Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARgamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARgamma(1/)- and RXRalpha(1/)- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARgamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARgamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARgamma and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.

Chemical and carbon isotopic evolution of hydrocarbons during prograde metamorphism from 100°C to 550°C: Case study in the Liassic black shale formation of Central Swiss Alps

Hydrocarbon distributions and stable isotope ratios of carbonates (delta(13)C(car), delta(18)O(car)), kerogen (delta(13)C(ker)), extractable organic matter (delta(13)C(EOM)) and individual hydrocarbons of Liassic black shale samples from a prograde metamorphic sequence in the Swiss Alps were used to identify the major organic reactions with increasing metamorphic grade. The studied samples range from the diagenetic zone (< 100 degrees C) to amphibolite facies (similar to 550 degrees C). The samples within the diagenetic zones (< 100 and 150 degrees C) are characterized by the dominance of C-< 20 n-alkanes, suggesting an origin related with marine and/or bacterial inputs. The metamorphic samples (200 to 550 degrees C) have distributions significantly dominated by C-12 and C-13 n-alkanes, C-14, C-16 and C-18 n-alkylcyclopentanes and to a lesser extend C-15, C-17 and C-21 n-alkylcyclohexanes. The progressive C-13-enrichment (up to 3.9 parts per thousand) with metamorphism of the C-> 17 n-alkanes suggests the occurrence of cracking reactions of high molecular weight compounds. The isotopically heavier (up to 5.6 parts per thousand) C-< 17 n-alkanes in metamorphic samples are likely originated by thermal degradation of long-chain homologous with preferential release of isotopically light C-1 and C-2 radicals. The dominance of specific even C-number n-alkylcyclopentanes suggests an origin related to direct cyclization mechanism (without decarboxylation step) of algal or bacterial fatty acids occurring in reducing aqueous metamorphic fluid conditions. The regular increase of the concentrations of n-alkylcycloalkanes vs. C-> 13 n-alkanes with metamorphism suggests progressive thermal release of kerogen-linked fatty acid precursors and degradation of n-alkanes. Changes of the steroid and terpenoid distributions are clearly related to increasing metamorphic temperatures. The absence of 18 alpha(H)-22,29,30-trisnorneohopane (Ts), the occurrence of 17 beta(H)-trisnorhopane, 17 beta(H), 21 alpha(H)-hopanes in the C-29 to C-31 range and 5 alpha(H),14 alpha(H),17 alpha(H)-20R C-27, C-29 steranes in the low diagenetic samples (< 100 degrees C) are characteristic of immature bitumens. The higher thermal stress within the upper diagenetic zone (150 degrees C) is marked by the presence of Ts, the disappearance of 17 beta(H)-trisnorhopane and thermodynamic equilibrium of the 22S/(22S + 22R) homohopane ratios. The increase of the alpha alpha alpha-sterane 20S/(20S + 20R) and 20R beta beta/(beta beta + alpha alpha) ratios (from 0.0 to 0.55 and from 0.0 to 0.40, respectively) in the upper diagenetic zone indicates the occurrence of isomerization reactions already at < 150 degrees C. However, the isomerization at C-20 (R -> S) reaches thermodynamic equilibrium values already at the upper diagenesis (similar to 150 degrees C) whereas the epimerisation at C-14 and C-17 (alpha alpha ->beta beta) arrives to constant values in the lower anchizone (similar to 200 degrees C). The ratios Ts vs. 17 alpha(H)-22,29,30-trisnorneohopane [(Ts/(Ts + Tm)] and 18 alpha(H)-30-norneohopane (C29Ts) vs. 17 alpha(H),21 beta(H)-30-norhopane [C29Ts/(C29Ts + C-29)] increase until the medium anchizone (200 to 250 degrees C) from 0.0 to 0.96 and from 0.0 to 0.44, respectively. An opposite trend owards lower values is observed in the higher metamorphic samples. The occurrence of specific hydrocarbons (e.g., n-alkylcyclopentanes, cadalene, hydrogenated aromatic compounds) in metamorphic samples points to kerogen degradation reactions most probably occurring in the presence of water and under reducing conditions. The changes of hydrocarbon distributions and carbon isotopic compositions of n-alkanes related to metamorphism suggest that the organic geochemistry may help to evaluate the lowest grades of prograde metamorphism. Copyright (c) 2005 Elsevier Ltd.

