Survival in patients with pulmonary arterial hypertension treated with first-line bosentan

Background  Pulmonary arterial hypertension (PAH) is a devastating disease of the small pulmonary arteries and arterioles, characterized by intimal fibrosis, medial hypertrophy and plexiform lesions. When untreated both the idiopathic form (IPAH, formerly termed primary pulmonary hypertension, PPH) and PAH related to various other conditions such as scleroderma (SSc) often take a progressive course with high mortality. There is ongoing search for disease-specific treatments that are able to improve survival in these patients. The oral dual endothelin (ET A /ET B ) antagonist bosentan has been shown to improve exercise capacity, time to clinical worsening, haemodynamics and quality of life in short-term studies. Materials and methods  To determine the long-term effects of bosentan on survival, patients from the two double-blind, randomized trials and their open-label extensions, treated with first-line bosentan, were followed for up to 3 years. Data on survival were collected between September 1999 (first patient included in the placebo-controlled trials) and December 2002. Vital status was verified in each patient. The survival cohorts of these patients were compared with either the predicted survival for each patient based on an equation from the National Institutes of Health (NIH) PPH registry or with historical controls. Results  Observed survival up to 36 months was reported as a Kaplan-Meier estimate in three cohorts: (1) In 169 PPH patients treated with first-line bosentan, 1- and 2-year survival was 96% and 89%, respectively, vs. predicted untreated survival at 1 and 2 years of 69% and 57%, respectively; (2) in 50 patients with PAH associated with SSc (PAH-SSc), 1-, 2- and 3-year survival was 82%, 67% and 64%, respectively, vs. ∼45%, ∼35% and ∼28%, respectively, from registry data of untreated PAH-SSc patients; and (3) in 139 PPH patients in WHO functional class III, 1- and 2-year survival was 97% and 91%, respectively, vs. 91% and 84% in a historical cohort of 346 patients treated with epoprostenol in five major referral centres. Conclusions  The present analyses suggest that first-line bosentan therapy, followed by the addition of other disease-specific therapies as required, improves survival in patients with advanced PAH. Eur J Clin Invest 2006; 36 (Suppl. 3): 10 –15Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71978/1/j.1365-2362.2006.01688.x.pd

BC4707 Is a Major Facilitator Superfamily Multidrug Resistance Transport Protein from Bacillus cereus Implicated in Fluoroquinolone Tolerance

Transcriptional profiling highlighted a subset of genes encoding putative multidrug transporters in the pathogen Bacillus cereus that were up-regulated during stress produced by bile salts. One of these multidrug transporters (BC4707) was selected for investigation. Functional characterization of the BC4707 protein in Escherichia coli revealed a role in the energized efflux of xenobiotics. Phenotypic analyses after inactivation of the gene bc4707 in Bacillus cereus ATCC14579 suggested a more specific, but modest role in the efflux of norfloxacin. In addition to this, transcriptional analyses showed that BC4707 is also expressed during growth of B. cereus under non-stressful conditions where it may have a role in the normal physiology of the bacteria. Altogether, the results indicate that bc4707, which is part of the core genome of the B. cereus group of bacteria, encodes a multidrug resistance efflux protein that is likely involved in maintaining intracellular homeostasis during growth of the bacteria.Peer reviewe

Role of aldosterone on lung structural remodelling and right ventricular function in congestive heart failure

