed diagnosis of MG. Data was compared to healthy controls (HC). Subjects were asked to lift a device (250 and 500 g) equipped with electromagnetic sensors that measured grip force (GF) and three- dimensional changes in position and orientation. These were used to calculate the position index (PI) and orientation index (OI) as measures for involuntary movements due to muscular weakness. Results Overall, 40 MG patients and 23 HC were included. PI and OI were significantly higher in MG patients for both weights in the dominant and non-dominant hand. Subgroup analysis revealed that patients with clinically ocular myasthenia gravis (OMG) also showed significantly higher values for PI and OI in both hands and for both weights. Disease severity correlates with QIMA performance in the non-dominant hand. Conclusion Q-Motor tests and particularly QIMA may be useful objective tools for measuring motor impairment in MG and seem to detect subclinical generalized motor signs in patients with OMG. Q-Motor parameters might serve as sensitive endpoints for clinical trials in MG