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Different extensions of the standard model of particle physics, such as braneworld or mirror matter models, predict the existence of a neutron sterile state, possibly as a dark matter candidate. This Letter reports a new experimental constraint on the probability $p$ for neutron conversion into a hidden neutron, set by the STEREO experiment at the high flux reactor of the Institut Laue-Langevin. The limit is $p, 5 pages, 3 figures

Resume Introduction Le pemetrexed est une chimiotherapie de la classe des antifolates frequemment prescrite en oncologie thoracique. Nous rapportons un cas de toxicite cutanee rare au pemetrexed a type d’œdemes inflammatoires et sclerodermiformes des membres inferieurs. Observation Un homme de 63 ans etait traite par pemetrexed pour un adenocarcinome pulmonaire metastatique. Quatorze mois apres l’initiation de la chimiotherapie, apparaissaient des œdemes inflammatoires et sclereux des membres inferieurs genant la flexion des genoux. Une origine cardiaque, renale, hepatique, thrombotique et infectieuse des œdemes etait ecartee. La responsabilite du pemetrexed etait alors evoquee et ce traitement suspendu. Un dermocorticoide de classe tres forte etait prescrit, permettant une remission partielle des symptomes. En accord avec les oncologues, un traitement par nivolumab etait introduit en relais du pemetrexed. Discussion Les œdemes inflammatoires et sclereux des membres inferieurs sont un effet secondaire rare du pemetrexed, mais classiquement decrit. La prise de dexamethasone la veille, le jour et le lendemain de la perfusion permettrait d’en limiter l’apparition. L’arret de la chimiotherapie n’est pas systematique et depend de la balance entre l’impact fonctionnel des lesions et les alternatives therapeutiques sur le plan oncologique.

Introduction L’atteinte genitale de la dermatite atopique (DA) est peu decrite dans la litterature et sa prevalence chez l’adulte est mal connue. Materiel et methodes Nous avons mene une etude observationnelle prospective au sein du service de Dermatologie du CHU de Lille, entre aout 2019 et aout 2020. Nous presentons une analyse intermediaire des resultats a 6 mois. Les patients inclus etaient majeurs et consultaient pour une DA extra-genitale. Les donnees sociodemographiques et anamnestiques, les scores de severite globale, la description clinique de l’atteinte genitale, les scores evaluant la qualite de vie et la fonction sexuelle (en cas d’atteinte genitale) etaient recueillis. L’objectif principal etait d’estimer la frequence de l’atteinte genitale de la DA. Resultats 34 patients etaient inclus, 18 hommes et 16 femmes, avec un âge median (q1;q3) de 39 ans (26;51). L’atteinte genitale etait trouvee chez 11 patients [32,4 %, IC95 (17,4–50,5)]. La region pileuse (63,6 %) et la region peri-genitale (54,5 %) etaient les plus atteintes. La xerose (90,9 %) et l’erytheme (63,6 %) etaient les caracteristiques semiologiques les plus evoquees, mais la lichenification (note mediane [min-max] 7,5/10]5–10]) et les excoriations (6,0/10 [2–8]) etaient les manifestations les plus severes quand elles sont presentes. La presence de lesions genitales etait associee de maniere significative a la severite de la pathologie selon le score EASI (p = 0,025). L’atteinte genitale semblait associee au sexe masculin, au jeune âge, a l’atteinte cutanee diffuse et a une atteinte cutanee plus severe selon le SCORAD (tendance statistique). La qualite de vie des patients, appreciee par le score DLQI, semblait plus alteree dans le groupe avec atteinte (DLQI median 11 versus 8, p = 0,3). Uniquement evaluee dans le groupe avec atteinte, 3 hommes (37,5 %) et 2 femmes (66,7 %) presentaient une alteration de la fonction sexuelle selon les scores IIEF et FSFI. Discussion Dans cette analyse intermediaire, la frequence de l’atteinte genitale de la DA est importante, et ce d’autant plus que la pathologie est severe. Celle-ci est plus frequente chez les hommes, mais quand elle est presente chez les femmes, elle est plus severe. La qualite de vie est egalement plus alteree dans le groupe avec atteinte genitale sans que la difference ne soit statistiquement significative. Les resultats finaux de cette etude sont prevus pour aout 2020 ce qui nous permettra de confirmer ces resultats preliminaires sur un effectif plus important et de mettre en evidence d’eventuels facteurs associes a l’atteinte genitale. Dans notre etude, seulement 25 % des patients declaraient avoir deja beneficie anterieurement d’un examen genital par un dermatologue. Cette atteinte merite pourtant d’etre connue des dermatologues afin d’optimiser la prise en charge de la DA.

