Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule.

BACKGROUND: Chest pain can be caused by various conditions, with life-threatening cardiac disease being of greatest concern. Prediction scores to rule out coronary artery disease have been developed for use in emergency settings. We developed and validated a simple prediction rule for use in primary care. METHODS: We conducted a cross-sectional diagnostic study in 74 primary care practices in Germany. Primary care physicians recruited all consecutive patients who presented with chest pain (n = 1249) and recorded symptoms and findings for each patient (derivation cohort). An independent expert panel reviewed follow-up data obtained at six weeks and six months on symptoms, investigations, hospital admissions and medications to determine the presence or absence of coronary artery disease. Adjusted odds ratios of relevant variables were used to develop a prediction rule. We calculated measures of diagnostic accuracy for different cut-off values for the prediction scores using data derived from another prospective primary care study (validation cohort). RESULTS: The prediction rule contained five determinants (age/sex, known vascular disease, patient assumes pain is of cardiac origin, pain is worse during exercise, and pain is not reproducible by palpation), with the score ranging from 0 to 5 points. The area under the curve (receiver operating characteristic curve) was 0.87 (95% confidence interval [CI] 0.83-0.91) for the derivation cohort and 0.90 (95% CI 0.87-0.93) for the validation cohort. The best overall discrimination was with a cut-off value of 3 (positive result 3-5 points; negative result <or= 2 points), which had a sensitivity of 87.1% (95% CI 79.9%-94.2%) and a specificity of 80.8% (77.6%-83.9%). INTERPRETATION: The prediction rule for coronary artery disease in primary care proved to be robust in the validation cohort. It can help to rule out coronary artery disease in patients presenting with chest pain in primary care.

Deep hypothermia and rewarming alters glutamate levels and glycogen content in cultured astrocytes.

BACKGROUND: Deep hypothermia has been associated with an increased incidence of postoperative neurologic dysfunction after cardiac surgery in children. Recent studies suggest an excitotoxic mechanism involving overstimulation of glutamate receptors. Extracellular glutamate uptake occurs primarily by astrocytes. Astrocytes also store glycogen, which may be used to sustain the energy-consuming glutamate uptake. Extracellular glutamate and glycogen content were studied during temperature changes mimicking cardiopulmonary bypass in vivo. METHODS: Primary cultures of cerebral cortical astrocytes were used in a specially designed incubator allowing continuous changes of temperature and ambient gas concentrations. The sequence of events was as follows: normothermia, rapid cooling (2.8 degrees C/min) followed by 60 min of deep hypothermia (15 degrees C), followed by rewarming (3.0 degrees C/min) and subsequent 5 h of mild hyperthermia (38.5 degrees C). Two different conditions of oxygenation were studied: (1) normoxia (25% O2, 70% N2, 5% CO2); or (2) hyperoxia (95% O2, 5% CO2). The extracellular glutamate concentrations and intracellular glycogen levels were measured at nine time points. RESULTS: One hundred sixty-two cultures were studied in four independent experiments. The extracellular concentration of glutamate in the normoxic group increased significantly from 35+/-10 nM/mg protein at baseline up to 100+/-15 nM/mg protein at the end of 5 h of mild hyperthermia (P < 0.05). In contrast, extracellular glutamate levels did not vary from control in the hyperoxic group. Glycogen levels decreased significantly from 260+/-85 nM/mg protein at baseline to < 25+/-5 nM/mg protein at the end of 5 h in the normoxic group (P < 0.05) but returned to control levels after rewarming in the hyperoxic group. No morphologic changes were observed in either group. CONCLUSION: The extracellular concentration of glutamate increases, whereas the intracellular glycogen content decreases when astrocytes are exposed to a sequence of deep hypothermia and rewarming. This effect of hypothermia is prevented when astrocytes are exposed to hyperoxic conditions.

Self-reported non-adherence to antiretroviral therapy repeatedly assessed by two questions predicts treatment failure in virologically suppressed patients.

