Superior venous drainage in the "LifeBox": a portable extracorporeal oxygenator with a self-expanding venous cannula.

BACKGROUND: In an experimental setting, the performance of the LifeBox, a new portable extracorporeal membrane oxygenator (ECMO) system suitable for patient transport, is presented. Standard rectilinear percutaneous cannulae are normally employed for this purpose, but have limited flow and pressure delivery due to their rigid structure. Therefore, we aimed to determine the potential for flow increase by using self-expanding venous cannulae. METHODS: Veno-arterial bypass was established in three pigs (40.6+/-5.1 kg). The venous line of the cardiopulmonary bypass was established by cannulation of the external jugular vein. The arterial side of the circulation was secured by cannulation of the common carotid artery. Two different venous cannulae (SmartCanula 18/36F 430mm and Biomedicus 19F) were examined for their functional integrity when used in conjunction with the centrifugal pump (500-3000 RPM) of the LifeBox system. RESULTS: At 1500, 2000, 2500, and 3000 RPM, the blood flow increased steadily for each cannula, but remained higher in the self-expanding cannula. That is, the 19F rectilinear cannula achieved a blood flow of 0.93+/-0.14, 1.47+/-0.37, 1.9+/-0.68, and 1.5+/-0.9 l/min, respectively, and the 18/36F self-expanding cannula achieved 1.1+/-0.1, 1.9+/-0.33, 2.8+/-0.39 and 3.66+/-0.52 l/min. However, when tested for venous line pressure, the standard venous cannula achieved -29+/-10.7mmHg while the self-expanding cannula achieved -13.6 +/-4.3mmHg at 1500 RMP. As the RPM increased from 2500 to 3000, the venous line pressure accounted for -141.9+/-20 and -98+/-7.3mmHg for the 19F rectilinear cannula and -30.6+/-6.4 and -45+/-11.6mmHg for the self-expanding cannula. CONCLUSION: The self-expanding cannula exhibited superior venous drainage ability when compared to the performance of the standard rectilinear cannula with the use of the LifeBox. The flow rate achieved was approximately 40% greater than the standard drainage device, with a maximal pump flow recorded at 4.3l/min.

Antagonism of neuromuscular blockade but not muscle relaxation affects depth of anaesthesia

