Ratio between positive lymph nodes and total dissected axillaries lymph nodes as an independent prognostic factor for disease-free survival in patients with breast cancer

The number of positive axillary lymph nodes involved by tumor is one of the main prognostic factors for women with locoregional breast cancer (BC) for whom adjuvant chemotherapy is being considered. The prognostic importance of the ratio (P/D) between positive lymph nodes (P) and total dissected lymph nodes (D), previously demonstrated in the high-dose chemotherapy (HDC) setting has not yet been tested, however, in the conventional adjuvant chemotherapy setting. The data of 168 patients who were from 2 institutions and who were treated with adjuvant chemotherapy for BC were retrospectively analyzed, and univariate and multivariate analysis were performed, including the other traditional prognostic factors and P/D ratio as possible predictors of disease free survival (DFS). Disease-free survival for quartile 4 of P/D ratio (ratio >0.30) was statistically different from that for the other quartiles (log-rank test p < 0.001). Mean DFS for this series was not reached as well as for quartiles 1, 2, and 3, while mean DFS for quartile 4 was 44.5 months. In univariate analysis, number of positive lymph nodes (r2 = 0.055; p = 0.023), P/D ratio (r2 = 0.213; p < 0.001), and stage (r2 = 0.105; p = 0.002) were predictive of relapse, while in multivariate analysis, only P/D ratio remained an independent predictor of relapse (r2 = 0.213; p < 0.001). It is concluded that P/D ratio could become a simple, inexpensive, and easily available prognostic factor for patients undergoing conventional chemotherapy for BC.     

Modulation of DNA hypomethylation as a surrogate endpoint biomarker for chemoprevention of colon cancer

Surrogate end-point biomarkers are being developed as indicators of the efficacy of chemopreventive agents. These biomarkers are molecular and biological end-points that can be modulated by chemopreventive agents in accordance with their efficacy to prevent cancer. DNA hypomethylation is a common alteration found in colon tumors that has the potential of being modulated by chemopreventive agents and thus being useful as a surrogate end-point biomarker. Agents that were either effective or ineffective in preventing colon cancer were evaluated for the ability to modulate DNA hypomethylation in azoxymethane-induced colon tumors in male F344 rats. DNA methylation was determined by Dot Blot Analysis using a mouse monoclonal anti-5-methylcytosine antibody. Colon tumors had a 70% reduction in DNA methylation relative to normal colonic mucosa. DNA methylation in the tumors was increased by 7 days of treatment with agents that have been shown to prevent colon cancer (calcium chloride, alpha-diflouromethylornithine [DFMO], piroxicam, and sulindac), whereas agents shown not to prevent colon cancer in rats (low dose aspirin, 2-carboxyphenyl retinamide [2-CPR], quercetin, 9-cis retinoic acid, and rutin) did not increase DNA methylation. The results suggest that the ability to reverse the DNA hypomethylation in colon tumors could be useful as a surrogate end-point biomarker for chemoprevention of colon cancer.     

CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors

To determine if: (1) 5' CpG island methylation is related to Fhit inactivation; (2) there are tumor or carcinogen-specific methylation patterns, we examined 35 CpG sites in the promoter, exon and intron 1 of the mouse Fhit gene. In primary tumors of lung, urinary bladder and tongue, induced by different carcinogens, 15-35% of sites were methylated, with specific methylation patterns associated with each cancer type, suggesting cancer- or tissue-specific methylation patterns. The methylation patterns were associated with reduced Fhit expression, as determined by immunohistochemical analyses. Methylation of rat Fhit 5' CpGs in mammary adenocarcinomas, detected by methylation specific PCR amplification, also correlated with reduced gene expression. Thus, there was an overall association between promoter/exon 1 methylation and decreased Fhit expression. In contrast, in cancer-derived cell lines 70-95% of the CpG sites were methylated. This is the first detailed study of the relationship between Fhit 5' CpG island methylation and Fhit expression in murine tumors, our main models for preclinical cancer studies, and provides evidence that loss of Fhit expression and methylation are correlated in these mouse models and these models will be useful to examine the complex relationships among gene expression, methylation patterns and organ specificity.     

Managing HIV-infected patients on antiretroviral therapy in Rio de Janeiro, Brazil: do providers follow national guidelines?

The objective of the paper was to compare provider practices in prescribing antiretroviral (ARV) drug regimens and use of laboratory monitoring at three health care facilities and to determine whether Brazilian national guidelines are being followed. A retrospective, cross-sectional survey was employed. We selected a sequential sample of patients on ARV therapy who registered at three health care facilities in Rio de Janeiro, Brazil, during 2001. We abstracted 2001 patient visit data from medical records using standardized data forms. Provider practice was compared to the 2000 Brazil national guidelines for ARV use. Providers who prescribed recommended or acceptable regimens were considered as having conformed to guidelines. Only 2% of patient records (N=984) reported use of inappropriate regimens as defined by the Brazil 2000 national ARV guidelines. Forty-nine per cent of patients at the Evandro Chagas hospital, 17% of those at Hospital Geral, and 57% of those at Centro da Saude were prescribed recommended therapies. Twenty per cent of patients seen at the public district hospital received dual ARV therapy, an acceptable regimen at the time. Although the national guidelines do not provide recommendations on laboratory monitoring, during the 1 year study period a majority of patients had at least one CD4+ cell count (92%) or viral load measurement (86%). Providers' practices in prescribing ARV regimens at these Rio de Janeiro facilities conform to national guidelines. Physicians would benefit from Brazilian ARV guidelines which incorporate the international consensus on the frequency of laboratory monitoring appropriate for patients in resource-constrained settings.     

