Clinical associations and characteristics of the polyspecific intrathecal immune response in elderly patients with non-multiple sclerosis chronic autoimmune-inflammatory neurological diseases - a retrospective cross-sectional study.

Introduction: The polyspecific intrathecal immune response (PSIIR), aka MRZ reaction (M = measles, R = rubella, Z = zoster, optionally Herpes simplex virus, HSV) is defined as intrathecal immunoglobulin synthesis (IIS) for two or more unrelated viruses. Although an established cerebrospinal fluid (CSF) biomarker for multiple sclerosis (MS), a chronic autoimmune-inflammatory neurological disease (CAIND) of the central nervous system (CNS) usually starting in young adulthood, the full spectrum of CAINDs with a positive PSIIR remains ill defined. Methods: In this retrospective, cross-sectional study, patients with CSF-positive oligoclonal bands (OCB) and - to enrich for non-MS diagnoses - aged ≥50 years were enrolled. Results: Of 415 with PSIIR testing results (MRZ, HSV optional), 76 were PSIIR-positive. Of these, 25 (33%) did not meet the diagnostic criteria for MS spectrum diseases (MS-S) comprising clinically or radiologically isolated syndrome (CIS/RIS) or MS. PSIIR-positive non-MS-S phenotypes were heterogenous with CNS, peripheral nerve and motor neuron involvement and often defied unequivocal diagnostic classification. A rating by neuroimmunology experts suggested non-MS CAINDs in 16/25 (64%). Long-term follow-up available in 13 always showed a chronically progressive course. Four of five responded to immunotherapy. Compared to MS-S patients, non-MS CAIND patients showed less frequent CNS regions with demyelination (25% vs. 75%) and quantitative IgG IIS (31% vs. 81%). MRZ-specific IIS did not differ between both groups, while additional HSV-specific IIS was characteristic for non-MS CAIND patients. Discussion: In conclusion, PSIIR positivity occurs frequently in non-MS-S patients ≥50 years. Although sometimes apparently coincidental, the PSIIR seems to represent a suitable biomarker for previously unnoticed chronic neurologic autoimmunities, which require further characterization.

Predictive parameters of early respiratory decline in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Respiratory insufficiency is a common symptom during the course of amyotrophic lateral sclerosis (ALS). The diagnostic workup may be challenging and includes a wide array of diagnostic measures. In this study, the aim was to analyze the relationship between hypercapnia-associated symptoms, blood gas parameters and pulmonary function tests. METHODS: In total, 109 patients (56 women, 53 men, 62.4 ± 11.9 years) with definite, possible or probable ALS according to El Escorial criteria were included. All patients received either arterial blood gas analysis, nocturnal capnometry or both. Pulmonary function was assessed by spirometry and peak cough flow. Clinical symptoms potentially indicating hypercapnia were assessed using 17 dichotomous (yes/no) items. RESULTS: Of 109 ALS patients, 40 had hypercapnia. The highest accuracy and specificity for predicting hypercapnia was observed for dyspnea at rest (Youden's index 17%, 95% confidence interval [CI] 2%-34%; sensitivity 23%, 95% CI 9%-38%; specificity 95%, 95% CI 88%-100%). Daytime fatigue yielded the highest sensitivity of 58% (95% CI 40%-76%). Logistic regression for all assessed symptoms combined yielded an area under the receiver operating charteristic curve of 0.8 (95% CI 0.7-0.9). Compared to the clinical symptoms, forced vital capacity and peak cough flow showed higher sensitivity (70% and 87%, respectively) but lacked specificity (33% and 20%). CONCLUSION: Evaluation of the presence of hypercapnic symptoms can be utilized to predict incipient respiratory insufficiency and should complement pulmonary function tests. Further studies are needed to validate specific questionnaires in this regard. No single hypercapnia-associated symptom or pulmonary function test on its own seems sufficient to safely predict hypercapnia.

Associations between multiple sclerosis and incidence of heart diseases: Systematic review and meta-analysis of observational studies.

