Eritema induratum de Bazin : a propósito de um caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Examen instructivo sobre la música multiforme, métrica y rythmica : en el cual por preguntas y respuestas se da la razón de muchas cosas necesarias para el contrapunto y composición ... /

Mode of access: Internet.

The “Great Masquerader" Strikes Again: Secondary Syphilis Presentation with Erythema Multiforme (EM)-Like Lesions

Syphilis is a sexually transmitted disease known to present with highly variable manifestations, especially when left untreated. Patients who present to Internal Medicine Departments with fever and a rash are always a diagnostic challenge since mild viral diseases and life-threatening bacterial infections may manifest themselves similarly. In the following case presentation, we describe a patient with 1 month’s duration of fever and rash on the palms of the hand and soles of the feet, in the form of erythema multiforme (EM)-like lesions. His disease was diagnosed as secondary syphilis, once again justifying its name: the “great masquerader".

A Novel integration approach : perturbation studies in vitro using PDK1 inhibitors in glioblastoma multiforme

Os objetivos a atingir em 2020 no que respeita ao processo de investigação e desenvolvimento de medicamentos estão claramente focados na redução em termos temporais na investigação pré-clínica e clínica e na diminuição da taxa de atrito entre as novas moléculas. De forma a atingir estes objetivos, um novo conceito tem sido desenvolvido e aplicado a este complexo e moroso processo, este é a Farmacologia Quantitativa e de Sistemas. Além disso, esta abordagem inovadora pode ser crucial para o tratamento de determinados tipos de tumores cerebrais letais – Glioblastoma Multiforme (GBM) – que permanecem um desafio terapêutico, e por tanto, uma doença com um destino fatal para os doentes. Por estas razões, esta dissertação de mestrado apresenta uma especial relevância, tendo por objetivos avaliar o potencial impacto e importância biológica da variação de parâmetros farmacológicos, para além da potência, no contexto da resposta celular ao fármaco, pela avaliação da perturbação induzida em células do GBM por inibidores do PDK1 e pela realização de uma caracterização multiparamêtrica dose-resposta destas novas moléculas. A presente dissertação assume em Portugal a vanguarda na área da Farmacologia Quantitativa e de Sistemas aplicada ao processo de investigação e desenvolvimento de medicamentos. Em última estância, esta dissertação poderá contribuir para uma melhor previsão dos fármacos durante este processo, significando assim possíveis vantagens para os utentes, indústrias farmacêuticas, institutos de investigação, governo e institutos superiores.

Silenciamento do canal de potássio Eag1 potencializa efeitos da temozolomida em células U-87 MG de glioblastoma multiforme

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2015.

The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells

Glioblastoma multiforme (GBM) is a malignant astrocytoma of the central nervous system associated with a median survival time of 15 months, even with aggressive therapy. This rapid progression is due in part to diffuse infiltration of single tumor cells into the brain parenchyma, which is thought to involve aberrant interactions between tumor cells and the extracellular matrix (ECM). Here, we test the hypothesis that mechanical cues from the ECM contribute to key tumor cell properties relevant to invasion. We cultured a series of glioma cell lines (U373-MG, U87-MG, U251-MG, SNB19, C6) on fibronectin-coated polymeric ECM substrates of defined mechanical rigidity and investigated the role of ECM rigidity in regulating tumor cell structure, migration, and proliferation. On highly rigid ECMs, tumor cells spread extensively, form prominent stress fibers and mature focal adhesions, and migrate rapidly. As ECM rigidity is lowered to values comparable with normal brain tissue, tumor cells appear rounded and fail to productively migrate. Remarkably, cell proliferation is also strongly regulated by ECM rigidity, with cells dividing much more rapidly on rigid than on compliant ECMs. Pharmacologic inhibition of nonmuscle myosin II–based contractility blunts this rigidity-sensitivity and rescues cell motility on highly compliant substrates. Collectively, our results provide support for a novel model in which ECM rigidity provides a transformative, microenvironmental cue that acts through actomyosin contractility to regulate the invasive properties of GBM tumor cells.

Proton magnetic resonance spectroscopy of a boron neutron capture therapy 10B-carrier, L-p-boronophenylalanine-fructose complex

