Aromatic dioxygenases: Molecular biocatalysis and applications

Aromatic dioxygenases have been found to catalyse single and tandem oxidation reactions of conjugated polyenes. Rational selection and design of dioxygenases, allied to substrate shape, size and substitution pattern, has been used to control regiochemistry and stereochemistry during the oxygenation process. The resulting enantiopure bioproducts have been increasingly utilised as precursors for new and alternative routes in chiral synthesis.

Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice

Background and purpose: Galegine and guanidine, originally isolated from Galega officinalis, led to the development of the biguanides. The weight-reducing effects of galegine have not previously been studied and the present investigation was undertaken to determine its mechanism(s) of action.

Experimental approach: Body weight and food intake were examined in mice. Glucose uptake and acetyl-CoA carboxylase activity were studied in 3T3-L1 adipocytes and L6 myotubes and AMP activated protein kinase (AMPK) activity was examined in cell lines. The gene expression of some enzymes involved in fat metabolism was examined in 3T3-L1 adipocytes.

Key results: Galegine administered in the diet reduced body weight in mice. Pair-feeding indicated that at least part of this effect was independent of reduced food intake. In 3T3-L1 adipocytes and L6 myotubes, galegine (50 µm-3 mm) stimulated glucose uptake. Galegine (1–300 µm) also reduced isoprenaline-mediated lipolysis in 3T3-L1 adipocytes and inhibited acetyl-CoA carboxylase activity in 3T3-L1 adipocytes and L6 myotubes. Galegine (500 µm) down-regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 µm and above) produced a concentration-dependent activation of AMP activated protein kinase (AMPK) in H4IIE rat hepatoma, HEK293 human kidney cells, 3T3-L1 adipocytes and L6 myotubes.

Conclusions and implications: Activation of AMPK can explain many of the effects of galegine, including enhanced glucose uptake and inhibition of acetyl-CoA carboxylase. Inhibition of acetyl-CoA carboxylase both inhibits fatty acid synthesis and stimulates fatty acid oxidation, and this may to contribute to the in vivo effect of galegine on body weight.

Patient removals from general practitioner lists in Northern Ireland:1987-1996

Being struck off a general practitioner's list is a major event for patients and a subject for much media attention. However, it has not hitherto received much research attention.

CNV analysis in a large schizophrenia sample implicates deletions at 16p12.1 and SLC1A1 and duplications at 1p36.33 and CGNL1

Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analysed 6,882 cases and 11,255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in an additional 14,568 cases and 15,274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P500kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.

Multidimensional rehabilitation programmes for adult cancer survivors

Background: Multidimensional rehabilitation programmes (MDRPs) have developed in response to the growing number of people living with and surviving cancer. MDRPs comprise a physical component and a psychosocial component. Studies of the effectiveness of these programmes have not been reviewed and synthesised.

Objectives: To conduct a systematic review of studies examining the effectiveness of MDRPs in terms of maintaining or improving the physical and psychosocial well-being of adult cancer survivors.

Search methods: We conducted electronic searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsychINFO up to February 2012.

Selection criteria: Selection criteria focused on randomised controlled trials (RCTs) of multidimensional interventions for adult cancer survivors. Interventions had to include a physical component and a psychosocial component and to have been carried out on two or more occasions following completion of primary cancer treatment. Outcomes had to be assessed using validated measures of physical health and psychosocial well-being. Non-English language papers were included.

Data collection and analysis: Pairs of review authors independently selected trials, rated their methodological quality and extracted relevant data. Although meta-analyses of primary and secondary endpoints were planned there was a high level of study heterogeneity and only one common outcome measure (SF-36) could be statistically synthesised. In addition, we conducted a narrative analysis of interventions, particularly in terms of inspecting and identifying intervention components, grouping or categorising interventions and examining potential common links and outcomes.

Main results: Twelve RCTs (comprising 1669 participants) met the eligibility criteria. We judged five studies to have a moderate risk of bias and assessed the remaining seven as having a high risk of bias. It was possible to include SF-36 physical health component scores from five studies in a meta-analysis. Participating in a MDRP was associated with an increase in SF-36 physical health component scores (mean difference (MD) 2.22, 95% confidence interval (CI) 0.12 to 4.31, P = 0.04). The findings from the narrative analysis suggested that MDRPs with a single domain or outcome focus appeared to be more successful than programmes with multiple aims. In addition, programmes that comprised participants with different types of cancer compared to cancer site-specific programmes were more likely to show positive improvements in physical outcomes. The most effective mode of service delivery appeared to be face-to-face contact supplemented with at least one follow-up telephone call. There was no evidence to indicate that MDRPs which lasted longer than six months improved outcomes beyond the level attained at six months. In addition, there was no evidence to suggest that services were more effective if they were delivered by a particular type of health professional.

