General Synthesis of -Alkylindoles from ,-Dialkylanilines via [4 + 1] Annulative Double C-H Functionalization.

Strategies enabling the construction of indoles and novel polycyclic heterocycles from simple building blocks streamline syntheses in synthetic and medicinal chemistry. Herein, we report a C-H functionalization approach to -alkylindoles proceeding via a double, site-selective C(sp)-H/C(sp)-H [4 + 1] annulation of readily accessed -dialkylanilines. This protocol features a site-selective hydrogen atom transfer by a tuned -Bu amidyl radical and addition of a sulfonyl diazo coupling partner, which promotes highly site-selective homolytic aromatic substitution of the (hetero)aromatic core.

Regulatory standards and processes for over-the-counter availability of hormonal contraception and drugs for medical abortion in five countries in the Eastern Mediterranean Region.

The World Health Organization 2019 WHO consolidated guideline on self-care interventions for health: sexual and reproductive health and rights includes recommendations on self-administration of injectable contraception, over-the-counter (OTC) oral contraception and self-management of medical abortion. A review of the regulatory status of these two self-care interventions can highlight processes required to ensure that the quality of the medicines and safety of individuals are safeguarded in the introduction and scale-up in countries. This review outlines the legal regulatory status of prescription-only medicine (POM) and OTC contraceptives, including emergency contraception, and drugs for medical abortion in Egypt, Jordan, Lebanon, Morocco and Tunisia using information obtained from internet searches, regulatory information databases and personal contacts.

Identification and Reactivity of -,--Dihydroxycarbene, a New [CHO] Intermediate.

We report the first preparation of the -,- conformer of dihydroxycarbene () by means of pyrolysis of oxalic acid, isolation of the lower-energy -,- () and -,- () product conformers at cryogenic temperatures in a N matrix, and subsequent narrow-band near-infrared (NIR) laser excitation to give . Carbene converts quickly to via quantum-mechanical tunneling with an effective half-life of 22 min at 3 K. The potential energy surface features around were pinpointed by convergent focal point analysis targeting the AE-CCSDT(Q)/CBS level of electronic structure theory.

In Situ Switching of Site-Selectivity with Light in the Acetylation of Sugars with Azopeptide Catalysts.

We present a novel concept for the in situ control of site-selectivity of catalytic acetylations of partially protected sugars using light as external stimulus and oligopeptide catalysts equipped with an azobenzene moiety. The isomerizable azobenzene-peptide backbone defines the size and shape of the catalytic pocket, while the π-methyl-l-histidine (Pmh) moiety transfers the electrophile. Photoisomerization of the - to the -azobenzene catalyst (monitored via NMR) with an LED (λ = 365 nm) drastically changes the chemical environment around the catalytically active Pmh moiety, so that the light-induced change in the catalyst shape alters site-selectivity.

Conformer-specific [1,2]-tunnelling in captodatively-stabilized cyanohydroxycarbene (NC-C[combining umlaut]-OH).

We report the gas-phase preparation of cyanohydroxycarbene by high-vacuum flash pyrolysis of ethyl 2-cyano-2-oxoacetate and subsequent trapping of the pyrolysate in an inert argon matrix at 3 K. After irradiation of the matrix with green light for a few seconds singlet -cyanohydroxycarbene rearranges to its -conformer. Prolonged irradiation leads to the formation of cyanoformaldehyde and isomeric isocyanoformaldehyde.

Developing and sustaining quality improvement partnerships in the VA: the Colorectal Cancer Care Collaborative.

Objective: The Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) seeks to develop partnerships between VA health services researchers and clinical managers, with the goal of designing and evaluating interventions to improve the quality of VA health care.

Methods: In the present report we describe one such initiative aimed at enhancing the continuum of colorectal cancer (CRC) care, including diagnosis, treatment and surveillance-the Colorectal Cancer Care Collaborative (C4).

