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The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Summary Background Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. Methods In this randomised, double-blind, controlled trial, we recruited patients aged 18–60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. Findings Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68·5 [IQR 34·0 to 83·5] at the beginning and 62·5 [51·5 to 72·0] at the end, median change 1·1% [IQR −23·9 to 38·1]; sham group 73·0 [69·0 to 79·0] and 79·0 [59·0 to 81·5], median change 0·0% [–10·6 to 4·8]; p=0·39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). Interpretation 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. Funding French Ministry of Health.

International audience; Objective: To evaluate the efficacy and safety of zonisamide in patients with myoclonus-dystonia. Methods: We conducted a randomized, double-blind, placebo-controlled crossover trial of zonisamide (300 mg/d) in 24 patients with myoclonus-dystonia. Each treatment period consisted of a 6-week titration phase followed by a 3-week fixed-dose phase. The periods were separated by a 5-week washout period. The co–primary outcomes were action myoclonus severity (section 4 of the Unified Myoclonus Rating Scale [UMRS 4]) and myoclonus-related functional disability (UMRS 5). Secondary outcomes included dystonia severity, assessed with the movement and disability subscales of the Burke-Fahn-Marsden-Dystonia Rating Scale (BFM), the Clinical Global Impression–Improvement scale (CGI), and safety measures. Wilcoxon signed-rank tests for paired data were used to analyze treatment effects. Results: Twenty-three patients (11 men, 12 women) were analyzed in the intention-to-treat analysis. Zonisamide significantly improved both action myoclonus (median improvement [95% confidence limits] −5 [−9.25 to −1.44], p = 0.003) and myoclonus-related functional disability (median improvement [95% confidence limits] −2 [−2.58 to −2.46], p = 0.007) compared to placebo. Zonisamide also significantly improved dystonia (BFM movement) compared to placebo (median improvement [95% confidence limits] −3 [−8.46 to 0.03], p = 0.009). No difference was found between zonisamide and placebo with respect to the CGI (median improvement [95% confidence limits] −1 [−1.31 to 0.09], p = 0.1). Zonisamide was well-tolerated. Conclusions: Zonisamide is well-tolerated and effective on the motor symptoms of myoclonus-dystonia. Classification of evidence: This study provides Class I evidence that zonisamide improves myoclonus and related disability in patients with myoclonus-dystonia

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Arnica and other homoeopathic extracts have been used in various obstetrical, surgical and postsurgical conditions in attempts to control inflammation, swelling and haemorrhage with controversial results. • However, no homoeopathic combination with haemostatic and anti-inflammatory properties has been used in cardiac surgery that is often followed by haemorrhage and involves substantial systemic inflammation. • In this setting, exudation and blood loss are precisely quantified. WHAT THIS STUDY ADDS • A homoeopathic combination of Arnica montana and Bryonia alba was used in aortic valve surgery in a prospective double-blind, randomized, placebo-controlled clinical trial to evaluate its effectiveness. • This combination did not show any benefit in avoiding bleeding, pain, inflammation, and myocardial ischaemia. AIMS Arnica montana is a popular homoeopathic treatment with potential haemostatic and anti-inflammatory properties. A homoeopathic combination of A. montana and Bryonia alba was used in aortic valve surgery to evaluate its effectiveness in reducing bleeding, inflammation, pain and myocardial ischaemia. METHODS One day before surgery, 92 adult patients were randomly assigned to a double-blind parallel trial with either homoeopathic granules or a matching placebo until 4 days after surgery. The primary outcome was the volume of blood/liquid in the drains at their removal. The secondary outcomes included postoperative blood/liquid losses at 12 and 24 h as well as C-reactive protein (CRP), pain, temperature and plasma troponin Ic. RESULTS At 12 h and 24 h after surgery, then at drain removal, blood losses in homoeopathy and placebo groups were not statistically significant (362 ± 218, 520 ± 269 and 640 ± 297 ml vs. 456 ± 440, 620 ± 477 and 796 ± 717 ml; P= 0.19, 0.23 and 0.35, respectively). The statistical modelling did not show significantly different patterns of CRP, troponin and body temperature changes or of pain perception. The number of transfused packed red cells was not significantly different either (P= 0.58). Two patients from each group died during the study period and the number of serious adverse events was not statistically different (six in homoeopathy vs. 10 in placebo groups; Fisher's exact test P= 0.41). CONCLUSIONS In the study setting, there was no evidence of effects of A. montana and B. alba combination on bleeding, inflammation, pain or myocardial ischaemia.

Little is known about quality of life of adolescents with neuromuscular diseases or the factors that influence it. We searched whether physical impairment, physical disability, and medical complications were predictors of low quality of life.Motor function, health, orthopedic status, and rehabilitation were assessed in 43 adolescents with neuromuscular diseases (mean age, 13.8 years, standard deviation 1.7 year; sex ratio 2.9/1). Quality of life was measured with the VSP-A ("Vécu Santé Perçu par l'Adolescent"; self-perceived health state in adolescents), a validated health-related quality of life self-perception test. A mixed linear regression related quality of life to impairment, disability, and respiratory status. Comparisons were made with results from an age/sex-matched nondisabled group.On the average, the VSP-A scores in physically disabled adolescents were: (1) similar to those of the nondisabled group with regard to vitality, body image, relationships with parents and friends, and physical and psychological well-being; (2) higher with regard to school performance (score 68 vs. 52.8) and relationships with teachers (67.4 vs. 43.2); and (3) lower with regard to leisure activities (43.9 vs. 60.9). Physical disability and physical impairment were not negatively associated with seven of the nine VSP-A dimensions, but physical impairment was negatively associated with leisure activities and vitality (p.001 and p.01, respectively). Adolescents with ventilatory support did not express lower scores than adolescents not requiring ventilatory support (67.7+/-11 vs. 62.9+/-15, p=.39).These surprising results should lead us question our medical, educational, and rehabilitation practices. Already well-managed disabled adolescents should benefit from less compassionate but more daring and dynamic interpersonal contacts.

Objective: Intracranial stereotactic EEG recordings (SEEG) in presurgical epilepsy assessment are currently carried out in our department. The SEEG method generally used for exploration can also be used to perform radiofrequency thermocoagulations (RFTC) of the epileptic foci. To assess the indications of the RFTC procedure in the therapeutic arsenal of drug-resistant epilepsies, we report the results obtained in 41 patients to whom RFTC was proposed as a first therapeutic step before surgery or as a palliative treatment when surgery was not possible. Methods: RFTC were produced by applying a 50-volt, 110 mA current, during 10–30 seconds within the epileptogenic zone, as identified by the SEEG investigation. Two to 31 RFTC (mean, 12) were performed per patient. The median follow-up was 19 months (range: 4 to 72). Results: Twenty patients (48.7%) experienced a seizure frequency decrease of at least 50%, which was over 80% in eight of them. One patient was seizure-free. The tolerance was excellent. A total of 67% of the 21 patients presenting a cortical development malformation benefited from RFTC ( p = 0.052). In the group of noneligible patients for resective surgery (n = 13), six were responders to SEEG-guided RFTC and one of them was seizure-free. Conclusions: This study suggests that stereotactic EEG-guided radiofrequency thermocoagulations can be proposed only as a palliative procedure, able to bring a substantial improvement of seizure frequency, to drug-resistant patients with epilepsy for whom conventional resection surgery is risky or contraindicated on the basis of invasive presurgical evaluation.

