Diffuse dermatophytosis occurring on dimethyl fumarate therapy.

BACKGROUND: Opportunistic infections have occurred during dimethyl fumarate (DMF) therapy. OBJECTIVE: Diffuse skin dermatophytosis which occurred during DMF therapy in the setting of lymphopenia is described. METHODS AND RESULTS: The clinical course, the lymphocyte subset profile, and dermatologic evaluations were reviewed. In both instances, there was no other cause of lymphopenia or immune suppression, and it is likely that the tinea infections are associated with DMF therapy. CONCLUSION: The occurrence of dermatophytosis widens the spectrum of opportunistic infections associated with DMF therapy. Further research is necessary to fully elucidate the mechanism of lymphopenia and potentially impaired immune competence during DMF therapy.

Effect of dimethyl fumarate on lymphocyte subsets in patients with relapsing multiple sclerosis.

BACKGROUND: In patients treated with dimethyl fumarate, absolute lymphocyte count decline typically occurs during the first year and then plateaus; early drops have been associated with the development of severe prolonged lymphopenia. OBJECTIVE: We investigated the effect of dimethyl fumarate on absolute lymphocyte counts and CD4+/CD8+ T cells in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate in routine practice. METHODS: Lymphocyte data were collected via medical chart abstraction. Primary endpoint: change from baseline in absolute lymphocyte count and CD4+/CD8+ counts at 6-month intervals following dimethyl fumarate initiation. RESULTS: Charts of 483 patients were abstracted and 476 patients included in the analysis. Mean baseline absolute lymphocyte count (2.23 × 109/l) decreased by ∼39% (95% confidence interval: -41.1 to -37.2) by month 6 and 44% (95% confidence interval: -46.6 to -42.1) by month 12. CD4+ and CD8+ T-cell subsets strongly correlated with absolute lymphocyte count, with greater decreases from baseline to 6 months vs 6-12 months, and in CD8+ vs CD4+ T cells. Prior natalizumab was not a risk factor for lymphopenia. CONCLUSION: Dimethyl fumarate-associated decline in absolute lymphocyte count in the first 12 months correlated with decline in CD4+ and CD8+ T cells and was independent of prior natalizumab. Absolute lymphocyte count monitoring continues to be an effective strategy to identify patients at risk of prolonged lymphopenia.

Heptamer Peptide Disassembles Native Amyloid in Human Plasma Through Heat Shock Protein 70.

Proteostasis, which includes the repair and disposal of misfolded proteins, depends, in part, on the activity of heat shock proteins (HSPs), a well-known class of chaperone molecules. When this process fails, abnormally folded proteins may accumulate in cells, tissues, and blood. These species are a hallmark of protein aggregation diseases, but also amass during aging, often in the absence of an identified clinical disorder. We report that a neuroprotective cyclic heptapeptide, CHEC-7, which has been applied systemically as a therapeutic in animal neurodegeneration models, disrupts such aggregates and inhibits amyloidogenesis when added in nanomolar concentrations to human plasma. This effect includes aggregates of amyloid beta (Aß1-40, 1-42), prominent features of Alzheimer's disease pathology. The activity of endogenous HSP70, a recently discovered target of the peptide, is required as demonstrated by both antibody blocking and application of pifithrin-µ, an HSP70 inhibitor. CHEC-7 is the first high-affinity compound to stimulate HSP70's disaggregase activity and therefore enable this endogenous mechanism in a human systemic environment, increasing the likelihood of a convenient therapy for protein aggregate disease, including age-related failures of protein repair.

Secreted phospholipase A2 activity in experimental autoimmune encephalomyelitis and multiple sclerosis.

BACKGROUND: There is increased interest in the contribution of the innate immune system to multiple sclerosis (MS), including the activity of acute inflammatory mediators. The purpose of this study was to test the involvement of systemic secreted phospholipase A2 (sPLA2) enzymes in experimental autoimmune encephalomyelitis (EAE), an MS model, and to determine if enzyme activity is elevated in MS patients. METHODS: A non-invasive urinary assay was developed in order to monitor enzymatically active sPLA2 levels in Dark Agouti rats after induction of EAE. Some Rats were treated with nonapeptide CHEC-9, an uncompetitive sPLA2 enzyme inhibitor, during the initial rise in urinary enzyme levels. Body weight and clinical EAE score were measured for 18 days post immunization (PI), after which the rats were sacrificed for H&E and myelin staining, and for ED-1 immunocytochemistry, the latter to quantify macrophages and activated microglia. The urinary sPLA2 assay was also applied to un-timed samples collected from a cross section of 44 MS patients and 14 healthy controls. RESULTS: Mean levels of enzymatically active sPLA2 in the urine increased following immunization and peaked between days 8-10 PI which was just prior to the onset of EAE symptoms. At this time, a transient attenuation of activity was detected in the urine of CHEC-9 treated rats consistent with the activity-dependent properties of the inhibitor. The peptide also reduced or abolished EAE symptoms compared to vehicle-injected controls. Histopathological changes in the spinal cords of the EAE rats correlated generally with clinical score including a significant reduction in ED-1+ cells after peptide treatment. Multiple Sclerosis patients also showed elevations in sPLA2 enzyme activity. Mean levels of sPLA2 were increased 6-fold in the urine of patients with active disease and 4-fold for patients in remission, regardless of immunomodulating therapy. CONCLUSION: The results suggest that sPLA2 enzymes, traditionally thought to be part the acute phase inflammatory response, are therapeutic targets for MS.

