Oxidative Stress and Immune System in Vitiligo and Thyroid Diseases.

Vitiligo is an acquired dermatological disease frequently associated with autoimmune thyroid disorders. Several theories have been proposed so far to unravel the complex vitiligo pathogenesis. Currently, the autocytotoxic and the autoimmune theories are the most accredited hypothesis, since they are sustained by several important clinical and experimental evidences. A growing body of evidences shows that autoimmunity and oxidative stress strictly interact to finally determine melanocyte loss. In this scenario, associated thyroid autoimmunity might play an active and important role in triggering and maintaining the depigmentation process of vitiligo

Targeting MAML for the inhibition of notch signalling, using Antp fusion proteins

The highly conserved Notch signalling pathway plays a major role in both metazoan development and adult tissue renewal. Deregulation of this pathway is linked to several diseases, including cancer. Various strategies for Notch signalling inhibition are now being investigated as promising new approaches for cancer therapy. Notch receptor activation results in the release of the Notch cytoplasmic domain (NIC) which translocates to the nucleus to bind the transcription factor CSL. Subsequent recruitment of MAML-1 is necessary to form the active complex that initiates transcription of Notch target genes. In this study, the strategy used to inhibit Notch signalling consists of blocking the CSL-NIC-MAML tripartite complex formation by targeting MAML-1 interactions with NIC and CSL. The first tool is a fusion protein composed of the membrane translocating protein Antennapedia (Antp) and a dominant negative version of MAML-1 (DN-MAML1). A Notch activity reporter-gene assay revealed that addition of Antp-DN-MAML1 leads to a dose dependent decrease in luminescence, corresponding to an inhibition of Notch signalling. At the transcriptional level, treatment of MDA-MB-231 and bone marrow dendritic cells with Antp-DN-MAML1 resulted in a significant decrease in the mRNA levels of Notch target gene Hes1. In a cell proliferation assay, addition of Antp-DN-MAML1 had a strong growth-inhibitory effect when added to MDA-MB-231 breast cancer cells. Our in vitro data is further supported by preclinical studies where administration of Antp-DN-MAML1 halted MDA-MB-231 tumour growth. The second strategy of Notch signalling inhibition presented here attempts the intranuclear delivery of single-chain variable-fragment (scFv) antibodies fused to Antp. Suitable scFvs were selected from a phage display library for their ability to bind residues 13–74 of MAML-1. This constitutes the minimal portion of MAML-1 necessary to form the active tripartite complex, therefore we expect any scFvs that bind this portion to inhibit downstream signalling. Our study illustrates two novel strategies for inhibition of Notch signalling at the transcriptional level which represent potential future therapeutic alternatives

Adult Onset Vitiligo: Multivariate Analysis Suggests the Need for a Thyroid Screening.

Background. There are limited epidemiological studies evaluating the effect of age at onset on disease features in vitiligo. Objectives. To identify factors associated with adult onset vitiligo in comparison with childhood onset vitiligo. Patients and Methods. We retrospectively collected medical records of 191 patients. Such records included clinical examination, personal and familial medical history, laboratory evaluations, concomitant vitiligo treatment and drug assumption. Results. 123 patients with a disease onset after the age of 40 (adult onset vitiligo) were compared with 68 patients who developed vitiligo before the age of 12 (childhood onset vitiligo). Multivariate analysis revealed that personal history of thyroid diseases (P=0.04; OR 0.4), stress at onset (P=0.002; OR = 0.34), personal history of autoimmune thyroid disease (ATD) (P=0.003; OR = 0.23), and thyroid nodules (P=0.001; OR 0.90) were independently associated with adult onset vitiligo, whereas family history of dermatological diseases (P=0.003; OR = 2.87) and Koebner phenomenon (P<0.001; OR = 4.73) with childhood onset vitiligo. Moreover, in the adult onset group, concomitant thyroid disease preceded vitiligo in a statistically significant number of patients (P=0.014). Conclusions. Childhood onset and adult onset vitiligo have different clinical features. In particular, ATD and thyroid nodules were significantly associated with adult onset vitiligo, suggesting that a thyroid screening should be recommended in this group of patients

