Enteral versus parenteral nutrition: comparison of energy metabolism in lean and moderately obese women.

Continuous respiratory-exchange measurements were performed on ten moderately obese and ten lean young women for 1 h before, 3 h during, and 3 h after either parenteral (IV) or intragastric (IG) administration of a nutrient mixture infused at twice the postabsorptive, resting energy expenditure (REE). REE rose significantly from 0.98 +/- 0.02 to 1.13 +/- 0.03 kcal/min (IV) and from 0.99 +/- 0.02 to 1.13 +/- 0.02 kcal/min (IG) in the lean group; from 1.10 +/- 0.02 to 1.27 +/- 0.03 kcal/min (IV) and from 1.11 +/- 0.02 to 1.29 +/- 0.03 (IG) in the obese group. These increases resulted in similar nutrient-induced thermogenesis of 10.0 +/- 0.7% (IV) and 9.3 +/- 0.9% (IG) in the lean group; of 9.2 +/- 0.7% (IV) and 10.1 +/- 0.8% (IG) in the obese. Nutrient utilization was comparable in both groups and in both routes of administration, although the response time to IG feeding was delayed. These results showed no significant difference in both the thermogenic response and nutrient utilization between moderately obese and control groups using acute IV or IG feeding.

Decision-support tools to manage drug incompatibilities: evaluation by nurses

Introduction Preventing drug incompatibilities has a high impact onthe safety of drug therapy. Although there are no internationalguidelines to manage drug incompatibilities, different decision-supporttools such as handbooks, cross-tables and databases are available.In a previous study, two decision-support tools have been pre-selectedby pharmacists as fitting nurses' needs on the wards1. The objective ofthis study was to have these both tools evaluated by nurses todetermine which would be the most suitable for their daily practice.Materials & Methods Evaluated tools were:1. Cross-table of drug pairs (http://files.chuv.ch/internet-docs/pha/medicaments/pha_phatab_compatibilitessip.pdf)2. Colour-table (a colour for each drug according to the pH: red =acid; blue = basic; yellow = neutral; black = to be infused alone)2Tools were assessed by 48 nurses in 5 units (PICU, adult andgeriatric intensive care, surgery, onco-hematology) using a standardizedform1. The scientific accuracy of the tools was evaluated bydetermining the compatibility of five drugs pairs (rate of correctanswers according to the Trissel's Handbook on Injectable Drugs,chi-square test). Their ergonomics, design, reliability and applicabilitywere estimated using visual analogue scales (VAS 0-10; 0 =null, 10 = excellent). Results are expressed as the median and interquartilerange (IQR) for 25% and 75% (Wilcoxon rank sum test).Results The rate of correct answers was above 90% for both tools(cross-table 96.2% vs colour-table 92.5%, p[0.05).The ergonomics and the applicability were higher for the crosstable[7.1 (IQR25 4.0, IQR75 8.0) vs 5.0 (IQR25 2.7, IQR75 7.0), p =0.025 resp. 8.3 (IQR25 7.4, IQR75 9.2) vs 7.6 (IQR25 5.9, IQR75 8.8)p = 0.047].The design of the colour-table was judged better [4.6 (IQR25 2.9,IQR75 7.1) vs 7.1 (IQR25 5.4, IQR75 8.4) p = 0.002].No difference was observed in terms of reliability [7.3 (IQR25 6.5,IQR75 8.4) vs 6.7 (IQR25 5.0, IQR758.6) p[0.05].The cross-table was globally preferred by 65% of the nurses (27%colour-table, 8% undetermined) and 68% would like to have thisdecision-support tool available for their daily practice.Discussion & Conclusion Both tools showed the same accuracy toassess drug compatibility. In terms of ergonomics and applicabilitythe cross-table was better than the colour-table, and was preferred bythe nurses for their daily practice. The cross-table will be implementedin our hospital as decision-support tool to help nurses tomanage drug incompatibilities.

