Probiotic interventions promote metabolic health in high fat-fed hamsters in association with gut microbiota and endocannabinoidome alterations.

Probiotics represent a promising tool to improve metabolic health, including lipid profiles and cholesterol levels. Modulation of the gut microbiome and the endocannabinoidome - two interrelated systems involved in several metabolic processes influenced by probiotics - has been proposed as a potential mechanism of action. This study establishes the impact of probiotics on metabolic health, gut microbiota composition and endocannabinoidome mediators in an animal model of hypercholesterolaemia. Syrian hamsters were fed either a low-fat low-cholesterol or high-fat high-cholesterol (HFHC) diet to induce hypercholesterolaemia and gavaged for 6 weeks with either Lactobacillus acidophilus CL1285, Lactiplantibacillus plantarum CHOL-200 or a combination of the two. Globally, probiotic interventions ameliorated, at least partially, lipid metabolism in HFHC-fed hamsters. The interventions, especially those including L. acidophilus, modified the gut microbiota composition of the small intestine and caecum in ways suggesting reversal of HFHC-induced dysbiosis. Several associations were observed between changes in gut microbiota composition and endocannabinoidome mediators following probiotic interventions and both systems were also associated with improved metabolic health parameters. For instance, potential connexions between the Eubacteriaceae and Deferribacteraceae families, levels of 2­palmitoylglycerol, 2­oleoylglycerol, 2­linoleoylglycerol or 2­eicosapentaenoylglycerol and improved lipid profiles were found. Altogether, our results suggest a potential crosstalk between gut microbiota and the endocannabinoidome in driving metabolic benefits associated with probiotics, especially those including L. acidophilus, in an animal model of hypercholesterolaemia.

COVID-19 wastewater based epidemiology: long-term monitoring of 10 WWTP in France reveals the importance of the sampling context.

SARS-CoV-2 wastewater-based epidemiology (WBE) has been advanced as a relevant indicator of distribution of COVID-19 in communities, supporting classical testing and tracing epidemiological approaches. An extensive sampling campaign, including ten municipal wastewater treatment plants, has been conducted in different cities of France over a 20-week period, encompassing the second peak of COVID-19 outbreak in France. A well-recognised ultrafiltration - RNA extraction - RT-qPCR protocol was used and qualified, showing 5.5 +/- 0.5% recovery yield on heat-inactivated SARS-CoV-2. Importantly the whole, solid and liquid, fraction of wastewater was used for virus concentration in this study. Campaign results showed medium- to strong- correlation between SARS-CoV-2 WBE data and COVID-19 prevalence. To go further, statistical relationships between WWTP inlet flow rate and rainfall were studied and taken into account for each WWTP in order to calculate contextualized SARS-CoV-2 loads. This metric presented improved correlation strengths with COVID-19 prevalence for WWTP particularly submitted and sensitive to rain. Such findings highlighted that SARS-CoV-2 WBE data ultimately require to be contextualized for relevant interpretation.

Five-year survival and prognostic factors according to histology in 6101 non-small-cell lung cancer patients.

