833 resultados para Tuberculosis -- complications -- drug therapy -- immunology


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BACKGROUND Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. METHODS Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. RESULTS The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. CONCLUSIONS The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.

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The use of cancer-related therapies in cancer patients hospitalized at the end of life has increased in many countries over time. Given the scarcity of published Swiss data, the objective of this study was to evaluate the influence of hospital type and other factors on the delivery of health care during the last month before death. Claims data were used to assess health care utilization of cancer patients (identified by cancer registry data of four participating Swiss cantons) who deceased between 2006 and 2008. Primary endpoints were delivery of cancer-related therapies during the last 30 days before death. Multivariate logistic regression assessed the explanatory value of hospital type, patient and geographic characteristics. Of 3,809 identified cancer patients in the claims database, 2,086 patients dying from cancer were hospitalized during the last 30 days before death, generating 2,262 inpatient episodes. Anticancer drug therapy was given in 22.2% and radiotherapy in 11.7% of episodes. Besides age and cancer type, the canton of residence and hospital type showed independent, statistically significant associations with intensity of care, which was highest in university hospitals. These results should initiate a discussion among oncologists in Switzerland and may question the compliance with standard of care guidelines for terminal cancer patients.

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BACKGROUND: Clinical Trials (CTs) are essential for bridging the gap between experimental research on new drugs and their clinical application. Just like CTs for traditional drugs and biologics have helped accelerate the translation of biomedical findings into medical practice, CTs for nanodrugs and nanodevices could advance novel nanomaterials as agents for diagnosis and therapy. Although there is publicly available information about nanomedicine-related CTs, the online archiving of this information is carried out without adhering to criteria that discriminate between studies involving nanomaterials or nanotechnology-based processes (nano), and CTs that do not involve nanotechnology (non-nano). Finding out whether nanodrugs and nanodevices were involved in a study from CT summaries alone is a challenging task. At the time of writing, CTs archived in the well-known online registry ClinicalTrials.gov are not easily told apart as to whether they are nano or non-nano CTs-even when performed by domain experts, due to the lack of both a common definition for nanotechnology and of standards for reporting nanomedical experiments and results. METHODS: We propose a supervised learning approach for classifying CT summaries from ClinicalTrials.gov according to whether they fall into the nano or the non-nano categories. Our method involves several stages: i) extraction and manual annotation of CTs as nano vs. non-nano, ii) pre-processing and automatic classification, and iii) performance evaluation using several state-of-the-art classifiers under different transformations of the original dataset. RESULTS AND CONCLUSIONS: The performance of the best automated classifier closely matches that of experts (AUC over 0.95), suggesting that it is feasible to automatically detect the presence of nanotechnology products in CT summaries with a high degree of accuracy. This can significantly speed up the process of finding whether reports on ClinicalTrials.gov might be relevant to a particular nanoparticle or nanodevice, which is essential to discover any precedents for nanotoxicity events or advantages for targeted drug therapy.

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Effective antiviral agents are thought to inhibit hepatitis B virus (HBV) DNA synthesis irreversibly by chain termination because reverse transcriptases (RT) lack an exonucleolytic activity that can remove incorporated nucleotides. However, since the parameters governing this inhibition are poorly defined, fully delineating the catalytic mechanism of the HBV-RT promises to facilitate the development of antiviral drugs for treating chronic HBV infection. To this end, pyrophosphorolysis and pyrophosphate exchange, two nonhydrolytic RT activities that result in the removal of newly incorporated nucleotides, were characterized by using endogenous avian HBV replication complexes assembled in vivo. Although these activities are presumed to be physiologically irrelevant for every polymerase examined, the efficiency with which they are catalyzed by the avian HBV-RT strongly suggests that it is the first known polymerase to catalyze these reactions under replicative conditions. The ability to remove newly incorporated nucleotides during replication has important biological and clinical implications: these activities may serve a primer-unblocking function in vivo. Analysis of pyrophosphorolysis on chain-terminated DNA revealed that the potent anti-HBV drug β-l-(−)-2′,3′-dideoxy-3′-thiacytidine (3TC) was difficult to remove by pyrophosphorolysis, in contrast to ineffective chain terminators such as ddC. This disparity may account for the strong antiviral efficacy of 3TC versus that of ddC. The HBV-RT pyrophosphorolytic activity may therefore be a novel determinant of antiviral drug efficacy, and could serve as a target for future antiviral drug therapy. The strong inhibitory effect of cytoplasmic pyrophosphate concentrations on viral DNA synthesis may also partly account for the apparent slow rate of HBV genome replication.

