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BACKGROUND: We previously reported that CEA kinetics are a marker of progressive disease (PD) in metastatic colorectal cancer (mCRC). This study was specifically designed to confirm CEA kinetics for predicting PD and to evaluate CA19-9, cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) kinetics. METHODS: Patients starting a chemotherapy (CT) with pre-treatment CEA > 5 ng/mL and/or CA19.9 > 30 UI/mL were prospectively included. Samples were collected from baseline to cycle 4 for CEA and CA19-9 and at baseline and the sixth week for other markers. CEA kinetics were calculated from the first to the third or fourth CT cycle. RESULTS: A total of 192 mCRC patients were included. CEA kinetics based on the previously identified >0.05 threshold was significantly associated with PD (p

Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy., This work was supported by Cancer Research UK (CRUK) C33043/A12065 and C33043/ A24478 (V.S.-M., I.R.-H., O.M., L.K., G.C. B.F. and J.L.O.); Royal Society RG110591 (V. S.-M.); Barts Charity (V.S.-M., I.R.-H., O.M., J.M. and J.L.O.); Fundacion Alfonso Martin Escudero and Marie Sklodowska-Curie Action, grant agreement No 659022 (I.R.-H.); MRC C97993H (G.C.); The Harry J. Lloyd Charitable Trust (J.L.O. and V.S.-M.); Francis Crick Institute core funding from CRUK FC001112, MRC FC001112 and the Wellcome Trust FC001112 (I.M. and A.P.); CRUK C48390/A21153, CRUK/EPSRC and Wellcome Trust/EPSRC WT 203148/Z/16/Z (G.O.F.); NIHR BRC at Guy’s and St Thomas’ NHS Foundation Trust and KCL IS-BRC-1215–20006, CRUK C30122/A11527 and C30122/ A15774, MRC MR/L023091/1, CRUK/NIHR in England/DoH for Scotland, Wales and Northern Ireland ECMC C10355/A15587 (S.N.K.); ISCIII/FEDER “Una manera de hacer Europa” FIS-PI1500711 and PI18/00573 (R.M.M.); CIBERONC CB16/12/0023 (R.M.M and X.M.-G).

Objective To perform a head-to-head comparison of coronary CT angiography (CCTA) and dobutamine-stress echocardiography (DSE) in patients presenting recent chest pain when troponin and ECG are negative. Methods Two hundred seventeen patients with recent chest pain, normal ECG findings, and negative troponin were prospectively included in this multicenter study and were scheduled for CCTA and DSE. Invasive coronary angiography (ICA), was performed in patients when either DSE or CCTA was considered positive or when both were non-contributive or in case of recurrent chest pain during 6month follow-up. The presence of coronary artery stenosis was defined as a luminal obstruction >50% diameter in any coronary segment at ICA. Results ICA was performed in 75 (34.6%) patients. Coronary artery stenosis was identified in 37 (17%) patients. For CCTA, the sensitivity was 96.9% (95% CI 83.4–99.9), specificity 48.3% (29.4–67.5), positive likelihood ratio 2.06 (95% CI 1.36–3.11), and negative likelihood ratio 0.07 (95% CI 0.01–0.52). The sensitivity of DSE was 51.6% (95% CI 33.1–69.9), specificity 46.7% (28.3–65.7), positive likelihood ratio 1.03 (95% CI 0.62–1.72), and negative likelihood ratio 1.10 (95% CI 0.63–1.93). The CCTA: DSE ratio of true-positive and false-positive rates was 1.70 (95% CI 1.65–1.75) and 1.00 (95% CI 0.91–1.09), respectively, when non-contributive CCTA and DSE were both considered positive. Only one missed acute coronary syndrome was observed at six months. Conclusions CCTA has higher diagnostic performance than DSE in the evaluation of patients with recent chest pain, normal ECG findings, and negative troponine to exclude coronary artery disease.

Cardiac involvement is the leading cause of death in systemic sclerosis (SSc), although the condition may remain clinically asymptomatic for a long time [(1)][1]. SSc remains underdiagnosed despite repeated transthoracic echocardiography (TTE). This prospective longitudinal study included all

Background A better understanding of the influenza epidemiology among primary care workers could guide future recommendations to prevent transmission in primary care practices. Therefore, we designed a pilot study to assess the feasibility of using a work-based online influenza surveillance system among primary care workers. Such an approach is of particular relevance in the context of the coronavirus disease (COVID-19) pandemic, as its findings could apply to other infectious diseases with similar mechanisms of transmission. Objective This study aims to determine the feasibility of using a work-based online influenza surveillance system for primary care workers in Switzerland. Methods Physicians and staff of one walk-in clinic and two selected primary care practices were enrolled in this observational prospective pilot study during the 2017-2018 influenza season. They were invited to record symptoms of influenza-like illness in a weekly online survey sent by email and to self-collect a nasopharyngeal swab in case any symptoms were recorded. Samples were tested by real-time polymerase chain reaction for influenza A, influenza B, and a panel of respiratory pathogens. Results Among 67 eligible staff members, 58% (n=39) consented to the study and 53% (n=36) provided data. From the time all participants were included, the weekly survey response rate stayed close to 100% until the end of the study. Of 79 symptomatic episodes (mean 2.2 episodes per participant), 10 episodes in 7 participants fitted the definition of an influenza-like illness case (attack rate: 7/36, 19%). One swab tested positive for influenza A H1N1 (attack rate: 3%, 95% CI 0%-18%). Swabbing was considered relatively easy. Conclusions A work-based online influenza surveillance system is feasible for use among primary care workers. This promising methodology could be broadly used in future studies to improve the understanding of influenza epidemiology and other diseases such as COVID-19. This could prove to be highly useful in primary care settings and guide future recommendations to prevent transmission. A larger study will also help to assess asymptomatic infections.

Exposure to particulate matter (PM) is leading to various respiratory health outcomes. Compared to coarse and fine particles, less is known about the effects of chronic exposure to ultrafine particles, despite their higher number and reactivity. In the present study, we performed a time-course experiment in mice to better analyze the lung impact of atmospheric ultrafine particles, with regard to the effects induced by fine particles collected on the same site. Trace element and PAH analysis demonstrated the almost similar chemical composition of both particle fractions. Mice were exposed intranasally to FF or UFP according to acute (10, 50 or 100 &micro, g of PM) and repeated (10 &micro, g of PM 3 times a week during 1 or 3 months) exposure protocols. More particle-laden macrophages and even greater chronic inflammation were observed in the UFP-exposed mice lungs. Histological analyses revealed that about 50% of lung tissues were damaged in mice exposed to UFP for three months versus only 35% in FF-exposed mice. These injuries were characterized by alveolar wall thickening, macrophage infiltrations, and cystic lesions. Taken together, these results strongly motivate the update of current regulations regarding ambient PM concentrations to include UFP and limit their emission.

Summary Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors., Graphical Abstract, Highlights • Therapy-resistant melanoma cells restore myosin II activity to increase survival • High myosin II activity identifies targeted and immunotherapy-resistant melanomas • ROCK-myosin II inhibition increases ROS-DNA damage and decreases PD-L1 and Tregs • ROCK inhibition enhances efficacy of MAPK inhibitors and immunotherapies, Orgaz et al. show that myosin II activity increases during melanoma adaptation to MAPK pathway inhibition. ROCK-myosin II signaling supports survival of resistant melanoma cells and promotes immunosuppression. ROCK inhibitors improve the efficacy of MAPK inhibitors and immunotherapies in melanoma models.