Potential Infectious Etiology of Behçet's Disease

Behçet's disease is a multisystem inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. The cause of Behçet's disease remains unknown, but epidemiologic findings suggest that an autoimmune process is triggered by an environmental agent in a genetically predisposed individual. An infectious agent could operate through molecular mimicry, and subsequently the disease could be perpetuated by an abnormal immune response to an autoantigen in the absence of ongoing infection. Potentia bacterial are Saccharomyces cerevisiae, mycobacteria, Borrelia burgdorferi, Helicobacter pylori, Escherichia coli, Staphylococcus aureus, and Mycoplasma fermentans, but the most commonly investigated microorganism is Streptococcus sanguinis. The relationship between streptococcal infections and Behçet's disease is suggested by clinical observations that an unhygienic oral condition is frequently noted in the oral cavity of Behçet's disease patients. Several viral agents, including herpes simplex virus-1, hepatitis C virus, parvovirus B19, cytomegalovirus, Epstein-Barr virus and varicella zoster virus, may also have some role

Chronic adult T-cell Leukemia in a young male after blood transfusion as a newborn

Human T-cell Lymphotropic virus type 1 (HTLV-1) is the etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HTM/TSP). Areas of extremely high HTLV-1 prevalence are surrounded by areas of middle or very low prevalence. ATLL is an aggressive lymphoproliferative malignancy of peripheral T cells, with an incidence of less than 5% in HTLV-1-infected individuals. ATLL develops in the majority of cases in individuals who were infected with HTLV-1 by their mothers due to prolonged breastfeeding. In non-endemic areas, ATLL is usually limited to immigrants from endemic regions. Very few cases of ATLL have been diagnosed in recipient patients few years after an organ transplantation or blood transfusion worldwide. Achieving an accurate and fast diagnosis of ATLL can be challenging due to the lack of professional experience, delayed consultation and difficulty in its subclassification. We present a case of a delayed onset of a chronic ATLL in an 18-years-old male that was transfused with blood components as a premature newborn in Buenos Aires, a non-endemic city of South America.Fil: Colucci, Magalí. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cánepa, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Ruggieri, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Berini, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Halperin, Nora Silvia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Rojas, Francisca. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Altube, Alejandra. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cabral Lorenzo, María Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Deves, Alberto. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Hermine, Olivier. Universite de Paris V; FranciaFil: Biglione, Mirna Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin

Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration

Background: Parkinson's disease (PD) is frequently associated with gastrointestinal (GI) symptoms, including constipation and defecatory dysfunctions. The mechanisms underlying such disorders are still largely unknown, although the occurrence of a bowel inflammatory condition has been hypothesized. This study examined the impact of central dopaminergic degeneration, induced by intranigral injection of 6-hydroxydopamine (6-OHDA), on distal colonic excitatory tachykininergic motility in rats. Methods: Animals were euthanized 4 and 8 weeks after 6-OHDA injection. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. SP, tachykininergic NK1 receptor, and glial fibrillary acidic protein (GFAP) expression, as well as the density of eosinophils and mast cells in the colonic wall, were examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay), TNF, and IL-1 beta (ELISA assay) levels were also examined. The polarization of peritoneal macrophages was evaluated by real-time PCR. Results: In colonic preparations, electrically and SP-evoked tachykininergic contractions were increased in 6-OHDA rats. Immunohistochemistry displayed an increase in SP and GFAP levels in the myenteric plexus, as well as NK1 receptor expression in the colonic muscle layer of 6-OHDA rats. MDA, TNF, and IL-1 beta levels were increased also in colonic tissues from 6-OHDA rats. In 6-OHDA rats, the number of eosinophils and mast cells was increased as compared with control animals, and peritoneal macrophages polarized towards a pro-inflammatory phenotype. Conclusions: The results indicate that the induction of central nigrostriatal dopaminergic degeneration is followed by bowel inflammation associated with increased oxidative stress, increase in pro-inflammatory cytokine levels, activation of enteric glia and inflammatory cells, and enhancement of colonic excitatory tachykininergic motility

Enteric dysfunctions in experimental Parkinson's disease: alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats

Parkinson's disease (PD) is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiological assay. Electrically and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, while acetylcholine levels were assayed in their incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors. As compared with control rats, at week 4 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate; impaired electrically evoked neurogenic cholinergic contractions; enhanced carbachol-induced contractions; decreased basal and electrically stimulated acetylcholine release from colonic tissues; decreased ChAT immunopositivity in the neuromuscular layer; unchanged density of HuC/D immunoreactive myenteric neurons; increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were detected also at week 8 post-6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate