Une méta-analyse GWA de la glycémie après 2h d'HGPO révèle que GIPR est associé avec la sécrétion de l'insuline en réponse au glucose et que l'ADCY5 est un nouveau gène de suseptibilité au diabète de type 2. [A meta-analysis of GWA blood glucose after 2 h of OGTT revealed that GIPR is associated with the secretion of insulin based on glucose and ADCY5 is a new susceptibility gene for type 2 diabetes.]

Introduction: Les études GVvA (Genome-wide association ,-studies) ont identifié et confirmé plus de 20 gènes de susceptibilité au DT2 et ont contribué à mieux comprendre sa physiopathologie. L'hyperglycémie à jeun (GJ), et 2 heures après une HGPO (G2h) sont les deux mesures cliniques du diagnostic du DT2. Nous avons identifié récemment la G6P du pancréas (G6PC2) comme déterminant de la variabilité physiologique de la GJ puis Ie récepteur à la mélatonine (MTNRIB) qui de plus lie la régulation du rythme circadien au DT2. Dans ce travail nous avons étudié la génétique de la G2h à l'aide de l'approche GWA. Résultats: Nous avons réalisé une méta-analyse GWA dans le cadre de MAGIC (Meta-Analysis of Glucose and Insulin related traits Consortium) qui a inclus 9 études GWA (N=15'234). La réplication de 29 loci (N=6958-30 121, P < 10-5 ) a confirmé 5 nouveaux loci; 2 étant connus comme associés avec Ie DT2 (TCF7L2, P = 1,6 X 10-10 ) et la GJ (GCKR, p = 5,6 X 10-10 ); alors que GIPR (p= 5,2 X 10-12), VSP13C (p= 3,9 X 10-8) et ADCY5 (p = 1,11 X 10-15 ) sont inédits. GIPR code Ie récepteur au GIP (gastric inhibitory polypeptide) qui est sécrété par les ceIlules intestinales pour stimuler la sécrétion de l'insuline en réponse au glucose (l'effet incrétine). Les porteurs du variant GIPR qui augmente la G2h ont également un indice insulinogénique plus bas, (p= 1,0 X 10-17) mais ils ne présentent aucune modification de leur glycémie suite à une hyperglycémie provoquée par voie veineuse (p= 0,21). Ces résultats soutiennent un effet incrétine du locus GIPR qui expliquerait ~9,6 % de la variance total de ce trait. La biologie de ADCY5 et VPS13C et son lien avec l'homéostasie du glucose restent à élucider. GIPR n'est pas associé avec le risque de DT2 indiquant qu'il influence la variabilité physiologique de la G2h alors que le locus ADCY5 est associé avec le DT2 (OR = 1,11, P = 1,5 X 10-15). Conclusion: Notre étude démontre que l'étude de la G2h est une approche efficace d'une part pour la compréhension de la base génétique de la physiologie de ce trait clinique important et d'autre part pour identifier de nouveaux gènes de susceptibilité au DT2.

BMP-2 and TGF-beta1 differentially control expression of type II procollagen and alpha 10 and alpha 11 integrins in mouse chondrocytes.

Bone morphogenetic protein (BMP)-2 and transforming growth factor (TGF)-beta1 are multifunctional cytokines both proposed as stimulants for cartilage repair. Thus it is crucial to closely examine and compare their effects on the expression of key markers of the chondrocyte phenotype, at the gene and protein level. In this study, the expression of alpha 10 and alpha 11 integrin subunits and the IIA/IIB spliced forms of type II procollagen have been monitored for the first time in parallel in the same in vitro model of mouse chondrocyte dedifferentiation/redifferentiation. We demonstrated that TGF-beta1 stimulates the expression of the non-chondrogenic form of type II procollagen, IIA isoform, and of a marker of mesenchymal tissues, i.e. the alpha 11 integrin subunit. On the contrary, BMP-2 stimulates the cartilage-specific form of type II procollagen, IIB isoform, and a specific marker of chondrocytes, i.e. the alpha 10 integrin subunit. Collectively, our results demonstrate that BMP-2 has a better capability than TGF-beta1 to stimulate chondrocyte redifferentiation and reveal that the relative expressions of type IIB to type IIA procollagens and alpha 10 to alpha 11 integrin subunits are good markers to define the differentiation state of chondrocytes. In addition, adenoviral expression of Smad6, an inhibitor of BMP canonical Smad signaling, did not affect expression of total type II procollagen or the ratio of type IIA and type IIB isoforms in mouse chondrocytes exposed to BMP-2. This result strongly suggests that signaling pathways other than Smad proteins are involved in the effect of BMP-2 on type II procollagen expression.

