Computational studies on the mechanism of the gold(I)-catalysed rearrangement of cyclopropenes.

Density functional theory calculations have been employed to investigate the mechanism of gold(I)-catalysed rearrangements of cyclopropenes. Product formation is controlled by the initial ring-opening step which results in the formation of a gold-stabilised carbocation/gold carbene intermediate. With 3-phenylcyclopropene-3-methylcarboxylate, the preferred intermediate allows cyclisation via nucleophilic attack of the carbonyl group and hence butenolide formation. Further calculations on simple model systems show that substituent effects can be rationalised by the charge distribution in the ring-opening transition state and, in particular, a loss of negative charge at what becomes the ß-position of the intermediate. With 1-C(3)H(3)R cyclopropenes (R = Me, vinyl, Ph), ring-opening therefore places the substituent at the ß-position.

Experimental and computational investigation of C-N bond activation in ruthenium N-heterocyclic carbene complexes.

A combination of experimental studies and density functional theory calculations is used to study C-N bond activation in a series of ruthenium N-alkyl-substituted heterocyclic carbene (NHC) complexes. These show that prior C-H activation of the NHC ligand renders the system susceptible to irreversible C-N activation. In the presence of a source of HCl, C-H activated Ru(I(i)Pr(2)Me(2))'(PPh(3))(2)(CO)H (1, I(i)Pr(2)Me(2) = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene) reacts to give Ru(I(i)PrHMe(2))(PPh(3))(2)(CO)HCl (2, I(i)PrHMe(2) = 1-isopropyl-4,5-dimethylimidazol-2-ylidene) and propene. The mechanism involves (i) isomerization to a trans-phosphine isomer, 1c, in which hydride is trans to the metalated alkyl arm, (ii) C-N cleavage to give an intermediate propene complex with a C2-metalated imidazole ligand, and (iii) N-protonation and propene/Cl(-) substitution to give 2. The overall computed activation barrier (ΔE(++)(calcd)) corresponds to the isomerization/C-N cleavage process and has a value of +24.4 kcal/mol. C-N activation in 1c is promoted by the relief of electronic strain arising from the trans disposition of the high-trans-influence hydride and alkyl ligands. Experimental studies on analogues of 1 with different C4/C5 carbene backbone substituents (Ru(I(i)Pr(2)Ph(2))'(PPh(3))(2)(CO)H, Ru(I(i)Pr(2))'(PPh(3))(2)(CO)H) or different N-substituents (Ru(IEt(2)Me(2))'(PPh(3))(2)(CO)H) reveal that Ph substituents promote C-N activation. Calculations confirm that Ru(I(i)Pr(2)Ph(2))'(PPh(3))(2)(CO)H undergoes isomerization/C-N bond cleavage with a low barrier of only +21.4 kcal/mol. Larger N-alkyl groups also facilitate C-N bond activation (Ru(I(t)Bu(2)Me(2))'(PPh(3))(2)(CO)H, ΔE(++)(calcd) = +21.3 kcal/mol), and in this case the reaction is promoted by the formation of the more highly substituted 2-methylpropene.

Activation of an alkyl C-H bond geminal to an agostic interaction: an unusual mode of base-induced C-H activation.

Deuterium labeling studies indicate that base-induced intramolecular C-H activation in the agostic complex 2-D proceeds with exclusive removal of a proton from the methyl arm of an (i)Pr substituent on the N-heterocyclic carbene (NHC) ligand. Computational studies show that this alkyl C-H bond activation reaction involves deprotonation of one of the C-H bonds that is geminal to the agostic interaction, rather than the agostic C-H bond itself. The reaction is readily accessible at room temperature, and a computed activation barrier of DeltaE (double dagger)(calcd) = +11.8 kcal/mol is found when the NHC 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene is employed as the external base. Charge analysis reveals that the geminal hydrogens are in fact more acidic than the agostic proton, consistent with their more facile deprotonation.

Formation of [Ru(NHC)4(eta(2)-O2)H]+: an unusual, high frequency hydride chemical shift and facile, reversible coordination of O2.

Reaction of the purple tetrakiscarbene ruthenium cation [Ru(I(i)Pr(2)Me(2))(4)H](+) (1, I(i)Pr(2)Me(2) = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene) with oxygen affords the pink eta(2)-O(2) hydride species [Ru(I(i)Pr(2)Me(2))(4)(eta(2)-O(2))H](+) (2). 2 displays (i) a very facile, reversible O(2) coordination and (ii) an unexpectedly positive hydride chemical shift, and both these features can be predicted and explained by density functional theory (DFT) calculations.

