Effects of bisoprolol fumarate on left ventricular size, function, and exercise capacity in patients with heart failure: analysis with magnetic resonance myocardial tagging.

BACKGROUND: Recent data suggest that beta-blockers can be beneficial in subgroups of patients with chronic heart failure (CHF). For metoprolol and carvedilol, an increase in ejection fraction has been shown and favorable effects on the myocardial remodeling process have been reported in some studies. We examined the effects of bisoprolol fumarate on exercise capacity and left ventricular volume with magnetic resonance imaging (MRI) and applied a novel high-resolution MRI tagging technique to determine myocardial rotation and relaxation velocity. METHODS: Twenty-eight patients (mean age, 57 +/- 11 years; mean ejection fraction, 26 +/- 6%) were randomized to bisoprolol fumarate (n = 13) or to placebo therapy (n = 15). The dosage of the drugs was titrated to match that of the the Cardiac Insufficiency Bisoprolol Study protocol. Hemodynamic and gas exchange responses to exercise, MRI measurements of left ventricular end-systolic and end-diastolic volumes and ejection fraction, and left ventricular rotation and relaxation velocities were measured before the administration of the drug and 6 and 12 months later. RESULTS: After 1 year, heart rate was reduced in the bisoprolol fumarate group both at rest (81 +/- 12 before therapy versus 61 +/- 11 after therapy; P <.01) and peak exercise (144 +/- 20 before therapy versus 127 +/- 17 after therapy; P <.01), which indicated a reduction in sympathetic drive. No differences were observed in heart rate responses in the placebo group. No differences were observed within or between groups in peak oxygen uptake, although work rate achieved was higher (117.9 +/- 36 watts versus 146.1 +/- 33 watts; P <.05) and exercise time tended to be higher (9.1 +/- 1.7 minutes versus 11.4 +/- 2.8 minutes; P =.06) in the bisoprolol fumarate group. A trend for a reduction in left ventricular end-diastolic volume (-54 mL) and left ventricular end-systolic volume (-62 mL) in the bisoprolol fumarate group occurred after 1 year. Ejection fraction was higher in the bisoprolol fumarate group (25.0 +/- 7 versus 36.2 +/- 9%; P <.05), and the placebo group remained unchanged. Most changes in volume and ejection fraction occurred during the latter 6 months of treatment. With myocardial tagging, insignificant reductions in left ventricular rotation velocity were observed in both groups, whereas relaxation velocity was reduced only after bisoprolol fumarate therapy (by 39%; P <.05). CONCLUSION: One year of bisoprolol fumarate therapy resulted in an improvement in exercise capacity, showed trends for reductions in end-diastolic and end-systolic volumes, increased ejection fraction, and significantly reduced relaxation velocity. Although these results generally confirm the beneficial effects of beta-blockade in patients with chronic heart failure, they show differential effects on systolic and diastolic function.

Abnormalities of sodium excretion and other disorders of renal function in fulminant hepatic failure

Renal function was evaluated in 40 patients with fulminant hepatic failure, They were divided into two groups on the basis of glomerular filtration rates greater than 40 ml/min or less than 25 ml/min. A number of patients in group 1 had markedly abnormal renal retention of sodium together with a reduced free water clearance and low potassium excretion which could be explained by increased proximal tubular reabsorption of sodium. The patients in group 2 had evidence that renal tubular integrity was maintained when the glomerular filtration rate was greater than or equal ml/min (functional renal failure), but evidence of tubular damage was present when this was less than 3 ml/min (acute tubular necrosis).

Sequencing of Lp-PLA2-encoding PLA2G7 gene in 2000 Europeans reveals several rare loss-of-function mutations.

Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8±63.2 vs 204.6±41.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor.

Dry matter production of Tanzania grass as a function of agrometeorological variables

The objective of this work was to develop and validate linear regression models to estimate the production of dry matter by Tanzania grass (Megathyrsus maximus, cultivar Tanzania) as a function of agrometeorological variables. For this purpose, data on the growth of this forage grass from 2000 to 2005, under dry‑field conditions in São Carlos, SP, Brazil, were correlated to the following climatic parameters: minimum and mean temperatures, degree‑days, and potential and actual evapotranspiration. Simple linear regressions were performed between agrometeorological variables (independent) and the dry matter accumulation rate (dependent). The estimates were validated with independent data obtained in São Carlos and Piracicaba, SP, Brazil. The best statistical results in the development and validation of the models were obtained with the agrometeorological parameters that consider thermal and water availability effects together, such as actual evapotranspiration, accumulation of degree‑days corrected by water availability, and the climatic growth index, based on average temperature, solar radiation, and water availability. These variables can be used in simulations and models to predict the production of Tanzania grass.

TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease.

T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A-DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A(-/-) dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A(-/-) animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A-DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

CO2-response function of radiation use efficiency in rice for climate change scenarios

The objective of this work was to evaluate a generalized response function to the atmospheric CO2 concentration [f(CO2)] by the radiation use efficiency (RUE) in rice. Experimental data on RUE at different CO2 concentrations were collected from rice trials performed in several locations around the world. RUE data were then normalized, so that all RUE at current CO2 concentration were equal to 1. The response function was obtained by fitting normalized RUE versus CO2 concentration to a Morgan-Mercer-Flodin (MMF) function, and by using Marquardt's method to estimate the model coefficients. Goodness of fit was measured by the standard deviation of the estimated coefficients, the coefficient of determination (R²), and the root mean square error (RMSE). The f(CO2) describes a nonlinear sigmoidal response of RUE in rice, in function of the atmospheric CO2 concentration, which has an ecophysiological background, and, therefore, renders a robust function that can be easily coupled to rice simulation models, besides covering the range of CO2 emissions for the next generation of climate scenarios for the 21st century.

Regulation of mass and function of pancreatic β-cells: identification of anti-apoptotic peptides and role of GLP-1

Résumé La masse de cellules β sécrétrices d'insuline est un tissu dynamique qui s'adapte aux variations de la demande métabolique pour assurer une normoglycémie. Cette adaptation se fait par un changement de sécrétion d'insuline et de la masse totale des cellules β. Une perte complète ou partielle des cellules β conduit respectivement à un diabète de type 1 et de type 2. Les mécanismes qui régulent la masse de cellules β et maintiennent leur phénotype differencié sont encore peu connus. Leur identification est nécessaire pour comprendre le développement du diabète et développer des stratégies de traitement. La greffe d'îlots est une approche thérapeutique prometteuse pour le diabète de type 1, mais est limitée par une perte précoce des cellules β due à une apoptose induite par des cytokines. Afin d'améliorer la survie des cellules β lors de la greffe d'îlots, le premier but était de trouver des peptides pouvant bloquer l'apoptose induite par FasL et TNF-α. Pour ce faire, deux librairies de phages ont été criblées pour sélectionner des peptides se liant au Fas DD ou au TNFRl DD. Nous avons identifié six peptides différents. Cependant, aucun d'entre eux n'était capable de protéger les cellules de l'apoptose induite par FasL ou TNF-α. Deuxièmement, le GLP-1 est une hormone qui stimule la sécrétion d'insuline, et est impliquée dans la prolifération des cellules β, la différentiation, et inhibe l'apoptose. Nous avons fait l'hypothèse que le GLP-1 joue un rôle crucial dans le contrôle de la masse et de la fonction des cellules β. Afin de l'évaluer, une analyse par puce à ADN a été réalisée en comparant des cellules βTC-Tet traitées avec du GLP-1 à des cellules non-traitées. 376 gènes régulés ont été identifiés, dont RGS2, CREM, ICERI et DUSP14, augmentés significativement par le GLP-1. Nous avons confirmé que le GLP-1 augmente l'expression de ces gènes, aussi bien au niveau des transcripts que des protéines. De plus, nous avons montré que le GLP-1 induit leur expression par activation de la voie cAMP/PKA, et nécessite l'entrée de calcium extracellulaire. D'après leur fonction biologique, nous avons ensuite supposé que ces gènes pourraient agir comme régulateurs négatifs de la signalisation du GLP-l, et donc freiner son effet proliférateur. Pour vérifier notre hypothèse, des siRNAs contre ces gènes ont été développés, et leurs effets sur la prolifération des cellules β seront évalués ultérieurement. Abstract The pancreatic β-cell mass is a dynamic tissue which adapts to variations in metabolic demand in order to ensure normoglycemia. This adaptation occurs through a change in both insulin secretion and the total mass of ,β-cells. An absolute or relative loss of β-cells leads to type 1 and type 2 diabetes, respectively. The mechanisms that regulate the pancreatic β-cell mass and maintain the fully differentiated phenotype of the insulin-secreting β-cells are only poorly defined. Their identification is required to understand the progression of diabetes, but also to design strategies for the treatment of diabetes. Islet transplantation is a promising therapeutic approach for type 1 diabetes, but it is still limited by an early graft loss due to cytokine-induced apoptosis. In order to improve β-cell survival during islet transplantation, our first goal was to find novel blockers of FasL- and TNF-α-mediated cell death in the form of peptides. To that end, we screened two phage display libraries to select Fas DD- or TNFR1 DD-binding peptides. We identified six different small peptides. However, none of these peptides was able to prevent cells from FasL- or TNF-α-mediated apoptosis. Secondly, GLP-1 is a hormone that has been shown to stimulate insulin secretion and to be involved in β-cell proliferation, differentiation and inhibition of apoptosis. We hypothesized that GLP-1 plays a crucial role to control mass and function of β-cells. To evaluate this hypothesis, we performed a cDNA microarray analysis with GLP-1-treated βTC-Tet cells compared to untreated cells. We found 376 regulated genes, among these, RGS2, CREM, ICERI and DUSP14, which were significantly upregulated by GLP-1. We confirmed that both their mRNA and protein levels were strongly and rapidly increased after GLP-1 treatment. Moreover, we found that GLP-1 activates their expression mainly through the activation of the cAMP/PKA signaling pathway, and requires extracellular calcium entry. According to their biological function, we then hypothesized that these genes might act as negative regulators of the GLP-1 signaling. In particular, they might brake the effects of GLP-1 on β-cell proliferation. To verify this hypothesis, siRNAs against these genes were developed. The effect of these siRNAs on GLP-1-induced β-cell proliferation will be evaluated later.