The objective of this study was to evaluate mechanisms of the synergy between high intensity-focused ultrasound (HIFU) and docetaxel and to determine the best sequence of chemotherapy administration in relation to HIFU treatment for obtaining optimum control of tumoral growth. A total of 15 days after s.c. implantation of the tumor, 52 Copenhagen rats studied were randomized in 4 groups of 13: controls, docetaxel alone (group 1), HIFU and docetaxel concomitant (group 2) and HIFU and docetaxel administered 24 h before treatment (group 3). The number of HIFU shots was calculated in order to cover 75% of the tumor volume. The effects of docetaxel, HIFU and their interaction on tumor volumes were analyzed using a linear regression. The distributions of the tumor volumes were significantly greater in the control group than in the group 1 (P=0.002) and than in both groups 2 and 3 (P < 0.0001 and P = 0.0001). These volumes were also significantly greater in group 1 than in both groups 2 and 3 and there was no difference between the groups 2 and 3. The tumor doubling times were 7.8 days for the group 1, 43.8 days for the group 2, 16.1 days for the group 3 and 5.9 days for the controls. The mechanism of the synergy between HIFU and docetaxel on the growth of Dunning tumors is apparently multifaceted. The results are encouraging because in the two groups of rats treated with the combination of HIFU and docetaxel, the percentage of complete remission was approximately 30%.

Background: An association between alcohol consumption and injury is clearly established from volume of drinking, heavy episodic drinking (HED), and consumption before injury. Little is known, however, about how their interaction raises risk of injury and what combination of factors carries the highest risk. This study explores which of 11 specified groups of drinkers (a) are at high risk and (b) contribute most to alcohol-attributable injuries. Methods: In all, 8,736 patients, of whom 5,077 were injured, admitted to the surgical ward of the emergency department of Lausanne University Hospital between January 1, 2003, and June 30, 2004, were screened for alcohol use. Eleven groups were constructed on the basis of usual patterns of intake and preattendance drinking. Odds ratios (ORs) comparing injured and noninjured were derived, and alcohol-attributable fractions of injuries were calculated from ORs and prevalence of exposure groups. Results: Risk of injury increased with volume of drinking, HED, and preattendance drinking. For both sexes, the highest risk was associated with low intake, HED, and 4 (women), 5 (men), or more drinks before injury. At the same level of preattendance drinking, high-volume drinkers were at lower risk than low-volume drinkers. In women, the group of low-risk non-HED drinkers taking fewer than 4 drinks suffered 47.5% of the alcohol-attributable injuries in contrast to only 20.4% for men. Low-volume male drinkers with HED had more alcohol-attributable injuries than that of low-volume female drinkers with HED (46.9% vs 23.2%). Conclusions: Although all groups of drinkers are at increased risk of alcohol-related injury, those who usually drink little but on occasion heavily are at particular risk. The lower risk of chronic heavy drinkers may be due to higher tolerance of alcohol. Prevention should thus target heavy-drinking occasions. Low-volume drinking women without HED and with only little preattendance drinking experienced a high proportion of injuries; such women would be well advised to drink very little or to take other special precautions in risky circumstances.

Objective Early cell death remains a major limitation of skeletal myoblast transplantation. Because the poor vascularization of the target scars contributes to cell loss, we assessed the effects of combining skeletal myoblast transplantation with administration of hypoxia-inducible factor 1α, a master gene that controls the expression of a wide array of angiogenic factors. Methods A myocardial infarction was created in 56 rats by means of coronary artery ligation. Eight days later, rats were randomly allocated to receive in-scar injections of culture medium (control animals, n=11), skeletal myoblasts (5 × 10 6 , n=13), adenovirus-encoded hypoxia-inducible factor 1α (1.0 × 10 10 pfu/mL, n=7), or skeletal myoblasts (5 × 10 6 ) in combination with an empty vector (n = 3) or active hypoxia-inducible factor 1α (1.0 × 10 10 pfu/mL, n=13). A fifth group (n = 9) underwent a staged approach in which hypoxia-inducible factor 1α (1.0 × 10 10 pfu/mL) was injected at the time of infarction, followed 8 days later by skeletal myoblasts (5 × 10 6 ). Left ventricular function was assessed echocardiographically before transplantation and 1 month thereafter. Explanted hearts were then processed for the immunohistochemical detection of myotubes, quantification of angiogenesis, myoblast engraftment, and cell survival. Results Baseline ejection fractions were not significantly different among groups (35%–40%). One month later, ejection fraction had decreased from baseline in control hearts and in those injected with hypoxia-inducible factor 1α. In contrast, it did not deteriorate after injections of skeletal myoblasts alone or combined with either the empty vector or active hypoxia-inducible factor 1α administered sequentially. The most striking change occurred in the skeletal myoblast plus hypoxia-inducible factor 1α combined group in which ejection fraction increased dramatically (by 27%) above baseline levels and was thus markedly higher than in all other groups ( P = .0001 and P = .001 vs control animals and animals receiving hypoxia-inducible factor 1α, respectively). Compared with skeletal myoblasts alone, the coadministration of hypoxia-inducible factor 1α resulted in a significantly greater degree of angiogenesis, cell engraftment, and cell survival. Conclusion Induction of angiogenesis is an effective means of potentiating the functional benefits of myoblast transplantation, and hypoxia-inducible factor 1α can successfully achieve this goal.

ObjectivesSeveral studies have shown that an increase in abdominal aortic aneurysm (AAA) growth rate occurs when the diameter reaches 40 to 50 mm. AAA expansion is related to remodeling of the parietal extracellular matrix. The parietal mechanisms involved in this critical phase of sudden increase remain unexplained. Analysis of AAA wall movements and determination of AAA compliance may provide information about the constitution of the arterial wall. If a change in parietal wall motion somewhere between 40 and 50 mm could be shown, this would contribute to the understanding of the growth of AAA. Furthermore, it would provide a valuable additional parameter for AAA monitoring. This study had two aims: first, to evaluate the relationship between AAA compliance and maximum diameter using the tissue Doppler imaging system; and second, to test the hypothesis of a change in AAA behavior at around 45 mm in diameter.MethodsFifty-six patients with AAA (mean diameter, 39 mm) were prospectively investigated using the tissue Doppler imaging system, which provides information concerning arterial wall motion. Maximum mean segmental dilation (MMSD), segmental compliance, pressure strain elastic modulus (Ep), and stiffness were determined and related to the maximum diameter of AAA.ResultsAfter natural log transformation of all variables, there was a significant positive linear relationship between maximum diameter and both MMSD (P < .001) and segmental compliance (P < .001) but not with Ep or stiffness (P = .37 and .22, respectively). MMSD and segmental compliance were significantly higher in AAA ≥ 45 mm than in AAA < 45 mm (P < .0002 and

Objectives: To compare the views of healthcare professionals and patients regarding compliance with standards of care concerning patient information. Design: Self-rated questionnaire survey. Setting: Nine wards in short stay French hospitals. Participants: 939 patients and 359 healthcare professionals (physicians, nurses, assistants and other professionals). Main outcome measure: Patients’ and healthcare professionals’ views of compliance with 20 standards of patient care described in the French accreditation manual. Comparison of the rank order of the standards within the two samples. Results: The response rate was 61.5% in the patient group and 85.8% in the healthcare professionals. The rank orders for the 20 items were similar in both groups (Spearman rank order correlation 0.6, p = 0.004). The two items ranked highest by healthcare professionals (“consent request for a surgical procedure” and “the doctors ask the visitors to leave the room before examining a patient”) were also the two ranked highest by the patients. Three items were ranked low by both groups: “consent request for students to be present”, “health education given to patients”, and “possibility to express satisfaction during discharge”. Patients were more satisfied with their pain management than were healthcare providers. Professionals were more satisfied with the social services than the patients. Conclusion: There are both similarities and differences between patients’ and healthcare professionals’ views of care. Accurate assessments of quality performed during the accreditation procedure require that both patients’ and professionals’ views be taken into account.

The criteria for acetabular cup positioning during total hip replacement are a matter of considerable discussion, particularly with regards to the optimal degree of anteversion. "Anatomical anteversion" is defined in the transverse plane, and "surgical anteversion" in the sagittal plane. Computed tomography measurements of anteversion are characteristic of a given transverse section plane and fail to take into account the position of the pelvis. We suggest a simple method for evaluating acetabular cup position in both the transverse and sagittal planes during standing and sitting. By shedding new light on the relationships between the pelvis and the spine, this method may help to understand some cases of impingement, instability or abnormal wear.