BACKGROUND: Observational studies have described associations between multiple sclerosis (MS) and heart diseases, but the results were mixed. METHODS: Medline, Embase, and Cochrane CENTRAL were searched up to 5 October 2020 according to a protocol (PROSPERO registration number CRD42020184493). We included longitudinal non-randomized studies of exposure comparing the incidence of acquired heart diseases between people with multiple sclerosis (pwMS) and people without multiple sclerosis. We used ROBINS-E and the GRADE approach to assess risk of bias and the certainty of evidence, respectively. Data were pooled using random-effect models. RESULTS: Of 5,159 studies, nine studies met the inclusion criteria. MS was associated with an increased risk for myocardial infarction (HR 1.6, 95% CI 1.2 to 2.0, I2 86%, n = 1,209,079) and heart failure (HR 1.7, 95% CI 1.3 to 2.2, I2 49%, n = 489,814). The associations were more pronounced among women and younger people in subgroup analyses. We found no difference for ischemic heart disease (HR 1.0, 95% CI 0.8 to 1.4, I2 86%, n = 679,378) and bradycardia (HR 1.5, 95% CI 0.4 to 5.0, I2 50%, n = 187,810). The risk of atrial fibrillation was lower in pwMS (HR 0.7, 95% CI 0.6 to 0.8, I2 0%, n = 354,070), but the risk of bias was high, and the certainty of evidence was rated as very low. One study found more cases of infectious endocarditis among pwMS (HR 1.2, 95% CI 1.0 to 1.4, n = 83,712). CONCLUSIONS: Myocardial infarction and heart failure should be considered in people with multiple sclerosis during follow-up examinations.

Tick-Borne Encephalitis: A Differential Pattern of Intrathecal Humoral Immune Response and Inflammatory Cell Composition Compared with Other Viral CNS Infections.

To investigate whether and how cerebrospinal fluid (CSF) findings can contribute to distinguish tick-borne encephalitis (TBE) from herpes simplex virus (HSV) and varicella zoster virus (VZV) induced central nervous system (CNS) infections (HSV-I, VZV-I). Chart review and identification of TBE, HSV- I, and VZV-I was carried out, fulfilling the following criteria: (1) clinical signs of encephalitis and/or meningitis, (2) complete CSF analysis and confirmed viral etiology by either PCR or antibody testing in CSF, (3) hospitalized patients, and (4) available brain magnetic resonance imaging (MRI). Fifty-nine patients with 118 CSF/serum pairs were included. These comprised 21 with TBE (35 CSF/serum pairs), 20 (40 CSF/serum pairs) with HSV-I, and 18 (43 CSF/serum pairs) with VZV-I. In contrast to HSV-I and VZV-I, CSF cell differentiation in TBE showed more often an increased (>20%) proportion of granulocytes (p < 0.01) and a more frequent quantitative intrathecal IgM synthesis (p = 0.001 and p < 0.01, respectively), while the second was even more pronounced when follow-up CSF analyses were included (p < 0.001). CSF findings help to distinguish TBE from other viral infections. In cases with CSF pleocytosis and a positive history for a stay in or near an endemic area, TBE antibodies in CSF and serum should be determined, especially if granulocytes in CSF cell differentiation and/or an intrathecal IgM synthesis is present.

Stress cardiomyopathy associated with the first manifestation of multiple sclerosis: a case report.

BACKGROUND: We present a case with a close temporal association of the first diagnosis of multiple sclerosis and stress cardiomyopathy. CASE PRESENTATION: A 19-year-old man experienced severe dyspnoea. The cardiac biomarkers troponin T and NT-proBNP were elevated, and transthoracic echocardiography showed basal hypokinesia. The man was diagnosed with stress cardiomyopathy after main differential diagnoses such as acute coronary syndrome, myocarditis, and pheochromocytoma were excluded. Furthermore, the patient reported vertigo and paraesthesia. Brain and spinal MRI revealed T2-hyperintense lesions with a prominent acute lesion in the pontomedullary area. Cerebrospinal fluid findings revealed a lymphocytic pleocytosis and intrathecal IgG synthesis. Serum neurofilaments were elevated. The patient was diagnosed with MS, and treatment with intravenous Methylprednisolone was initiated. The brainstem lesion due to multiple sclerosis was assumed to be the cause of stress cardiomyopathy. The patient fully recovered. CONCLUSION: Stress cardiomyopathy may be linked with the first manifestation of multiple sclerosis in the presented case since pontomedullary lesions could affect the sympathetic nervous system. This case highlights the importance of neurological history and examination in young patients with unexplained acute cardiac complaints.

Exposure of patients to di(2-ethylhexy)phthalate (DEHP) and its metabolite MEHP during extracorporeal membrane oxygenation (ECMO) therapy.