The influence of N-heterocyclic carbenes (NHC) on the reactivity of [Ru(NHC)(4)H](+) with H(2), N(2), CO and O(2).

The five-coordinate ruthenium N-heterocyclic carbene (NHC) hydrido complexes [Ru(IiPr(2)Me(2))(4)H][BAr(F) (4)] (1; IiPr(2)Me(2)=1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene; Ar(F)=3,5-(CF(3))(2)C(6)H(3)), [Ru(IEt(2)Me(2))(4)H][BAr(F) (4)] (2; IEt(2)Me(2)=1,3-diethyl-4,5-dimethylimidazol-2-ylidene) and [Ru(IMe(4))(4)H][BAr(F) (4)] (3; IMe(4)=1,3,4,5-tetramethylimidazol-2-ylidene) have been synthesised following reaction of [Ru(PPh(3))(3)HCl] with 4-8 equivalents of the free carbenes at ambient temperature. Complexes 1-3 have been structurally characterised and show square pyramidal geometries with apical hydride ligands. In both dichloromethane or pyridine solution, 1 and 2 display very low frequency hydride signals at about delta -41. The tetramethyl carbene complex 3 exhibits a similar chemical shift in toluene, but shows a higher frequency signal in acetonitrile arising from the solvent adduct [Ru(IMe(4))(4)(MeCN)H][BAr(F) (4)], 4. The reactivity of 1-3 towards H(2) and N(2) depends on the size of the N-substituent of the NHC ligand. Thus, 1 is unreactive towards both gases, 2 reacts with both H(2) and N(2) only at low temperature and incompletely, while 3 affords [Ru(IMe(4))(4)(eta(2)-H(2))H][BAr(F) (4)] (7) and [Ru(IMe(4))(4)(N(2))H][BAr(F) (4)] (8) in quantitative yield at room temperature. CO shows no selectivity, reacting with 1-3 to give [Ru(NHC)(4)(CO)H][BAr(F) (4)] (9-11). Addition of O(2) to solutions of 2 and 3 leads to rapid oxidation, from which the Ru(III) species [Ru(NHC)(4)(OH)(2)][BAr(F) (4)] and the Ru(IV) oxo chlorido complex [Ru(IEt(2)Me(2))(4)(O)Cl][BAr(F) (4)] were isolated. DFT calculations reproduce the greater ability of 3 to bind small molecules and show relative binding strengths that follow the trend CO >> O(2) > N(2) > H(2).

Neptunium(vi) chain and neptunium(vi/v) mixed valence cluster complexes.

The synthesis of [Np(VI)O(2)Cl(2)(thf)](n) offers the potential for more detailed exploration of neptunyl(vi) chemistry, while the synthesis of the mixed valence cluster complex [{Np(VI)O(2)Cl(2)}{Np(V)O(2)Cl(thf)(3)}(2)] allows molecular neptunyl(v) 'cation-cation' interactions to be probed.

[Intra-uterine insemination at either 24 or 48hours after ovulation induction: Pregnancy and birth rates]. / Insémination intra-utérine à 24 ou 48heures du déclenchement de l'ovulation : taux de grossesse et d'accouchement.

OBJECTIVE: Comparing rates of pregnancy and childbirth between IUI at either 24 or 48hours after injection of HCG. METHODS: This is a single-center retrospective study of couples who underwent intrauterine insemination between January 2013 and December 2014 at Medical-Surgical Obstetrical Centre of Schiltigheim. Stimulation of ovulation was done by FSH or HMG, and ovulation induction by 250µg of recombinant HCG. The insemination was performed after 2 days (group D2) or the day after (group D1). RESULTS: Among the 1092 intrauterine insemination cycles included in our study, 62 were done the day after ovulation induction by HCG (D1), and 1030 the day after (D2). Our study showed no significant difference in the rate of biological pregnancy, defined by a rate of BHCG>15IU/L, between the group D1 (19.35%) and the group D2 (18.12%), P=0.94, and no difference in live birth rate: respectively 14,50% and 11.75%, P=0.18. CONCLUSION: Our study reported similar rates of pregnancy and childbirth in the group who underwent IUI at D1 and D2 of ovulation induction, suggesting the possibility of IUI on day 1 when the organization of the service needs it, without loss of opportunity for pregnancy.

