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Objective Circulating tumor DNA (ctDNA) has been shown to correlate with therapy response in different types of cancer.Little is known about the value of liquid biospies in locally advanced rectal cancer (LARC) to select patients for non-operative management. Our aim was to explore the value of serial liquid biopsies for response monitoring after neo-adiuvant chemoradiation therapy (nCRT) in LARC. Methods Twenty-five consecutive LARC patients undergoing long course nCRT therapy were included. Applying next-generation sequencing (NGS), we characterized DNA extracted from formalin-fixed paraffin embedded tissue (diagnostic biopsy and surgical specimen)and from plasma ctDNA collected at different time points: on the first and last day of radiotherapy (T0, Tend), at 4 (T4), 7 (T7) weeks after radiotherapy, at the day of surgery (Top) prior to resection, and 3–7 days after surgery (Tpost-op). At the day of surgery a mesenteric vein sample was also collected (Timv). The relationship between the ctDNA at those time-points and the Tumor Regression Grade (TRG) of the surgical specimen was statistically explored. Results ctDNA was detected in 87% of samples at baseline but only in 13%, 10%, 25% and 17% at T4, T7, Top and Tpost-op respectively. Pathological complete response (TRG1) was not statistically associated with gradual negativization of ctDNA mutations in plasma samples obtained in the aforementioned time points compared to tissue biopsy. However a positive liquid biopsy at Top was significantly associated to no response to nCRT (TRG 4) . Conclusion ctDNA evaluation by NGS technology was not a good marker for defining LARC patients that are more prone to develop complete response to nCRT, however persistence of ctDNA molecular alterations after this treatment could be a marker of poor-response.

Graphical abstract, Highlights • The intrauterine exposure of carbiamzole (CBZ) on male fertility is not well defined. • CBZ exposure in utero results in spermatotoxic effects and impaired steroidogenesis in offspring rats at their adulthood. • Gestational exposure to CBZ augmented testicular oxidative damage in offspring rats. • α-lipoic acid supplementation with its antioxidant properties ameliorated diminished male reproductive health in rats exposed to CBZ prenatally., The aim of this study was to evaluate the probable protective effect of α-lipoic acid against testicular toxicity in rats exposed to carbimazole during the embryonic period. Time-mated pregnant rats were exposed to carbimazole from the embryonic days 9–21. After completion of the gestation period, all the rats were allowed to deliver pups and weaned. At postnatal day 100, F1 male pups were assessed for the selected reproductive endpoints. Gestational exposure to carbimazole decreased the reproductive organ indices, testicular daily sperm count, epididymal sperm variables viz., sperm count, viable sperm, motile sperm and HOS-tail coiled sperms. Significant decrease in the activity levels of 3β- and 17β-hydroxysteroid dehydrogenases and expression of StAR mRNA levels with a significant increase in the total cholesterol levels were observed in the testis of experimental rats over the controls. These events were also accompanied by a significant reduction in the serum testosterone levels in CBZ exposed rats, indicating reduced steroidogenesis. In addition, the deterioration of the testicular architecture and reduced fertility ability were noticed in the carbimazole exposed rats. Significant reduction in the activity levels of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and reduced glutathione content with a significant increase in the levels of lipid peroxidation were observed in the testis of carbimazole exposed rats over the controls. Conversely, supplementation of α-lipoic acid (70 mg/Kg bodyweight) ameliorated the male reproductive health in rats exposed to carbimazole during the embryonic period as evidenced by enhanced reproductive organ weights, selected sperm variables, testicular steroidogenesis, and testicular enzymatic and non-enzymatic antioxidants. To conclude, diminished testicular antioxidant balance associated with reduced spermatogenesis and steroidogenesis might be responsible for the suppressed reproduction in rats exposed to the carbimazole transplacentally. On the other hand, α-lipoic acid through its antioxidant and steroidogenic properties mitigated testicular toxicity which eventually restored the male reproductive health of carbimazole-exposed rats.