Renin release into plasma has been used to investigate the drug dose-dependence of renin-angiotensin system inhibition because it is proportional to the interruption of the permanent negative feedback loop of angiotensin II on renin secretion. We investigated the 24-hour between-subject differences in renin profiles by analyzing the time-dependence of individual renin responses in 16 mildly sodium-depleted normotensive subjects exposed in a 4-period crossover study to single oral doses of 8- and 16-mg (C8 and C16) candesartan cilexetil and 80- and 160-mg (V80 and V160) valsartan. C8 had a similar effect to V160 in terms of the increase in active renin concentration and decrease in blood pressure. C16 had the strongest effect and V80 the weakest effect on renin release. Within- and between-subject variability was more marked for valsartan pharmacokinetics than for candesartan pharmacokinetics and influenced variability in renin response. To eliminate some of the variability caused by the pharmacokinetics of each drug, we corrected the area under time curve of plasma renin levels by that of plasma drug levels to obtain an individual normalized index of renin release or “renin/pharmacokinetic index”. In these experimental conditions, this index was found to be a reproducible individual characteristic affecting renin response, in addition to the pharmacokinetics and pharmacological properties of angiotensin II type-1 receptor antagonists. The pharmacokinetic–pharmacodynamic model of renin release described here could be of value for the identification and investigation of renin release abnormalities in patients with hypertension and for the comparison of renin-angiotensin system blockers.

Background The prevailing sodium intake and renin–angiotensin system status influence the blood pressure response to an angiotensin II type 1 (AT1) receptor antagonist or an angiotensin I converting enzyme inhibitor, which is known to be reinforced by a low sodium intake or administration of a diuretic. Objective To investigate the possibility that combining both drugs might be more effective in conditions of high sodium intake than blocking the renin–angiotensin system in a single step. Methods In a placebo-controlled, four-period crossover study in 12 normotensive volunteers who received a high sodium chloride intake (more than 250 mmol/day for 6 days), the haemodynamic and renin effects of a single oral dose of irbesartan 150 mg combined with fosinopril 20 mg were compared with those of a usual daily dose of fosinopril (20 mg) and a high dose of irbesartan (300 mg). Results The changes in blood pressure induced by fosinopril and irbesartan alone were not different from those of placebo, whereas the combination significantly decreased blood pressure. Simultaneously, it increased plasma active renin and prorenin concentrations to a greater extent than did each single-site blocker. Conclusion In low-renin conditions, combined renin–angiotensin system blockade enables the demonstration of a persistent renin-dependency of the blood pressure. Through its more efficient blockade of the renin–angiotensin system, demonstrated by the increase in renin and prorenin, combined renin–angiotensin system blockade is more effective than doubling the usual dose of an AT1 receptor antagonist. This may offer an alternative strategy for treating patients with a range of renin concentrations, and may potentially increase the cardio- and nephrotective benefits through a more complete blockade of the renin–angiotensin system.

Docetaxel is a new taxoid compound with a broad spectrum of antitumor activity. Previous studies have shown that in vitro treatment of specific human tumor lines with docetaxel is associated with the phosphorylation and inactivation of the bcl-2 protein and the occurrence of apoptosis. The goal of this study was to examine whether bcl-2 expression is truly required for in vivo responsiveness to docetaxel. The expression and state of phosphorylation of bcl-2 was examined in human MX-1 breast or DU-145 prostate tumors explanted from nu/nu mice treated with docetaxel. The MX-1 cells accumulated in the G2/M phase of the cell cycle and exhibited phosphorylation of bcl-2 after treatment with docetaxel. By Western blot analysis DU-145 prostate tumor cells did not express bcl-2 protein before or following in vivo treatment with docetaxel. However, docetaxel was highly active against the DU-145 tumor xenograft model. Thus, docetaxel induces apoptosis and cell death through a different, bcl-2-independent mechanism in the DU-145 human prostate tumor, indicating that bcl-2 may not have prognostic value for treatment with docetaxel.

The relevance of circadian rhythms in irinotecan and oxaliplatin tolerability was investigated with regard to antitumour activity. Mice bearing Glasgow osteosarcoma (GOS) received single agent irinotecan (50 or 60 mg kg−1 per day) or oxaliplatin (4 or 5.25 mg kg−1 per day) at one of six dosing times expressed in hours after light onset (3, 7, 11, 15, 19 or 23 hours after light onset). Irinotecan (50 mg kg−1 per day) and oxaliplatin (4 or 5.25 mg kg−1 per day) were given 1 min apart at 7 or 15 hours after light onset, or at their respective times of best tolerability (7 hours after light onset for irinotecan and 15 hours after light onset for oxaliplatin) or worst tolerability (15 hours after light onset for irinotecan and 7 hours after light onset for oxaliplatin). Tumour growth rate was nearly halved and per cent increase in estimated life span (% ILS) was – doubled in the mice receiving irinotecan at 7 hours after light onset as compared to 15 hours after light onset (P

While first-generation taxanes are valuable treatment options for many solid tumors, they are limited by an inability to cross the blood-brain barrier (BBB) and by limited efficacy in pediatric patients. Following promising preclinical data for the next-generation taxane cabazitaxel, including activity in tumor models fully sensitive, poorly sensitive or insensitive to docetaxel, and its ability to cross the BBB, further preclinical studies of cabazitaxel relevant to these two clinical indications were performed.Cabazitaxel brain distribution was assessed in mice, rats and dogs. Cabazitaxel antitumor activity was assessed in mice bearing intracranial human glioblastoma (SF295; U251) xenografts, and subcutaneous cell line-derived human pediatric sarcoma (rhabdomyosarcoma RH-30; Ewing's sarcoma TC-71 and SK-ES-1) or patient-derived pediatric sarcoma (osteosarcoma DM77 and DM113; Ewing's sarcoma DM101) xenografts. The activity of cabazitaxel-cisplatin combination was evaluated in BALB/C mice bearing the syngeneic murine colon adenocarcinoma, C51.Cabazitaxel penetrated rapidly in the brain, with a similar brain-blood radioactivity exposure relationship across different animal species. In intracranial human glioblastoma models, cabazitaxel demonstrated superior activity to docetaxel both at early (before BBB disruption) and at advanced stages, consistent with enhanced brain penetration. Compared with similar dose levels of docetaxel, cabazitaxel induced significantly greater tumor growth inhibition across six pediatric tumor models and more tumor regressions in five of the six models. Therapeutic synergism was observed between cisplatin and cabazitaxel, regardless of administration sequence.These preclinical data suggest that cabazitaxel could be an effective therapy in CNS and pediatric tumors, supporting ongoing clinical evaluation in these indications.

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin currently in clinical trials. In vitro, CPT-11 presented preferential cytotoxicity toward some solid tumor cells (mouse colon 38 and pancreas 03; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), whereas SN-38, a metabolite of CPT-11, was not solid tumor selective. In vivo, schedule of administration studies in P388 leukemia and mammary adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly schedule dependent. In order to determine its spectrum of anticancer activity, CPT-11 was evaluated against a variety of mouse and human tumors. The end points used were total log cell kill (Lck) for solid tumors and increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreatic ductal adenocarcinoma 03 (P03), with 60% long-term survivors and 100% complete regressions, respectively. Other responsive tumors included: colon adenocarcinomas 38 and 51 (both 1.0 Lck); MA16/C (3.4 Lck); MA13/C (1.0 Lck); human Calc18 breast adenocarcinoma (2.8 Lck); Glasgow osteogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melanoma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). Of interest, CPT-11 was active against tumors with acquired resistance to vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel (Calc18/TXT). CPT-11 was also found highly active after oral administration in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluations performed i.v. at the highest non-toxic dosage in mice bearing P03 tumors revealed CPT-11 peak plasma concentrations (Cmax) of 8.9 micrograms/ml and a terminal half-life of 0.6 h. The metabolite SN-38 plasma concentrations presented a Cmax of 1.6 micrograms/ml and a terminal half-life of 7.4 h. Although the CPT-11 tumor levels were similar to the plasma concentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor levels reached concentrations in the range of 0.32-0.34 micrograms/g and decayed with a half-life of 6.9 h. No significant difference in plasma or tumor pharmacokinetics of either CPT-11 or SN-38 were noted after one or five daily i.v. injections. Overall, these data show that CPT-11 has good activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of administration independence was observed and similar CPT-11 levels could be reached at efficacious dosages although metabolite SN-38 levels were found higher in mice.