RÉSUMÉ Introduction L'effet des agents myorelaxants ainsi que des anticholinestérases sur la profondeur d'anesthésie a été étudié avec des résultats contradictoires. C'est pourquoi nous avons évalué l'effet de l'atracurium et de la néostigmine sur le BIS (bispectral index) ainsi que sur les potentiels auditives évoqués (middle-latency auditory evoked potentials, A-Line® autoregressive index [AAI]). Méthodes Après avoir obtenu l'accord du comité d'éthique local, nous avons étudié 40 patients ayant donné leur consentement écrit, ASA I-II, âgé de 18-69 ans. L'anesthésie générale a consisté en anesthésie intra-veineuse à objectif de concentration avec du propofol et du remifentanil. La fonction de la jonction neuromusculaire était monitorée en continu au moyen d'un électromyographe. Le BIS et l'AAI ont été enregistrés en continu. Après avoir atteint des valeurs stables au niveau du BIS, les patients ont été attribués à deux groupes par randomisation. Les patients du groupe 1 ont reçu 0.4 mg kg-1 d'atracurium et 5 minutes plus tard le même volume de NaCI 0.9%, dans le groupe 2 la séquence d'injection était inversée, le NaCI 0.9% en premier et l'atracurium en deuxième. Au moment où le premier « twitch » d'un train de quatre atteignait 10% de l'intensité avant la relaxation, les patients ont été randomisés une deuxième fois. Les patients du groupe N ont reçu 0.04 mg kg-1 de néostigmine et 0.01 rn9 kg-1 de glycopyrrolate alors que le groupe contrôle (G) ne recevait que 0.01 mg kg-] de glycopyrrolate. Résultats : L 'injection d'atracurium ou de NaCI 0.9% n'a pas eu d'effet sur le BIS ou l'AAI. Après l'injection de néostigmine avec glycopyrrolate, le BIS et I `AAI a augmenté de manière significative (changement maximal moyen du BIS 7.1 ± 7.5, P< 0.001, de l'AAI 9.7 ± 10.5, P< 0.001). Suite à l'injection de glycopyrrolate seule, le BIS et l'AAI a augmenté également (changement maximal moyen du BIS 2.2 ± 3.4, P< 0.008, de l'AAI 3.5 ± 5.7, P< 0.012), mais cette augmentation était significativement moins importante que dans le groupe N (P< 0.012 pour le BIS, P< 0.027 pour l'AAI). Conclusion Ces résultats laissent supposer que la néostigmine peut altérer la profondeur de l'anesthésie. La diminution de la profondeur d'anesthésie enregistrée par le BIS et l'AAI correspond probablement à une réapparition brusque d'une stimulation centrale liée à la proprioception. Au contraire, lors de la curarisation, le tonus musculaire diminue de manière beaucoup plus progressive, pouvant ainsi expliquer l'absence d'effet sur la profondeur d'anesthésie. ABSTRACT Background. Conflicting effects of neuromuscular blocking drugs and anticholinesterases on depth of anaesthesia have been reported. Therefore we evaluated the effect of atracurium and neostigmine on bispectral index (BIS) and middle-latency auditory evoked potentials (AAI). Methods. We studied 40 patients (ASA I-II) aged 18-69 yr. General anaesthesia consisted of propofol and remifentanil by target-controlled infusion and neuromuscular function was monitored by electromyography. When BIS reached stable values, patients were randomly assigned to one of two groups. Group I received atracurium 0.4 mg kg-1 and, 5 min later, the same volume of NaCl 0.9%; group 2 received saline first and then atracurium. When the first twitch of a train of four reached 10% of control intensity, patients were again randomized: one group (N) received neostigmine 0.04 mg kg-1 and glycopyrrolate 0.01 mg kg-1, and the control group (G) received only glycopyrrolate. Results. Injection of atracurium or NaCl 0.9% had no effect on BIS or AAI. After neostigmine¬glycopyrrolate, BIS and AAI increased significantly (mean maximal change of BIS 7.1 [SD 7.5], P<0.001; mean maximal change of AAI 9.7 [10.5], P<0.001). When glycopyrrolate was injected alone BIS and AAI also increased (mean maximal change of BIS 2.2 [3.4], P=0.008; mean maximal change of AAI 3.5 [5.7], P=0.012), but this increase was significantly less than in group N (P=0.012 for BIS; P=0.027 for AAI). Conclusion. These data suggest that neostigmine alters the state of propofol-remifentanil anaesthesia and may enhance recovery.

Coronary magnetic resonance angiography in adolescents and young adults with kawasaki disease.

BACKGROUND: In patients with Kawasaki disease, serial evaluation of the distribution and size of coronary artery aneurysms (CAA) is necessary for risk stratification and therapeutic management. Although transthoracic echocardiography is often sufficient for this purpose initially, visualization of the coronary arteries becomes progressively more difficult as children grow. We sought to prospectively compare coronary magnetic resonance angiography (MRA) and x-ray coronary angiography findings in patients with CAA caused by Kawasaki disease. METHODS AND RESULTS: Six subjects (age 10 to 25 years) with known CAA from Kawasaki disease underwent coronary MRA using a free-breathing T2-prepared 3D bright blood segmented k-space gradient echo sequence with navigator gating and tracking. All patients underwent x-ray coronary angiography within a median of 75 days (range, 1 to 359 days) of coronary MRA. There was complete agreement between MRA and x-ray angiography in the detection of CAA (n=11), coronary artery stenoses (n=2), and coronary occlusions (n=2). Excellent agreement was found between the 2 techniques for detection of CAA maximal diameter (mean difference=0.4 +/- 0.6 mm) and length (mean difference=1.4 +/- 1.6 mm). The 2 methods showed very similar results for proximal coronary artery diameter (mean difference=0.2 +/- 0.5 mm) and CAA distance from the ostia (mean difference=0.1 +/- 1.5 mm). CONCLUSION: Free-breathing 3D coronary MRA accurately defines CAA in patients with Kawasaki disease. This technique may provide a non-invasive alternative when transthoracic echocardiography image quality is insufficient, thereby reducing the need for serial x-ray coronary angiography in this patient group.

Whole-body vibration training: metabolic cost of synchronous, side-alternating or no vibrations.

