Sustained 24-hour blockade of the renin-angiotensin system: a high dose of a long-acting blocker is as effective as a lower dose combined with an angiotensin-converting enzyme inhibitor.

Whether a higher dose of a long-acting angiotensin II receptor blocker (ARB) can provide as much blockade of the renin-angiotensin system over a 24-hour period as the combination of an angiotensin-converting enzyme inhibitor and a lower dose of ARB has not been formally demonstrated so far. In this randomized double-blind study we investigated renin-angiotensin system blockade obtained with 3 doses of olmesartan medoxomil (20, 40, and 80 mg every day) in 30 normal subjects and compared it with that obtained with lisinopril alone (20 mg every day) or combined with olmesartan medoxomil (20 or 40 mg). Each subject received 2 dose regimens for 1 week according to a crossover design with a 1-week washout period between doses. The primary endpoint was the degree of blockade of the systolic blood pressure response to angiotensin I 24 hours after the last dose after 1 week of administration. At trough, the systolic blood pressure response to exogenous angiotensin I was 58% +/- 19% with 20 mg lisinopril (mean +/- SD), 58% +/- 11% with 20 mg olmesartan medoxomil, 62% +/- 16% with 40 mg olmesartan medoxomil, and 76% +/- 12% with the highest dose of olmesartan medoxomil (80 mg) (P = .016 versus 20 mg lisinopril and P = .0015 versus 20 mg olmesartan medoxomil). With the combinations, blockade was 80% +/- 22% with 20 mg lisinopril plus 20 mg olmesartan medoxomil and 83% +/- 9% with 20 mg lisinopril plus 40 mg olmesartan medoxomil (P = .3 versus 80 mg olmesartan medoxomil alone). These data demonstrate that a higher dose of the long-acting ARB olmesartan medoxomil can produce an almost complete 24-hour blockade of the blood pressure response to exogenous angiotensin in normal subjects. Hence, a higher dose of a long-acting ARB is as effective as a lower dose of the same compound combined with an angiotensin-converting enzyme inhibitor in terms of blockade of the vascular effects of angiotensin.

La chirurgie combinée phacoémulsification/pelage de membrane épirétinienne et oedème maculaire [Combined phacoemulsification/membrane resection and macular edema].

PURPOSE: To evaluate the occurrence of macular edema (ME) after epiretinal membrane resection, managed either with simple vitrectomy or with combined vitrectomy and phacoemulsification. MATERIAL AND METHODS: Two groups of 12 patients had a vitrectomy for epiretinal membrane associated or not to a phacoemulsification. A fundus fluorescein angiography was performed pre and postoperatively and at least 3 months after the surgery. RESULTS: In the group of patients who had a simple vitrectomy, a ME was observed in 50% of the cases preoperatively and in 25% of the cases at the end of follow-up. In 3 cases, preoperative ME was worsened after the surgery. In the group of patients who were treated by a combined vitrectomy and phacoemulsification, a ME was observed in 25% of the cases preoperatively and in 50% of the cases at the end of follow-up. A de novo ME was observed in 3 cases. CONCLUSION: Combined vitrectomy and cataract surgery could allow a rapid recovery of visual acuity but might increase the occurrence of ME.

The Quorum-Sensing Molecules Farnesol/Homoserine Lactone and Dodecanol Operate via Distinct Modes of Action in Candida albicans.

