Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment.

BACKGROUND AND OBJECTIVE: Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment. METHODS: We included 209 patients in methadone maintenance treatment on the basis of their response to treatment and their daily methadone dose. Patients were genotyped for CYP2B6, CYP2C9, and CYP2C19. Steady-state trough and peak (R)-, (S)-, and (R,S)-plasma levels and peak-to-trough plasma level ratios were measured. RESULTS: CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng . kg/mL . mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004). CYP2C9 and CYP2C19 genotypes do not influence methadone plasma levels. Lower peak and trough plasma levels of methadone and higher peak-to-trough ratios were measured in patients considered as nonresponders [median (R,S)-methadone trough plasma levels of 183 and 249 ng . kg/mL . mg (P = .0004) and median peak-to-trough ratios of 1.82 and 1.58 for high-dose nonresponders and high-dose responders, respectively (P = .0003)]. CONCLUSION: Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study. Lower plasma levels of methadone in nonresponders, suggesting a higher clearance, and higher peak-to-trough ratios, suggesting a shorter elimination half-life, are in agreement with the usual clinical measures taken for such patients, which are to increase methadone dosages and to split the daily dose into several intakes.

Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength.

A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone - and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. INTRODUCTION: The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. METHODS: Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. RESULTS: As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. CONCLUSIONS: This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.

Changing molecular epidemiology of methicillin-resistant Staphylococcus aureus in an Algerian hospital.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of both hospital- and community-acquired infections worldwide. However, data about the molecular epidemiology of MRSA in North Africa are still scarce. METHODOLOGY: All MRSA isolates recovered between January 2006 and July 2011 from one Algerian hospital were genetically and phenotypically characterized. RESULTS: The predominance of a European community-associated-MRSA (CA-MRSA) clone (ST80-SCCmec IV-PVL positive) was revealed by this analysis. CONCLUSION: Our data suggest that a CA-MRSA clone recently invaded the hospital setting in Algiers and replaced a typical hospital-associated pandemic clone such as the Brazilian clone (ST239-SCCmec IIImercury-PVL negative).

The T309G Murine Double Minute 2 Gene Polymorphism Is an Independent Prognostic Factor for Patients with Renal Cell Carcinoma.

The purpose of this study was to evaluate the association of the T309G MDM2 gene polymorphism with renal cell carcinoma (RCC) risk, pathology, and cancer-specific survival (CSS). T309G MDM2 was genotyped in 449 Caucasians, including 240 with RCC and 209 cancer-free controls. The T309G MDM2 genotype was TT in 174 (38.8%), GT in 214 (47.7%), and GG in 61 (13.6%) subjects, without any significant differences between cases and controls on both univariable (p=0.58) and multivariable logistic regression (each p>0.25). Furthermore, T309G MDM2 was not linked with T stage (p=0.75), N stage (p=0.37), M stage (p=0.94), grade (p=0.21), and subtype (p=0.55). There was, however, a statistically significant association of T309G MDM2 with CSS (p=0.022): patients with TT had significantly worse survival than GG/GT (p=0.009), while those with GT and GG had similar outcomes (p=0.92). The 5-year survival rate for patients with TT, GT, and GG was 69.5%, 84.5%, and 89.7%, respectively. On the multivariable analysis, T309G was identified as an independent prognostic factor. The T309G MDM2 polymorphism is an independent prognostic factor for patients with RCC, with the TT genotype being associated with worse prognosis. In this study, there were no significant associations with RCC risk and pathology.

Melt/peridotite interaction in the Southern Lanzo peridotite: Field, textural and geochemical evidence

