Searching for therapeutic strategies in a mouse modelo of Machado-Joseph disease: targeting proteostases

Tese de Doutoramento em Ciências da Saúde

Prevalence of thyroiditis and immunohistochemistry study searching for a morphologic consensus in morphology of autoimmune thyroiditis in a 4613 autopsies series

We sought to verify the prevalence of lymphocytic thyroiditis (LT) and Hashimoto's thyroiditis (HT) in autopsy materials. Cases examined between 2003 and 2007 at the Department of Pathology of Faculty of Medicine of São Paulo University were studied. Immunohistochemical analyses were conducted in selected cases to characterize the type of infiltrating mononuclear cells; in addition, we evaluated the frequency of apoptosis by TUNEL assay technique and caspase-3 immunostaining. Significant increase in overall thyroiditis frequency was observed in the present series when compared with the previous report (2.2978% vs. 0.0392%). Thyroiditis was more prevalent among older people. Selected cases of LT and HT (5 cases each) had their infiltrating lymphocytes characterized by immunohistochemical analyses. Both LT and HT showed similar immunostaining patterns for CD4, CD8, CD68, thus supporting a common pathophysiology mechanism and indicating that LT and HT should be considered different presentations of a same condition, that is, autoimmune thyroiditis. Moreover, apoptosis markers strongly evidenced that apoptosis was present in all studied cases. Our results demonstrated an impressive increase in the prevalence of thyroiditis during recent years and our data support that the terminology of autoimmune thyroiditis should be used to designate both LT and HT. This classification would facilitate comparison of prevalence data from different series and studies.

Búsqueda de marcadores de evolución y tratamiento en la miocardiopatía por Enfermedad de Chagas. Searching for indicators of evolution and treatment of Chagas disease miocardiopathy.

El 30 por ciento de personas infectadas con T. cruzi desarrollará una cardiopatía chagásica de expresión clínica variada. Por esta razón es relevante identificar marcadores genéticos y de evolución de la miocardiopatía a fin de clasificar a los pacientes, acorde al grado de riesgo de desarrollar la enfermedad, así como es necesario investigar sobre mejores tratamientos.Los marcadores genéticos de riesgo (polimorfismos relacionados con enfermedades) colaboran identificando genes involucrados en enfermedades poligénicas. Analizaremos SNPs (single nucleotide polymorphism) localizados en zonas potencialmente funcionales de los genes de endotelina-1, su receptor A, de SOD-Mn, y de TNF alfa, factores que intervendrían en la expresión de severidad de la cardiopatía.El corazón es un órgano altamente dependiente de la energía provista por las mitocondrias y éstas son blanco de mediadores inflamatorios que se producen con el ingreso del parásito; por eso estudiaremos en corazones de ratones y de pacientes chagásicos las alteraciones genéticas, morfológicas y funcionales mitocondriales con el fin de determinar lesiones y evolución de las mismas.Existen controversias en tratar la Enfermedad de Chagas fuera de la etapa aguda por la toxicidad de las drogas. La clomipramina antidepresivo usado en siquiatría, demostró impedir la evolución de la infección aguda en modelos experimentales; proponemos el tratamiento con benznidazol a la mitad de la dosis habitual asociada a clomipramina en bajas concentraciones en modelos experimentales en el estadío crónico. Estos resultados aportarán a la fisiopatogenia de la miocardiopatía chagásica, al contar con marcadores de evolución, severidad y de probable riesgo de desarrollar la cardiopatía y serán un aporte a la prevención y nuevos tratamientos.

Arctic searching expedition: a journal of a boat-voyage through Rupert's Land and the Arctic Sea, in search of the discovery ships under command of Sir John Franklin. With an appendix on the physical geography of North America. By Sir John Richardson ...

v. 1

When is the Best Time for the Second Antiplatelet Agent in Non-St Elevation Acute Coronary Syndrome?