OBJECTIVE: To estimate five-year survival in non-small-cell lung cancer (NSCLC) patients according to histology and to identify independent prognostic factors by histology. METHODS: Data were obtained during the KBP-2010-CPHG study, which included all new cases of primary lung cancer diagnosed in 2010 in 104 non-academic hospitals. RESULTS: In all, 3199 patients had adenocarcinoma (ADC), 1852 squamous cell carcinoma (SCC), 754 large cell carcinoma (LCC). Five-year survival was 13.3% [12.1%-14.5%] for ADC, 14.3% [12.7%-16.0%] for SCC, 9.6% [7.6%-11.9%] for LCC (P<0.001). Performance status, weight loss prior to diagnosis and tumour stage were consistently significant independent prognostic factors. Age (>70 years; P=0.004), male gender (P<0.001), and smoking (P<0.001) were independent negative prognostic factors for ADC. Epidermal Growth Factor Receptor (EGFR)-mutation tests, performed in 1638 ADC patients, were positive for 186. Five-year survival was 14.7% [10.3%-21%] and 10.9% [9.4%-12.6%] for mutated and wild-type EGFR, respectively (P<0.001). EFGR mutation was an independent positive prognostic factor (HR=0.5 [0.4-0.6], P<0.001); however, the proportional hazards assumption was not fulfilled and hazards were inverted after 35 months. CONCLUSIONS: Five-year survival in patients managed in French non-academic hospitals for primary NSCLC in 2010 remained poor (<15%), whatever the histologic type. The independent negative prognostic factors for five-year survival were: weight, particularly weight loss prior to diagnosis; smoking (active or former) at diagnosis in ADC and LCC and smoking level at diagnosis in smoker patients with SCC. The independent positive prognostic factors were young age and female gender for ADC.

Predictability of the duration of motor blockade induced by unique injection of intrathecal prilocaine - an observational study.

Prilocaine is widely used for spinal anesthesia. Its intermediate effect makes it a valuable choice for one-day surgery. The duration of the motor blockade (DMB) may have an impact on the length of stay. The goal of this study was to establish a correlation between the DMB and different parameters (hyperbaric prilocaine dose, puncture level, surgical position, age, patient weight, and patient height). We prospectively enrolled adult patients scheduled for ambulatory surgery (n = 384). Univariate and multivariate regressions (backward stepwise) were applied. A P value lower than 0.05 was considered significant. We performed first analyzes on the entire population. We achieved same on a subgroup only composed of patients who received 60 mg of hyperbaric prilocaine between L4 and L5 and staying on dorsal position during surgery. The univariate analyses of the entire population demonstrate a significant correlation between DMB and 1) the prilocaine dose (P < 0.001), and 2) the BMI (P = 0.011). On the same population, the multivariate analyses confirm these two independent parameters correlated to the DMB: the patient height (P = 0.03) and the hyperbaric prilocaine dose (P < 0.001). The second analyses performed on the subgroup (n = 65), demonstrate a wide variability in the DBM (mean ± SD): 90.12 ± 30.36 minutes. For this concern, univariate analyses illustrate that only the patient height was significantly correlated to the DMB (P = 0.005). The multivariate analyses confirm that patient height could be considered as an independent parameter of DBM (P = 0.005). Within our entire population, there exists a considerable variation in the duration of the motor block after a unique injection of hyperbaric prilocaine. The prilocaine dose and the patient height were the only independent factors of the extension of the DMB. However, this relation is extremely weak and only allows explaining the variability of the DMB in a minority of the patients. This unknown pharmacological property of hyperbaric prilocaine could restrict its use for day-care surgery.

Integrable Coupled σ Models.

A systematic procedure for constructing classical integrable field theories with arbitrarily many free parameters is outlined. It is based on the recent interpretation of integrable field theories as realizations of affine Gaudin models. In this language, one can associate integrable field theories with affine Gaudin models having arbitrarily many sites. We present the result of applying this general procedure to couple together an arbitrary number of principal chiral model fields on the same Lie group, each with a Wess-Zumino term.

Endometriosis fertility index predicts live births following surgical resection of moderate and severe endometriosis.