In this contribution, small-angle neutron scattering (SANS) studies of the micro-structural radiation damage in technical steels, developed for application in future fusion reactors, are presented. The effect of neutron irradiation at 250 °C–450 °C, up to dose levels of 16 dpa (displacement per atom), has been investigated in the European reference ferritic/martensitic steel Eurofer97 (0.12 C, 9 Cr, 0.2 V, 1.08 W wt%), both in its standard composition and mechanically alloyed with B (up to 1000 appm) to enhance the helium production, via transmutations, and reproduce fusion relevant helium/dpa ratios. The obtained SANS results suggest that in the irradiated standard Eurofer97 micro-voids distributions are present, with very small average radii (a few A) and volume fractions (around 0.01); such low values, close to the SANS resolution limit, are consistent with the good resistance of this steel to radiation damage, for low helium concentrations. In the irradiated B-alloyed Eurofer97, more complex changes are observed: the helium bubble distributions appear strongly dependent on the irradiation temperature and on the helium concentration; furthermore, micro-structural effects possibly related to modifications in the steel matrix are detected.

The problem of nonlinear uncertainty propagation represents a crucial issue in celestial mechanics. In this paper, a method for nonlinear propagation of uncertainty based on differential algebra is presented. Working in the differential algebra framework enables a general approach to nonlinear uncertainty propagation that can provide highly accurate estimate with low computational cost. The nonlinear mapping of the statistics is shown here, adopting the two-body problem as the working framework, including coordinate system transformations. The general feature of the proposed method is also demonstrated by presenting long-term integrations in complex dynamic systems, such as the n-body problem or the simplified general perturbation model.

Background Health-related quality of life is an important measure of treatment outcome; its evaluation requires the use of internationally validated ad hoc questionnaires. The McMaster Inflammatory Bowel Disease Questionnaire (IBDQ) is the most used specific instrument. Aim To assess the validity and reliability of the Italian translation of the IBDQ. Methods The IBDQ underwent forward and backward translation; 13 patients were enrolled for cognitive testing of the Italian version to increase clarity. For field testing, 113 patients (65 with Crohn's disease and 48 with ulcerative colitis) completed both the IBDQ and the generic instrument 36-item Short Form Health Survey scale (SF-36). Results Data quality was optimal with high completeness and low floor and ceiling effect. Item internal consistency was satisfied for 100% of patients, while discriminant validity showed a few items with higher correlations with other scales. Cronbach's alpha coefficient was 0.96. Test–retest correlations indicated good reliability (Pearson R 0.81). Exploratory factor analysis indicated that the original grouping of the item was suboptimal. The score proved sensitive to disease activity, gender and quality of life as measured by the SF-36. Conclusions The Italian translation of the McMaster Inflammatory Bowel Disease Questionnaire sounds natural and is easy to understand. A field test gave results comparable to other international validations, supporting its use in cross-national surveys.

Small-angle neutron scattering (SANS) is a powerful experimental tool to investigate the microstructural evolution under irradiation in steels for fission and future fusion reactor systems. We present recent SANS results concerning the modelling of helium bubble growth in F82H-mod. steel implanted with α-particles and the dose dependence of microstructural radiation damage in Eurofer-97 steel for fusion reactors irradiated at 250 °C. The discussion of these results is focussed on the quality of the metallurgical information obtained by such SANS measurements and consequently on their usefulness also for engineering and design purposes.

Because of their capacity to modulate the immune response and promote tissue repair, mesenchymal stromal cells (MSC) represent a potential novel treatment for autoimmune/inflammatory diseases, including Crohn's disease (CD). The aim of the study was in vitro characterization of MSC from active CD patients for future clinical application.MSC from the bone marrow (BM) of seven CD patients (median age 32 years) were expanded ex vivo in the presence of 5% platelet lysate; cells were investigated for clonogenic efficiency, proliferative capacity, morphology, immunophenotype, differentiation potential, genetic stability and ability to suppress in vitro proliferation of both autologous and allogeneic lymphocytes to polyclonal mitogens. Results were compared with those of BM MSC of four healthy donors (HD).MSC were successfully expanded from all patients. Colony-forming unit-fibroblast (CFU-F) frequency and proliferative capacity were comparable in CD and HD MSC. CD MSC showed typical spindle-shaped morphology and differentiated into osteoblasts, adipocytes and chondrocytes. Surface immunologic markers did not differ between CD and HD MSC, with the only exception of sizeable levels of HLA-DR at early culture passages [12-84% at passage (P)1] in the former. CD MSC ceased their growth at variable passages (from P8 to P25) and entered senescence without any change in morphology/proliferation rate. Array-comparative genomic hybridization demonstrated that CD MSC do not show imbalanced chromosomal rearrangements. Both CD and HD MSC inhibited in vitro proliferation of lymphocytes to mitogens.CD MSC show biologic characteristics similar to HD MSC and can be considered for anti-inflammatory and reparative cell therapy approaches in patients with refractory disease.