Introduction Le scorbut est la manifestation clinique de la carence en vitamine C. Les signes cutanes sont au premier plan et le dermatologue joue un role primordial dans le diagnostic. Observations Nous rapportons le cas de 5 patients, le ratio H/F etait de 4/1, l’âge median (q1 ; q3) de 55 ans (44 ; 57). Tous presentaient un alcoolisme chronique et 2/5 avaient des antecedents psychiatriques. L’aspect clinique etait similaire, a type d’œdeme unilateral de jambe, sclereux, chaud, douloureux et ecchymotique et evoluait de maniere subaigue depuis 2 mois. L’examen attentif montrait un purpura et une hyperkeratose perifolliculaire ainsi que des poils en tire-bouchon. En reprenant l’interrogatoire, l’enquete alimentaire revelait l’absence de consommation de fruits et legumes et une carence en apport protidique. Un patient presentait une hypertrophie gingivale mais tous avaient un mauvais etat bucco-dentaire. La biopsie cutanee realisee chez 2 patients n’etait pas specifique. L’echographie doppler des membres inferieurs (4/5) ne mettait pas en evidence de thrombose veineuse. Tous les patients presentaient des carences vitaminiques [B9 (5/5), B12 (1/5), K (1/5)], une denutrition severe et une anemie. Le syndrome inflammatoire etait constant et 4 patients avaient des troubles de l’hemostase [D-Dimeres elevees (2/5), TCA allonge (2/5), TP bas (1/5)]. L’evolution clinique, connue chez 4 patients, etait rapidement favorable apres une supplementation en vitamine C (1 g/j pendant 1 mois), associee a une regression du syndrome inflammatoire. L’aspect sclereux de la jambe persistait pour 2 patients. Discussion L’acide ascorbique joue un role dans l’absorption du fer et la synthese du collagene par hydroxylation de la proline et de la lysine. Un deficit provoque une fragilite des petits vaisseaux et des troubles de la cicatrisation, expliquant les signes cliniques classiques du scorbut (purpura perifolliculaire, ecchymoses). Une carence chronique en vitamine C pourrait provoquer de minimes hemorragies repetees avec extravasation d’hemosiderine dans les tissus sous-cutanes. Celle-ci, en stimulant la proliferation fibroblastique, induirait la sclerose cutanee. Les symptomes se manifestent apres 3 mois de privation alimentaire et la confirmation diagnostique repose sur le dosage sanguin du taux de vitamine C qui est effondre (

Introduction L’efficacite therapeutique de l’omalizumab, un anticorps monoclonal anti-IgE, a ete rapportee dans la pemphigoide bulleuse dans plusieurs petites series. Nous rapportons une observation de pemphigoide a 200 KDa, forme rare de maladie bulleuse auto-immune (MBAI), traitee efficacement par omalizumab. Observations Un homme de 69 ans presentait une dermatose bulleuse extensive profuse. A l’examen, il presentait des bulles tendues predominantes dans la region cervico-cephalique, des erosions de la muqueuse buccale et de l’epiglotte, evocatrice de pemphigoide cicatricielle. L’immunofluorescence sur peau clivee etait positive et mixte. Les ELISA anti-BPAG 1 et 2 (technique Euroimmun) etaient positifs respectivement a 59 et > 190 UA/mL. La mise en evidence d’une bande a 200 kDa sur l’immunoblot faisait retenir le diagnostic de pemphigoide a 200 kDa (P200). Les traitements par corticotherapie locale tres forte (CL), dapsone 125 mg par jour, immunoglobulines intraveineuses et rituximab (4 perfusions de 1 g) ne permettaient pas de controler la maladie apres deux ans d’evolution. Un traitement par omalizumab etait introduit a la posologie de 300 mg en sous-cutane toutes les 4 semaines, en association a la CL a 30 g/j. L’efficacite clinique etait alors visible des la deuxieme injection permettant la decroissance de la CL a 10 g/j et la remission clinique obtenue a 3 mois ( Fig. 2 ). Aucun effet secondaire n’etait rapporte. Discussion La P200 est une MBAI rare de la jonction dermo-epidermique caracterisee par la presence d’anticorps ciblant la laminine gamma-1. Son traitement n’est pas codifie et parfois difficile. Plusieurs cas de P200 ont ete traites avec succes par dapsone en cas d’echec des dermocorticoides. Les formes resistantes font appel aux traitements immunosuppresseurs ou aux immunoglubulines, utilises egalement dans d’autres MBAI refractaires. L’omalizumab est un anticorps anti-IgE monoclonal humanise indique dans l’asthme et l’urticaire chronique qui presente un excellent profil de tolerance. Plusieurs series ont montre son efficacite hors AMM dans la pemphigoide bulleuse, souvent aux doses usuelles dans l’asthme. Aucun cas de P200 traite par omalizumab n’a ete decrit a notre connaissance dans la litterature a ce jour. Conclusion Nous rapportons la premiere observation de P200 refractaire aux traitements immunosuppresseurs, traitee avec succes par omalizumab.