Effectiveness of intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy on placental malaria, maternal anaemia and birthweight in areas with high and low malaria transmission intensity in Tanzania.

OBJECTIVE: To assess the effectiveness of IPTp in two areas with different malaria transmission intensities. METHODS: Prospective observational study recruiting pregnant women in two health facilities in areas with high and low malaria transmission intensities. A structured questionnaire was used for interview. Maternal clinic cards and medical logs were assessed to determine drug intake. Placental parasitaemia was screened using both light microscopy and real-time quantitative PCR. RESULTS: Of 350 pregnant women were recruited and screened for placental parasitaemia, 175 from each area. Prevalence of placental parasitaemia was 16.6% (CI 11.4-22.9) in the high transmission area and 2.3% (CI 0.6-5.7) in the low transmission area. Being primigravida and residing in a high transmission area were significant risk factors for placental malaria (OR 2.4; CI 1.1-5.0; P = 0.025) and (OR 9.4; CI 3.2-27.7; P < 0.001), respectively. IPTp was associated with a lower risk of placental malaria (OR 0.3; CI 0.1-1.0; P = 0.044); the effect was more pronounced in the high transmission area (OR 0.2; CI 0.06-0.7; P = 0.015) than in the low transmission area (OR 0.4; CI 0.04-4.5; P = 0.478). IPTp use was not associated with reduced risk of maternal anaemia or low birthweight, regardless of transmission intensity. The number needed to treat (NNT) was four (CI 2-6) women in the high transmission area and 33 (20-50) in the low transmission area to prevent one case of placental malaria. CONCLUSION: IPTp may have an effect on lowering the risk of placental malaria in areas of high transmission, but this effect did not translate into a benefit on risks of maternal anaemia or low birthweight. The NNT needs to be considered, and weighted against that of other protective measures, eventually targeting areas which are above a certain threshold of malaria transmission to maximise the benefit.

Propagation du virus de la grippe dans les transports aériens et survie du virus dans l'air ambiant

Chaque hiver en France, la grippe saisonnière touche entre 2 et 7 millions de personnes, dont environ 1 000 cas mortels, surtout parmi les personnes de plus de 65 ans. Elle constitue ainsi la première cause de mortalité par maladie infectieuse. L'agent causal est un virus à ARN très contagieux, pouvant appartenir à différent type (A, B ou C). Le type A est composé d'une large gamme de sous-types classés selon les différentes sortes et associations de protéines de surface du virus. Parmi ceux-ci, les sous-types H1N1 et H3N2 circulent actuellement chez l'Homme. La transmission inter-humaine de la maladie se fait principalement par voie aéroportée par le biais des gouttelettes riches en virus provenant des accès de toux et des éternuements des sujets infectés. Le coût sanitaire et social annuel de la grippe est estimé à 460 millions d'euros pour une épidémie moyenne. La prévention de la grippe repose sur une vaccination annuelle, proposée dans la plupart des pays industrialisés aux personnes à risque. Cependant, la couverture vaccinale en France n'était que de 23 % de la population générale en 2011-2012 (62 % chez les plus de 50 ans). Dès lors, environ 80 % des individus sont susceptibles de contracter la maladie. Les transports en commun constituent des environnements idéaux pour la dissémination des virus. En effet, la grande promiscuité entre les passagers potentiellement malades et les passagers sains favorise la propagation de la maladie. Dans ces conditions, l'évaluation du risque d'infection est utile pour appliquer une prévention ciblée. Le but du premier article analysé (Gupta et al., 2012) était, précisément, d'évaluer le risque, pour un passager sain, de contracter le virus de la grippe dans un avion transportant un passager malade. Les auteurs du second article analysé (Pyankov et al., 2012) ont estimé le temps de survie de différents sous-types de virus de la grippe dans l'air ambiant d'une chambre expérimentale.