Effects of Road Construction Intensity and Operations on Rural Freeway Work Zone Capacity, TPF-5(081), 2014

Capacity is affected by construction type and its intensity on adjacent open traffic lanes. The effect on capacity is a function of vehicles moving in and out of the closed lanes of the work zone, and the presence of heavy construction vehicles. Construction activity and its intensity, however, are not commonly considered in estimating capacity of a highway lane. The main purpose of this project was to attempt to quantify the effects of construction type and intensity (e.g. maintenance, rehabilitation, reconstruction, and milling) on work zone capacity. The objective of this project is to quantify the effects of construction type and its intensity on work zone capacity and to develop guidelines for MoDOT to estimate the specific operation type and intensity that will improve the traffic flow by reducing the traffic flow and queue length commonly associated with work zones. Despite the effort put into field data collection, the data collected did not show a full speed-flow chart therefore extracting a reliable capacity value was difficult. A statistical comparison between the capacity values found in this study using either methodologies indicates that there is an effect of construction activity on the values work zone capacity. It was found that the heavy construction activity reduces the capacity. It is very beneficial to conduct similar studies on the capacity of work zone with different lane closure barriers, which is also directly related to the type of work zone being short-term or long-term work zones. Also, the effect of different geometric and environmental characteristics of the roadway should be considered in future studies.

Diabète de type 2: n'oubliez pas les troubles du comportement alimentaire [Patient with type 2 diabetes: don't forget eating disorders!]

The coexistence of diabetes and eating disorder (ED) is more prevalent than we think; indeed it seems to occur in 10 to 20% of cases. Therefore ED deserve attention to be detected and treated in order to permit a decreased in morbidity and better outcomes in body weight loss. The association of type 2 diabetes and ED is frequently seen in younger, overweighed or obese patients suffering of at least one psychiatric co-morbidities and frequently in a difficult psychosocial setting. To succeed in ED treatment, a multidisciplinary and specialised team in eating disorder is requested, however these patients are highly fragile and complex and therapeutic failure has to be feared.

Adipocytokines, Hepatic and Inflammatory Biomarkers and Incidence of Type 2 Diabetes. The CoLaus Study.

CONTEXT: There is contradictory information regarding the prognostic importance of adipocytokines, hepatic and inflammatory biomarkers on the incidence of type 2 diabetes. The objective was to assess the prognostic relevance of adipocytokine and inflammatory markers (C-reactive protein - CRP; interleukin-1beta - IL-1β; interleukin-6- IL-6; tumour necrosis factor-^5; - TNF-^5;; leptin and adiponectin) and gamma-glutamyl transpeptidase (γGT) on the incidence of type 2 diabetes. METHODS: Prospective, population-based study including 3,842 non-diabetic participants (43.3% men, age range 35 to 75 years), followed for an average of 5.5 years (2003-2008). The endpoint was the occurrence of type 2 diabetes. RESULTS: 208 participants (5.4%, 66 women) developed type 2 diabetes during follow-up. On univariate analysis, participants who developed type 2 diabetes had significantly higher baseline levels of IL-6, CRP, leptin and γGT, and lower levels of adiponectin than participants who remained free of type 2 diabetes. After adjusting for a validated type 2 diabetes risk score, only the associations with adiponectin: Odds Ratio and (95% confidence interval): 0.97 (0.64-1.47), 0.84 (0.55-1.30) and 0.64 (0.40-1.03) for the second, third and forth gender-specific quartiles respectively, remained significant (P-value for trend = 0.05). Adding each marker to a validated type 2 diabetes risk score (including age, family history of type 2 diabetes, height, waist circumference, resting heart rate, presence of hypertension, HDL cholesterol, triglycerides, fasting glucose and serum uric acid) did not improve the area under the ROC or the net reclassification index; similar findings were obtained when the markers were combined, when the markers were used as continuous (log-transformed) variables or when gender-specific quartiles were used. CONCLUSION: Decreased adiponectin levels are associated with an increased risk for incident type 2 diabetes, but they seem to add little information regarding the risk of developing type 2 diabetes to a validated risk score.