BACKGROUND: The aim of this study was to explore the predictive value of longitudinal self-reported adherence data on viral rebound. METHODS: Individuals in the Swiss HIV Cohort Study on combined antiretroviral therapy (cART) with RNA <50 copies/ml over the previous 3 months and who were interviewed about adherence at least once prior to 1 March 2007 were eligible. Adherence was defined in terms of missed doses of cART (0, 1, 2 or >2) in the previous 28 days. Viral rebound was defined as RNA >500 copies/ml. Cox regression models with time-independent and -dependent covariates were used to evaluate time to viral rebound. RESULTS: A total of 2,664 individuals and 15,530 visits were included. Across all visits, missing doses were reported as follows: 1 dose 14.7%, 2 doses 5.1%, >2 doses 3.8% taking <95% of doses 4.5% and missing > or =2 consecutive doses 3.2%. In total, 308 (11.6%) patients experienced viral rebound. After controlling for confounding variables, self-reported non-adherence remained significantly associated with the rate of occurrence of viral rebound (compared with zero missed doses: 1 dose, hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.72-1.48; 2 doses, HR 2.17, 95% CI 1.46-3.25; >2 doses, HR 3.66, 95% CI 2.50-5.34). Several variables significantly associated with an increased risk of viral rebound irrespective of adherence were identified: being on a protease inhibitor or triple nucleoside regimen (compared with a non-nucleoside reverse transcriptase inhibitor), >5 previous cART regimens, seeing a less-experienced physician, taking co-medication, and a shorter time virally suppressed. CONCLUSIONS: A simple self-report adherence questionnaire repeatedly administered provides a sensitive measure of non-adherence that predicts viral rebound.

Task 6: Material Thermal Input for Iowa Materials, May 2008

The present research project was designed to determine thermal properties, such as coefficient of thermal expansion (CTE) and thermal conductivity, of Iowa concrete pavement materials. These properties are required as input values by the Mechanistic-Empirical Pavement Design Guide (MEPDG). In this project, a literature review was conducted to determine the factors that affect thermal properties of concrete and the existing prediction equations for CTE and thermal conductivity of concrete. CTE tests were performed on various lab and field samples of portland cement concrete (PCC) at the Iowa Department of Transportation and Iowa State University. The variations due to the test procedure, the equipment used, and the consistency of field batch materials were evaluated. The test results showed that the CTE variations due to test procedure and batch consistency were less than 5%, and the variation due to the different equipment was less than 15%. Concrete CTE values were significantly affected by different types of coarse aggregate. The CTE values of Iowa concrete made with limestone+graval, quartzite, dolomite, limestone+dolomite, and limestone were 7.27, 6.86, 6.68, 5.83, and 5.69 microstrain/oF (13.08, 12.35, 12.03, 10.50, and 10.25 microstrain/oC), respectively, which were all higher than the default value of 5.50 microstrain/oF in the MEPDG program. The thermal conductivity of a typical Iowa PCC mix and an asphalt cement concrete (ACC) mix (both with limestone as coarse aggregate) were tested at Concrete Technology Laboratory in Skokie, Illinois. The thermal conductivity was 0.77 Btu/hr•ft•oF (1.33 W/m•K) for PCC and 1.21 Btu/hr•ft•oF (2.09 W/m•K) for ACC, which are different from the default values (1.25 Btu/hr•ft•oF or 2.16 W/m•K for PCC and 0.67 Btu/hr•ft•oF or 1.16 W/m•K for ACC) in the MEPDG program. The investigations onto the CTE of ACC and the effects of concrete materials (such as cementitious material and aggregate types) and mix proportions on concrete thermal conductivity are recommended to be considered in future studies.

Mechanisms involved in the maintenance of inbreeding depression in gynodioecious "Silene vulgaris" (Caryophyllaceae): an experimental investigation

