Thrombin generation in severe haemophilia A and B: the endogenous thrombin potential in platelet-rich plasma

Thrombin generation was investigated in platelet-rich plasma (PRP) from 11 healthy controls, 17 patients with severe haemophilia A and 7 patients with severe haemophilia B. Mean endogenous thrombin potential (ETP) in arbitrary fluorescence units (FU) was 226.9 +/- 44.6, 186.4 +/- 22.5, 154.2 +/- 41.3 in controls, haemophilia A and B, respectively, all at a platelet count of 200 x 10(9)/l (p = 0.004 for controls vs. haemophilia A, p = 0.003 for controls vs. haemophilia B, no significant difference between haemophilia A and B). The contribution of FVIII to thrombin generation in haemophilia A was 1.31 +/- 0.16 FU/% of FVIII:C activity, while for FIX in haemophilia B this was 0.80 +/- 0.21 FU/% of FIX activity. There was an almost linear relationship between increasing platelet count and thrombin generation up to a mean platelet count of 100 x 10(9)/l. Further increase in platelet count has only a marginal influence on thrombin generation. Platelets increase ETP in haemophilia A by 0.184 +/- 0.022 FU/10(9) platelets/l and in haemophilia B by 0.319 +/- 0.085 FU/10(9) platelets/l, and this was significantly different between the two groups (p = 0.0002). This influence of plate-lets diminishes with increasing concentration of either FVIII or FIX. In conclusion, there is a difference in thrombin generation between haemophilia A and B, and this may be attributed to the role of platelets in the assembly of the tenase complex on their surface.     

Preoperative plasma fibrinogen levels predict mortality after coronary artery bypass grafting

This study was designed to investigate whether plasma fibrinogen levels as well as the beta-fibrinogen -455 G/A genotype are associated with outcome after coronary artery bypass graft (CABG) operation. We enrolled 249 consecutive CAD patients one day before they underwent a CABG operation. Data from 220 patients with available plasma fibrinogen levels were analyzed. The primary end-point was total mortality, the secondary end-point mortality from cardiac causes or the need for myocardial revascularization. The 2-year total mortality was 9.1% in the entire cohort. Multivariable analysis revealed an independent relationship between the primary end-point and preoperative plasma fibrinogen levels but not the beta-fibrinogen -455 G/A genotype. Neither preoperative plasma fibrinogen levels nor the beta-fibrinogen -455 G/A genotype could predict the secondary end-point. We conclude, that elevated preoperative plasma fibrinogen levels, but not the beta-fibrinogen -455 G/A genotype predict the total mortality after CABG operation.     

Loss of nicotinic acetylcholine receptor subunits alpha4 and alpha7 in the cerebral cortex of Parkinson patients

Cerebral cortical cholinergic deficits, represented by a decrease in choline acetyltransferase activity, severe losses of nicotinic binding sites as well as cell degeneration in the basal forebrain can be observed in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. The potential role of nicotinic acetylcholine receptor subunits as pharmacological targets for the treatment of cognitive deficits raises the question as to what extent these subunits are affected in neurodegenerative diseases. We here report on a significant decrease of the alpha4 and the alpha7 nicotinic acetylcholine receptor subunit in cortices of Parkinson patients which turns out to be similar to recent findings in Alzheimer patients.     

Perioperative morbidity of the extended radical perineal prostatectomy

PURPOSE: Perioperative morbidity is an essential indicator for the quality of an operative technique. This fact is especially important in radical prostatectomy since different treatment modalities may provide similar outcome in terms of local tumor control. MATERIALS AND METHODS: The conventional type of radical perineal prostatectomy is associated with a significant percentage of positive surgical margins and was therefore substituted by a modified extended radical perineal prostatectomy at our institution. This procedure which includes partial resection of the dorsal vein complex and extrafascial resection of the seminal vesicals was performed in 200 patients with clinical T1 to T3 prostate cancer. The medical records were retrospectively reviewed for perioperative morbidity. RESULTS: There was no perioperative mortality and only 7% of the patients experienced postoperative complications. Blood substitution was indicated in 14% of the patients and could be reduced to 4% in the last 50 patients. The reintervention rate was 2.5% including 3 patients in whom a rectocutaneous fistula had to be repaired. The suction drainage was removed in 92% patients within 5 days. The indwelling catheter stayed in place for less than 14 days in 89% of all patients and was removed as early as after 2-7 days in 92% of the last 50 patients. Anastomotic strictures were observed in 8 (5%) of 160 patients followed for more than 6 months. 87.4% of patients were considered continent after at least 6 months follow-up. However, pad use was reported in 33.6%. CONCLUSION: The extended type of radical perineal prostatectomy provides excellent results in terms of perioperative morbidity, although a significant learning curve can be noted, which is indicated by blood substitution and duration of necessary catheter drainage. Since the rate of positive surgical margins in pT3 tumors is low (21%) and iatrogenic positive margins in pT2 tumors are avoided, this type of prostatectomy should be performed in case a potency sparing procedure is not indicated.     