Whole-body vibration training improves strength and can increase maximal oxygen consumption ([·V]O(2max)). No study has compared the metabolic demand of synchronous and side-alternating whole-body vibration. We measured [·V]O₂ and heart rate during a typical synchronous or side-alternating whole-body vibration session in 10 young female sedentary participants. The 20-min session consisted of three sets of six 45-s exercises, with 15 s recovery between exercises. Three conditions were randomly tested on separate days: synchronous at 35 Hz and 4 mm amplitude, side-alternating at 26 Hz and 7.5 mm amplitude (peak acceleration matched at 20 g in both vibration conditions), and no vibrations. Mean [·V]O₂ (expressed as %[·V]O(2max)) did not differ between conditions: 29.7 ± 4.2%, 32.4 ± 6.5%, and 28.7 ± 6.7% for synchronous, side-alternating, and no vibrations respectively (P = 0.103). Mean heart rate (% maximal heart rate) was 65.6 ± 7.3%, 69.8 ± 7.9%, and 64.7 ± 5.6% for synchronous, side-alternating, and no vibrations respectively, with the side-alternating vibrations being significantly higher (P = 0.019). When analysing changes over exercise sessions, mean [·V]O₂ was higher for side-alternating (P < 0.001) than for synchronous and no vibrations. In conclusion, side-alternating whole-body vibration elicits higher heart rate responses than synchronous or no vibrations, and could elevate [·V]O₂, provided the session lasts more than 20 min.

Stratigraphie, morphodynamique, paléoenvironnements des terrains sédimentaires meubles à forte déclivité du domaine périglaciaire alpin