Influence of triamcinolone intravitreal injection on retinochoroidal healing processes.

To analyze the effects of triamcinolone intravitreal injection on the wound healing processes after argon laser retinal photocoagulation, wild type C57BL/6J mice, 8-12 weeks old underwent a standard argon laser photocoagulation protocol. After pentobarbital anesthesia and pupil dilatation, argon laser lesions were induced (50microm, 400mW, 0.05s). Two photocoagulation impacts created two disc diameters from the optic nerve in both eyes. The photocoagulated mice were divided into four groups: Group I (n=12), photocoagulation controls, did not receive any intravitreous injection. Group II (n=12), received an intravitreous injection of 1microl of balanced salt solution (BSS). Group III (n=12), received an intravitreous injection of 1microl containing 15microg of triamcinolone acetonide (TAAC) in BSS. Two mice from each of these three groups were sacrificed at 1, 3, 7, 14 days and 2 and 4 months after photocoagulation. Group IV (n=10) received 1.5, 3, 7.5, 15, or 30microg of TAAC and were all sacrificed on day 14. The enucleated eyes were subjected to systematic analysis of the cellular remodeling processes taking place within the laser lesion and its vicinity. To this purpose, specific antibodies against GFAP, von Willebrand factor, F4/80 and KI67 were used for the detection of astrocytes, activated Müller cells, vascular endothelial cells, infiltrating inflammatory cells and actively proliferating cells. TUNEL reaction was also carried out along with nuclear DAPI staining. Temporal and spatial observations of the created photocoagulation lesions demonstrate that 24h following the argon laser beam, a localized and well-delineated affection of the RPE cells and choroid is observed in mice in Groups I and II. The inner retinal layers in these mice eyes are preserved while TUNEL positive (apoptotic) cells are observed at the retinal outer nuclear layer level. At this stage, intense staining with GFAP is associated with activated retinal astrocytes and Müller cells throughout the laser path. From day 3 after photocoagulation, dilated new choroidal capillaries are detected on the edges of the laser lesion. These processes are accompanied by infiltration of inflammatory cells and the presence of proliferating cells within the lesion site. Mice in Group III treated with 15microg/mul of triamcinolone showed a decreased number of infiltrating inflammatory cells and proliferating cells, which was not statistically significant compared to uninjected laser treated controls. The development of new choroidal capillaries on the edges of the laser lesion was also inhibited during the first 2 months after photocoagulation. However, on month 4 the growth of new vessels was observed in these mice treated with TAAC. Mice of Group IV did not show any development of new capillaries even with small doses. After argon laser photocoagulation of the mouse eye, intravitreal injection of triamcinolone markedly influenced the retina and choroid remodeling and healing processes. Triamcinolone is a powerful inhibitor of the formation of neovessels in this model. However, this inhibition is transient. These observations should provide a practical insight for the mode of TAAC use in patients with wet AMD.

Prevalence and significance of anti-HILA antibodies after liver transplantation : P236

Background: The pathogenic role of anti-HLA antibodies (AHA) after kidney transplantation is well established. However, its significance after liver transplantation remains unclear. The aim of our study was to determine the prevalence and significance of AHA after liver transplantation. Methods: Between January 2007 and November 2007, all liver transplant recipients who were greater than 6 months posttransplantation and followed regularly at our transplant outpatient clinic (n = 95) were screened for AHA. All clinical and electronic records were reviewed. Serum samples were tested using multiplex technology (Luminex). A liver biopsy had been performed in 55 out of the 95 patients based on clinical grounds but no routine protocol biopsies were performed. Immunosuppression was calcineurin inhibitor-based in 90 patients, sirolimus-based in 4 patients and one patient had no anti-rejection therapy (operationally tolerant recipient). Results: The mean time from transplantation to study was 85 months (range 6-248 months). Overall, AHA were found in 23/95 (24.2%) of patients (5 had anti-class I alone, 13 anti-class II alone, and 4 had both anti-class I and II). However, only 4/95 patients (4.2%) had donor-specific antibodies (DSA) (one anti-class I and 3 anti-class II). Twenty-one out of 95 patients (22.1%) had a history of past or current biopsy-proven or radiological biliary complications (chronic rejection, ischemic cholangitis, ischemic type biliary lesions or biliary anastomosis stricture). Among patients with AHA, 4/23 (17,4%) had biliary complications, while it was 17/72 (23.6%) in patients without AHA (NS). Among patients with DSA, 3/4 (75%) had biliary complications (two with biopsy-proven chronic rejection in association with biliary strictures and one with ischemic cholangitis following hepatic artery thrombosis), versus 1/19 (5.3%) patients with AHA but no DSA (p = 0.009), versus 16/72 (22.2%) patients without AHA (p = 0.046). In patients with DSA, immunosuppression was not different than in patients without DSA. Conclusions: We found a 24% AHA prevalence. The presence of DSA, but not of AHA, was significantly associated with an increased incidence of biliary complications including chronic liver allograft rejection. The exact mechanisms and possible causal relationship linking DSA to biliary complications remain to be studied. Larger prospective trials are thus needed to further define the role of AHA and in particular of DSA after liver transplantation.

