In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

Gender-specific Differences in Clinicopathologic Outcomes Following Radical Cystectomy: An International Multi-institutional Study of More Than 8000 Patients

Background

The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood.

Objective

To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC).

Design, setting, and participants

Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed.

Outcome measurements and statistical analysis

Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI).

Results and limitations

Female patients were older at the time of RC (p = 0.033) and had higher rates of pathologic stage T3/T4 disease (p < 0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p = 0.022 and p = 0.11, respectively). Female gender was an independent predictor for CSM (p = 0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05).

Conclusions

We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB.     

Prospective randomized controlled trial evaluating cap-assisted colonoscopy vs standard colonoscopy

AIM: To study the significance of cap-fitted colonoscopy in improving cecal intubation time and polyp detection rate. METHODS: This study was a prospective randomized controlled trial conducted from March 2008 to February 2009 in a tertiary referral hospital at Sydney. The primary end point was cecal intubation time and the secondary endpoint was polyp detection rate. Consecutive cases of total colonoscopy over a 1-year period were recruited. Randomization into either standard colonoscopy (SC) or cap-assist...     

TAVI: How to best predict postprocedural outcomes?

• Baseline risk scores for TAVI patients, including STS and EuroSCORE, might not predict long‐term outcomes.
• Including postprocedural data might improve risk stratification.
• The ACEF‐7 risk score includes the lowest creatinine clearance in the first 7 postprocedural days and appears to be a good predictor of worse long‐term outcomes.

     

Factor V G1691A (Leiden) and prothrombin G20210A single-nucleotide polymorphisms in type 2 diabetes mellitus

The association of the single nucleotide polymorphisms (SNPs) G1691A in coagulation factor V (FV)-Leiden and G20210A in prothrombin (PRT) genes with type 2 diabetes mellitus (T2DM) were analyzed in 112 T2DM patients (58 males, 54 females; mean age 55.24 +/- 13.5 years) and 249 healthy control subjects (118 males, 131 females; mean age 53.03 +/- 13.8 years). No association was found for FV-Leiden with T2DM, as the frequency of the G/G (82.1% vs. 85.5%), G/A (17.0% vs. 14.1%), and A/A (0.9% vs. 0.4%) genotypes was not different between patients and controls, respectively (P = 0.644). Similarly, lack of association of PRT G20210A with T2DM was seen among the population studied, and the frequency of the G/G (92.9% vs. 97.2%), G/A (6.3% vs. 2.8%), and A/A (0.9% vs. 0.0%) genotypes was similar among patients and controls, respectively (P = 0.094). Neither FV-Leiden nor PRT G20210A was associated with, and no evidence for interactions between these mutations was seen in, T2DM.