Dans le contexte d'un climat de plus en plus chaud, une étude « géosystémique » de la répartition du pergélisol dans l'ensemble d'un versant périglaciaire alpin, de la paroi rocheuse jusqu'au glacier rocheux, s'avère primordiale. S'insérant dans cette problématique, ce travail de thèse vise comme objectif général l'étude des versants d'éboulis situés à l'intérieur de la ceinture du pergélisol discontinu selon deux volets de recherche différents : une étude de la stratigraphie et de la répartition du pergélisol dans les éboulis de haute altitude et des processus qui lui sont associés ; une reconstitution de l'histoire paléoenvironnementale du domaine périglaciaire alpin pendant le Tardiglaciaire et l'Holocène. La stratigraphie et la répartition spatiale du pergélisol a été étudiée dans cinq éboulis des Alpes Valaisannes (Suisse), dont trois ont fait l'objet de forages profonds, grâce à la prospection géophysique de détail effectuée à l'aide de méthodes thermiques, de résistivité, sismiques et nucléaires. Les mesures effectuées ont permis de mettre en évidence que, dans les cinq éboulis étudiés, la répartition du pergélisol est discontinue et aucun des versants n'est intégralement occupé par du pergélisol. En particulier, il a été possible de prouver de manière directe que, dans un éboulis, le pergélisol est présent dans les parties inférieures du versant et absent dans les parties supérieures. Trois facteurs de contrôle principaux de la répartition du pergélisol déterminée au sein des éboulis étudiés ont été individualisés, pouvant agir seuls ou de manière combinée : la ventilation ascendante, l'augmentation de la granulométrie en direction de l'aval et la redistribution de la neige par le vent et les avalanches. Parmi ceux-ci, la relation ventilation-granulométrie semble être le facteur de contrôle principal permettant d'expliquer la présence de pergélisol dans les parties inférieures d'un éboulis et son absence dans les parties supérieures. Enfin, l'analyse de la structure des éboulis périglaciaires de haute altitude a permis de montrer que la stratigraphie du pergélisol peut être un élément important pour l'interprétation de la signification paléoclimatique de ce type de formes. Pour le deuxième volet de la recherche, grâce aux datations relatives effectuées à l'aide de l'utilisation conjointe de la méthode paléogéographique et du marteau de Schmidt, il a été possible de définir la chrono-stratigraphie du retrait glaciaire et du développement des glaciers rocheux et des versants d'éboulis des quatre régions des Alpes suisses étudiées (régions du Mont Gelé - Mont Fort, des Fontanesses et de Chamosentse, dans les Alpes Valaisannes, et Massif de la Cima di Gana Bianca, dans les Alpes Tessinoises). La compilation de toutes les datations effectuées a permis de montrer que la plupart des glaciers rocheux actifs étudiés se seraient développés soit juste avant et/ou pendant l'Optimum Climatique Holocène de 9.5-6.3 ka cal BP, soit au plus tard juste après cet évènement climatique majeur du dernier interglaciaire. Parmi les glaciers rocheux fossiles datés, la plupart aurait commencé à se former dans la deuxième moitié du Tardiglaciaire et se serait inactivé dans la première partie de l'Optimum Climatique Holocène. Pour les éboulis étudiés, les datations effectuées ont permis d'observer que leur surface date de la période entre le Boréal et l'Atlantique récent, indiquant que les taux d'éboulisation après la fin de l'Optimum Climatique Holocène ont dû être faibles, et que l'intervalle entre l'âge maximal et l'âge minimal est dans la plupart des cas relativement court (4-6 millénaires), indiquant que les taux d'éboulisation durant la période de formation des éboulis ont dû être importants. Grâce au calcul des taux d'érosion des parois rocheuses sur la base du volume de matériaux rocheux pour quatre des éboulis étudiés, il a été possible mettre en évidence l'existence d'une « éboulisation parapériglaciaire » liée à la dégradation du pergélisol dans les parois rocheuses, fonctionnant principalement durant les périodes de réchauffement climatique rapide comme cela a été le cas au début du Bølling, du Préboréal à la fin de l'Atlantique récent et, peut-être, à partir des années 1980. - In the context of a warmer climate, a « geosystemical » study of the permafrost distribution in a whole alpine periglacial hillslope, from the rockwall to the rockglacier, is of great importance. With respect to this problem, the general objective of this PhD thesis is the global study of talus slopes located within the alpine periglacial belt following two different research axes: the analysis of the internal structure and of the permafrost distribution of high altitude talus slopes and of the related processes; the reconstruction of the palaeoenvironmental history of the alpine periglacial belt during the Lateglacial and the Holocene. The stratigraphy and the permafrost distribution were studied in five talus slopes of the Valais Alps (Switzerland) with the analysis of borehole data (on three of the five talus slopes) and other methods of permafrost prospecting: Electrical Resistivity Tomography (ERT), Refraction Seismic Tomography (RST) and nuclear well logging. The collected data shows that, in all of the studied talus slopes, permafrost distribution is discontinuous and that neither of the hillslopes is integrally characterised by permafrost. In particular, this data proves by direct investigations that, in talus slopes, permafrost is present in the lower parts of the hillslope, whereas it is absent in the upper parts. Permafrost distribution in alpine talus slopes is depending of the combination of almost three controlling factors, whose respective importance is variable: the chimney effect, the increase of grain size downslope and the redistribution of snow by avalanches. Depending on the size of the talus and on topographical and geomorphological heterogeneities, various cases are possible: one dominant controlling factor or the combination of various factors. Nevertheless, it would be an error to consider each controlling factor independently, without considering their relationships. Between these controlling factors, the relationship chimney effect/grain size seems to be the most important factor controlling the presence of permafrost in the lowest part of periglacial talus slopes, and its absence in the upper parts. Finally, the analysis of the talus structure shows that the permafrost stratigraphy may be an important element of interpretation of the palaeoclimatic significance of an alpine talus slope. The second research axe focused on the establishment of a chronology of the Lateglacial glacier retreat and the dating of rockglaciers and talus slopes development in four studied regions of the Swiss Alps (Mont Gelé - Mont Fort, Fontanesses and Chamosentse regions, in the Valais Alps, and the Cima di Gana Bianca Massif, in the Ticino Alps). The compilation of the dates acquired through the combination of the palaeogeographical method and of the Schmidt hammer indicates that most of the investigated active rockglaciers started to evolve during the early phases of the Holocene or, at the latest, after the early-to-mid Holocene Climatic Optimum (ending around 6.3 ka cal BP). For the dated relict rockglaciers, most of them started to evolve in the second half of the Lateglacial, and probably became inactive at the beginning of the Holocene Climatic Optimum. For the investigated talus slopes, the relative dating carried out allowed to show that their surface date from the period included between the Boreal and the end of the Atlantic, pointing out that the rockwall retreat after the end of the Holocene Climatic Optimum was weak, and that the interval between maximal and minimal ages is in most cases relatively short (4-6 millennia). Therefore, the rockwall retreat during the development period of the talus slopes must has been considerable. Thanks to the calculation of rockwall erosion rates based on the volume of talus accumulations for four of the investigated hillslopes, it was possible to find evidences of the existence of "paraperiglacial rockfall phases" related to the permafrost degradation in rockwalls. These phases coincide with rapid climate warming periods, as at the beginning of the Bølling, during the Preboreal or, maybe, since 1980.