This paper presents field, petrographic-structural and geochemical data on spinet and plagioclase peridotites from the southern domain of the Lanzo ophiolitic peridotite massif (Western Alps). Spinet lherzolites, harzburgites and dunites crop out at Mt. Arpone and Mt. Musine. Field evidence indicates that pristine porphyroclastic spinet lherzolites are transformed to coarse granular spinet harzburgites, which are in turn overprinted by plagioclase peridotites, while strongly depleted spinet harzburgite and dunite bands and bodies replace the plagioclase peridotites. On the northern flank of Mt. Arpone, deformed, porphyroclastic (lithospheric) lherzolites, with diffuse pyroxenite banding, represent the oldest spinel-facies rocks. They show microstructures of a composite subsolidus evolution, suggesting provenance from deeper (asthenospheric) mantle levels and accretion to the lithosphere. These protoliths are locally transformed to coarse granular (reactive) spinet harzburgites and dunites, which show textures reminiscent of melt/rock reaction and geochemical characteristics suggesting that they are products of peridotite interaction with reactively percolating melts. Geochemical data and modelling suggest that <1-5% fractional melting of spinel-facies DMM produced the injected melts. Plagioclase peridotites are hybrid rocks resulting from pre-existing spinet peridotites and variable enrichment of plagioclase and micro-gabbroic material by percolating melts. The impregnating melts attained silica-saturation, as testified by widespread orthopyroxene replacement of olivine, during open system migration in the lithosphere. At Mt. Musine, coarse granular spinet harzburgite and dunite bodies replace the plagioclase peridotites. Most of these replacive, refractory peridotites have interstitial magmatic clinopyroxene with trace element compositions in equilibrium with MORB, while some Cpx have REE-depleted patterns suggesting transient geochemical features of the migrating MORB-type melts, acquired by interaction with the ambient plagioclase peridotite. These replacive spinet harzburgite and dunite bodies are interpreted as channels exploited for focused and reactive migration of silica-undersaturated melts with aggregate MORB compositions. Such melts were unrelated to the silica-saturated melts that refertilized the pre-existing plagioclase peridotites. Finally, MORB melt migration occurred along open fractures, now recorded as gabbroic dikes. Our data document the complexity of rock-types and mantle processes in the South Lanzo peridotite massif and describe a composite tectonic and magmatic scenario that is not consistent with the ``asthenospheric scenario'' proposed by previous authors. We envisage a ``transitional scenario'' in which extending subcontinental lithospheric mantle was strongly modified (both depleted and refertilized) by early melts with MORB-affinity formed by decompression partial melting of the upwelling asthenosphere, during pre-oceanic rifting and lithospheric thinning in the Ligurian Tethys realm. (C) 2006 Elsevier B.V. All rights reserved.

Low seroprevalence of hepatitis E virus among blood donors in Switzerland

Introduction: Hepatitis E virus (HEV) emerged as an autochthonous food-borne disease in developed countries, transmitted mainly through pork meat. Cases of transmission through blood transfusion have been reported. Recent studies revealed sero-prevalence rates of 13.5%, 16.6% and 20.6% among blood donors in England, France and Denmark, respectively. The aim of this study was to determine the sero-prevalence of HEV among Swiss blood donors. Method: We screened 550 consecutive blood donations from the Service Régional Vaudois de Transfusion Sanguine of Epalinges, for the presence of anti-HEV IgG (MP Diagnostics HEV ELISA). The sample size was based on the Lorentz formula considering an expected prevalence of 3% with a precision of 1.5%. For each donor, we studied the following variables: age, sex and alanine aminotransferase (ALT) value. Results: All blood donors were Caucasian, and included 332 men (60.4%) and 218 women (39.6%). The median age was 55 years (IQR 46-63 years). Overall, anti-HEV IgG were found in 27 of 550 samples (4.9%). The sero-prevalence was 5.4% (18/314) in men and 4.1% (9/209) in women. The presence of anti-HEV IgG was not correlated to age, gender or ALT values. Conclusion: Compared to other European countries, the HEV sero-prevalence among blood donors in Switzerland is surprisingly low. Possible explanations include the strict regulation of animals and meat import. However, to confirm this hypothesis, further studies assessing the prevalence of HEV in Swiss swine will be necessary.

La formation des psychologues conseillères et conseillers en orientation en Suisse

Il existe quatre filières de formation pour les psychologues conseillères et conseillers en orientation scolaire et professionnelle en Suisse. Une d'entre elles est de niveau universitaire et les trois autres sont de niveau post-grade (deuxième ou troisième cycle). Une des filières post-grade est proposée par une Université de sciences appliquées. Tout en étant spécifiques aux régions linguistiques, ces formations rendent compte d'un profil de compétences défini au niveau national. Le modèle théorique qui fonde généralement ces formations est éclectique. L'apprentissage social et la problématique de l'ajustement au contexte sont également des aspects qui constituent cette approche intégrative.

Awakening dormant haematopoietic stem cells.

