Variable sensitivity to complement-mediated lysis among <Emphasis Type="Italic">Trypanosoma rangeli</Emphasis> reference strains

Six reference strains of Trypanosoma rangeli from different days of growth in axenic cultures were assayed for susceptibility to complement-mediated lysis by non-immune guinea-pig serum. Their authenticity was also confirmed by isoenzyme analyses. Parasites were incubated with 25% active or 68°C-inactivated serum (37°C, 30 min) for all tests; thereafter the lysis rates were determined. Highly variable lysis percentages were observed among T. rangeli strains and in the same stock at different growing days. In a few assays, three strains (Macias, R-1625 and Choachi) presented total or very high resistance. The others (H-14, San Agustín and SC-58) were generally most susceptible, and could reach lysis rates as high as Trypanosoma cruzi. After incubation with active sera, the epimastigotes were usually the predominant stages, being followed by spheromastigotes and/or transitional forms. Those stages and trypomastigotes could also be partially susceptible. In four strains, the short epimastigotes were more resistant to lysis than the long ones. Experiments with C3-deficient serum displayed total or partial participation of the alternative-complement pathway in T. rangeli lysis. This study confirmed the variable complement sensitivity of T. rangeli, which can be related to its intraspecific heterogeneity, to the remarkable complexity of its life-cycle stages, and to the methodology employed.     

Prevalence of disability and associated social and health-related factors among the elderly in Spain: a population-based study

Objectives: To estimate the prevalence of disability and its association with morbidity and other social and health-related factors among Spain’s non-institutionalized elderly population. Methods: Cross-sectional survey, by home-based personal interview, covering a sample of 4000 subjects representative of the non-institutionalized Spanish population aged 60 years and over. The relationship between disability and social and health-related study variables was studied using logistic regression. Results: A total of 72.9% of subjects reported some type of disability: 59.1% in agility, 51.6% in mobility, 40.1% in instrumental activities and 19.1% in activities of daily living. After adjusting for all relevant variables, disability showed to be significantly more frequent for: female gender (OR=1.83; 1.53–2.19); more advanced age (OR=4.54; 3.27–6.32); low/no educational level (OR=2.01; 1.67–2.42); deteriorated cognitive status (OR=1.67; 1.24–2.23); at least two chronic diseases (OR=2.54; 2.01–3.20); poor perceived health status (OR=3.02; 2.48–3.69); little physical activity (OR=2.57; 1.94–3.42); and greater use of hospital care (OR=1.34; 1.10–1.64). Conclusions: Prevalence of disability among Spain’s non-institutionalized elderly population is very high. This might be explained by a greater number of chronic diseases, a higher percentage of subjects with low educational level and a higher proportion of community-dwelling elderly persons than in Anglo-Saxon countries.     

Proteomic analysis of Escherichia coli with experimentally induced resistance to piperacillin/tazobactam

The worldwide emergence of antibiotic-resistant bacteria poses a serious threat to human health. In addition to the difficulties in controlling infectious diseases, the phenotype of resistance can generate metabolic changes which, in turn, can interfere with host–pathogen interactions. The aim of the present study was to identify changes in the subproteome of a laboratory-derived piperacillin/tazobactam-resistant strain of Escherichia coli (minimal inhibitory concentration [MIC] = 128 mg/L) as compared with its susceptible wild-type strain E. coli ATCC 25922 (MIC = 2 mg/L) using 2-D fluorescence difference gel electrophoresis (2D-DIGE) followed by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF MS). In the resistant strain, a total of 12 protein species were increased in abundance relative to the wild-type strain, including those related to bacterial virulence, antibiotic resistance and DNA protection during stress. Fourteen proteins were increased in abundance in the wild-type strain compared to the resistant strain, including those involved in glycolysis, protein biosynthesis, pentose-phosphate shunt, amino acid transport, cell division and oxidative stress response. In conclusion, our data show overall changes in the subproteome of the piperacillin/tazobactam-resistant strain, reporting for the first time the potential role of a multidrug efflux pump system in E. coli resistance to piperacillin/tazobactam.     

Prognostic Value of the Combination of Circulating Tumor Cells Plus KRAS in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab

ObjectiveCirculating tumor cells (CTCs) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status were identified as prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab in analyses of the MACRO (Maintenance Treatment in Advanced Colorectal Cancer) trial. In this post hoc analysis of the MACRO trial, the potential additive effect of these 2 factors on patient outcomes was explored.MethodsA total of 158 of the 480 patients involved in the MACRO trial were included in the biological marker substudy. CTC isolation and enumeration were centralized and performed using the CellSearch System (Veridex LLC, Raritan, NJ) in 7.5 mL of whole blood. Evaluation of KRAS status was performed retrospectively by the standard method used at each center. PFS and OS were analyzed by the Kaplan–Meier method according to CTC count and KRAS status.ResultsPatients with < 3 CTC per 7.5 mL blood at baseline and KRAS wild-type tumors had a median PFS of 14.2 months compared with 6.2 months in patients with ≥ 3 CTCs and KRAS mutated tumors (P < .0001; hazard ratio, 3.0; 95% confidence interval, 1.8-5.2). Similar findings were observed for OS (28.9 and 13.7 months, respectively, P = .0004; hazard ratio 2.8; 95% confidence interval, 1.6-4.9). Multivariate analyses showed that CTC count ≥ 3 and KRAS status were the only independent prognostic factors for both PFS and OS.ConclusionsThis post hoc analysis showed that CTC count and KRAS status were independent prognostic factors for outcomes in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy. These factors should be taken into account in the design of future phase III trials.     

