Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination.

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

DDR1 and Its Ligand, Collagen IV, Are Involved in In Vitro Oligodendrocyte Maturation.

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor expressed in epithelial cells from different tissues in which collagen binding activates pleiotropic functions. In the brain, DDR1 is mainly expressed in oligodendrocytes (OLs), the function of which is unclear. Whether collagen can activate DDR1 in OLs has not been studied. Here, we assessed the expression of DDR1 during in vitro OL differentiation, including collagen IV incubation, and the capability of collagen IV to induce DDR1 phosphorylation. Experiments were performed using two in vitro models of OL differentiation: OLs derived from adult rat neural stem cells (NSCs) and the HOG16 human oligodendroglial cell line. Immunocytofluorescence, western blotting, and ELISA were performed to analyze these questions. The differentiation of OLs from NSCs was addressed using oligodendrocyte transcription factor 2 (Olig2) and myelin basic protein (MBP). In HOG16 OLs, collagen IV induced DDR1 phosphorylation through slow and sustained kinetics. In NSC-derived OLs, DDR1 was found in a high proportion of differentiating cells (MBP+/Olig2+), but its protein expression was decreased in later stages. The addition of collagen IV did not change the number of DDR1+/MBP+ cells but did accelerate OL branching. Here, we provide the first demonstration that collagen IV mediates the phosphorylation of DDR1 in HOG16 cells and that the in vitro co-expression of DDR1 and MBP is associated with accelerated branching during the differentiation of primary OLs.

Pericytes in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease that affects the central nervous system (CNS), particularly, in young adults. Current MS treatments aim to reduce demyelination; however, these have limited efficacy, display side effects and lack of regenerative activities. Oligodendrocyte progenitor cells (OPCs) represents the major source for new myelin. Upon demyelination, OPCs get activated, proliferate, migrate towards the lesion, and differentiate into remyelinating oligodendrocytes. Although myelin repair (remyelination) represents a robust response to myelin damage, during MS, this regenerative phenomenon decays in efficiency or even fails. CNS-resident pericytes (CNS-PCs) are essential for vascular homeostasis regulating blood-brain barrier (BBB) permeability and stability as well as endothelial cells (ECs) function during angiogenesis and neovascularization. Recent studies indicate that CNS-PCs also play a crucial role regulating OPC function during remyelination, and very importantly, these cells are substantially affected in MS. This chapter summarizes important aspects of MS and CNS remyelination as well as it provides new insights supporting the contribution of CNS-PCs to myelin regeneration and to MS pathology. Currently, there is evidence arguing in favor of CNS-PCs as novel therapeutic targets for the development of future treatments for MS.

Pericytes Favor Oligodendrocyte Fate Choice in Adult Neural Stem Cells.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Upon demyelination, oligodendrocyte progenitor cells (OPCs) are activated and they proliferate, migrate and differentiate into myelin-producing oligodendrocytes. Besides OPCs, neural stem cells (NSCs) may respond to demyelination and generate oligodendrocytes. We have recently shown that CNS-resident pericytes (PCs) respond to demyelination, proliferate and secrete Laminin alpha2 (Lama2) that, in turn, enhances OPC differentiation. Here, we aimed to evaluate whether PCs influence the fate choice of NSCs in vitro, towards the production of new myelin-producing cells. Indeed, upon exposure to conditioned medium derived from PCs (PC-CM), the majority of NSCs gave rise to GalC- and myelin basic protein (MBP)-expressing oligodendrocytes at the expense of the generation of GFAP-positive astrocytes. Consistent with these findings, PC-CM induces an increase in the expression of the oligodendrocyte fate determinant Olig2, while the expression level of the astrocyte determinant ID2 is decreased. Finally, pre-incubation of PC-CM with an anti-Lama2 antibody prevented the generation of oligodendrocytes. Our findings indicate that PCs-derived Lama2 instructs NSCs to an oligodendrocyte fate choice favoring the generation of myelin-producing cells at the expense of astrocytes in vitro. Further studies aiming to reveal the role of PCs during remyelination may pave the way for the development of new therapies for the treatment of MS.

-759C>T Polymorphism of the HTR2C Gene is Associated with Second Generation Antipsychotic-Induced Weight Gain in Female Patients with Schizophrenia.

