Assessment of eosinophilic airway inflammation as a contribution to the diagnosis of occupational asthma.

BACKGROUND: Ascertaining the presence of asthma through the assessment of nonspecific bronchial hyperresponsiveness (NSBH) is a key step in the diagnosis of occupational asthma (OA). We aimed at investigating whether indices of airway inflammation including fractional exhaled nitric oxide (FeNO) and sputum eosinophils would be useful adjuncts to the measurement of NSBH in diagnosing OA defined as a positive specific inhalation challenge (SIC). METHODS: The study included 240 consecutive subjects with a suspicion of OA who completed a SIC, of whom 133 showed a positive response. The sensitivity, specificity, and predictive values of NSBH, and FeNO, as well as sputum eosinophil counts assessed at baseline of the SIC were determined. RESULTS: A concentration of histamine inducing a 20% decline in FEV1 (PC20 ) ≤16 mg/mL showed a sensitivity of 87% and a specificity of 36%. A FeNO level ≥25 ppb and a sputum eosinophil count ≥2% provided lower sensitivity rates (47% and 39%, respectively) than the PC20 value. Eight of the 17 subjects without baseline NSBH despite a positive SIC showed a sputum eosinophil count ≥2%, a FeNO level ≥25 ppb, or both outcomes. Combining either a PC20 value ≤16 mg/mL or a FeNO ≥25 ppb increased the sensitivity to 91%. Using either a PC20 ≤16 mg/mL or a sputum eosinophil count ≥1% increased the sensitivity to 94%. CONCLUSION: Adding the assessment of FeNO level and sputum eosinophils to NSBH improves the identification of subjects who may have OA and require further objective testing before excluding the possibility of OA.

[Overview of feelings and practices of gynecologists and obstetricians for the noninvasive prenatal testing in France]. / État des lieux du ressenti et des pratiques des gynécologues-obstétriciens face au dépistage prénatal non invasif en France.

OBJECTIVES: To evaluate the feelings and practices of French obstetrician-gynecologists in prescribing the noninvasive prenatal testing (NIPT) before the release of the French High Authority of Health recommendations. METHODS: Descriptive, declarative and transversal study, analyzing the feelings and practices of obstetrician-gynecologists, members of the French College of Gynecologists and Obstetricians (CNGOF) between February and May 2017 using an online questionnaire. Practitioners' feedback was self-assessed for several clinical situations using a numerical scale ranging from 1 to 10. This experience was rated as "good" (grades 6 to 10) or "bad" (grades 1-5). RESULTS: Overall, 529 practitioners (29.2%) of 1812 CNGOF members, answered the online questionnaire. A "good" feeling was found for more than 65% of the practitioners audited. Feelings were significantly better for obstetricians, sonographers (P<0.05) and CPDPN members (P=0.003) compared to other practitioners. Situations where the DPNI was proposed "systematically" were risks greater than 1/250 (70.9%), between 1/250 and 1/500 (59.4%), greater than 1/250 associated with history of spontaneous miscarriages and/or fetal death in utero (66%), greater than 1/250 associated with pregnancy resulting from PMA (68.3%), history of fetal aneuploidy (54%) and a parent carrying a Robertsonian translocation (51.6%). CONCLUSION: This study highlights a good overall feeling of the practitioners with the NIPT.

Occupational asthma caused by an epoxy amine hardener.

We describe a 43-year-old epoxy floor layer who developed work-related asthma while exposed to an epoxy hardener based on isophorone diamine (IPDA). Challenge exposures to the curing of the epoxy resin system and subsequently to the polyfunctional amine hardener containing IPDA both elicited delayed asthmatic reactions. This report further indicates that exposure to epoxy hardeners containing polyfunctional amines should be considered as a potential cause of occupational asthma. Appropriate work hygiene measures should be implemented to minimize airborne exposure to these volatile compounds.

DNA image cytometry and human papillomavirus (HPV) detection help to select smears at high risk of high-grade cervical lesions.