Introduction La dermatite auto-immune a la progesterone (DAIP) est une pathologie rare liee a une reaction d’hypersensibilite a la progesterone endogene chez les femmes en âge de procreer. Elle survient parfois apres une phase de sensibilisation a la progesterone exogene (pilule ou sterilet). Observations Une femme de 27 ans consultait pour une eruption cutanee dorsale evoluant par poussees depuis 4 ans. Ses antecedents etaient marques par un syndrome des ovaires polykystiques traite par acetate de cryproterone et ethinylestradiol puis par chlormadinone (progestatif). Cette eruption mensuelle debutait en general 2 jours avant les menstruations et disparaissait quelques jours apres. Les lesions etaient invalidantes car douloureuses et recidivantes. Depuis l’introduction d’un traitement hormonal par dydrogesterone (progestatif de synthese) et clomifene (inducteur de l’ovulation) dans le cadre d’une procreation medicalement assistee, les poussees etaient de plus en plus etendues. L’examen clinique revelait des papules erythemateuses et des vesicules excoriees du dos. Le diagnostic de DAIP etait evoque. Les patch-tests et les intradermoreactions (IDR) a l’acetate de medroxyprogesterone (50 mg/mL, dilution 1/1000, 1/100, 1/10) realisees en phase folliculaire etaient negatifs. Mais les IDR declenchaient a 48 h une nouvelle poussee papulo-vesiculeuse dorsale plus etendue et prolongee ( Fig. 1 et 2 ). Discussion Le diagnostic de DAIP a ete retenu sur les deux criteres suivants : eruption cutanee cyclique, survenant en phase luteale s’aggravant sous dydrogesterone ; declenchement par l’intradermoreaction a l’acetate de medroxyprogesterone d’une poussee cutanee en phase folliculaire du cycle menstruel. Le troisieme critere diagnostique de la DAIP propose par Warin en 2001, a savoir l’amelioration apres blocage de l’ovulation, n’a pu etre evalue du fait du projet actuel de grossesse. Conclusion L’originalite de ce cas de DAIP reside dans le declenchement d’une poussee par l’intradermoreaction a l’acetate de medroxyprogesterone en phase folliculaire, alors que les patch-tests et les IDR etaient restees negatifs.

The main change in soil use in Amazonia is, after slash and burn deforestation followed by annual crops, the establishment of pastures. This conversion of forest to pasture induces changes in the carbon cycle, modifies soil organic matter content and quality and affects biological activity responsible for numerous biochemical and biological processes essential to ecosystem functioning. The aim of this study was to assess changes in microbial biomass and activity in fallow and pasture soils after forest clearing. The study was performed in smallholder settlements of eastern Brazilian Amazonia. Soil samples from depths of 0–2, 2–5 and 5–10 cm were gathered in native forest, fallow land 8–10 yr old and pastures with ages of 1–2, 5–7 and 10–12 yr. Once fallow began, soil microbial biomass and its activity showed little change. In contrast, conversion to pasture modified soil microbial functioning significantly. Microbial biomass and its basal respiration decreased markedly after pasture establishment and continued to decrease with pasture age. The increase in metabolic quotient in the first years of pasture indicated a disturbance in soil functioning. Our study confirms that microbial biomass is a sensitive indicator of soil disturbance caused by land-use change.

As more and more consumers around the world integrate the choice of healthier, more ethical and eco-friendlier food and beverages in their lifestyle, the wine industry is pushed to develop more sustainable production, distribution and consumption solutions. In search of wine preservation improvements that would have both economic and ecological positive impacts, the wine industry has been investing resources in research, development and innovation regarding alternative packaging and distribution solutions for years. The keg Ecofass® is made of recyclable plastic material, high density polyethylene (HDPE) in which there is an aluminium pouch containing the liquid food. It was a question of knowing if this type of container was adapted to the conservation of the wines during several months. The method of storage and distribution has also been studied to know the impact on the oenological and sensory quality of the wines. Likewise, the nature of the pressure gas (nitrogen or compressed air) has also been tested. The contents of free and total SO2 and CO2 were monitored, and sensory analysis tests were carried out. Nevertheless, at the sensory level, the judges were able to note significant differences between the wines.

Introduction Le pemetrexed (Alimta®) est une chimiotherapie prescrite en premiere intention dans le mesotheliome malin et le cancer bronchique non a petites cellules. Nous rapportons un cas d’œdeme inflammatoire des membres inferieurs sous pemetrexed. Observations Un homme de 63 ans, tabagique sevre, etait traite par pemetrexed et cisplatine pour un adenocarcinome pulmonaire. Il developpait 14 mois apres l’introduction du traitement des œdemes inflammatoires bilateraux des membres inferieurs, sans fievre. Les œdemes etaient infiltres et sclerodermiformes par endroit, chauds et douloureux, etendus de la malleole jusque mi-cuisse, bilateraux, asymetriques. La flexion des genoux etait limitee en raison des douleurs et de la sclerose cutanee. Une origine cardiaque, renale, hepatique et infectieuse des œdemes etait ecartee. Une biopsie cutanee etait realisee mettant en evidence une legere spongiose ainsi que de discrets remaniements inflammatoires dermiques peu specifiques. Le diagnostic d’œdemes inflammatoires induits par le pemetrexed etait retenu. Le traitement etait arrete et un dermocorticoide de classe tres forte etait applique, permettant une evolution favorable des symptomes. Apres avis aupres des oncologues, un traitement par nivolumab etait introduit pour son adenocarcinome pulmonaire ( Fig. 1et 2 ). Discussion Les toxicites cutanees du pemetrexed sont frequentes (14 a 22 %) et se presentent le plus souvent sous forme d’eruptions cutanees non specifiques. Plus rarement, ont ete decrits des radiodermites, des syndromes de Lyell, des vascularites urticariennes, des eczemas craqueles. Une supplementation vitaminique (acide folique, vitamine B12) et une premedication par dexamethasone permettent une diminution de ces toxicites. Les œdemes inflammatoires sclereux des membres sous pemetrexed sont rares et se presentent sous la forme d’un œdeme inflammatoire a predominance acrale evoluant vers une sclerose hyperpigmentee. Le delai d’apparition est variable (6 a 21 mois) et la severite augmente avec le nombre de cycles. La physiopathologie n’est pas connue. La prise en charge repose sur les dermocorticoides ou une corticotherapie systemique. L’arret de la chimiotherapie n’est pas systematique, fonction de la severite et de l’impact de la sclerose cutanee. Conclusion Nous rapportons un cas d’œdeme inflammatoire sclereux des membres inferieurs survenu sous pemetrexed. Cet effet indesirable peu decrit doit etre evoque rapidement afin d’eviter tout retentissement fonctionnel de la sclerose.