Self-reported drinking habits were examined in a random sample of 1067 persons aged 25–64 years in the Seychelles, a country in epidemiological transition where consumption of home-brewed, mostly unregistered beverages has been traditionally high. Alcohol consumption was calculated from respondents reporting at least one drink per week (‘regular drinkers’). Among men, 51.1% were regular drinkers and had average intake of 112.1 ml alcohol a day. Among women, 5.9% were regular drinkers and had 49.7 ml alcohol a day. Frequency of drinking, but not amount per drinker, was slightly less in the 25–34-year than older-age categories. Home-brews (mostly palm toddy and fermented sugar cane juice) were consumed by 52% of regular drinkers and accounted for 54% of the total alcohol intake reported by all regular drinkers. Based on the reported consumption by regular drinkers only, the average annual alcohol consumption amounted respectively to 20.7 litres and 1.2 litres per man and woman aged 25–64 years, or, using extrapolation, 13.2 litres and 0.8 litres per man and woman respectively of the total population. These values may underestimate the true figures by half, since reported beer consumption accounted for 53% of beer sales. Socio-economic status was associated strongly and inversely with home-brew consumption, but slightly and positively with consumption of commercially marketed beverages. Alcohol intake was associated with smoking, high-density lipoprotein cholesterol, carbohydrate-deficient transferrin and blood pressure, but not with age and body mass index. In conclusion, these data show high alcohol consumption in the Seychelles with an important gender difference, a large proportion of alcohol derived from home-brews, and opposite tendencies for the relationships between socio-economic status and home-made or commercially marketed beverages.

International audience; Background: The direct comparison of CA19.9, circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has never been performed for the diagnosis of solid pancreatic tumours (SPTs).Methods: We included 68 patients with a SPT referred for EUS-FNA. CTCs were analysed using size-based platform and ctDNA using digital PCR. The sensitivity, specificity, negative and positive predictive values were evaluated for each marker and their combination.Results: SPTs corresponded to 58 malignant tumours (52 pancreatic adenocarcinoma (PA) and 6 others) and 10 benign lesions. The sensitivity and specificity for PA diagnosis were 73% and 88% for EUS-FNA, 67% and 80% for CTC, 65% and 75% for ctDNA and 79% and 93% for CA19.9, respectively. The positivity of at least 2 markers was associated with a sensitivity and specificity of 78% and 91%, respectively. CtDNA was the only marker associated with overall survival (median 5.2 months for ctDNA þ vs 11.0 months for ctDNA , P 1⁄4 0.01).Conclusions: CA19.9 alone and in combination with ctDNA and/or CTC analysis may represent an efficient method for diagnosing PA in patients with SPTs. Further studies including a larger cohort of patients with both malignant and benign lesions will be necessary to confirm these promising results.

Background Air pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection. Our first aim was to collect urban coarse particulate matter (PM) and to characterize them for elemental content, gastric bioaccessibility, and oxidative potential; our second aim was to determine the short-term effects of urban coarse PM inhalation on pulmonary and colonic mucosae in mice, and to test the hypothesis that the well-known antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of PM inhalation. Results The collected PM had classical features of urban particles and possessed oxidative potential partly attributable to their metal fraction. Bioaccessibility study confirmed the high solubility of some metals at the gastric level. Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 15 days at a concentration relevant to episodic elevation peak of air pollution. Coarse PM inhalation induced systemic oxidative stress, recruited immune cells to the lung, and increased cytokine levels in the lung and colon. Concomitant oral administration of NAC reversed all the observed effects relative to the inhalation of coarse PM. Conclusions Coarse PM-induced low-grade inflammation in the lung and colon is mediated by oxidative stress and deserves more investigation as potentiating factor for inflammatory diseases. Electronic supplementary material The online version of this article (10.1186/s12989-017-0227-z) contains supplementary material, which is available to authorized users.

We report the results of an echocardiographic substudy carried out in a trial comparing the effects of two different treatment strategies - mineralocorticoid receptor blockade (MRB) and dual renin-angiotensin system blockade (RASB) - in patients with resistant hypertension. Both strategies reduce left ventricular mass index (LVMI), but they have not been compared in patients with resistant hypertension.After 4-week treatment with 300 mg irbesartan + 12.5 mg hydrochorothiazide + 5 mg amlodipine, 86 patients with resistant hypertension were randomized to the add-on 25 mg spironolactone (MRB group, n = 46) or 5 mg ramipril (RASB group, n = 40) groups for 12 weeks. Treatment intensity was increased at week 4, 8 or 10 if home blood pressure (BP) was equal to or above 135/85 mmHg, by sequentially adding 20-40 mg furosemide and 5 mg amiloride (MRB group), or 10 mg ramipril and 5-10 mg bisoprolol (RASB group). Transthoracic echography was performed at baseline and week 12.Daytime ambulatory BP decreased by 19 ± 12/11 ± 8 mmHg in the MRB group and by 8 ± 13/7 ± 7 mmHg in the RASB group (P = 0.0003/0.03). LVMI decreased by 8.2 ± 18.9 g/m in the MRB group, whereas it increased by 1.8 ± 19.1 g/m in the RASB group (P = 0.03). The decreases in posterior wall thickness, left ventricular (LV) end-systolic diameter, E/e' ratio and left atrial area were significantly greater with MRB than with RASB. The difference between groups remained significant after adjustment for the decrease in ambulatory BP.In patients with resistant hypertension, MRB-based treatment decreased both BP and LVMI more efficiently than a strategy based on dual RASB.

Is fertility preservation feasible after the onset of puberty in adolescents with Klinefelter syndrome (KS)?Fertility preservation counseling should be an integral part of the care of XXY adolescents. Frozen ejaculated or testicular spermatozoa and even frozen immature germ cells can give them the potential to conceive their genetic progeny. However, no biological or clinical parameters were predictive of mature or immature germ cell retrieval.KS is the commonest sex chromosome disorder observed in azoospermic infertile males. Testicular sperm extraction success decreases with age and after testosterone therapy. Arguably, spermatozoa should be retrieved from KS males at the onset of puberty and before testosterone therapy to increase the chance of success.A retrospective study was performed in eight KS adolescents, aged between 15 and 17 years, who were referred for counseling about their future fertility to the center CECOS (Centre d'Etude et de Conservation des Oeufs et du Sperme humain) at Rouen University Hospital between October 2008 and December 2011.The patients were first seen with their parents and then separately. It was proposed to them that they should provide a semen sample, if this was azoospermic, two other semen samples spaced by 3 months were collected. If azoospermia was confirmed, a bilateral testicular biopsy was proposed for sperm retrieval and testicular tissue preservation. Each adolescent met the psychologist before undergoing testicular biopsy. Paraffin-embedded testicular tissue was evaluated after staining with hematoxylin-eosin and saffron and immunostaining using vimentin, anti-Müllerian hormone, androgen receptor and MAGE-A4 antibodies. Sertoli cell maturity, germ cell identification and lamina propria alteration were assessed on seminiferous tubules.KS adolescents were not deeply concerned about their future fertility and only became involved in the process of fertility preservation after at least three medical consultations. The parents agreed immediately that fertility preservation should be attempted. Seven non-mosaic XXY adolescents presented with azoospermia and one XXY/XY adolescent had oligozoospermia. Increased plasma levels of FSH and LH as well as bilateral testicular hypotrophy were observed in all patients. The XXY/XY adolescent banked four semen samples before testosterone replacement therapy. Two patients refused testicular biopsy. Five patients accepted a bilateral testicular biopsy. Spermatozoa were retrieved in one patient, elongated spermatids and spermatocytes I in a second patient.The number of patients enrolled in our study was low because the diagnosis of KS is only rarely made before or at the onset of puberty. Most XXY males are diagnosed in adulthood within the context of male infertility.Spermatozoa can be retrieved in semen sample and in testicular tissue of adolescent Klinefelter patients. Furthermore, the testis may also harbor spermatogonia and incompletely differentiated germ cells. However, the physician should discuss with the patient and his parents over a period of several months before collecting a semen sample and performing bilateral testicular biopsy. Fertility preservation might best be proposed to adolescent Klinefelter patients just after the onset of puberty when it is possible to collect a semen sample and when the patient is able to consider alternative options to achieve fatherhood and also to accept the failure of spermatozoa or immature germ cell retrieval.