Summary Gynodioecy, the joint occurrence of females and hermaphrodites within natural populations, is a widely studied mating system ever since Darwin (1877). It is an exceptional mating system because continuous selection is necessary to maintain it. Since females only reproduce through ovules whereas hermaphrodites transmit genes through ovules and pollen, larger female fitness, in terms of seed output, is required to allow their maintenance. Two non-exclusive mechanisms can account for the maintenance of females. First, as females do not produce pollen they can reallocate their resources towards a higher ovule production. Second, hermaphrodites can self- and cross-fertilize whereas females are obligate outcrossers. Thus hermaphrodites should partly suffer from inbreeding depression (i.e.: the fitness decline of inbred relative to outbred individuals) and thereby produce less fit progeny than females. This thesis investigated the effects of self- and cross-fertilization of heimaphrodites over two consecutive generations. Inbreeding depression increased across the successive stages of the life- cycle (i.e.: from "seed traits" to "reproductive traits") displaying large inbreeding depression estimates (up to 0.76). This investigation not only detected large inbreeding depression estimates but also detected mechanisms involved in the maintenance of inbreeding depression. For instance cryptic self-incompatibility which is here a larger in vivo pollen performance of distant pollen compared to self-pollen; the expression of inbreeding depression especially in late life-cycle stages, and the appearance of females in the progeny of selfed hermaphrodites. The female biased sex ratio in the progeny of selfed hermaphrodites was a surprising result and could either come from the sex determining mechanisms (complex nucleo-cytoplasmic interaction(s)) and/or from inbreeding depression. Indeed, we not only got females and hermaphrodites but also partial male-sterile (PMS) individuals (i.e.: individuals with differing number of viable stamens). We detected that inbred pollen bearing plants (excluding females) have less viable stamens per flower than outbred plants. A positive correlation was detected between inbreeding depression for the number of viable stamens per flower and the difference in sex ratio between inbred and outbred individuals. A positive relationship was also detected between inbreeding depression for pollen viability and inbreeding depression for number of viable stamens per flower. Each correlation can either account for pleiotropic effects (a major gene acting on the two considered traits) or linkage disequilibrium between genes controlling each of the two related traits. If we hypothesize that these correlations are due to a major gene with pleiotropic effects, the positive relationship between inbreeding depression for number of viable stamens per flower and inbreeding depression for pollen viability showed that deleterious alleles present on a major gene coding for pollen production and viability depressed male fitness within inbred plants. The positive relationship between sex ratio difference between inbred and outbred individuals and inbreeding depression for number of viable stamens per flower indicates that (1) either number of viable stamens per flower is, in addition to inbreeding, also affected by the loci coding for sex determinism or, (2) the presence of females within the progeny of selfed hermaphrodites is a consequence of large inbreeding depression inhibiting pollen production, or (3) sex is here determined by a combination of loci coding for sex expression and inbreeding depression for male reproductive traits. In conclusion, Silene vulgaris has been shown to be a good model for understanding the evolution of mating systems that promote outbreeding. Résumé La gynodïoécie est définie comme étant la présence simultanée d'hermaphrodites et de femelles au sein de populations naturelles d'une même espèce. Ce système de reproduction a toujours fasciné le monde scientifique depuis Darwin, comme en témoigne ses écrits (1876, 1877) sur les systèmes de reproduction chez les plantes. Les femelles ne transmettent leurs gènes qu'à travers leurs ovules alors que les hermaphrodites transmettent leurs gènes à la fois par la voie mâle (le pollen) et la voie femelle (les ovules). La condition pour que la gynodïoécie se maintienne nécessite donc une fitness de la fonction femelle plus élevée chez les femelles que chez les hermaphrodites. Deux mécanismes mutuellement non exclusifs peuvent expliquer le maintien des femelles au sein de ces populations gynodioïques. D'une part, les femelles peuvent réallouer les ressources non utilisées pour la production de pollen et peuvent par conséquent produire plus d'ovules. D'autre part, la reproduction des femelles ne peut se faire que par allo-fécondation alors que les hermaphrodites, peuvent se reproduire à la fois par auto- et allo-fécondation. L'autofécondation s'accompagne en général d'une diminution de fitness de la descendance relativement à la progéniture issue d'allo-fécondation ; ce phénomène est connu sous le nom de dépression de consanguinité. Cette thèse avait pour but de mettre en évidence une éventuelle dépression de consanguinité chez Silene vulgaris, une espèce gynodioïque. Des hermaphrodites, issus de trois vallées alpines, ont été auto- et allo¬fécondés sur deux générations successives. La dépression de consanguinité pouvant s'exprimer à tous les stades de vie d'un individu, plusieurs traits de fitness, allant du nombre de graines par fruit à la production de gamètes ont été mesurés sur différents stades de vie successifs. L'estimation de la dépression de consanguinité totale atteignait des valeurs allant de 0.52 à 0.76 selon la vallée considérée, ce qui indiquerait que les hermaphrodites ont tout intérêt à limiter l'autofécondation et que les femelles ne devraient pas avoir de peine à subsister dans les vallées étudiées. Par la même occasion des mécanismes diminuant la purge potentielle du fardeau génétique, et permettant ainsi le maintien du « niveau » de dépression de consanguinité et par conséquence le maintien de la gynodïoécie ont été mis en évidence. En effet, nos résultats montrent que la dépression de consanguinité s'exprimait tard dans le cycle de vie permettant ainsi à un certain nombre individus consanguins de transmettre leurs allèles délétères à la génération suivante. D'autre part, la croissance in vivo des tubes polliniques d'auto-pollen était plus lente que celle de l'allo-pollen et donc en situation de compétition directe, les ovules devraient plutôt être issus d'allo-fécondation, diminuant ainsi les chances de purges d'allèles délétères. Enfin, l'apparition de femelles dans la progéniture d'hermaphrodites autofécondés diminue aussi les chances de purge d'allèles délétères. Il nous a été impossible de déterminer si l'apparition de femelles dans la descendance d'hermaphrodites autofécondés était due au déterminisme génétique du sexe ou si la différence de sexe ratio entre la descendance auto- et allo-fécondée était due à une éventuelle dépression de consanguinité inhibant la production de pollen. Nous avons observé que S. vulgaris ne présentaient pas uniquement des hermaphrodites et des femelles mais aussi toute sorte d'individus intermédiaires avec un nombre variable d'étamines viables. Nous avons pu mettre' en évidence des corrélations positives entre (1) la différence de sexe ratio (la proportion d'individus produisant du pollen) entre individus consanguins et non consanguins et une estimation de la dépression de consanguinité pour le nombre d'étamines viables d'individus produisant du pollen, ainsi qu'entre (2) la dépression de consanguinité pour le nombre d'étamines viables et celle estimée pour la viabilité du pollen. Chaque corrélation indique soit l'effet d'un (ou plusieurs) gène(s) pléiotropique(s), soit un déséquilibre de liaison entre les gènes. En considérant que ces corrélations sont le résultat d'effet pléiotropiques, la relation entre le nombre d'étamines viables par fleur et la viabilité du pollen, indiquerait un effet négatif de la consanguinité sur la production et la viabilité du pollen due partiellement à un gène majeur. La seconde corrélation indiquerait soit que les gènes responsables de la détermination du sexe agissent aussi sur l'expression de la fonction mâle soit que l'expression du sexe est sujette à la dépression de consanguinité, ou encore un mélange des deux. Aux regards de ces résultats, Silene vulgaris s'est avéré être un bon modèle de compréhension de l'évolution des systèmes de reproduction vers la séparation des sexes.