Structure function relationships of ENaC and its role in sodium handling.

The epithelial sodium channel (ENaC) in the apical membrane of polarized epithelial cells is the rate-limiting step for Na entry into the cell; in series with the basolateral Na pump, it allows the vectorial transepithelial transport of Na ions. ENaC is expressed in different epithelia like the distal nephron or colon, and the airways epithelium. In the lung ENaC controls the composition and the amount of pulmonary fluid, whereas in the distal nephron ENaC under the control of aldosterone and vasopressin, is essential to adapt the amount of Na+ reabsorbed with the daily sodium intake. Activating mutations of ENaC cause severe disturbances of Na+ homeostasis leading to hypertension in human and in mouse models. Functional expression of ENaC in different cell systems allowed the identification of structural domains of the protein that are essential for channel function and/or modulation of channel activity. Site-directed mutations in specific domains of the channel protein lead to channel hyperactivity or channel loss of function. Knowledge about ENaC structure-function relationships opens new opportunities for development of pharmacological tools for controlling ENaC activity, such as channel activators of potential benefit in the treatment of pulmonary edema, or highly potent ENaC blockers with natriuretic effects.

CCL21 is sufficient to mediate DC migration, maturation and function in the absence of CCL19.

Mice deficient in CCR7 signals show severe defects in lymphoid tissue architecture and immune response. These defects are due to impaired attraction of CCR7+ DC and CCR7+ T cells into the T zones of secondary lymphoid organs and altered DC maturation. It is currently unclear which CCR7 ligand mediates these processes in vivo as CCL19 and CCL21 show an overlapping expression pattern and blocking experiments have given contradictory results. In this study, we addressed this question using CCL19-deficient mice expressing various levels of CCL21. Complete deficiency of CCL19 and CCL21 but not CCL19 alone was found to be associated with abnormal frequencies and localization of DC in naïve LN. Similarly, CCL19 was not required for DC migration from the skin, full DC maturation and efficient T-cell priming. Our findings suggest that CCL21 is the critical CCR7 ligand regulating DC homeostasis and function in vivo with CCL19 being redundant for these processes.

Palliative surgical procedures to restore shoulder function in obstetric brachial palsy. Critical analysis of Narakas' series.