Demographic data point to a substantial proportion of women in the population of elderly patients with an increasing prevalence of aortic stenosis. Implantation of an aortic bioprosthesis via an endovascular approach known as Transcatheter aortic valve implantation (TAVI) in patients presenting with a symptomatic tight aortic stenosis (severe aortic stenosis) (AS) is an alternative therapeutic option to surgical aortic valve replacement in patients at high surgical risk or ineligible for surgery. The literature has shown that this technique seems to be particularly beneficial in female patients. In the Partner A trial, the 1-year mortality rate was significantly lower in women compared to their male counterparts. Other data revealed that although women have a higher risk of experiencing periprocedural complications (vascular events, bleeding and stroke), their outcome is good and often better than that of men. These results are continuously improving thanks to the enhancement of techniques and devices. In view of the published reports reflecting the increasing experience of the teams, it clearly appears that the simplification of TAVI procedures has resulted in improved outcomes. We report here the case of a patient treated by means of a "minimalist" approach to TAVI allowing a reduction of the risks inherent in the procedure. This simplified strategy relies on an optimal use of CT scan findings prior to TAVI. The procedure is carried out under local anesthesia and the main access site is sutured percutaneously (Proglides). The radial artery is used as a secondary access site. Contrast medium is diluted and stimulation is administered via the intraventricular guidewire. Direct stenting is performed when deemed feasible on the basis of CT scan results. Simplified procedures such as these contribute to the improvement of TAVI outcomes. However, further studies focusing on female patients are warranted in order to corroborate these findings.

International audience; Purpose: Valvuloarterial impedance (ZVA ), estimating left ventricle (LV) afterload, has been proposed in transthoracic echocardiography (TTE) as a predictor of mortality in aortic valve stenosis (AVS). However, its calculation differs from arterial characteristic impedance (ZC ). Our aim was to apply the concept of ZC calculation to estimate ZVA from MR with carotid tonometry and to evaluate these indices through their associations with symptoms, LV diastolic function and aortic stiffness.Materials and methods: In 40 patients with AVS (76 ± 13 years), ZVA-TI derived from velocity time integral and E/Ea were estimated by TTE. ZVA-INS , based on ZC formula, calculated as the instantaneous pressure gradient to peak flow ratio and aortic compliance were estimated by using MRI at 1.5 Tesla.Results: Both ZVA estimates were higher in symptomatic than asymptomatic patients (707 ± 22 versus 579 ± 53 dyne.s/cm5 , P = 0.031 for ZVA-INS and 4.35 ± 0.16 versus 3.33 ± 0.38 mmHg.m2 /mL, P = 0.018 for ZVA-TI ). Although they were both associated with aortic compliance (r = -0.45; P = 0.006 for ZVA-INS and r = -0.43; P = 0.008 for ZVA-TI ) only ZVA-INS was associated with E/Ea (r = 0.50; P < 0.001). In multivariate analysis to identify determinants of E/Ea, a model including age, mean blood pressure, LV ejection fraction, LV mass, and aortic valve area was performed (R2 = 0.41; P < 0.01). When ZVA-INS was added to the model, its overall significance was higher R2 = 0.56 (P < 0.01) and ZVA-INS and LV mass were the only significant determinants.Conclusion: ZVA-INS was more strongly associated with diastolic dysfunction than usual parameters quantifying AVS severity. This new ZVA estimate could improve LV afterload evaluation.

Importance of left atrial (LA) phasic function evaluation is increasingly recognized for its incremental value in terms of prognosis and risk stratification. LA phasic deformation in the pathway of normal aging has been characterized using echocardiographic speckle tracking. However, no data are available regarding age-related variations using feature-racking (FT) techniques from standard cine magnetic resonance imaging (MRI). We studied 94 healthy adults (41 ± 14 yr, 47 women), who underwent MRI and Doppler echocardiography on the same day for left ventricular (LV) diastolic function evaluation. From cine MRI, longitudinal strain and strain rate, radial motion fraction, and radial relative velocity, respectively, corresponding to the reservoir, conduit, and LA contraction phases, were measured using dedicated FT software. Longitudinal strain and radial motion fraction decreased gradually and significantly with aging for both reservoir ( r > 0.31, P < 0.003) and conduit ( r > 0.54, P < 0.001) phases, whereas they remained unchanged during the LA contraction phase. Subsequently, the LA contraction-to-reservoir ratio increased significantly with age ( r > 0.44, P < 0.001). Longitudinal strain rate and radial relative velocity significantly decreased with age (reservoir: r = 0.39, P < 0.001, conduit: r > 0.54, P < 0.001), and these associations tended to be stronger in women than in men. Finally, associations of LA functional indexes with age were stronger in individuals with lower transmitral early-to-atrial maximal velocity ratio and mitral annulus maximal longitudinal velocity, as well as higher transmitral early maximal-to-mitral annulus maximal longitudinal velocity ratio, highlighting the LV-LA interplay. Age-related changes in LA phasic function indexes were quantified by cine MRI images using a FT technique and were significantly related to age and LV diastolic function.

Fertility preservation has been included in the management of childhood cancer treatment. Cryopreservation of immature testicular tissue is the only available solution for pre-pubertal boys. Different freezing protocols have been developed in several species but without a clearly identified procedure. We tried to evaluate several protocols for cryopreservation of rat immature testicular tissue. Twelve different freezing protocols using different (i) cryoprotectant (dimethylsulphoxide [DMSO] or 1,2-propanediol [PROH]), (ii) cryoprotectant concentration (1.5M or 3M), (iii) equilibration time (30 or 60 min), (iv) equilibration temperature (4 °C or room temperature), (v) size of testicular fragment (7.5mg or 15 mg), (vi) package (straws or cryovials), were compared using cord morphological damage evaluation. A testicular tissue piece of 7.5mg cryopreserved in cryovial using 1.5M DMSO, an equilibration time of 30 min at 4 °C showed fewer morphological alterations than the other protocols tested. The selected freezing protocol was able to maintain rat immature testicular tissue architecture, functionality after testicular pieces organotypic culture, and could be proposed in a human application.

Summary Background An accurate assessment of left ventricular (LV) mass is important for the detection of LV hypertrophy. Aims To assess the accuracy of four echocardiographic imaging modalities for assessing LV mass compared with cardiac magnetic resonance (CMR). Methods We prospectively studied 40 consecutive patients, who underwent an echocardiographic examination using four imaging modalities (M-mode fundamental imaging [FI], M-mode harmonic imaging [HI], two-dimensional [2D] FI and 2D HI) and CMR (our gold standard for LV mass measurement). All echocardiographic measurements were performed by two independent observers. Results All echocardiographic modes significantly overestimated LV mass compared with CMR (P ≤ 0.04), except 2D FI (P = 0.25). This overestimation was significantly higher with HI (up to 15.5%) compared with FI (up to 5.7%; P ≤ 0.04). Significant correlations were observed between the different echocardiographic methods and the two observers. The interobserver agreement over LV mass measurement was lower with FI (intraclass coefficient [ICC] range, 0.66–0.73) than with HI (ICC range, 0.72–0.82), and the best agreement was obtained with 2D HI (ICC, 0.82). Good agreement between CMR and all echocardiographic methods was observed among the smallest LV diameters (ICC range, 0.62–0.85), but not among the largest LV diameters (ICC range, 0–0.22). Conclusions HI overestimates LV mass compared with FI and CMR; this leads to overestimation of prevalence of LV hypertrophy in a population of hypertensive patients. HI improves interobserver reproducibility of LV mass measurement compared with FI, leading to a significant decrease in the number of patients required for clinical trials evaluating LV mass regression. Accuracy of LV mass measurement by echocardiography is affected by LV geometry.