Introduction: The HTR2C gene is an important candidate in pharmacogenetic studies of antipsychotic-induced weight gain (AIWG). However, inconsistent results have been obtained. The present study investigated the association between -759C>T, functional polymorphism of the HTR2C receptor, and AIWG. Methods: A prospective cohort of 48 female inpatients with schizophrenia and related illness treated according to normal clinical practice with second generation antipsychotics (SGAs) risperidone, clozapine, quetiapine, and olanzapine were evaluated. Patients were weighted at admission and again at 6 weeks of hospitalization. Weight gain was defined as an increase≥7% of baseline weight. The association between polymorphisms HTR2C and weight gain was evaluated. Multiple logistic regression was run to determine potential confounders. Results: Patients with the T allele at position -759 (TT or CT) gained less weight as compared to patients who did not have the allele. This association was not affected by possible confounding factors such as age, baseline BMI, and prior psychopharmacological treatment. Discussion: The T allele at position -759 protects against AIWG in female patients with schizophrenia.

Community Involvement in a Dengue Prevention Project in Malaria, Sao Paulo, State, Brazil

Since dengue fever has only recently appeared in the city of Marília, São Paulo, State, Brazil, and no fatal cases of the disease have yet to occur, dengue prevention is not a local priority. A dengue prevention program in one neighborhood made the tires, cans and bottles where mosquitoes breed its focus, and conducted an “ethnography of refuse,” including local classification of materials as useful or disposable in preparation for and educational intervention. The initial assumption was that patterns of refuse disposal are and individual choice, influenced by relatively static cultural definitions of what constitutes refuse. This gave way over the course of the project to a new, more dynamic and contextualized view, allowing for the influence of a system of selective refuse collection with participation of both householders and informal refuse collectors. The implications of the findings for programs to control other emerging infectious diseases are discussed.

Disposable containers a larval habitats for Aedes aegypti in city with regular refuse collection: a study in Marília, São Paulo State, Brazil

In Marilia, Brazil, refuse ins collected at least every other day, yet non-useful, non- returnable containers such as cans, plastic bottles and tires account for almost half of the container habitats found positive for the Aedes aegypti mosquito. A study was therefore conducted to investigate why these containers exist despite regular refuse collection and a high level of awareness of dengue prevention, and how the control program could most effectively respond. Differing community perceptions as to what constitutes refuse were found to lead people to store a variety of containers in their yard. Other dimensions of the problem include the presence of informal refuse collectors in search of saleable materials, and dumping of refuse in vacant lots and along roads. An intervention based on these data will involve the informal refuse collectors in implementation of a community-base recycling project.

Bacteremias en un hospital de cáncer. experiencia entre 1980 y 1993 en el INEN / Bacteremia at cancer hospital between 1980 and 1993

Con el objeto de evaluar la distribución epidemiológica de las bacteremias detectadas en el INEN entre 1980 y 1993 revisamos los archivos de la institución. Los gérmenes Gram positivos representan aproximadamente el 60 por ciento de la serie. Entre 1980 a 1984 el S. aureus fue el Gram positivo más frecuente y S. epidermidis entre 1985 y 1993. Los gérmenes negativos representaron el 40 por ciento del total y cinco fueron los más frecuentes: Pseudomona, E. coli, Klebsiella, Acinetobacter y Enterobacter.

Elaboración y administración de dos formas farmaceuticas preparadas con sangre de ganado vacuno, Sucre 1988

Segun la OMS, la anemia es una de las enfermeades mas frecuentemente observadas en el mundo de hoy. Es especialmente prevalente en los niños pequeños y en las mujeres en edadde reproducción, sobre todo durante el embarazo. Las causas de la anemia son multiples, pero es indudable que los niños y las mujeres son afectados porque sus necesidades de hierro son elevadas y Bolivia no constituye una excepción. La deficiencia de hierro ejerce sin embargo ademas de la anemia, un profundo afecto sobre el comportamiento psicologico y fisico del sujeto. Las anemias leves y moderadas mucho mas frecuentes, se toleran mas o menos bien en circunstancias normales no obstante, reducen la resistencia a las infeciones y afectan a la capacidad del trabajo en condiciones de tensión; incluso las formas muy leves alteran la sensación de bienestar. Resulta por lo tanto, evidente que ante la magnitud que alcanza en el ser humano, los esfuerzos deben encausarse hacia la prevención y el tratamiento. El empleo de sangre vacuna por su alto contenido en hierro resulta el metodo mas practico para curar la anemia carencial en la población. Con esta finalidad se diseño un trabajo observacinal, analitico y prospectivo. La mayoria de los medicamentos antianemicos, llevan en mayor o en menor proporción hierro inorganico al estado de sales, sobre todo sulfato; sin embargo se ha demostrado en estudios últimos que el hierro presente en la hemoglobina, tiene un mecanismo de absorción superior al hierro inorganico por su alta biodisponibilidad. Es esta la razón del presente trabajo para demostrar que el producto farmaceutico obtenido de sangre vacuna cura la anemia a corto plazo y siendo de bajo costo, puede llegar a las clases de bajos recursos economicos...