STUDY QUESTION: Can live birth be accurately predicted following surgical resection of moderate-severe (Stage III-IV) endometriosis? SUMMARY ANSWER: Live births can accurately be predicted with the endometriosis fertility index (EFI), with adnexal function being the most important factor to predict non-assisted reproductive technology (non-ART) fertility or the requirement for ART (www.endometriosisefi.com). WHAT IS KNOWN ALREADY: Fertility prognosis is important to many women with severe endometriosis. Controversy persists regarding optimal post-operative management to achieve pregnancy and the counselling of patients regarding duration of conventional treatments before undergoing ART. The EFI is reported to correlate with expectant management pregnancy rate, although external validation has been performed without specifically addressing fertility in women with moderate and severe endometriosis. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 279 women from September 2001 to June 2016. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We included women undergoing laparoscopic resection of Stage III-IV endometriosis who attempted pregnancy post-operatively. The EFI was calculated based on detailed operative reports and surgical images. Fertility outcomes were obtained by direct patient contact. Kaplan-Meier model, log rank test and Cox regression were used for analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The follow-up rate was 84% with a mean duration of 4.1 years. A total of 147 women (63%) had a live birth following surgery, 94 of them (64%) without ART. The EFI was highly associated with live births (P < 0.001): for women with an EFI of 0-2 the estimated cumulative non-ART live birth rate at five years was 0% and steadily increased up to 91% with an EFI of 9-10, while the proportion of women who attempted ART and had a live birth, steadily increased from 38 to 71% among the same EFI strata (P = 0.1). A low least function score was the most significant predictor of failure (P = 0.003), followed by having had a previous resection (P = 0.019) or incomplete resection (P = 0.028), being older than 40 compared to <35 years of age (P = 0.027), and having leiomyomas (P = 0.037). LIMITATIONS REASONS FOR CAUTION: The main limitation of this study is its retrospective design. Imprecision was higher with low EFI due to smaller sample size in this subgroup. Finally, the EFI is somewhat subjective and could be prone to intra- and inter-observer variations. WIDER IMPLICATIONS OF THE FINDINGS: Women with a high EFI score have excellent fertility prognosis and may be advised to try to become pregnant with timed intercourse compared to women with a low score, for which prompt referral to ART seems more reasonable. Other prognostic factors can be used to guide the management of women with an intermediate EFI score. These data follow women over many years post-resection and represent longitudinal fertility data rarely demonstrated in such a cohort. The location and impact of lesions on the ability of the adnexa to function seems crucial for the fertility prognosis and should be further investigated. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the GRACE Research funds. S.M.-L. is the recipient of a Training Award from the Fonds de Recherche Quebec-Sante. D.A. is the primary author of the Endometriosis Fertility Index. All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Variability in the diagnostic performance of a bedside rapid diagnostic influenza test over four epidemic seasons in a pediatric emergency department.

We wanted to determine the diagnostic performance of a rapid influenza diagnostic test (RIDT) used bedside in a pediatric emergency department (PED). This was a prospective study over four consecutive winters (2009-2013), comparing the results of a RIDT (QuickVue®) with RT-PCR in children admitted to a PED. Among the 764 children included, we did not observe any significant differences in the diagnostic performance of RIDT except during the H1N1 pandemic. The overall sensitivity of the test was 0.82; the specificity 0.98; the positive and negative likelihood ratios 37.8 and 0.19. The positive and negative post-test probabilities of infection were 98% and 17%. The diagnostic performance was increased for influenza B cases (P = 0.03). RIDTs are suitable for use every winter with few differences in its diagnostic value, except during specific pandemic periods. This test could limit unnecessary complementary exams and guide the prescription of antivirals during influenza epidemic periods in PEDs.

Integrated production of polyhydroxyalkanoates (PHAs) with municipal wastewater and sludge treatment at pilot scale.

A pilot-scale process was operated over 22 months at the Brussels North Wastewater Treatment Plant (WWTP) in order to evaluate polyhydroxyalkanoate (PHA) production integration with services of municipal wastewater and sludge management. Activated sludge was produced with PHA accumulation potential (PAP) by applying feast-famine selection while treating the readily biodegradable COD from influent wastewater (average removals of 70% COD, 60% CODsol, 24% nitrogen, and 46% phosphorus). The biomass PAP was evaluated to be in excess of 0.4gPHA/gVSS. Batch fermentation of full-scale WWTP sludge at selected temperatures (35, 42 and 55 °C) produced centrate (6-9.4 gCODVFA/L) of consistent VFA composition, with optimal fermentation performance at 42 °C. Centrate was used to accumulate PHA up to 0.39 gPHA/gVSS. The centrate nutrients are a challenge to the accumulation process but producing a biomass with 0.5 gPHA/gVSS is considered to be realistically achievable within the typically available carbon flows at municipal waste management facilities.