Transitional B cells have been recently identified in human peripheral blood. However, their precise role in human B cell differentiation has not been established. Therefore, besides characterizing them further in the blood of healthy adults and children and cord blood, we used the immune reconstitution after hematopoietic stem cell transplantation (HSCT) model to define their role in human B cell development. Human transitional B cells are reliably identified as CD19(+) CD24(high) CD38(high) lymphocytes and represent approximately 4% of B cells in healthy adult peripheral blood. In contrast, they are abundant in cord blood (near 50% of B cells) and their percentage progressively decreases during infancy. Similarly, after HSCT, all B cells first appearing in peripheral blood are transitional B cells; afterwards, the transitional B cell percentage progressively decreases while the mature naïve B cell proportion rises. Our results now formally demonstrate that transitional B cells are necessary developmental intermediates for human mature B cell generation.

Our objectives were to assess the ability of phasecontrast MRI (PC-MRI) to detect sub-clinical age-related variations of left ventricular (LV) diastolic parameters and thus to provide age-related reference ranges currently available for echocardiography but not for MRI-PC, and to identify independent associates of such variations. We studied 100 healthy volunteers (age = 42 ± 15years, 50 females) who had MRI with simultaneous blood pressure measurements. LV mass and volumes were assessed. Semiautomated analysis of PC-MRI data provided: 1) early transmitral (Ef) and atrial (Af) peak filling flow-rates (ml/s) and filling volume (FV), 2) deceleration time (DT), isovolumic relaxation time (IVRT), and 3) early myocardial longitudinal (E’) peak velocity. MRI-PC diastolic parameters were reproducible as reflected by low coefficients of variations (ranged between 0.31 to 6.26 %). Peak myocardial velocity E’ (r = −0.63, p

Several studies have shown that vitamin D supplementation could be useful for treating diffuse musculoskeletal (DMS) pain in adults.The aim of this study was to evaluate the effects of correcting a vitamin D deficiency (≤ 50 nmol/l) on DMS pain and quality of life in adults.A pragmatic prospective study was conducted in a general practice setting in the Rhone-Alps area between 1 February and 30 April 2009. Patients between the ages of 18 and 50 years old who consulted their general practitioner (GP) for DMS pain or chronic unexplained asthenia and had a deficient serum 25 (OH) D level with no signs of any other disease were enrolled in this study. The patients received high doses of vitamin D supplements (400 000 to 600 000 units). Mean pain evaluation scores were evaluated before and after vitamin D supplementation using mixed models and accounting for repeated measures.Before vitamin D supplementation, the adult study cohort (n = 49) had an adjusted mean serum 25 (OH) D level of 23.7 nmol/l, a mean pain evaluation score of 5.07 and a mean quality of life score of 3.55. After vitamin D supplementation, the adjusted mean serum 25 (OH) D level increased to 118.8 nmol/l (P0.001), the mean quality of life score increased to 2.8 nmol/l (P0.001) and the mean pain evaluation score decreased to 2.8 (P0.001).In this small before-and-after study, vitamin D supplementation decreased pain scores in adult patients with diffuse musculoskeletal pain and vitamin D deficiency. These results must be confirmed by further studies.

Fentanyl, a synthetic opioid, undergoes important biotransformation to several metabolites. A gas chromatographic-mass spectrometric assay was applied for the simultaneous analysis of fentanyl and its major metabolites in biological samples. The identification of different metabolites was performed by gas chromatography-mass spectrometry (electronic impact and chemical ionisation modes) and gas chromatography-Fourier transform infrared spectroscopy. In the present study, rat and human microsomes incubation mixtures and human urines were analysed. In vitro formation of already known fentanyl metabolites was confirmed. The presence of metabolites not previously detected in human urine is described.

BACKGROUND Approximately 10 years after the first publication introducing the motile sperm organelle morphology examination (MSOME), many questions remained about sperm vacuoles: frequency, size, localization, mode of occurrence, biological significance and impact on male fertility potential. Many studies have tried to characterize sperm vacuoles, to determine the sperm abnormalities possibly associated with vacuoles, to test the diagnostic value of MSOME for male infertility or to question the benefits of intracytoplasmic morphologically selected sperm injection (IMSI). METHODS We searched PubMed for articles in the English language published in 2001-2012 regarding human sperm head vacuoles, MSOME and IMSI. RESULTS A bibliographic analysis revealed consensus for the following findings: (i) sperm vacuoles appeared frequently, often multiple and preferentially anterior; (ii) sperm vacuoles and sperm chromatin immaturity have been associated, particularly in the case of large vacuoles; (iii) teratozoospermia was a preferred indication of MSOME and IMSI. CONCLUSION The high-magnification system appears to be a powerful method to improve our understanding of human spermatozoa. However, its clinical use remains unclear in the fields of male infertility diagnosis and assisted reproduction techniques (ARTs).

Testicular tissue cryopreservation is the only potential option for fertility preservation in pre-pubertal boys exposed to gonadotoxic treatment. Completion of spermatogenesis after in vitro maturation is one of the future uses of harvested testicular tissue. The purpose of the current study was to evaluate the effects of vitamin A on in vitro maturation of fresh and frozen-thawed mouse pre-pubertal spermatogonial stem cells in an organ culture system. Pre-pubertal CD1 mouse fresh testes were cultured for 7 (D7), 9 (D9) and 11 (D11) days using an organ culture system. Basal medium was supplemented with different concentrations of retinol (Re) or retinoic acid (RA) alone or in combination. Seminiferous tubule morphology (tubule diameter, intra-tubular cell type), intra-tubular cell death and proliferation (PCNA antibody) and testosterone level were assessed at D7, D9 and D11. Pre-pubertal mouse testicular tissue were frozen after a soaking temperature performed at -7 °C, -8 °C or -9 °C and after thawing, were cultured for 9 days, using the culture medium preserving the best fresh tissue functionality. Retinoic acid at 10(-6)M and retinol at 3.3.10(-7)M, as well as retinol 10(-6)M are favourable for seminiferous tubule growth, maintenance of intra-tubular cell proliferation and germ cell differentiation of fresh pre-pubertal mouse spermatogonia. Structural and functional integrity of frozen-thawed testicular tissue appeared to be well-preserved after soaking temperature at -8 °C, after 9 days of organotypic culture using 10(-6)M retinol. RA and Re can control in vitro germ cell proliferation and differentiation. Re at a concentration of 10(-6)M maintains intra-tubular cell proliferation and the ability of spermatogonia to initiate spermatogenesis in fresh and frozen pre-pubertal mouse testicular tissue using a soaking temperature at -8 °C. Our data suggested a possible human application for in vitro maturation of cryopreserved pre-pubertal testicular tissue.

The occupational exposure of 19 men to hexamethylene diisocyanate (HDI) vapour was monitored during one 8-h shift. It ranged from 0.30 to 97.7 micrograms/m3. This was compared with the urinary output of hexane diamine (HDA) liberated by acid hydrolysis from its conjugates in post-shift samples. The excretion varied from 1.36 to 27.7 micrograms g creatinine, and there was a linear association of HDI air concentration with urinary HDA excretion. The validity of the urinary analysis was confirmed by simultaneous blind analysis in another laboratory. The results had an excellent linear concordance. Thus, it seems that while the gas chromatographic-mass spectrometric detection method requires sophisticated apparatus, the results are very useful to occupational health practices. A biological exposure index limit of 19 micrograms HDA/g creatinine in a post-shift urine specimen is proposed as an occupational limit level of HDI monomer (time-weighted average = 75 micrograms/m3). Most importantly, biological monitoring of HDA is sensitive enough to be used at and below the current allowable exposure limit levels.