This contribution presents a comparative microstructural investigation, carried out by Small-Angle Neutron Scattering (SANS), of ferritic/martensitic steel Eurofer97 (0.12 C, 9 Cr, 0.2 V, 1.08 W wt%) neutron irradiated at two different neutron sources, the HFR-Petten (SPICE experiment) and the BOR60 reactor (ARBOR experiment). The investigated “SPICE” sample had been irradiated to 16 dpa at 250 °C, the investigated “ARBOR” one had been irradiated to 32 dpa at 330 °C. The SANS measurements were carried under a 1 T magnetic field to separate nuclear and magnetic SANS components; a reference, un-irradiated Eurofer sample was also measured to evaluate as accurately as possible the genuine effect of the irradiation on the microstructure. The detected increase in the respective SANS cross-sections of these two samples under irradiation is attributed primarily to the presence of micro-voids, for neutron contrast reasons; it is quite similar in the two samples, despite the higher irradiation dose and temperature of the “ARBOR” sample with respect to the “SPICE” one. This is tentatively correlated with the higher helium content produced under HFR irradiation, playing an important role to stabilize the micro-voids under irradiation. In fact, the size distributions obtained by transformation of the SANS data yield a micro-void volume fraction of 1.3% for the “SPICE” sample and of 0.6% for the “ARBOR” one.

This contribution presents the results of an experimental study on high temperature stress evolution in brazed Glidcop/W model structures. The investigated sample (23 mm x 23 mm x 8 mm in volume) had been obtained by brazing a W alloy and a Glidcop (Cu alloy) platelet at 650 degrees C using TiCuAg alloy as a filler. Neutron diffraction was utilized to determine the strains, then the stresses in the bulk of the sample, between room temperature and 300 degrees C; unstrained Glidcop and W reference samples were measured as well in the same temperature range. The measurements were carried out at the D1A diffractorneter of the High Flux Reactor at the Institut Laue Langevin, Grenoble. It is found that the residual stresses present at room temperature in the as-brazed sample vanish almost completely at 300 degrees C that provides relevant engineering information such as the zero strain temperature.

This contribution presents the results of small-angle neutron scattering (SANS) measurements carried out to investigate the microstructure of Eurofer97 neutron irradiated with 2.7 dpa, at 60 °C and 300 °C. For comparison, samples of a laboratory heat of this same steel, irradiated under the same conditions, have also been investigated. The SANS measurements have been carried out at the High Flux Reactor of the ILL-Grenoble. SANS data analysis, based on the comparison of nuclear and magnetic scattering, shows that the microstructural defects produced under irradiation are mostly non-magnetic ones (He bubbles, microvoids). Their distribution strongly varies with the irradiation conditions, namely with increasing irradiation temperature. A consistent increase is observed both in the average size (up to approximately 100 A) as well as in the volume fraction.

The growth of He-bubbles after low temperature He-implantation and subsequent high temperature tempering in F82H-mod steel has been studied by using transmission electron microscopy (TEM) and small-angle neutron scattering (SANS). The results obtained by both techniques show that after implantation the bubbles are homogeneously distributed around an average size of 11 A, while after subsequent tempering He-bubbles one order of magnitude larger grow in size and volume fraction. Additionally, the SANS data show a consistent population of bubbles smaller than 10 A, which is discussed with reference to the possible migration and coalescence mechanisms during high temperature tempering.

Transmission electron microscopy (TEM) and small-angle neutron scattering (SANS) were used to characterize the microstructure of two variants of oxide-dispersion strengthened (ODS) Eurofer-97 steel (9% CrWVTa), that is being developed for future fusion reactors. More specifically the Y2O3 particle size distributions obtained with different Y2O3 contents have been characterized, since the mechanical properties are strongly correlated with such features. The SANS measurements have been carried out by the D22 instrument at the High Flux Reactor of the Institut Laue-Langevin, Grenoble. There is a good agreement between TEM histograms and SANS distributions of the Y2O3 particles. Furthermore, relevant and unique information is provided by the SANS measurements that reveals particles of size smaller than 1 nm approximately.

This work presents the results of polarised small-angle neutron scattering (SANS) measurements of modified martensitic steel DIN1.4914, originally developed for application in future fusion reactors (MANET steel). SANS measurements were made using the D22 instrument at the ILL Grenoble using an ad hoc polarised beam set-up. The investigated MANET samples were neutron irradiated and subsequently post-irradiation tempered to reproduce as much as possible the expected service conditions. The results, based on the analysis of the nuclear-magnetic interference, are discussed taking into account both the occurrence of Cr redistribution phenomena with correlated changes in the composition of the precipitate phases, and the growth of non-magnetic defects (He-bubbles or microvoids).