International audience; The aims of this study were to describe the clinical, biological and radiological features of community-acquired (CA) Legionnaires' disease (LD) and identify the predictors of mortality in hospitalised patients. Demographic data, risk factors, clinical and biological features, medical management, complications, and outcome from 540 hospitalised patients with confirmed CA LD were prospectively recorded. 8.1% of patients (44 out of 540) died. The predictors of survival after Kaplan-Meier analysis were male sex (p = 0.01), age 500 mg * L(-1) (RH 2.14, 95% CI 1.02-4.48). Appropriate antibiotic therapy was prescribed for 70.8% (292 out of 412) of patients after admission and for 99.8% (537 out of 538) of patients after diagnosis confirmation. In conclusion, female sex, age, ICU stay, renal failure, corticosteroid treatment and increased level of CRP are significant risk factors for mortality in CA LD.

Mouse colon adenocarcinoma Co38 is widely used as a screening model for human colon tumors. To understand better the influence of tumor size on the main drug-metabolizing enzyme systems, we tested 15 mouse Co38 tumors at different sizes. The average weight was 917 +/- 444 mg (range, 300-1,400 mg). Cytochromes P-450 (1A1/1A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase (EH), and glutathione-S-transferases (GST-alpha, -mu, and -pi) were assayed by immunoblotting. The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: 1-chloro-2,4-dinitrobenzene-GST (CDNB-GST), selenium-independent glutathione peroxidase (GPX), 3,4-dichloronitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), total glutathione (GSH), uridine diphosphate-glucuronosyltransferase (UDP-GT), beta-glucuronidase (beta G), sulfotransferase (ST), and sulfatase (S). Our results showed the absence of all probed P-450s and EH in Co38 tumors. No relationship was found between the Co38 tumor weights and GPX, GST-alpha, and EA-GST (regression analysis). However, a significant correlation was found between the tumor weights and all other enzymes investigated. For certain enzymes or cofactors, a linear decrease (P0.05) was observed as a function of tumor weight (CDNB-GST, DCNB-GST, GST-mu, GST-pi, GSH, and beta G). Other enzymatic activities (UDP-GT, S, and ST) were found to decrease in medium-size tumors and to increase in large tumors (P0.05; quadratic correlation). These data demonstrate that the expression of many drug-metabolizing enzyme systems is altered during tumor growth and suggest that tumoral response to chemotherapy could be altered as a function of tumor size.

Correction of anemia in type 2 diabetes (T2DM) patients with chronic kidney disease stages 3-4 may slow the decline of kidney function but may increase cardiovascular risk through higher hematocrit. The NEPHRODIAB2 study was designed to assess efficacy and safety of complete hemoglobin (Hb) normalization in these patients.We randomly assigned 89 T2DM patients with an estimated glomerular filtration rate (eGFR; abbreviated 175 Modification of Diet in Renal Disease formula) of 25 to 60 ml/min per 1.73 m(2) and moderate anemia (Hb, 100-129 g/l) to a target Hb value in subnormal range (110-129g/l, group 1, n=43) or normal range (130-149 g/l, group 2, n=46). The primary end point was eGFR decline after 2 years of follow-up. Secondary end points included iron and erythropoietin dosage, quality of life (Medical Outcomes Study 36-item Short-Form Health Survey scores) and adverse events.Six months after randomization, the mean Hb levels were120 g/l in group 1 and130 g/l in group 2 (P.05 at 6, 12, 18 and 24 months). Blood pressure, 24-h proteinuria and HbA1c did not differ during follow-up (P.05). Two-year declines in eGFR were -8.7±12.2 in group 1 and -5.1±7.8 ml/min per 1.73 m(2) in group 2 (P=.29). Mean weekly use of erythropoietin was 7.8±11.6 μg in group 1 and 30.1±33.6 μg in group 2 (P.0001). There was no significant difference regarding Medical Outcomes Study 36-item Short-Form Health Survey score change or adverse event occurrence.In this trial, normalization of Hb level in T2DM patients with chronic kidney disease was safe but did not significantly slow renal function decline and increased treatment cost due to erythropoietin use.

Summary Background Compared with administration in the catheterization laboratory, early treatment with glycoprotein IIb/IIIa inhibitors provides benefits to patients with ST-segment elevation myocardial infarction who undergo primary percutaneous intervention. Whether this benefit is maintained on top of a 600 mg loading dose of clopidogrel is unknown. Methods In a multicentre, controlled, randomized study, 320 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention received a high-dose bolus of tirofiban given either in the ambulance (prehospital group) or in the catheterization laboratory. The primary endpoint was a TIMI flow grade 2–3 of the infarct-related vessel at initial angiography. Secondary endpoints included ST-segment resolution 1 h after percutaneous coronary intervention and peak serum troponin I concentration. Results Tirofiban was administered 48 (95% confidence interval 21.4–75.0) min earlier in the prehospital group. At initial angiography, the combined incidence of TIMI 2–3 flow was 39.7% in the catheterization-laboratory group and 44.2% in the prehospital group ( p = 0.45). No difference was found on postpercutaneous intervention angiography or peak troponin concentration. Complete ST-segment resolution 60 min after the start of intervention was 55.4% in the catheterization-laboratory group and 52.6% in the prehospital group ( p = 0.32). Conclusion Prehospital initiation of high-dose bolus tirofiban did not improve significantly initial TIMI 2 or 3 flow of the infarct-related artery or complete ST-segment resolution after coronary intervention compared with initiation of tirofiban in the catheterization laboratory ( NCT00538317 ).

We sought to determine whether online use of a beat-by-beat cardiovascular index, CARDEAN (Alpha-2, Lyon, France), modifies the incidence of patient movement during colonoscopy under anesthesia.Monitoring included an electrocardiogram, oscillometric and noninvasive beat-by-beat arterial blood pressure, O2 saturation, bispectral index (BIS), and CARDEAN. CARDEAN consists of beat-by-beat Finapres (Ohmeda, Madison, WI) combined with an algorithm that detects hypertension followed by tachycardia and produces an index scaled 0 to 100. The anesthesiologist was denied access to Finapres and CARDEAN. Propofol was adjusted to keep 40BIS60. Alfentanil 3.5 microg x kg(-1) was administered according to conventional signs (tachycardia, hypertension, and movement), unless the patient had signs of brady/apnea or Spo(2)95%. One hundred fifty-nine patients presenting for colonoscopy under propofol anesthesia were prospectively randomized to (i) control: no other intervention, or (ii) CARDEAN: in addition to conventional signs, an observer instructed the anesthesiologist to administer alfentanil when CARDEAN was60. The primary outcome was the number of observed movements.Data were analyzed in 146 patients (control: 75; CARDEAN: 71). The doses of propofol and alfentanil were similar in both groups. When BIS was60, movements were less frequent in the CARDEAN group (3.3 movements/100 min [2.3-4.8]) than in the control group (6.7 [5.3-8.5]) (odds ratio: 0.5 [0.32; 0.76], P = 0.001). During the first 10 minutes of the procedure, the incidence of movements was 38% and 59% in the CARDEAN and control groups, respectively (P = 0.04).With BIS60, CARDEAN-guided opioid administration is associated with a reduction of 51% of clinically unpredictable movements in unparalyzed patients undergoing colonoscopy. More studies are required to refine the role of CARDEAN in surgical settings.

