Introduction: Chronic kidney disease (CKD) and congestive heart failure (CHF) patients have higher serum B-type natriuretic peptide (BNP), which alters the test interpretation. We aim to define BNP cutoff levels to diagnose acute decompensated heart failure (ADHF) in CKD according to CHF subtype: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Material and methods: We reviewed 1,437 charts of consecutive patients who were admitted for dyspnea. We excluded patients with normal kidney function, without measured BNP, echocardiography, or history of CHF. BNP cutoff values to diagnose ADHF for CKD stages according to CHF subtype were obtained for the highest pair of sensitivity (Sn) and specificity (Sp). We calculated positive and negative likelihood ratios (LR+ and LR–, respectively), and diagnostic odds ratios (DOR), as well as the area under the receiver operating characteristic curves (AUC) for BNP. Results: We evaluated a cohort of 348 consecutive patients: 152 had ADHF, and 196 had stable CHF. In those with HFpEF with CKD stages 3–4, BNP < 155 pg/ml rules out ADHF (Sn90%, LR– = 0.26 and DOR = 5.75), and BNP > 670 pg/ml rules in ADHF (Sp90%, LR+ = 4 and DOR = 6), with an AUC = 0.79 (95% CI: 0.71–0.87). In contrast, in those with HFrEF with CKD stages 3–4, BNP < 412.5 pg/ml rules out ADHF (Sn90%, LR– = 0.19 and DOR = 9.37), and BNP > 1166.5 pg/ml rules in ADHF (Sp87%, LR+ = 3.9 and DOR = 6.97) with an AUC = 0.78 (95% CI: 0.69–0.86). All LRs and DOR were statistically significant. Conclusions: BNP cutoff values for the diagnosis of ADHF in HFrEF were higher than those in HFpEF across CKD stages 3–4, with moderate discriminatory diagnostic ability. / Revisión por pares

Les plantes sont de plus en plus confrontées à une diminution de la disponibilité en eau du sol, constituant une contrainte hydrique et osmotique impactant leur survie. La tolérance des plantes face à cette contrainte sera conditionnée par la perception de celle-ci. Un des mécanismes de signalisation de cette contrainte est appelé MultiStep Phosphorelay (MSP) et est composé de 3 partenaires : un récepteur Histidine-aspartate Kinase (HK), des protéines Histidine Phosphotransfert (HPt) et des Régulateurs de Réponse (RR), dont les facteurs de transcription RR-B. Chez Arabidopsis, un MSP constitué d’AHK1, AHP2 et ARR18 a été identifié dans le cadre de la contrainte osmotique. Pour le peuplier, HK1a et b, gènes paralogues et homologues à AHK1, ainsi que 10 et 9 gènes codant respectivement des HPt et des RR-B ont été isolés. La fonction d’osmosenseur d’HK1a a été avancée, et une voie de signalisation de la contrainte osmotique chez le peuplier constituée de ce récepteur, 3 HPt et 6 RR-B a été proposée. L’objectif de la thèse visait à déterminer et caractériser des facteurs de transcription RR-B liés à la contrainte osmotique de façon spécifique. Les résultats phares de cette thèse sont la mise en évidence de la fonction de facteur de transcription de deux RR-B, RR13 et RR19, via l’étude de leur capacité à dimériser et à transactiver ou non des gènes de réponses à la contrainte osmotique. Le RR13 semblerait spécifique de la voie cytokinines et le RR19 de la voie osmosensing. Ce travail étaye fortement l’implication du RR19 dans le MSP dédié à cette contrainte. De nombreuses études ont par ailleurs été initiées durant ce travail de thèse et pourront faciliter la caractérisation du MSP étudié. / Plants are increasingly faced with a decrease in soil’s water availability, leading to a hydric and osmotic stress and impacting on their survival. Plant tolerance to this stress will be dependent on its perception. One of the signaling mechanisms related to this stress is called MultiStep Phosphorelay (MSP) and is composed by 3 partners: a histidine-aspartate receptor kinase (HK), histidine phosphotransfer proteins (HPt) and response regulators (RR), including the B-type RR transcription factors. In Arabidopsis, an MSP with AHK1, AHP2 and ARR18 has been identified for osmotic stress signaling. For poplar, HK1a and b, paralogous genes and homologous with AHK1, 10 HPt and 9 B-type RR genes have been isolated respectively. The osmosensor function of HK1a was proposed, and an osmosensing signaling pathway composed by HK1a, 3 HPt proteins, and 6 B-type RR has been suggested. The purpose of this work was focused on the identification and characterization of B-type RR transcription factors specifically linked to osmotic stress in poplar. The main results of this work are the highlight of the transcription factor function of two B-type RR, RR13 and RR19, through the study of their ability to dimerize and transactivate or not osmotic stress-responsive genes. The RR13 seems to be specific for cytokinins signaling pathway, whereas the RR19 seems to be specific for the osmosensing one. This work strongly supports the involvement of RR19 in the osmosensing MSP. Many studies have also been initiated during this work and will facilitate the characterization of the studied MSP.