Haematopoietic stem cells (HSCs) in mouse bone marrow are located in specialized niches as single cells. During homeostasis, signals from this environment keep some HSCs dormant, which preserves long-term self-renewal potential, while other HSCs actively self renew to maintain haematopoiesis. In response to haematopoietic stress, dormant HSCs become activated and rapidly replenish the haematopoietic system. Interestingly, three factors - granulocyte colony-stimulating factor, interferon-alpha and arsenic trioxide - have been shown to efficiently activate dormant stem cells and thereby could break their resistance to anti-proliferative chemotherapeutics. Thus, we propose that two-step strategies could target resistant leukaemic stem cells by priming tumours with activators of dormancy followed by chemotherapy or targeted therapies.

Overlapping Pathways to Transplant Glomerulopathy: Chronic Humoral Rejection, Hepatitis C Infection and Thrombotic Microangiopathy

Background:Transplant glomerulopathy (TG) has received much attention in recent years as a manifestation of chronic humoral rejection (CHR). However, many cases lack C4d deposition and/or circulating donor-specifi c antibodies, and the contribution of other potential causes has not been fully addressed.Methods: Of 209 consecutive renal allograft indication biopsies performed for chronic allograft dysfunction, 25 that met pathologic criteria of TG (>10% duplication of the GBM without immune complex deposition) were examined for various etiologies, including hepatitis C infection (HCV), thrombotic microangiopathy (TMA), and CHR. 29 cases of biopsy-proven isolated chronic calcineurin inhibitor toxicity from the same time period were used as controls for comparing the prevalence of HCV.Results: Three partially overlapping categories accounted for 84% of the cases: C4d+TG (48%), HCV+TG (36%) and TMA+TG (32%). The majority of TMA+ cases were HCV+ (63%) and the majority of HCV+ cases had TMA (56%). Donor specifi c antibodies were associated with C4d+TG (7/8 vs. 1/4 C4d-TG; P<0.02), but not with HCV+TG. The prevalence of HCV was higher in the TG group than in 29 control patients without TG (36% vs. 7%, P<0.01). HCV+TG patients developed allograft failure earlier than HCV-TG patients (67.2 ± 60.2 mo versus 153.4 ± 126.2 mo, P=0.02). On a multivariate analysis, out of HCV, TG and C4d, only HCV was found to be a signifi cant risk factor for a more rapid allograft loss.Conclusion: We conclude that TG is not a specifi c diagnosis, but a pattern of pathologic injury with 3 major overlapping pathways involving CHR, HCV infection and TMA. It is important to distinguish these mechanisms, as they may have differentprognostic and therapeutic implications.

Is screening for fetal anomalies reliable in HIV-infected pregnant women? A multicentre study.

OBJECTIVE: To assess the impact of HIV infection on the reliability of the first-trimester screening for Down syndrome, using free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A and fetal nuchal translucency, and of the second-trimester screening for neural tube defects, using alpha-fetoprotein. PATIENTS AND METHODS: Multicentre study comparing the multiples of the median of markers for Down syndrome and neural tube defect screening among 214 HIV-infected pregnant women and 856 HIV-negative controls undergoing a first-trimester Down syndrome screening test, and 209 HIV-positive women and 836 HIV-negative controls with a risk evaluation for neural tube defect. The influence of treatment, chronic hepatitis and HIV disease characteristics were also evaluated. RESULTS: Multiples of the median medians for pregnancy-associated plasma protein-A and beta-human chorionic gonadotrophin were lower in HIV-positive women than controls (0.88 vs. 1.05 and 0.84 vs. 1.09, respectively; P < 0.005), but these differences had no impact on risk estimation; no differences were observed for the other markers. No association was found between HIV disease characteristics, antiretroviral treatment use at the time of screening or chronic hepatitis and marker levels. CONCLUSION: Screening for Down syndrome during the first trimester and for neural tube defect during the second trimester is accurate for HIV-infected women and should be offered, similar to HIV-negative women.

