High prevalence of Plasmodium falciparum pfcrt K76T mutation in pregnant women taking chloroquine prophylaxis in Senegal

OBJECTIVES: The risk of malaria infection is increased during pregnancy, and many countries recommend chloroquine prophylaxis in pregnant women, despite Plasmodium falciparum chloroquine resistance. Chloroquine resistance is associated with the pfcrt gene K76T mutation. The aim of this study was to compare the prevalence rate of pfcrt T76 mutation in P. falciparum isolates from infected pregnant and non-pregnant individuals from Senegal. METHODS: The study was conducted in the rural maternity hospital of Thiadiaye, Senegal, where malaria is seasonal. Sixty-nine P. falciparum isolates from infected women were collected at delivery. These women were part of a cohort study; they were followed from their first antenatal visit and advised to take chloroquine prophylaxis. For each woman, the earliest P. falciparum-infected blood sample was also used. A control group of 49 non-pregnant individuals with asymptomatic P. falciparum infection was enrolled. RESULTS: During pregnancy, prevalence of T76 mutant parasites was higher than in the 49 non-pregnant controls (P<0.001). Among pregnant women, this rate was highest at delivery (P=0.06), and tended to be higher in women who had taken chloroquine prophylaxis, as assessed in urine samples (P=0.08). CONCLUSIONS: Chloroquine prophylaxis is responsible for increased drug consumption and increased drug pressure that may lead to the selection of drug-resistant parasites. This is the first report showing that P. falciparum-infected pregnant women harbour pfcrt T76 mutant parasites more often than non-pregnant individuals, and that the prevalence of this mutation is higher at term than earlier during pregnancy.     

Le syndrome SAPHO

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare entity characterized by the association of heterogeneous osteoarticular and cutaneous manifestations that have for common denominator an aseptic inflammatory process. The etiopathogeny of this disease is still a matter of debate. Although it has been related to the spondylarthritis family, an infectious origin is suggested. Diagnosis is based on the presence of at least one of the three diagnostic criteria proposed by Kahn. The treatment includes NSAIDs, antibiotics, corticosteroids, methotrexate and more recently the bisphosphonates and the TNFα inhibitors.     

Immune responsiveness against allogeneic platelet transfusions is determined by the recipient's major histocompatibility complex class II phenotype

BACKGROUND: Immunoglobulin G (IgG) anti-platelet (PLT) immunity has been shown to be initiated by indirect allorecognition where recipient T cells recognize donor PLT antigens presented by class II molecules encoded by the major histocompatibility complex (MHC) on recipient antigen-presenting cells. To understand how the recipient's MHC class II molecules may influence PLT alloimmunity, immune responsiveness against transfused PLTs was tested in different mouse strains. STUDY DESIGN AND METHODS: Various inbred and mutant mouse strains were transfused with allogeneic PLTs and IgG donor antibodies were measured by flow cytometry. RESULTS: When recipient mice, expressing both MHC class II I-A and MHC class II I-E molecules, were transfused weekly with allogeneic PLTs, high titers of IgG donor antibodies were generated. In comparison, however, recipient mice expressing only MHC class II I-A molecules had significantly (p < 0.001) reduced IgG antibody responsiveness against PLT transfusions. The low IgG responder status against allogeneic PLT transfusions was rescued in transgenic mice expressing I-E molecules and in mice genetically deficient in either beta2-microglobulin or CD8+ T cells. CONCLUSION: IgG immune responsiveness against allogeneic PLT transfusions is dependent on recipient expression of I-E MHC class II molecules, whereas I-A expression is linked with CD8-mediated suppression of PLT immunity. The data suggest that strategies to modify recipient MHC class II presentation of donor PLT antigens would be effective in eliminating PLT alloimmunity.     

Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease

Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.     

Inhaled sildenafil nanocomposites: lung accumulation and pulmonary pharmacokinetics*

Context: Administration of sildenafil citrate (SC) is considered as a strategy in the treatment of pulmonary hypertension.

Objective: This study reports production of the inhalable microparticles containing SC-loaded poly(lactide-co-glycolic acid)-nanoparticles.

Methods: SC-nanoparticles were prepared by the double emulsion solvent evaporation method. Next, free SC and SC-loaded nanoparticles were spray dried in the presence of appropriate excipients (lactose, maltose and trehalose). Physicochemical properties and aerodynamic behavior of prepared powders were evaluated. In addition, drug accumulation from selected formulations in the rat lung tissue was compared with oral and IV administration.