Quality Assessment of Cardiac Magnetic Resonance Images at 1.5/3.0 T: Description and Validation of Standardized Criteria

PURPOSE: Cardiovascular magnetic resonance (CMR) has become a robust and important diagnostic imaging modality in cardiovascular medicine. However,insufficient image quality may compromise its diagnostic accuracy. No standardized criteria are available to assess the quality of CMR studies. We aimed todescribe and validate standardized criteria to evaluate the quality of CMR studies including: a) cine steady-state free precession, b) delayed gadoliniumenhancement, and c) adenosine stress first-pass perfusion. These criteria will serve for the assessment of the image quality in the setting of the Euro-CMR registry.METHOD AND MATERIALS: First, a total of 45 quality criteria were defined (35 qualitative criteria with a score from 0-3, and 10 quantitative criteria). Thequalitative score ranged from 0 to 105. The lower the qualitative score, the better the quality. The quantitative criteria were based on the absolute signal intensity (delayed enhancement) and on the signal increase (perfusion) of the anterior/posterior left ventricular wall after gadolinium injection. These criteria were then applied in 30 patients scanned with a 1.5T system and in 15 patients scanned with a 3.0T system. The examinations were jointly interpreted by 3 CMR experts and 1 study nurse. In these 45 patients the correlation between the results of the quality assessment obtained by the different readers was calculated.RESULTS: On the 1.5T machine, the mean quality score was 3.5. The mean difference between each pair of observers was 0.2 (5.7%) with a mean standarddeviation of 1.4. On the 3.0T machine, the mean quality score was 4.4. The mean difference between each pair of onservers was 0.3 (6.4%) with a meanstandard deviation of 1.6. The quantitative quality assessments between observers were well correlated for the 1.5T machine: R was between 0.78 and 0.99 (pCONCLUSION: The described criteria for the assessment of CMR image quality are robust and have a low inter-observer variability, especially on 1.5T systems.CLINICAL RELEVANCE/APPLICATION: These criteria will allow the standardization of CMR examinations. They will help to improve the overall quality ofexaminations and the comparison between clinical studies.

Systematic difference between blood pressure readings caused by cuff type.

In this study we determine whether blood pressure readings using a cuff of fixed size systematically differed from readings made with a triple-bladder cuff (Tricuff) that automatically adjusts bladder width to arm circumference and assessed subsequent clinical and epidemiological effects. Blood pressure was measured with a standard cuff or a Tricuff in 454 patients visiting an outpatient clinic in the Seychelles (Indian Ocean). Overall means of within-individual standard cuff-Tricuff differences in systolic and diastolic blood pressures were examined in relation to arm circumference and sex. The standard cuff-Tricuff difference in systolic and diastolic blood pressures increased monotonically with circumference (from 4.7 +/- 0.8/3.2 +/- 0.7 mm Hg for arm circumference of 30 to 31 cm to 10.0 +/- 1.1/8.0 +/- 0.9 mm Hg for arm circumference &gt; or = 36 cm) and was larger in women than men. Multivariate linear regression indicated independent effects of arm circumference and sex. Forty percent of subjects with a diastolic blood pressure of &gt; or = 95 mm Hg measured with a standard cuff had values less than 95 mm Hg measured with a Tricuff. Extrapolation to the entire population of the Seychelles decreased the prevalence of blood pressure greater than or equal to 160/95 mm Hg by 11.5% and 24.0% in men and women, respectively, aged 35 to 64 years. The age-adjusted effect of body mass index on systolic and diastolic blood pressures decreased twofold using blood pressure readings made with a Tricuff instead of a standard cuff.(ABSTRACT TRUNCATED AT 250 WORDS)

Change in physical activity after smoking cessation: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