Cytotoxic effects of combination of oxidosqualene cyclase inhibitors with atorvastatin in human cancer cells.

Ten oxidosqualene cyclase inhibitors with high efficacy as cholesterol-lowering agents and of different chemical structure classes were evaluated as potential anticancer agents against human cancer cells from various tissue origins and nontumoral human-brain-derived endothelial cells. Inhibition of cancer cell growth was demonstrated at micromolar concentrations, comparable to the concentrations of statins necessary for antitumor effect. Human glioblastoma cells were among the most sensitive cells. These compounds were also able to decrease the proliferation of angiogenic brain-derived endothelial cells, as a model of tumor-induced neovasculation. Additive effects in human glioblastoma cells were also demonstrated for oxidosqualene cyclase inhibitors in combination with atorvastatin while maintaining selectivity against endothelial cells. Thus, not only statins targeting the 3-hydroxy-3-methylglutaryl coenzyme A reductase but also inhibitors of oxidosqualene cyclase decrease tumor growth, suggesting new therapeutic opportunities of combined anti-cholesterol agents for dual treatment of glioblastoma.

Biological monitoring of exposure to solvents using the chemical itself in urine: application to toluene

Objective Biomonitoring of solvents using the unchanged substance in urine as exposure indicator is still relatively scarce due to some discrepancies between the results reported in the literature. Based on the assessment of toluene exposure, the aim of this work was to evaluate the effects of some steps likely to bias the results and to measure urinary toluene both in volunteers experimentally exposed and in workers of rotogravure factories. Methods Static headspace was used for toluene analysis. o-Cresol was also measured for comparison. Urine collection, storage and conservation conditions were studied to evaluate possible loss or contamination of toluene in controlled situations applied to six volunteers in an exposure chamber according to four scenarios with exposure at stable levels from 10 to 50 ppm. Kinetics of elimination of toluene were determined over 24 h. A field study was then carried out in a total of 29 workers from two rotogravure printing facilities. Results Potential contamination during urine collection in the field is confirmed to be a real problem but technical precautions for sampling, storage and analysis can be easily followed to control the situation. In the volunteers at rest, urinary toluene showed a rapid increase after 2 h with a steady level after about 3 h. At 47.1 ppm the mean cumulated excretion was about 0.005% of the amount of the toluene ventilated. Correlation between the toluene levels in air and in end of exposure urinary sample was excellent (r = 0.965). In the field study, the median personal exposure to toluene was 32 ppm (range 3.6-148). According to the correlations between environmental and biological monitoring data, the post-shift urinary toluene (r = 0.921) and o-cresol (r = 0.873) concentrations were, respectively, 75.6 mu g/l and 0.76 mg/g creatinine for 50 ppm toluene personal exposure. The corresponding urinary toluene concentration before the next shift was 11 mu g/l (r = 0.883). Conclusion Urinary toluene was shown once more time a very interesting surrogate to o-cresol and could be recommended as a biomarker of choice for solvent exposure. [Authors]

Effect of moderate hyperventilation and induced hypertension on cerebral tissue oxygenation after cardiac arrest and therapeutic hypothermia.