Background: Hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM 201300) is a rare recessive neuropathy typically diagnosed in the first decade. The 1973 study of a French Canadian family led to the definition of HSAN2. Objectives: To demonstrate that the apparent higher prevalence of HSAN2 in Quebec is due to the presence of two HSN2 mutations and that carriers of different mutations appear to have a similar phenotype. Methods: Through attending physicians, the authors recruited French Canadian patients with HSAN2. Exclusion of linkage to the known HSAN loci and linkage to the HSAN2 was performed using standard methods. Sequencing of the HSN2 gene was used to uncover the causal mutations. Results: A large cluster of HSAN2 patients comprising 16 affected individuals belonging to 13 families was identified. The mode of inheritance is clearly autosomal recessive. All patients originated from southern Quebec, and 75% are from the Lanaudiere region. Whereas linkage to the HSAN1, 3, and 4 loci was excluded, linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencing of the HSN2 gene uncovered two French Canadian mutations and a novel nonsense mutation in a patient of Lebanese origin, all predicted to lead to truncations of the HSN2 protein. The comparison of clinical variables between patients with different genotypes does not suggest any difference in phenotype. Conclusions: Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability.

The charge dependent stopping cross-section of partially ionized heavy ions in a carbon target is determined in the energy range of a few MeV/n. It is done by calculating during an ion–atom collision the classical evolution of the Wigner function of the target electrons. A special emphasis in our calculations is put on the contribution of the 1s electrons for which we analyze the influence of the overlapping domain, concerning the impact parameter, of the charge transfer and energy loss processes. We give a detail comparison with the experimental results provided by Blazevic of 2 MeV/n neon ions interacting with a thin carbon foil target.

The two chiral isomers of ethyl 5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate, NSC 613863 (R-isomer)-(1) and NSC 613862 (S-isomer)-(2) (CI980) and the three achiral analogs NSC 330770 (2-demethylated analog A), NSC 337238 and C179 are potent microtubule inhibitors. These ligands interact with tubulin overlapping the colchicine binding site. This study addresses the effects of recognition by tubulin on the conformational properties of the ligands. The near-UV CD (circular dichroism) band of the R-isomer was suppressed, while that of the S-isomer displayed a more intense negative band when these compounds were bound to tubulin. Interestingly, the three other initially achiral compounds became optically active upon binding to tubulin; particularly, analog A exhibited a negative CD band on the order of magnitude of chiral compounds. The CD changes are reversible, highly specific and actually permit measuring the binding of the ligands by tubulin. These CD changes are compatible with the deformation of the bound ligands. Fluorescence emission is strongly enhanced and blue shifted upon binding to tubulin. Water among a solvent series had a specific solvent effect, except on the 1,2-dehydro analogs NSC 337238 and C179, suggesting hydrogen bonding to N1. The emission of tubulin-bound R-isomer, S-isomer and analog A could be mimicked by solvent viscosity, supporting the notion that the intramolecular rotation between the pyridopyrazine and phenyl rings is frozen upon binding.