Function and sport participation was analyzed via a self-administered questionnaire in 347 patients with unilateral noncomplicated TKA. It was 227 women and 120 men with a mean age of 75 (range, 28 to 94) and a mean follow-up of 44 months (range 13-71). Two hundred and thirty-seven patients (68%) reported that their knee was "normal", 56% that their activities were limited by their knee, and 66% that they were as active as they expected to be before the intervention. Of them, 98% were satisfied. Of the patients who were insufficiently active, 52% were not satisfied with their outcome (P < 0.0001). Neither the duration of preoperative pain, the age at evaluation or the number of previous surgeries influenced the subjective result or the degree of patient satisfaction. Among patients under 75 years, 10% regularly participated in strenuous sports but only 13% felt that this ability was important. When participation was analyzed in the motivated patients subgroup, 63% regularly took part in at least one impact sport.

We assessed the accuracy of T2-weighted (T2w) and dynamic contrast-enhanced (DCE) 1.5-T magnetic resonance imaging (MRI) in localizing prostate cancer before transrectal ultrasound-guided repeat biopsy. Ninety-three patients with abnormal PSA level and negative prostate biopsy underwent T2w and DCE prostate MRI using pelvic coil before repeat biopsy. T2w and DCE images were interpreted using visual criteria only. MR results were correlated with repeat biopsy findings in ten prostate sectors. Repeat biopsy found prostate cancer in 23 patients (24.7%) and 44 sectors (6.6%). At per patient analysis, the sensitivity, specificity, positive and negative predictive values were 47.8%, 44.3%, 20.4% and 79.5% for T2w imaging and 82.6%, 20%, 24.4% and 93.3% for DCE imaging. When all suspicious areas (on T2w or DCE imaging) were taken into account, a sensitivity of 82.6% and a negative predictive value of 100% could be achieved. At per sector analysis, DCE imaging was significantly less specific (83.5% vs. 89.7%, p < 0.002) than T2w imaging; it was more sensitive (52.4% vs. 32.1%), but the difference was hardly significant (p = 0.09). T2w and DCE MRI using pelvic coil and visual diagnostic criteria can guide prostate repeat biopsy, with a good sensitivity and NPV.

Background Lumbar punctures (LPs) are common in children with cancer. Although pain management during the lumbar puncture has been well standardized, dealing with stress and anxiety is not well addressed yet. Our objective was to evaluate the potential improvement of the LP success rate using a positioning pillow, to ensure maximum lumbar flexion, and allow paravertebral muscles to relax, in children who are awake, with either conscious sedation or no sedation. Methods Children aged 2–18 years undergoing LP were randomly assigned to a positioning pillow or no intervention. The primary outcome was the rate of success, i.e. achieving the LP (sampling or injection) at the first attempt, without bleeding (RBC < 50/mm3). The secondary outcomes included: the child's pain, assessed by a self-administered visual analogical scales (VAS) for children over 6 years of age; the parents' and caregivers' perception of the child's pain; the satisfaction of the children, the parents, the caregivers and the physician. The child's cooperation and the occurrence of post-LP syndrome were also evaluated. Results 124 children (62 in each group) were included. The LP pillow tended to increase the success rate of LPs (67% vs. 57%, p = 0.23), and decreased the post-LP syndromes (15% vs. 24%, p = 0.17) but the differences were not statistically significant. In children over 6-year of age (n = 72), the rate of success was significantly higher in the pillow group (58.5% vs. 41.5%, p = 0.031), with a tendency to feel less pain (median VAS 25 vs. 15 mm, p = 0.39) and being more satisfied (84.4% vs. 75.0%, p = 0.34). Conclusion Overall results do not demonstrate a benefit in using this pillow for lumbar punctures. This study results also suggest a benefit in the sub group of children over 6-year of age; this result needs confirmation. Trial Registration The trial was registered with Clinical Trials.gov (number NCT00775112).

1. Plasma levels of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are potential markers of many diseases involving extracellular matrix remodelling such as hypertension. Our aim was to determine whether the anticoagulant used to collect plasma and several freeze-thaw cycles may influence the accuracy of plasma MMP and TIMP determinations. 2. Plasma samples of 18 healthy volunteers were collected on three anticoagulants: heparinate, citrate and EDTA. For each anticoagulant, we compared: (i) MMP-2 and MMP-9 levels using gelatin zymography and TIMP-1 and TIMP-2 concentrations using enzyme-linked immunosorbent assay; (ii) intra- and interassay coefficients of variation (CV); and (iii) MMP and TIMP levels after up to five freeze-thaw cycles. 3. The choice of anticoagulant influenced TIMP-2 and TIMP-1 concentrations (TIMP-2, P < 0.0001; paired comparisons, citrate vs EDTA, P < 0.0001; EDTA vs heparin, P < 0.0001; citrate vs heparin, P < 0.0001; TIMP-1, P < 0.001; paired comparisons, citrate vs EDTA, P = 0.10; EDTA vs heparin, P < 0.01; citrate vs heparin, P < 0.0001), but not those of MMP. We observed a bias with heparinate for TIMP-2, TIMP-1 and MMP-9 determinations. The anticoagulant did not influence intra-assay or interassay CV. Performing freeze-thaw cycles led to alterations in the TIMP-1 plasma levels (P < 0.0001), regardless of the anticoagulant used, whereas MMP and TIMP-2 concentrations were not significantly affected. 4. Anticoagulant influences the measured levels of MMP and TIMP in plasma and should be systematically reported. However, it does not influence the reproducibility of the measurements. Repeated freeze-thaw cycles alter the measurement of TIMP-1 levels and should be avoided.

SummaryIntroductionNo agreement has been reached regarding the best strategy to detect left ventricular hypertrophy (LVH). This study examined the role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis of LVH in hypertensive patients and the potential factors that may influence its diagnostic performance.MethodsThe global accuracy of NT-proBNP in diagnosing LVH was assessed using a receiver-operating characteristic (ROC) curve. The influence of patients’ characteristics on test accuracy was studied with a ROC regression based on a probit model. Ninety-three subjects were included. All had NT-proBNP measured and underwent electrocardiography and echocardiography, with calculation of the left ventricular mass index (LVMI).ResultsThe diagnostic performance of NT-proBNP in LVH varied slightly depending on the indexation mode of LVMI. In cases of body surface area indexation, the area under the ROC curve of 81.6% suggested a good performance. The accuracy of the marker was significantly higher in women than in men (p

Background and Objectives: An AT 1 receptor antagonist induces a counterregulatory renin release whose intensity and duration reflect the magnitude of the renin-angiotensin blockade. We investigated whether a renin inhibitor may neutralize this counterregulation and amplify the effects of AT 1 receptor antagonists. Design, Setting, Participants, & Measurements: In 12 normotensive male individuals who were on a high-sodium diet, a double-blind, placebo-controlled, randomized, crossover design was used to study the hormonal and BP effects of single oral administrations of 300 mg of the renin inhibitor aliskiren, 320 mg of valsartan, and a combination of these two drugs, each at half dosage (150 mg of aliskiren and 160 mg of valsartan). Results: Valsartan (320 mg) increased plasma renin activity and angiotensin I and angiotensin II levels, but 300 mg of aliskiren decreased them for 48 h. Aliskiren (300 mg) stimulated immunoreactive renin release more strongly than 320 mg of valsartan, decreased urinary aldosterone excretion for longer than 320 mg of valsartan, and had a similar BP-lowering effect as 320 mg of valsartan. In combination, 150 mg of aliskiren neutralized the valsartan (160 mg)-induced increase in plasma angiotensins for 48 h. The renin and aldosterone effects of the combination of 150 mg of aliskiren and 160 mg of valsartan were similar to those of 300 mg of aliskiren and greater than those of 320 mg of valsartan. When plasma drug concentrations were taken into account, the combination of 150 mg of aliskiren and 160 mg of valsartan had a synergistic effect on renin release. The BP-lowering effect of 150 mg of aliskiren and 160 mg of valsartan was similar to that of 300 mg of aliskiren and 320 mg of valsartan at peak but was more prolonged. Conclusion: The stronger and longer lasting effects on plasma active renin and urinary aldosterone of aliskiren, alone or in combination, demonstrate a more effective blockade of the renin-angiotensin system than that obtained with 320 mg of valsartan alone.

