In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) the cytokines tumour necrosis factor-alpha (TNF), lymphotoxin-alpha (LT), and interferon-gamma (IFN-gamma) are of central pathogenetic importance. A therapy capable of stopping neurological deterioration in MS patients is not yet available. Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-gamma in human and rat auto-reactive T cells. Moreover, we show that rolipram is an effective treatment for EAE. Rolipram has extensively been studied in humans for the treatment of depression, but has not yet been marketed. The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials.

ObjectiveTo determine demographic characteristics, clinical features, treatment regimens, and outcome of myasthenic crisis (MC) requiring mechanical ventilation (MV).MethodsAnalysis of patients who presented with MC between 2006 and 2015 in a German multicenter retrospective study.ResultsWe identified 250 cases in 12 participating centers. Median age at crisis was 72 years. Median duration of MV was 12 days. Prolonged ventilation (>15 days) depended on age (p = 0.0001), late-onset myasthenia gravis (MG), a high Myasthenia Gravis Foundation of America Class before crisis (p = 0.0001 for IVb, odds ratio [OR] = infinite), number of comorbidities (>3 comorbidities: p = 0.002, OR 2.99), pneumonia (p = 0.0001, OR 3.13), and resuscitation (p = 0.0008, OR 9.15). MV at discharge from hospital was necessary in 20.5% of survivors. Patients with early-onset MG (p = 0.0001, OR 0.21), thymus hyperplasia (p = 0.002, OR 0), and successful noninvasive ventilation trial were more likely to be ventilated for less than 15 days. Noninvasive ventilation in 92 cases was sufficient in 38%, which was accompanied by a significantly shorter duration of ventilation (p = 0.001) and intensive care unit (ICU) stay (p = 0.01). IV immunoglobulins, plasma exchange, and immunoadsorption were more likely to be combined sequentially if the duration of MV and the stay in an ICU extended (p = 0.0503, OR 2.05). Patients who received plasma exchange or immunoadsorption as first-line therapy needed invasive ventilation significantly less often (p = 0.003). In-hospital mortality was 12%, which was significantly associated with the number of comorbidities (>3) and complications such as acute respiratory distress syndrome and resuscitation. Main cause of death was multiorgan failure, mostly due to sepsis.ConclusionMortality and duration of MC remained comparable to previous reports despite higher age and a high disease burden in our study. Prevention and treatment of complications and specialized neurointensive care are the cornerstones in order to improve outcome.

Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.

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CD26 or dipeptidyl peptidase IV (DP IV) is expressed on various cell types, including T cells. Although T cells can receive activating signals via CD26, the physiological role of CD26/DP IV is largely unknown. We used the reversible DP IV inhibitor Lys[Z(NO2)]-pyrrolidide (I40) to dissect the role of DP IV in experimental autoimmune encephalomyelitis (EAE) and to explore the therapeutic potential of DP IV inhibition for autoimmunity. I40 administration in vivo decreased and delayed clinical and neuropathological signs of adoptive transfer EAE. I40 blocked DP IV activity in vivo and increased the secretion of the immunosuppressive cytokine TGF-β1 in spinal cord tissue and plasma during acute EAE. In vitro, while suppressing autoreactive T cell proliferation and TNF-α production, I40 consistently up-regulated TGF-β1 secretion. A neutralizing anti-TGF-β1 Ab blocked the inhibitory effect of I40 on T cell proliferation to myelin Ag. DP IV inhibition in vivo was not generally immunosuppressive, neither eliminating encephalitogenic T cells nor inhibiting T cell priming. These data suggest that DP IV inhibition represents a novel and specific therapeutic approach protecting from autoimmune disease by a mechanism that includes an active TGF-β1-mediated antiinflammatory effect at the site of pathology.

BACKGROUND. Doxorubicin exhibits high efficacy in malignant glioma cell cultures.

Objective We aimed to estimate the incidence of cerebral sinus and venous thrombosis (CVT) within 1 month from first dose administration and the frequency of vaccine‐induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA‐1273, in Germany. Methods A web‐based questionnaire was e‐mailed to all departments of neurology. We requested a report of cases of CVT occurring within 1 month of a COVID‐19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of 9 German states. Results A total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were younger than 60 years. Fifty‐three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%) vaccination, and none after mRNA‐1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within 1 month from first dose administration was 0.55 (95% confidence interval [CI] = 0.38–0.78) per 100,000 person‐months (which corresponds to a risk of CVT within the first 31 days of 0.55 per 100,000 individuals) for all vaccines and 1.52 (95% CI = 1.00–2.21) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (95% CI = 3.46–34.98) for ChAdOx1 compared to mRNA‐based vaccines and 3.14 (95% CI = 1.22–10.65) for females compared to non‐females. In 26 of 45 patients with CVT (57.8%), VITT was graded highly probable. Interpretation Given an incidence of 0.02 to 0.15 per 100,000 person‐months for CVT in the general population, these findings point toward a higher risk for CVT after ChAdOx1 vaccination, especially for women. ANN NEUROL 2021

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