<p>Abstract</p> <p>Background</p> <p>The mechanisms of benefit of mineralocorticoid receptors antagonists in congestive heart failure (CHF) are still debated. We hypothesized that aldosterone contributes to pulmonary remodelling and right ventricular (RV) dysfunction associated with CHF by stimulation of lung myofibroblasts (MYFs) proliferation.</p> <p>Methods</p> <p>Rats with moderate to large myocardial infarcts (MI) and CHF were studied. Two weeks after MI, spironolactone 100 mg/kg/day (n = 21) or no treatment (n = 24) were given for 3 weeks and compared to sham (n = 8).</p> <p>Results</p> <p>Infarct size was similar by ultrasound and pathologic measures in both MI groups.</p> <p>The MI-untreated group developed important lung remodelling with nearly doubling of dry lung weight (p < 0.01), reduced left ventricular (LV) fractional shortening (16 ± 2% vs. 53 ± 1%; mean ± SEM, p < 0.0001), pulmonary hypertension (RV systolic pressure: 40 ± 3 mmHg vs. 27 ± 1 mmHg, p < 0.01) and RV hypertrophy (RV/(LV + septum): 38 ± 3% vs. 24 ± 1%, p < 0.05). Spironolactone had no effect on these parameters and did not improve LV or RV performance (tricuspid annular plane systolic excursion and RV myocardial performance index) measured by echocardiography. CHF induced a restrictive respiratory syndrome with histological lung fibrosis: this was also unaffected by spironolactone. Finally, isolated lung MYFs did not proliferate after exposure to aldosterone.</p> <p>Conclusion</p> <p>Aldosterone does not significantly contribute to pulmonary remodelling and RV dysfunction associated with CHF. Other mechanisms are responsible for the beneficial effects of spironolactone in CHF.</p

A systematic autopsy survey of human infant bridging veins

In the first years of life, subdural haemorrhage (SDH) within the cranial cavity can occur through accidental and non-accidental mechanisms as well as from birth-related injury. This type of bleeding is the most common finding in victims of abusive head trauma (AHT). Historically, the most frequent cause of SDHs in infancy is suggested to be traumatic damage to bridging veins traversing from the brain to the dural membrane. However, several alternative hypotheses have been suggested for the cause and origin of subdural bleeding. It has also been suggested by some that bridging veins are too large to rupture through the forces associated with AHT. To date, there have been no systematic anatomical studies on infant bridging veins. During 43 neonatal, infant and young child post-mortem examinations, we have mapped the locations and numbers of bridging veins onto a 3D model of the surface of a representative infant brain. We have also recorded the in situ diameter of 79 bridging veins from two neonatal, one infant and two young children at post-mortem examination. Large numbers of veins, both distant from and directly entering the dural venous sinuses, were discovered travelling between the brain and dural membrane, with the mean number of veins per brain being 54.1 and the largest number recorded as 94. The mean diameter of the bridging veins was 0.93 mm, with measurements ranging from 0.05 to 3.07 mm. These data demonstrate that some veins are extremely small and subjectively, and they appear to be delicate. Characterisation of infant bridging veins will contribute to the current understanding of potential vascular sources of subdural bleeding and could also be used to further develop computational models of infant head injury

Host preferences and differential contributions of deciduous tree species shape mycorrhizal species richness in a mixed Central European forest

Mycorrhizal species richness and host ranges were investigated in mixed deciduous stands composed of Fagus sylvatica, Tilia spp., Carpinus betulus, Acer spp., and Fraxinus excelsior. Acer and Fraxinus were colonized by arbuscular mycorrhizas and contributed 5% to total stand mycorrhizal fungal species richness. Tilia hosted similar and Carpinus half the number of ectomycorrhizal (EM) fungal taxa compared with Fagus (75 putative taxa). The relative abundance of the host tree the EM fungal richness decreased in the order Fagus > Tilia >> Carpinus. After correction for similar sampling intensities, EM fungal species richness of Carpinus was still about 30–40% lower than that of Fagus and Tilia. About 10% of the mycorrhizal species were shared among the EM forming trees; 29% were associated with two host tree species and 61% with only one of the hosts. The latter group consisted mainly of rare EM fungal species colonizing about 20% of the root tips and included known specialists but also putative non-host associations such as conifer or shrub mycorrhizas. Our data indicate that EM fungal species richness was associated with tree identity and suggest that Fagus secures EM fungal diversity in an ecosystem since it shared more common EM fungi with Tilia and Carpinus than the latter two among each other

Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension

Background: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats. Methods: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed. Results: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling. Conclusion: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension

Caveolin-1 Influences Vascular Protease Activity and Is a Potential Stabilizing Factor in Human Atherosclerotic Disease

Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery [0% vs. 4%] and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice.This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value