The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism

Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share many risk factors, it is uncertain whether thrombophilic abnormalities may impact differently on the development of these two clinical manifestations of venous thromboembolism (VTE). To give further insight into this issue, we estimated the association of PE with different types of thrombophilia and evaluated whether these abnormalities have a different prevalence in patients presenting with PE, alone or associated with DVT, as compared with those with isolated DVT. In this study 443 consecutive patients with a first episode of VTE and 304 matched healthy controls underwent laboratory screening for thrombophilia, including natural anticoagulants, factor V Leiden and prothrombin G20210A polymorphisms, antiphospholipid antibodies, homocysteine, factor VIII, and lipoprotein(a). Of the 443 patients, 224 patients had isolated DVT, 144 had combined DVT/PE, and 75 had isolated PE. At least one thrombophilic abnormality was detected in 72.8% of DVT, 66% of DVT/EP, and 60% of isolated PE patients. A high prevalence of hyperhomocysteinemia and elevated lipoprotein(a) levels was found in all patients with no significant differences among the three groups. The prevalence of prothrombin G20210A polymorphism and of elevated factor VIII levels was significantly higher in patients with DVT and DVT/PE than in controls, but not in those with isolated PE, whereas factor V Leiden polymorphism was associated with isolated DVT but not with DVT/PE or isolated PE. In conclusion, the thrombophilic burden seems different in isolated PE versus DVT with or without PE, suggesting that PE may encompass a different pathophysiological process of thrombosis to DVT.     

ASIC proteins regulate smooth muscle cell migration

The purpose of the present study was to investigate Acid Sensing Ion Channel (ASIC) protein expression and importance in cellular migration. We recently demonstrated that Epithelial Na(+)Channel (ENaC) proteins are required for vascular smooth muscle cell (VSMC) migration; however, the role of the closely related ASIC proteins has not been addressed. We used RT-PCR and immunolabeling to determine expression of ASIC1, ASIC2, ASIC3 and ASIC4 in A10 cells. We used small interference RNA to silence individual ASIC expression and determine the importance of ASIC proteins in wound healing and chemotaxis (PDGF-bb)-initiated migration. We found ASIC1, ASIC2, and ASIC3, but not ASIC4, expression in A10 cells. ASIC1, ASIC2, and ASIC3 siRNA molecules significantly suppressed expression of their respective proteins compared to non-targeting siRNA (RISC) transfected controls by 63%, 44%, and 55%, respectively. Wound healing was inhibited by 10, 20, and 26% compared to RISC controls following suppression of ASIC1, ASIC2, and ASIC3, respectively. Chemotactic migration was inhibited by 30% and 45%, respectively, following suppression of ASIC1 and ASIC3. ASIC2 suppression produced a small, but significant, increase in chemotactic migration (4%). Our data indicate that ASIC expression is required for normal migration and may suggest a novel role for ASIC proteins in cellular migration.     

Transcriptomic immune profiles of human flavivirus-specific T-cell responses

The Flavivirus genus of viruses includes dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and West Nile (WNV) viruses. Infections with these species combined are prevalent in tropical and sub-tropical areas, affecting millions of people and ranging from asymptomatic to severe forms of the disease. They therefore pose a serious threat to global public health. Several studies imply a role for T cells in the protection but also pathogenesis against the different flavivirus species. Identifying flavivirus-specific T-cell immune profiles and determining how pre-exposure of one species might affect the immune response against subsequent infections from other species is important to further define the role of T cells in the immune response against infection. Understanding the immune profiles of the flavivirus-specific T-cell response in natural infection is important to understand the T-cell response in the context of vaccination. In this review, we summarize the current knowledge on human immune profiles of flavivirus-specific T-cell reactivity, comparing natural infection with the acute form of the disease and vaccination in different flavivirus infections.     