Mutations in penicillin-binding protein (PBP) genes and in non-PBP genes during selection of penicillin-resistant Streptococcus gordonii.

Penicillin resistance in Streptococcus spp. involves multiple mutations in both penicillin-binding proteins (PBPs) and non-PBP genes. Here, we studied the development of penicillin resistance in the oral commensal Streptococcus gordonii. Cyclic exposure of bacteria to twofold-increasing penicillin concentrations selected for a progressive 250- to 500-fold MIC increase (from 0.008 to between 2 and 4 microg/ml). The major MIC increase (> or = 35-fold) was related to non-PBP mutations, whereas PBP mutations accounted only for a 4- to 8-fold additional increase. PBP mutations occurred in class B PBPs 2X and 2B, which carry a transpeptidase domain, but not in class A PBP 1A, 1B, or 2A, which carry an additional transglycosylase domain. Therefore, we tested whether inactivation of class A PBPs affected resistance development in spite of the absence of mutations. Deletion of PBP 1A or 2A profoundly slowed down resistance development but only moderately affected resistance in already highly resistant mutants (MIC = 2 to 4 microg/ml). Thus, class A PBPs might facilitate early development of resistance by stabilizing penicillin-altered peptidoglycan via transglycosylation, whereas they might be less indispensable in highly resistant mutants which have reestablished a penicillin-insensitive cell wall-building machinery. The contribution of PBP and non-PBP mutations alone could be individualized in DNA transformation. Both PBP and non-PBP mutations conferred some level of intrinsic resistance, but combining the mutations synergized them to ensure high-level resistance (> or = 2 microg/ml). The results underline the complexity of penicillin resistance development and suggest that inhibition of transglycosylase might be an as yet underestimated way to interfere with early resistance development.