Testicular cancer is the most common cancer in young men. Several studies have reported an alteration in semen quality in nonseminoma tumors, but this result has not been confirmed in all of the published data. We performed a retrospective study in a population of 1158 men with testicular cancer who banked sperm between 1999 and 2003 in 11 French Centre d'Etude et de Conservation des Oeufs et du Sperme humain laboratories. Our study evaluated prefreeze and postthaw sperm parameters according to patient medical history, tumor histological type, and disease stage. Pure seminomas were found in 48% of our population. Testicular cancer was generally diagnosed at stage I. In cases of a history of unilateral cryptorchidism, testicular cancer occurred preferentially in the maldescended testis. Semen samples were preferentially collected after orchiectomy. The sperm concentration and total sperm number were significantly lower before orchiectomy in seminomas compared with nonseminoma tumors (P < .001). After orchiectomy, these parameters decreased for nonseminoma tumors and did not vary for seminomas. Semen parameters were more severely impaired for stage III tumors, and when patients had a history of cryptorchidism or when they were less than 20 years of age. Azoospermia was more frequently observed before than after orchiectomy. In this study, we determined that sperm cryobanking should preferentially be performed before orchiectomy and that testicular sperm extraction concurrent with orchiectomy should be used in severe spermatogenesis impairment. Our study highlights that seminomas alter sperm production more significantly than nonseminoma tumors and seem to preferentially impair spermatogenesis in tumor-bearing testes.

Background— Accurate quantification of aortic valve stenosis (AVS) is needed for relevant management decisions. However, transthoracic Doppler echocardiography (TTE) remains inconclusive in a significant number of patients. Previous studies demonstrated the usefulness of phase-contrast cardiovascular magnetic resonance (PC-CMR) in noninvasive AVS evaluation. We hypothesized that semiautomated analysis of aortic hemodynamics from PC-CMR might provide reproducible and accurate evaluation of aortic valve area (AVA), aortic velocities, and gradients in agreement with TTE. Methods and Results— We studied 53 AVS patients (AVA TTE =0.87±0.44 cm 2 ) and 21 controls (AVA TTE =2.96±0.59 cm 2 ) who had TTE and PC-CMR of aortic valve and left ventricular outflow tract on the same day. PC-CMR data analysis included left ventricular outflow tract and aortic valve segmentation, and extraction of velocities, gradients, and flow rates. Three AVA measures were performed: AVA CMR1 based on Hakki formula, AVA CMR2 based on continuity equation, AVA CMR3 simplified continuity equation=left ventricular outflow tract peak flow rate/aortic peak velocity. Our analysis was reproducible, as reflected by low interoperator variability (r =0.92 with mean bias=−29±62 cm/s and r =0.86 with mean bias=−12±15 mm Hg, respectively). Although good agreement was found between TTE and continuity equation–based CMR-AVA ( r >0.94 and mean bias=−0.01±0.38 cm 2 for AVA CMR2 , −0.09±0.28 cm 2 for AVA CMR3 ), AVA CMR1 values were lower than AVA TTE especially for higher AVA (mean bias=−0.45±0.52 cm 2 ). Besides, ability of PC-CMR to detect severe AVS, defined by TTE, provided the best results for continuity equation–based methods (accuracy >94%). Conclusions— Our PC-CMR semiautomated AVS evaluation provided reproducible measurements that accurately detected severe AVS and were in good agreement with TTE.

Lab tests are frequently used in primary care to guide patient care. This is particularly the case when a severe disorder, or one that will affect patients' initial care, needs to be excluded rapidly. At the PMU-FLON walk-in clinic the use of HIV testing as recommended by the Swiss Office of Public Health was hampered by the delay in obtaining test results. This led us to introduce rapid HIV testing which provides results within 30 minutes. Following the first 250 tests the authors discuss the results as well as the benefits of rapid HIV testing in an urban walk-in clinic.

In the management of asthenozoospermia, the spermogram-spermocytogram plays an important role during diagnosis. It is of major importance to distinguish between necrozoospermia and sperm vitality. An ultrastructural study of spermatozoa is processed in the case of primary infertility without female implication, severe, unexplained and irreversible asthenozoospermia, sperm vitality at least 50 % and normal concentration of spermatozoa. Ultrastructural flagellar abnormalities are numerous and involve most spermatozoa. ICSI provides a suitable solution for patients with sperm flagellar defects to conceive children with their own gametes but the rate of ICSI success may be influenced by the type of flagellar abnormality. Some fertilization and birth rate failures which are related to some flagellar abnormalities might occur.

The objective of this study was to evaluate the effect of the correction of vitamin D deficiency (defined by a rate≤50 nmol/l) on the pain, fatigue and quality of life.A pragmatic prospective study was conducted in Rhone-Alpes area, in general practices between February 1 and April 30, 2009. All patients aged 18 to 50 years consulting for diffuse musculoskeletal pain and/or chronic unexplained fatigue, with the only abnormality deficient serum vitamin D were enrolled in this study. They might agree to complete questionnaires on quality of life, pain assessment and control their vitamin D levels after treatment.Forty-nine complete records were analyzed. The deficiency was severe (mean 26 nmol/l). High doses of vitamin were necessary to correct deficiency, between 400,000 to 600,000 units. The correction of vitamin D deficiency resulted in a significant decrease in the level of pain intensity according to verbal rating scale (P=0.034) and the Digital Scale (P0.001), consumption of analgesics (P=0.002) and discomfort in carrying out activities of daily living following: the shopping, cleaning, walking for more than a kilometer (P0.001) and dressing (P=0.012).The correction has had a positive impact both physical, mental and social activities. Non-specific musculoskeletal pain or unexplained asthenia are common in primary care. Make a dosage of vitamin D and correct deficits is a necessity before performing complex and expensive examinations.

Normal spermatogenesis results from a balance between process of cell proliferation, cell differentiation and apoptosis that concern somatic cells and germ cells. Dysfunction of spermatogenesis may be the result of constitutional or acquired abnormalities of spermatogonia stem cells or somatic cells. To overcome these problems, it seems necessary to implement preventive measures for germ stem cell preservation or substitute measures to replace them, the objective being to replicate in vivo or in vitro the process of spermatozoa production. This article will discuss the different experimental strategies for considering the in vivo or in vitro production of spermatozoa, outside the physiological process.

Improving our practice by a constant evaluation is essential in the field of donor semen insemination (DI). Our center examined the prognosis factors for DI success in order to standardize patient treatment options.We retrospectively analysed all couples referred for DI from January 2000 till December 2010.We analysed 551 cycles among 188 patients. Pregnancy rate by stimulation cycle was 19,8% with birth rate of 16.7%. The rate of pregnancy was improved till the fourth trial then plateau. On a patient-based analysis, success factors were age (P=0.04), previous successful DSI (P=0.02), and no previous failure of an ICSI-C (P=0.035). On a cycle-based analysis, success factors were the number of follicles greater than 15mm (P=0.04) and than 18mm (P=0.001). The percentage of 68.1 patients obtained a child by IVF-D after a failed DI.There are two predictive factors for DI success: the age of the patient and the number of mature follicles. It seems accurate to referred patients to IVF-D after four unsuccessful cycles of DSI. This recommendation may be adapted according to patient's age and hormonal evaluation.

With the motile sperm organelle morphology examination (MSOME), spermatozoa morphology may be assessed directly on motile spermatozoa at high magnification (up to 6600×). This procedure describes more precisely spermatozoa abnormalities, especially head vacuoles. However, no consensus has been established concerning normal or abnormal MSOME criteria. The aim of our study was to define MSOME vacuole criteria assessed objectively with a digital imaging system software to establish a potential relationship between conventional semen parameters. A total of 440 semen samples were obtained from males consulting in Rouen University Hospital Reproductive Biology Laboratory. Conventional semen analysis (volume, sperm concentration, progressive motility, vitality and morphology) and MSOME assessment {sperm head length, width and area as well as vacuole number, vacuole area and relative vacuole area to sperm head [RVA (%) = [vacuole area (μm(2))/head area (μm(2))] × 100)]} were performed for each semen sample. Among our 440 males, 109 presented normal conventional semen parameters and 331 abnormal ones. Sperm head vacuoles were significantly larger in abnormal semen samples (p0.0001). RVA was the most discriminative MSOME criterion between normal and abnormal semen samples according to ROC curves analysis, and was negatively correlated with poor sperm morphology (r = -0.53, p0.0001). We concluded to (i) the normal occurrence of vacuoles in sperm head whatever the normality or abnormality of semen parameters, (ii) the discriminative function of the RVA to distinguish semen samples with normal and abnormal parameters, and (iii) the strong correlation between high RVA and poor sperm morphology.