Prevalence, awareness and treatment of type 2 diabetes mellitus in Switzerland: the CoLaus study.

ABSTRACT: Aims To assess the prevalence, awareness and treatment levels of Type 2 diabetes in a Swiss city. Methods Population-based cross-sectional study of 6181 subjects (3246 women) aged 35-75 years living in Lausanne, Switzerland. Type 2 diabetes was defined as fasting plasma glucose >/= 7 mmol/l and/or oral hypoglycaemic treatment and/or insulin. Results Total prevalence of Type 2 diabetes was 6.3% (95% confidence interval: 5.7-7.0%), higher in men (9.1%) than in women (3.8%, P < 0.001) and increased with age. Two-thirds (65.3%; 60.4-70.0%) of participants with Type 2 diabetes were aware of their status and among those aware 86.0% (81.5-90.3%) were treated. Treatment was more frequent in men (91.3%) than in women (75.9%, P < 0.001). Two-thirds of those treated for Type 2 diabetes were on monotherapy. Biguanides were prescribed in 65.0% of Type 2 diabetes patients and represented 48% of all antidiabetic drugs. Multivariable analysis showed male gender, increasing age, waist or BMI to be positively associated with prevalence of Type 2 diabetes, while leisure-time physical activity and alcohol consumption were negatively associated. Among participants presenting with Type 2 diabetes, increasing age was positively associated with awareness of Type 2 diabetes. Among subjects diagnosed with Type 2 diabetes, male gender and increasing age were positively associated with treatment. Conclusion Prevalence of Type 2 diabetes in Switzerland is estimated to be between 5.7% and 7.0%. Two-thirds of patients with Type 2 diabetes are aware of their status, and over three quarters of those aware are treated.

L'implication des cellules de type cellules souches cancéreuses dans la résistance aux drogues du neuroblastome

Le neuroblastome (NB), tumeur spécifique de l'enfant, se situe au second rang en terme de¦fréquence des tumeurs solides dans la population pédiatrique (1). Il dérive des cellules¦primitives de la crête neurale, une population de cellules embryonnaires dotées d'une¦capacité de différentiation en une panoplie de tissus très variés, dont le système nerveux¦sympathique (2). Cette origine explique la très grande hétérogénéité du NB, tant du point de¦vue biologique que clinique (3). Malgré un traitement intensif et multimodal (chirurgie,¦chimiothérapie à haute dose, greffe de moelle osseuse et immunothérapie), seuls 30 % des¦patients de haut risque (stade IV) survivent sans rechute. La forte résistance du¦neuroblastome de haut grade aux diverses thérapies est une des causes probable du¦pronostic sombre de cette tumeur. Les thérapies actuelles étant insuffisamment efficaces, il¦est primordial de comprendre les mécanismes impliqués dans le processus de résistance¦afin d'élaborer de nouveaux traitements, mieux ciblés, capables de contrer toute résistance¦(4).¦Il a été démontré que certains cancers, tels que les tumeurs du poumon, du sein, de la¦prostate ou du colon, possédaient des cellules souches cancéreuses (CSCs) (5). Ces¦dernières, définies comme étant une petite sous-population de cellules malignes, jouent un¦rôle prépondérant dans l'initiation et la progression tumorale. Elles partagent certaines¦propriétés avec les cellules souches physiologiques, telles que la capacité d'autorenouvellement,¦un potentiel de prolifération indéfini, une dépendance à un¦microenvironnement spécifique, une faculté de pluripotence et une résistance accrue aux¦drogues (6). Ce modèle de CSCs a également été étudié pour le NB (7), permettant ainsi¦d'avancer l'hypothèse selon laquelle cette population de CSCs serait responsable de la¦résistance aux chimiothérapies des cellules tumorales du NB.¦Afin de tenter d'éclaircir le caractère résistant aux drogues des CSCs du NB, nous avons¦sélectionné des sous-populations cellulaires résistantes, en traitant par divers agents¦cytotoxiques (cisplatine, doxorubicine, rapamycine et vincristine) cinq lignées différentes de¦neuroblastes. Dans le but d'établir un potentiel enrichissement en CSCs au sein de ces¦sous-populations par rapport aux populations contrôles non traitées, nous avons testé leurs¦fonctions d'auto-renouvellement et de clonogénicité. Ces propriétés ont été respectivement¦mises en évidence par la capacité des cellules à former des sphères de plusieurs¦générations dans des conditions de culture inhibant l'adhésion cellulaire et par la mesure de¦la croissance cellulaire en milieu semi-solide (soft agar assay). Une analyse d'expression¦génique effectuée préalablement par microarray (Human Genome U133Plus 2.0 Affymetrix¦GeneChip oligonucleotide) dans le laboratoire avait révélé une liste de gènes surexprimés¦dans les CSCs, dont fait partie mdr1 (8). Ce gène code la protéine de transport Pgp (Pglycoprotein),¦impliquée dans le mécanisme de résistance (9,10). Une étude par cytométrie¦en flux de l'expression de MDR1 dans nos diverses populations a également été réalisée¦afin de mettre en évidence une potentielle surexpression de ce gène au sein des cellules¦résistantes aux chimiothérapies.