Three samples were submitted from women undergoing routine screening (n=910): two smears (one for routine cytology and one for DNA image cytometry) and a scrape for human papillomavirus (HPV) testing. DNA histograms were classified as suspect in cases of aneuploidy, polyploidy, and/or diploidy with a high proliferation rate. Follow-up was available in 239 cases. The primary end-point was the presence of a high-grade squamous intraepithelial lesion (HGSIL) at biopsy. Seventy women (7.7%) had a high-risk (HR) HPV infection and a suspect DNA profile. In 77 women with cytological abnormalities, 28 HGSILs were detected: four with a prior diagnosis of ASCUS (all HR-HPV infected including three with a suspect DNA profile), three with smears evocative of LGSIL (all with HR-HPV infection and a suspect DNA profile), and 21 with smears evocative of HGSIL (all with HR-HPV infection and 20 with a suspect DNA profile). During the follow-up period, out of 239 women with a cytologically normal smear at first entry, five developed a HGSIL; all were HR-HPV-positive and four had a suspect DNA profile at the first smear. HR-HPV detection alone gives a sensitivity of 100% for the detection of HGSIL, with a specificity of 84.3%, whereas DNA measurement associated with HPV testing significantly enhances the specificity to 95.4%. Thus, the combination of HPV testing and DNA measurement provides a highly sensitive and specific evaluation of the risk of HGSIL on cervical smears.

Molecular analysis of the beta-polymorphic form of trielaidin: crystal structure at low temperature

This work reports on the structure of trielaidin [EEE, 1,2,3-tri(trans-9-octadecenoyl)glycerol], a trans unsaturated triglyceride present in many refined fatty materials (margarines, chocolate products etc.). Firstly, the polymorphism, i.e. the existence of different crystalline forms at various temperature ranges, was defined. Secondly, the crystal growth was examined. By developing a particular growing system, monocrystals of the most stable polymorphic form, i.e. the beta-form, were obtained. To reduce thermal vibrations the X-ray data were collected at low temperature (173 K) and the structure was solved using direct methods. The structure was then analyzed in terms of conformation and crystal packing and compared with those of the other known triglycerides.

A reversible monoamine oxidase A inhibitor, befloxatone: structural approach of its mechanism of action.

Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase.

Molecular structure and stereoelectronic properties of sarmazenil--a weak inverse agonist at the omega modulatory sites (benzodiazepine receptors): comparison with bretazenil and flumazenil.

X-ray diffraction and ab initio MO theoretical calculations were used in order to investigate the structural and electronic properties of sarmazenil, a weak inverse agonist at the omega modulatory sites (benzodiazepine receptors). This compound was compared to bretazenil, a partial agonist, and to the antagonist flumazenil on the basis of structural and electronic data. The conformational and theoretical properties (interatomic pi overlap populations, molecular electrostatic potential (MEP), the topology of frontier orbitals, and proton affinity) of these three imidazobenzodiazepinones were determined in order to analyse the stereoelectronic properties in relation with their distinct intrinsic efficacies at the omega modulatory sites.

Synthesis, structure and biological properties of Z-17alpha-(2-iodovinyl)-11beta-chloromethyl estradiol-17beta (Z-CMIV), a high affinity ligand for the characterization of estrogen receptor-positive tumors.

Linkage of a 11beta-chloromethyl group to estradiol-17beta (E2) dramatically increases the binding affinity of the steroid for the estrogen receptor (ER) with the formation of a quasi-irreversible steroid-receptor complex. We have synthesized the two isomers of 11beta-chloromethyl-17alpha-iodovinyl-estradiol (E-CMIV and Z-CMIV) by a novel route. Both derivatives demonstrated high binding affinity and selectivity for ER (RBAs: ER = 820 and 1008; SHBG = 1.2 and 0.25, respectively; E2 = 100). On the basis of X-ray crystallographic data for Z-CMIV and its precursor, we have postulated that Z-CMIV might interact strongly with aromatic amino-acids within a hydrophobic groove of the ER hormone binding domain (HBD) that incorporates pockets corresponding to the 11beta and 17alpha steroid substituents. The binding properties of Z-CMIV labeled with 125I were investigated, especially its ability to detect and quantify altered ER forms with low binding affinity for E2. Sucrose density gradient analysis revealed that Z-CMIV has a higher activation potency than E2 as it converts a higher proportion of non-activated monomers in the cytosol into activated monomers with the potential to dimerize. In in vitro (MCF-7 cells) and in vivo (rat uterus) determinations of estrogenic activity, Z-CMIV was as potent as E2 in increasing progesterone receptor (PgR) concentrations and decreasing ER levels and in stimulating uterine growth. [125I]-Z-CMIV could open the way to new applications in the diagnosis and therapy of ER-positive breast cancers, especially those containing altered (variant) ERs.

Relationship between structural properties and affinity for herpes simplex virus type 1 thymidine kinase of bromine substituted 5-heteroaromatic 2'-deoxyuridines.