Human normal spermatozoa present a specific chromatin organization, illustrated particularly by the non-random chromosome positioning. Spermatozoa with large vacuoles, described using motile sperm organelle morphology organization (MSOME), are associated with nuclear alterations, such as abnormal chromatin condensation and aneuploidy. To question a probable association between large nuclear vacuoles and chromatin disorganization, we evaluated chromosomes X, Y and 18 topography in normal spermatozoa (NS) compared with spermatozoa with large vacuoles (SLV). After centrifugation on a gradient density system, 229 NS (spermatozoa presenting a normal nuclear shape and a vacuole area6.5% of head area) from 10 normal semen samples and 221 SLV (spermatozoa presenting a vacuole area13% of head area) from 10 semen samples with teratozoospermia were selected using MSOME. A three-colour FISH was carried out using α-satellite centromeric probes for chromosomes X, Y and 18. For each chromosome, longitudinal and spatial positioning of centromeres was analysed. Distribution of each chromosome was non-random in NS and in SLV, whatever the methodology used. Using longitudinal positioning, distribution of chromosome 18 and chromosome Y centromeres did not differ significantly between SLV and NS. On the contrary, chromosome X centromeres were more frequently positioned in the posterior region of sperm nucleus in SLV (p = 0.01). Considering spatial positioning, distributions differed significantly between SN and SLV for chromosome Y (p = 0.02) and chromosome 18 (p 10(-4) ) and marginally for chromosome X (p = 0.08). Our study concluded to a modification in chromosomes X, Y and 18 centromere topography between NS and SLV, representing a novel and supplementary evidence to argue chromatin disorganization in SLV.

Objective To understand patients’ perceptions of decision making and identify relationships among decision-making models. Methods This qualitative study was made up of four focus group interviews (elderly persons, users of health support groups, students, and rural inhabitants). Participants were asked to report their perceptions of decision making in three written clinical scenarios (hypertension, breast cancer, prostate cancer). The analysis was based on the principles of grounded theory. Results Most patients perceived decision making as shared decision making, a deliberative question–response interaction with the physician that allowed patients to be experts in obtaining clearer information, participating in the care process, and negotiating compromises with physician preferences. Requesting second opinions allowed patients to maintain control, even within the paternalistic model preferred by elderly persons. Facilitating factors (trust, qualitative non-verbal communication, time to think) and obstacles (serious/emergency situations, perceived inadequate scientific competence, problems making requests, fear of knowing) were also part of shared decision making. Conclusion and practice implications In the global concept of patient-centered care, shared decision making can be flexible and can integrate paternalistic and informative models. Physicians’ expertise should be associated with biomedical and relational skills through listening to, informing, and advising patients, and by supporting patients’ choices.

BACKGROUND: Spermatozoa with large vacuoles (SLV) may have a negative impact on embryo development. The origin of these vacuoles is unknown. We evaluated acrosome and nucleus alterations in isolated SLV, versus unselected spermatozoa. METHODS: We studied 20 patients with teratozoospermia. Spermatozoa from the native semen sample and spermatozoa presenting a vacuole occupying > 13.0% total head area, isolated under high magnification (× 6600), were assessed. Confocal and transmission electron microscope evaluations were performed on SLV and native sperm, respectively. Acrosome morphology and DNA fragmentation were analysed using proacrosin immunolabelling (monoclonal antibody 4D4) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay. Chromatin condensation was evaluated with aniline blue staining. Sperm aneuploidy was assessed using fluorescence in situ hybridization. RESULTS: SLV represented 38.0 ± 5.10% of motile spermatozoa obtained after gradient density centrifugation. Vacuoles were mainly in the anterior and median sperm head (45.7 ± 2.90 and 46.1 ± 3.00%, respectively). Abnormal acrosomes were increased in SLV compared with unselected spermatozoa (77.8 ± 2.49 versus 70.6 ± 2.62%; P = 0.014). Microscopic observations showed an exclusively nuclear localization of large vacuoles. Complete DNA fragmentation was higher in native spermatozoa (P < 0.0001) than SLV, while chromatin condensation was altered in SLV (P < 0.0001). Aneuploidy and diploidy rates were increased in SLV (P < 0.0001). CONCLUSIONS: Sperm vacuoles were exclusively nuclear. In our selected teratozoospermic population, aneuploidy and chromatin condensation defects were the main alterations observed in SLV. Based on results from this small sample of spermatozoa, we propose a global impairment of the spermatogenesis process as a common origin of the morphological alterations.

To evaluate the results of the initial in vitro fertilization (IVF) procedure after intrauterine insemination (IUI) failure where half of the oocytes were inseminated as for conventional IVF and half of the oocytes where treated for intra cytoplasmic sperm injection (ICSI).From the first of January 2001 to the 31st of December 2008, 75 couples failing to conceive with ovarian stimulation and IUI were included in this retrospective study.Among the 75 couples, 53 had IVF and ICSI in sibling oocytes and 22 had just ICSI because of an insufficient oocyte cohort. No significant difference was observed in fertilization, implantation and pregnancy rates between the different groups; however, a total fertilization failure was observed more frequently when conventional IVF was used compared to ICSI (11.3% vs 3.8%). These patients with fertilization failure on conventional IVF had a lower sperm count than those who obtained embryos but sperm parameters were normal according to World Health Organisation (WHO) criteria and our study did not find any predictive factor of fertilization failure.Couples failing to conceive after controlled ovarian hyperstimulation and IUI may be proposed a mixed in vitro fertilization procedure (with conventional IVF and ICSI) in order to avoid a total fertilization failure. Moreover, this procedure will indicate the better IVF technology (conventional or ICSI) for the subsequent attempt.

Background Early detection of diastolic dysfunction is crucial for patients with incipient heart failure. Although this evaluation could be performed from phase-contrast (PC) cardiovascular magnetic resonance (CMR) data, its usefulness in clinical routine is not yet established, mainly because the interpretation of such data remains mostly based on manual post-processing. Accordingly, our goal was to develop a robust process to automatically estimate velocity and flow rate-related diastolic parameters from PC-CMR data and to test the consistency of these parameters against echocardiography as well as their ability to characterize left ventricular (LV) diastolic dysfunction. Results We studied 35 controls and 18 patients with severe aortic valve stenosis and preserved LV ejection fraction who had PC-CMR and Doppler echocardiography exams on the same day. PC-CMR mitral flow and myocardial velocity data were analyzed using custom software for semi-automated extraction of diastolic parameters. Inter-operator reproducibility of flow pattern segmentation and functional parameters was assessed on a sub-group of 30 subjects. The mean percentage of overlap between the transmitral flow segmentations performed by two independent operators was 99.7 ± 1.6%, resulting in a small variability ( 0.71) and receiver operating characteristic (ROC) analysis revealed their ability to separate patients from controls, with sensitivity > 0.80, specificity > 0.80 and accuracy > 0.85. Slight superiority in terms of correlation with echocardiography (r = 0.81) and accuracy to detect LV abnormalities (sensitivity > 0.83, specificity > 0.91 and accuracy > 0.89) was found for the PC-CMR flow-rate related parameters. Conclusions A fast and reproducible technique for flow and myocardial PC-CMR data analysis was successfully used on controls and patients to extract consistent velocity-related diastolic parameters, as well as flow rate-related parameters. This technique provides a valuable addition to established CMR tools in the evaluation and the management of patients with diastolic dysfunction.