The plasticizer di(2-ethylhexyl)phthalate (DEHP) is often used for PVC medical devices, that are also largely used for intensive care medical treatments, like extracorporeal membrane oxygenation (ECMO) therapy. Due to the toxicological potential of DEHP, the inner exposure of patients with this plasticizer is a strong matter of concern as many studies have shown a high leaching potential of DEHP into blood. In this study, the inner DEHP exposure of patients undergoing ECMO treatment was investigated. The determined DEHP blood levels of ECMO patients and the patients of the control group ranged from 31.5 to 1009 µg/L (median 156.0 µg/L) and from 19.4 to 75.3 µg/L (median 36.4 µg/L), respectively. MEHP blood levels were determined to range from < LOD to 475 µg/L (median 15.9 µg/L) in ECMO patients and from < LOD to 9.9 µg/L (median 3.7 µg/L) in the control group patients, respectively. Increased DEHP exposure was associated with the number of cannulas and membranes of the ECMO setting, whereas residual diuresis decreased the exposure. Due to the suspected toxicological potential of DEHP, its use in medical devices should be further investigated, in particular for ICU patients with long-term exposure to PVC, like in ECMO therapy.

Reference values for peak oxygen uptake: cross-sectional analysis of cycle ergometry-based cardiopulmonary exercise tests of 10 090 adult German volunteers from the Prevention First Registry.

OBJECTIVE: This study aims to construct quantile reference values for peak oxygen uptake (V̇O2peak) measured by cycle ergometry-based incremental cardiopulmonary exercise tests. DESIGN: Cross-sectional study using quantile regressions to fit sex-specific and age-specific quantile curves. Exercise tests were conducted using cycle ergometry. Maximal effort in the exercise tests wass assumed when respiratory exchange ratio ≥1.1 or lactate ≥8 mmol/L or maximal heart rate ≥90% of the age-predicted maximal heart rate. This was assessed retrospectively for a random subsample with an a priori calculated sample size of n=252 participants. SETTING: A network of private outpatient clinics in three German cities recorded the results of cycle ergometry-based cardiopulmonary exercise tests to a central database (Prevention First Registry) from 2001 to 2015. PARTICIPANTS: 10 090 participants (6462 men, 3628 women) from more than 100 local companies volunteered in workplace health promotion programmes. Participants were aged 21 to 83 years, were free of acute complaints and had primarily sedentary working environments. MAIN OUTCOME MEASURE: Peak oxygen uptake was measured as absolute V̇O2peak in litres of oxygen per minute and relative V̇O2peak in millilitres of oxygen per kilogram of body mass per minute. RESULTS: The mean age for both men and women was 46 years. Median relative V̇O2peak was 36 and 30 mL/kg/min at 40 to 49 years, as well as 32 and 26 mL/kg/min at 50 to 59 years for men and women, respectively. An estimated proportion of 97% of the participants performed the exercise test until exertion. CONCLUSIONS: Reference values and nomograms for V̇O2peak were derived from a large sample of preventive healthcare examinations of healthy white-collar workers. The presented results can be applied to participants of exercise tests using cycle ergometry who are part of a population that is comparable to this study.

Plastic ingestion by Tristram's Storm-petrel (Oceanodroma tristrami) chicks from French frigate shoals, Northwestern Hawaiian Islands.

This study provides the first quantification of plastic ingestion in the Tristram's Storm-petrel (Oceanodroma tristrami) in over 20 years. We found 100% plastic incidence in 57 chicks collected opportunistically over four breeding seasons (2007, 2010, 2011, 2012), with the mass of ingested plastic per individual ranging from 0.1 to 2.8 g (≤3.3% adult mass). While plastic occurred in every bird we examined, the proventriculus contained significantly more plastic, more fragments, and larger fragments than the gizzard. Most of the ingested plastic (97.5% by mass) consisted of fragments, ranging in length from 0.4 to 11.6 mm and ranging in surface area from 0.07 to 45.21 mm2. While fragments were ubiquitous, occurring in every proventriculus and gizzard we analyzed, Tristram's Storm-petrels also ingested foam, line and sheets. Digital analysis of 1425 ingested plastic fragments documented a wide range of colors, involving shades of white, yellow, orange, red, blue, green, and black.

High Serum Bilirubin Levels, NT-pro-BNP, and Lactate Predict Mortality in Long-Term, Severely Ill Respiratory ECMO Patients.