The crystal structures of 5-(5-furan-2-yl)-2'-deoxyuridine (II), 5-(5-bromofuran-2-yl)-2'-deoxyuridine (IV) and 5-(3-bromothien-2-yl)-2'-deoxyuridine (V) have been studied in order to explain the different affinity of the compounds for the herpes simplex virus type 1 (HSV-1) thymidine kinase. These compounds present a variable affinity according to the position of the heteroatom substituting the five-membered ring. An unfavourable substitution in the five-membered ring for interaction with the HSV-1 thymidine kinase has been identified.

Prevalence of occupational asthma due to latex among hospital personnel.

Latex has been documented as causing immediate hypersensitivity reactions ranging from contact urticaria to severe anaphylaxis. Latex proteins may also act as airborne allergens causing rhinitis and asthma. The prevalence of occupational asthma due to latex gloves among health care workers is unknown. We surveyed the employees of a primary care hospital including nurses (n = 201), members of the cleaning staff (n = 50), and laboratory technologists (n = 38). In the initial part of the study, a questionnaire and skin-prick tests with latex and common inhalant allergens were administered to 273 of 289 (94%) members of the target population. Thirteen of the 273 subjects (4.7%; 95% CI: 2.6 to 8.1%) showed skin reactivity to latex. All latex-sensitive subjects reported glove-related urticaria, which was associated with rhinoconjunctivitis in 12 subjects and asthma in five subjects. No subject had a history suggestive of occupational asthma among those who had negative skin tests to latex. In the second part of the study, a histamine inhalation challenge was performed on 12 of 13 latex-sensitive subjects, including the five subjects with a history of occupational asthma. These 12 subjects demonstrated significant bronchial hyperresponsiveness. All underwent specific inhalation challenges with latex gloves in the laboratory. Seven subjects developed a significant bronchial response (four immediate and three dual reactions) to latex glove exposure. We conclude that occupational asthma due to latex occurred in 2.5% (95% CI: 1.0 to 5.2%) of hospital employees. Widespread use of latex gloves should therefore be considered a significant risk to the respiratory health of hospital employees.

Stereoelectronic properties of five anti-HSV-1 2'-deoxynucleosides analogues with heterocyclic substituents in the 5-position: a comparison with BVDU.

Structural and electronic characteristics of 5-(5-chlorothien-2-yl)-2'-deoxyuridine (I), 5-(furan-2-yl)-2'-deoxyuridine (II), 5-(5-bromofuran-2-yl)-2'-deoxyuridine (III), 5-(3-bromoisoxazol-5-yl)-2'-deoxyuridine (V) and 5-(isoxazol-5-yl)-2'-deoxyuridine (IV) have been determined and compared to the BVDU (VI) characteristics in order to explain their respective affinity for the herpes simplex virus type 1 thymidine kinase (TK). Molecular structure of 5-(5-chlorothien-2-yl)-2'-deoxyuridine has been obtained using single crystal X-ray crystallography. Electrostatic potential maps, energy and topology of frontier orbitals were computed at the ab initio MO STO-3G and STO-3G level. These studies reveal that the electrostatic potential energy maps are clearly dependent on the affinity of the compound for the enzyme.

Experimental and theoretical study of reversible monoamine oxidase inhibitors: structural approach of the active site of the enzyme.

Experimental and theoretical physico-chemical methods were used to investigate the interaction between aryl-oxazolidinones and monoamine oxidase (MAO). Several arguments suggest that these compounds interact with the flavin adenine dinucleotide (FAD) cofactor of MAO. The calculation using ab initio molecular orbital methods of the electronic properties of flavin and befloxatone, a reversible inhibitor of MAO A, led to a description of the interaction between aryl-oxazolidinones and the cofactor of the enzyme. Structure activity relationship results revealed additional sites of interaction with the protein core of MAO A. As a result of this work, a model is proposed for the reversible inhibition of MAO by oxazolidinones via long distance, reversible interactions with the FAD cofactor of the enzyme.

Discrepancies of DNA content of various solid tumours before and after culture measured by image analysis. Comparison of cytogenetical data.

Parallel cytophotometric ploidy studies and cytogenetic analysis were performed on 15 various human solid tumours. The quantification of DNA by image analysis was carried out on cytological imprints of fresh tumours and on smears obtained after cell culture. The results obtained by both sets of calculations were compared with each other and with the cytogenetic results. 6 cases (40%) showed concordance between the 3 techniques. One case was aneuploid for both DNA image analysis measurements but the cytogenetic data showed only a diploid stem line. In 3 cases out of 15 (20%), smears DNA analysis and cytogenetic results were concordant: in 2 tumours, the culture step failed to preserve aneuploid stem lines that were present in the imprint analysis. In the third one, a minority tetraploid peak observed after culture was absent on the imprint slide. Concordance between imprints and cytogenetic data and discordance with smears' analysis was observed in 3 cases (20%). These 3 cases were diploid or near diploid but the DNA analysis on the smears after culture showed an aneuploid stem line in each case. The last 2 cases showed a total disagreement between the 3 techniques. By measuring the DNA content with an image analyser, the observer can ensure that only tumoral cells are taken into account. The present study revealed that cytogenetic data represent only about 60% of the population that is effectively present in the culture dish and that the cultured population represents only 47% of the population present on the fresh tumour imprint.