cGMP-dependent protein kinase type I is implicated in the regulation of the timing and quality of sleep and wakefulness.

Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1-4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep.

Reduction of Concrete Deterioration by Ettringite Using Crystal Growth Inhibition Techniques: Part II Field Evaluation of Inhibitor Effectiveness, TR-469, 2004

The effects of diethylenetriaminpenta(methylenephosphonic acid) (DTPMP), a phosphonate inhibitor, on the growth of delayed ettringite have been evaluated using concrete in highway US 20 near Williams, Iowa, and the cores of six highways subject to moderate (built in 1992) or minor (built in 1997) deterioration. Application of 0.01 and 0.1 vol. % DTPMP to cores was made on a weekly or monthly basis for one year under controlled laboratory-based freeze-thaw and wet-dry conditions over a temperature range of -15 degrees to 58 degrees C to mimic extremes in Iowa roadway conditions. The same concentrations of phosphonate were also applied to cores left outside (roof of Science I at Iowa State University) over the same period of time. Nineteen applications of 0.1 vol. % DTPMP with added deicing salt solution (about 23 weight % NACL) were made to US 20 during the winters of 2003 and 2004. In untreated samples, air voids, pores, and occasional cracks are lined with acicular ettringite crystals (up to 50 micrometers in length) whereas air voids, pores, and cracks in concrete from the westbound lane of US 20 are devoid of ettringite up to a depth of about 0.5 mm from the surface of the concrete. Ettringite is also absent in zones up to 6 mm from the surface of concrete slabs placed on the roof of Science I and cores subject to laboratory-based freeze-thaw experiments. In these zones, the relatively high concentration of DTPMP caused it to behave as a chelator. Stunted ettringite crystals 5 to 25 micrometers in length, occasionally coated with porlandite, form on the margins of these zones indicating that in these areas DTPMP behaved as an inhibitor due to a reduction in the concentration of phosphonate. Analyses of mixes of ettringite and DTPMP using electrospray mass spectrometry suggests that the stunting of ettringite growth is caused by the adsorption of a Ca2+ ion and a water molecule to deprotonated DTPMP on the surface of the {0001} face of ettringite. It is anticipated that by using a DTPMP concentration of between 0.001 and 0.01 vol. % for the extended life of a highway (i.e. >20 years), deterioration caused by the expansive growth of ettringite will be markedly reduced.

The ADVANCE trial: clarifying the role of perindopril/indapamide fixed-dose combination in the reduction of cardiovascular and renal events in patients with diabetes mellitus.