Authors' conclusions: There is some evidence to support the effectiveness of brief, focused MDRPs for cancer survivors. Rigorous and methodologically sound clinical trials that include an economic analysis are required.

L'Écho de Paris

1888/10/17 (Numéro 1669).

Recueil des règlements, tarifs et instructions concernant les droits réservés par édits des mois d'août 1716, janvier et novembre 1717... par Monsieur Le M***, directeur général

[Acte royal. 1669-1722]

Mémoire relatif au projet de l'ouverture d'une nouvelle porte dans la face gauche du bastion de Champmars pour communiquer dans l'enceinte du grand Champmars

Ancien possesseur : Argenson, Antoine-René de Voyer (1722-1787 ; marquis de Paulmy d')

Notulae biographicae præpositorum generalium carmelitarum discalceatorum congregationis italicae, 1600-1787.

Ce ms. constitue la mise au net du ms. B. n. F., lat. 17652 qui a servi de brouillon. F. 1 Titre : «Series chronologica præpositorum generalium carmelitarum discalceatorum congregationis italicae, cum singulorum effigie ad vivum nitidissime æri incisa [ce dernier membre de phrase est cancellé], necnon elogio manuscripto». F. 3-14v Notice biographique de chacun des préposés généraux des Carmes déchaux de la congrégation d'Italie de 1600 à 1787; chaque nom est précédé d'un ou plusieurs chiffres romains donnant le numéro d'ordre du préposé. Pour les derniers, seul figure le nom et le numéro d'ordre. Chaque page est divisée en deux cadres, et chaque notice en occupe un, rarement deux. «I. IV. IX. Ferdinandus a Sancta Maria. In saeculo dictus Ferdinandus Martinez...-... LIII. Hilarion ab Omnibus Sanctis» (14v); cf. A. Fortes, Acta capituli generalis O. C. D. congregationis s. Eliae, 3 vol., Rome, 1990-1992 (Monumenta historica Carmeli Teresiani 11, 13-14). À noter, parmi les références bibliographiques, celles qui concernent directement les Carmes déchaux : elles sont données ci-dessous sous une forme normalisée (entre parenthèses le feuillet où figure la première occurrence), alors que l'auteur donne en général le titre et le nom de l'auteur, sous une forme latinisée approximative, avec parfois le lieu et la date d'impression : Juan Caramuel Lobkowitz, Caramuelis Dominicus..., Vienne, 1655 (3v); Jean Chardin, Voyages de Monsieur le chevalier Chardin en Perse, Paris, 1723 (4v); Daniel a Virgine Maria, Speculum carmelitanum, Anvers, 1680 (3); Eusebius ab Omnibus Sanctis, Enchyridion chronologicum carmelitarum discalceatorum congregationis Italiae, Rome, 1737 (4), cet ouvrage est le plus fréquemment cité, on en trouve un exemplaire à la Vaticane et un microfilm à la Library of Congress; Francisco de Santa Maria, Historia general profetica de la orden de Nuestra Señora del Carmen, Madrid, 1630 (3); Franciscus Joseph a Sancta Margarita, Necrologium præpositorum generalium, non identifié (5); Isidore de Saint-Joseph, Historia reformationis s. Theresiae, non identifié (4v); Isidore de Saint-Joseph et Pierre de Saint-André, Historia generalis Fratrum discalceatorum ordinis B. M. V. de Monte Carmelo congregationis s. Eliae, Rome, 1668-1671 (4v); Louis Jacob, Bibliotheca carmelitana manuscripta, non identifié (5v); Juan de Jesus Maria, Historia missionum; Vita Petri a Matre Dei (3), ces deux ouvrages n'ont pu être identifiés, ils ne figurent pas dans les Opera omnia publiées à Cologne en 1622; Aubert Le Mire, Bibliotheca ecclesiastica, 2e partie, Anvers, 1649 (3v); Louis de Sainte-Thérèse, Annales carmelitarum excalceatorum Galliae (4v), non identifié; Martial de Saint-Jean-Baptiste, Bibliotheca scriptorum utriusque congregationis et sexus carmelitarum discalceatorum, Bordeaux, 1730 (3); Paulus ab Omnibus Sanctis, Clavis aurea thesauri partheno-carmelitici..., Vienne, 1669, si ce titre correspond au «Catalogus scriptorum» du f. 3; Philippe de la Très Sainte Trinité, Decus carmelitanum, ouvrage non identifié (4v); Id., Historia carmelitani ordinis..., Lyon, 1656 (3); Id., Itinerarium orientale R.P.F. Philippi a SS. Trinitate, Lyon, 1649 (4v); Id., La Vie du vénérable père Dominique de Jésus Maria..., Lyon, 1669 (5); le P.Théophile Raynaud, Scapulare partheno-carmeliticum, Paris, 1654 (3v); [Cosme de Villiers de Saint-Étienne] «editor anonymus», Bibliotheca carmelitana, Orléans, 1752 (5).