International audience; The mobile French Guiana coast is a shoreface region downdrift of the Amazon River, where enormous quantities of inorganic and organic materials are exchanged with the Atlantic Ocean. The rapid accumulation of these materials forms highly unstable shore-attached mud banks, which can be temporally emerged and then rapidly colonized and stabilized by microphytobenthos and opportunistic mangroves (i.e. Avicennia germinans). Mud banks are preferential sites for the accumulation and significant remineralization of organic matter (OM) due to intense erosion/deposition cycles and potential biological colonization. The distribution and sources of bulk sedimentary OM were characterized by elemental and isotopic analyses of four sediment cores, together with samples from three potential OM sources (mangrove plants, suspended particulate matter (SPM) and microphytobenthos), all collected from the landward face of the Macouria mud bank (French Guiana). Total organic carbon (TOC) and nitrogen (TN) concentrations in the sediment cores showed that OM sources were characterized by spatio-temporal variations in this mud bank. The relative contributions of mangrove plants, SPM and microphytobenthos were estimated using a three end-member mixing model based on [TN/TOC]atomic ratios and δ13C values. Sedimentary OM is mostly controlled by SPM associated with variable amounts of OM derived from mangrove plants and microphytobenthos. These variations could be explained by topography and bed elevation, which decrease submersion time and increase desiccation. Higher contributions of microphytobenthos are associated with black OM-rich laminae, identified in sedimentary cores and linked to temporal emersion phases of the mud bank, which favor the growth of benthic microalgae. This result is confirmed by the calculation of the average sediment accumulation rate (around 36.7 ± 14.8 cm yr− 1), taking into account the emersion of the study site every spring tide (a fortnightly cycle). This value is within the range of the previous results from other mud banks in French Guiana but is more than ten times greater than values generally obtained in other coastal contexts.

NSC 613863 (R)-(+) and NSC 613862 (S)-(-) (CI980) are two chiral isomers of ethyl 5-amino 2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate which have potent antitubulin activity. The S-isomer is a more potent antimitotic compound than the R-isomer, and the two isomers differ markedly in binding to tubulin [Leynadier, D., Peyrot, V., Sarrazin, M., Briand, C., Andreu, J. M., Rener, G. A., & Temple, C., Jr. (1993) Biochemistry 32, 10675-10682]. To understand the origin of such differences, we studied the interactions of three R- and S-isomer structural analogs which differ in C2 (the chiral carbon), i.e., C179, NSC 337238, and NSC 330770. C179 is a methylated dehydrogenated achiral compound. It bound to tubulin with an apparent affinity Ka of (2.29 +/- 0.17) x 10(4) M-1, inhibited tubulin polymerization in vitro at a half-inhibitory concentration (IC50) of 100 microM, and presented no GTPase activity. The substitution of -CH3 by -H leads to the NSC 337238 compound. It bound to tubulin with a higher affinity [Ka = (2.62 +/- 0.35) x 10(5) M-1] and inhibited tubulin polymerization at a lower concentration (IC50 = 14 microM). It presented no GTPase activity and induced the formation of abnormal polymers at a protein critical concentration (Cr) of 2 mg mL-1. NSC 330770, a demethylated hydrogenated molecule, interacted strongly with tubulin [Ka = (3.30 +/- 0.56) x 10(6) M-1].(ABSTRACT TRUNCATED AT 250 WORDS)

Occupational transmission of hepatitis C (HCV) is rare but has been repeatedly described in the published literature. Early diagnosis and therapy of acute hepatitis C is associated with an excellent chance of permanent HCV elimination. The majority of chronic HCV infections, however, lead to a slowly progressive hepatitis with associated morbidity and risk of liver cirrhosis. For this reason the need for antiviral therapy has to be evaluated immediately.

Due to the increasing proportion of women in health care, as well as changes in working conditions (implementation of safety devices, minimally invasive/endoscopic procedures) the question arises whether the applicable laws and regulations for the protection of working mothers are outdated and should be updated.Individual risk analysis, as well as the inclusion of the pregnant health care worker in the decision-making process with regard to continuation or modification of the work practice serves as a protection of the expectant mother and unborn child and allows a continuation of the occupational activities.

Several fluorescence properties of two enantiomers, NSC 613862 (S)-(-) and NSC 613863 (R)-(+), have been compared. Even though the two isomers showed the same fluorescence behavior in solution in different solvents, drastic differences were observed after binding to purified calf brain tubulin. Binding measurements for the two compounds were performed both by fluorescence spectroscopy and by column gel permeation, a direct method of measurement. For both isomers, the binding was characterized by the presence of one high-affinity binding site with an apparent association constant of (3.2 +/- 0.5) x 10(6) M-1 and (4.1 +/- 0.9) x 10(6) M-1 for the R- and S-isomer, respectively, and by several low-affinity sites. Both isomers were also shown to induce GTPase activity in tubulin. The high-affinity binding site seems to be the same for the two isomers. Moreover, fluorescence competition experiments suggest at least a partial overlap of the colchicine and podophyllotoxin site. To explain the differences in fluorescence behavior after binding to tubulin, we hypothesize that the R-isomer is positioned differently in its binding locus as compared with the S-isomer.

MDL 27048 [trans-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2- methyl-2-propen-1-one] fluoresces when bound to tubulin but not in solution. This effect has been investigated and found to be mimicked by viscous solvents. Therefore, MDL 27048 appears to be a fluorescent compound whose intramolecular rotational relaxation varies as a function of microenvironment viscosity. The binding parameters of MDL 27048 to tubulin have been firmly established by fluorescence of the ligand, quenching of the protein fluorescence, and gel equilibrium chromatography. The apparent binding equilibrium constant was (2.75 +/- 0.45) x 10(6)M-1, and the binding site number was 0.81 +/- 0.12 (10 mM sodium phosphate-0.1 mM GTP, pH 7.0, at 25 degrees C). The binding is exothermic. The binding of MDL 27048 overlaps the colchicine and podophyllotoxin binding sites. Binding of MDL 27048 to the colchicine site was also measured by competition with MTC [2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-one] , a well-characterized reversibly binding probe of the colchicine site [Andreu et al. (1984) Biochemistry 23, 1742-1752; Bane et al., (1984) J. Biol. Chem. 259, 7391-7398]. In contrast with close analogues of colchicine, MDL 27048 and podophyllotoxin neither affected the far-ultraviolet circular dichroism spectrum of tubulin, within experimental error, nor induced tubulin GTPase activity. Like podophyllotoxin, an excess of MDL 27048 over tubulin induced no abnormal cooperative polymerization of tubulin, which is characteristic of colchicine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