Mortality in patients treated with extracorporeal membrane oxygenation (ECMO) is high. Therefore, it is crucial to better understand conditions that are associated with mortality in ECMO patients. In this retrospective analysis, we observed 51 patients treated with high-flow ECMO in 2013 and 2014 at our center. We recorded laboratory values and intensive care procedures. The hypothesis of bilirubin being a predictor of mortality during ECMO treatment was initially addressed. Therefore, laboratory values were obtained before initiation and at the time of highest bilirubin throughout the procedure. Receiver operating characteristic (ROC) curves and survival analysis were conducted. Our cohort consisted of patients with advanced age (median: 55 years; range: 22-76) and high mortality (26/51; 51%). Lactate, bilirubin, and NT-pro-BNP were significantly (p < 0.05) associated with mortality in univariable analyses. The cut-off values with highest Youden's index were bilirubin ≥10 mg/dl, lactate ≥2.25 mmol/L, and NT-pro-BNP ≥11,500 pg/ml. A multivariable analysis, revealed an area under the curve (AUC) of 0.85 (95% confidence interval [CI]: 0.74-0.97), sensitivity of 0.79, and specificity of 0.91. Bilirubin, lactate, and NT-pro-BNP were associated with mortality during ECMO treatment. However, laboratory values were only evaluated at the time of peak bilirubin.

Probenecid-treatment reduces demyelination induced by cuprizone feeding.

Recent experiments showed that a pannexin-1 inhibitor, probenecid, reduced clinical symptoms in the murine experimental autoimmune encephalomyelitis when applied during the initial phase of neuronal inflammation. An inflammatory component is also present in a toxically induced inflammation and demyelination using cuprizone diet. Probenecid is a pannexin-1 antagonist and a probenecid therapy was investigated. Mice were fed for 10days with a cuprizone diet. In the following, the diet was continued but combined with a daily injection of a low dose of probenecid or solvent for 10days. Electron microscopy revealed demyelination in the optic nerve. The demyelination as measured by the axonal diameter was significantly reduced in the animals treated with 100mg per kg body weight probenecid. In comparison to controls, the number of leukocytes and lymphocytes in the peripheral blood was reduced in all cuprizone groups including the treatment group. In conclusion, early demyelination in the optic nerve was moderately reduced by 10days treatment with a low dose probenecid. This is a hint for the involvement of pannexin-1 modulated inflammation in cuprizone feeding induced toxic demyelination. Thus, probenecid is a candidate for the treatment of neuro-inflammation and multiple sclerosis.

Runtime and aPTT predict venous thrombosis and thromboembolism in patients on extracorporeal membrane oxygenation: a retrospective analysis.

BACKGROUND: Even though bleeding and thromboembolic events are major complications of extracorporeal membrane oxygenation (ECMO), data on the incidence of venous thrombosis (VT) and thromboembolism (VTE) under ECMO are scarce. This study analyzes the incidence and predictors of VTE in patients treated with ECMO due to respiratory failure. METHODS: Retrospective analysis of patients treated on ECMO in our center from 04/2010 to 11/2015. Patients with thromboembolic events prior to admission were excluded. Diagnosis was made by imaging in survivors and postmortem examination in deceased patients. RESULTS: Out of 102 screened cases, 42 survivors and 21 autopsy cases [mean age 46.0 ± 14.4 years; 37 (58.7 %) males] fulfilling the above-mentioned criteria were included. Thirty-four patients (54.0 %) underwent ECMO therapy due to ARDS, and 29 patients (46.0 %) with chronic organ failure were bridged to lung transplantation. Despite systemic anticoagulation at a mean PTT of 50.6 ± 12.8 s, [VT/VTE 47.0 ± 12.3 s and no VT/VTE 53.63 ± 12.51 s (p = 0.037)], VT and/or VTE was observed in 29 cases (46.1 %). The rate of V. cava thrombosis was 15/29 (51.7 %). Diagnosis of pulmonary embolism prevailed in deceased patients [5/21 (23.8 %) vs. 2/42 (4.8 %) (p = 0.036)]. In a multivariable analysis, only aPTT and time on ECMO predicted VT/VTE. There was no difference in the incidence of clinically diagnosed VT in ECMO survivors and autopsy findings. CONCLUSIONS: Venous thrombosis and thromboembolism following ECMO therapy are frequent. Quality of anticoagulation and ECMO runtime predicted thromboembolic events.

Trainee colonoscopists fulfil quality standards for the detection of adenomatous polyps.