Results: We describe the process and thinking that led to two parallel quality improvement "collaboratives" that addressed (1) CRC screening and diagnostic follow-up and (2) the guideline concordance and timeliness of CRC treatment.

Using a framework for spread: The case of patient access in the Veterans Health Administration.

Background: Experience indicates that an effective operational system will spread much more slowly than, for example, a new antinausea drug. The Veterans Health Administration (VHA) used a Framework for Spread to spread improvements in access to more than 1800 outpatient clinics between April 2001 and December 2003. The framework identifies strategies and methods for planning and guiding the spread of new ideas or new operational systems, including the responsibilities of leadership, packaging the new ideas, communication, strengthening the social system, measurement and feedback, and knowledge management.

Comparative genotoxicity of halogenated acetic acids found in drinking water.

Three short-term assays (SOS chromotest, Ames fluctuation test and newt micronucleus test) were performed to detect the genotoxic activity of organohalides, compounds likely to be found in chlorinated and/or ozonated drinking water: monochloro-, dichloro- and trichloroacetic acids and monobromo-, dibromo- and tribromoacetic acids. With the SOS chromotest, only three of the chemicals studied (dichloroacetic acid, dibromo- and tribromoacetic acids) were found to induce primary DNA damage in Escherichia coli PQ 37. In the Ames fluctuation test, all the compounds except monochloroacetic acid showed mutagenic activity in Salmonella typhimurium strain TA100.

1H NMR investigation of toxic effects of lindane and paraquat on Hep 3B and Hep G2 human hepatoma cell lines.

Lindane and paraquat induce biochemical changes in the liver. In order to specify their molecular impact at the cellular level, a 300 MHz 1H NMR investigation of hepatoma cell lines Hep 3B and Hep G2 responses was performed. Cells were exposed over 24 h to 50 mg/L lindane (0.

Assay of free-radical toxicity and antioxidant effect on the Hep 3B cell line: a test survey using lindane.

The content of reduced glutathione and of glutathione disulfide as well as the activities of glutathione reductase, glutathione peroxidase, glutathione S-transferases, catalase and superoxide dismutases were determined in human hepatoma Hep 3B cells in relation to free-radical toxicity in order to appreciate the defense capacities of these cells compared to data on normal hepatocytes. When Hep 3B cells were exposed to lindane, a known inducer of free-radical production, superoxide dismutase activity appeared as the best-adapted cellular parameter for early detection of the resulting free-radical toxicity.

Genotoxicity assay of chloral hydrate and chloropicrine.

The chlorination by-products chloral hydrate and chloropicrine were assayed for genotoxicity in three short-term tests. Chloropicrine was 100-fold more potent than chloral in inducing mutations in strain TA100 of S. typhimurium (fluctuation test) and, at variance with chloral, was positive in the SOS chromotest using strain PQ37 of E.

[Erythrocyte ketone reductase activity, total plasma haloperidol and acute psychoses].

Haloperidol (HAL) is a widely used and clinically effective neuroleptic. Its metabolism differs in various animal species. In humans, reduced haloperidol (RHAL), a hydroxy metabolite of HAL, is produced by a cytosolic ketone reductase.

Use of the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test to study the genotoxicity of four trihalomethanes.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of four trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane and bromoform). With the SOS chromotest, all the chemicals studied except chloroform were found to induce primary DNA damage in Escherichia coli PQ37. In the Ames-fluctuation test, only bromoform showed mutagenic activity on Salmonella typhimurium strain TA100.

Study of the genotoxic activity of six halogenated acetonitriles, using the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of six halogenated acetonitriles identified in chlorinated waters (monochloro-, dichloro-, trichloro-, monobromo-, dibromo- and bromochloroacetonitrile). With the SOS chromotest, three of the chemicals studied (dichloro-, dibromo- and bromochloroacetonitrile) were found to induce primary DNA damage in Escherichia coli PQ37. In the Ames-fluctuation test, all the compounds except dibromoacetonitrile showed mutagenic activity on Salmonella typhimurium strain TA100.