Partial depletion of the proinflammatory monocyte population is neuroprotective in the myenteric plexus but not in the basal ganglia in a MPTP mouse model of Parkinson's disease.

Parkinson's disease (PD) patients often suffer from gastrointestinal (GI) impairments that are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric nervous system. Growing evidence suggests that inflammation originating from the gut may have a major impact in both the initiation and progression of PD. Here, we investigated the role of the innate immune response in neurodegeneration occurring in central nervous system (CNS) and enteric nervous system (ENS) in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism in both humans and animal models. We found a strong immune response in the gut of mice treated with MPTP, as demonstrated by the prominent presence of macrophages derived from CD115(+) CD11b(+) Ly6C(Hi) monocytes, known as M1 monocytes, and increased production of IL-1ß and IL-6. Partial depletion of proinflammatory M1 monocytes through intravenous injections of clodronate-encapsulated liposome protects against MPTP-induced reduction of tyrosine hydroxylase (TH) expression in the ENS. In contrast, loss of striatal TH expression in the CNS after MPTP intoxication occurs regardless of partial monocyte depletion. Examination of brain tissue revealed that microglial activation, comprising the majority of the immune response in the CNS after MPTP injections is unaffected by M1 depletion. In vitro experiments revealed that MPTP and MPP(+) act directly on monocytes to elicit a proinflammatory response that is, in part, dependent on the MyD88/NF-κB signaling pathway resulting in nitrite and proinflammatory cytokine production. Taken together, our results demonstrate a critical role for proinflammatory M1 monocytes/macrophages in DAergic alterations occurring in the GI, but not in the brain, in the MPTP model of PD.

[Pemetrexed-induced scleroderma-like changes in the lower legs]. / Sclérose cutanée des deux membres inférieurs sous pemetrexed.

BACKGROUND: Pemetrexed (Alimta(®)) is a new-generation antifolate used to treat malignant pleural mesothelioma and non-small cell lung cancer (NSCLC). We report two cases of a new toxicity induced by pemetrexed: scleroderma-like induration of the lower extremities. PATIENTS AND METHODS: The first case concerned a 66-year-old man diagnosed with pulmonary adenocarcinoma metastatic from the outset and in whom maintenance treatment comprised pemetrexed after first-line therapy comprising six courses of cisplatin-pemetrexed. After the fourth cycle of pemetrexed, he presented an erythematous oedema of the left leg, which was subsequently bilateral. Clinically, there was painful cellulitis associated with areas of bruising. The lesions had an appearance of erysipeloid-like infection, and there was no fever. The second case concerned a 70-year-old woman diagnosed with metastatic NSCLC. From the first course of pemetrexed, given as maintenance therapy, she presented erythematous oedema of both legs, without fever. After the second course, we observed the recurrence of the lesions consisting of erythemato-violaceous plaques on both legs, with severe bilateral indurated and painful oedema, associated with major functional disability. A diagnosis of bilateral erysipelas was made, and antibiotic treatment with cloxacillin was given. In both cases, pemetrexed was discontinued and the local outcome was very slowly favourable, with persistence of scleroderma. DISCUSSION: This cutaneous adverse effect is unrecognized, resulting in delayed diagnosis. It is often initially confused with bilateral erysipelas, despite absence of fever. According to some studies, the severity of the cutaneous toxicity may be connected with patients' folate status. Thus folate and vitamin B12 supplementation combined with dexamethasone could decrease the incidence of this side effect. There was no recurrence and no worsening with taxanes, chemotherapy agents known to induce scleroderma. We feel that this cutaneous toxicity must be recognised on account of its potential severity.