When NADPH was added in excess to a bovine liver DHFR solution, a fluorescence peak due to an energy transfer mechanism was apparent at 450 nm. It did not vary over time. The intrinsic fluorescence peak of DHFR at 320 nm was quenched and this phenomenon increased over the time-course after NADPH addition. This result was ascribed to a slow DHFR conformational change induced by NADPH binding, which has never been previously described in such a long time scale (more than 30 min). A kinetic scheme accounting for this mechanism has been proposed. Furthermore, this interconversion between two protein conformers led to an increase in the initial apparent rate of the enzymatic reaction catalyzed by DHFR.

Changes in intra-erythrocytic pH values over time, during and after bicarbonate hemodialysis, were studied with 31P Nuclear Magnetic Resonance. Simultaneously, pH values of whole blood were obtained by a gazometric method. A two-compartment model appeared to be the simplest kinetic model to explain the shifts in proton concentrations in extra- and intracellular media. Non-linear regression was used to determine exchange constant values. There was a very good correlation between the experimental and calculated proton concentrations. This model can describe all patients but individual experimental constants must be determined. Under these conditions a single blood pH determination before dialysis will permit determination of the initial intra-erythrocytic pH and monitoring of intra-erythrocytic pH during hemodialysis.

The interaction of antimitotic compounds with tubulin has been studied in detail in our laboratory; among them, the two chiral isomers of ethyl 5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4- b ]pyrazin-7-yl carbamate, NSC 613863 ( R )-(+) and NSC 613862 ( S )-(−) (CI980) and the three achiral analogs NSC 330770 (ethyl 5-amino-1,2-dihydro-3-phenylpyrido[3,4- b ]pyrazin-7-yl carbamate), NSC 337238 (ethyl 5-amino-3-phenylpyrido[3,4- b ]pyrazin-7-yl carbamate) and C179 (ethyl 5-amino-2-methyl-3-phenylpyrido[3,4- b ]pyrazin-7-yl carbamate). In this study, by AM1 calculations, we have investigated the ground state (S 0 ), the near-UV absorption, the fluorescence emission properties of these compounds in the order to better understand the behavior of each drug and to enlighten their binding mechanism to tubulin. A modification of the ring B such as a methyl substituent or a second insaturation center drastically modified the affinity for tubulin. AM1 results indicated that ring A and B were mainly involved in the first step of binding to tubulin, the second step consisted in the interaction of the phenyl ring C. The spectra of the compounds have shown that an excited state rearrangement took place and that the molecules in the S 1 state are rendered more planar. The rotation of the phenyl appeared to be an unfavorable pathway but an imino form, stabilized by an intramolecular hydrogen bond between the COO moiety of the side chain and an hydrogen at atom N6 could play a role either in the S 0 and/or in the S 1 state.

The human colon adenocarcinoma HT29-D4 cell line is an interesting model for studies on epithelial cell differentiation. Undifferentiated cells are malignant proliferating cells, whereas differentiated cells act like epithelial polarized cells. In the present study, we first characterized the action of taxoids on the microtubular network of HT29-D4 cells according to the state of differentiation. Microtubular bundles were found in undifferentiated cells but not in differentiated cells, even with 500-fold higher taxoid concentrations for 96 h. This finding led us to study changes in microtubules according to the polarity status of the cell. E-MAP-115 was expressed only in differentiated cells; expression of β-tubulin isotypes was altered in them relative to undifferentiated cells. Classes I, II, III, IVa and IVb isotypes were expressed in both phenotypes; however, differentiated epithelial cells displayed a specific increase in class III β-tubulin. Thus, the increase in expression of this β-tubulin isotype in differentiated cells is not restricted to neuronal cells. Moreover, these expression changes may reflect a higher stability of microtubular network in differentiated cells, which may explain the lower activity of anti-microtubule agents, independently of the mitotic process. These results indicate that the composition of microtubules should be considered as one of the criteria involved in the response of tumour cells to chemotherapy with anti-microtubule agents. © 1999 Cancer Research Campaign

A previously healthy girl died suddenly and unexpectedly at three months of age in her sleep and an autopsy failed to reveal an adequate cause of death. As the father was known to have myophosphorylase (PPL) deficiency (McArdle's disease), we performed molecular genetic analysis of the PPL gene in autopsy muscle of the proposita. The girl was homozygous for the nonsense mutation at codon 49 most commonly associated with typical McArdle's disease. This report suggests that among children presenting as Sudden Infant Death Syndrome (SIDS) there may be cases associated with myophosphorylase deficiency.