AIMS: To estimate physical activity trajectories for people who quit smoking, and compare them to what would have been expected had smoking continued. DESIGN, SETTING AND PARTICIPANTS: A total of 5115 participants in the Coronary Artery Risk Development in Young Adults Study (CARDIA) study, a population-based study of African American and European American people recruited at age 18-30 years in 1985/6 and followed over 25 years. MEASUREMENTS: Physical activity was self-reported during clinical examinations at baseline (1985/6) and at years 2, 5, 7, 10, 15, 20 and 25 (2010/11); smoking status was reported each year (at examinations or by telephone, and imputed where missing). We used mixed linear models to estimate trajectories of physical activity under varying smoking conditions, with adjustment for participant characteristics and secular trends. FINDINGS: We found significant interactions by race/sex (P = 0.02 for the interaction with cumulative years of smoking), hence we investigated the subgroups separately. Increasing years of smoking were associated with a decline in physical activity in black and white women and black men [e.g. coefficient for 10 years of smoking: -0.14; 95% confidence interval (CI) = -0.20 to -0.07, P < 0.001 for white women]. An increase in physical activity was associated with years since smoking cessation in white men (coefficient 0.06; 95% CI = 0 to 0.13, P = 0.05). The physical activity trajectory for people who quit diverged progressively towards higher physical activity from the expected trajectory had smoking continued. For example, physical activity was 34% higher (95% CI = 18 to 52%; P < 0.001) for white women 10 years after stopping compared with continuing smoking for those 10 years (P = 0.21 for race/sex differences). CONCLUSIONS: Smokers who quit have progressively higher levels of physical activity in the years after quitting compared with continuing smokers.

Outcome after surgical treatment of symptomatic delayed unions and nonunions of midshaft clavicle fractures

Introduction: Nonoperative treatment of displaced midshaft clavicle fractures is associated with higher nonunion rate than previously reported. Moreover, its occurrence can compromise shoulder function. The aim of this study was to evaluate the outcome of surgical treatment of symptomatic clavicle midshaft delayed and nonunion. Methods: Between 1999 and 2008, 19 clavicle delayed unions and nonunions were treated by open reduction and reconstructive plate fixation with augmentation by autologous bone graft. Iliac bone graft was used in 15 atrophic cases, and graft from the callus was used in 4 hypertrophic nonunions. There were 14 men and 5 women, with an average age of 41 years (range, 19 to 59 years) at time of surgery. No patient had undergone a previous surgery and all complained of shoulder pain. Delayed unions and nonunions were defined as non-healing after 3 and 6 months respectively. The mean time to surgery was 8 months (range, 4 to 23 months). All patients were pre and postoperatively clinically evaluated and imaged with standard radiographs until complete healing. Results: After a mean time of 3 months (range, 2 to 7 months) all fractures were completely healed. All patients reported full range of motion at time of last follow-up. Nine patients (47%) reported slight shoulder pain but all returned to their previous professional activities after a mean time of 3 months (range, 1 to 8 months). We reported 12 (63%) minor complications. There were 6 (32%) plate-related discomforts which resolved after hardware removal, two (11%) scar numbness, two (11%) adhesive capsulitis with spontaneous complete recovery, and two (11%) AC-joint pain treated successfully with local corticosteroids injection. Conclusion: Surgical treatment of delayed unions and nonunions of midshaft clavicle fractures yields satisfactory results and a high union rate. However, 50% of the patients may still complain of slight residual shoulder pain.

Revue des cas d'intoxication aux champignons dans un service d'urgence entre 2005 et 2011

