Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system.

Interactions between sodium and calcium regulating systems are poorly characterized but clinically important. Parathyroid hormone (PTH) levels are increased shortly after furosemide treatment by an unknown mechanism, and this effect is blunted by the previous administration of a calcimimetic in animal studies. Here, we explored further the possible underlying mechanisms of this observation in a randomized crossover placebo-controlled study performed in 18 human males. Volunteers took either cinacalcet (60 mg) or placebo and received a 20 mg furosemide injection 3 h later. Plasma samples were collected at 15-min intervals and analyzed for intact PTH, calcium, sodium, potassium, magnesium, phosphate, plasma renin activity (PRA), and aldosterone up to 6 h after furosemide injection. Urinary electrolyte excretion was also monitored. Subjects under placebo presented a sharp increase in PTH levels after furosemide injection. In the presence of cinacalcet, PTH levels were suppressed and marginal increase of PTH was observed. No significant changes in electrolytes and urinary excretion were identified that could explain the furosemide-induced increase in PTH levels. PRA and aldosterone were stimulated by furosemide injection but were not affected by previous cinacalcet ingestion. Expression of NKCC1, but not NKCC2, was found in parathyroid tissue. In conclusion, our results indicate that furosemide acutely stimulates PTH secretion in the absence of any detectable electrolyte changes in healthy adults. A possible direct effect of furosemide on parathyroid gland needs further studies.

Cardiologie [Cardiology update in 2014].

Important clinical trials and therapeutic advances in the field of cardiology have been presented in 2014. New evidences on the management of acute myocardial infarction and the duration of dual antiplatelet therapy after coronary stent implantation have been published. A new class of therapeutic agents seems to offer promising perspectives for patients with heart failure and reduced ejection fraction. The new generation of subcutaneous or MRI-compatible implantable defibrillators is a major technological breakthrough. Finally, the European Society of Cardiology published new recommendations for the management of patients with cardiovascular diseases. This selective review of the literature summarizes the most important studies in the field of interventional cardiology, rhythmology, heart failure and cardiac imaging.

Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes.

AIMS: We aimed to assess the prevalence and management of clinical familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS). METHODS AND RESULTS: We studied 4778 patients with ACS from a multi-centre cohort study in Switzerland. Based on personal and familial history of premature cardiovascular disease and LDL-cholesterol levels, two validated algorithms for diagnosis of clinical FH were used: the Dutch Lipid Clinic Network algorithm to assess possible (score 3-5 points) or probable/definite FH (>5 points), and the Simon Broome Register algorithm to assess possible FH. At the time of hospitalization for ACS, 1.6% had probable/definite FH [95% confidence interval (CI) 1.3-2.0%, n = 78] and 17.8% possible FH (95% CI 16.8-18.9%, n = 852), respectively, according to the Dutch Lipid Clinic algorithm. The Simon Broome algorithm identified 5.4% (95% CI 4.8-6.1%, n = 259) patients with possible FH. Among 1451 young patients with premature ACS, the Dutch Lipid Clinic algorithm identified 70 (4.8%, 95% CI 3.8-6.1%) patients with probable/definite FH, and 684 (47.1%, 95% CI 44.6-49.7%) patients had possible FH. Excluding patients with secondary causes of dyslipidaemia such as alcohol consumption, acute renal failure, or hyperglycaemia did not change prevalence. One year after ACS, among 69 survivors with probable/definite FH and available follow-up information, 64.7% were using high-dose statins, 69.0% had decreased LDL-cholesterol from at least 50, and 4.6% had LDL-cholesterol ≤1.8 mmol/L. CONCLUSION: A phenotypic diagnosis of possible FH is common in patients hospitalized with ACS, particularly among those with premature ACS. Optimizing long-term lipid treatment of patients with FH after ACS is required.

Implantation de valve aortique par voie transcatheter (TAVI): update sur les indications [Transcatheter aortic valve implantation (TAVI): update on the indications].

Although surgical aortic valve replacement has been the standard of care for patient with severe aortic stenosis, transcatheter aortic valve implantation (TAVI) is now a fair standard of care for patients not eligible or high risk for surgical treatment. The decision of therapeutic choice between TAVI and surgery considers surgical risk (estimated by the Euro-SCORE and STS-PROM) as well as many parameters that go beyond the assessment of the valvular disease's severity by echocardiography: a multidisciplinary assessment in "Heart Team" is needed to assess each case in all its complexity.

