Stratégies thérapeutiques en présence d'un diabète de type 2 [Therapeutic strategies in type 2 diabetes]

UKPDS and DCCT studies have demonstrated the critical role of tight glycaemic control to reduce the micro- and macro-vascular damage linked to diabetes. Unfortunately, the insulin requirement of type 2 diabetic patients remains elevated since 5 to 7% of these patients will required, yearly, a change from oral antidiabetic drug to insulin treatment to maintain a good glycaemic control. This manuscript is intended to review the currently available oral antidiabetic drugs, their benefits as well as potential arms and to propose a simplified therapeutic strategy in presence of type 2 diabetes.

Doses, fontes e épocas de aplicação de nitrogênio em trigo irrigado em plantio direto

O objetivo deste trabalho foi avaliar os efeitos de doses e fontes de nitrogênio, sobre os componentes de produção e a produtividade de trigo irrigado (Triticum aestivum), aplicados na semeadura ou em cobertura, sob plantio direto. Foram utilizadas fontes com e sem inibidor de nitrificação (Entec), aplicadas ao sulco de semeadura ou em cobertura. O trigo foi cultivado em Selvíria, MS, em região de cerrado de baixa altitude. Utilizou-se o delineamento experimental de blocos ao acaso, com quatro repetições, em esquema fatorial 5x3x2. Os tratamentos consistiram da combinação de: cinco doses de N, 0, 50, 100, 150 e 200 kg ha-1; três fontes, Entec, sulfato de amônio e ureia; e duas épocas de aplicação, na semeadura, ao lado das linhas, ou em cobertura. As fontes de N tiveram efeito semelhante sobre a altura de plantas e a produtividade de grãos do trigo irrigado. A aplicação total de N na semeadura e a aplicação tradicional, em semeadura e cobertura, são igualmente viáveis. O incremento das doses de N até a dose de 121,5 kg ha-1, em média, aumenta a produtividade de grãos, independentemente da época de aplicação e da fonte de N utilizada.

Podridão por Fusicoccum em mangas submetidas a baixas doses de radiação gama

O objetivo deste trabalho foi avaliar o efeito da radiação gama em doses baixas no controle pós-colheita da podridão por Fusicoccum em manga 'Tommy Atkins', bem como avaliar o efeito desse método sobre as características físico-químicas da fruta. Frutos aparentemente livres de doenças no estádio de maturação 1,5 foram inoculados com 10 μL de suspensão de Fusicoccum parvum a 10(6) conídios mL-1. Após a inoculação, os frutos foram irradiados com as doses de 0,24, 0,35 e 0,45 kGy e armazenados a 13ºC, durante 15 dias, seguidos de mais seis dias em temperatura ambiente, a 25ºC. A dose mais alta de radiação gama foi eficiente em retardar o desenvolvimento da doença em razão do atraso causado na maturação das frutas. Não houve efeito significativo da radiação sobre as características físico-químicas das frutas. Os frutos mantiveram características ideais para comercialização, mesmo após o armazenamento refrigerado, com a presença de filme plástico, por 15 dias.

Milho verde e feijão-caupi cultivados em consórcio sob diferentes lâminas de irrigação e doses de fósforo

O objetivo deste trabalho foi avaliar a resposta de milho verde (Zea mays) e de feijão-caupi (Vigna unguiculata), cultivados em consórcio, a lâminas de irrigação e doses de fósforo. Os experimentos foram realizados em 2008 e 2009, em delineamento de blocos ao acaso, com 25 tratamentos e quatro repetições. Os tratamentos consistiram de cinco lâminas de irrigação, a 70, 110, 140, 180 e 220% da evapotranspiração da cultura, e de cinco doses de P2O5 a 0, 50, 100, 150 e 200% da dose de P recomendada. O milho foi semeado no espaçamento 0,80x0,40 m, e o feijão-caupi foi semeado dentro das linhas entre as plantas de milho. Não houve efeito das doses de P2O5; porém, a resposta às lâminas de irrigação foi quadrática em milho e linear em feijão-caupi. As máximas produtividades técnicas de espigas de milho verde com palha (10,76 Mg ha-1) e sem palha (7,62 Mg ha-1) foram obtidas com a lâmina de 530 mm, intermediária às lâminas referentes a 180 e 220% da evapotranspiração da cultura. A maior produtividade de grãos verdes de feijão-caupi (3,40 Mg ha-1) foi obtida com a maior lâmina de água aplicada, de 644 mm.

Patient with hepatocellular carcinoma related to prior acute arsenic intoxication and occult HBV: epidemiological, clinical and therapeutic results after 14 years of follow-up

Little is known about the long-term survivors of acute arsenic intoxication. We present here a clinical case report of a man with chronic hepatitis B virus (HBV) infection who developed hepatocellular carcinoma four years after acute arsenic poisoning. HBsAg was detected in serum in 1990 when he voluntarily donated blood. In 1991, the patient suffered from severe psychological depression that led him to attempt suicide by massive ingestion of an arsenic-containing rodenticide. He survived with polyneuropathy and paralysis of the lower limbs, and has been wheelchair-bound since then. During participation in a follow-up study conducted among HBV carriers, abdominal ultrasound detected a two-centimeter liver mass consistent with hepatocellular carcinoma. The tumor was confirmed by computed tomography (CT) and magnetic resonance image (MRI). Because of his significant comorbidity, the patient received palliative treatment with transarterial lipiodol chemoembolization (TACE) on three occasions (1996, 1997 and 1999). At his most recent visit in May 2005, the patient was asymptomatic, liver enzymes were normal and the tumor was in remission on ultrasound.

Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives.

Chronic intake of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing gastrointestinal tumors, in particular colon cancer. Increasing evidence indicates that NSAID exert tumor-suppressive activity on pre-malignant lesions (polyps) in humans and on established experimental tumors in mice. Some of the tumor-suppressive effects of NSAIDs depend on the inhibition of cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxane, which is highly expressed in inflammation and cancer. Recent findings indicate that NSAIDs exert their anti-tumor effects by suppressing tumor angiogenesis. The availability of COX-2-specific NSAIDs opens the possibility of using this drug class as anti-angiogenic agents in combination with chemotheapy or radiotherapy for the treatment of human cancer. Here we will briefly review recent advances in the understanding of the mechanism by which NSAIDs suppress tumor angiogenesis and discuss their potential clinical application as anti-cancer agents.

CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses.

Despite the well-established antitumor activity of CD1d-restricted invariant natural killer T lymphocytes (iNKT), their use for cancer therapy has remained challenging. This appears to be due to their strong but short-lived activation followed by long-term anergy after a single administration of the CD1d agonist ligand alpha-galactosylceramide (αGC). As a promising alternative, we obtained sustained mouse iNKT cell responses associated with prolonged antitumor effects through repeated administrations of tumor-targeted recombinant sCD1d-antitumor scFv fusion proteins loaded with αGC. Here, we demonstrate that CD1d fusion proteins bound to tumor cells via the antibody fragment specific for a tumor-associated antigen, efficiently activate human iNKT cell lines leading to potent tumor cell lysis. The importance of CD1d tumor targeting was confirmed in tumor-bearing mice in which only the specific tumor-targeted CD1d fusion protein resulted in tumor inhibition of well-established aggressive tumor grafts. The therapeutic efficacy correlated with the repeated activation of iNKT and natural killer cells marked by their release of TH1 cytokines, despite the up-regulation of the co-inhibitory receptor PD-1. Our results demonstrate the superiority of providing the superagonist αGC loaded on recombinant CD1d proteins and support the use of αGC/sCD1d-antitumor fusion proteins to secure a sustained human and mouse iNKT cell activation, while targeting their cytotoxic activity and cytokine release to the tumor site.

Intraocular implants for extended drug delivery: therapeutic applications.

An overview of ocular implants with therapeutic application potentials is provided. Various types of implants can be used as slow release devices delivering locally the needed drug for an extended period of time. Thus, multiple periocular or intraocular injections of the drug can be circumvented and secondary complications minimized. The various compositions of polymers fulfilling specific delivery goals are described. Several of these implants are undergoing clinical trials while a few are already commercialized. Despite the paramount progress in design, safety and efficacy, the place of these implants in our clinical therapeutic arsenal remains limited. Miniaturization of the implants allowing for their direct injection without the need for a complicated surgery is a necessary development avenue. Particulate systems which can be engineered to target specifically certain cells or tissues are another promising alternative. For ocular diseases affecting the choroid and outer retina, transscleral or intrasscleral implants are gaining momentum.

Stratégies thérapeutiques pour le traitement des gliomes [Therapeutic strategies for the management of gliomas]

The management of gliomas remains challenging and requires a multidisciplinary approach that involves neurosurgeons, radiation therapists and oncologists. For patients with glioblastomas, progress has been made in recent years with the introduction of a combined modality treatment associating radiation therapy and concomitant chemotherapy with the novel alkylating agent temozolomide. This combination resulted in a significant prolongation of survival and increase in the number of patients with survival well beyond two years. Since then, interest in developing new agents in this disease has dramatically increased. In parallel, molecular markers, such as methylation status of MGMT or identification of the translocation of 1p and 19q in oligodendrogliomas have allowed to identify distinct subtypes with exquisite response to treatment or different prognosis. These developments have implications for the development of clinical trials of new potential drug treatments. In this article, we provide a review of the current management of low- and high-grade gliomas, including astrocytomas, oligodendrogliomas and glioblastomas and provide an outlook into future potential therapies.

Preclinical evaluation of the immunogenicity of C-type HIV-1-based DNA and NYVAC vaccines in the Balb/C mouse model.

As part of a European initiative (EuroVacc), we report the design, construction, and immunogenicity of two HIV-1 vaccine candidates based on a clade C virus strain (CN54) representing the current major epidemic in Asia and parts of Africa. Open reading frames encoding an artificial 160-kDa GagPolNef (GPN) polyprotein and the external glycoprotein gp120 were fully RNA and codon optimized. A DNA vaccine (DNA-GPN and DNA-gp120, referred to as DNA-C), and a replication-deficient vaccinia virus encoding both reading frames (NYVAC-C), were assessed regarding immunogenicity in Balb/C mice. The intramuscular administration of both plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial T-cell responses against both antigens as well as Env-specific antibodies. Whereas low doses of NYVAC-C failed to induce specific CTL or antibodies, high doses generated cellular as well as humoral immune responses, but these did not reach the levels seen following DNA vaccination. The most potent immune responses were detectable using prime:boost protocols, regardless of whether DNA-C or NYVAC-C was used as the priming or boosting agent. These preclinical findings revealed the immunogenic response triggered by DNA-C and its enhancement by combining it with NYVAC-C, thus complementing the macaque preclinical and human phase I clinical studies of EuroVacc.