Integrated fixed-film activated sludge ANITA™Mox process--a new perspective for advanced nitrogen removal.

ANITA™Mox is a Veolia process using moving-bed biofilm reactor (MBBR) technology tested and validated in full-scale for energy- and cost-effective autotrophic N-removal from sidestream effluent using anammox (ANaerobic AMMonium OXidation) bacteria. In order to increase the ANITA™Mox process performances under different operating conditions (e.g. mainstream and sidestream application), substrate transport and accessibility inside the biofilm must be enhanced. In this work, (i) two laboratory scale biofilm ANITA™Mox reactors were operated using different configurations (IFAS - integrated fixed-film activated sludge - and MBBR) and (ii) the distribution of the anammox (AnAOB) and ammonia-oxidizing bacteria (AOB) in the suspended sludge and the biofilm was characterized using molecular tools (qPCR). This study showed that in IFAS configuration, the ANITA™Mox process achieved very high N-removal rate (up to 8 gN/m².d), which was three to four times higher than that achieved in the pure MBBR mode. The high concentration of suspended solids (mixed liquor suspended solids (MLSS)) in the bulk obtained within the IFAS mode induces a very efficient bacterial distribution between the AOB and AnAOB population. AnAOB activity mainly occurs in the biofilm (96% of total AnAOB in the reactor), whereas nitritation by AOB mostly takes place in the suspended phase (93% of total AOB). This spatial distribution observed in the IFAS reactor results from a natural selection due to more easily substrate accessibility for AOB in the bulk (NH4(+), O2) creating higher nitrite concentration in the bulk liquid compare to pure MBBR mode. The efficient control of MLSS level in the IFAS reactor is a key parameter to enhance the nitrite production by AOB and increase the substrate availability in the AnAOB-enriched biofilm leading to higher N-removal rate. These promising results obtained at laboratory scale have been further confirmed in on-going full-scale IFAS ANITA™Mox trials opening new roads for the widespread application of a very compact and robust ANITA™Mox process for sidestream but also mainstream cost-effective N-removal.

Hysterosalpingosonography for diagnosing tubal occlusion in subfertile women: a systematic review with meta-analysis.

STUDY QUESTION: Is hysterosalpingosonography (sono-HSG) an accurate test for diagnosing tubal occlusion in subfertile women and how does it perform compared with hysterosalpingography (HSG)? SUMMARY ANSWER: sono-HSG is an accurate test for diagnosing tubal occlusion and performs similarly to HSG. WHAT IS KNOWN ALREADY: sono-HSG and HSG are both short, well-tolerated outpatient procedures. However, sono-HSG has the advantage over HSG of obviating ionizing radiation and the risk of iodine allergy, being associated with a greater sensitivity and specificity in detecting anomalies of the uterine cavity and permitting concomitant visualization of the ovaries and myometrium. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis of studies published in any language before 14 November 2012 were performed. All studies assessing the accuracy of sono-HSG for diagnosing tubal occlusion in a subfertile female population were considered. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched Medline, Embase, Cochrane Library, Web of Science and Biosis as well as related articles, citations and reference lists. Diagnostic studies were eligible if they compared sono-HSG (±HSG) to laparoscopy with chromotubation in women suffering from subfertility. Two authors independently screened for eligibility, extracted data and assessed the quality of included studies. Risk of bias and applicability concerns were investigated according to the Quality Assessment of Diagnostic Accuracy Study (QUADAS-2). Bivariate random-effects models were used to estimate pooled sensitivity and specificity with their 95% confidence intervals (95% CIs), to generate summary receiver operating characteristic curves and to evaluate sources of heterogeneity. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 4221 citations identified, 30 studies were eligible. Of the latter, 28 reported results per individual tube and were included in the meta-analysis, representing a total of 1551 women and 2740 tubes. In nine studies, all participants underwent HSG in addition to sono-HSG and laparoscopy, allowing direct comparison of the accuracy of sono-HSG and HSG. Pooled estimates of sensitivity and specificity of sono-HSG were 0.92 (95% CI: 0.82-0.96) and 0.95 (95% CI: 0.90-0.97), respectively. In nine studies (582 women, 1055 tubes), sono-HSG and HSG were both compared with laparoscopy, giving pooled estimates of sensitivity and specificity of 0.95 (95% CI: 0.78-0.99) and 0.93 (95% CI: 0.89-0.96) for sono-HSG, and 0.94 (95% CI: 0.74-0.99) and 0.92 (95% CI: 0.87-0.95) for HSG, respectively. Doppler sonography was associated with significantly greater sensitivity and specificity of sono-HSG compared with its non-use (0.93 and 0.95 versus 0.86 and 0.89, respectively, P = 0.0497). Sensitivity analysis regarding methodological quality of studies was consistent with these findings. We also found no benefit of the commercially available contrast media over saline solution in regard to the diagnostic accuracy of sono-HSG. LIMITATIONS, REASONS FOR CAUTION: Methodological quality varied greatly between studies. However, sensitivity analysis, taking methodological quality of studies into account, did not modify the results. This systematic review did not allow the distinction between distal and proximal occlusion. This could be interesting to take into account in further studies, as the performance of the test may differ for each localization. WIDER IMPLICATIONS OF THE FINDINGS: Given our findings and the known benefits of sono-HSG over HSG in the context of subfertility, sono-HSG should replace HSG in the initial workup of subfertile couples. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by personal funds. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This review has been registered at PROSPERO: Registration number #CRD42013003829.