Severely presenting strokes : profile & outcome

Etat des connaissances: Les Accidents vasculaires cérébraux (AVC) sévères sont une cause importante de mortalité et de handicap en Suisse. Les buts de cette étude sont de déterminer les caractéristiques des patients avec un AVC à présentation initiale sévère "severely presenting", ainsi que d'identifier les facteurs prédicteurs en phase aigüe et subaigüe d'un devenir favorable chez ces patients. Methodologie: En utilisant le registre des AVC "Acute STroke Registry and Analysis of Lausanne (ASTRAL), nous avons comparé tous les patients avec un AVC "à présentation sévère", defini comme un score National Institute of Health Stroke Scale (NIHSS) > 20 à l'admission aux urgences, avec tous les autres patients du registre. Dans une analyse statistique multivariée, les associations avec les caractéristiques démographiques, cliniques, pathophysiologiques, métaboliques et radiologiques des patients on été déterminées. Dans un deuxième temps, nous avons analysé les facteurs prédicteurs d'un devenir favorable à 3 mois (modified Rankin scale (mRS) <3) dans ce groupe d'AVC à présentation sévère. Resultats: Parmi les 1 '915 patients consécutifs, 243 (12.7%) présentaient un AVC rejoignant la définition de sévère. Ceux-cis étaient associés de manière significative avec un méchanisme ischémique cardio-embolique (OR=1.74 / 95% CI 1.19 - 2.54), un début inconnu de la Symptomatologie (OR=2.35 / 95% CI 1.14 - 4.83), avaient plus de trouvailles d'origine ischémique aigüe lors de l'imagerie dJentrée (la majorité sont des CT-scan, OR=2.65 / 95% CI 1.79 - 3.92), plus d'occlusions dans l'imagerie vasculaire d'admission (OR=27.01 / 95% CI 11.5 - 62.9), moins d'anciens infarctus cérébraux sur l'imagerie (OR=0.43 / 95% 0.26¬0.72), un taux d'haemoglobine plus bas en g/1 (OR=0.97 / 95% CI 0.96 - 0.99), un taux de leucocytes plus élevé par 1000 cells/1 (OR=1.05 / 95%CI 1.00 - 1.11). parmi les 68 (28%) patients avec un devenir favorable malgré un AVC initialement sévère, leur évolution favorable à été associée avec un âge plus jeune (OR=0.94 / 95% CI 0.92 - 0.97), la présence d'évenements cérébrovasculaires antécédants (OR=3.00 / 95% CI 1.01 - 8.97), un traitement hypolipémiant déjà présent (OR= 3.82 / 95% CI 1.34 - 10.90), une température corporelle d'admission plus basse (0R=0.43 1 95% CI 0.23 - 0.78), une concentration subaigüe de glucose plus basse (OR=0.74 1 95% CI 0.56 - 0.97), et une recanalisation spontanée ou par thrombolyse à 24h (OR= 4.51 1 95%CI 1.96- 10.41). Conclusion: les AVC à présentation initiale severe sont associés à des facteurs prédicteurs cliniques, radiologiques, et métaboliques multiples, dont certains sont modifiables. Les facteurs prédicteurs des 28% de patients avec un devenir favorable en dépit d'un AVC intitialement sévère sont un pré-traitement par hypolipémiants, une temperature corporelle plus basse à l'admission, une glycémie plus basse à 24heures et la recanalisation artérielle.

Dosimetry of 90Y-ibritumomab tiuxetan as consolidation of first remission in advanced-stage follicular lymphoma: results from the international phase 3 first-line indolent trial.