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The resistance of acquired immunodeficiency syndrome (AIDS) to traditional drug therapy has prompted a search for alternative treatments for this disease. One potential approach is to provide genetic resistance to viral replication to prolong latency. This strategy requires the definition of effective antiviral genes that extend the survival of T cells in human immunodeficiency virus (HIV)-infected individuals. We report the results of a human study designed to determine whether a genetic intervention can prolong the survival of T cells in HIV-infected individuals. Gene transfer was performed in enriched CD4+ cells with plasmid expression vectors encoding an inhibitory Rev protein, Rev M10, or a deletion mutant control, deltaRev M10, delivered by gold microparticles. Autologous cells separately transfected with each of the vectors were returned to each patient, and toxicity, gene expression, and survival of genetically modified cells were assessed. Cells that expressed Rev M10 were more resistant to HIV infection than those with deltaRev M10 in vitro. In HIV-infected subjects, Rev M10-transduced cells showed preferential survival compared to deltaRev M10 controls. Rev M10 can therefore act as a specific intracellular inhibitor that can prolong T-cell survival in HIV-1-infected individuals and potentially serve as a molecular genetic intervention which can contribute to the treatment of AIDS.

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A via de administração oral é a forma favorita de administração de fármacos em função das vantagens que apresenta, dentre elas destacam-se: a adesão do paciente, conveniência e praticidade. Em função disto, a maioria dos medicamentos comercializados encontra-se disponível na forma farmacêutica de administração oral, entretanto, o sucesso de um tratamento medicamentoso por esta via requer que a absorção gastrointestinal do fármaco seja suficiente para assegurar a sua disponibilidade no local de ação (VOLPE, 2010). No entanto, a absorção do fármaco no trato gastrointestinal é complexa e pode ser influenciada por vários fatores, os quais têm impacto sobre a dissolução, solubilidade e permeabilidade do fármaco. Com o intuito de aumentar a biodisponibilidade de fármacos, que possuem absorção dificultada pela via oral, a via de administração pela mucosa bucal vem sendo uma alternativa na atualidade farmacêutica. Esta mucosa é um tecido não queratinizado, altamente vascularizado e apresenta poucas enzimas metabolizadoras. Tais características possibilitam boa absorção de fármacos sem que ocorra a metabolização pré-sistêmica, ou efeito de primeira passagem, somando-se ao fato desta apresentar fácil acessibilidade para a administração de fármacos (VRIES, M. E et al., 1991; NIELSEN, H. M &RASSING, M. R, 1999). Nesse sentido, o presente trabalho teve como objetivo avaliar a permeabilidade dos fármacos antirretrovirais (lamivudina e estavudina) por meio de modelo ex vivo em segmentos da mucosa bucal de suínos, com emprego de câmaras de difusão do tipo células de Franz. Para avaliação da permeabilidade bucal dos fármacos antirretrovirais, lamivudina e estavudina, e dos marcadores para transporte transcelular (metoprolol) e paracelular (fluoresceína sódica), empregou-se método ex-vivo, em células de Franz, com segmento de mucosa bucal de suíno ( a 37ºC, meio Ringer- Krebs- HEPES, pH 7,4), e Franz posterior análise das concentrações das substâncias permeadas (fármacos e marcadores) por cromatografia líquida de alta eficiência. Os resultados obtidos, por meio do protocolo desenvolvido, demonstram que o transporte através da via paracelular (marcador fluoresceína) foi mais expressivo que o transporte transcelular (marcador metoprolol), o que provavelmente se deve ao fato dos espaços intercelulares da mucosa bucal serem mais frouxos do que aqueles observados na mucosa intestinal (junções íntimas). Quanto à lamivudina e estavudina, os resultados de permeabilidade indicaram que estes fármacos permearam por mecanismo semelhante ao do metoprolol, isto é, por via transcelular.