Wavelet-based clustering for mixed-effects functional models in high dimension.

We propose a method for high-dimensional curve clustering in the presence of interindividual variability. Curve clustering has longly been studied especially using splines to account for functional random effects. However, splines are not appropriate when dealing with high-dimensional data and can not be used to model irregular curves such as peak-like data. Our method is based on a wavelet decomposition of the signal for both fixed and random effects. We propose an efficient dimension reduction step based on wavelet thresholding adapted to multiple curves and using an appropriate structure for the random effect variance, we ensure that both fixed and random effects lie in the same functional space even when dealing with irregular functions that belong to Besov spaces. In the wavelet domain our model resumes to a linear mixed-effects model that can be used for a model-based clustering algorithm and for which we develop an EM-algorithm for maximum likelihood estimation. The properties of the overall procedure are validated by an extensive simulation study. Then, we illustrate our method on mass spectrometry data and we propose an original application of functional data analysis on microarray comparative genomic hybridization (CGH) data. Our procedure is available through the R package curvclust which is the first publicly available package that performs curve clustering with random effects in the high dimensional framework (available on the CRAN).

The beta-1 adrenergic antagonist, atenolol, decreases acylation stimulating protein, exercise capacity and plasma free fatty acids in men with type 2 diabetes.

BACKGROUND AND AIMS: Atenolol is a beta-1 adrenergic antagonist commonly prescribed for the treatment of systemic hypertension or coronary artery disease yet its use in individuals with type 2 diabetes mellitus (T2DM) is controversial due to potentially negative side effects on insulin resistance. Non-esterified fatty acid (NEFA) metabolism is altered in T2DM especially under conditions of metabolic stress such as exercise or the postprandial state. We evaluated atenolol effects on circulating NEFA and related hormones in men with T2DM during acute cardiorespiratory exercise in both the fasting and postprandial state, including the adipokine acylation stimulating protein (ASP) which stimulates adipose tissue NEFA uptake. METHODS AND RESULTS: Ten men with T2DM underwent four 1-h exercise sessions at 60% of their maximal oxygen uptake (VO(2max)) under the following conditions: 1) fasting (F), and 2) 2 h postprandial (PP) without medication; and 3) fasting (F-Atenolol), and 4) 2 h postprandial (PP-Atenolol) after a one-week treatment with atenolol. Results were tested for the effects of atenolol via two-way ANOVA for the F vs F-Atenolol and PP vs PP-Atenolol states separately. Atenolol treatment decreased fasting and postprandial glycerol (p < 0.0001) and NEFA (p < 0.0001), postprandial epinephrine (p = 0.048), postprandial cortisol (p = 0.02), postprandial ASP (p = 0.04) and postprandial dopamine (p < 0.004). CONCLUSION: Atenolol alters fatty acid metabolism and associated metabolic hormones including ASP during exercise in men with T2DM and its effects are more apparent during conditions of stress such as the postprandial state, acute exercise and obesity.

