Modified Melodic Intonation Therapy for Aphasia

B.A. (Bachelor of Arts

Contribution of the different modules in the utrophin carboxy-terminal region to the formation and regulation of the DAP complex

AbstractThe carboxy-terminal region of utrophin, like the homologous proteins dystrophin, Drp2 and dystrobrevins, contains structural domains frequently involved in protein–protein interaction. These domains (WW, EF hands, ZZ and H1–H2) mediate recognition and binding to a multicomponent complex of proteins, also known as dystrophin-associated proteins (DAPs) for their association with dystrophin, the product of the gene, mutated in Duchenne muscular dystrophy. We have exploited phage display and in vitro binding assays to study the recognition specificity of the different domains of the utrophin carboxy-terminus. We found that none of the carboxy-terminal domains of utrophin, when isolated from its structural context, selects specific ligand peptides from a phage-displayed peptide library. By contrast, panning with an extended region containing the WW, EF hands, and ZZ domain defines the consensus binding motif, PPxY which is also found in β-dystroglycan, a component of the DAP complex that interacts with utrophin in several tissues. WW-mediated binding to PPxY peptides and to β-dystroglycan requires the presence of the EF hands and ZZ domain. When the ZZ domain is either deleted or engaged in binding to calmodulin, the utrophin β-dystroglycan complex cannot be formed. These findings suggest a potential regulatory mechanism by means of which the attachment of utrophin to the DAP complex can be modulated by the Ca2+-dependent binding of calmodulin. The remaining two motifs found in the carboxy-terminus (H1–H2) mediate the formation of utrophin–dystrobrevin hybrids but do not select ligands in a repertoire of random nonapeptides

Bullous pemphigoid in diabetic patients treated by gliptins: the other side of the coin

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease that affects primarily patients older than 60 years. The majority of BP cases are spontaneous, but BP can also be triggered by certain drugs’ exposures. Since 2011, a growing number of observations has been reporting cases of BP in Type 2 diabetic patients. These forms have been linked to the use of a new category of anti-diabetic drugs called dipeptidyl peptidase inhibitors (DPP-4i) or gliptins, but to date, the exact pathophysiological mechanisms underlying this association are not completely elucidated. Although conventional and gliptin-associated BP are thought to share similar clinical and histopathological features, our thorough review of the most recent literature, shows that these 2 forms are quite distinct: DPP-4-i-associated BP seems to appear at an earlier age than spontaneous BP, it may manifest either as a noninflammatory or inflammatory phenotype, while the conventional form presents with a typical inflammatory phenotype. Additionally, an important distinctive histological feature was recently shown in Gliptin-associated BP: these forms may present a less significant eosinophils infiltrate in the upper dermis of peri-blister lesions compared to the skin of patients with spontaneous BP, and this seems a specific feature of the clinically non-inflammatory forms. In accordance with previous literature, we found that the direct immunofluorescence (DIF) gives identical findings in both DPP-4i-associated and conventional forms of BP which is an IgG and complement C3 deposition as a linear band at the dermal–epidermal junction in perilesional skin. Indirect immunofluorescence shows the presence of IgG circulating autoantibodies in the patient's serum which titer does not differ between spontaneous and DPP-4i-associated BP, while the specificity of these autoantibodies, may be different in spontaneous, induced non-inflammatory and induced inflammatory forms, epitope spreading phenomenon seems to play a role in determining these specificities. Further research, based on integrated epidemiological, clinical, histo-immunological and pharmacogenomic approaches, may give more insight into these forms of BP. This combined approach will allow to better define BP endotypes and to unveil the mechanism of spontaneous or drug-induced breakage of the immunotolerance to skin self-antigens

Paraneoplastic Pemphigus Presenting as Mild Cutaneous Features of Pemphigus Foliaceus and Lichenoid Stomatitis with Antidesmoglein 1 Antibodies

Herein, we report a case of paraneoplastic pemphigus with mild skin features of pemphigus foliaceus and lichenoid stomatitis associated with B-cell lymphoma. A 49-year-old man presented with scattered blisters and erosions on the trunk along with mucosal blisters and erosions. Skin biopsy showed subcorneal acantholytic bulla and oral mucosal biopsy demonstrated lichenoid dermatitis. Direct immunofluorescence showed cell surface deposits of IgG and C3. Indirect immunofluorescence identified circulating IgG autoantibodies to the cell surfaces of normal human skin and also on the transitional epithelium of rat bladder. Enzyme-linked immunosorbent assay using recombinant baculoproteins showed positive antidesmoglein 1 autoantibodies (index 46) but negative antidesmoglein 3 autoantibodies (index 8). Immunoblot analysis using normal human epidermal extract detected BP230 and the 190 kDa periplakin, while immunoprecipitation using radiolabeled cultured keratinocyte immunoprecipitated BP230 and the 210 kDa envoplakin. We consider that the skin lesion was produced by humoral immunity whereas the oral lesion was produced by cellular immunity

The pathogenesis of pemphigus: controversy versus complexity.

Life is highly complex and, as quantum physics would predict, follows the rule of "everything is possible with varying probabilities". Accordingly, science may be sometimes as confusing as political debates, where the same matter is addressed in different and misleading ways even in the absence of a real controversy. The Viewpoint by Ahmed et al. provides a paradigmatic example of a debate about two theories for pemphigus pathogenesis, i.e. "Monopathogenic vs. multipathogenic explanations of pemphigus pathophysiology", both being possible but occurring with variable probabilities (1). This article is protected by copyright. All rights reserved

Blistering lesions associated with Waldenström macroglobulinemia: New insights into pathogenesis.

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Identification of a novel non-desmoglein autoantigen in Pemphigus Vulgaris

Pemphigus vulgaris (PV) is an autoimmune bullous disease of the skin and mucous membranes characterized by the presence of circulating and tissue-bound autoantibodies against keratinocyte cell surface antigens, specifically desmoglein (Dsg) 1 and 3. The pathogenic role of anti-Dsg antibodies is well-established, while the mechanism of blister formation is only partly defined. We have applied a previously developed method for the efficient immortalization of IgG+ memory B cells to identify novel target antigens in PV. A human monoclonal antibody reactive with a hitherto unreported non-Dsg antigen was isolated. Immunoprecipitation and immunoblotting studies with keratinocyte extracts indicated α-catenin as the putative antigen, then confirmed by immunoblotting on the recombinant protein. Four of ten PV sera reacted with recombinant α- catenin. Although the isolated human monoclonal antibody was per se unable to dissociate keratinocyte monolayers and also to synergize with a pathogenic antibody in vitro, further studies are warranted to assess its possible in vivo contribution in the multifactorial pathogenesis and heterogeneous manifestations of PV disease

Paraneoplastic epidermolysis bullosa acquisita associated with thyroid carcinoma

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