Summary. Background: GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease. Methods: A family with a novel bleeding disorder was identified and characterized. Genetic linkage analysis and massively parallel sequencing were used to localize the mutation causing the disease phenotype on chromosome 9. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript. Results: We have identified a family with an autosomal dominant bleeding disorder associated with macrothrombocytopenia, red cell anisopoikilocytosis, and platelet dysfunction. The severity of bleeding is variable with some affected individuals experiencing spontaneous bleeding while other family members exhibit only abnormal bleeding with surgery. A single nucleotide insertion was identified in GFI1B that predicts a frameshift mutation in the fifth zinc finger DNA-binding domain. This mutation alters the transcriptional activity of the protein, resulting in a reduction in platelet a-granule content and aberrant expression of key platelet proteins. Conclusions: GFI1B mutation represents a novel human bleeding disorder, and the described phenotype identifies GFI1B as a critical regulator of platelet shape, number, and function.

Summary. Background: Depression is associated with an increased risk of cardiovascular disease (CVD). Although the mechanism is uncertain, prothrombotic and inflammatory factors may play a role. Objectives: As platelets play a key role in CVD, we determined first, whether depressed individuals had more activated platelets than non-depressed individuals and second, whether treatment of depression reduced platelet activation levels. Patients/methods: We recruited 108 depressed outpatients and 45 control subjects all without a history of CVD. After psychological assessment, the depressed patients were offered treatment with medication and/or psychotherapy. Flow cytometric markers of platelet activation and level of depression were assessed at baseline and at 4 weeks and 6 months after treatment. Results: Depression was associated with increased platelet activation with a higher number of circulating CD62p (0.76 · 10 9 L )1 vs. 0.46, P = 0.019) and CD63 (P = 0.05) positive platelets compared with controls. Patients with depression also had more circulating plateletleukocyte aggregates than controls (P < 0.001). There was a positive correlation between the severity of depression and the level of platelet activation. Platelets from depressed patients were also hyperreactive to adenosine 5´-diphosphate (ADP) stimulation with increased CD62p and CD63 exposure (P = 0.003 and 0.019, respectively). Six months of treatment resulted in a reduced number of circulating CD62p and CD63 positive platelets (29.84% and 53.38% decrease) and a 20.9% reduction in CD63 exposure after ADP activation. Conclusions: Depression is associated with increased in vivo platelet activation and resolution of depression using psychotherapy and/or medication reduces platelet activation. These findings provide insights into the link between depression and cardiovascular risk.

Aberrant DNA promoter methylation with associated gene silencing is a common epigenetic abnormality in acute lymphoblastic leukaemia (ALL) and is associated with poor survival. We have identified a family of transmembrane tyrosine phosphatase proteins as targets of hypermethylation in ALL and high-grade B cell lymphoma and demonstrated that this abnormal methylation correlates with transcript expression. PTPRG was methylated in 63% of ALL samples, PTPRK in 47%, PTPRM in 64% and PTPRO in 54% of cases, with most ALL samples containing methylation at multiple phosphatase loci. PTPRK promoter methylation was associated with a decreased overall survival in the cohort. Restoration of PTPRK transcript levels in leukaemia cells, where phosphatase transcript was silenced, reduced cell proliferation, inhibited colony formation and increased sensitivity to cytotoxic chemotherapy. These biological changes were associated with a reduction in levels of phosphorylated Erk1/2, Akt, STAT3 and STAT5 suggesting functional phosphatase activity after transcript re-expression. Methylation of the phosphatase promoters was reversible with decitabine and a histone deacetylase inhibitor, suggesting that PTPRK-mediated cell signalling pathways may be targeted with epigenetic therapies in lymphoid malignancy.

Interleukin (IL)-18, a proinflammatory cytokine, induces T-helper 1 differentiation and cytotoxic T-lymphocyte functions, both of which have been proposed in the pathogenesis of oral lichen planus (OLP) - an oral disease resembles oral mucosal graft-versus-host disease (GVHD) both clinically and histologically. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the IL18 gene on the chromosome 11q22 in patients with OLP. Four SNPs of the IL18 gene at positions -137G/C (rs187238), -607C/A (rs1946518), -656G/T (rs1946519), and 1248A/G (rs189667) were analyzed in 151 patients with OLP and 143 normal controls using polymerase chain reaction-sequence-specific primers method, and the serum level of IL-18 protein was determined by enzyme-linked immunosorbent assay (ELISA). The data revealed that there is a significant difference in IL18-607 genotype distributions between the patient group and the control group (P < 0.001), and the polymorphism -137G/C also appears to be statistically associated with the more severe erosive subtype (eOLP) (P = 0.023). The identified polymorphisms at the IL-18 promoter region (i.e. -137GG) are likely to exert positive effect on the production of IL-18 protein in OLP, as detected by ELISA. Using phase software, four haplotypes were deduced from the two polymorphisms -607C/A and -137G/C, named haplotypes I to IV, and the haplotypes I, II, and IV are significantly associated with OLP (P < 0.001). Our data suggest that the identified IL18 polymorphisms may be associated with the pathogenesis of OLP in this Chinese cohort by upregulation of IL-18 production in vivo.

Platelet MPD measurements are a useful guide to classify IT, but the time taken to record measurements may limit clinical applicability.

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