The objective of this analysis was to assess the radiation exposure associated with (90)Y-ibritumomab tiuxetan when used as consolidation therapy in adults with low or minimal tumor burden after first-line therapy of advanced follicular lymphoma (FL). METHODS: The patients who were enrolled in the phase 3 first-line indolent trial were 18 y or older, with CD20(+) grade 1 or 2 stage III or IV FL, and a partial response, complete response, or unconfirmed complete response to first-line chemotherapy. The patients were allocated randomly to receive a single infusion of unlabeled rituximab 250 mg/m(2) on day -7 and consolidation on day 0 with a single dose of (90)Y-ibritumomab tiuxetan, 14.8 MBq/kg, immediately after unlabeled rituximab, 250 mg/m(2), or no further treatment. On day -7, a subset of patients received an injection of 185 MBq of (111)In-ibritumomab tiuxetan immediately after unlabeled rituximab, 250 mg/m(2), for central dosimetry analysis. Correlations were assessed between organ radiation absorbed dose and toxicity, body weight, body mass index, and progression-free survival. RESULTS: Central dosimetry evaluations were available from 57 of 70 patients. Median radiation absorbed doses were 100 cGy (range, 28-327 cGy) for the red marrow and 72 cGy (range, 46-106 cGy) for the whole body. Radiation absorbed doses did not differ significantly between patients who had a partial response or complete response to initial therapy. Progression-free survival correlated significantly with the whole-body (r = 0.4401; P = 0.0006) and bone marrow (r = 0.2976; P = 0.0246) radiation dose. Body weight was significantly negatively correlated with whole-body radiation dose (r = -0.4971; P < 0.0001). Neither the whole-body radiation dose nor the bone marrow radiation dose correlated with hematologic toxicity. CONCLUSION: In patients with low or minimal residual tumor burden after first-line chemotherapy of advanced FL, whole-body and bone marrow exposure after (90)Y-ibritumomab tiuxetan consolidation showed a significant positive correlation with progression-free survival, whereas dosimetric data could not predict hematologic toxicity.

Accuracy of prehospital triage of trauma patients by emergency physicians: a retrospective study in western Switzerland.

OBJECTIVE: Accurate identification of major trauma patients in the prehospital setting positively affects survival and resource utilization. Triage algorithms using predictive criteria of injury severity have been identified in paramedic-based prehospital systems. Our rescue system is based on prehospital paramedics and emergency physicians. The aim of this study was to evaluate the accuracy of the prehospital triage performed by physicians and to identify the predictive factors leading to errors of triage.METHODS: Retrospective study of trauma patients triaged by physicians. Prehospital triage was analyzed using criteria defining major trauma victims (MTVs, Injury Severity Score >15, admission to ICU, need for immediate surgery and death within 48 h). Adequate triage was defined as MTVs oriented to the trauma centre or non-MTV (NMTV) oriented to regional hospitals.RESULTS: One thousand six hundred and eighti-five patients (blunt trauma 96%) were included (558 MTV and 1127 NMTV). Triage was adequate in 1455 patients (86.4%). Overtriage occurred in 171 cases (10.1%) and undertriage in 59 cases (3.5%). Sensitivity and specificity was 90 and 85%, respectively, whereas positive predictive value and negative predictive value were 75 and 94%, respectively. Using logistic regression analysis, significant (P<0.05) predictors of undertriage were head or thorax injuries (odds ratio >2.5). Predictors of overtriage were paediatric age group, pedestrian or 2 wheel-vehicle road traffic accidents (odds ratio >2.0).CONCLUSION: Physicians using clinical judgement provide effective prehospital triage of trauma patients. Only a few factors predicting errors in triage process were identified in this study.

Coronary artery disease screening in diabetic patients: how good is guideline adherence?