Living as a commensal, Candida albicans must adapt and respond to environmental cues generated by the mammalian host and by microbes comprising the natural flora. These signals have opposing effects on C. albicans, with host cues promoting the yeast-to-hyphal transition and bacteria-derived quorum-sensing molecules inhibiting hyphal development. Hyphal development is regulated through modulation of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and it has been postulated that quorum-sensing molecules can affect filamentation by inhibiting the cAMP pathway. Here, we show that both farnesol and 3-oxo-C(12)-homoserine lactone, a quorum-sensing molecule secreted by Pseudomonas aeruginosa, block hyphal development by affecting cAMP signaling; they both directly inhibited the activity of the Candida adenylyl cyclase, Cyr1p. In contrast, the 12-carbon alcohol dodecanol appeared to modulate hyphal development and the cAMP signaling pathway without directly affecting the activity of Cyr1p. Instead, we show that dodecanol exerted its effects through a mechanism involving the C. albicans hyphal repressor, Sfl1p. Deletion of SFL1 did not affect the response to farnesol but did interfere with the response to dodecanol. Therefore, quorum sensing in C. albicans is mediated via multiple mechanisms of action. Interestingly, our experiments raise the possibility that the Burkholderia cenocepacia diffusible signal factor, BDSF, also mediates its effects via Sfl1p, suggesting that dodecanol's mode of action, but not farnesol or 3-oxo-C(12)-homoserine lactone, may be used by other quorum-sensing molecules.

Les stratégies politiques et foncières des grands propriétaires fonciers en action : études de cas

Ce cahier présente une analyse comparée de quatre études de cas menées au sein du projet consacré aux stratégies politiques et foncières des grands propriétaires fonciers suisses à l'IDHEAP en 2007-2008. Ces études de cas concernent le complexe immobilier de « La Maladière » à Neuchâtel, le pôle de développement économique du Wankdorf à Berne, le « Centre Boujean » à Bienne ainsi que la place d'armes de Thoune. De chacun de ces cas sont présentés la chronologie des événements, les étapes et régimes du projet, les configurations et stratégies des acteurs, les impacts sur la durabilité ainsi qu'une discussion des résultats à la lumière des hypothèses du projet. L'analyse comparée fait le point des configurations et stratégies des acteurs qui sont ensuite mises en relation avec les régimes institutionnels et la durabilité des usages du sol. L'un des messages principaux est que, aujourd'hui, on ne peut plus séparer l'aménagement du territoire du foncier si l'on veut atteindre les objectifs politiques du développement du territoire. Die vorliegende Publikation enthält eine vergleichende Analyse von vier Fallstudien, die im Rahmen des Projektes zu den Strategien der grossen Grundeigentümer der Schweiz im Bereich der Ausübung ihrer Eigentumsrechte und ihrer Interventionen auf der Ebene der Raumplanung durchgeführt wurden. Sie betreffen den Immobilienkomplex ,,La Maladière" in Neuenburg, den Entwicklungsschwerpunkt Wankdorf in Bern, das ,,Centre Boujean" in Biel und den Waffenplatz Thun. Die Zusammenfassungen der Fallstudien enthalten Angaben zur Chronologie der Ereignisse, zu den verschiedenen Etappen der Projektentwicklung und der entsprechenden Regime, zu den Akteurkonfigurationen und -strategien, zu den Auswirkungen der Projekte auf die nachhaltige Entwicklung sowie eine Diskussion der empirischen Befunde im Lichte der Projekthypothesen. Die vergleichende Analyse nimmt eine Typologie der Akteurkonfigurationen vor und diskutiert deren Folgen für die institutionellen Regime und für die nachhaltige Entwicklung der Ressource Boden. Eines der Hauptergebnisse liegt in der Feststellung, dass sich heute Raumplanung mehr den je mit den Bodeneigentumsverhältnissen befassen muss, um die beabsichtigten politischen Entwicklungsziele zu erreichen.

Light receptor action is critical for maintaining plant biomass at warm ambient temperatures.

The ability to withstand environmental temperature variation is essential for plant survival. Former studies in Arabidopsis revealed that light signalling pathways had a potentially unique role in shielding plant growth and development from seasonal and daily fluctuations in temperature. In this paper we describe the molecular circuitry through which the light receptors cry1 and phyB buffer the impact of warm ambient temperatures. We show that the light signalling component HFR1 acts to minimise the potentially devastating effects of elevated temperature on plant physiology. Light is known to stabilise levels of HFR1 protein by suppressing proteasome-mediated destruction of HFR1. We demonstrate that light-dependent accumulation and activity of HFR1 are highly temperature dependent. The increased potency of HFR1 at warmer temperatures provides an important restraint on PIF4 that drives elongation growth. We show that warm ambient temperatures promote the accumulation of phosphorylated PIF4. However, repression of PIF4 activity by phyB and cry1 (via HFR1) is critical for controlling growth and maintaining physiology as temperatures rise. Loss of this light-mediated restraint has severe consequences for adult plants which have greatly reduced biomass.