Introduction: Les services d'urgences sont régulièrement confrontés à des intoxications par ingestion de champignons. Ces situations, souvent banales, peuvent nécessiter une prise en charge intensive et comporter un risque réel de morbi-mortalité, en particulier lors de cytolyse hépatique aiguë. La prévalence, ainsi que la fréquence réelle des complications liées à l'ingestion de champignons sont mal connues. Méthodes: Etude rétrospective dans un service d'urgence universitaire entre décembre 2004 et octobre 2011. Les codes diagnostics «intoxication aux champignons», ainsi que les termes «amanite» ou «champignons» ont été extraits de la base de données des urgences. Les caractéristiques des patients, leurs présentations cliniques, durées de séjour et complications ont été analysées. Résultats: 72 cas ont été répertoriés et revus, âge 44,3 ± 2,0 ans (moy ± SE, 95%CI 40,2-48,4), ratio H:F 1:1,2 (33H, 39F). 81% des cas sont survenus entre août et décembre. 14 cas sont arrivés sous forme de clusters familiaux (35 patients, moyenne = 2,6 cas/cluster, min: 2, max: 7). Un spécialiste en mycologie a été contacté dans 25 cas pour identifier les champignons. 69 patients (96%) sont rentrés à domicile depuis les urgences (séjour de 10,8 ± 1,3 heures, 95%CI 8,2-13,4 h). Lorsque les symptômes survenaient <= 4 heures après l'ingestion, les patients restaient moins longtemps (N = 57, durée séjour médiane 6,1 h, P25-P75 3,2-11,8 h) que les cas avec des symptômes plus tardifs (N = 15, durée séjour médiane 13,3 h, P25-P75 10,2-36,2) (p = 0,0001 selon Mann-Whitney). Une patiente a nécessité un transfert dans un centre spécialisé (intoxication par amanite phalloïde, avec dosage positif de l'alpha-amanitine). Elle a bénéficié de silibinine et d'une hospitalisation (9 jours), avec une évolution favorable sans nécessité de transplantation. Les symptômes étaient apparus tardivement (7 h). Conclusions: Sur les 72 cas, un seul (1,4%) a nécessité une prise en charge spécialisée. Les autres patients ont pu rentrer à domicile dans les heures qui ont suivi leur admission. Une grande partie des cas est survenue entre août et décembre, période favorable pour la récolte ou la consommation de champignons. Cette analyse confirme que la plupart des cas sont bénins et que les patients peuvent rentrer rapidement à domicile une fois les symptômes passés. Le seul cas potentiellement grave a présenté des symptômes tardifs et une longue hospitalisation, ce qui réaffirme les données de la littérature.

Increase of [(18)F]FLT tumor uptake in vivo mediated by FdUrd: toward improving cell proliferation positron emission tomography.

PURPOSE: 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2'-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [(18)F]FLT in tumor xenografts. METHODS: The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[(125)I]iodo-2'-deoxyuridine biodistribution measurements. In [(18)F]FLT studies, FdUrd pretreatment was generally performed 1 h before radiotracer injection. [(18)F]FLT biodistributions were measured 1 to 3 h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [(18)F]FDG tumor uptake. Using microPET, the dynamic distribution of [(18)F]FLT was followed for 1.5 h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation. RESULTS: FdUrd induced an immediate increase in tumor uptake of 5-[(125)I]iodo-2'-deoxyuridine, that vanished after 6 h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [(18)F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [(18)F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [(18)F]FLT uptake in all tumors increased steadily up to 1.5 h. MRI showed a well-vascularized homogenous lymphoma with high [(18)F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis. CONCLUSION: We showed a reliable and significant uptake increase of [(18)F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [(18)F]FLT PET.

Phenotypes influencing low physical activity in maintenance dialysis.