Evaluating pharmaceutical services for people living with HIV/AIDS in the city of Rio de Janeiro

This study evaluates access by people living with HIV/AIDS to pharmaceutical care provided by public health care facilities in the city of Rio de Janeiro, Brazil, focusing on availability, accessibility, and accommodation. The evaluation was conducted using the implementation analysis approach, assessing the process of producing intervention outcomes, considering its relationship to the organizational context. A case study was performed in 11 public health facilities selected according to: different health program areas; diverse levels of complexity; and more than 100 HIV/AIDS patients registered. The degree of implementation (89%) was considered acceptable. Problems with human resources skills and lack of a quality program were identified. Some limitations of the indicators are discussed. Finally, the study highlights the importance of this kind of evaluation as a methodology for continuous monitoring of quality in pharmaceutical care.     

Pharmacogenetic approach for capecitabine or 5-fluorouracil selection to be combined with oxaliplatin as first-line chemotherapy in advanced colorectal cancer

We studied the role of TS (5’VNTR, 5’SNP and 3’UTR), XRCC1-399, XPD-751, ERCC1-118 and XRCC3-241 genetic polymorphisms in tailoring fluroropyrimidine/oxaliplatin treatment. For this purpose, 110 XELOX (capecitabine/oxaliplatin)- or FUOX (fluorouracil/oxaliplatin)-treated metastatic colorectal cancer patients were selected prospectively for genotyping. In the FUOX group, TS-3’UTR +6 bp/+6 bp (hazards ratio, HR = 2.62, p = 0.007) and ERCC1-118 C/T or C/C (HR = 1.96, p = 0.050) genotypes correlated with a shorter progression free survival (PFS). When analysed jointly, the higher the number of favourable genotypes (FG) the longer the PFS (6.8 m, 9.6 m and 25.8 m for 0, 1 or 2 FG; p = 0.005). Disease-control rate was 100% in patients with 2 FG (87% and 38.5% for 1 or 0 FG; p = 0.001). In the multivariate analysis, ERCC1-118 (HR = 2.12, p = 0.0037) and TS-3’UTR (HR = 2.68, p = 0.006) were strong independent prognostic factors. According to this, patients harbouring TS-3’UTR +6 bp/+6 bp and ERCC1-118 C/T or C/C genotypes may better receive capecitabine instead of 5FU in an oxaliplatin-based first-line treatment.     

Enhanced susceptibility to Trichuris muris infection of B10Br mice treated with the probiotic Lactobacillus casei

The aim of this paper was to establish a suitable model for exploring the immunoregulatory bases of the interaction of probiotics with intestinal helminth infections. The mouse whipworm Trichuris muris, was used in the susceptible B10Br mice. Mice were treated orally with either viable or dead probiotic L. casei and 1 week later they were submitted to a challenge infection of 400 embryonated eggs of T. muris. Treatment with either viable or dead bacteria significantly increased the intestinal worm burden by day 22 post-infection. Viable L. casei significantly reduced the levels of faecal IgA induced by challenge infection. The proliferation response of MNL cells against mitogens was significantly reduced by dead bacteria and abrogated by viable bacteria. Furthermore the presence of the probiotic was associated to a significant decrease in IFN-gamma, TNF-alpha, IL-4 and Il-13 with no effect on IL-5 in both MNL and PP with regard to challenge control infection. The presence of L. casei did not significantly modify the proportion of CD4(+) and CD8(+) cells in both MLN and PP. In summary, in the susceptible B10Br mouse strain the presence of probiotic L. casei is associated to an increased susceptibility to infection by the intestinal whipworm T. muris. The mechanisms underlying this evidence could be related to the deactivation of TNF-alpha dependent Th2 effector responses against T. muris due to the strong down-regulation of this cytokine that is induced by the probiotic agent.     

Logic models from an evaluability assessment of pharmaceutical services for people living with HIV/AIDS

Brazil was the first developing country to provide people living with HIV/AIDS (PLWA) with comprehensive, universal, free access to antiretroviral medicines (ARV). Pharmaceutical services are considered a strategic action that has the goal of providing access to rational use of quality medicines while also promoting user satisfaction. User satisfaction is a complex concept, and evaluation models for pharmaceutical services for PLWA were not found in the literature. Therefore, an evaluation approach to help assess this issue had to be developed. This article seeks to describe a theoretical evaluation model of user satisfaction with the dispensing of ARV, developed as part of an Evaluability Assessment (EA). It presents a brief review of the EA and user satisfaction and describes the development of models created during the EA. The lessons learned in the process are presented as a conclusion.     

Lung cancer as a cardiotoxic state: a review

As the overall survival of patients with lung cancer continues to increase, more cancer survivors are faced with the risk of developing treatment-related cardiovascular toxicities. The increased knowledge of the molecular biology of non-small cell lung cancer has led to new and more personalized treatments. Nevertheless, the usual chemotherapy schemes and radiation therapy induce cardiac toxicities that are frequently underappreciated or go unnoticed. Up to date, the majority of cardiotoxicity studies have been focused in breast cancer, but new treatments in lung cancer patients, such as immune checkpoint-blocking antibodies or tyrosine kinase inhibitors, may also exert these cardiac toxic effects and therefore demand of the close collaboration of oncologists and cardiologists, in order to be addressed. The aim of this review is to provide more detailed information in regard to drug-induced cardiac toxicity focused in non-small cell lung cancer patients.     

First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study

Purpose.

The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC).

Patients and Methods.

Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety.

Results.

The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0–53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand–foot syndrome, and neuropathy.

Conclusion.

Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.