Inhibitory effect of a matrix metalloproteinase inhibitor on growth and spread of human pancreatic ductal adenocarcinoma evaluated in an orthotopic severe combined immunodeficient (SCID) mouse model

The present study was aimed at evaluating the effect of the matrix metalloproteinase (MMP) inhibitor prinomastat (AG3340) on tumor progression using an orthotopic pancreatic carcinoma model in severe combined immunodeficient mice. In controls, receiving vehicle only, the poorly differentiated ductal adenocarcinoma invaded into adjacent organs and metastasized to different sites in the abdomen and to the lungs. Treatment with prinomastat, intraperitoneally twice daily for 21 days, reduced primary tumor volume significantly to 19.0 (+/-7.7)% of control, with induction of necrosis, differentiation, and fibrotic tissue in the pancreatic tumors. Invasion was not observed in 63% of prinomastat-treated mice, and metastases were reduced markedly. Surprisingly, prinomastat-treated tumors had on average higher microvessel densities as a consequence of an increased angiogenesis in perinecrotic tumor areas. We conclude that prinomastat is highly effective in inhibiting pancreatic carcinoma growth and progression in an orthotopic cancer model. This model appears to be a valuable tool to investigate the potency of novel antimetastatic strategies in pancreatic ductal adenocarcinoma by specifically targeting certain MMPs.     

Vascular endothelial growth factor in exercising humans under different environmental conditions

It was the aim of this study to investigate the time course of changes in the serum concentrations of vascular endothelial growth factor (VEGF) during a regular survival training programme combined with food and fluid deprivation and during a high altitude marathon run. We studied soldiers of the Austrian Special Forces performing survival training at sea-level and marathon runners of the Posta Atletica who crossed the border between Chile and Argentina at altitudes up to 4722?m. Baseline data collected before the 1-week of survival training showed that the soldiers had normal VEGF [n=8, 246.7?(SD 118.5)?pg?·?ml^?1] serum concentrations which remained unchanged during the course of the study. Before the high altitude marathon the subjects showed normal VEGF serum concentrations [178?(SD 84.5)?pg?·?ml^?1]. After the run VEGF concentrations were found to be significantly decreased [41.0?(SD 41.6)?pg?·?ml^?1, P?相似文献   

Myocardial fibrosis is associated with biventricular dysfunction in patients with hypertrophic cardiomyopathy

Aims: To assess left (LV) and right ventricular (RV) function by two‐dimensional (2D) speckle tracking echocardiography and its relation to myocardial fibrosis in hypertrophic cardiomyopathy (HCM). Methods: We enrolled 50 HCM patients (30 male; 47.3 ± 9.9 years) in our study. Each patient received echocardiography with modern high‐end scanners. For speckle tracking analysis of LV and RV function the dedicated software was used. The presence of myocardial fibrosis was detected by cardiac magnetic resonance imaging (MRI). Results: For intraobserver variability of RV global longitudinal strain, we found a correlation of r = 0.89 (p < 0.001) with a minor bias of 4.9 ± 2.9%. On cardiac MRI 30 patients (60%) demonstrated late gadolinium‐enhancement (LGE) of the LV. Of these patients only 7% showed LGE of the RV. HCM patients with myocardial fibrosis had less global longitudinal LV strain in comparison to patients without myocardial fibrosis (?12.8 ± 2.2 vs ?21.1 ± 2.6, P < 0.001), thicker interventricular septums (23.7 ± 4.0 vs 19.2 ± 5.1, P < 0.001), larger left atria (34.9 ± 7.1 vs 23.9 ± 5.1, P < 0.001), and impaired diastolic function (E/A‐ratio: 1.02 ± 0.22 vs 1.15 ± 0.18, P < 0.01). Comparable results were found for RV function. LV and RV strain correlated with r = 0.85 (p < 0.001). Conclusions: HCM is not only a disease of the LV. LGE in HCM is associated with both LV and RV dysfunction. Although RV LGE occurs only in a minority of patients with HCM and LV fibrosis, speckle tracking echocardiography is feasible for evaluating LV and RV dysfunction in these patients. (Echocardiography 2012;29:438‐444)     

Trifluoperazine: a rynodine receptor agonist

Trifluoperazine (TFP), a phenothiazine, is a commonly used antipsychotic drug whose therapeutic effects are attributed to its central anti-adrenergic and anti-dopaminergic actions. However, TFP is also a calmodulin (CaM) antagonist and alters the Ca²⁺ binding properties of calsequestrin (CSQ). The CaM and CSQ proteins are known modulators of sarcoplasmic reticulum (SR) Ca²⁺ release in ventricular myocytes. We explored TFP actions on cardiac SR Ca²⁺ release in cells and single type-2 ryanodine receptor (RyR2) channel activity in bilayers. In intact and permeabilized ventricular myocytes, TFP produced an initial activation of RyR2-mediated SR Ca²⁺ release and over time depleted SR Ca²⁺ content. At the single channel level, TFP or nortryptiline (NRT; a tricyclic antidepressant also known to modify CSQ Ca²⁺ binding) increased the open probability (Po) of CSQ-free channels with an EC₅₀ of 5.2 μM or 8.9 μM (respectively). This Po increase was due to elevated open event frequency at low drug concentrations while longer mean open events sustained Po at higher drug concentrations. Activation of RyR2 by TFP occurred in the presence or absence of CaM. TFP may also inhibit SR Ca uptake as well as increase RyR2 opening. Our results suggest TFP and NRT can alter RyR2 function by interacting with the channel protein directly, independent of its actions on CSQ or CaM. This direct action may contribute to the clinical adverse cardiac side effects associated with these drugs.