Impact of physical activity on activity of daily living in moderate to severe dementia: a critical review

The objectives of this study were to describe the different modalities of physical activity programs designed for moderate to severe dementia and to identify their impact on functional independence in activities of daily living (ADL). A critical review of randomized controlled trials related to the impact of physical activity programs in moderately to severely demented persons on ADL performance and meta-analysis of the identified studies were performed. Among the 303 identified articles, five responded to the selection criteria. Four out of the five studies demonstrated limited methodological quality. In one high-quality study, physical activity programs significantly delayed deterioration of ADL performance. The program components and ADL assessment tools vary widely across studies. Although the proposed treatments have not proven their efficiency in improving the ADL status of the patients, they were able to limit the decline in ADL functioning. Future research is warranted in order to identify clinically relevant modalities for physical activity programs for people with moderate to severe dementia.

Hyperuricaemia and gout: state of the art and future perspectives.

Major progress has been made in the past decade in understanding the pathogenesis and treatment of gout. These advances include identification of the genetic and environmental risk factors for gout, recognition that gout is an important risk factor for cardiovascular disease, elucidation of the pathways regulating the acute gout attack and the development of novel therapeutic agents to treat both the acute and chronic phases of the disease. This review summarises these advances and highlights the research agenda for the next decade.

A critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis.

APO866, an inhibitor of NAD biosynthesis, exhibits potent antitumor properties in various malignancies. Recently, it has been shown that APO866 induces apoptosis and autophagy in human hematological cancer cells, but the role of autophagy in APO866-induced cell death remains unclear. Here, we report studies on the molecular mechanisms underlying APO866-induced cell death with emphasis on autophagy. Treatment of leukemia and lymphoma cells with APO866 induced both autophagy, as evidenced by an increase in autophagosome formation and in SQSTM1/p62 degradation, but also increased caspase activation as revealed by CASP3/caspase 3 cleavage. As an underlying mechanism, APO866-mediated autophagy was found to deplete CAT/catalase, a reactive oxygen species (ROS) scavenger, thus promoting ROS production and cell death. Inhibition of autophagy by ATG5 or ATG7 silencing prevented CAT degradation, ROS production, caspase activation, and APO866-induced cell death. Finally, supplementation with exogenous CAT also abolished APO866 cytotoxic activity. Altogether, our results indicated that autophagy is essential for APO866 cytotoxic activity on cells from hematological malignancies and also indicate an autophagy-dependent CAT degradation, a novel mechanism for APO866-mediated cell killing. Autophagy-modulating approaches could be a new way to enhance the antitumor activity of APO866 and related agents.

A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer.

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

El cos en el net.art

L'objectiu d'aquest projecte és l'estudi del cos en el net.art en el període comprès entre el 1996 i el 1999. La intenció d'aquest estudi és utilitzar tècniques qualitatives i de comparació per poder realitzar l'anàlisi de les obres que ens ajudin a arribar a unes conclusions sobre la manera d'interpretar el cos en el net.art.

Increased macrophage migration inhibitory factor (MIF) plasma levels in acute HIV-1 infection.

Considering macrophage migratory inhibitory factor (MIF) as a critical pro-inflammatory cytokine of the immune system, we evaluated plasma MIF levels in 89 HIV-infected adults. Plasma MIF levels were higher in HIV-infected than in HIV-negative individuals. Highest MIF levels were observed during acute HIV infection (AHI) whilst patients on antiretroviral therapy (ART) had lower MIF levels, regardless of ART efficacy. Our results suggest that MIF is an integral component of the cytokine storm characteristic of AHI.

Phosphorylation of CARMA1 by HPK1 is critical for NF-kappaB activation in T cells.

Activation of the NF-kappaB pathway in T cells is required for induction of an adaptive immune response. Hematopoietic progenitor kinase (HPK1) is an important proximal mediator of T-cell receptor (TCR)-induced NF-kappaB activation. Knock-down of HPK1 abrogates TCR-induced IKKbeta and NF-kappaB activation, whereas active HPK1 leads to increased IKKbeta activity in T cells. Yet, the precise molecular mechanism of this process remains elusive. Here, we show that HPK1-mediated NF-kappaB activation is dependent on the adaptor protein CARMA1. HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. In addition, CARMA1 S551A or S5549A/S551A point mutants failed to restore HPK1-mediated and TCR-mediated NF-kappaB activation and IL-2 expression in CARMA1-deficient T cells. Thus, we identify HPK1 as a kinase specific for CARMA1 and suggest HPK1-mediated phosphorylation of CARMA1 as an additional regulatory mechanism tuning the NF-kappaB response upon TCR stimulation.