Computation provides chemical insight into the diverse hydride NMR chemical shifts of [Ru(NHC)4(L)H]0/+ species (NHC = N-heterocyclic carbene; L = vacant, H2, N2, CO, MeCN, O2, P4, SO2, H-, F- and Cl-) and their [Ru(R2PCH2CH2PR2)2(L)H]+ congeners.

Relativistic density functional theory calculations, both with and without the effects of spin-orbit coupling, have been employed to model hydride NMR chemical shifts for a series of [Ru(NHC)4(L)H]0/+ species (NHC = N-heterocyclic carbene; L = vacant, H2, N2, CO, MeCN, O2, P4, SO2, H-, F- and Cl-), as well as selected phosphine analogues [Ru(R2PCH2CH2PR2)2(L)H]+ (R = iPr, Cy; L = vacant, O2). Inclusion of spin-orbit coupling provides good agreement with the experimental data. For the NHC systems large variations in hydride chemical shift are shown to arise from the paramagnetic term, with high net shielding (L = vacant, Cl-, F-) being reinforced by the contribution from spin-orbit coupling. Natural chemical shift analysis highlights the major orbital contributions to the paramagnetic term and rationalizes trends via changes in the energies of the occupied Ru dπ orbitals and the unoccupied σ*Ru-H orbital. In [Ru(NHC)4(η2-O2)H]+ a δ-interaction with the O2 ligand results in a low-lying LUMO of dπ character. As a result this orbital can no longer contribute to the paramagnetic shielding, but instead provides additional deshielding via overlap with the remaining (occupied) dπ orbital under the Lz angular momentum operator. These two effects account for the unusual hydride chemical shift of +4.8 ppm observed experimentally for this species. Calculations reproduce hydride chemical shift data observed for [Ru(iPr2PCH2CH2PiPr2)2(η2-O2)H]+ (δ = -6.2 ppm) and [Ru(R2PCH2CH2PR2)2H]+ (ca. -32 ppm, R = iPr, Cy). For the latter, the presence of a weak agostic interaction trans to the hydride ligand is significant, as in its absence (R = Me) calculations predict a chemical shift of -41 ppm, similar to the [Ru(NHC)4H]+ analogues. Depending on the strength of the agostic interaction a variation of up to 18 ppm in hydride chemical shift is possible and this factor (that is not necessarily readily detected experimentally) can aid in the interpretation of hydride chemical shift data for nominally unsaturated hydride-containing species. The synthesis and crystallographic characterization of the BArF4- salts of [Ru(IMe4)4(L)H]+ (IMe4 = 1,3,4,5-tetramethylimidazol-2-ylidene; L = P4, SO2; ArF = 3,5-(CF3)2C6H3) and [Ru(IMe4)4(Cl)H] are also reported.

Sequence of the Candida albicans erg7 gene.

The nucleotide sequence of the Candida albicans erg7 gene, which complements erg7 mutants of Saccharomyces cerevisiae and restores oxidosqualene cyclase activity, was determined. The gene encodes a 728-aa protein that displays homology with squalene-hopene cyclase, providing further evidence that erg7 is the gene encoding 2,3-oxidosqualene cyclase.

Clinical and pathological aspects of human African trypanosomiasis (T. b. gambiense) with particular reference to reactive arsenical encephalopathy.

Fourteen of 330 patients treated with melarsoprol (Mel B) for human African trypanosomiasis (HAT) developed a severe reactive arsenical encephalopathy (RAE). Six of these cases were fatal and postmortem examination was performed on 5 patients. Symptoms of "sleeping sickness" were compared with symptoms after treatment with arsenicals and the subsequent onset of RAE. There are 3 characteristic syndromes of RAE: convulsive status associated with acute cerebral edema, rapidly progressive coma without convulsions, and acute nonlethal mental disturbances without neurological signs. Three subjects revealed hypoxic brain damage with acute cerebral edema, and multiple hemorrhages of brain stem in those comatose. The pathology of the underlying HAT (chronic perivascular inflammation and plasma cytic infiltration of the brain) and the pathology of the RAE (characterized by acute vasculitis) are distinct. RAE occurs in the first as well as in the second stage (CNS involvement) of trypanosomiasis but the reason for this is unclear; an exclusive toxicity of the drug, or a Herxheimer reaction are possible but seem unlikely. Both clinical and laboratory findings point rather to a drug-related, delayed immune response.