AIM: Improving cerebral perfusion is an essential component of post-resuscitation care after cardiac arrest (CA), however precise recommendations in this setting are limited. We aimed to examine the effect of moderate hyperventilation (HV) and induced hypertension (IH) on non-invasive cerebral tissue oxygenation (SctO2) in patients with coma after CA monitored with near-infrared spectroscopy (NIRS) during therapeutic hypothermia (TH). METHODS: Prospective pilot study including comatose patients successfully resuscitated from out-of-hospital CA treated with TH, monitored with NIRS. Dynamic changes of SctO2 upon HV and IH were analyzed during the stable TH maintenance phase. HV was induced by decreasing PaCO2 from ∼40 to ∼30 mmHg, at stable mean arterial blood pressure (MAP∼70 mmHg). IH was obtained by increasing MAP from ∼70 to ∼90 mmHg with noradrenaline. RESULTS: Ten patients (mean age 69 years; mean time to ROSC 19 min) were studied. Following HV, a significant reduction of SctO2 was observed (baseline 74.7±4.3% vs. 69.0±4.2% at the end of HV test, p<0.001, paired t-test). In contrast, IH was not associated with changes in SctO2 (baseline 73.6±3.5% vs. 74.1±3.8% at the end of IH test, p=0.24). CONCLUSIONS: Moderate hyperventilation was associated with a significant reduction in SctO2, while increasing MAP to supra-normal levels with vasopressors had no effect on cerebral tissue oxygenation. Our study suggests that maintenance of strictly normal PaCO2 levels and MAP targets of 70mmHg may provide optimal cerebral perfusion during TH in comatose CA patients.

Drug monographs on drugs which are frequently analysed in the context of Therapeutic Drug Monitoring = Arzneimittel-Monographien für Medikamente, die regelmässig im Rahmen des Therapeutic Drug Monitorings analysiert werden

In addition to the monographs which were published last year by the working group "Drug Monitoring" of the Swiss Society of Clinical Chemistry (SSCC) [1], new monographs have been written. The aim of these monographs is to give an overview of the most important information necessary for ordering a drug analysis or interpreting the results. Therefore, the targeted readers comprise laboratory health professionals and all receivers of laboratory reports. There is information provided on the indication for therapeutic drug monitoring, protein binding, metabolic pathways and enzymes involved, elimination half-life and elimination routes, and on therapeutic or toxic concentrations. Preanalytical considerations are of particular importance for therapeutic drug monitoring. Therefore, information is provided regarding a reasonable timing for the determination of drug concentrations as well as steady-state concentrations after changing the dose. Furthermore, the stability of the drug and its metabolite(s) after blood sampling is described. For readers with a specific interest in drug analysis, references to important publications are given. The number of monographs will be continuously enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch).

Application de la modélisation moléculaire à de nouvelles approches thérapeutiques du cancer [Application of molecular modeling to new therapeutic cancer approaches].

Recent progress in the experimental determination of protein structures allow to understand, at a very detailed level, the molecular recognition mechanisms that are at the basis of the living matter. This level of understanding makes it possible to design rational therapeutic approaches, in which effectors molecules are adapted or created de novo to perform a given function. An example of such an approach is drug design, were small inhibitory molecules are designed using in silico simulations and tested in vitro. In this article, we present a similar approach to rationally optimize the sequence of killer T lymphocytes receptors to make them more efficient against melanoma cells. The architecture of this translational research project is presented together with its implications both at the level of basic research as well as in the clinics.

Assessment of Therapeutic Response of Plasmodium vivax and Plasmodium falciparum to Chloroquine in a Malaria Transmission Free Area in Colombia

In order to determine the frequency of therapeutic failures to chloroquine (CQ) in patients with malaria due to either Plasmodium falciparum or P. vivax, and to explore the usefulness of a malaria-free city as a sentinel site to monitor the emergence of drug resistance, 53 patients (44 infected with P. vivax and 9 with P. falciparum) were evaluated at the Laboratory of Parasitology, Universidad del Valle in Cali, Colombia. Patients received 25 mg/kg of CQ divided in three doses over 48 h; they were followed during 28 days according to WHO/PAHO protocols. While therapeutic failures to CQ in the P. vivax group were not detected, the proportion of therapeutic failures in the P. falciparum group was high (78%) and consistent with the reports from endemic areas in Colombia. The diverse origin of cases presenting therapeutic failure confirmed that P. falciparum resistant to CQ is widespread in Colombia, and further supports the change in the national antimalarial drug scheme. Monitoring of drug resistance in malaria free areas would be useful to identify sites requiring efficacy evaluation, and in some situations could be the most appropriate alternative to collect information from endemic areas where therapeutic efficacy studies are not feasible.