OBJECTIVE: The "Pas à Pas" initiative aimed at evaluating the weekly physical activity (PA) and its determinants in a large cohort of dialysis patients. SETTING: Physical inactivity is a risk factor for mortality in maintenance dialysis patients and is still poorly documented in this population. DESIGN: A prospective national epidemiological study was performed. SUBJECTS: A total of 1,163 patients on maintenance dialysis (hemodialysis and peritoneal dialysis) were included. INTERVENTION AND MAIN OUTCOME MEASURE: PA was recorded during seven consecutive days using a pedometer to measure daily step numbers. RESULTS: Median age was 63 years (Q1 51-Q3 75). Sixty-three percent were sedentary (<5000 steps/day) with a median of 3,688 steps/day (1,866-6,271)]. PA level was similar between hemodialysis patients and those on peritoneal dialysis (3,693 steps [1,896-6,307] vs. 3,320 [1,478-5,926], P = .33). In hemodialysis patients, PA was lower on dialysis days compared with nondialysis days (2,912 [1,439-5,232] vs. 4,054 [2,136-7,108], respectively, P < .01). PA gradually decreased with age, 57% being sedentary between 50 and 65 years and 83% of patients after 80 years. Beyond this age effect, we identified, for the first time, specific phenotypes of patients with lower PA, such as inflammation, cardiovascular disease, protein energy wasting, obesity, and diabetes. By contrast, previous kidney transplantation and a higher muscle mass were associated with higher PA. CONCLUSIONS: Dialysis patients present a very low level of PA with high sedentary. Acting on patient's modifiable phenotypes may help to increase PA to improve morbidity, mortality, and quality of life.

Effect of obesity onset on pendular energy transduction at spontaneous walking speed: Prader-Willi versus nonsyndromal obese individuals.

OBJECTIVE: To compare the mechanical external work (Wext ) and pendular energy transduction (Rstep ) at spontaneous walking speed (Ss ) in individuals with Prader-Willi syndrome (PWS) versus subjects with nonsyndromal obesity (OB) to investigate whether the early onset of obesity allows PWS subjects to adopt energy conserving gait mechanics. DESIGN AND METHODS: Wext and Rstep were computed using kinematic data acquired by an optoelectronic system and compared in 15 PWS (BMI = 39.5 ± 1.8 kg m(-2) ; 26.7 ± 1.5 year) and 15 OB (BMI = 39.3 ± 1.0 kg m(-2) ; 28.7 ± 1.9 year) adults matched for gender, age and BMI and walking at Ss . RESULTS: Ss was significantly lower in PWS (0.98 ± 0.03 m s(-1) ) than in OB (1.20 ± 0.02 m s(-1) ; P < 0.001). There were no significant differences in Wext per kilogram between groups (PWS: 0.37 ± 0.04 J kg(-1) m(-1) ; OB: 0.40 ± 0.05 J kg(-1) m(-1) ; P = 0.66) and in Rstep (PWS: 69.9 ± 2.9%; OB: 67.7 ± 2.4%; P = 0.56). However, Rstep normalized to Froude number (Rstep /Fr) was significantly greater in PWS (6.0 ± 0.6) than in OB (3.8 ± 0.2; P = 0.001). Moreover, Rstep /Fr was inversely correlated with age of obesity onset (r = -0.49; P = 0.006) and positively correlated with obesity duration (r = 0.38; P = 0.036). CONCLUSION: Individuals with PWS seem to alter their gait to improve pendular energy transduction as a result of precocious and chronic adaptation to loading.

Rapid Improvement in Health-Related Quality of Life in Gouty Arthritis Patients Treated with Canakinumab (ACZ885) Compared to Triamcinolone Acetonide