Comparative pharmacoscintigraphic and pharmacokinetic evaluation of two new formulations of inhaled insulin in type 1 diabetic patients.

In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2 U/kg b.w.), which had been radiolabelled with (99m)Tc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6 h. Lung deposition was found to be 50 ± 9% and 24 ± 8% for the F1 and F2 formulations, respectively. The insulin AUC0₋360 ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate. The two formulations showed interesting pharmacokinetic profiles (T(max) of 26 and 16 min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.

Visible supercontinuum generation controlled by intermodal four-wave mixing in microstructured fiber.

We present an experimental and numerical study of supercontinuum generation extended in the visible part of the spectrum by using a selective optical coupling of the pump wave in the largely anomalous dispersion regime. The broadband frequency generation is induced by an initial four-wave mixing process that converts the pump wave at 1064 nm into 831 nm anti-Stokes and 1478 nm Stokes wavelengths. Phase matching is ensured on such a large frequency shift thanks to a microstructured multimodal fiber with a specific design. Continuum generation is therefore enhanced around the two generated sidebands.

Understanding power leakage in tapered solid core microstructured fibers.

The cause of fundamental core-mode leakage in a tapered photonic crystal fiber is examined in terms of modal coupling from the core-mode to the ring modes. Experimental data are compared to predictions. The main features of the transmission are convincingly explained by the proposed model.

Evidence of genotoxicity related to high PAH content of sediments in the upper part of the Seine estuary (Normandy, France).

In order to characterize the genotoxicity in the Seine estuary and Seine bay, chemical and toxicological analyses were performed on 17 sediments collected in June 2001 and June 2003. Many potent mutagenic and/or carcinogenic compounds - including polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB) and metals - were detected. Those compounds were found to be at relatively high concentrations in the upper part of the Seine estuary but were barely detectable at sites outside the plume from the Seine. The levels of pollution did not vary significantly between the two sampling periods, except that PAH concentrations in sediments collected at Oissel and Le Havre showed a marked increase in June 2003. The toxicity of organic extracts from sediments was evaluated by both embryotoxicity and in vitro genotoxicity (SOS Chromotest) assays. Organic extracts from sediments taken from the Seine estuary appeared significantly more embryotoxic than those from the Seine bay. In addition, the sediment extracts from the upper part of the Seine estuary exhibited higher genotoxicity than those from the lower part, and no genotoxicity was reported for sediments from the Seine bay. The genotoxic activity was detected only after adding an S9 microsomal fraction, suggesting the preponderant involvement of pro-genotoxic organic compounds. In addition, SOS Chromotest responses obtained with purified organic fractions revealed that PAH and, to a lesser extent, unknown polar organic compounds were probably responsible for this genotoxicity. Altogether, these results suggest that sediments from the upper Seine estuary are genotoxic and embryotoxic, and therefore, could be potentially hazardous for species living or feeding in the area.

Dynamics of parabolic pulses in an ultrafast fiber laser.

We report experimental and numerical results on the dynamics and propagation of parabolic pulses in a passively mode-locked ytterbium-doped fiber laser. Experimental data and numerical simulations are shown to match. Particular importance is attached to the pulse-shaping process in the different sections of the resonator. The paramount role of the gain fiber and saturable absorber in the laser is explicated.