was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/143933 doi: bioRxiv preprint first posted online Jul. 13, 2017; 2
Abstract:We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain-resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.
Cerebral blood flow (CBF) was measured by xenon-133 inhalation and single photon emission tomography in 17 demented patients with normal-pressure hydrocephalus before and after shunt treatment. All patients had a decreased conductance to outflow (C out) of cerebrospinal fluid as measured by lumboventricular perfusion (C out less than 0.12 ml X mm Hg-1 X min-1). Computerized tomography (CT) scanning, clinical assessment, and neuropsychological grading were performed pre- and postoperatively. The preoperative CBF studies revealed abnormal flow patterns in all patients. Fourteen patients showed moderate-sized, large, or very large central low-flow areas, and four patients had reduced flow bilaterally in the occipital and contiguous temporoparietal regions. After shunting, six patients had a significant reduction in the size of the central low-flow area on the CBF map, agreeing well with the changes of ventricular size on the CT scan. All six patients showed an improvement in either clinical or neuropsychological grading. In 10 of the remaining 11 patients flow patterns were essentially unchanged; one patient deteriorated further. Four of these 11 patients improved on postoperative clinical or neuropsychological testing. Thus, a positive correlation was found between the changes in CBF and the reduction of the ventricular size on the CT scan, but changes in CBF as measured by the present technique did not accompany improvement in the functional state in all patients.
We conclude that patients primarily with spasticity, concomitant with hampering or painful spasms and co-contractions should be offered treatment with baclofen. Only some will experience improvement of their gait disorders, when treated with baclofen.
The majority of disease-modifying drugs (DMDs) available for the management of active relapsing-remitting multiple sclerosis (RMS) depend on continuous drug intake for maintained efficacy, with escalation to a more active drug when an unacceptable level of disease activity returns. Among continuously applied regimens, interferons and glatiramer acetate act as immunomodulators, while dimethyl fumarate, fingolimod, ocrelizumab, natalizumab and teriflunomide are associated with continuous immunosuppression. By contrast, immune reconstitution therapy (IRT) provides efficacy that outlasts a short course of treatment. Autologous hemopoietic stem cell transplantation is perhaps the classic example of IRT, but Digital Features To view digital features for this article go to
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