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A adesão ao tratamento ocorre quando o conselho médico ou de saúde coincide com o comportamento do indivíduo, ao uso de medicamentos, cumprimento da dieta e mudanças no estilo de vida, não sendo, portanto, um ato não passivo do paciente. Em pacientes com hipertensão arterial sistêmica a adesão ao tratamento pode ser definida como o grau de cumprimento das medidas terapêuticas indicadas, sejam elas medicamentosas ou não, com o objetivo de manter a pressão arterial em níveis pressóricos normais. A não adesão em pacientes com doenças crônicas em tratamento a longo prazo em países desenvolvidos é em média de 50%, revelando a importância de serem avaliados os motivos que levam a esse comportamento. O estudo teve como objetivo avaliar a não adesão em idosos hipertensos de uma unidade pública de saúde de Ribeirão Preto - SP. Trata-se de um estudo de corte transversal, desenvolvido com uma amostra de 196 pessoas. A coleta de dados ocorreu entre agosto de 2014 até junho de 2015, após aprovação do Comitê de Ética em Pesquisa. Para essa etapa foram utilizados os instrumentos Brief Medication Questionnaire, Medical Outcomes Studies 36-item Short Form Survey, Escore de Risco Global e Escore de Risco pelo Tempo de Vida. Após a coleta dos dados, as entrevistas foram codificadas, os dados foram tabulados e foi realizada a análise estatística descritiva e de correlação. Como resultado, constatou-se que houve predomínio de mulheres, com idade média de 69,4 anos, casados/união estável, não moravam sozinhos, com 1,85 pessoas na casa em média, de cor branca, com ensino fundamental incompleto, renda de até dois salários mínimos e aposentados/pensionistas, atendidos pelo SUS. Apresentaram hábitos de vida razoáveis, sem predomínio de consumo de bebidas alcoólicas, tabagismo, uso excessivo de sal e sedentarismo. A mais frequente comorbidade associada à HAS foi a dislipidemia. Foi observado elevado predomínio de fatores de risco cardiovasculares como obesidade abdominal, obesidade geral, comorbidades, razão de lipídeos e fatores agravantes como proteína c reativa ultrassensível, microalbuminúria e síndrome metabólica. A maioria da amostra foi classificada como sendo portador de risco cardiovascular alto após estratificação do risco. A percepção da qualidade de vida relacionada à saúde foi considerada baixa na maioria principalmente devido a limitações emocionais. A não adesão esteve presente em quase metade dos idosos, relacionada principalmente à complexidade da farmacoterapia e dificuldade em lembrar sobre o uso de seus medicamentos. Não foi observada correlação entre a não adesão e as variáveis estudadas. Conclui-se que o comportamento de não adesão observado não esteve relacionada às variáveis estudadas nessa amostra e que são necessárias intervenções urgentes para reduzir o risco cardiovascular e prevenir doenças cardiovasculares e mortalidade, bem como melhora da percepção da qualidade de vida relacionada à saúde.

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Dissertação de mestrado, Psicologia (Ciência Cognitiva), Universidade de Lisboa, Faculdade de Ciências, Faculdade de Letras, Faculdade de Medicina, Faculdade de Psicologia, 2016

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Primary treatment of rectal cancer was the focus of the second St. Gallen European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Conference. In the context of the conference, a multidisciplinary international expert panel discussed and voted on controversial issues which could not be easily answered using published evidence. Main topics included optimal pretherapeutic imaging, indication and type of neoadjuvant treatment, and the treatment strategies in advanced tumours. Here we report the key recommendations and summarise the related evidence. The treatment strategy for localised rectal cancer varies from local excision in early tumours to neoadjuvant radiochemotherapy (RCT) in combination with extended surgery in locally advanced disease. Optimal pretherapeutic staging is a key to any treatment decision. The panel recommended magnetic resonance imaging (MRI) or MRI + endoscopic ultrasonography (EUS) as mandatory staging modalities, except for early T1 cancers with an option for local excision, where EUS in addition to MRI was considered to be most important because of its superior near-field resolution. Primary surgery with total mesorectal excision was recommended by most panellists for some early tumours with limited risk of recurrence (i.e. cT1-2 or cT3a N0 with clear mesorectal fascia on MRI and clearly above the levator muscles), whereas all other stages were considered for multimodal treatment. The consensus panel recommended long-course RCT over short-course radiotherapy for most clinical situations where neoadjuvant treatment is indicated, with the exception of T3a/b N0 tumours where short-course radiotherapy or even no neoadjuvant therapy were regarded to be an option. In patients with potentially resectable tumours and synchronous liver metastases, most panel members did not see an indication to start with classical fluoropyrimidine-based RCT but rather favoured preoperative short-course radiotherapy with systemic combination chemotherapy or alternatively a liver-first resection approach in resectable metastases, which both allow optimal systemic therapy for the metastatic disease. In general, proper patient selection and discussion in an experienced multidisciplinary team was considered as crucial component of care.

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Contains a reissue of four numbers (April 1937, June-Dec. 1938, Feb. 1939 and Dec. 1940) of the author's journal, the Badger pharmacist. Each number includes a reprint of the document discussed.

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Includes bibliography.

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Includes bibliographical references; v. 2 includes indexes.

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"International archives of pharmacology."