Analysis of functional and anatomical success following endonasal dacryocystorhinostomy

RésuméLes sténoses des voies lacrymales sont fréquentes surtout chez les patients âgés et provoquent en général un epiphora avec parfois des dacryocystites aiguës ou chroniques. La dacryocystorhinostomie par voie externe (DCREX) a été la technique de choix pour traiter les sténoses post-canaliculaires au XXe siècle. Avec l'avènement de l'endoscopie nasale, l'abord endonasal est devenu facilement accessible et depuis une dizaine d'années, la dacryocystorhinostomie par voie endonasale (DCREN) est en train de supplanter la DCREX dans la majorité des cas.Le but de ce travail est de déterminer les étiologies des sténoses des voies lacrimales, d'évaluer le taux de succès et les complications de la DCREN et de détailler les gestes associés peropératoires.Cette étude rétrospective porte sur 98 patients ayant subi 104 DCREN entre janvier 1994 et février 2006. 78 patients (53 femmes et 25 hommes) présentant 84 sténoses post- canaliculaires remplissent les critères d'inclusion de l'étude. L'âge moyen est de 59 ans (4 - 89 ans).Les résultats obtenus montrent un taux de succès fonctionnel de 94.9% après une première intervention (59/84 DCREN) et de 63.6% pour les DCREN secondaires qui nous ont été référées après d'autres interventions des voies lacrymales (25/84 DCREN). Le suivi postopératoire est de 36,8 mois (12-77 mois). On dénombre 61 gestes rhino-sinusaux associés à la DCREN. Les complications per- et postopératoires sont rares, essentiellement liées aux drains bicanaliculaires. Une étiologie n'a été retrouvée que dans 28% des cas.En conclusion, la DCREN donne d'excellents résultats et peu de complications. En raison des nombreux avantages par rapport à la voie externe et la possibilité du traitement simultané de la pathologie ORL parfois associée, la DCREN est devenue le traitement de premier choix pour les sténoses postcanaliculaires. Le principal défi, quelque soit le type de DCR, est de poser la bonne indication opératoire et en cas d'échec opératoire savoir méticuleusement analyser ses causes

Descriptive epidemiology of skin cancer in the Swiss Canton of Vaud.

Incidence registration and survival data for non-melanocytic skin neoplasms and cutaneous melanoma have been abstracted from the population-based system of the Cancer Registry of the Swiss Canton of Vaud, which has been operating in a particularly favourable environment, since the large majority of cutaneous lesions resected in the area are examined by a pathologist. Among the 5,712 cases registered, 66.7% were basal-cell carcinomas, 20.6% squamous-cell cancers, 9.3% cutaneous melanomas and 3.4% other miscellaneous histological types. The distribution by histological type did not differ appreciably in the 2 sexes, but there were marked inter-sex differences as regards anatomical site. In both sexes, head and neck was by far the commonest localization for non-melanomatous neoplasms (69 to 81% of all incident cases), followed by trunk for basal-cell cancers (18% in males, 15% in females) and upper limb for squamous-cell (10% in males, 17% in females). The distribution of skin melanomas differed considerably between the 2 sexes, by far the commonest site being the trunk for males (45% of cases) and lower limbs for females (40%), followed by head and neck (22% in both sexes). Incidence rates for both basal- and squamous-cell cancers increased with age, and rates were higher in males for each localization except the lower limb. In contrast, incidence for melanoma was higher in females, and incidence rates did not increase with age above 55 years for all sites except head and neck. This can be interpreted in terms of cohort effect, since mortality from melanoma has substantially increased in Switzerland across subsequent birth cohorts. Although this study is essentially descriptive, accurate inspection of these data provides some support for the major aetiological hypotheses of skin carcinogenesis, i.e., the observation that the large majority of basal- and squamous-cell cancers arise on the head and neck confirms the importance of long-term ultraviolet exposure; the relative excess of squamous-cell as compared to basal-cell neoplasms on the upper limb may suggest the role of exposure to other (chemical) carcinogens; and the proportional excess of melanomas on the trunk in males and lower limb in females further indicates that intermittent exposure to sunlight is probably the relevant aetiologic factor for melanocytic skin neoplasms.