Abstract Dual antiplatelet therapy is a well-established treatment in patients with non-ST elevation acute coronary syndrome (NSTE-ACS), with class I of recommendation (level of evidence A) in current national and international guidelines. Nonetheless, these guidelines are not precise or consensual regarding the best time to start the second antiplatelet agent. The evidences are conflicting, and after more than a decade using clopidogrel in this scenario, benefits from the routine pretreatment, i.e. without knowing the coronary anatomy, with dual antiplatelet therapy remain uncertain. The recommendation for the upfront treatment with clopidogrel in NSTE-ACS is based on the reduction of non-fatal events in studies that used the conservative strategy with eventual invasive stratification, after many days of the acute event. This approach is different from the current management of these patients, considering the established benefits from the early invasive strategy, especially in moderate to high-risk patients. The only randomized study to date that specifically tested the pretreatment in NSTE-ACS in the context of early invasive strategy, used prasugrel, and it did not show any benefit in reducing ischemic events with pretreatment. On the contrary, its administration increased the risk of bleeding events. This study has brought the pretreatment again into discussion, and led to changes in recent guidelines of the American and European cardiology societies. In this paper, the authors review the main evidence of the pretreatment with dual antiplatelet therapy in NSTE-ACS.

Implementation of the ordinal shapley value for a three-agent economy

We propose a simple mechanism that implements the Ordinal Shapley Value (Pérez-Castrillo and Wettstein [2005]) for economies with three or less agents.

The Instrumental voter goes to the news-agent: demand for information, election closeness, and the media

This paper studies the impact of instrumental voting on information demand and mass media behaviour during electoral campaigns. If voters act instrumentally then information demand should increase with the closeness of an election. Mass media are modeled as profit-maximizing firms that take into account information demand, the value of customers to advertisers and the marginal cost of customers. Information supply should be larger in electoral constituencies where the contest is expected to be closer, there is a higher population density, and customers are on average more profitable for advertisers. The impact of electorate size is theoretically undetermined. These conclusions are then tested with comfortable results on data from the 1997 general election in Britain.

The principal-agent matching market

We propose a model based on competitive markets in order to analyze an economy with several principals and agents. We model the principal-agent economy as a two-sided matching game and characterize the set of stable outcomes of this principal-agent matching market. A simple mechanism to implement the set of stable outcomes is proposed. Finally, we put forward examples of principal-agent economies where the results fit into.

Incorporació del català en agent conversacional animat per computador

Dins del marc del projecte europeu HERMES, al Centre de Visió per Computador de la Universitat Autònoma de Barcelona s'està desenvolupant un agent conversacional animat per ordinador el qual haurà de ser capaç d'interactuar amb l'usuari a través de diferents canals de forma simultània, o, el que és el mateix, parlar, gesticular, expressar emocions... Partint, doncs, d'un software capaç de fer que un model 3D d'un cap humà expressi emocions i parli en anglès, donat un arxiu d'àudio prèviament generat, en el treball que aquí es presenta es duu a terme la recerca d'una eina sintetitzadora de parla a partir de text que permeti fer això mateix en català. En aquest document s'explica el procés seguit per a trobar aquesta eina, la investigació realitzada sobre el funcionament d'ambdues per tal d'entendre-les i poder-hi treballar, així com, finalment, les modificacions realitzades per a fer que aquestes puguin interactuar i generar parla inteligible en català a partir de textos escrits en aquest idioma.

Study of an outbreak of cutaneous leishmaniasis in Venezuela: the role of domestic animals

During an outbreak of cutaneous leishmaniasis in a locality (Las Rosas, Cojedes State, venezuela) previously non-endemic, 12.9% of humans, 7% of dogs and 21.4% of donkeys (Equus asinus) had lesions with paraites. The agent in the three hosts was identified as Leishmania braziliensis, subspecies braziliensis at least in man and donkey. The probable vector was Lutzomyia panamensis. No infection was found in a small sample of wild mammals examined. The outbreak was apparently linked with the importation of donkeys with ulcers, from endemic areas. The Authors call attention to the fact that not only in the foci of "uta", but also in areas of the other forms of American cutaneous leishmaniasis, dogs are frequently found infected. They emphasize the necessity of searching for the infection in donkeys and of performing hemocultures and xenodiagnosis with sandflies in human, canine and equine cases, to verify their possible role as sources of infection, and not merely as dead ends in the epidemiological chain of the disease.