Dr. Narakas intended to study a series of 61 cases of shoulder sequelae of obstetric palsy. His vast experience would have enriched our clinical knowledge of this ailment. The authors carry on with that study to clarify his therapeutic approach and share the benefit of his experience.

Connexins: key mediators of endocrine function.

The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their function. Some of these mechanisms depend on the intercellular diffusion of signal molecules in the extracellular spaces, whereas others require cell-to-cell contact. Among the latter mechanisms, those provided by the proteins of the connexin family are widespread in most tissues. Connexin signaling is achieved via direct exchanges of cytosolic molecules between adjacent cells at gap junctions, for cell-to-cell coupling, and possibly also involves the formation of membrane "hemi-channels," for the extracellular release of cytosolic signals, direct interactions between connexins and other cell proteins, and coordinated influence on the expression of multiple genes. Connexin signaling appears to be an obligatory attribute of all multicellular exocrine and endocrine glands. Specifically, the experimental evidence we review here points to a direct participation of the Cx36 isoform in the function of the insulin-producing β-cells of the endocrine pancreas, and of the Cx40 isoform in the function of the renin-producing juxtaglomerular epithelioid cells of the kidney cortex.

Real-time MR imaging of myocardial regional function using strain-encoding (SENC) with tissue through-plane motion tracking.

PURPOSE: To implement real-time myocardial strain-encoding (SENC) imaging in combination with tracking the tissue displacement in the through-plane direction. MATERIALS AND METHODS: SENC imaging was combined with the slice-following technique by implementing three-dimensional (3D) selective excitation. Certain adjustments were implemented to reduce scan time to one heartbeat. A total of 10 volunteers and five pigs were scanned on a 3T MRI scanner. Spatial modulation of magnetization (SPAMM)-tagged images were acquired on planes orthogonal to the SENC planes for comparison. Myocardial infarction (MI) was induced in two pigs and the resulting SENC images were compared to standard delayed-enhancement (DE) images. RESULTS: The strain values computed from SENC imaging with slice-following showed significant difference from those acquired without slice-following, especially during systole (P < 0.01). The strain curves computed from the SENC images with and without slice-following were similar to those computed from the orthogonal SPAMM images, with and without, respectively, tracking the tag line displacement in the strain direction. The resulting SENC images showed good agreement with the DE images in identifying MI in infarcted pigs. CONCLUSION: Correction of through-plane motion in real-time cardiac functional imaging is feasible using slice-following. The strain measurements are more accurate than conventional SENC measurements in humans and animals, as validated with conventional MRI tagging.

The effects of losartan on renal function in the newborn rabbit.

The low GFR of newborns is maintained by various factors including the renin-angiotensin system. We previously established the importance of angiotensin II in the newborn kidney, using the angiotensin-converting enzyme inhibitor perindoprilat. The present study was designed to complement these observations by evaluating the role of angiotensin-type 1 (AT(1)) receptors, using losartan, a specific AT(1)-receptor blocker. Increasing doses of losartan were infused into anesthetized, ventilated, newborn rabbits. Renal function and hemodynamic variables were assessed using inulin and para-aminohippuric acid clearances as markers of GFR and renal plasma flow, respectively. Losartan 0.1 mg/kg slightly decreased mean blood pressure (-11%) and increased diuresis (+22%). These changes can be explained by inhibition of the AT(1)-mediated vasoconstrictive and antidiuretic effects of angiotensin, and activation of vasodilating and diuretic AT(2) receptors widely expressed in the neonatal period. GFR and renal blood flow were not modified. Losartan 0.3 mg/kg decreased mean blood pressure significantly (-15%), probably by inhibiting systemic AT(1) receptors. GFR significantly decreased (-25%), whereas renal blood flow remained stable. The decrease in filtration fraction (-21%) indicates predominant efferent vasodilation. At 3 mg/kg, the systemic hypotensive effect of losartan was marked (mean blood pressure, -28%), with decreased GFR and renal blood flow (-57% and -51%, respectively), a stable filtration fraction, and an increase in renal vascular resistance by 124%. The renal response to this dose can be considered as reflex vasoconstriction of afferent and efferent arterioles, rather than specific receptor antagonism. We conclude that under physiologic conditions, the renin-angiotensin is critically involved in the maintenance of GFR in the immature kidney.