We present a comprehensive study of X-ray emission by, and wind properties of, massive magnetic early B-type stars. Dedicated XMM–Newton observations were obtained for three early-type B-type stars, ξ1 CMa, V2052 Oph and ζ Cas, with recently discovered magnetic fields. We report the first detection of X-ray emission from V2052 Oph and ζ Cas. The latter is one the softest X-ray sources among the early-type stars, while the former is one of the X-ray faintest. The observations show that the X-ray spectra of our programme stars are quite soft with the bulk of X-ray emitting material having a temperature of about 1 MK. We compile the complete sample of early B-type stars with detected magnetic fields to date and existing X-ray measurements, in order to study whether the X-ray emission can be used as a general proxy for stellar magnetism. We find that the X-ray properties of early massive B-type magnetic stars are diverse, and that hard and strong X-ray emission does not necessarily correlate with the presence of a magnetic field, corroborating similar conclusions reached earlier for the classical chemically peculiar magnetic Bp–Ap stars. We analyse the ultraviolet (UV) spectra of five non-supergiant B stars with magnetic fields (τ Sco, β Cep, ξ1 CMa, V2052 Oph and ζ Cas) by means of non-local thermodynamic equilibrium (non-LTE) iron-blanketed model atmospheres. The latter are calculated with the Potsdam Wolf–Rayet (PoWR) code, which treats the photosphere as well as the wind, and also accounts for X-rays. With the exception of τ Sco, this is the first analysis of these stars by means of stellar wind models. Our models accurately fit the stellar photospheric spectra in the optical and the UV. The parameters of X-ray emission, temperature and flux are included in the model in accordance with observations. We confirm the earlier findings that the filling factors of X-ray emitting material are very high. Our analysis reveals that the magnetic early-type B stars studied here have weak winds with velocities not significantly exceeding vesc. The mass-loss rates inferred from the analysis of UV lines are significantly lower than predicted by hydrodynamically consistent models. We find that, although the X-rays strongly affect the ionization structure of the wind, this effect is not sufficient in reducing the total radiative acceleration. When the X-rays are accounted for at the intensity and temperatures observed, there is still sufficient radiative acceleration to drive a stronger mass-loss than we empirically infer from the UV spectral lines.

We present a comprehensive study of X-ray emission and wind properties of magnetic early B-type stars. We compile the complete sample of early B-type stars with detected magnetic fields to date and existing X-ray measurements, in order to study whether the X-ray emission can be used as a general proxy for stellar magnetism. For the first time we analyze the UV spectra of B stars with magnetic fields by means of non-LTE iron-blanketed stellar atmosphere model that account for the X-rays at the intensity and temperatures observed. The mass-loss rates inferred from the analysis of UV lines are significantly lower than predicted by hydrodynamically consistent models. We find that the X-ray properties of early B-type magnetic stars are diverse, and that hard and strong X-ray emission does not necessarily correlate with the presence of a magnetic field.

