Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project

Deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) or an impaired PC anticoagulant pathway increase the risk of venous thrombosis (VT). By conducting a genome-wide association study (GWAS) on two independent samples of VT patients totalling 951 subjects typed for 472 173 single nucleotide polymorphisms (SNPs), we observed that common SNPs explain 21% and 27% of the genetic variance of plasma AT and PS levels, even though no SNP reached genome-wide significance. For PC, we showed that two PROCR SNPs, rs867186 (Ser219Gly) and rs6060278, additionally explained c. 20% (P = 1·19 × 10(-31)) of the variance of plasma PC levels. We also observed that c. 40% of the remaining genetic variance of PC levels could be due to yet unidentified common SNPs. The PROCR locus was also found to explain c. 8% (P < 10(-10)) of agkistrodon contortrix venom (ACV) (exploring the PC pathway) variability which was under the main control of the F5 and F2 loci that further explained about 40% and 10%, respectively. We presented here the first GWAS for plasma AT and free-PS levels and ACV in Caucasian samples. We identified three independent loci associated with ACV (F2, F5 and PROCR) and replicated two independent effects on plasma PC levels at the PROCR locus.     

Dementia syndrome in an elderly subject related to valproic acid use: a case report

In addition to the usual adverse effects, the chronic use of the valproic acid can entail dementia syndrome. We describe the case of a 68-year-old woman who had presented a dementia syndrome due to the use of valproic acid for one year. This drug was prescribed in order to prevent a potential convulsive crisis after an ischemic stroke in a patient who did not have a history of epilepsy. This case shows that each clinician must be careful about all medications consumed by the patient in the face of cognitive disorders.     

Microencapsulation by solvent evaporation: state of the art for process engineering approaches

Microencapsulation by solvent evaporation technique is widely used in pharmaceutical industries. It facilitates a controlled release of a drug, which has many clinical benefits. Water insoluble polymers are used as encapsulation matrix using this technique. Biodegradable polymer PLGA (poly(lactic-co-glycolic acid)) is frequently used as encapsulation material. Different kinds of drugs have been successfully encapsulation: for example hydrophobic drugs such as cisplatin, lidocaine, naltrexone and progesterone; and hydrophilic drugs such as insulin, proteins, peptide and vaccine. The choice of encapsulation materials and the testing of the release of drug have been intensively investigated. However process-engineering aspects of this technique remain poorly reported. To succeed in the controlled manufacturing of microspheres, it is important to investigate the latter. This article reviews the current state of the art concerning this technique by focusing on the influence of the physical properties of materials and operating conditions on the microspheres obtained. Based on the existing results and authors' reflection, it gives rise to reasoning and suggested choices of materials and process conditions. A part of this paper is also dedicated to numerical models on the solvent evaporation and the solidification of microspheres. This review reveals also the surprising lack of knowledge on certain aspects, such as the mechanism of formation of pores in the microspheres and the experimental study on the solidification of microspheres.     

Trauma among children and parents within the context of international adoption

Although the large majority of international adoptions are problem free, some of them involve a certain degree of suffering as much for the children as for the adoptive parents. These stumbling blocks in the relationship need to be studied taking into account the trauma experienced by each of the protagonists.     

Assessment of the SD Bioline Ag MPT64 Rapid™ and the MGIT™ TBc identification tests for the diagnosis of tuberculosis

Successful control of tuberculosis relies on the rapid detection of Mycobacterium tuberculosis. Few chromatographic lateral flow assays for the discrimination of the M. tuberculosis complex were developed from culture media. We compared the values of 2 assays to assess their place in diagnosis of tuberculosis. We conclude of their efficiency and relevance to supplant the conventional methods.     