Relaxation induced by histamine is not endothelium dependent in tail arteries of L-NAME-treated rats

The present study was carried out to evaluate the relaxation induced by histamine in tail arteries of rats after chronic inhibition of nitric oxide (NO) synthesis with the inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) compared to tail arteries of control rats. The maximum relaxation induced by histamine was greater in control (88.09% +/-5.50, n=6) than in L-NAME arteries (47.33% +/-6.40, n=6), although pD(2) values were not different between the two groups (control: 4.89+/-0.08; L-NAME: 4.81+/-0.10). After incubation with 100 microM L-NAME in vitro, the maximum relaxation induced by histamine was only reduced in the control arteries (44.93% +/-2.35, n=6), whereas it had no effect on aortas of rats pretreated with this inhibitor. The incubation with 100 microM L-NAME had the same effect as endothelium removal in both arterial groups. Furthermore, the relaxation induced by histamine was unaffected by indomethacin. The combination of L-NAME and the histamine antagonist cimetidine completely abolished the relaxation induced by histamine in both arterial groups. These results show that when NO synthesis is impaired, the relaxation induced by histamine is endothelium independent, and when NO-synthase is active, the relaxation involves both NO released from endothelial cells and an endothelium-independent mechanism that is sensitive to cimetidine.     

A pilot study of low-dose subcutaneous alemtuzumab therapy for patients with hemotherapy-refractory chronic lymphocytic leukemia

Subcutaneous low-dose alemtuzumab (10 mg t.i.w. for 18 weeks) induced a 50% response rate, including 25% complete response, in 16 patients with refractory chronic lymphocytic leukemia (CLL) patients. The responses were substantial even in patients with unfavorable cytogenetics, fludarabine/rituximab refractoriness, Rai stage IV, previous infections, and age over 65 years. Subcutaneous low-dose alemtuzumab is effective in poor prognosis B-CLL, and has a particularly favourable toxicity profile.     

Winter air-mass-based synoptic climatological approach and hospital admissions for myocardial infarction in Florence, Italy

The aim of this study was to evaluate the relationship between the risk of hospital admission for myocardial infarction (MI) and the daily weather conditions during the winters of 1998-2003, according to an air-mass-based synoptic climatological approach. The effects of time lag and 2-day sequences with specific air mass types were also investigated. Studies concerning the relationship between atmospheric conditions and human health need to take into consideration simultaneous effects of many weather variables. At the moment few studies have surveyed these effects on hospitalizations for MI. Analyses were concentrated on winter, when the maximum peak of hospitalization occurred. An objective daily air mass classification by means of statistical analyses based on ground meteorological data was carried out. A comparison between air mass classification and hospital admissions was made by the calculation of a MI admission index, and to detect significant relationships the Mann-Whitney U test, the analysis of variance, and the Bonferroni test were used. Significant increases in hospital admissions for MI were evident 24h after a day characterized by an anticyclonic continental air mass and 6 days after a day characterized by a cyclonic air mass. Increased risk of hospitalization was found even when specific 2-day air mass sequences occurred. These results represent an important step in identifying reliable linkages between weather and health.     

Timing and significance of exercise-induced left ventricular outflow tract pressure gradients in hypertrophic cardiomyopathy

The relation of exercise-induced left ventricular (LV) outflow tract obstruction to functional capacity in hypertrophic cardiomyopathy (HC) is incompletely defined. Thus, we assessed the patterns of onset of physiologically provoked LV outflow gradients and exercise performance in 74 consecutive patients with HC (age 45 ± 16 years; 74% men) without LV outflow obstruction at rest. The subaortic gradients were measured serially using echocardiography in these 74 patients during maximum, symptom-limited, upright bicycle exercise testing. The time course of the provoked gradients and the relation to exercise performance were assessed. Of the 74 patients, 30 (41%) developed a dynamic LV outflow gradient of ≥30 mm Hg (mean 78 ± 37 mm Hg) during upright exercise testing that correlated highly with the gradients measured with the patients supine during the immediate recovery period (R2 = 0.97). The 16 patients in whom outflow obstruction developed rapidly at low exercise levels (≤5 METs) had a significantly reduced exercise capacity (6.1 ± 1.3 vs 8.0 ± 1.6 METs; p <0.01) compared to the other 14 patients in whom obstruction appeared later at greater exercise levels of >5 METs. The timing of the gradient onset was not predictable from the baseline clinical and echocardiographic features, peak exercise LV outflow tract gradient, or symptoms. In conclusion, in patients with HC without outflow obstruction at rest, the earlier onset of LV outflow tract gradients during physiologic exercise was associated with impaired exercise performance. These findings have provided insights into the determinants of functional impairment in HC and support the potential value of exercise echocardiography in the clinical assessment of patients with HC.