Application of the kinetic of RNA synthesis on Hep 3B cells. Study of the medium-term cytotoxicity of atrazine.

The test based on measuring the RNA synthesis rate, already described on Hela S3 in culture (Fauris et al., Les colloques de l'INSERM 106 (1981) 455-463), has been adapted to a human hepatoma cell line Hep 3B which retains a certain capacity towards metabolising. These modifications make it easier to point to the presence of possible water micropollutions and to envisage the study of the medium-term toxicity of such pollutants to be found in traces in water, with adequate sensitivity if we take into account their low concentration level.

Study of the genotoxic activity of five chlorinated propanones using the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of five chlorinated propanones identified in several chlorinated waters (monochloropropanone, 1,1-dichloropropanone, 1,3-dichloropropanone, 1,1,1-trichloropropanone and 1,1,3-trichloropropanone). In the SOS chromotest, all the compounds except monochloropropanone were found to induce primary DNA damage in Escherichia coli. With the fluctuation test, all five chloropropanones showed mutagenic activity on Salmonella typhimurium strain TA100.

[Erythrocyte superoxide dismutase (eSOD) determination in positive moments of psychosis].

Dysregulation of free radical metabolism has been supposed to be involved in schizophrenia etiopathogeny. Recently, Wang et al. showed a red blood cell super oxide dismutase increase in positive schizophrenia (Crow's type I), but neither in negative schizophrenia (Crow's type II) nor in controls.

Correlation of clinical response (PANSS) and plasma levels of haloperidol and reduced haloperidol in schizophrenia.

1. The authors attempted to correlate plasma concentrations in H/rH and clinical efficacy from 8 schizophrenic patients (DSM IIIR) on H. 2.

[Value of the determination of erythrocyte haloperidol ketone reductase activity in the evaluation of haloperidol therapy].

Serum levels of haloperidol and reduced haloperidol as well as the reduced haloperidol/haloperidol ratios were determined in nine acute schizophrenics on oral haloperidol medication and correlated over 21 days with psycho pathology and extra-pyramidal symptom scores. We have investigated red blood cells haloperidol reductase activity in the group of patients. Significant correlations were found between haloperidol plasma levels and positive sub scale for each patient (r = 0.

Comparison of three short-term assays: results on seven chemicals. Potential contribution to the control of water genotoxicity.

Three short-term assays (the SOS chromotest, the Ames fluctuation test and the newt micronucleus test) were used to evaluate the genotoxicity of seven chemicals (4-nitroquinoline 1-oxide, potassium dichromate, formaldehyde, sodium hypochlorite, benzo[a]pyrene, cyclophosphamide and 2-naphthylamine). In the SOS chromotest, all seven compounds except sodium hypochlorite and cyclophosphamide were found to induce primary DNA damage in E. coli.

Comparison of metabolic activities in two human hepatoma cell lines, HEP 3B and HEP G2. Application to lindane.

In a preliminary investigation, the evolution with time of the levels of ATP and glutathione species [reduced glutathione (GSH) and glutathione disulphide (GSSG)], glutathione reductase activity and RNA synthesis rate were studied in two human hepatoma cell lines, Hep 3B and Hep G2. Both cell lines exhibited higher cellular activities, during the first 48 hr. In a second investigation, the cells were exposed to lindane.

Cellular uptake and biotransformation of arsenic V in transformed human cell lines HeLa S(3) and Hep G(2).

The biotransformation of arsenate was studied in two human transformed cell lines (epithelial HeLa S(3) and hepatoma Hep G(2) cells) by the determination of several arsenic species both in the culture medium and in the cells. Arsenate reduction, which was observed in the two cell lines, was higher in Hep G(2) cells. Methylation appeared to be a minor pathway for HeLa cells, but was more important in the hepatoma cells.