Patients with type 2 diabetes mellitus exhibit a marked increase in cardiovascular and renal risk. A number of interventional trials have shown that these patients benefit greatly from aggressive BP lowering, especially when the drug regimen comprises an inhibitor of the renin-angiotensin system. The results of the placebo-controlled ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial, conducted in patients with type 2 diabetes, are exemplary in this respect. The systematic use of a fixed-dose combination containing the ACE inhibitor perindopril and the diuretic indapamide afforded substantial protection against cardiovascular mortality and myocardial infarction, while providing important renoprotection, reducing the development of micro- and macroalbuminuria, and allowing regression of nephropathy. The beneficial effects were obtained regardless of baseline BP and whether or not the patients were receiving antihypertensive therapy.

Phenotypic and molecular characterization of a novel case of dyssegmental dysplasia, Silverman-Handmaker type.

Dyssegmental dysplasia, Silverman-Handmaker type (DDSH; #MIM 224410) is an autosomal recessive form of lethal dwarfism characterized by a defect in segmentation and fusion of vertebral bodies components ("anisospondyly") and by severe limb shortening. It is caused by mutations in the perlecan gene (HSPG2), but so far, only three molecularly confirmed cases have been reported. We report a novel case of DDSH in a fetus that presented at 15 weeks gestation with encephalocele, severe micromelic dwarfism and narrow thorax. After termination of pregnancy, radiographs showed short ribs, short and bent long bones and anisospondyly of two vertebral bodies. The fetus was homozygous for a previously undescribed null mutation in HSPG2.

French Swiss physicians' attitude toward palliative sedation: Influence of prognosis and type of suffering.

OBJECTIVE: Palliative sedation is a last resort medical act aimed at relieving intolerable suffering induced by intractable symptoms in patients at the end-of-life. This act is generally accepted as being medically indicated under certain circumstances. A controversy remains in the literature as to its ethical validity. There is a certain vagueness in the literature regarding the legitimacy of palliative sedation in cases of non-physical refractory symptoms, especially "existential suffering." This pilot study aims to measure the influence of two independent variables (short/long prognosis and physical/existential suffering) on the physicians' attitudes toward palliative sedation (dependent variable). METHODS: We used a 2 × 2 experimental design as described by Blondeau et al. Four clinical vignettes were developed (vignette 1: short prognosis/existential suffering; vignette 2: long prognosis/existential suffering; vignette 3: short prognosis/physical suffering; vignette 4: long prognosis/physical suffering). Each vignette presented a terminally ill patient with a summary description of his physical and psychological condition, medication, and family situation. The respondents' attitude towards sedation was assessed with a six-point Likert scale. A total of 240 vignettes were sent to selected Swiss physicians. RESULTS: 74 vignettes were completed (36%). The means scores for attitudes were 2.62 ± 2.06 (v1), 1.88 ± 1.54 (v2), 4.54 ± 1.67 (v3), and 4.75 ± 1.71 (v4). General linear model analyses indicated that only the type of suffering had a significant impact on the attitude towards sedation (F = 33.92, df = 1, p = 0.000). Significance of the results: The French Swiss physicians' attitude toward palliative sedation is more favorable in case of physical suffering than in existential suffering. These results are in line with those found in the study of Blondeau et al. with Canadian physicians and will be discussed in light of the arguments given by physicians to explain their decisions.

Mating type, mefenoxam sensitivity, and pathotype diversity in Phytophthora infestans isolates from tomato in Brazil

The objective of this work was to characterize 79 Phytophthora infestans isolates collected in tomato (Solanum lycopersicum) fields, as to mating type, mefenoxam sensitivity, and pathotype composition. The isolates were sampled in 2006 and 2007 in seven Brazilian states as well as in the Distrito Federal. They were characterised as to mating type (n=79), sensitivity to fungicide mefenoxam (n=79), and virulence to three major resistance genes Ph-1, Ph-2, and Ph-3/Ph-4 (n=62). All isolates were of the mating type A1. Resistant isolates were detected in all sampled states, and its average frequency was superior to 50%. No difference was detected in pathotype diversity, neither between subpopulations collected in 2006 and 2007 nor between isolates grouped as resistant or intermediately sensitive to mefenoxam. All major resistance genes were overcome at different frequencies: Ph-1, 88.7%; Ph-2, 64.5%; and Ph-3/Ph-4, 25.8%. Isolates with virulence genes able to overcome all major resistance genes were detected at low frequencies. Tomato breeding programs in Brazil must avoid the development of cultivars with resistance based exclusively on major genes.