It has been shown that ethyl 5-amino-l,2-dihydro-2-methyl-3-phenyl pyrido (3,4-b)pyrazin-7-yl carbamate (NSC 370147) inhibits microtubule formation, that this racemic compound binds to tubulin at or near the colchicine site, and that it enhances the binding of Vincristine to tubulin1. It appeared of interest to evaluate the activity of the R-enantiomer (NSC 613863) and the S-enantiomer (NSC 613862, CI 980). Hence, their interactions were examined at molecular level. Furthermore, we compared the binding properties of these new compounds to those of colchicine and colchicine analogues, which are firmly established. The influence of chirality on the polymerization of microtubule proteins and tubulin is also discussed.

Changes in intra-erythrocytic pH values over time, during and after bicarbonate hemodialysis, were studied with 31P Nuclear Magnetic Resonance. Simultaneously, pH values of whole blood were obtained by a gazometric method. A two-compartment model appeared to be the simplest kinetic model to explain the shifts in proton concentrations in extra- and intra-cellular media. Non-linear regression was used to determine exchange constant values. There was a very good correlation between the experimental and calculated proton concentrations. This model can describe all patients but individual experimental constants must be determined. Under these conditions a single blood pH determination before dialysis will permit determination of the initial intra-erythrocytic pH and monitoring of intra-erythrocytic pH during hemodialysis.

The study of the radiation yields of free radical formation in deaerated dioxane solutions containing a fluorescent solute (PPO or PBD) or a chlorinated compound (CCl 4 or CHCl 3 ) shows that there are two possible mechanisms for energy transfer from superexcited states: transfer of the electronic excitation energy, and the ionc mechanism which involves the electrons formed by autoionization. We propose a kinetic scheme which agrees with experimental results.

A numerical integration rule is given for the calculation of three dimensional integrals on a spherical coordinate grid: integrals are considered as a weighted sum of integrand values. The program computes the points of the grid where the functions are to be determined and the associated weights. Two examples of integration are performed to normalize and integrate a numerical function.

Les modifications, en fonction de la temperature, des spectres RMN de cinq benzodiazepinones permettent de mettre en evidence un equilibre entre deux formes pseudo-bateaux du cycle a sept liaisons. Les auteurs calculent les parametres d'activation et la constante de vitesse d'inversion et discutent le rǒle des substituants. The NMR spectra of five benzodiazepinones are determined over a range of temperature. They indicate that the seven ring has a twist-boat shape, which inverts more or less rapidly according to the nature of substituents. The activation parameters and the rates of inversion are determined and the substituent effects are discussed.

La solubilite de differents halogenoalcanes (Halons) dans l'eau, l'acide oleique, la serum albumine humaine (SAH) et le plasma humain a ete etudiee par RMN du Fluor.Les parametres thermodynamiques de leur interaction avec la SAH ont ete determines par Microcalorimetrie Isotherme.La concentration de ces composes est plus elevee dans une solution de SAH et de plasma que dans l'eau. Ceci peut etre explique par les interactions hydrophobes des Halons a la fois avec la Serum Albumine et la fraction lipidique du plasma.La cinetique de desorption dans une solution de SAH et de plasma semble etre independante de la nature du Halon, la duree de demi-vie est dans tous les cas approximativement egale a 90 minutes.

Complexes formed in aqueous solution between cisplatin or hydrolysis species and 5′ adenosine monophosphate (AMP) or 5′ adenosine triphosphate (ATP), the latter with and without chloride ions, have been determined using 195 Pt, 31 P, 13 C and 1 H NMR. The present results lead to the conclusion that the only monodentate complexes with AMP are cis -Pt(NH 3 ) 2 (AMP-N7)Cl at acid pH and cis -Pt(NH 3 ) 2 (AMP-N7)OH at neutral and basic pH. Other bidentate complexes were identified as cis -Pt(NH 3 ) 2 (AMP-N7) 2 and cis -Pt(NH 3 ) 2 (AMP-N7)(AMP-PO). Also discussed herein are the binding of platinum to the phosphate group Pγ with ATP and at acid pH, and the formation of the [ cis -Pt(NH 3 ) 2 (ATP-N7)H 2 O] + complex. In neutral and basic pH ranges, the phosphate moiety of ATP is the most reactive site. In the presence of an excess of chloride ions, the complexation rates between the ATP and the cisplatin are decreased. Furthermore, in the experimental conditions used neither the ATP nor the AMP have shown binding to N1.

The authors have employed a microcalorimetric method to study the nature of the interactions between several benzodiazepin molecules and human serum albumin. The thermodynamic functions of complexation have been determined at different pH, ionic strength and electrolyte support conditions. Both electrostatic and hydrophobic interactions have been demonstrated to exist in proportions which vary according to the drug's molecular structure.