Boron neutron capture therapy (BNCT) is a radiotherapy that has mainly been used to treat malignant brain tumours, melanomas, and head and neck cancer. In BNCT, the patient receives an intravenous infusion of a 10B-carrier, which accumulates in the tumour area. The tumour is irradiated with epithermal or thermal neutrons, which result in a boron neutron capture reaction that generates heavy particles to damage tumour cells. In Finland, boronophenylalanine fructose (BPA-F) is used as the 10B-carrier. Currently, the drifting of boron from blood to tumour as well as the spatial and temporal accumulation of boron in the brain, are not precisely known. Proton magnetic resonance spectroscopy (1H MRS) could be used for selective BPA-F detection and quantification as aromatic protons of BPA resonate in the spectrum region, which is clear of brain metabolite signals. This study, which included both phantom and in vivo studies, examined the validity of 1H MRS as a tool for BPA detection. In the phantom study, BPA quantification was studied at 1.5 and 3.0 T with single voxel 1H MRS, and at 1.5 T with magnetic resonance imaging (MRSI). The detection limit of BPA was determined in phantom conditions at 1.5 T and 3.0 T using single voxel 1H MRS, and at 1.5 T using MRSI. In phantom conditions, BPA quantification accuracy of ± 5% and ± 15% were achieved with single voxel MRS using external or internal (internal water signal) concentration references, respectively. For MRSI, a quantification accuracy of <5% was obtained using an internal concentration reference (creatine). The detection limits of BPA in phantom conditions for the PRESS sequence were 0.7 (3.0 T) and 1.4 mM (1.5 T) mM with 20 × 20 × 20 mm3 single voxel MRS, and 1.0 mM with acquisition-weighted MRSI (nominal voxel volume 10(RL) × 10(AP) × 7.5(SI) mm3), respectively. In the in vivo study, an MRSI or single voxel MRS or both was performed for ten patients (patients 1-10) on the day of BNCT. Three patients had glioblastoma multiforme (GBM), and five patients had a recurrent or progressing GBM or anaplastic astrocytoma gradus III, and two patients had head and neck cancer. For nine patients (patients 1-9), MRS/MRSI was performed 70-140 min after the second irradiation field, and for one patient (patient 10), the MRSI study began 11 min before the end of the BPA-F infusion and ended 6 min after the end of the infusion. In comparison, single voxel MRS was performed before BNCT, for two patients (patients 3 and 9), and for one patient (patient 9), MRSI was performed one month after treatment. For one patient (patient 10), MRSI was performed four days before infusion. Signals from the tumour spectrum aromatic region were detected on the day of BNCT in three patients, indicating that in favourable cases, it is possible to detect BPA in vivo in the patient’s brain after BNCT treatment or at the end of BPA-F infusion. However, because the shape and position of the detected signals did not exactly match the BPA spectrum detected in the in vitro conditions, assignment of BPA is difficult. The opportunity to perform MRS immediately after the end of BPA-F infusion for more patients is necessary to evaluate the suitability of 1H MRS for BPA detection or quantification for treatment planning purposes. However, it could be possible to use MRSI as criteria in selecting patients for BNCT.

Dermatofitosis en caninos procedentes de dos barrios de Managua, atendidos en la clínica Emergencia Veterinaria, agosto – septiembre 2014

El presente estudio de caso, se realizó para la valoración de la presencia de la dermatofitosis en especies caninas, siendo las especies más comunes Microsporum y Trichopyton. El estudio se realizó en la Clínica “Emergencias Veterinarias” ubicada en el casco urbano de Managua” para obtener un diagnóstico definitivo se realizó el diagnóstico clínico tomando en cuenta el historial de los pacientes, sintomatología y lesiones: pústula, pápula, eritema, descamación, costra, alopecia, pelo quebradizo, foliculítis así como factores predisponente: factores ambientales, humedad, ph, edad, raza, sexo, individuo, realizando el diagnóstico por laboratorio en tres pacientes. Las muestras fueron remitidas al laboratorio veterinario con los siguientes estudios clínicos ; Raspado de piel por KoH al 10% Y 20%, determinaron la presencia de estructuras micóticas asociadas a hifas y levaduras en el caso N°1, estructuras asociadas a artrosporas e hifas en el caso N°2, y estructuras asociadas a hifas y levaduras en el caso N°3, además se realizó un control de crecimiento de contaminantes en agar Sabouraud con glucosa al 2%, donde se observó por caracterización macroscópica el crecimiento de contaminantes en mayor abundancia en el caso N°3. Una vez obtenidos los resultados se procesaron las muestras en Dermatofitos Test Medium (Urano Test Dermatofitos) donde se observó que el caso N°1 y caso N°3 dieron negativo a DTM, el caso N°2 resulto ser positivo y se prosiguió a la caracterización microscópica del agente por tinción de contraste, donde se identificó al Microsporum gypseum como el agente causal de la lesión y como factores predisponentes se verificaron los ambientales y la edad del paciente, la aplicación de tratamiento fue de forma tópico y sistémico a través de fungicida o fungistático , baño con clorhexidina y miconazol 1 vez a la semana por 6 semanas , ketoconazol en tableta a una dosis de 10 mg /kg/día por 30 días , dándola en la comida para conseguir un ph gástrico acido, regulador del sistema inmune (caseína) 1 tableta al día por 30 días, vitamina ADɜE intramuscular . Palabras claves: Canino; Dermatofitos; Microsporum; Trichophyton; Raspado de piel; Cultivo micotico.

Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

Background The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. Methods A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. Results The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. Conclusions In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation.

A Responsabilidade Civil do Advogado sob a perspectiva civil-constitucional

A responsabilidade civil do advogado é um tema que merece destaque sob a perspectiva civil constitucional. A abrangência dessa relação jurídica pelo Código de Defesa do Consumidor e a natureza negocial multiforme da relação estabelecida entre o advogado e o cliente, cuja normativa deve ser estabecida tendo em vista o caso concreto, são pontos de destaque desse trabalho, assim como a aplicabilidade do consentimento informado. Nessa toada, pretende-se conferir o enfoque funcional a partir da releitura das classificações tradicionais da responsabilidade civil em contratual, extracontratual, subjetiva, objetiva e entre as obrigações de meio e resultado para em seguida, analisarmos das hipóteses mais frequentes de responsabilização, quais sejam: a perda de uma chance, o abuso do direito processual e a reversão de liminares revertidas ao final do processo. Por fim, dentre as tendências de prevenção e precaução de danos da responsabilidade civil, revela-se a formalização de seguros de responsabilidade profissional para advogados.

Technology for Single Cell Protein Analysis in Immunology and Cancer Prognostics

The first chapter of this thesis deals with automating data gathering for single cell microfluidic tests. The programs developed saved significant amounts of time with no loss in accuracy. The technology from this chapter was applied to experiments in both Chapters 4 and 5.

The second chapter describes the use of statistical learning to prognose if an anti-angiogenic drug (Bevacizumab) would successfully treat a glioblastoma multiforme tumor. This was conducted by first measuring protein levels from 92 blood samples using the DNA-encoded antibody library platform. This allowed the measure of 35 different proteins per sample, with comparable sensitivity to ELISA. Two statistical learning models were developed in order to predict whether the treatment would succeed. The first, logistic regression, predicted with 85% accuracy and an AUC of 0.901 using a five protein panel. These five proteins were statistically significant predictors and gave insight into the mechanism behind anti-angiogenic success/failure. The second model, an ensemble model of logistic regression, kNN, and random forest, predicted with a slightly higher accuracy of 87%.

The third chapter details the development of a photocleavable conjugate that multiplexed cell surface detection in microfluidic devices. The method successfully detected streptavidin on coated beads with 92% positive predictive rate. Furthermore, chambers with 0, 1, 2, and 3+ beads were statistically distinguishable. The method was then used to detect CD3 on Jurkat T cells, yielding a positive predictive rate of 49% and false positive rate of 0%.

The fourth chapter talks about the use of measuring T cell polyfunctionality in order to predict whether a patient will succeed an adoptive T cells transfer therapy. In 15 patients, we measured 10 proteins from individual T cells (~300 cells per patient). The polyfunctional strength index was calculated, which was then correlated with the patient's progress free survival (PFS) time. 52 other parameters measured in the single cell test were correlated with the PFS. No statistical correlator has been determined, however, and more data is necessary to reach a conclusion.

Finally, the fifth chapter talks about the interactions between T cells and how that affects their protein secretion. It was observed that T cells in direct contact selectively enhance their protein secretion, in some cases by over 5 fold. This occurred for Granzyme B, Perforin, CCL4, TNFa, and IFNg. IL- 10 was shown to decrease slightly upon contact. This phenomenon held true for T cells from all patients tested (n=8). Using single cell data, the theoretical protein secretion frequency was calculated for two cells and then compared to the observed rate of secretion for both two cells not in contact, and two cells in contact. In over 90% of cases, the theoretical protein secretion rate matched that of two cells not in contact.

Talidomida

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Programmazione e controllo dei gruppi pubblici locali. Dagli strumenti esistenti alle soluzioni innovative per la governance.

Il tema dei servizi pubblici locali è sicuramente centrale nell'attuale contesto socio-economico nazionale ed internazionale, in quanto essi hanno un impatto determinante sulle condizioni di vita dei cittadini e sulla competitività dei sistemi economici. In ragione di ciò, negli ultimi anni in Italia numerose riforme si sono susseguite, con lo scopo di individuare l'assetto più efficace ed efficiente per tale settore. Le suddette riforme hanno così ridisegnato il ruolo degli Enti Locali, che saranno sempre meno gestori diretti e sempre più direttori di una multiforme orchestra composta dalle aziende esterne chiamate a fornire in prima persona le prestazioni agli utenti finali. Il presente lavoro si propone di individuare, anche attraverso una ricerca sui Comuni capoluogo di Emilia-Romagna e Toscana, strumenti di programmazione e controllo in ottica di gruppo che consentano agli Enti Locali di svolgere questo nuovo delicato ruolo. Tali strumenti verranno disegnati sulla base delle necessità informative delle amministrazioni indagate e nel rispetto delle più recenti riforme in tema di programmazione, rilevazione, gestione, controllo, valutazione e comunicazione delle performance pubbliche.