INTRODUCTION: Diabetic patients are at high risk for coronary artery disease (CAD), which is the leading cause of death in this population. The Swiss Society of Endocrinology-Diabetology (SSED) recommends CAD screening for diabetic patients with > or = 2 additional cardiovascular risk factors (CVRF), by stress echocardiography (SE) or myocardial perfusion imaging (MPI). The aim of this study was to assess the application of these guidelines and the treatment of CVRF in the diabetes outpatient clinics of the five Swiss University Hospitals. METHODS: The study was initiated in Lausanne and the study questionnaires were circulated to the endocrinologists of the five Swiss University Hospitals. Practitioners were asked to include consecutive patients attending the diabetes outpatient clinics over one month. Prevalence of CAD, screening methods for CAD, prevalence of CVRF, biological analyses over the last 6 months and medical therapy were recorded. RESULTS: A total of 302 subjects were included. The mean age was 53 +/- 14 years, 68% had type 2 diabetes, 27% type 1 and 5% other types. Among T2DM with > or = 2 CVRF, 45% were screened for CAD according to SSED guidelines. In T2DM 25% had blood pressure < or = 130/80 mm Hg, 15% a lipid profile within target, 23% HbA1c < or = 7.0%. Overall, 2% achieved all 3 targets. CONCLUSIONS: Only 45% of T2DM with > or = 2 CVRF were screened for CAD according to SSED guidelines and 2% of T2DM had proper control over all CVRF. Efforts are still necessary to improve CAD prevention and screening of diabetic patients in Swiss University Hospitals.

Early production of IL-4 in susceptible mice infected with Leishmania major rapidly induces IL-12 unresponsiveness.

Previous results have documented a burst of IL-4 mRNA that peaks in draining lymph nodes of susceptible BALB/c mice 16 h after infection with Leishmania major. The importance of this early IL-4 response in subsequent Th2 cell maturation is supported by observations showing that 1) neutralization of IL-4 at the initiation of infection or 2) administration of IL-12, which results in an inhibition of the 16 h IL-4 mRNA burst, inhibits Th2 cell development. However, both treatments are effective in hampering Th2 cell development only if given at a time when IL-4 has been produced for &lt;48 h. At this time after infection, lymph node CD4+ T cells from BALB/c mice no longer respond to IL-12. This IL-12 unresponsiveness is prevented in mice treated with anti-IL-4 Abs at the initiation of infection. Finally, the inhibition of Th2 development in BALB/c mice treated with anti-IL-4 Abs at the onset of infection results from maintenance of IL-12 responsiveness, since it requires IL-12. Together, these results reveal a narrow window of time, between 16 h and &lt;48 h after infection, during which IL-4 produced rapidly in BALB/c mice renders T cells unresponsive to IL-12, allowing their differentiation toward the Th2 phenotype.

Effect of different G protein-coupled receptor kinases on phosphorylation and desensitization of the alpha1B-adrenergic receptor.

The alpha1B-adrenergic receptor (alpha1BAR), its truncated mutant T368, different G protein-coupled receptor kinases (GRK) and arrestin proteins were transiently expressed in COS-7 or HEK293 cells alone and/or in various combinations. Coexpression of beta-adrenergic receptor kinase (betaARK) 1 (GRK2) or 2 (GRK3) could increase epinephrine-induced phosphorylation of the wild type alpha1BAR above basal as compared to that of the receptor expressed alone. On the other hand, overexpression of the dominant negative betaARK (K220R) mutant impaired agonist-induced phosphorylation of the receptor. Overexpression of GRK6 could also increase epinephrine-induced phosphorylation of the receptor, whereas GRK5 enhanced basal but not agonist-induced phosphorylation of the alpha1BAR. Increasing coexpression of betaARK1 or betaARK2 resulted in the progressive attenuation of the alpha1BAR-mediated response on polyphosphoinositide (PI) hydrolysis. However, coexpression of betaARK1 or 2 at low levels did not significantly impair the PI response mediated by the truncated alpha1BAR mutant T368, lacking the C terminus, which is involved in agonist-induced desensitization and phosphorylation of the receptor. Similar attenuation of the receptor-mediated PI response was also observed for the wild type alpha1BAR, but not for its truncated mutant, when the receptor was coexpressed with beta-arrestin 1 or beta-arrestin 2. Despite their pronounced effect on phosphorylation of the alpha1BAR, overexpression of GRK5 or GRK6 did not affect the receptor-mediated response. In conclusion, our results provide the first evidence that betaARK1 and 2 as well as arrestin proteins might be involved in agonist-induced regulation of the alpha1BAR. They also identify the alpha1BAR as a potential phosphorylation substrate of GRK5 and GRK6. However, the physiological implications of GRK5- and GRK6-mediated phosphorylation of the alpha1BAR remain to be elucidated.