Further investigation of the Karle-Hauptman determinants leads to several new relations: the DN determinant is simply related to interatomic vectors; also obtained is a probabilistic restriction on the atomic positions inside the algebraically allowed regions, as defined by von Eller. On the other hand new Gram determinants are defined and shown to be useful in relating moduli, phases and interatomic vectors. A practical application is given of fitting a stereochemically known fragment in the unit cell.

Resume Les auteurs etudient les rendements de scintillation de plusieurs liquides scintillants a base de dioxanne dont les solutes primaires presentent des affinites electroniques differentes. Ils comparent quantitativement les effets inhibiteurs du tetrachlorure de carbone et du chloroforme sur les liquides etudies. Ils en deduisent le role important de l'affiniteelectronique du solute en ce qui concerne le transfert d'energie solvant-solute et par suite le rendement de scintillation.

Phillipson, J., Sarrazin-Comans M. & Stomatopoulos C., 1983: Food consumption by Microtus agrestis and the unsuitability of faecal analysis for the determination of food preference. Acta theriol., 28 26: 397—416 [With 6 Tables, 4 Figs. & Plate XIII] In the laboratory adult Microtus agrestis (Linnaeus, 1761) consumed an average of 21.4 g wet wt. (=6.3 g dry wt.) of fresh grass indiv"1 d" 1 with an annual mean digestibility of 52.8%. When four common species of food grass were on offer consumption in Autumn and Winter was directly proportional to availability. A preference for the more "succulent" species was exhibited in Spring and Summer. Over the year digestibility coefficients ranged between 33.6 and 67.8%, the highest values occurring in Spring and Summer. Faecal analysis suggested an order of food preference different to that determined by direct observation, the differences being attributable to the differential "desirability" and "digestibility" of the food grasses during the course of the year.

1H and 13C chemical shifts, obtained by two-dimensional homonuclear and heteronuclear shift correlation, are reported for 8,8-diethyl-N,N-dimethyl-2-aza-8-germaspiro[4,5]decane-2-propanamine dihydrochloride (spirogermanium). The chemical shift variations as a function of pH and the coupling constants of the azacyclopentane moiety of the molecule are analysed, and a conformation is proposed for the molecule.

Dialysis and microcalorimetric methods were used to calculate the binding parameters of some cephalosporins to human serum albumin (HSA) and to study the nature of the interactions involved in the binding process. Dialysis results agree with microcalorimetric data for cephapirin, cephradin, cefamandole, and cefazolin. Binding forces seem to be principally electrostatic. The parts of the drug molecule involved in HSA drug binding have been identified by high-resolution NMR. The major binding site for cephalosporins with high HSA affinity is thought to be the electron-rich heterocyle fixed on the methylene at position 3. Four classes of cephalosporin have been defined: (a) very weak affinity for HSA (cephalexin, cephradin); (b) moderate affinity (cephapirin, cefoxitin, and cefotaxime) in which binding to the protein involves the heterocycle substituent of the acetamide chain carbon atom; (c) strongly binding (cefamandole), in which binding to HSA is by means of the methyltetrazole ring; and, finally (d), cefazolin, with two classes of binding sites for protein, showing strong and moderate affinity.

The interaction of cis-dichlorodiammineplatinum (II) (cisplatin) with human serum albumin (HSA), dissolved in phosphate buffer with or without sodium chloride (0ṁ1 M) has been examined at pH 7ṁ4 and μ = 0ṁ154. Equal volumes of cisplatin and HSA solutions were incubated at 37 °C for various times and filterable platinum concentrations versus time measured by flameless atomic absorption spectrophotometry. Binding kinetics differed depending on the buffer solutions used and on the time elapsing between cisplatin dissolution and outset of incubation with HSA. Experimental data were fitted to a theoretical equation used to calculate the number of nucleophilic sites per HSA molecule. Titrations of the HSA sulphydryl group content before and after incubation with a cisplatin solution were made, from which it was shown that the lone SH-group of the HSA macromolecule is involved in cisplatin binding. We also studied HSA's sensitivity towards denaturing agents when it was complexed with cisplatin. This sensitivity was decreased upon cisplatin binding. Also, the binding capacities of HSA and the HSA-Pt(II) complex to both tryptophan and warfarin were compared to determine the possible influence of cisplatin upon the binding to HSA of other drugs; this influence was negligible.

The kinetics of five cisplatin analogs binding to human plasma fractions possessing a molecular weight greater than 50,000 daltons were studied. Each drug solution in plasma ultrafiltrate or phosphate buffer ( pH = 7.4, μ = 0.154) was mixed with human plasma and filterable platinum concentrations were measured versus time by atomic absorption spectrophotometry. The only Pt IV compound studied did not bind. All the other Pt II complexes bound, but their binding kinetics were quite different. The experimental data were fitted to a theoretical equation based on the hypothesis that plasma nucleophilic agents possessing a molecular weight greater than 50,000 daltons are able to react with Pt compounds with an apparent second order rate constant. The apparent reaction rate constants and initial concentrations of these nucleophilic agents were calculated. The difference between the respective values obtained for each cisplatin analog could be explained by differences in their chemical formulas. Therefore our result should contribute towards a better understanding of the pharmacokinetics of the cisplatin analogs studied.