T cells, which constitute an essential arm in the adaptive immunity, complete their development in the thymus through a process called thymopoiesis. However, thymic involution can be induced by a couple of factors, which impairs T cell functions and is slow to recover. Therefore, understanding how thymopoiesis is regulated may lead effort to accelerate thymic recovery and improve immune functions in thymocyte-depleted patients. In this project, we identified scavenger receptor BI (SR-BI), a high density lipoprotein (HDL) receptor, as a novel modulator in thymopoiesis. In mice, absence of SR-BI causes a significant reduction in thymus size after puberty and a remarkable decrease in thymic output. Consequently, SR-BI-null mice show a narrowed naïve T cell pool in the periphery and blunted T cell responses, indicating that the impaired thymopoiesis due to SR-BI deficiency leads to compromised T cell homeostasis and functions. The impaired thymopoiesis of SR-BI-null mice is featured by a significant reduction in the percentage of earliest T progenitors (ETPs) but unchanged percentages of other thymocyte subtypes, suggesting that SR-BI deficiency causes a reduction in progenitor thymic entry. Further investigations reveal that SR-BI deficiency impairs thymopoiesis through affecting bone marrow progenitor thymic homing without influencing the lymphoid progenitor development in bone marrow. Importantly, SR-BI-null mice exhibit delayed thymic recovery after sublethal irradiation, indicating that SR-BI is also required for thymic regeneration. Using bone marrow transplantation models, we elucidate that it is non-hematopoietic rather than hematopoietic SR-BI deficiency that results in the defects in thymopoiesis. However, SR-BI deficiency-induced hypercholesterolemia is not responsible for the impaired thymopoiesis. Using adrenal transplantation models, we found that absence of adrenal SR-BI is responsible for the impaired thymopoiesis, as shown by that adrenalectomized mice transplanted with SR-BI-null adrenal gland display reduced thymus size, decreased percentage of ETPs and delayed thymic regeneration compared with those transplanted with wild-type adrenal. Altogether, results from this study elucidate a previously unrecognized role of SR-BI in thymopoiesis. We reveal that SR-BI expressed in adrenal gland is critical in maintaining normal T cell development and enhancing thymic regeneration, providing novel links between adrenal functions and T cell development.

Abstract Heart failure (HF) is a complex pathological state, involving simultaneous alterations in several signalling pathways and changes in gene programming. In HF, activation of the neurohumoral factors and renin-angiotensin-aldosterone (RAA) system occurs as a compensatory mechanism to combat the abnormal ventricular function. Developments in cardiac gene delivery methods have exerted a significant impact to treat HF and to discover the novel molecular mechanisms associated with HF and other cardiac diseases. This study demonstrated that adenovirus–mediated gene delivery of B-type natriuretic peptide (BNP) into the anterior wall of the left ventricle decreased myocardial fibrosis and increased capillary density. Post-infarction BNP improved systolic function associated with normalization of cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA) 2 expression and phospholamban phosphorylation at Thr17. On the other hand, (Pro)renin receptor ([P]RR) gene delivery resulted deleterious effects on cardiac function and (P)RR activation induced distinct angiotensin II (Ang II)-independent extracellular matrix remodelling and worsening of cardiac function. (P)RR gene delivery resulted in Ang II-independent activation of extracellular-signal regulated (ERK1/2) phosphorylation and increased myocardial fibrosis. In conclusion, the present study indicates that myocardial BNP gene delivery can achieve pleiotropic, context-dependent, favourable effects on cardiac function and that BNP can act locally as a mechanical load–activated regulator of angiogenesis and fibrosis. These results also implicate that (P)RR blockers may display additional cardiac effects in addition to its ability to evoke effective RAA system blockade. Overall, the findings of this study provide a better understanding of the molecular mechanisms involved in the biological actions of BNP and (P)RR, and identify BNP and (P)RR as potential novel drug targets for the treatment of HF. / Tiivistelmä Neuroendokriinisellä aktivaatiolla, jonka seurauksena aiheutuu muun muassa verisuonten supistumista ja laajenemista sekä nesteen kertymistä elimistöön, on tärkeä merkitys sydämen vajaatoiminnan kehittymisessä. Neuroendokriininen aktivaatio kompensoi sydämen vajaatoiminnan seurauksena tapahtuvaa kammioiden poikkeavaa toimintaa. Yksi keskeisimmistä verisuonia supistavista tekijöistä on reniini-angiotensiini-aldosteroni (RAA) -järjestelmä, ja verisuonia laajentaviin tekijöihin kuuluvat muun muassa natriureettiset peptidit, kuten B-tyypin natriureettinen peptidi (BNP) ja A-tyypin natriureettinen peptidi. Geeninsiirtomenetelmillä on ollut merkittäviä vaikutuksia uusien hoitomenetelmien kehittämisessä, sydämen vajaatoiminnan syiden selvittämisessä ja uusien kohdegeenien tunnistamisessa sydämen vajaatoiminnan hoitoon. Väitöskirjan tutkimustulokset osoittivat, että suora adenovirusvälitteinen geeninsiirto rotan sydämen vasemman kammion etuseinään on toimiva menetelmä uusien kohdegeenien löytämiseksi sydämen vajaatoiminnan hoitoon. BNP:n geeninsiirto vähensi merkitsevästi fibroosin muodostumista ja lisäsi verisuonten uudismuodostumista sydämessä. Sydäninfarktin jälkeen BNP paransi sydämen systolista toimintaa, johon liittyi aktiivisen kalsiumpumpun, SERCA2:n ja fosfolambaani-proteiinin fosforylaation normalisoituminen. (Pro)reniini reseptorin ([P]RR) geeninsiirto aiheutti angiotensiini II:sta riippumatonta solunulkoisen matriksin uudelleenmuotoutumista ja sydämen toiminnan huonontumista sekä lisääntynyttä sydämen fibroosia. Väitöskirjatutkimus antaa uutta tietoa solunsisäisistä molekulaarisista mekanismeista sydänsoluissa. BNP geeninsiirto aiheutti sydämen tautitilasta riippuvia suotuisia tapahtumia, ja se toimi paikallisesti muun muassa fibroosia ehkäisevänä tekijänä. (P)RR geeninsiirtotulosten perusteella voidaan olettaa, että (P)RR:n salpaus saattaa olla uusi tehokas hoitokeino sydämen vajaatoiminnan hoitoon.