Resume Objectif. – Le lithium est utilise dans le traitement des troubles bipolaires. Afin de mieux preciser les differentes circonstances d’intoxication, les auteurs presentent les observations colligees au centre antipoison de Marseille entre janvier 1991 et decembre 2000. Type d’etude. – Etude retrospective. Methodes. – Trois cent quatre dossiers ont ete etudies (1 patient par dossier), correspondant a 6 circonstances differentes. Pour 3 d’entre elles, les symptomes ont ete moderes : ingestions accidentelles de comprimes par des enfants (13 cas), erreurs therapeutiques sur les quantites ingerees (43 cas), elevation de la lithemie lors d’association avec des diuretiques (8 cas). Pour 2 autres circonstances, les signes cliniques etaient plus graves : patients traites par lithium ayant developpe une insuffisance renale debutante (15 cas, 6 patients en reanimation, 1 deces) ou ayant presente une deshydratation (35 cas, 8 patients en reanimation, 1 deces). Enfin, les cas les plus graves ont ete observes parmi les tentatives de suicide. Cinquante-six pour cent des patients ont ete pris en charge en reanimation, 5 % ont necessite une hemodialyse, 10 % ont presente des complications cardiaques (troubles de la repolarisation) ou neurologiques (convulsions) et 2 % sont decedes. Conclusion. – La gravite des intoxications par sels de lithium depend des circonstances. L’ingestion de grandes quantites de comprimes a liberation prolongee est la situation la plus dangereuse. Les ingestions accidentelles, y compris chez les enfants, doivent etre considerees comme moins graves.

Small-angle neutron scattering (SANS) and transmission electron microscopy (TEM) have been used to investigate the correlation between photoluminescence properties and particle size distributions in laser synthesized Si nanopowders, of interest for application in optoelectronics. The Si nanoparticle volume distributions obtained from the SANS data are in good agreement with the TEM histogram for particle diameters ranging between 30 and 200 Å approximately. Furthermore the SANS data confirm that, as it is known from photoemission spectra, in the case of highly luminescent powders a secondary distribution of particles ranging between 10 and 20 Å approximately (hardly visible by TEM) is present. Finally the SANS data analysis suggests that tiny inhomogeneities (5-10 Å in diameter), possibly micropores which may have relevant consequences on material performance, are also present in all the investigated samples.

Background. Ciguatera is a disease caused by the ingestion of fish containing the toxins of Gambierdiscus toxicus. This dinoflagellate is frequently found in damaged coral reef systems. Previously rare in Europe, this disease entity is now seen in tourists returning from tropical countries. Case series. Eighteen patients were examined between 1997 and 2002. Nine poisonings occurred in Atlantic Ocean islands, eight in Pacific Ocean islands, and one in the Egyptian Red Sea coast. Gastrointestinal signs were always present in the Atlantic areas, but were less severe or absent in the Pacific areas. All patients had sensory disturbances, and two of them had motor disturbances affecting the respiratory muscles and leading to the death of a 73-year-old man in Cuba. The 17 surviving patients returned to France and for 2 to 18 months suffered from arthralgias, myalgias, or pruritis. Conclusion. Ciguatera is a newly imported intoxication in Europe. As the number of international tourists grows each year, this type of poisoning will be seen more frequently. Furthermore, as the condition of coral reefs declines around the world and the prevalence of G. toxicus increases, physicians in non-tropical countries should be prepared to manage such poisoned patients.

The bactericidal activity of levofloxacin, ciprofloxacin, moxifloxacin and norfloxacin against clinical isolates conventionally classified as resistant to fluoroquinolones were compared at their maximum concentrations in serum, urine (except moxifloxacin) and bronchial mucosa (except norfloxacin). Time killing curves against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Streptococcus pneumoniae were performed. Serum concentrations of the tested drugs were not able to produce a bactericidal effect on fluoroquinolone-resistant strains. In the urine series, levofloxacin was always bactericidal (decreaseor = 3 logs CFU/ml), while norfloxacin and ciprofloxacin were bactericidal on E. coli (both), P. mirabilis (norfloxacin) and P. aeruginosa (ciprofloxacin). In the bronchial mucosa series, S. pneumoniae was rapidly killed by levofloxacin and moxifloxacin, and K. pneumoniae by levofloxacin after 12 hours. In conclusion, the maximum levofloxacin concentrations achievable at certain body sites allowed killing even of strains defined as resistant by conventional breakpoints.