Neonatal BCG protection against leprosy: a study in Manaus, Brazilian Amazon

There is clear evidence that BCG protects against leprosy, but cross-immunity with environmental mycobacteria can interfere with vaccination protection. Some have cast doubts whether BCG vaccination can offer a significant impact against leprosy in the Brazilian Amazon, which is an endemic area for leprosy and with a high prevalence of environmental mycobacteria. This study was designed to estimate the vaccine effectiveness of neonatal BCG against leprosy in Amazon region, in Brazil. This is a cohort study nested in a randomized community trial. The study had two main results. First, neonatal BCG vaccination in Brazilian Amazon elicited protection of 74% (95% CI 57-86) against all forms of leprosy cases. Second, the highest protection was observed for multibacillary cases, 93% (95% CI 71-98). It is concluded that the study provides evidence that neonatal BCG may have an important and overlooked impact on the occurrence and transmission of leprosy, maybe even more in the future when the cohort which received a high coverage of BCG reaches the age of high incidence of leprosy.     

Distribution and morphometry of skeletal muscle fibers in patients with chronic obstructive pulmonary disease and chronic hypoxemia

This study was designed to assess the size and distribution of muscle fiber types in patients with severe chronic obstructive pulmonary disease and stable chronic hypoxemia. Brachial biceps biopsies were performed in 8 patients and 12 controls. Histochemistry was used to count and determine the cross-sectional area of the various fiber-types (1, 2a, and 2b). A significant reduction (P < 0.05) in the proportion of type 2a fibers and an increase in the proportion and cross-sectional area of type 2b fibers were seen in hypoxemic patients. These findings suggest an adaptation of the muscle fibers to a low partial pressure of oxygen in arterial blood.     

Voxel-based morphometry reveals gray matter network atrophy in refractory medial temporal lobe epilepsy

BACKGROUND: Conventional volumetric studies have shown that brain structures functionally and anatomically related to the hippocampus are smaller in patients with drug-refractory medial temporal lobe epilepsy (MTLE). OBJECTIVES: To determine the extent of gray matter atrophy in the brains of patients with MTLE and to examine the pattern of atrophy. DESIGN: We performed a voxel-based morphometric study of 43 consecutive patients with unilateral drug-refractory MTLE (21 patients with right-sided MTLE and 22 patients with left-sided MTLE) whose magnetic resonance images showed signs of unilateral hippocampal atrophy. The data from the patients with MTLE were compared with the data from 49 healthy control subjects to identify differences between groups in gray matter concentration (GMC). SETTING: Academic hospital's epilepsy clinic. RESULTS: We observed that patients with left- and right-sided MTLE exhibited GMC reduction in the hippocampus ipsilateral to the seizure origin. In addition, we found GMC reduction in the ipsilateral parahippocampal and isocortical temporal regions. Patients with MTLE also showed GMC reduction in subcortical nuclei such as the thalamus and caudate, in the cerebellum, in the midbrain, and in parieto-occipital regions. CONCLUSIONS: Patients with MTLE exhibit a reduction in GMC in regions outside the temporal lobe, specifically in areas that are connected to the hippocampus and parahippocampal region, suggesting an anatomical route for atrophy.     

Brain-derived neurotrophic factor facilitates glutamate and inhibits GABA release from hippocampal synaptosomes through different mechanisms

Brain-derived neurotrophic factor (BDNF) has an acute excitatory effect on rat hippocampal synaptic transmission. To compare the action of BDNF upon the release of excitatory and inhibitory neurotransmitters in the hippocampus, we studied the effect of acutely applied BDNF on the K+-evoked glutamate and on the K+-evoked gamma-aminobutyric acid (GABA) release from rat hippocampal nerve terminals (synaptosomes). The acute application of BDNF (30-100 ng/ml) enhanced the K+-evoked [3H]glutamate release. This effect involved tyrosine-kinase B (TrkB) receptor phosphorylation and Ca2+ entry into synaptosomes through voltage-sensitive calcium channels, since it was abolished by K252a (200 nM), which prevents TrkB-mediated phosphorylation, and by CdCl2 (0.2 mM), a blocker of voltage-sensitive calcium channels. In contrast, BDNF (3-100 ng/ml) inhibited K+-evoked [3H]GABA release from hippocampal synaptosomes. This action was also mediated by phosphorylation of the TrkB receptor, but was independent of Ca2+ entry into synaptosomes through voltage-sensitive calcium channels. Blockade of transport of GABA with SKF 89976a (20 microM) prevented the inhibitory action of BDNF upon GABA release, indicating that BDNF influences the activity of GABA transporters. It is concluded that BDNF influences in an opposite way, through distinct mechanisms, the release of glutamate and the release of GABA from hippocampal synaptosomes.