16 research outputs found
Pulmonary Vascular Defects in Congenital Diaphragmatic Hernia : the quest for early factors and intervention
Congenital diaphragmatic hernia (CDH) is a severe anomaly characterized by a diaphragmatic defect, lung hypoplasia and pulmonary hypertension. The associated pulmonary abnormalities are responsible for the high morbidity and mortality among patients with this disease. Vasodilator therapy often has no effect and little is known about the possibly aberrant expressions of the targeted factors of current drugs.
In this thesis we analyzed the expression of important factors in the pulmonary vasculature of CDH patients. In human CDH lungs, we found upregulation of the endothelin A and B receptors and of the endothelin converting enzyme. The latter is a key molecule in the endothelin pathway, by converting endothelin-1 (ET-1) into its active form. Expression of the prostacyclin receptor in human control lungs gradually increased over time, but was decreased in CDH lungs in the fetal, preterm and term phases. The aberrant expressions of the above-mentioned factors could explain why treatment of pulmonary hypertension in patients with CDH fails. Furthermore, we initiated antenatal treatment with sildenafil and selexipag in the nitrofen rat model. We found that the decreased saccular airspaces had enlarged after treatment with sildenafil, and that the pulmonary vessel wall was less muscularized. Treatment with NS-304 alone was followed by improvement in the aberrant cardiac and pulmonary vascularity. Combination therapy of sildenafil and NS-304 did not have added value to each of these compounds separately.
In conclusion, our work shows important alterations already early during development in all three major vasoactive pathways in both human CDH and the well-established nitrofen rat model. Furthermore, it shows the feasibility of antenatal treatment of pulmonary vascular defects in this disease with two different vasodilators acting on the NO and PGI2 pathway. These results indicate the importance of a precision medicine approach, potentially even already starting antenatally
Pulmonary vascular development in congenital diaphragmatic hernia
Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality
Changes in vasoactive pathways in congenital diaphragmatic hernia associated pulmonary hypertension explain unresponsiveness to pharmacotherapy
Background: Patients with congenital diaphragmatic hernia (CDH) have structural and functional different pulmonary vessels, leading to pulmonary hypertension. They often fail to respond to standard vasodilator therapy targeting the major vasoactive pathways, causing a high morbidity and mortality. We analyzed whether the expression of crucial members of these vasoactive pathways could explain the lack of responsiveness to therapy in CDH patients. Methods: The expression of direct targets of current vasodilator therapy in the endothelin and prostacyclin pathway was analyzed in human lung specimens of control and CDH patients. Results: CDH lungs showed increased expression of both ETA and ETB endothelin receptors and the rate-limiting Endothelin Converting Enzyme (ECE-1), and a decreased expression of the prostaglandin-I2 receptor (PTGIR). These data were supported by increased expression of both endothelin receptors and ECE-1, endothelial nitric oxide synthase and PTGIR in the well-established nitrofen-CDH rodent model. Conclusions: Together, these data demonstrate aberrant expression of targeted receptors in the endothelin and prostacyclin pathway in CDH already early during development. The analysis of this unique patient material may explain why a significant number of patients do not respond to vasodilator therapy. This knowledge could have important implications for the choice of drugs and the design of future clinical trials internationally
First observation of the decay and a measurement of the ratio of branching fractions
The first observation of the decay using
data collected by the LHCb detector at a centre-of-mass energy of 7 TeV,
corresponding to an integrated luminosity of 36 pb, is reported. A
signal of events is obtained and the absence of signal is
rejected with a statistical significance of more than nine standard deviations.
The branching fraction is measured relative to
that of : , where the first uncertainty is statistical, the second systematic and
the third is due to the uncertainty on the ratio of the and
hadronisation fractions.Comment: 10 pages, 3 figures, submitted to Phys. Lett. B; ISSN 0370-269
Prompt K_short production in pp collisions at sqrt(s)=0.9 TeV
The production of K_short mesons in pp collisions at a centre-of-mass energy
of 0.9 TeV is studied with the LHCb detector at the Large Hadron Collider. The
luminosity of the analysed sample is determined using a novel technique,
involving measurements of the beam currents, sizes and positions, and is found
to be 6.8 +/- 1.0 microbarn^-1. The differential prompt K_short production
cross-section is measured as a function of the K_short transverse momentum and
rapidity in the region 0 < pT < 1.6 GeV/c and 2.5 < y < 4.0. The data are found
to be in reasonable agreement with previous measurements and generator
expectations.Comment: 6+18 pages, 6 figures, updated author lis
Clinically relevant timing of antenatal sildenafil treatment reduces pulmonary vascular remodeling in congenital diaphragmatic hernia
Cardiovascular Aspects of Radiolog
La censure de lâĂ©dition de langue française aux Provinces-Unies: mythe et rĂ©alitĂ©
Cardiovascular Aspects of Radiolog
First observation of Bs â J/Ïf0(980) decays
Using data collected with the LHCb detector in protonâproton collisions at a centre-of-mass energy of 7 TeV, the hadronic decay is observed. This CP eigenstate mode could be used to measure mixing-induced CP violation in the system. Using a fit to the Ï+Ïâ mass spectrum with interfering resonances gives . In the interval ±90 MeV around 980 MeV, corresponding to approximately two full f0 widths we also find , where in both cases the uncertainties are statistical and systematic, respectively
Observation of J/Ï-pair production in pp collisions at âs=7 TeV
The production of J/Ï pairs in protonâproton collisions at a centre-of-mass energy of 7 TeV has been observed using an integrated luminosity of 37.5 pbâ1 collected with the LHCb detector. The production cross-section for pairs with both J/Ï in the rapidity range 2 < yJ/Ï < 4.5 and transverse momentum pJ/Ï T <10 GeV/c is ÏJ/ÏJ/Ï =5.1±1.0±1.1 nb, where the ïŹrst uncertainty is statistical and the second systematic