Anti-inflammatory peptide regulates the supply of heat shock protein 70 monomers: implications for aging and age-related disease.

Reducing the levels of toxic protein aggregates has become a focus of therapy for disorders like Alzheimer's and Parkinson's diseases, as well as for the general deterioration of cells and tissues during aging. One approach has been an attempt to influence the production or activity of a class of reparative chaperones called heat shock proteins (HSPs), of which HSP70 is a promising candidate. Manipulation of HSP70 expression results in disposal of misfolded protein aggregates that accumulate in aging and disease models. Recently, HSP70 has been shown to bind specifically to an amino-terminal sequence of a human diffusible survival evasion peptide (DSEP), dermcidin. This sequence includes CHEC-9, an orally available anti-inflammatory and cell survival peptide. In the present study, we found that the CHEC-9 peptide also binds HSP70 in the cytosol of the cerebral cortex after oral delivery in normal rats. Western analysis of non-heat-denatured, unreduced samples suggested that peptide treatment increased the level of active HSP70 monomers from the pool of chaperone oligomers, a process that may be stimulated by potentiation of the chaperone's adenosine triphosphatase (ATPase). In these samples, a small but consistent gel shift was observed for glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a multifunctional protein whose aggregation is influenced by HSP70. CHEC-9 treatment of an in vitro model of α-synuclein aggregation also results in HSP70-dependent dissolution of these aggregates. HSP70 oligomer-monomer equilibrium and its potential to control protein aggregate disease warrant increased experimental attention, especially if a peptide fragment of an endogenous human protein can influence the process.

Current concepts of the cellular and molecular pathophysiology of multiple sclerosis.

Multiple sclerosis (MS) is the most common demyelinating disease. It poses many challenges both clinically and scientifically. Progress made in understanding the genetics, immunology, and neurobiology of MS to date has positioned the field for further breakthroughs both in understanding the etiology and pathogenesis as well as the development of rationally based therapeutics. This review will cover fundamental aspects of the clinical and pathologic features of MS. Identified genetic markers will be considered as well as the evolving understanding of immunologic and neurobiological aspects of the disease. The development of immune therapy based on this knowledge is already apparent and it is likely that neuroprotective therapies will evolve to complement immune modulation in treating the disease.

Insights into neurologic localization by Rhazes, a medieval Islamic physician.

Rhazes was born at Ray near modern Teheran in 864 AD. He wrote over 200 scientific treatises, many of which had a major impact on European medicine. His best known manuscript is Liber Continens, a medical encyclopedia. Herein are described Rhazes's contributions to neurology, focusing on his description of cranial and spinal cord nerves and his clinical case reports, which illustrate his use of neuroanatomy to localize lesions. Relevant passages from facsimiles of the manuscripts Kitab al-Hawi (Liber Continens) and Al-Mansuri Fi At-Tibb (Liber Al Mansoori) were translated, reviewed, and used as references. In addition, Medline, Web, and manuscript searches on Rhazes and the history of medieval and Islamic medicine and neurology were conducted. Rhazes stated that nerves had motor or sensory functions, describing 7 cranial and 31 spinal cord nerves. He assigned a numerical order to the cranial nerves from the optic to the hypoglossal nerves. He classified the spinal nerves into 8 cervical, 12 thoracic, 5 lumbar, 3 sacral, and 3 coccygeal nerves. Rhazes showed an outstanding clinical ability to localize lesions, prognosticate, and describe therapeutic options and reported clinical observations, emphasizing the link between the anatomic location of a lesion and the clinical signs. Rhazes was a pioneer in applied neuroanatomy. He combined a knowledge of cranial and spinal cord nerve anatomy with an insightful use of clinical information to localize lesions in the nervous system.