Measurement of Ice Scraping Forces on Snow-Plow Underbody Blades, HR-372, 1997

In this study, several new cutting edges for removal of ice from the roadway were tested in a series of closed road tests. These new cutting edges consisted of a variety of serrated shapes. The study also included measurement of ice scraping forces by in-service trucks. These trucks were instrumented in a similar manner as the truck used in the closed-road tests. Results from the closed-road and in-service tests were analyzed by two parameters. The first parameter is the scraping effectiveness, which is defined as the average horizontal force experienced by a cutting edge. The amount of ice scraped from the roadway is directly proportional to the magnitude of the scraping effectiveness. Thus an increase in scraping effectiveness indicates an increase in the amount of ice being scraped from the roadway. The second parameter is force angle, which is defined as tan to the -1 power [vertical force/horizontal force]. A combination of a minimal force angle and a maximized scraping effectiveness represents a case in which the maximal amount of ice is being removed from the pavement without an exceptionally large vertical force. Results indicate that each cutting edge produced a maximal scraping effectiveness with a testing configuration of a 15 deg blade angle and a 23,000 lb. download force. Results also indicate that each cutting edge produced a minimal force angle with a testing configuration of a 15 deg blade angle and a 10,000 lb. download force. Results from the in-service trucks produced similar data and also similar trends within the data when compared to the results of the closed-road tests. This result is most important, as it suggests that the closed-road tests do provide an accurate measure of ice scraping forces for a given blade and configuration of that blade. Thus if the closed-road tests indicate that certain blades perform well, there is now excellent reason to conduct full scale tests of such blades.

Reproducibility of Fatmax and Fat Oxidation Rates during Exercise in Recreationally Trained Males.

Aerobic exercise training performed at the intensity eliciting maximal fat oxidation (Fatmax) has been shown to improve the metabolic profile of obese patients. However, limited information is available on the reproducibility of Fatmax and related physiological measures. The aim of this study was to assess the intra-individual variability of: a) Fatmax measurements determined using three different data analysis approaches and b) fat and carbohydrate oxidation rates at rest and at each stage of an individualized graded test. Fifteen healthy males [body mass index 23.1±0.6 kg/m2, maximal oxygen consumption ([Formula: see text]) 52.0±2.0 ml/kg/min] completed a maximal test and two identical submaximal incremental tests on ergocycle (30-min rest followed by 5-min stages with increments of 7.5% of the maximal power output). Fat and carbohydrate oxidation rates were determined using indirect calorimetry. Fatmax was determined with three approaches: the sine model (SIN), measured values (MV) and 3rd polynomial curve (P3). Intra-individual coefficients of variation (CVs) and limits of agreement were calculated. CV for Fatmax determined with SIN was 16.4% and tended to be lower than with P3 and MV (18.6% and 20.8%, respectively). Limits of agreement for Fatmax were -2±27% of [Formula: see text] with SIN, -4±32 with P3 and -4±28 with MV. CVs of oxygen uptake, carbon dioxide production and respiratory exchange rate were <10% at rest and <5% during exercise. Conversely, CVs of fat oxidation rates (20% at rest and 24-49% during exercise) and carbohydrate oxidation rates (33.5% at rest, 8.5-12.9% during exercise) were higher. The intra-individual variability of Fatmax and fat oxidation rates was high (CV>15%), regardless of the data analysis approach employed. Further research on the determinants of the variability of Fatmax and fat oxidation rates is required.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 3040% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

Some common indexes of group diversity: upper boundaries

Workgroup diversity can be conceptualized as variety, separation, or disparity. Thus, the proper operationalization of diversity depends on how a diversity dimension has been defined. Analytically, the minimal diversity must be obtained when there are no differences on an attribute among the members of a group, however maximal diversity has a different shape for each conceptualization of diversity. Previous work on diversity indexes indicated maximum values for variety (e.g., Blau"s index and Teachman"s index), separation (e.g., standard deviation and mean Euclidean distance), and disparity (e.g., coefficient of variation and the Gini coefficient of concentration), although these maximum values are not valid for all group characteristics (i.e., group size and group size parity) and attribute scales (i.e., number of categories). We demonstrate analytically appropriate upper boundaries for conditional diversity determined by some specific group characteristics, avoiding the bias related to absolute diversity. This will allow applied researchers to make better interpretations regarding the relationship between group diversity and group outcomes.

Incorporation and washout of n-3 PUFA after high dose intravenous and oral supplementation in healthy volunteers.