Efficacy and tolerability of a low-dose mefloquine-sulfadoxine-pyrimethamine combination compared with chloroquine in the treatment of acute malaria infection in a population with multiple drug-resistant Plasmodium falciparum.

The efficacy and tolerability of single, low-dose mefloquine, sulfadoxine-pyrimethamine (MSP) combination was compared with chloroquine (CQ) for malaria treatment in a malaria-endemic area of Nigeria with multiple drug-resistant Plasmodium falciparum. The two drug regimens (MSP and CQ) were tested in a 12-month prospective population study. The patients were divided into two groups. Group 1 patients were treated presumptively, based on malaria symptoms. Group 2 patients were treated based on a parasitologic diagnosis using the World Health Organization seven-day in vivo test and extended to a 28-day follow-up period. Tolerability was assessed by the incidence and intensity of adverse events. One thousand nine hundred thirty-five patients visiting 10 health facilities, including the University of Calabar Teaching Hospital, were enrolled. The study showed that the low-dose MSP was efficacious, with day 7 response rates of 95% and 91% for (presumptive) Group 1 and (in vivo) Group 2, respectively, while CQ had day 7 response rates of 82% and 66% in Groups 1 and 2, respectively. The low-dose MSP was significantly (P < 0.0001) more efficacious, with faster fever and parasite clearance times than CQ in this area of CQ-resistant P. falciparum malaria. Eight patients treated with CQ, including seven severe cases (RII-RIII) were successfully re-treated with MSP. Adverse events were generally more common among those treated with MSP (29%) than those treated with CQ (17%). However, the adverse events caused by both drugs were mild to moderate and self-limited. The MSP combination appears to be a good substitute for CQ, in view of multiple drug resistance, especially in areas with severe (RII-RIII) malaria.

Melanin granula distribution and phagocytosis in psoriasis vulgaris after PUVA therapy.

Melanin-containing basal cells of the epidermis, melanin-containing macrophages, mast cells, eosinophilic granulocytes and plasma cells were quantitatively investigated with the purpose of gaining an understanding of the quantitative changes in these cell systems under PUVA therapy. This patients have been exposed to solar radiation some weeks or months before the begin of the PUVA-treatment. Different dying-processes were used to investigate biopsy samples of psoriatically healthy and psoriatically affected skin, from 28 patients before, and 39 patients after PUVA therapy, using a 2 d micrometer with a field of view of 0.1 mm2. Altogether more than 9,000 fields of view have been analysed. The average radiation amount was 12 irradiations with an average total energy of 21.5 J/cm2. It was found that the count of granula-containing basal layer cells decreases in the psoriatic "healthy" region due to pigment incontinence and increase in the psoriatically affected region. The subepidermal melanin-containing phagocytes increase in both regions to a similar extent. In the case of the mast cells there was no trend to degranulation. The count of eosinophilic granulocytes and plasma cells was unchanged.

Forensic aspects of juvenile violence.

The juvenile justice system was created because it was recognized that youthful offenders needed to be managed differently from adults. They were to receive habilitation services instead of punishment. It is now more than a century since the creation of the first juvenile court. After 67 years, the US Supreme Court, in Kent v United States stated that the model was not working because juveniles in the criminal justice system received no treatment and they had no rights. Because the issue that had been appealed was the lack of rights (not lack of treatment), the Court mandated that juveniles, like adults, be given certain rights. The following year, in In re Gault, the Court expanded these rights. Subsequent Supreme Court cases have dealt with these kinds of issues--that is, whether juvenile offenders are entitled to the same rights as adults and subject to the same penalties. The Supreme Court has never heard a "right to treatment" case, which is the other part of the juvenile court system. Cases have been brought in lower courts (e.g., Nelson v. Heyne, 1972) alleging inadequate treatment services, but no national impact has resulted. Thus, in general, children in the juvenile court system do not have an enforceable right to treatment and can obtain only what services are available in their jurisdictions. The services often are woefully inadequate. Sentencing a youth to probation, with the requirement that he or she participate in counseling or mental health treatment, is meaningless if services are not available. Community-based, model programs that provide effective treatment do exist. They are, as yet, the rare exception rather than the norm and, therefore, are not available to most youthful offenders. Incarcerated juveniles, obviously, cannot avail themselves of community programs. Litigation to give these youth the same rights as adults in penal institutions is not the answer because incarcerated adults don't have a right to treatment, only a right to be free from "deliberate indifference" to their medical needs. It is hoped that a way will be found to provide effective services for the juvenile delinquent population. Federal laws have been enacted to mandate special services for educationally handicapped children. Those statutes, and litigation based on them, have led to some improvements for that group of children. Perhaps the same can be accomplished for the youthful offender population. Mandatory early intervention will serve them far better than mandatory waiver to adult court or incarceration in adult prison.