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A two-dimensional hydrodynamic numerical model is extended and applied to simulate the interaction between stellar winds and the interstellar medium (ISM). In particular, the stellar wind evolution of O- and B-type stars is calculated. First, the evolution of a stellar wind into the ambient interstellar medium and also a more dense molecular cloud are considered for the case of no relative motion between the star and the interstellar medium. This interaction results in a cavity being blown into the ISM. Of importance in this work is the boundary radius (astropause) of the stellar wind and also the location where the outflow speed decreases from supersonic to subsonic speeds, called the termination shock. Different parameters like ISM density, outflow speed and mass-loss rate were varied to study the effect these have on the computed astropause (AP) and termination shock (TS) radii. The evolution of these structures is presented up to a simulation time of 1 My. However, stars are not stationary relative to the ISM, and the evolution of stellar winds into the interstellar medium including relative motion is also considered. It is shown that the positions of the TS and AP are dependent on the mass-loss rate and stellar wind outflow speed of the star and the interstellar medium density and relative speed. When these massive stars reach the end of their life, they end their life in a supernova explosion. The explosion results in a blast wave moving outward, called the forward shock (FS) and a reverse shock (RS) also forms which moves inward. Previous work done by Ferreira and de Jager (2008) to simulate supernova remnant (SNR) evolution, was only done for the case of evolution into the undisturbed ISM (no cavity). In this work, the evolution of SNR is simulated taking also into account the pre-existing cavity blown out by the stellar winds of these massive stars. The results of this study showed that the evolution of the SNR is definitely influenced by the presence of a stellar wind cavity even if the cavity is only a few pc in extent. / Thesis (MSc (Space Physics))--North-West University, Potchefstroom Campus, 2011.

A two-dimensional hydrodynamic numerical model is extended and applied to simulate the interaction between stellar winds and the interstellar medium (ISM). In particular, the stellar wind evolution of O- and B-type stars is calculated. First, the evolution of a stellar wind into the ambient interstellar medium and also a more dense molecular cloud are considered for the case of no relative motion between the star and the interstellar medium. This interaction results in a cavity being blown into the ISM. Of importance in this work is the boundary radius (astropause) of the stellar wind and also the location where the outflow speed decreases from supersonic to subsonic speeds, called the termination shock. Different parameters like ISM density, outflow speed and mass-loss rate were varied to study the effect these have on the computed astropause (AP) and termination shock (TS) radii. The evolution of these structures is presented up to a simulation time of 1 My. However, stars are not stationary relative to the ISM, and the evolution of stellar winds into the interstellar medium including relative motion is also considered. It is shown that the positions of the TS and AP are dependent on the mass-loss rate and stellar wind outflow speed of the star and the interstellar medium density and relative speed. When these massive stars reach the end of their life, they end their life in a supernova explosion. The explosion results in a blast wave moving outward, called the forward shock (FS) and a reverse shock (RS) also forms which moves inward. Previous work done by Ferreira and de Jager (2008) to simulate supernova remnant (SNR) evolution, was only done for the case of evolution into the undisturbed ISM (no cavity). In this work, the evolution of SNR is simulated taking also into account the pre-existing cavity blown out by the stellar winds of these massive stars. The results of this study showed that the evolution of the SNR is definitely influenced by the presence of a stellar wind cavity even if the cavity is only a few pc in extent. / Thesis (MSc (Space Physics))--North-West University, Potchefstroom Campus, 2011.