BACKGROUND & AIMS: Although the physiological effects of n-3 polyunsaturated fatty acids (n-3PUFA) are generally thought to require several weeks of exposure to allow their incorporation into plasma membranes, intravenous (IV) n-3PUFA attenuate the cardiovascular and neuroendocrine response to stress within 3 h. Whether oral n-3 PUFA exert similar early effects remains unknown. OBJECTIVE: To assess whether acute IV or short term oral n-3PUFA administration reproduces the metabolic effects of long term oral supplements during exercise, and how it relates to their incorporation into platelets and red blood cells (RBC) membranes. DESIGN: Prospective single center open label study in 8 healthy subjects receiving a 3-h infusion of 0.6 g/kg body weight n-3PUFA emulsion, followed one week later by an oral administration of 0.6 g/kg over 3 consecutive days. Maximal power output (cycling exercise), maximal heart rate (HR), blood lactate at exhaustion, and platelet function were measured at baseline and after IV or 3-day oral supplementation; platelet and RBC membrane composition were assessed until 15 days after n-3PUFA administration. RESULTS: Both IV and oral n-3PUFA significantly decreased maximal HR (-6% and -5%), maximal power output (-10%) and peak blood lactate (-47% and -52%) Platelet function tests were unchanged. The EPA and DHA membrane contents of RBC and platelets increased significantly, but only to 1.7-1.9% of fatty acid content. CONCLUSION: The cardiovascular and metabolic effects of n-3 PUFA during exercise occur already within 1-3 days of exposure, and may be unrelated to changes in membranes composition. Effects occur within hours of administration and are unrelated to lipid membrane composition. Trial registered at clinicaltrials.gov as NCT00516178.

Pharmacokinetic evaluation of losartan.

Introduction: Blockade of the renin-angiotensin system is one of the major therapeutic strategies in the management of patients with essential hypertension, congestive heart failure and diabetic as well as non-diabetic renal diseases. As the first angiotensin II receptor blocker (ARB) on the market, losartan belongs to the most frequently prescribed ARB. Area covered : The present review examines the pharmacokinetics of losartan with a special discussion on the dose of losartan that should be used in clinical practice to obtain the maximal benefits of the drug. Readers are provided with arguments suggesting that the dose of 50 mg losartan is probably too low and that losartan should preferably be prescribed at the dose of 100 mg/day or higher. Expert opinion : Losartan is an effective antagonist of angiotensin II AT(1) receptors which has been shown to provide important clinical benefits in patients with hypertension, congestive heart failure and renal diseases. Losartan should be prescribed at the dose of 100 mg/day and the use of higher doses should be reconsidered in future studies to improve its clinical efficacy.

Clinical pharmacology of the angiotensin II receptor antagonist losartan potassium in healthy subjects

INTRODUCTION: The evaluation of a new drug in normotensive volunteers provides important pharmacodynamic and pharmacokinetic information as long as the compound has a specific mechanism of action which can be evaluated in healthy subjects as well as in patients. The purpose of the present paper is to discuss the results that have been obtained in normal volunteers with the specific angiotensin II receptor antagonist, losartan potassium. DOSE-FINDING: Over the last few years, studies in normotensive subjects have demonstrated that the minimal dose of losartan that produces maximal efficacy is 40-80 mg. Losartan has a long duration of action and its ability to produce a sustained blockade of the renin-angiotensin system is due almost exclusively to the active metabolite E3174. HORMONAL EFFECTS: Angiotensin II receptor blockade with losartan induces an expected increase in plasma renin activity and plasma angiotensin II levels. A decrease in plasma aldosterone levels has been found only with a high dose of losartan (120 mg). RENAL AND BLOOD PRESSURE EFFECTS: In normotensive subjects, losartan has little or no effect on blood pressure unless the subjects are markedly salt-depleted. Losartan causes no change in the glomerular filtration rate and either no modification or only a slight increase in renal blood flow. Losartan significantly increases urinary sodium excretion, however, and surprisingly produces a transient rise in urinary potassium excretion. Finally, losartan increases uric acid excretion and lowers plasma uric acid levels. CONCLUSIONS: These results suggest that losartan is an effective angiotensin II receptor antagonist in normal subjects. Its safety and clinical efficacy in hypertensive patients will be addressed in large clinical trials.