Electron cryo-microscopy reveals mechanism of action of propranolol on artificial membranes.

The pharmacological activity of several amphiphilic drugs is often related to their ability to interact with biological membranes. Propranolol is an efficient multidrug resistance (MDR) modulator; it is a nonselective beta-blocker and is thought to reduce hypertension by decreasing the cardiac frequency and thus blood pressure. It is used in drug delivery studies in order to treat systemic hypertension. We are interested in the interaction of propranolol with artificial membranes, as liposomes of controllable size are used as biocompatible and protective structures to encapsulate labile molecules, such as proteins, nucleic acids or drugs, for pharmaceutical, cosmetic or chemical applications. We present here a study of the interaction of propranolol, a cationic surfactant, with pure egg phosphatidylcholine (EPC) vesicles. The gradual transition from liposome to micelle of EPC vesicles in the presence of propranolol was monitored by time-resolved electron cryo-microscopy (cryo-EM) under different experimental conditions. The liposome-drug interaction was studied with varying drug/lipid (D/L) ratios and different stages were captured by direct thin-film vitrification. The time-series cryo-EM data clearly illustrate the mechanism of action of propranolol on the liposome structure: the drug disrupts the lipid bilayer by perturbing the local organization of the phospholipids. This is followed by the formation of thread-like micelles, also called worm-like micelles (WLM), and ends with the formation of spherical (globular) micelles. The overall reaction is slow, with the process taking almost two hours to be completed. The effect of a monovalent salt was also investigated by repeating the lipid-surfactant interaction experiments in the presence of KCl as an additive to the lipid/drug suspension. When KCl was added in the presence of propranolol the overall reaction was the same but with slower kinetics, suggesting that this monovalent salt affects the general lipid-to-micelle transition by stabilizing the membrane, presumably by binding to the carbonyl chains of the phosphatidylcholine.

Constitutively active G protein-coupled receptor mutants: implications on receptor function and drug action.

Mutations of GPCRs can increase their constitutive (agonist-independent) activity. Some of these mutations have been artificially introduced by site-directed mutagenesis; others occur spontaneously in human diseases. The analysis of constitutively active GPCR mutants has attracted a large interest in the past decade, providing an important contribution to our understanding of the molecular mechanisms underlying receptor function and drug action.

Retinal dysfunction in combined methylmalonic aciduria and homocystinuria (Cblc) disease: a spectrum of disorders.

BACKGROUND: Cobalamin C methylmalonic aciduria with homocystinuria (cblC disease) is a rare hereditary inborn error of cobalamin metabolism, characterised by neurological, haematological and ophthalmological abnormalities. PATIENTS AND METHODS: Three consecutive patients with Cblc disease were examined. Investigations included slit lamp and fundus examination and full-field ERG. RESULTS: A maculopathy associated with both photopic and scotopic abnormal ERG was present in two cases and a salt and pepper retinopathy with abnormal photopic ERG was detected in the third patient. CONCLUSIONS: Despite early treatment and regular metabolic controls, all our patients exhibited both retinal and ERG abnormalities. There was no correlation between funduscopic appearance and the type of photoreceptor dysfunction. A literature review disclosed a retinopathy in 29 / 70 cases with cblC disease, with an abnormal ERG in 8 of the 12 tested cases, most with retinopathy. Retinal dysfunction in cblC disease may be more frequent than previously thought, and can involve cones only or both rods and cones. We recommend a formal ocular examination with full-field ERG in patients with Cblc disease.