To evaluate the impact of local recommendations on off label use of recombinant activated factor VII.Observational, retrospective.Recommendations have been diffused by a local working group in 2004, concerning seven groups of indications (traumatology, cardiac, hepatic and various surgeries, obstetrics, neurology and haematology). Conformity to recommendations was studied according to 4 axes: respect of prescribing procedure, indication, posology, and pre ones required with the administration.There were thirty-one uses from 2004 to 2006. Thirty patients presented a massive haemorrhage (blood products before administration of recombinant activated factor VII expressed in median [min-max]: red blood cell unit=15 [0-37], fresh frozen plasma=11 [0-21]). Gravity score at the admission: SAPSII=55+/-22 (average+/-SD), 87% patients presented haemorrhagic shock. Prescribing procedure was in conformity with recommendations in 45%, indications were correct in 74%, posology in 55%, and 16% of prescriptions were completely conform.With the tariffing to the activity reform, the reimbursement of off label use of expensive molecules will depend on the respect of the evidence-based medicine. According to this study, the observance of local recommendations was insufficient. Rationalizing prescriptions for practice improvement seemed to be difficult and challenging.

The aim of this retrospective study was to compare the appropriateness of cardiac risk factors (CV-RF) management in a Swiss cardiac rehabilitation center. The comparison of the control of CV-RF among 342 patients with coronary artery disease (CHD) agedor =65 years was improved. The CV-RF management has globally improved during the two periods of observation (1994-95 and 1999-2000). Nevertheless, according to the recommendations published between 1994 and 1999, an underuse of the cardioprotective agents was still observed. Using a standardized protocol for the management of CHD which allows the benchmarking among the network of cardiac rehabilitation centers network could increase the quality of care for such high risk patients.

1/1 atrial flutter is a regularly described complication of class I anti-arrhythmics. It is, however, very rarely encountered with class III anti-arrhythmics because prolongation of the atrio-ventricular node refractory period prevents 1/1 nodo-ventricular conduction. There have only been seven cases of 1/1 atrial flutter with amiodarone reported in the literature. Here we describe a new case of 1/1 atrial flutter with amiodarone. Our case clearly illustrates not only the different pro-arrhythmic effects of amiodarone (prolongation of the flutter cycle, and infra-Hissian block) but also the pathophysiological mechanisms possible with 1/1 conduction (prolongation of the flutter cycle, considerable permeability of the AV node). It demonstrates the difficulties of diagnosing such a rhythm disturbance, and that it is sometimes poorly tolerated, as well as underlining the importance of early diagnosis (in this case by oesophageal recording). Preventive treatment of 1/1 flutter can include amiodarone, digitalis, a betablocker or a bradycardic calcium inhibitor.

Background The pharmacokinetics of propofol in man is characterized by a rapid metabolic clearance linked to glucuronidation of the parent drug to form the propofol-glucuronide (PG) and sulfo- and glucuro-conjugation of hydroxylated metabolite via cytochrome P450 to produce three other conjugates. The purpose of this study was to assess the urine metabolite profile of propofol following i.v. propofol anaesthesia in a Caucasian population. Methods The extent of phase I and phase II metabolism of propofol was studied in 18 female and 17 male patients after an anaesthesia induced and maintained for at least 4 h with propofol. The infusion rates (mg kg−1 h−1) of propofol were (mean (sd)) 4.1 (1.0) and 4.5 (1.3) for males and females, respectively. Urine was collected from each patient for the periods 0–4, 4–8, 8–12, and 12–24 h after the start of propofol administration. In a preliminary study, the three main glucuro-conjugated metabolites were isolated from urine and characterized by magnetic resonance spectroscopy. The quantification of these metabolites for the different collection periods was then performed by a HPLC–UV assay. Results Total recovery of propofol in the metabolites studied amounts to 38%, of which 62% was via the PG metabolite and 38% via cytochrome P-450. This percentage is significantly higher than that previously reported from patients after a bolus dose of propofol. Extreme values for PG (0–24 h period) were included from 73 to 49%. There was no significant difference between female and male patients in the metabolite ratio. Conclusions We conclude that the extent of hydroxylation in propofol metabolism was higher than in previous findings after administration of anaesthetic doses of propofol. Moreover, the ratio between hydroxylation and glucuronidation of propofol is subject to an inter-patient variability but this does not correlate with the dose of propofol. However, the variation of the metabolite profile observed in the present report does not seem to indicate an extended role of metabolism in pharmacokinetic variability.

The under-reporting of occupational lung cancer is due to insufficient recognition of occupational exposure and inadequate medico-legal action.All cases of primary bronchial carcinoma seen at the University Hospital of Grenoble between October 1996 and December 1998 completed a standardised questionnaire set by a physician in occupational medicine. When evidence of exposure to occupational carcinogens was established a claim for occupational disease was made and the outcomes of these claims were obtained from the Department of Social Security at the end of 2000.Asbestos was the most common carcinogenic agent found, followed by crystalline silica, diesel fumes, metals, paints and ionising radiation. Among the 305 patients in the study with primary bronchial carcinoma 20% were able to make a claim for occupational disease whereas only 2% would have claimed otherwise. The Department of Social Security accepted 77% of the 39 claims for occupational disease submitted, thus giving a 12% incidence of occupational bronchial carcinoma in this group.It is important to inform and instruct doctors of the environmental risks that are additional to those of tobacco smoking and of the need of inquire into any exposure to carcinogenic agents in order to ensure that the victims receive the appropriate medico-legal benefits. Improved primary prevention alone might eventually avoid the development of up to 3 500 cases of occupation bronchial carcinoma per year in France.

Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect.To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome.Cross-sectional comparison.University hospital in Lausanne, Switzerland.102 persons in whom triglyceride levels increased at least 1.0 mmol/L (or =89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L (or =9 mg/dL) or less (nonresponders) during isotretinoin therapy for acne. Parents of 71 hyperresponders and 60 nonresponders were also evaluated.Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype.Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level2.0 mmol/L [177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level6.5 mmol/L [252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio0.90 [OR, 11.0 (CI, 2.0 to 59]), and hyperinsulinemia (insulin-glucose ratio7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperresponders had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene.Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.

In order that the occupational exposures and health risks for municipal waste incinerator operators be better determined, a study was carried out in three centres. A transversal study was carried out for 102 male incinerator workers matched for age with 94 male workers from other industrial activities. Three groups of exposed workers were considered (group 1: "crane operators" and "equipment operators"; group 2: "furnace " workers ; group 3: "maintenance" and "effluent-treatment" workers). Data were collected through a questionnaire and medical examination. The respiratory function was explored and blood samples were taken for biological analysis. Statistical analysis using chi2 or Student's test, and calculation of odds-ratio (OR) using logistic regression analysis were performed. There were no significant differences in general symptoms between the two groups. Skin symptoms (OR =4.85; 2.04–11.51 for the "maintenance and effluent" workers) were more often observed in the exposed group. An excess of respiratory problems was also encountered: daily coughing ["maintenance and effluent" groups (OR =2.55; 0.84–7.75); "furnace men" (OR =6.58; 2.18–19.85)]. A significant relationship between exposure and the decrease of several pulmonary parameters was observed. The liver and haematological tests were well within the normal range; nevertheless, a slight but significant increase in the white blood cells was observed in the exposed group. Higher blood lead levels were found for exposed workers. There were few adverse health effects in our morbidity study but skin irritation and cough were more frequent in the exposed workers. A slight decrease in pulmonary function was observed. These findings are in agreement with those of several other studies.