Association between foot growth and musculoskeletal loading in children with Prader-Willi syndrome before and during growth hormone treatment

OBJECTIVE: To explore how foot growth relates to musculoskeletal loading in children with Prader-Willi syndrome (PWS). STUDY DESIGN: In 37 children with PWS, foot length (FL) before and after 6 years of growth hormone therapy (GHT) was retrospectively evaluated with parental and sibling's FL, height, and factors reflecting musculoskeletal loading, such as weight for height (WfH), lean body mass (LBM; dual energy X-ray absorptiometry, deuterium labeled water), physical activity (accellerometry), and walk age. Because of the typically biphasic evolution of body mass and the late walk age in PWS, 2 age groups were separated (group 1, >2.5 years; group 2, < or =2.5 years). RESULTS: Children with PWS normalized height, but not FL after 6 years of GHT. Parental FL correlation with PWS's FL was lower than with sibling's FL. In group 1, FL positively correlated with WfH, LBM, and physical activity. In group 2, FL negatively correlated with age at onset of independent ambulation. Foot catch-up growth with GHT was slower in group 2 compared with group 1. CONCLUSION: In PWS, FL is positively associated with musculoskeletal loading. Small feet in children with PWS before and during long-term GHT may be more than just another dysmorphic feature, but may possibly reflect decreased musculoskeletal loading influencing foot growth and genetic and endocrine factors.

Female thyroid cancer : the role of reproductive and hormonal factors in Switzerland

We conducted a study on 91 women with thyroid cancer and 306 controls in hospital for acute nonneoplastic, non-hormone-related disorders in order to investigate the role of reproductive and hormonal factors in the etiology of epithelial thyroid cancer in the Canton of Vaud, Switzerland. Non-significant increases in cancer risk with an increasing number of full-term pregnancies (odds ratio, OR, after allowance for age and previous benign thyroid disease = 1.6, for > or = 3 vs. 0 full-term pregnancies, 95% confidence interval, CI: 0.7-3.6) and spontaneous abortions (OR = 2.0 for > or = 2 vs. 0 spontaneous abortions, 95% CI: 0.7-5.2) were seen. A significantly elevated OR (2.8, 95% CI: 1.1-7.2) was found in those women whose first pregnancy ended with an abortion. Whereas most other reproductive, menstrual and hormonal factors examined did not seem to affect the risk of thyroid cancer significantly, a clue emerged of an association between thyroid cancer and artificial menopause (OR = 6.3, for women who underwent artificial menopause vs. premenopausal women, 95% CI: 1.7-23.2). Although not necessarily causal, the relationship between the risk of epithelial thyroid cancer and the occurrence of spontaneous abortions and artificial menopause deserves attention in future studies, in the light of the high incidence of thyroid cancer in young and middle-aged women.

Previous thyroid disease and risk of thyroid cancer in Switzerland

A hospital-based case-control study of 86 cases of thyroid cancer and 317 controls was done in the Swiss Canton of Vaud. Patients with thyroid cancer tended to be better educated (odds ratio [OR] 2.1 for greater than or equal to 14 vs. less than or equal to 8 years of education 95% CI 1.1-4.1) and of higher social class than controls. Cases more often had a history of benign thyroid nodules (OR 25.2, 95% CI 7.6-83.6) and non-toxic goitre (OR 5.3, 95% CI 2.5-11.2). Furthermore, patients with thyroid cancer were more likely to have resided in endemic goitre areas (OR 1.7, 95% CI 1.0-3.0) and to have had first-degree relatives affected by benign thyroid disease (OR 3.9, 95% CI 2.1-7.1). Therefore, this study offers quantitative evidence of the association between various thyroid diseases and the risk of thyroid cancer which, despite difficulties in the classification of benign and malignant thyroid diseases, is remarkably consistent in studies from different countries.