The purpose of this study was to evaluate the accuracy of prostate cancer localization with simple visual diagnostic criteria using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). A total of 46 consecutive patients with biopsy-proven prostate cancer underwent prostate 1.5 T MRI with pelvic phased-array coils before prostatectomy. Besides the usual T2-weighted sequences, a 30-s DCE sequence was acquired three times after gadoterate injection. On DCE images, all early enhancing lesions of the peripheral zone were considered malignant. In the central gland, only early enhancing lesions appearing homogeneous or invading the peripheral zone were considered malignant. Three readers specified the presence of cancer in 20 prostate sectors and the location of distinct tumors. Results were compared with histology; p0.05 was considered significant. For localization of cancer in the sectors, DCE imaging had a significantly higher sensitivity [logistic regression, odds ratio (OR): 3.9, p0.0001] and a slightly but significantly lower specificity (OR: 0.57, p0.0001). Of the tumors0.3 cc, 50-60% and 78-81% were correctly depicted with T2-weighted and DCE imaging, respectively. For both techniques, the depiction rate of tumors0.3 cc was significantly influenced by the Gleason score (most Gleason/=6 tumors were overlooked), but not by the tumor volume.DCE-MRI using pelvic phased-array coils and simple visual diagnostic criteria is more sensitive for tumor localization than T2-weighted imaging.

Background There is no community standard for the treatment of glioblastoma in patients 70 years of age or older. We conducted a randomized trial that compared radiotherapy and supportive care with supportive care alone in such patients. Methods Patients 70 years of age or older with a newly diagnosed anaplastic astrocytoma or glioblastoma and a Karnofsky performance score of 70 or higher were randomly assigned to receive supportive care only or supportive care plus radiotherapy (focal radiation in daily fractions of 1.8 Gy given 5 days per week, for a total dose of 50 Gy). The primary end point was overall survival; secondary end points were progressionfree survival, tolerance of radiotherapy, health-related quality of life, and cognition. Results We randomly assigned 85 patients from 10 centers to receive either radiotherapy and supportive care or supportive care alone. The trial was discontinued at the first interim analysis, which showed that with a preset boundary of efficacy, radiotherapy and supportive care were superior to supportive care alone. A final analysis was carried out for the 81 patients with glioblastoma (median age, 73 years; range, 70 to 85). At a median follow-up of 21 weeks, the median survival for the 39 patients who received radiotherapy plus supportive care was 29.1 weeks, as compared with 16.9 weeks for the 42 patients who received supportive care alone. The hazard ratio for death in the radiotherapy group was 0.47 (95% confidence interval, 0.29 to 0.76; P = 0.002). There were no severe adverse events related to radiotherapy. The results of quality-of-life and cognitive evaluations over time did not differ significantly between the treatment groups. Conclusions Radiotherapy results in a modest improvement in survival, without reducing the quality of life or cognition, in elderly patients with glioblastoma. (ClinicalTrials.gov number, NCT00430911.)

In-vivo investigation of aldosterone-synthase inhibitors requires experimental models to characterize the biological effects of these compounds.Seven successive experiments were performed in groups of 2-month-old male spontaneously hypertensive rats. Urinary free aldosterone was the main end-point measured during two contrasted diets: low sodium-high potassium (LS), inducing high urinary aldosterone (839 pmol/24 h, 95% confidence interval 654-1077), and high sodium-normal potassium (HS), inducing low urinary aldosterone (38.1 pmol/24 h; 95% confidence interval, 32.4-44.9).FAD 286 A (10 and 30 mg/kg) decreased urinary free aldosterone by 53 and 87% on the LS diet, and 50 and 75% on the HS. Plasma renin concentration increased three-fold after a 4-week treatment of 30 mg/kg FAD 286 A on the LS diet and did not change on the HS. The combination of FAD 286 A (30 mg/kg) and spironolactone (30 mg/kg) on the LS diet induced a biological picture of severe hypoaldosteronism and was not tolerated, whereas the HS diet prevented these abnormalities. The combination of FAD 286 A (30 mg/kg) and furosemide (30 mg/kg) on the HS diet corrected the diuretic-induced hypokalemia (4.1 +/- 0.2 versus 3.7 +/- 2.2 mEq/l, P0.033).This experimental model will be useful to screen future aldosterone-synthase inhibitors and study their biological effects in various experimental conditions.

Growth-arrest-specific protein 6 (Gas6), an intracellular protein released by apoptotic cells, has been detected in normal plasma. As the Gas6 system has been implicated in mouse susceptibility to sepsis, and as leukocyte apoptosis is thought to play a major role in the physiopathology of human severe sepsis, we studied Gas6 plasma levels and possibly related variables in patients with severe sepsis.Matched case-control study.Adult intensive care unit in a university hospital.Thirty patients with severe sepsis, 30 patients with organ failure not related to infection, and 30 healthy subjects matched for age and gender.Blood draw.Gas6 plasma levels were quantified using enzyme-linked immunosorbent assay. Whole-blood gas6 messenger RNA levels were measured by quantitative real-time polymerase chain reaction. Gas6 plasma levels were elevated (110 ng/mL [75, 139]; median values [interquartile range]) in severe sepsis patients compared with organ failure patients (85 ng/mL [56, 101]) and healthy subjects (54 ng/mL [49, 68]). In patients with severe sepsis, this increase correlated with the Acute Physiology and Chronic Health Evaluation II severity score, the organ failure Organ Dysfunction and Infection (ODIN) score, and the existence of a septic shock. Gas6 messenger RNA levels were increased in patients with severe sepsis and correlated specifically with the monocyte count.In severe sepsis, the recently described anti-apoptotic protein Gas6 was found at high levels in plasma and correlated well with the degree of organ dysfunction.

Objective. Cell death remains a major limitation of skeletal myoblast (SM) transplantation but the patterns of cell survival and proliferation in heart and their potential modulation by thermic stresses like heat shock (HS) and cryopreservation (Cryo) are still incompletely characterized. Methods. To track SMs in situ, we developed a dual-marker system based on the semiconservative expression of the foreign soluble protein, β-Galactosidase (β-Gal) and the constitutive expression of the Y chromosome in a myocardial infarction model. Control medium or Lewis male rat SMs (fresh or subjected to Cryo or HS) were injected in Lewis female rats. Results. There was a massive cell loss early after transplantation in the fresh group, which was only partially compensated for by a subsequent proliferation. Conversely, both Cryo and HS significantly improved early cell survival but blunted subsequent proliferation so that, at 15 days posttransplantation, the total number of engrafted donor-derived Y-positive cells did not differ significantly between the three groups. Most of them expressed a skeletal muscle phenotype. Conclusions. These data confirm the high death rate of in-scar transplanted myoblasts, demonstrate the ability of those that survive to proliferate and differentiate along the myogenic pathway but do not support the efficacy of either Cryo or HS for increasing the ultimate magnitude of myoblast engraftment.

