Preimplantation genetic diagnosis as a source of human embryonic stem cells for disease research and drug discovery

Embryos surplus to therapeutic requirements following preimplantation genetic diagnosis can be used to derive human embryonic stem cell (hESC) lines carrying mutations significant to human disease. These cells provide a powerful in vitro tool for modelling disease progression in a number of cell types as well as having the potential to revolutionise drug discovery. Robust and reproducible directed differentiation protocols are needed to maximise the potential of these cells. In this review, we explore the current use of hESC and induced pluripotent stem cells in disease-specific research and discuss the use of stem cell technology in drug discovery and toxicity testing.     

Splenectomy and thrombosis: the case of thalassemia intermedia

See also Mannucci PM. Red cells playing as activated platelets in thalassemia intermedia. This issue, pp 2149–51. Summary. Background: Hypercoagulability in splenectomized patients with thalassemia intermedia (TI) has been extensively evaluated. However, clinical and laboratory characteristics of patients who eventually develop overt thromboembolic events (TEE) are poorly studied. Patients/Methods: Three Groups of TI patients (n = 73 each) were retrospectively identified from a registry involving six centers across the Middle East and Italy: Group I, all splenectomized patients with a documented TEE; Group II, age‐ and sex‐matched splenectomized patients without TEE; and Group III, age‐ and sex‐matched non‐splenectomized patients without TEE. Retrieved data included demographics, laboratory parameters, clinical complications, and received treatments that may influence TEE development, and reflected the period prior to TEE occurrence in Group I. Results: The mean age of Group I patients at development of TEE was 33.1 ± 11.7 years, with a male to female ratio of 33:40. TEE were predominantly venous (95%) while four patients (5%) had documented stroke. Among studied parameters, Group I patients were more likely to have a nucleated red blood cell (NRBC) count ≥ 300 × 10⁶ L^?1, a platelet count ≥ 500 × 10⁹ L^?1 and evidence of pulmonary hypertension (PHT), or be transfusion naïve. The median time to thrombosis following splenectomy was 8 years. Patients with an NRBC count ≥ 300 × 10⁶ L^?1, a platelet count ≥ 500 × 10⁹ L^?1, or who were transfusion naive also had a shorter time to thrombosis following splenectomy. Conclusion: Splenectomized TI patients who will develop TEE may be identified early on by high NRBC and platelet counts, evidence of PHT, and transfusion naivety.     

Single Nucleotide Polymorphism in Adiponectin Gene and Risk of Pancreatic Adenocarcinoma

Introduction: Adiponectin is anti-inflammatory and anti-tumor cytokine secreted exclusively from adipocytes. Thereis a growing evidence of association between adiponectin gene polymorphism and development of pancreatic cancer.The current study aimed at evaluation of the possible association between selected adiponectin gene polymorphism andthe risk of pancreatic cancer. Methods: Prospective case-control study included 77 patients (29 women and 48 men)with biopsy-proven pancreatic adenocarcinoma and 97 healthy control. Blood samples from all included participantswere genotyped for 3 single nucleotide polymorphism (SNPs) of adiponectin genes (rs1501299C>A, rs266729C>G andrs2241766G>T) by PCR. Clinical, biochemical, and radiological data analyzed. Results: We demonstrated a significantassociation between the three studied SNPs (rs1501299, rs266729, and rs2241766) and increased risk of pancreaticadenocarcinoma (p<0.001). Furthermore, in clinical correlation analysis, Patients with rs2241766 polymorphismhave a lower frequency of lymph node involvement (p 0.05). Smoking and older age were independent predictors ofpancreatic adenocarcinoma. Conclusion: We provided evidence that variants in adiponectin gene might influence thedevelopment and progression of pancreatic cancer.     

Pharmacokinetic modelling of valproic acid from routine clinical data in Egyptian epileptic patients

OBJECTIVE: This paper describes a developed pharmacokinetic model for the estimation of valproic acid (VPA) clearance (CL) calculated from routine clinical data taken from Egyptian epileptic patients. METHODS: Retrospective clinical data from 81 adult and paediatric epileptic patients with one trough VPA serum concentration per patient were analysed using NONMEM to estimate drug CL and determine the influence of different covariates. A qualification group of 20 epileptic children (3-13 years old) was used to evaluate the final model. RESULTS: The population CL as estimated by base model (no covariates) was 0.581 l h(-1) with inter-individual variability (C.V. %) of 17.4% and SD of residual error was 6.82 mg l(-1). Univariate selection and backward deletion of different covariates led to the development of the final regression model of CL as follows: CL(Lh-1) = 0.101 + 0.151 * CBZ + 0.000248 * VPADD + 0.0968 * age/20 + 0.0803 * INDI, in which CBZ indicates co-administration of carbamazepine, VPADD the daily dose of VPA and INDI uncontrolled epilepsy. The between-subject variability in CL was 23.6% while the standard deviation of the residual error was 5.24 mg l(-1). The model predictions in the qualification group were found to have no bias and satisfactory precision. CONCLUSION: The population pharmacokinetic model for VPA could be used for a priori recommendation and dose optimisation of that drug in the Egyptian population of epileptic patients.