Multi-agent contracting with countervailing incentives and limited liability

We consider a principal who deals with a privately informed agent protected by limited liability in a correlated information setting. The agent's technology is such that the fixed cost declines with the marginal cost (the type), so that countervailing incentives may arise. We show that, with high liability, the first-best outcome can be effected for any type if (1) the fixed cost is non-concave in type, under the contract that yields the smallest feasible loss to the agent; (2) the fixed cost is not very concave in type, under the contract that yields the maximum sustainable loss to the agent. We further show that, with low liability, the first-best outcome is still implemented for a non-degenerate range of types if the fixed cost is less concave in type than some given threshold, which tightens as the liability reduces. The optimal contract entails pooling otherwise.

Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent?

BACKGROUND: Patients with rheumatoid arthritis (RA) with an inadequate response to TNF antagonists (aTNFs) may switch to an alternative aTNF or start treatment from a different class of drugs, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit. OBJECTIVE: To analyse the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients. METHODS: A prospective cohort study of patients with RA who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA) was carried out. The primary outcome, longitudinal improvement in 28-joint count Disease Activity Score (DAS28), was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders. RESULTS: Of the 318 patients with RA included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than with an alternative aTNF (p = 0.03; at 6 months, -1.34 (95% CI -1.54 to -1.15) vs -0.93 (95% CI -1.28 to -0.59), respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar for RTX and alternative aTNFs (p = 0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of co-treatment with a disease-modifying antirheumatic drug. CONCLUSION: This observational study suggests that in patients with RA who have stopped a previous aTNF treatment because of ineffectiveness changing to RTX is more effective than switching to an alternative aTNF.

Seizures after single-agent overdose with pharmaceutical drugs: Analysis of cases reported to a poison center.

Abstract Context. Seizures during intoxications with pharmaceuticals are a well-known complication. However, only a few studies report on drugs commonly involved and calculate the seizure potential of these drugs. Objectives. To identify the pharmaceutical drugs most commonly associated with seizures after single-agent overdose, the seizure potential of these pharmaceuticals, the age-distribution of the cases with seizures and the ingested doses. Methods. A retrospective review of acute single-agent exposures to pharmaceuticals reported to the Swiss Toxicological Information Centre (STIC) between January 1997 and December 2010 was conducted. Exposures which resulted in at least one seizure were identified. The seizure potential of a pharmaceutical was calculated by dividing the number of cases with seizures by the number of all cases recorded with that pharmaceutical. Data were analyzed using descriptive statistics. Results. We identified 15,441 single-agent exposures. Seizures occurred in 313 cases. The most prevalent pharmaceuticals were mefenamic acid (51 of the 313 cases), citalopram (34), trimipramine (27), venlafaxine (23), tramadol (15), diphenhydramine (14), amitriptyline (12), carbamazepine (11), maprotiline (10), and quetiapine (10). Antidepressants were involved in 136 cases. Drugs with a high seizure potential were bupropion (31.6%, seizures in 6 of 19 cases, 95% CI: 15.4-50.0%), maprotiline (17.5%, 10/57, 95% CI: 9.8-29.4%), venlafaxine (13.7%, 23/168, 95% CI: 9.3-19.7%), citalopram (13.1%, 34/259, 95% CI: 9.5-17.8%), and mefenamic acid (10.9%, 51/470, 95% CI: 8.4-14.0%). In adolescents (15-19y/o) 23.9% (95% CI: 17.6-31.7%) of the cases involving mefenamic acid resulted in seizures, but only 5.7% (95% CI: 3.3-9.7%) in adults (≥ 20y/o; p < 0.001). For citalopram these numbers were 22.0% (95% CI: 12.8-35.2%) and 10.9% (95% CI: 7.1-16.4%), respectively (p = 0.058). The probability of seizures with mefenamic acid, citalopram, trimipramine, and venlafaxine increased as the ingested dose increased. Conclusions. Antidepressants were frequently associated with seizures in overdose, but other pharmaceuticals, as mefenamic acid, were also associated with seizures in a considerable number of cases. Bupropion was the pharmaceutical with the highest seizure potential even if overdose with bupropion was uncommon in our sample. Adolescents might be more susceptible to seizures after mefenamic acid overdose than adults. "Part of this work is already published as a conference abstract for the XXXIV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 27-30 May 2014, Brussels, Belgium." Abstract 8, Clin Toxicol 2014;52(4):298.