Background: Gout patients initiating urate lowering therapy have an increased risk of flares. Inflammation in gouty arthritis is induced by interleukin (IL)-1b. Canakinumab inhibits IL-1b effectively in clinical studies. This study compared different doses of canakinumab vs colchicine in preventing flares in gout patients initiating allopurinol therapy.Methods: In this 24 wk double blind study, gout patients (20-79 years) initiating allopurinol were randomized (1:1:1:1:1:1:2) to canakinumab s.c. single doses of 25, 50, 100, 200, 300 mg, or 150mg divided in doses every 4 wks (50þ50þ25þ25mg [q4wk]) or colchicine 0.5mg p.o. daily for 16 wks. Primary outcome was to determine the canakinumab dose giving comparable efficacy to colchicine with respect to number of flares occurring during first 16 wks. Secondary outcomes included number of patients with flares and C-reactive protein (CRP) levels during the first 16 wks.Results: 432 patients were randomized and 391 (91%) completed the study. All canakinumab doses were better than colchicine in preventing flares and therefore, a canakinumab dose comparable to colchicine couldn't be determined. Based on a negative binomialmodel, all canakinumab groups, except 25 mg, reduced the flare rate ratio per patient significantly compared to colchicine group (rate ratio estimates 25mg 0.60, 50mg 0.34, 100mg 0.28, 200mg 0.37, 300mg 0.29, q4wk 0.38; p_0.05). Percentage of patients with flares was lower for all canakinumab groups (25mg 27.3%, 50mg 16.7%, 100mg 14.8%, 200mg 18.5%, 300mg 15.1%, q4wk 16.7%) compared to colchicine group (44.4%). All patients taking canakinumab were significantly less likely to experience at least one gout flare than patients taking colchicine (odds ratio range [0.22 - 0.47]; p_0.05 for all). Median baseline CRP levels were 2.86 mg/L for 25 mg, 3.42 mg/L for 50 mg, 1.76 mg/L for 100 mg, 3.66 mg/L for 200 mg, 3.21 mg/L for 300 mg, 3.23 mg/L for q4wk canakinumab groups and 2.69 mg/L for colchicine group. In all canakinumab groups with median CRP levels above the normal range at baseline, median levels declined within 15 days of treatment and were maintained at normal levels (ULN¼3 mg/L) throughout the 16 wk period. Adverse events (AEs) occurred in 52.7% (25 mg), 55.6% (50 mg), 51.9% (100 mg), 51.9% (200 mg), 54.7% (300 mg), 58.5% (q4wk) of patients on canakinumab vs 53.7% of patients on colchicine. Serious AEs (SAE) were reported in 2 (3.6%; 25 mg), 2 (3.7%, 50 mg), 3 (5.6%, 100 mg), 3 (5.6%, 200 mg), 3 (5.7%, 300 mg), 1 (1.9%, q4wk) patients on canakinumab and in 5 (4.6%) patients on colchicine. 1 fatal SAE (myocardial infarction, not related to study drug) occurred in colchicine group.Conclusions: In this randomized, double-blind active controlled study of flare prevention in gout patients initiating allopurinol therapy, treatment with canakinumab led to a statistically significant reduction in flares compared with colchicine and was well tolerated.Disclosure statement: U.A., A.B., G.K., D.R. and P.S. are employees of and have stock options or bold holdings with Novartis Pharma AG. E.M. is a principal investigator for Novartis Pharmaceuticals Corporation. E.N. has received consulting fees from Roche. N.S. has received research grants from Novartis Pharmaceuticals Corporation. A.S. has received consultancy fees from Novartis Pharma AG, Abbott, Bristol-Myers Squibb, Essex, Pfizer, MSD, Roche, UCB and Wyeth. All other authors have declared no conflicts of interest.

Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia.

BACKGROUND: Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS: Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A •- ], via electron paramagnetic resonance spectroscopy, and nitrite [NO 2 2 ], via ozone-based chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n 5 13, CMS 1 ) and without CMS (n 5 12, CMS 2 ). Twelve age- and activity-matched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured fl ow-mediated dilatation (FMD), arterial stiffness defined by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT). RESULTS: Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS 2 group ( P , .05), as indicated by elevated A •- (3,191 457 arbitrary units [AU] vs 2,640 445 AU) and lower NO 2 2 (206 55 nM vs 420 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS 1 group (A •- , 3,765 429 AU; NO 2 2 , 148 50 nM) compared with both the CMS 2 group and lowlanders ( P , .05). This was associated with systemic vascular dysfunction as indicated by lower ( P , .05 vs CMS 2 ) FMD (4.2% 0.7% vs 7.6% 1.7%) and increased AIx-75 (23% 8% vs 12% 7%) and carotid IMT (714 127 m M vs 588 94 m M). CONCLUSIONS: Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.