KNG1 Ile581Thr and susceptibility to venous thrombosis

Three single nucleotide polymorphisms (SNPs) were recently found to be associated with activated partial thromboplastin time (aPTT). Because shortened aPTT levels have been observed in patients experiencing venous thrombosis (VT), we investigated the effects of these 3 aPTT-associated SNPs, rs2731672, rs9898, and rs710446, on the risk of VT in a sample of 1110 healthy patients and 1542 patients with VT. Among the 3 tested SNPs, only rs710446 was associated with VT risk; the rs710446-C allele was associated with an increased risk of VT (odds ratio 1.196, 95% confidence interval 1.071-1.336, P = .0012). This association also was observed in an independent sample of 590 controls and 596 patients (odds ratio 1.171, 95% confidence interval 0.889-1.541, P = .059). We also confirmed that the rs710446-C allele was associated with decreased aPTT levels, making this nonsynonymous Ile581Thr variant a new genetic risk factor for VT.     

Apomorphine infusion in advanced Parkinson's patients with subthalamic stimulation contraindications

BackgroundThe efficacy of continuous subcutaneous apomorphine infusion (APO) has been evaluated in advanced Parkinson’s disease in several open-label studies but never in a population of patients for whom subthalamic nucleus deep brain stimulation (STN-DBS) was contraindicated.MethodsThe aim of this study was to evaluate the efficacy and cognitive safety of APO at 12-month follow-up in 23 advanced parkinsonian patients (mean age: 62.3 years; mean disease duration: 13.9 years) whose dopa-resistant axial motor symptoms and/or cognitive decline constituted contraindications for STN-DBS. Their motor and cognitive status were evaluated before APO and 12 months afterwards.ResultsAfter one year, patients expressed high levels of satisfaction, with a mean rating on the Visual Analog Scale of 52.8% under APO. Daily OFF time, recorded in a 24-h diary, was reduced by 36% and ON time improved by 48%. There was a significant reduction (?26%) in mean oral levodopa equivalent dose. Dopa-resistant axial symptoms and neuropsychological performance remained stable. No adverse event was noted and none of the patients needed to take clozapine at any time.ConclusionsAPO is both safe and effective in advanced parkinsonian patients with untreatable motor fluctuations, for whom STN-DBS is contraindicated due to dopa-resistant axial motor symptoms and/or cognitive decline. As such, it should be regarded as a viable alternative for these patients.     

Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia

BACKGROUND: The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability. AIM: This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.     

Soluble VE‐cadherin in rheumatoid arthritis patients correlates with disease activity: Evidence for tumor necrosis factor α–induced VE‐cadherin cleavage

Objective

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that principally attacks synovial joints. However, accelerated atherosclerosis and increased cardiovascular morbidity and mortality are major clinical consequences of endothelial dysfunction in RA patients. Tumor necrosis factor α (TNFα) is the major mediator of inflammation in RA, related to vascular injury by targeting VE‐cadherin, an endothelium‐specific adhesion molecule of vital importance for endothelium integrity and angiogenesis. We undertook this study to examine the mechanisms regulating VE‐cadherin processing by TNFα and their occurrence in RA.

Methods

Human umbilical vein endothelial cells were used in primary culture and treated with recombinant TNFα to study VE‐cadherin cleavage. Cell lysates and conditioned media were analyzed by Western blotting for VE‐cadherin cytoplasmic domain and extracellular domain (VE‐90) generation, respectively. VE‐90 was analyzed at baseline and at the 1‐year followup in sera from 63 RA patients (from the Very Early Rheumatoid Arthritis cohort) with disease duration of <6 months.

Results

TNFα induced a time‐dependent shedding of VE‐90 in cell media. This effect was prevented by tyrosine kinase inhibitors (genistein and PP2) or by knocking down Src kinase. In contrast, tyrosine phosphatase blockade enhanced VE‐cadherin cleavage, confirming the requirement of tyrosine phosphorylation processes. In addition, using the matrix metalloproteinase (MMP) activator APMA and the MMP inhibitor GM6001, we demonstrated that MMPs are involved in TNFα‐induced VE‐cadherin cleavage. Of major importance, VE‐90 was detected in sera from the 63 RA patients and was positively correlated with the Disease Activity Score at baseline and after 1‐year followup.

Conclusion

These findings provide the first evidence of VE‐cadherin proteolysis upon TNFα stimulation and suggest potential clinical relevance of soluble VE‐cadherin in management of RA.