Properties of a risk measure derived from ruin theory

This paper studies a risk measure inherited from ruin theory and investigates some of its properties. Specifically, we consider a value-at-risk (VaR)-type risk measure defined as the smallest initial capital needed to ensure that the ultimate ruin probability is less than a given level. This VaR-type risk measure turns out to be equivalent to the VaR of the maximal deficit of the ruin process in infinite time. A related Tail-VaR-type risk measure is also discussed.

Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH).

FGFR1 mutations have been identified in both Kallmann syndrome and normosmic HH (nIHH). To date, few mutations in the FGFR1 gene have been structurally or functionally characterized in vitro to identify molecular mechanisms that contribute to the disease pathogenesis. We attempted to define the in vitro functionality of two FGFR1 mutants (R254W and R254Q), resulting from two different amino acid substitutions of the same residue, and to correlate the in vitro findings to the patient phenotypes. Two unrelated GnRH deficient probands were found to harbor mutations in FGFR1 (R254W and R254Q). Mutant signaling activity and expression levels were evaluated in vitro and compared to a wild type (WT) receptor. Signaling activity was determined by a FGF2/FGFR1 dependent transcription reporter assay. Receptor total expression levels were assessed by Western blot and cell surface expression was measured by a radiolabeled antibody binding assay. The R254W maximal receptor signaling capacity was reduced by 45% (p<0.01) while R254Q activity was not different from WT. However, both mutants displayed diminished total protein expression levels (40 and 30% reduction relative to WT, respectively), while protein maturation was unaffected. Accordingly, cell surface expression levels of the mutant receptors were also significantly reduced (35% p<0.01 and 15% p<0.05, respectively). The p.R254W and p.R254Q are both loss-of-function mutations as demonstrated by their reduced overall and cell surface expression levels suggesting a deleterious effect on receptor folding and stability. It appears that a tryptophan substitution at R254 is more disruptive to receptor structure than the more conserved glutamine substitution. No clear correlation between the severity of in vitro loss-of-function and phenotypic presentation could be assigned.

An SH2 domain-containing 5' inositolphosphatase inhibits insulin-induced GLUT4 translocation and growth factor-induced actin filament rearrangement.

Tyrosine kinase receptors lead to rapid activation of phosphatidylinositol 3-kinase (PI3 kinase) and the subsequent formation of phosphatidylinositides (PtdIns) 3,4-P2 and PtdIns 3,4, 5-P3, which are thought to be involved in signaling for glucose transporter GLUT4 translocation, cytoskeletal rearrangement, and DNA synthesis. However, the specific role of each of these PtdIns in insulin and growth factor signaling is still mainly unknown. Therefore, we assessed, in the current study, the effect of SH2-containing inositol phosphatase (SHIP) expression on these biological effects. SHIP is a 5' phosphatase that decreases the intracellular levels of PtdIns 3,4,5-P3. Expression of SHIP after nuclear microinjection in 3T3-L1 adipocytes inhibited insulin-induced GLUT4 translocation by 100 +/- 21% (mean +/- the standard error) at submaximal (3 ng/ml) and 64 +/- 5% at maximal (10 ng/ml) insulin concentrations (P < 0.05 and P < 0.001, respectively). A catalytically inactive mutant of SHIP had no effect on insulin-induced GLUT4 translocation. Furthermore, SHIP also abolished GLUT4 translocation induced by a membrane-targeted catalytic subunit of PI3 kinase. In addition, insulin-, insulin-like growth factor I (IGF-I)-, and platelet-derived growth factor-induced cytoskeletal rearrangement, i.e., membrane ruffling, was significantly inhibited (78 +/- 10, 64 +/- 3, and 62 +/- 5%, respectively; P < 0.05 for all) in 3T3-L1 adipocytes. In a rat fibroblast cell line overexpressing the human insulin receptor (HIRc-B), SHIP inhibited membrane ruffling induced by insulin and IGF-I by 76 +/- 3% (P < 0.001) and 68 +/- 5% (P < 0.005), respectively. However, growth factor-induced stress fiber breakdown was not affected by SHIP expression. Finally, SHIP decreased significantly growth factor-induced mitogen-activated protein kinase activation and DNA synthesis. Expression of the catalytically inactive mutant had no effect on these cellular responses. In summary, our results show that expression of SHIP inhibits insulin-induced GLUT4 translocation, growth factor-induced membrane ruffling, and DNA synthesis, indicating that PtdIns 3,4,5-P3 is the key phospholipid product mediating these biological actions.