Vipera aspis aspis (V.a.a.) is the most dangerous poisonous snake in South-Eastern France. The clinical symptoms observed after V.a.a. envenomations involve mostly local signs (pain, edema) associated in the more severe cases with systemic symptoms (gastro-intestinal and cardiovascular manifestations). Since 1992, several unusual cases of moderate and severe `neurotoxic’ envenomations by V.a.a. snakes have been reported in a very localized area in South-Eastern France. Most of the human patients mainly suffered neurological signs owing to cephalic muscle paralysis. Drowsiness and dyspnea were observed for the most severe cases. Envenomed animals suffered respiratory distress and paralysis. The local signs were never as severe as observed after envenomations by vipers in other French regions. Human patients with moderate or severe clinical features received two intravenous injections of Viperfav2 antivenom, the first dose inducing the decrease of the neurological signs and the second reducing significantly the edema. Neurotoxic components immunologically cross-reacting with toxins from V. ammodytes ammodytes venom from Eastern Europe were detected in the blood of all patients suffering neurological symptoms after a V.a.a. bite. The protective efficacy of various antivenoms was evaluated in mice. The existence of geographical variations in the composition of V.a.a. venom emphasizes on the use of polyvalent antivenom in the treatment of viper envenomations in France. Human & Experimental Toxicology (2002) 21, 137 – 145.

Usually, hyperresponsiveness to inhaled methacholine is considered closely associated with a diagnosis of bronchial asthma. Recently, it has been clearly pointed out that bronchial hyperreactivity (BHR) is not a constant feature of asthma and that this condition is not always related to airways inflammation. In the present study we evaluated 42 Patients (21 positive and 21 negative for bronchial hyperreactivity, BHR) with the aim to determine the effect of Methacholine Challenge Testing (MCT) on the levels of exhaled nitric oxide (NO). Higher FeNO levels were found before methacholine provocation in the group that eventually resulted positive to the challenge, while after the challenge in both groups FeNO decreased in similar way, with no statistical difference. These data confirm that MCT is a relevant test for asthma diagnosis, but it is not always related to the severity of bronchial inflammation, while FeNO levels in our study have limited clinical significance when evaluated out of asthma exacerbation.

This paper presents the results of a small-angle neutron scattering (SANS) study of He-bubble growth in martensitic steel F82H-mod. The investigated samples had been homogeneously implanted with 400 appm He at 250°C, then submitted to 2 h annealings up to 975°C, together with a non-implanted sample of the same material (one for each temperature) serving as a reference to isolate the SANS signal arising from the He-bubbles. An as-implanted sample was also investigated together with its thermal reference. The He-bubble volume distributions, obtained from the SANS data and discussed with reference to uncertainties arising from background subtraction, show that the uniform distribution of the as-implanted sample, with bubbles approximately 15 A in size, evolves during high temperature annealing into a bimodal one with a secondary population of bubbles as large as 100 A approximately.

ResumenSe han implicado anomalías en el sistema serotonérgico en la patofisiología de los trastornos depresivos. Las plaquetas humanas poseen receptores de serotonina-2A (5-HT2A), e investigaciones anteriores que han utilizado LSD o ketanserina como ligandos han indicado que su número se incrementa en los pacientes deprimidos. Comparado con otros ligandos utilizados antes en los estudios de plaquetas, el DOI es muy selectivo para el receptor 5-HT2A y se fija a su estado de alta afinidad, marcando por tanto sólo los receptores que están asociados biológicamente a la proteína G. Determinamos la densidad (Bmax) y la afinidad (Kd) de receptores 5-HT2A marcados por [l25I]-DOI en las plaquetas de 21 pacientes no tratados con depresión mayor y 21 voluntarios sanos. Se encontró que la densidad de los sitios de fijación de 5-HT2A se incrementaba en las plaquetas de las pacientes deprimidas en comparación con los controles. No se observaron cambios en la Kd. No encontramos ninguna relación entre los parámetros de fijación y la gravedad del episodio depresivo o las tendencias suicidas de los pacientes. Nuestros resultados muestran que el número de receptores 5-HT2A acoplados de las plaquetas se incrementa en los pacientes deprimidos, lo que indica que la función del receptor 5-HT2A de las plaquetas aumenta en la depresión.