Acid-sensing ion channel 1a drives AMPA receptor plasticity following ischemia and acidosis in hippocampal CA1 neurons

The CA1 region of the hippocampus is particularly vulnerable to ischemic damage. While NMDA receptors play a major role in excitotoxicity, it is thought to be exacerbated in this region by two forms of post-ischemic AMPA receptor (AMPAR) plasticity - namely, anoxic long-term potentiation (a-LTP), and a delayed increase in the prevalence of Ca2+ -permeable GluA2-lacking AMPARs (CP-AMPARs). The acid-sensing ion channel 1a (ASIC1a) which is expressed in CA1 pyramidal neurons, is also known to contribute to post-ischemic neuronal death and to physiologically induced LTP. This raises the question - does ASIC1a activation drive the post-ischemic forms of AMPAR plasticity in CA1 pyramidal neurons? We have tested this by examining organotypic hippocampal slice cultures (OHSCs) exposed to oxygen glucose deprivation (OGD), and dissociated cultures of hippocampal pyramidal neurons (HPN) exposed to low pH (acidosis). We find that both a-LTP and the delayed increase in the prevalence of CP-AMPARs are dependent on ASIC1a activation during ischemia. Indeed, acidosis alone is sufficient to induce the increase in CP-AMPARs. We also find that inhibition of ASIC1a channels circumvents any potential neuroprotective benefit arising from block of CP-AMPARs. By demonstrating that ASIC1a activation contributes to post-ischemic AMPAR plasticity, our results identify a functional interaction between acidotoxicity and excitotoxicity in hippocampal CA1 cells, and provide insight into the role of ASIC1a and CP-AMPARs as potential drug targets for neuroprotection. We thus propose that ASIC1a activation can drive certain forms of CP-AMPAR plasticity, and that inhibiting ASIC1a affords neuroprotection.

Impaired aldehyde dehydrogenase 1 subfamily member 2A-dependent retinoic acid signaling is related with a mesenchymal-like phenotype and an unfavorable prognosis of head and neck squamous cell carcinoma.

BACKGROUND: An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far. METHODS: Serial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model. RESULTS: Immunohistochemical analysis showed an improved prognosis of ALDH1A2(high) OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2(high)CRABP2(high) staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal-like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression. CONCLUSIONS: This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2(low) tumors might benefit from adjuvant treatment with retinoids.

Comparative Effect of a Renin Inhibitor and a Thiazide Diuretic on Renal Tissue Oxygenation in Hypertensive Patients.

BACKGROUND/AIMS: The purpose of the present study was to compare the direct renin inhibitor aliskiren to the diuretic hydrochlorothiazide (HCTZ) in their ability to modulate renal tissue oxygenation in hypertensive patients. METHODS: 24 patients were enrolled in this randomized prospective study and 20 completed the protocol. Patients were randomly assigned to receive either aliskiren 150-300 mg/d or HCTZ 12.5 - 25 mg/d for 8 weeks. Renal oxygenation was measured by BOLD-MRI at weeks 0 and 8. BOLD-MRI was also performed before and after an i.v. injection of 20 mg furosemide at week 0 and at week 8. BOLD-MRI data were analyzed by measuring the oxygenation in 12 computed layers of the kidney enabling to asses renal oxygenation according to the depth within the kidney and by the classical method of regions of interest (ROI). RESULTS: The classical ROI analysis of the data showed no difference between the groups at week 8. The analysis of renal oxygenation according to the 12 layers method shows no significant difference between aliskiren and HCTZ at week 8 before administration of furosemide. However, within group analyses show that aliskiren slightly but not significantly increased oxygenation in the cortex and decreased medullary oxygenation whereas HCTZ induced a significant overall decrease in renal tissue oxygenation. With the same method of analysis we observed that the response to furosemide was unchanged in the HCTZ group at week 8 but was characterized by an increase in both cortical and medullary oxygenation in aliskiren-treated patients. Patients responding to aliskiren and HCTZ by a fall in systolic blood pressure of >10 mmHg improved their renal tissue oxygenation when compared to non-responders. CONCLUSION: With the classical method of evaluation using regions no difference were found between aliskiren and HCTZ on renal tissue oxygenation after 8 weeks. In contrast, with our new method that takes into account the entire kidney, within group analyses show that aliskiren slightly increases cortical and medullary renal tissue oxygenation in hypertensive patients whereas HCTZ decreases significantly renal oxygenation at trough.