Synthesis and biochemical evaluation of baclofen analogues locked in the baclofen solid-state conformation.

The synthesis of six close analogues of baclofen [3-(4-chlorophenyl)-4-aminobutyric acid] (BAC), a potent GABAB agonist, are reported. The compounds were designed starting from the structural informations contained in the solid state of BAC, regarded as a possible bioactive conformation, in which the p-chlorophenyl ring is perpendicular to the GABA backbone. A similar conformational situation was created by rigidifying the BAC structure by means of methylene (1), ethylene (2 and 6), or propylene (3) units, or by introducing chlorine atoms (4 and 5) into the ortho positions ("ortho effect"). Only compound 5 showed affinity for the GABAB receptor. Compound 6 [1-(aminomethyl)-5-chloro-2,3-dihydro-1H-indene-1-acetic acid], which was initially considered as representing the optimal mimic of the solid-state conformation of BAC, was surprisingly found inactive. An extensive conformational analysis was performed on compounds 1-6 in order to evaluate their flexibility and the overlap of their conformational population with respect to BAC. For this purpose a distance map was generated from three possible pharmacophoric groups: the amino and the carboxylic functions, and the phenyl ring. Finally, several explanations are proposed to account for the poor affinities of the prepared compounds such as steric hindrance or flexibility demand of the receptor.

Structural requirements of Na+-dependent antidopaminergic agents: Tropapride, Piquindone, Zetidoline, and Metoclopramide. Comparison with Na+-independent ligands.

Molecular graphic design coupled with PCILO and crystallographic results have been used to investigate the three-dimensional structure of Tropapride, Piquindone, Zetidoline, and Metoclopramide, four dopamine D-2 receptor antagonists showing Na+-dependent binding. Three putative pharmacophoric elements, a nitrogen lone pair, a phenyl ring and a carbonyl moiety, are similarly oriented in all the Na+-dependent drugs. Conversely, for Na+-independent analogs, the two latter pharmacophoric elements play a subordinate role, but two pi-electron regions are systematically localized on the other side of the molecule: the first is a phenyl group while the second is a carbonyl function as in butyrophenones, a cyano group as in R48455, or a phenyl ring as in diphenylbutylpiperidines or tricyclics. The presence of a benzyl ring on this side in Tropapride might explain its weak extrapyramidal effects.

Stereoelectronic study of zetidoline, a dopamine D2 receptor antagonist.

A combination of experimental and theoretical methods were used to investigate the stereoelectronic structure of zetidoline, a dopamine D2 receptor antagonist showing Na+-dependent binding. The solid-state conformation of zetidoline is characterized by synplanarity (coplanarity of the two rings with the chloro substituent and the carbonyl group on the same side). The side chain in the crystal adopts a folded conformation which places the azetidine nitrogen atom at about 8 A from the center of the aromatic ring. Quantum mechanical calculations indicate the synperiplanar and antiperiplanar conformations of the ring system to be of approximately equal energies. The molecular electrostatic potential of zetidoline in a nearly extended conformation shows a remarkable similarity with that of orthopramides (e.g. metoclopramide) and indolones (e.g. piquindone), i.e. two groups of drugs displaying the same D2 selectivity and Na+-dependent binding. We postulate that the close stereoelectronic similarity between zetidoline, orthopramides, and indolones accounts for their identical mechanism of action in the molecular level.

[Vaginal smear cytology and hormonal tests before and after treatment with veralipride. Results in eleven cases (author's transl)]. / Etude cytologique hormonale des frottis vaginaux avant et après traitement par le véralipride. A propos de onze observations.

Vaginal smear cytology and hormonal tests were conducted in eleven patients in the natural menopause, before and after treatment with one capsule (100 mg) daily of veralipride alone for 20 days. Maturation of the vaginal epithelial cells unrelated to the degree of post-menopausal atrophy present was observed, without modification in plasma levels of gonadotropic LH, FSH and ovarian E2, E3 levels.