Synthesis, trypanocidal activity and molecular modeling studies of 2-alkylaminomethylquinoline derivatives

Research and development of new drugs effective in the treatment of Trypanosoma cruzi infections are a real need for the 16 million people infected in the Americas. In a previous work, a quinoline derivative substituted by a 2-piperidylmethyl moiety showed to be active against Chagas disease and was considered a lead compound for further optimization. A series of ten analogous derivatives were tested against epimastigotes as a first approach. In view of their promising results, six of them were evaluated against the blood and intracellular replicative forms of the parasite in humans. Among them, compound 12 which possesses a 6-acetamidohexylamino substituent showed remarkable improvement in activity against epimastigotes, trypomastigotes and amastigotes compared with the structure lead, as well as a good selectivity index for the two parasite stages present in humans. In addition, treatment of infected mice with compound 12 induced a significant reduction in parasitemia compared with non-treated mice. Molecular modeling studies were performed by computational methods in order to elucidate the factors determining these experimental bioactivities.     

Burden of disease and costs of treating rotavirus diarrhea in Mexican children for the period 2001-2006

Objectives

To estimate the health impact and the costs of treatment associated with rotavirus diarrhea in six yearly cohorts (2001-2006) of Mexican infants.

Methods

The perspective of study is from the health care system. We estimated the effect of rotavirus diarrhea on disability adjusted life years (DALYS) and diarrhea treatment costs in hypothetical cohorts of infants who are followed from birth up to five years of age beginning in years from 2001 to 2006. We used information from administrative databases on mortality and health care from the National System of Information on Health and from the Mexican Institute for Social Security to feed a decision analysis to project the burden of disease and costs of treatment.

Results

Estimates of DALYS were 19,426 in 2001 and decreased by 28.9% for 2006 meanwhile costs of treatment were relatively constant, estimated at US$ 38.7 million and increased only by 5%.

Conclusion

Rotavirus diarrhea in Mexican children is a major disease burden, presenting significant treatment costs. Rotavirus diarrhea mortality is decreasing; however this has not led to a steady decrease in treatment costs in the 6 years period of analysis. A sensitivity analysis showed that incidences of rotavirus diarrhea as well as the parameters associated with health-care access were the main factors, which had a significant effect on the projected burden of disease and costs.     

Validity and reliability of clinical tests for assessing hip passive stiffness

Inadequate levels of hip passive joint stiffness have been associated with the occurrence of movement dysfunction, development of pathologies and reduction in performance. Clinical tests, designed to evaluate hip joint stiffness, may allow the identification of improper stiffness levels. The purpose of this study was to determine the concurrent validity as well as the intra- and inter-examiners reliabilities of clinical measures used to assess hip passive stiffness during internal rotation. Fifteen healthy participants were subjected to test-retest evaluations by two examiners. Two clinical measures were performed: 'position of first detectable resistance' and 'change in passive resistance torque'. The results of these tests were compared to the passive stiffness measured with an isokinetic dynamometer (gold standard measure). A significant correlation was found between the stiffness measured with the isokinetic dynamometer and the clinical measures of 'position of first detectable resistance' (r=-0.85 to -0.86, p<0.001) and 'change in passive resistance torque' (r=0.78 to 0.84, p≤0.001). The Intraclass Correlation Coefficients for intra- and inter-examiners reliabilities varied from 0.95 to 0.99. Thus, the results demonstrated that the clinical measures have adequate validity and reliability for obtaining information on hip passive stiffness during internal rotation.     

Von Willebrand disease in children: diagnosis and management of a pediatric cohort in one single center in Argentina

Clinical and laboratory data of children with von Willebrand disease (VWD) types have been derived from retrospective studies and small case series. This article reports on the clinical and laboratory data of a large pediatric cohort in one single Argentinian center. The biological and clinical responses to desmopressin and replacement therapies are also described. Over a 15-year period, 194 of 1150 children (16.9%) were diagnosed as having type 1 VWD (80%), type 2 VWD (19%), and type 3 VWD (1%). The distribution of the different type 2 VWD subtypes was type 2A VWD, 43%; type 2B VWD, 32%; type 2M VWD, 19%; and type 2N VWD, 6%. Eighty patients with type 1 VWD and 12 patients with type 2 VWD were prospectively evaluated to desmopressin (DDAVP) response. A complete response was observed in all children with type 1 VWD, whereas 40% of the children with severe type 1 VWD and with type 2 VWD achieved a complete response. All the children who received DDAVP as prophylaxis or treatment for bleeding had good clinical evolution. Considering the restricted availability of specialized hemostasis centers, we believe our clinical and laboratory approach appropriate for the detection of patients with different types of VWD. Further studies are necessary to determine epidemiological aspects of VWD in Argentina to estimate the necessary facilities and trained personnel for the diagnosis and management of patients with VWD.     

Treatment of pulmonary arterial hypertension (PAH): updated Recommendations of the Cologne Consensus Conference 2011

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations on the diagnosis of pulmonary hypertension (PH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the treatment of pulmonary arterial hypertension (PAH). This commentary describes in detail the results and recommendations of the working group on treatment of PAH which were last updated in October 2011.     

Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation

The MHC class I antigen presentation pathway allows the immune system to distinguish between self and nonself. Despite extensive research on the processing of antigenic peptides, little is known about their origin. Here, we show that mRNAs carrying premature stop codons that prevent the production of full-length proteins via the nonsense-mediated decay pathway still produce a majority of peptide substrates for the MHC class I pathway by a noncanonical mRNA translation process. Blocking the interaction of the translation initiation factor eIF4E with the cap structure suppresses the synthesis of full-length proteins but has only a limited effect on the production of antigenic peptides. These results reveal an essential cell biological function for a class of translation products derived during the pioneer round of mRNA translation and will have important implications for understanding how the immune system detects cells harboring pathogens and generates tolerance.     

Increased iron supplied through Fet3p results in replicative life span extension of Saccharomyces cerevisiae under conditions requiring respiratory metabolism

We have previously shown that copper supplementation extends the replicative life span of Saccharomyces cerevisiae when grown under conditions forcing cells to respire. We now show that copper's effect on life span is through Fet3p, a copper containing enzyme responsible for high affinity transport of iron into yeast cells. Life span extensions can also be obtained by supplementing the growth medium with 1 mM ferric chloride. Extension by high iron levels is still dependent on the presence of Fet3p. Life span extension by iron or copper requires growth on media containing glycerol as the sole carbon source, which forces yeast to respire. Yeast grown on glucose containing media supplemented with iron show no extension of life span. The iron associated with cells grown in media supplemented with copper or iron is 1.4–1.8 times that of cells grown without copper or iron supplementation. As with copper supplementation, iron supplementation partially rescues the life span of superoxide dismutase mutants. Cells grown with copper supplementation display decreased production of superoxide as measured by dihydroethidium staining.