Virological and pharmacological factors associated with virological response to salvage therapy after an 8-week of treatment interruption in a context of very advanced HIV disease (GigHAART ANRS 097)

Both highly potent antiretroviral drug rescue multi therapy and treatment interruption (TI) have been suggested to be effective in HIV-1 infected-patients with multiple treatment failure. GigHAART-ANRS 097 was the only randomized trial during which an 8-week TI was beneficial in heavily pre-treated patients with multi-drug resistant virus on resuming a multiple-drug salvage regimen. The aim of this study was to analyze virological and pharmacological factors associated with a virological response. Clonal resistance analysis showed that although the viral population was highly mutated and nearly monoclonal at baseline, the 8-week interruption therapy allowed the re-emergence of more susceptible quasispecies to the subsequent salvage therapy, which were not detected by classical genotypic resistance testing. The fact that not every viral clone harbored all resistance viral mutations could explain a part of the virological response to a six to eight drug regimen for patients enrolled in the TI group. This phenomenon was associated with a transient virological response after the use of a GigHAART therapy, but was followed by the re-emergence of baseline resistance pattern and acquisition of additional mutations in patients failing this strategy. A combined factor of protease inhibitor (PI) concentration and genotypic score, expressed as a genotypic inhibitory quotient (GIQ), was used to assess the importance of genotypic resistance and plasma drug levels in the rate of response to multiple PI combination. The GIQ of each PI used in the regimen was not associated with virological success. However, the sum of PI GIQs was predictive of a virological response. These results suggest that pharmacological enhancement might overcome viral resistance and that there is some benefit in adding the activity of several boosted-PIs to improve the response to a salvage regimen.     

3D-QSAR analysis of anilinoquinoline inhibitors of colony stimulating factor-1 kinase (cFMS): implementation of field-based molecular alignment

Colony-stimulating factor-1 receptor (cFMS) serves as a binding site for colony-stimulating factor-1 and is primarily involved in the growth and differentiation of monocytes and macrophages. This crucial function of cFMS links it to various immune system-related disease conditions, such as rheumatoid arthritis, cancer, and immune nephritis. Hence, the potent inhibitors of cFMS may serve novel therapeutic benefits for the treatment of mentioned disease conditions. In the present study, a set of 46 anilinoquinoline derivatives was utilized to perform atom-based 3D-QSAR analysis. The best 3D-QSAR model was selected on the basis of the highest value of Q _test ² , i.e., 0.535. The selected model also displayed high values of R _train ² (0.974), Pearson-r (0.826), and the lowest value of SD (0.099). The contour plots generated for different properties helped to understand biological activity variation pattern with structural changes in molecule at appropriate sites. Therefore, the selected 3D-QSAR model and information revealed from it would provide beneficial guidance for the designing of new potent cFMS inhibitors that can further be explored as novel therapeutic agents for various immune system-related disease conditions.     

Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions

The goals of this study were to evaluate the efficacy of benznidazole (Bz) treatment in decreasing of the parasitic load during the acute phase of experimental Chagas disease and to analyze its influence in the development of cardiac chronic alterations in mice inoculated with drug-resistant Trypanosoma cruzi strains. Our results showed that the early Bz treatment (started at 4th day of infection) was efficient in reducing the parasite load in animals from both acute and chronic phase of the infection. Moreover, this reduction in the parasite load could not be associated with the intensity of the cardiac chronic lesions. The histopathological evaluation of cardiac tissue of Bz-treated mice showed three different patterns of response: (1) presence of a small number of inflammatory cells and fibrotic area similar to noninfected mice; (2) similar intensity of inflammatory infiltrate and smaller fibrotic area in relation to nontreated animals; (3) similar intensity of inflammatory infiltrated and fibrosis area among the Bz-treated and nontreated animals. Each specific pattern was obtained with different T. cruzi strain, suggesting that the pattern of the heart lesions in chronic phase of Bz-treated animals was T. cruzi strain dependent but not related with drug resistance levels.     

The Brazilian health system: history, advances, and challenges

Brazil is a country of continental dimensions with widespread regional and social inequalities. In this report, we examine the historical development and components of the Brazilian health system, focusing on the reform process during the past 40 years, including the creation of the Unified Health System. A defining characteristic of the contemporary health sector reform in Brazil is that it was driven by civil society rather than by governments, political parties, or international organisations. The advent of the Unified Health System increased access to health care for a substantial proportion of the Brazilian population, at a time when the system was becoming increasingly privatised. Much is still to be done if universal health care is to be achieved. Over the past 20 years, there have been other advances, including investments in human resources, science and technology, and primary care, and a substantial decentralisation process, widespread social participation, and growing public awareness of a right to health care. If the Brazilian health system is to overcome the challenges with which it is presently faced, strengthened political support is needed so that financing can be restructured and the roles of both the public and private sector can be redefined.     

Functionally navigated transcranial magnetic stimulation to evoke lingual pressure in stroke survivors with dysphagia and healthy adults: a proof of concept trial

ABSTRACT

Background

Post-stroke dysphagia is characterized by reduced corticolingual excitability and lingual pressure; however, it remains unknown if transcranial magnetic stimulation (TMS) directly facilitates lingual pressure generation.