isolation-primary-murine-skeletal-muscle-microvascular-endothelial

Isolation of Primary Murine Skeletal Muscle Microvascular Endothelial Cells

The endothelial cells of skeletal muscle capillaries (muscle microvascular endothelial cells, MMEC) build up the barrier between blood stream and skeletal ...

University of Muenster

The treatment of multiple sclerosis (MS) remains challenging despite the great efforts made in the development of novel therapies. Driven by the growing knowledge of the immunopathogenesis of the disease, a plethora of new pharmacological agents have been developed and tested in clinical trials. However, the therapeutic advantages and positive clinical trials of some of these agents are outweighed by studies of promising agents that either failed due to negative or inconclusive results or had to be withdrawn because of serious unexpected adverse events. Most failed clinical trials did not lack a well-considered pathophysiological rationale, but concepts from experimental models were proven wrong in humans. Lessons learned from these discrepancies help to optimize future study design and, potentially more importantly, provide further insight into the immunopathogenesis of MS. Here, we summarize trials on MS treatments since 2010 that failed or were interrupted, identifying potential underlying reasons for failure or inconclusiveness.

Failed, interrupted and inconclusive trials on relapsing multiple sclerosis treatment: update 2010-2015.

Severe mercury intoxication is very rare in developed countries, but still occurs as the result of volatile substance abuse, suicide attempts, occupational hazards, or endemic food ingestion as reported in the cases of public health disasters in Iraq and in Minamata Bay, Japan. Here, we describe the dramatic physical and cognitive decline of a 23-year-old patient caused by a severe methyl mercury (MeHg) intoxication of unknown origin. We show serial magnetic resonance imaging (MRI) of the patient's brain, as well as  analyses of blood and cerebrospinal fluid including multicolor flow cytometric measurements, functional assays of hemostaseologic efficacy, and evaluation of regulatory effector molecules. Together with the clinical history, our findings show the progressive neuronal degeneration accompanying the deterioration of the patient. Moreover, the  analyses display alterations of thrombocyte function and coagulation, as well as an immunological milieu facilitating autoimmunity. Despite the successful reduction of the MeHg concentration in the patient's blood with erythrocyte apheresis and chelator therapy, his condition did not improve and led to a persistent vegetative state. This case illustrates the neurotoxicity of MeHg following severe intoxication for the first time by serial MRI. Data on immune-cell and thrombocyte function as well as on coagulation in mercury poisoning reveal potential implications for anticoagulation and immunomodulatory treatment.

An Enigmatic Case of Acute Mercury Poisoning: Clinical, Immunological Findings and Platelet Function.

Sarcoidosis following alemtuzumab treatment: Autoimmunity mediated by T cells and interferon-γ.

Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce.

Article	Year
Failed, interrupted and inconclusive trials on relapsing multiple sclerosis treatment: update 2010-2015. Expert review of neurotherapeutics\| PubMed ID: 27058174	2016
An Enigmatic Case of Acute Mercury Poisoning: Clinical, Immunological Findings and Platelet Function. Frontiers in neurology\| PubMed ID: 29033890	2017
Sarcoidosis following alemtuzumab treatment: Autoimmunity mediated by T cells and interferon-γ. Multiple sclerosis (Houndmills, Basingstoke, England)\| PubMed ID: 30307361	2018
Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation. Journal of neurology\| PubMed ID: 30446966	2019

Steffen Pfeuffer

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