Results: Size and fine particle fraction of selected nanocomposites and free SC microparticles were 7 and 4.5?µm, and 60.2% and 68.2%, respectively. Following oral and IV administration, the drug was not detectable in the lung after 4 and 6?h, respectively, but in SC-loaded nanoparticles, the drug was detectable in the lung even after 12?h of inhalation. Respirable particles containing free SC provided high concentration at first that was detectable up to 6 after insufflation.

Conclusion: In vivo study demonstrated that pulmonary administration of sildenafil and sildenafil nanoparticles produced longer half-life and higher concentration of the drug in the lung tissue as compared to oral and IV administration. So, these formulations could be more effective than oral and IV administration of this drug.     

Optimizing the management of her2-positive early breast cancer: the clinical reality

Breast cancer positive for her2 (human epidermal growth factor receptor 2) is associated with a poor prognosis for patients with both early-stage and metastatic breast cancer. Trastuzumab has been shown to be effective and is now considered the standard of care for early-stage patients with her2-positive breast cancer. In that population, trastuzumab has been studied in six randomized clinical trials. Overall, use of this agent leads to a significant reduction in risk of disease recurrence and improvement in overall survival. Despite the strong evidence for the use of trastuzumab in managing her2-positive early breast cancer (ebc), a number of clinical controversies remain. The authors of this paper undertook a review of the available scientific literature on adjuvant trastuzumab to produce practical considerations from Canadian oncologists. The panel focused their discussion on five key areas:

• Management of node-negative disease with tumours 1 cm or smaller in size
• Management of her2-positive ebc across the spectrum of the disease (that is, nodal and steroid hormone receptor status, tumour size)
• Timing of trastuzumab therapy with chemotherapy for early-stage disease: concurrent or sequential
• Treatment duration of trastuzumab for ebc
• The role of non-anthracycline trastuzumab-based regimens

     

MDM2 SNP309T>G polymorphism and risk of hepatocellular carcinoma: A case–control analysis in a Moroccan population

Background: The Murine double minute 2 (MDM2) gene encodes a negative regulator of the p53 tumor suppressor protein. A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been reported to produce accelerated tumor formation. The aim of this study was to investigate whether this functional SNP is associated with an enhanced risk of liver tumorigenesis in Moroccan patients. Methods: The study consisted in the comparison of 96 hepatocellular carcinomas (HCC) cases and 222 controls without HCC matched for age, gender and ethnicity. PCR–RFLP and sequencing methods were used to determine the genotype at the MDM2 SNP309T>G locus. Results: Overall, our results indicate that the GG genotype of SNP309 is significantly associated with an increased risk of HCC (odds ratio, OR = 2.60, 95% CI, 1.08–6.28). Interestingly, despite a wide range of confidence interval, there is a trend associating the GG genotype with a high risk of HCC in males (OR = 3.31; 95% CI, 0.93–11.82) and in HCV-infected patients (OR = 3.7; 95% CI, 0.82–16.45). By contrast, no association between age at diagnosis and MDM2 SNP309 genotypes was observed in HCC patients (P = 0.610). Conclusion: Our findings suggest that the MDM2 309T>G polymorphism is an important modulator of hepatocellular carcinoma development in Moroccan patients.     

The Pro variant of the p53 codon 72 polymorphism is associated with hepatocellular carcinoma in Moroccan population

Aim: Codon 72 polymorphism of the p53 gene has been implicated in cancer risk, and it has been suggested that it may have an impact on the clinical outcome of the disease. Our objective was to evaluate the association between p53 polymorphism at codon 72 and hepatocellular carcinoma (HCC) in the Moroccan population. Methods: Genomic DNA was extracted from peripheral blood cells of 96 patients with HCC and 222 controls without HCC matched for age, gender and ethnicity. Codon 72 polymorphism of p53 was identified by PCR-restriction fragment length polymorphism, confirmed by sequencing. Results: Patients with HCC had higher frequencies of Pro/Pro (13.5% vs. 6.3%, P < 0.02) than controls and consequently a 2.3-fold increased risk of liver cancer development (odds ratio [OR], 2.304; 95% confidence interval [CI], 1.014-5.234). In addition, we found a significant association between the p53Arg72Pro polymorphism and the female gender in HCC. Men with Pro/Pro genotype had a 1.57-fold increased risk for HCC, whereas the corresponding genotype in women had a 4.4-fold increased risk of HCC (OR, 4.4; 95% CI, 1.18-16.42). No correlation between the polymorphism and HCC risk was found when comparing the hepatitis C virus (HCV)-positive cases to HCV-positive controls. However, HCV-negative subjects and Pro/Pro genotype had a 3.31-fold increased risk for HCC. Conclusion: These results provide evidence that p53 polymorphism at codon 72 is a modifier of hepatocarcinogenesis, especially in women and HCV-negative subjects.