Objective Our objective was to define the pharmacodynamic profile of the new dual neutral endopeptidase (NEP)/angiotensin-converting enzyme (ACE) inhibitor AVE7688. Methods We compared the effects of single oral doses of AVE7688 (5 and 25 mg) with those of 10 mg ramipril (R10), a selective ACE inhibitor, in a placebo-controlled crossover study in sodium-depleted normotensive subjects. We also compared the effects of 25 mg AVE7688 with those of a renin-angiotensin system (RAS) blockade induced by a high dose of an angiotensin II receptor antagonist (300 mg irbesartan) and a dual blockade of the RAS (150 mg irbesartan plus 10 mg ramipril) in sodium-replete normotensive subjects by use of the same study design. The in vivo inhibition of ACE and NEP was monitored by measuring the urinary excretion of N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) and atrial natriuretic peptide (ANP), respectively. The intensity of RAS blockade was assessed by the increase in plasma active renin concentration. Results The 24-hour urine AcSDKP cumulative excretion increased significantly more after 25 mg AVE7688 (919 nmol [95% confidence interval (CI), 803–1052 nmol], P

An open prospective study was conducted among the patients visiting an urban medical policlinic for the first time without an appointment to assess whether the immigrants (who represent more than half of our patients) are aware of the health effects of smoking, whether the level of acculturation influences knowledge, and whether doctors give similar advice to Swiss and foreign smokers. 226 smokers, 105 Swiss (46.5%), and 121 foreign-born (53.5%), participated in the study. 32.2% (95% CI [24.4%; 41.1%]) of migrants and 9.6% [5.3%; 16.8%] of Swiss patients were not aware of negative effects of smoking. After adjustment for age, the multivariate model showed that the estimated odds of "ignorance of health effects of smoking" was higher for people lacking mastery of the local language compared with those mastering it (odds ratio (OR) = 7.5 [3.6; 15.8], p < 0.001), and higher for men (OR = 4.3 [1.9; 10.0], p < 0.001). Advice to stop smoking was given with similar frequency to immigrants (31.9% [24.2%; 40.8%] and Swiss patients (29.0% [21.0%; 38.5%]). Nonintegrated patients did not appear to receive less counselling than integrated patients (OR = 1.1 [0.6; 2.1], p = 0.812). We conclude that the level of knowledge among male immigrants not integrated or unable to speak the local language is lower than among integrated foreign-born and Swiss patients. Smoking cessation counselling by a doctor was only given to a minority of patients, but such counselling seemed irrespective of nationality.

Resume en francais Cadre : Policlinique pediatrique a Lausanne en Suisse, pays rencontrant une proportion importante de tuberculose au sein de la population de migrants. But : Determiner les facteurs de risque associes a un test tuberculinique positif (ou test de Mantoux), notamment l'influence du BCG (Bacille Calmette Guerin) et d'un contact avec un personne ayant une tuberculose active. Les patients concernes etaient des enfants examines dans le cadre d'un controle de sante ou dans le cadre d'une etude d'entourage d'un cas declare de tuberculose. Methode : Etude descriptive comprenant des enfants ayant eu un test tuberculinique (2 unites RT23) entre novembre 2002 et avril 2004. L'âge, le sexe, l'anamnese de contact avec une personne ayant une tuberculose active, la vaccination par le BCG, le pays d'origine et le lieu de naissance (en Suisse ou hors de la Suisse) etaient repertories. Resultats : Parmi les 234 enfants de l'etude, 176 (75%) avaient une reaction tuberculinique egal a zero et 31 (13%) avaient une reaction positive (> 10mm). Dans le modele de regression lineaire, la taille de la reaction tuberculinique variait significativement selon l'anamnese de contact avec une personne ayant une tuberculose active, l'âge, l'incidence de la tuberculose dans le pays d'origine et la vaccination par le BCG. Le sexe ou le lieu de naissance n'influencait pas la taille de la reaction. Dans le modele de regression logistique incluant toutes les valeurs repertoriees, les parametres significativement associes avec un Mantoux positif etaient l'âge (Odds Ratio = 1.21, 95% CI 1.08 ; 1.35), l'anamnese de contact avec une personne ayant une tuberculose active (OR = 7.31, 95% CI 2.23 ; 24) et l'incidence de la tuberculose dans le pays d'origine (OR = 1.01, 95% CI 1.00 ; 1.02). Le sexe (OR = 1.18, 95% CI 0.50 ; 2.78) et la vaccination par le BCG (OR = 2.97, 95% CI 0.91 ; 9.72) n'etaient pas associes avec une reaction tuberculinique positive. Conclusions : L'incidence de la tuberculose dans le pays d'origine, la vaccination par le BCG et l'âge influencent le test de Mantoux (taille ou proportion de reaction > 10mm). Toutefois, le facteur de risque le plus important d'avoir une reaction tuberculinique positive est l'anamnese de contact avec. une personne ayant une tuberculose active.

Interrupting the renin-angiotensin system (RAS) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade. Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg (high dose) of the renin inhibitor aliskiren (A300) and 160 mg (standard antihypertensive dose) of the AT1 receptor antagonist valsartan (V160) and their combination each at half dose (A150+V80) in 12 mildly sodium-depleted normotensive individuals. In this double-blind, placebo-controlled, randomized, four-period crossover study, A300 decreased plasma renin activity and angiotensin I and II levels for 48 h, stimulated immunoreactive active renin release more strongly than V160, and decreased urinary aldosterone excretion for a longer duration than V160. In contrast to V160, the A150+V80 combination did not increase plasma angiotensins. The renin and aldosterone effects of the A150+V80 combination were similar to those of A300 and greater than those of V160. When plasma drug concentrations were taken into account, the A150 +V80 combination had a synergistic effect on renin release. The A150+V80 combination lowered BP at least as effectively as either higher dose monotherapy. In conclusion, in mildly sodium-depleted normotensive individuals, the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level. Moreover, a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels.

Background— The benefits of skeletal myoblast (SM) transplantation on infarcted myocardium have been investigated extensively; however, little is known about its effects in nonischemic cardiomyopathy models. To address this issue, we tested SM transplantation in CHF147 Syrian hamsters, a strain characterized by a δ-sarcoglycan deficiency that phenotypically features the human setting of primary dilated cardiomyopathy. Methods and Results— Cell culture techniques were used to prepare ≈5×10 6 muscle cells from autologous tibialis anterior muscle, of which 50% were SMs (desmin staining). The cells were injected in 6 sites across the left ventricular wall (n=14). Control animals (n=12) received equivalent volumes of culture medium. Left ventricular systolic function was assessed in a blinded fashion from 2D echocardiographic left ventricular fractional area change, before transplantation, and 4 weeks later. Explanted hearts were processed for the detection of myotubes and quantification of fibrosis. Baseline functional data did not differ between the 2 groups. Four weeks after transplantation, 6 of the 10 surviving grafted hamsters were improved compared with 0 of the 8 survivors of the control group. This translated into a 6% decrease in fractional area change in controls compared with a 24% increase in cell-transplanted hamsters ( P =0.001). Engrafted myotubes were consistently detected in all SM transplanted hearts by immunohistochemistry, whereas fibrosis was not worsened by cell injections. Conclusions— These data suggest that the functional benefits of SM transplantation might extend to nonischemic cardiomyopathy.

The aim of this study was to evaluate the comparative microbiological efficacy of hand rubbing and handwashing in healthcare workers from different wards, with particular emphasis on transient flora, and to assess predisposing factors for hand contamination after patient care in everyday practice. Over a six-month period, 50 healthcare workers were randomly assigned, using a crossover design, to perform handwashing with unmedicated soap and hand rubbing with an alcoholic solution following a healthcare procedure. Imprints of palms and fingertips were taken separately before and after each hand hygiene procedure. The number of colonies per plate was counted and transient pathogens were identified. Risk factors for hand contamination were determined. Hand rubbing produced a significantly greater reduction in microbiological load than handwashing (P

Summary. Background: The FIIG20210A polymorphism has been associated with arterial wall thickness and atherothrombotic diseases in selected subgroups. The FVArg506Gln polymorphism does not seem to be associated with arterial diseases. Few data are available on these polymorphisms and the risk of peripheral arterial disease (PAD). Objectives: To study the association between the FIIG20210A and FVArg506Gln polymorphisms and PAD and its clinical severity. To examine the potential interactions with traditional vascular risk factors. Patients and methods: We studied 184 consecutive male patients under 70 years of age with symptomatic PAD and 330 age-matched male controls free of symptomatic PAD and with no cardiovascular history. We evaluated the FIIG20210A and FVArg506Gln polymorphisms in all subjects. Results: Mean age was 57.1 ± 7.2 years (cases) and 56.7 ± 7.6 years (controls). The FII20210A allele was more frequent in PAD patients with odds ratios (OR) of 3.77 (1.39–10.2) in univariate analysis and 4.30 (1.3–14.7) after adjustment for diabetes, smoking, hypertension and hypercholesterolemia. In smokers or past smokers the magnitude of the association was markedly increased but there was no evidence of an interaction between tobacco exposure and FIIG20210A. In case subjects, the FII20210A allele was also associated with critical ischemia [OR = 4.1 (1.1–15.7), P = 0.039 in multivariate analysis]. FVArg506Gln was not associated with PAD [OR = 0.65 (0.27–1.54) and 0.77 (0.28–2.1) in univariate and multivariate analyses, respectively]. Conclusions: The FIIG20210A gene polymorphism may be a risk factor for PAD and its severity. In contrast, the FVArg506Gln polymorphism is not associated with PAD.

