Modifying platelets at their birth: anti-thrombotic therapy without haemorrhage.

Cardiovascular disease is a leading cause of death. The current approach to the prevention of arterial thrombosis in cardiovascular disease is dependent on the use of therapies which inhibit the activation of platelets. Predictably these are associated with an increased risk of haemorrhage which causes significant morbidity. The thrombotic potential of an activated platelet is modifiable; being determined before thrombopoiesis. Increased megakaryocyte ploidy is associated with larger and more active platelets carrying an increased risk of thrombosis. The reduction in the ploidy of megakaryocytes is therefore a novel area of therapeutic interest for reducing thrombosis. We propose a new therapeutic approach for the prevention and treatment of thrombosis by targeting the reduction in ploidy of megakaryocytes. We examine the role of a receptor mediated event causing megakaryocytes to increase ploidy, the potential for targeting the molecular mechanisms underpinning megakaryocyte endomitosis and the existence of two separate regulatory pathways to maintain haemostasis by altering the thrombotic potential of platelets as targets for novel therapeutic approaches producing haemostatically competent platelets which are not prothrombotic.

Factors Affecting Domiciliary Non-Invasive Ventilation Compliance.

Few international studies have investigated factors affecting domiciliary non-invasive ventilation (D-NIV) compliance, and data from the UK are limited. We assessed compliance (defined as ≥ 4 h/night for at least 70% of the time) in a retrospective UK population study, at three time points (0-1 month, 3-4 months and 11-12 months), for all patients commenced on D-NIV over a 5-year period. A total of 359 patients were included. Non-compliant vs. compliant patients were significantly younger (median age 64 (IQR 52-72) vs. 67 (58-75) years, p = 0.032) and more likely to have schizophrenia, consistent at both 3-4 months (5% vs. 1%, p = 0.033) and 11-12 months (5% vs. 2%, p = 0.049). Repeated measures ANOVA demonstrated that the minutes [median (IQR)] of D-NIV used significantly increased at the three time points (0-1 month, 3-4 months and 11-12 months) for patients with hypertension [310 (147.5-431) vs. 341 (89-450) vs. 378 (224.5-477.5), p = 0.003]; diabetes [296.5 (132.5-417.5) vs. 342.5 (94.5-438.5) vs. 382 (247.5-476.25), p = 0.002] and heart failure [293 (177-403) vs. 326 (123-398) vs. 365 (212-493), p = 0.04]. In conclusion, younger and comorbid schizophrenic patients have lower D-NIV compliance rates, and our data suggest that persistence with D-NIV over a year may improve overall use.

In vitro and in vivo characterization of the interaction, proinflammatory, immunomodulatory and antigenic properties of capsular polysaccharide from Streptococcus pneumoniae serotype 1.

Pneumococcal capsular polysaccharide (PCP) is the major virulence determinant of Streptococcus pneumoniae (pneumococcus). Strains devoid of the capsule are avirulent or highly attenuated. PCP is present in soluble form and on pneumococci in infected individuals. The present study was undertaken to study the interaction of PCP from serotype 1 (PCP1) with immune cells, and its proinflammatory, immunomodulatory and antigenic properties. Binding of PCP1 to the surface of immune cells led to proinflammatory cytokine production which was not cell line or cytokine restricted. HEK293T transfectants expressing TLR1 and TLR2 produced IL-8 upon stimulation with PCP1, untransfected cells did not do so. PCP1 failed to induce TNF-α production from RAW264.7 cells when pre-incubated with a TLR2 blocking antibody. The surface binding of PCP1 was abrogated in the presence of TLR2 blocking antibody. PCP1 failed to bind TLR2 deficient RAW264.7 cells and induce TNF-α production. Unlike PCP1, alkali-treated PCP1 failed to stimulate RAW264.7 cells to produce TNF-α indicating the importance of alkali-sensitive moieties like O-acetyl groups. Alkali-treated PCP1 elicited lower anti-PCP1 antibody response. Mice experiments suggested that alkali-sensitive groups are significant target of protective antibodies in PCP1 immunized mice. Our findings demonstrate that PCP1 is an important modulator of immune response against pneumococci.

An MRI-histological study of white matter in stroke-free SHRSP.

Hypertension is associated with cerebral small vessel disease (SVD) and with diffuse white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI). We tested whether stroke-prone spontaneously hypertensive rats (SHRSP), a model of chronic hypertension, exhibit WMH. Male SHRSP (age 10 months) without stroke symptoms were compared with age-matched male WKY rats. Stroke-prone spontaneously hypertensive rats exhibited no WMH on MRI scans (T2, T2*, diffusion tensor imaging) and no neuropathological lesions. While leptomeningeal arteries exhibited fibrohyaline wall thickening, with decreased smooth muscle actin relative to WKY, deep penetrating arterioles within the caudate nuclei had no vasculopathy. We conclude that WMH are not an obligate feature of stroke-free SHRSP aged up to 10 months.