To evaluate the efficiency of haemodynamic and respiratory monitoring system by a clinical analysis of the alarms.Observational prospective study.25 patients who presented acute respiratory distress syndrome and who were monitored with haemodynamic and respiratory monitoring.Each minute, a bedside clinical observer analysed alarms from the monitoring according to detection or absence to clinical events. Four situations were defined to statistical descriptive analysis: a) false positive (FP); b) true positive (TP); c) false negative (FN); and d) true negative (TN). True positive alarm which induced consequences on patients care were also analysed.15,013 minutes allowed the recordings of 3,665 alarms, 44% from arterial pressure, 17% from SpO2 and 12% from airways maximal pressure. 46% were false positive alarms inducing a noisy pollution. The positive predictive value PPV = TP/(TP + FP) of these alarms were respectively 51% for arterial pressure, 18% for SpO2 and 100% for Paw. Only 5% of true positive alarms induced consequences on patients care.This protocol allowed the evaluation of monitoring efficiency. This kind of evaluation may help to improve monitoring capacity with reducing noisy pollution from false positive alarms.

OBJECTIVES—To study the mortality from lung cancer from exposures to hard metal dust at an industrial site producing hard metals—pseudoalloys of cobalt and tungsten carbide—and other metallurgical products many of which contain cobalt. METHODS—A historical cohort was set up of all subjects who had worked for at least 3 months on the site since its opening date in the late 1940s. A full job history could be obtained for 95% of the subjects. The cohort was followed up from January 1968 to December 1992. The exposure was assessed by an industry specific job exposure matrix (JEM) characterising exposure to hard metal dust from 1 to 9 and other possibly carcinogenic exposures as present or absent. Smoking information was obtained by interview of former workers. Standard lifetable methods and Poisson regression were used for the statistical analysis of the data. RESULTS—Mortality from all causes was close to the expected (standardised mortality ratio (SMR) 1.02, 399 deaths) whereas mortality from lung cancer was significantly increased among men (SMR 1.70; 46 deaths, 95% confidence interval (95% CI) 1.24 to 2.26). By workshop, lung cancer mortality was significantly higher than expected in hard metal production before sintering (SMR 2.42; nine deaths; 95%CI 1.10 to 4.59) and among maintenance workers (SMR 2.56; 11 deaths; 95%CI 1.28 to 4.59), whereas after sintering the SMR was lower (SMR 1.28; five deaths; 95%CI 0.41 to 2.98). The SMR for all exposures to hard metal dust at a level >1 in the JEM was in significant excess (SMR 2.02; 26 deaths; 95%CI 1.32 to 2.96). The risks increased with exposure scores, duration of exposure, and cumulative dose reaching significance for duration of exposure to hard metal dust before sintering, after adjustment for smoking and known or suspected carcinogens. CONCLUSION—Excess mortality from lung cancer was found among hard metal production workers which cannot be attributed to smoking alone. This excess occurred mostly in subjects exposed to unsintered hard metal dust. Keywords: lung cancer; hard metals

We performed a prospective study in the 28 multidisciplinary intensive care units (ICUs) in the Rhône-Alpes area in France to investigate the role of initial versus delayed occurrence of acute renal failure (ARF) in patient outcome. ARF was defined as a serum creatinine concentration300 micromol/L, urine output500 ml/24 h (or180 ml/8 h), or hemodialysis requirement. Over the 1-yr study period, 1,086 patients presented with ARF on ICU admission or during the first 2 d of ICU stay (Group A; 736 patients), from Day 3 to Day 6 (Group B; 202 patients), or from Day 7 (Group C; 148 patients). The overall hospital mortality rate was 66% (61% in Group A, 71% in Group B, and 81% in Group C; p0.0001). Logistic regression analysis of a random sample of 510 patients showed that SAPS II score on ICU admission, number of ARF episodes, previous health status, absence of oliguria, absence of hemodialysis, and absence of ischemic acute tubular necrosis were predictive of patient survival. This model was tested and validated on the basis of the remaining patients. Thus, in this population, late ARF was not a predictive factor for patient outcome.

Quadricuspid aortic valve is an uncommon congenital anomaly. We report a case in a patient hospitalized for heart failure.A 62-year old patient with exercise-induced dyspnea was hospitalized for heart failure. Heart auscultation revealed a diastolic aortic murmur attributed to a quadricuspid aortic valve evidenced at echocardiography.Quadricuspid aortic valves usually have three cusps of equivalent size and a small fourth cusp between the right coronary cusp and the non-coronary cusp. Aortic regurgitation is usually observed requiring valve replacement in 50% of the cases. The anomaly may be associated with other congenital anomalies of the coronary arteries warranting systematic coronarography prior to valve replacement.

The abdominal wall lift (AWL) has been proposed for laparoscopic cholecystectomy to reduce hemodynamic effects caused by carbon dioxide (CO 2 ) and high intraabdominal pressures (IAP). Data concerning effects of AWL on respiratory mechanics are scant. We therefore used a noninvasive method to evaluate whether the AWL could offset these effects. The PETCO 2 , airflow, and airway pressure were continuously measured in nine patients undergoing laparoscopic cholecystectomy using an AWL with minimal CO 2 insufflation. We used a least-squares method to calculate maximal airway pressure (Pmax), elastance (Ers), and resistances (Rrs) of the respiratory system. After CO 2 insufflation, the initiation of AWL resulted in a significantly decreased IAP (from 13 to 6 mm Hg; P < 0.001) and Rrs (from 20.6 to 17.8 cm H 2 O. L -1 .s -1 ; P = 0.029), whereas Ers was partly modified (34.0 to 33.3 cm H 2 O/L; not significantly different). With AWL, we hypothesized that the diaphragm remained flat and stiff, outweighing the beneficial effect of the decrease of IAP on Ers. PETCO 2 significantly increased after AWL and at the end of the procedure. We conclude that AWL partly reverses the impairment of the respiratory mechanics induced by CO 2 insufflation during laparoscopic surgery. Implications: The abdominal wall lift (AWL), acting on the abdominal chest wall, had some benefits during laparoscopic surgery by limiting CO 2 peritoneal insufflation and several side effects, such as hemodynamics. We examined the consequences of this technique on respiratory mechanics in nine patients undergoing laparoscopic cholecystectomy. Our findings suggest that the AWL decreases intraabdominal pressure and respiratory resistances without a significant effect on respiratory elastance.

An industry-wide mortality study on the association between lung cancer and occupational exposure to cobalt and tungsten carbide was carried out in the French hard-metal industry. This case-control study was nested in the historical cohort of workers ever employed in this industry's 10 facilities, most of which are located in eastern France. Workers were followed up from 1968 to 1991. Occupational exposure was assessed using a job-exposure matrix that provided semiquantitative scores for 320 job periods. These scores were significantly correlated with the levels of cobalt measured in 744 historical air samples. In this cohort, which comprised 5,777 males and 1,682 females, the death rate from lung cancer was significant (63 deaths, standardized mortality ratio=1.30, 95% confidence interval (CI) 1.00-1.66) when compared with national death rates. Sixty-one cases and 180 controls were included in the study. When the exposures during the last 10 years were ignored, a twofold lung cancer risk was observed among workers simultaneously exposed to cobalt and tungsten carbide (odds ratio (OR)=1.93, 95% CI 1.03-3.62) adjusted for other cobalt exposure (OR=2.21, 95% CI 0.99-4.90). The odds ratios increased with cumulative exposure (first quartile, OR=1.00; second quartile, OR=2.64; third quartile, OR=2.59; fourth quartile, OR=4.13) and, to a lesser degree, with duration of exposure (one decade, OR=1.00; two decades, OR=1.61; three decades, OR=2.77; four decades, OR=2.03). Adjustments for smoking and for exposures to known or suspected carcinogens did not change the results, yet the odds ratio for smoking (3.38) was lower than expected, suggesting the possibility of some misclassification. Occupational risk was highest among smokers. This study supports the hypothesis that workers who manufacture hard metals have an increased mortality from lung cancer due to simultaneous exposure to cobalt and tungsten carbide.