Quand la culture entre dans les recherches en psychologie du développement

Dans la psychologie dévelopementale proposée par Jérôme Bruner, la question de la " culture " se traduit par l'attention particulière donnée aux processus par lesquels une personne rend signifiante la situation dans laquelle elle est engagée. De fait, dans la psychologie du développement de ces cinquante dernières années, la place de la " culture " varie parallèlement à celle des questions du sens (privé) et de la signification (partagée) des connaissances, des actions et des objets de culture. Dans cet article, nous identifions quatre traditions de travaux qui abordent la " culture " dans le développement. Cela met en évidence certains problèmes théoriques et méthodologiques, et nous permet de souligner certains enjeux actuels de la psychologie sociale et culturelle du développement.

Les paradoxes de l'argumentation en contexte d'éducation : s'accorder sur les désaccords. Analyse d'interactions argumentatives dans un dispositif de formation en psychologie à l'Université

Dans le chapitre « Les paradoxes de l'argumentation en contexte d'éducation: s'accorder sur les désaccords », Muller Mirza part de l'idée qu'à la différence des situations ordinaires de désaccords, les dispositifs utilisant l'argumentation dans des contextes d'éducation demandent aux participants précisément de résoudre ces désaccords. Leur sont donc interdites, par contrat plus ou moins implicite, les échappatoires auxquelles nous recourons volontiers dans les discours quotidiens qui permettent d'éviter de problématiser la question en discussion. C'est dire qu'elle aborde directement une difficulté souvent signalée dans les études sur l'argumentation en contexte éducatif : la tension entre d'une part l'expression de points de vue différents, étape nécessaire à la construction des connaissances, et d'autre part la préservation de la relation entre les interlocuteurs, de leurs faces. Le chapitre propose comme objet de discussion le rôle de cette tension dans des situations d'apprentissage en analysant des productions argumentatives réalisées dans le cadre d'un dispositif particulier. Il invite ainsi à une réflexion non seulement sur les ingrédients des dispositifs pédagogiques qui permettraient de prendre en compte cette tension mais aussi sur les méthodes d'analyse des interactions argumentatives. L'étude de cas met en scène des étudiants de master en psychologie sociale, dans le cadre d'un jeu de rôle : ils sont placés dans la perspective de leur futur métier, et figurent des psychologues conseillant des éducateurs face à des jeunes qui utilisent des insultes racistes entre eux. Le dispositif mis en oeuvre satisfait quatre exigences d'ordre théorique, favorables selon l'auteure à une bonne résolution des désaccords : le ménagement des faces des interlocuteurs en fixant des rôles ne correspondant pas nécessairement aux positions de chacun ; la construction de connaissances,préalable à la discussion ; la médiation de l'échange par un outil, ici un « chat », qui permet d'échanger les points de vue et d'apporter une dimension réflexive en cours d'interaction sur les points de vue exprimés ; le fait de donner du sens à l'activité, en simulant une situation professionnelle potentielle. L'analyse des échanges a été réalisée sur onze corpus constitués par les étudiants en petits groupes de trois ou quatre travaillant sur un logiciel de « chat ». Les questions abordées étaient les suivantes : Comment les interlocuteurs négocient-ils les désaccords qui apparaissent au cours des échanges? Ces désaccords sont-ils propices à une problématisation? Les participants mettent-ils en oeuvre des dynamiques d'« exploration » du désaccord relevé? Cette analyse, inspirée d'une approche socioculturelle reprise en partie des travaux de Neil Mercer sur les « discours exploratoires », met en évidence des dynamiques argumentatives de qualité au cours desquels les désaccords sont non seulement exprimés mais également problématisés au sein des groupes. Elle met entre autres en évidence que le sens de l'activité pour les étudiants est en partie tributaire d'un contrat didactique et pédagogique : leurs échanges sont la base de leur évaluation universitaire. Néanmoins la similitude entre situation d'enseignement et situation professionnelle a largement été perçue par les étudiants et motivante pour eux, ce qui a certainement concouru également à la qualité des échanges.