BACKGROUND: The detection of adenomatous lesions is a major indicator for quality and competence in colonoscopy. Little is known about adenoma detection rates (ADR) of endoscopy trainees. The aim of our study was to investigate the performance of trainee colonoscopists in detecting adenomas and to depict the shape of adenoma detection learning curves during apprenticeship. METHODS: We retrospectively investigated a prospectively maintained database of a single tertiary referral center to reveal colonoscopies performed by trainee endoscopists during 2001 and 2013. Colonoscopy reports were chronologically retrieved and separately analyzed for each trainee. Using cumulative curves, courses of trainee's Adenoma detection rates (ADR) during apprenticeship were displayed. Additionally, procedural data including cecal intubation rate and occurrence of complications were assessed. RESULTS: We retrospectively analyzed 4354 colonoscopies conducted by 10 trainee endoscopists (TE). A median number of 371 investigations were performed by each apprentice. Group ADR was 23%. No significant difference between aggregated ADRs at the beginning (23%) and at the end (22%) of apprenticeship could be determined (p = 0.70). However, individual learning curves showed considerable different slopes. Personal ADR values ranged between 17% and 31%. Overall cecum intubation rate was 99.0 %. Complication rates were low and fulfilled quality requirements recommended in guidelines. CONCLUSION: From the beginning of education, trainee colonoscopists are capable to provide high-quality investigations considering the detection of adenomas as a benchmark quality indicator. Nevertheless, performance differs markedly between investigators. Therefore, individual detection rates should be reviewed regularly to reveal further need for training.

Association between gap in spousal education and domestic violence in India and Bangladesh.

BACKGROUND: Domestic violence (DV) against women is a serious human rights abuse and well recognised global public health concern. The occurrence of DV is negatively associated with the educational level of spouses but studies dealing with educational discrepancies of spouses show contradicting results: Wives with higher education than their husbands were more likely to ever experience DV as compared to equally educated couples. The purpose of this study was to investigate the association between spousal education gap (SEG) and the prevalence and severity of DV in India and Bangladesh. METHODS: Nationally representative data collected through the 2005/2006 Indian National Family Health Survey (NFHS-3) and 2007 Bangladesh Demographic and Health Survey (BDHS) were used. In total, we analysed data of 69,805 women aged 15-49 years (Bangladesh: 4,195 women, India: 65,610 women). In addition to univariate and bivariable analyses, a multinomial logistic regression model was used to quantify the association between education gap and less severe as well as severe domestic violence. Adjustment was made for age, religion, and family structure. RESULTS: Wives with higher education than their husbands were less likely to experience less severe (OR = 0.83, 95% CI: 0.77-0.89) and severe (OR = 0.79, 95% CI: 0.72-0.87) DV as compared to equally low-educated spouses (reference group). Equally high-educated couples revealed the lowest likelihood of experiencing DV (severe violence: OR 0.43, CI 0.39-0.48; less severe violence: OR 0.59, CI 0.55-0.63). The model's goodness of fit was low (Nagelkerke's R2 = 0.152). CONCLUSIONS: Our analysis revealed no increased DV among wives with a higher educational level than their husbands. Moreover, the results point towards a decrease of severe violence with an increase in education levels among spouses. However, the model did not explain a satisfying amount of DV. Therefore, further research should be done to reveal unknown determinants so that suitable interventions to reduce DV can be developed.

A Highly Tunable Silicone-Based Magnetic Elastomer with Nanoscale Homogeneity.

Magnetic elastomers have been widely pursued for sensing and actuation applications. Silicone-based magnetic elastomers have a number of advantages over other materials such as hydrogels, but aggregation of magnetic nanoparticles within silicones is difficult to prevent. Aggregation inherently limits the minimum size of fabricated structures and leads to non-uniform response from structure to structure. We have developed a novel material which is a complex of a silicone polymer (polydimethylsiloxane-co-aminopropylmethylsiloxane) adsorbed onto the surface of magnetite (γ-Fe(2)0(3)) nanoparticles 7-10 nm in diameter. The material is homogenous at very small length scales (< 100 nm) and can be crosslinked to form a flexible, magnetic material which is ideally suited for the fabrication of micro- to nanoscale magnetic actuators. The loading fraction of magnetic nanoparticles in the composite can be varied smoothly from 0 - 50% wt. without loss of homogeneity, providing a simple mechanism for tuning actuator response. We evaluate the material properties of the composite across a range of nanoparticle loading, and demonstrate a magnetic-field-induced increase in compressive modulus as high as 300%. Furthermore, we implement a strategy for predicting the optimal nanoparticle loading for magnetic actuation applications, and show that our predictions correlate well with experimental findings.