Patient factors and central line infection.

The purpose of this prospective study was to examine the relationship between patient-related factors and the development of central venous catheter infection. Fifty-three patients, representing 64 central lines, were followed from catheter insertion to removal. Information about the patient's age, sex, immunocompetence status, central line characteristics, medication regimen, and laboratory results was obtained. Results showed that, of these factors, only the medication regimen was a promising predictor of infection status. Patients who were receiving antibiotics during central line catheterization were at less risk of developing infection than patients who were not receiving them.

[Vaccination against malaria: initial trial with an ant-sporozoite vaccine, (NANP)3-TT (RO 40-2361) in Africa (Bobo-Dioulasso, Burkina Faso)]. / Vaccination contre le paludisme: premier essai avec un vaccin antisporozoïte, le (NANP)3-TT (RO 40-2361) en Afrique (Bobo-Dioulasso, Burkina Faso).

The vaccine (NANP)3-TT is a synthetic peptide of the circumsporozoite protein (CS) of Plasmodium falciparum coupled to tetanus toxoid (TT) as protein carrier and adsorbed to aluminium hydroxide as adjuvant. The objectives of the study were to assess the immunogenicity and the protective efficacy of the vaccine in an area where malaria is endemic. The study was conducted in a zone of irrigated rice cultivation known as the Vallée du Kou to the North of Bobo-Dioulasso. Malaria transmission is permanent in the Vallée with maxima in July and November. The study was conducted from June to December 1988. It was a controlled randomised, double blind, prospective vaccine trial. A total of 123 infants from 3 to 5 months of age were randomly assigned to three groups. Group I (controls) received three doses of TT alone, group II received two doses of TT and one of (NANP)3-TT and group III received three doses of (NANP)3-TT. These vaccines were administered simultaneously with the Enlarged Program of Immunisation (EPI) vaccines. The clinical parasitological and immunological status of the children was then monitored over a period of five months. No systemic reactions to the vaccine were observed in the infants either immediately after administration or during the follow-up. Minor local tumefactions were observed in only 3% of the children. The vaccine was found to be immunogenic with a peak IgG response at day 75, when 56% (group II) and 60% (group III) showed antibody titres of at least four times that seen at day 0. The response, however, was a short duration; by day 150 the average antibody titres were not significantly different between the three groups. The incidence and the level of parasiaemia and the incidence of clinical malaria were also not significantly different for each of the three groups during the period of the study. The association of (NANP)3 with tetanus toxoid was not shown to be immunologically inhibitive. The results, despite not showing a protective effect for the vaccine (NANP)3-TT, have shown its immunogenicity and therefore suggest that further development of this vaccine may be worthwhile.

Smooth C(alkyl)-H bond activation in rhodium complexes comprising abnormal carbene ligands.

Rhodation of trimethylene-bridged diimidazolium salts induces the intramolecular activation of an alkane-type C-H bond and yields mono- and dimetallic complexes containing a formally monoanionic C,C,C-tridentate dicarbene ligand bound to each rhodium centre. Mechanistic investigation of the C(alkyl)-H bond activation revealed a significant rate enhancement when the carbene ligands are bound to the rhodium centre via C4 (instantaneous activation) as compared to C2-bound carbene homologues (activation incomplete after 2 days). The slow C-H activation in normal C2-bound carbene complexes allowed intermediates to be isolated and suggests a critical role of acetate in mediating the bond activation process. Computational modelling supported by spectroscopic analyses indicate that halide dissociation as well as formation of the agostic intermediate is substantially favoured with C4-bound carbenes. It is these processes that discriminate the C4- and C2-bound systems rather than the subsequent C-H bond activation, where the computed barriers are very similar in each case. The tridentate dicarbene ligand undergoes selective H/D exchange at the C5 position of the C4-bound carbene exclusively. A mechanism has been proposed for this process, which is based on the electronic separation of the abnormal carbene ligand into a cationic N-C-N amidinium unit and a metalla-allyl type M-C-C fragment.