To evaluate the intra- and interreader agreement of two-dimensional computed tomographic (CT) measurements of pulmonary nodules less than 2 cm in diameter.Three readers independently made three serial measurements of each of 54 pulmonary nodules measuring 3-18 mm that had been observed on standard-dose multisection CT images obtained in 24 patients who ranged in age from 36 to 81 years (mean age, 54.6 years). There were 14 women (58%), who ranged in age from 43 to 81 years (mean age, 58.9 years), and 10 men (42%), who ranged in age from 36 to 65 years (mean age, 48.5 years). The largest transverse cross-sectional diameter of each nodule was measured at picture archiving and communication system, or PACS, workstations by using high-spatial-resolution reconstructed CT images and identical window settings. Intra- and interreader agreement were determined by using methods described by Bland and Altman: the coefficient of repeatability for intrareader agreement, and methods derived from the 95% limits of agreement defined by Bland and Altman for interreader agreement.The repeatability coefficients were 1.70, 1.32, and 1.51 mm for readers 1, 2, and 3, respectively. The 95% limits of agreement for the difference among readers were -1.73 and 1.73.Two-dimensional CT measurements are not reliable in the evaluation of small noncalcified pulmonary nodules.

To evaluate software designed to calculate pulmonary nodule volume in three dimensions.Fifty-four solid noncalcified pulmonary nodules measuring 5-18 mm in diameter were studied with computed tomographic (CT) volumetric software. Baseline CT examinations were performed for various indications by using four-detector row multisection CT units, 1.25- or 2.50-mm sections, and a standard reconstruction algorithm. The percentage of successful nodule segmentations, as well as intraobserver variability, interreader agreement, and global repeatability of calculated volumes, was determined on the basis of consecutive measurements performed three times by three different radiologists by using the Bland and Altman method. The software was used to calculate the doubling time of 22 nodules for which a final diagnosis and comparable CT scans were available.Fifty-two (96%) of the 54 nodules were successfully segmented, allowing their volume to be calculated. Repeatability was high: There was no variation in the nine measurements of 35 (67%) of the 52 nodules. The coefficient of variation for the remaining 17 nodules (33%) was 2.26%. Bland and Altman 95% limits of acceptability, calculated on the basis of log-transformed data, yielded a maximum software measurement error of 6.38% of the previous volume measurement. Doubling time ranged from 4 to 188 years for the 13 benign nodules and from 37 to 216 days for the nine malignant nodules.Software volumetric analysis yielded repeatable estimates for 96% of the nodules examined. All software-calculated doubling times were in keeping with the benign or malignant nature of the nodules.

Expansion of abdominal aortic aneurysms (AAA) is due to remodeling of the parietal extra-cellular matrix and may lead to rupture. This remodeling is reflected by compliance which may be an indicator of AAA behavior and thus useful for clinicians. Tissue Doppler Imaging (TDI) is an ultrasonographic modality which allows wall motion measurements along an arterial segment. It has previously been evaluated in normal aortas and was then evaluated in thirty-five patients with AAA. Mean values (±standard deviation) characterizing maximum diameter AAA compliance were dilation 809 μm (±465), strain 2.2% (±1), pressure strain elastic modulus 3.94 10 5 Pa [3.25; 4.8] and stiffness 28.8 [24; 34.5], last values being expressed as geometric mean [interquartile range]. They were in accordance with those previously obtained with other systems. Segmental parameter values were maximum mean segmental dilation 534 μm (±305) and segmental compliance 14.6 (±8.3) 10 −2 μm/Pa. Reproducibility was appropriate for clinical studies. The TDI system is simple and reliable for measurement of AAA compliance, and compliance can easily be recorded during routine ultrasound control. (E-mail: along@chu-reims.fr)

Objectives: To improve processes of ambulatory care for patients with type 2 diabetes in a nationwide program.Methods: Interrupted time-series analysis with audits of practice. To implement selected recommendations of national guidelines, educational outreach visits (office visits or phone discussions) were offered to all French physicians who diagnosed one case of type 2 diabetes during a six-month intervention period. Outcome measures were the number of HBA1c measurements recorded monthly in the medical insurance computer database and the proportion of diabetic patients for whom one test had been reimbursed during the previous six months (HBA1c, fasting blood glucose) or previous twelve months (serum cholesterol, serum creatinine, urine microalbumin, electrocardiogram, ophthalmologic examination).Results: A total of 15,522 office visits and 9,062 telephone discussions were performed among 22,940 physicians. The increase in the monthly proportion of the number of HBA1c tests to the total number of laboratory tests was higher during the intervention period than during the preintervention (p valuep valueConclusions: Physician to physician outreach visits can be an effective way to improve the processes of care for diabetes and to routinize nationwide use of practice guidelines.

Summary. Background: A strong association between bilateral deep vein thrombosis (DVT) and cancer had been found in one retrospective study. To confirm this finding, consecutive patients with an objective diagnosis of bilateral DVT were followed over 12 months. Patients and methods: One-hundred and three patients, hospitalized for bilateral DVT, were included in the study. Twenty-six patients (25.2%) were already known to have a cancer, 26 (25.2%) had a previous history of venous thromboembolic disease, 44 (42.7%) had a symptomatic pulmonary embolism. The patients were scheduled to be prospectively followed up at 3, 6 and 12 months as outpatients. Information on recurrence, evidence of a new overt cancer and the cause of death were recorded for all patients. Results: A new cancer was diagnosed in 20 (26%) of the 77 patients without known cancer at admission. The risk of cancer was significantly more important in idiopathic thrombosis than in patients with secondary thrombosis (40.5% vs. 12.5%; odds ratio 4.8, 95% confidence interval 1.4, 18.8). Seventy percent of the cancers discovered had already spread. Age, gender, presence of pulmonary embolism, recurrence and location of the thrombosis were not statistically associated with the risk of cancer. The 1-year survival rates of patients with a previously known cancer and patients with a newly discovered cancer were, respectively, 26% and 35% (P = 0.33). Conclusion: Bilateral DVT is a significant risk indicator of malignancy. Cancer is present in 45% of patients with bilateral DVT and is associated with a poor prognosis.

Increased compliance of abdominal aortic aneurysms at maximum diameter over time might be related to rupture. Compliance could, therefore, be valuable in their management. However, such measurement requires a sophisticated system. An original arterial wall-motion measurement technique, based on tissue Doppler imaging (TDI) and providing segmental exploration, was applied to the study of aorta walls. We report its validation in healthy subjects. Technical feasibility was reliable. The time required for sequence acquisition and transfer was suitable for routine clinical use and the quality of the sequences provided precise identification of the aorta wall/lumen interface and accurate segmentation. The values characterising normal aortic compliance were similar to those previously published, and the initial results concerning reproducibility were appropriate for clinical studies. Further refinements may improve it. This study validates the TDI system for measurement of abdominal aortic compliance in healthy subjects. Study of application to aneurysm compliance is in progress.

We previously demonstrated a circadian rhythm in response to docetaxel chemotherapy in C3H/HeN mice bearing MA13/C mammary adenocarcinoma. We investigated the relation between this rhythm and the expression of BCL-2 in bone marrow and in tumor tissues. A circadian rhythm characterized BCL-2 expression in the bone marrow, which was hardly modified in tumor-bearing animals. BCL-2 acrophase coincided with the time of highest docetaxel tolerability and efficacy in this model. This suggests that BCL-2 protects the bone marrow from the drug toxicity, especially during the light phase.

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.

The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodium-depleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.