Ein unbekanntes Fragment der "Alexandreis" Walters von Châtillon

Das im letzten Viertel des 12. Jahrhunderts entstandene Alexander-Epos Walters von Châtillon, schon im 13. Jahrhundert in den ,,status of a classic" (Colker) und überdies zum Schultext avanciert, gehört zu den am reichhaltigsten überlieferten Erzähltexten der lateinischen Literatur des Mittelalters. Der Beitrag kann ausser den in der Ausgabe Colkers (1987) nachgewiesenen 209 Textzeugen 15 weitere Handschriften und Fragmente belegen und zudem einen Neufund vorstellen: Im Archiv der Bürgergemeinde Frauenfeld, Schweiz, erhielt sich als einzelnes Doppelblatt ein glossiertes Fragment des Textes aus dem späten 13. oder frühen 14. Jahrhundert. Sein Layout verrät, dass es für die begleitende Kommentierung von vornherein angelegt war und vermutlich einem Schulbuch entstammt. Die erhaltenen Scholien scheinen dem ,,Standardkommentar" (Killermann) zur ,Alexandreis' nahezustehen, könnten aber auch Bezüge zum Kommentar des Geoffrey de Vitry aufweisen, der in einer mit seinem Namen auktorial verbundenen, aus Rheinau stammenden Handschrift erhalten ist. In vergleichsweise dichter räumlicher und zeitlicher Nähe zu diesem Textzeugen entstand die Handschrift, aus der das neue Frauenfelder Fragment stammt: Die Untersuchung der Akte, als deren Schutzumschlag das Doppelblatt aus der ,Alexandreis' diente, zeigt, dass sie sich seit dem frühen 15. Jahrhundert im jetzigen Kontext, den Beständen des heutigen Archivs der Frauenfelder Bürgergemeinde, befunden hat, das auf eine seit dem 13. Jahrhundert geführte Sammlung zurückgeht. Da zudem in Frauenfeld eine Lateinschule seit dem 14. Jahrhundert nachweisbar und schon im 13. Jahrhundert zu vermuten ist, liegt es nahe, dass der Fundort des neuen Textzeugen auch der seiner Entstehung oder doch zumindest seiner Benutzung im Unterricht war. Das Fragment bietet einen trotz schlechter Abschrift (mit häufigen Korrekturen durch den Glossator) unverkennbar guten Text, in kritischer Hinsicht dabei nur geringen Gewinn. Seine textgeschichtliche Verortung kann angesichts der nach wie vor weitgehend unaufgearbeiteten Überlieferung der ,Alexandreis' nur in groben Zügen vorgenommen werden. - Mit einem durch einen kritischen Apparat erschlossenen diplomatischen Abdruck und zwei Abbildungen des neuen Fragments.

The fixation of metacentric chromosomes during the chromosomal evolution in the common shrew (Sorex araneus, Insectivora)

Rb fusions between acrocentric chromosomes leading to metacentrics tend to become fixed during the chromosomal evolution in the common shrew. Using microsatellite markers preliminary results show that populations are only slightly subdivided and genetic drift seems not to play an important role for the fixation of metacentrics. A significant segregation distortion in favour of metacentric chromosomes was found during male meiosis. This suggests that cytological factors such as facilitated fusion between acrocentric chromosomes or choice-effects at the level of gametes are more likely to play a role for the chromosomal evolution in the common shrew.

Medical and pharmacological direct costs of a 9-week smoking cessation programme.

Background: Medical and pharmacological direct costs of cigarette smoking cessation programmes are not covered by health insurance in several countries despite documented cost-effectiveness. Design: prospective cost identification study of a 9-week programme in Switzerland. Methods: A total of 481 smokers were followed-up for 9 weeks. Socio-demographic characteristics, number of outpatient visits, dosage and frequency of use of nicotine replacement therapy (NRT) as well as date of relapse were prospectively collected. Individual cost of care until relapse or programme end as well as cost per week of follow-up were computed. Comparisons were carried out between the groups with or without relapse at the end of the programme. Results: Of the 209 men and 272 women included, 347 patients (72%) finished the programme. Among them, 240 patients (70%) succeeded in quitting and 107 patients (30%) relapsed. As compared with the group relapsing by the end of the programme, the group succeeding in quitting was more often living in a couple (68% vs. 55%, p = 0.029). Their mean weekly costs of visits were higher (CHF 81.2 ± 6.1 vs. 78.4 ± 7.6, p = 0.001), while their mean weekly costs for NRT were similar (CHF 24.2 ± 12.6 vs. 25.4 ± 15.9, p = 0.711). Mean total costs per week were similar (CHF 105.4 ± 15.4 vs. 103.8 ± 19.4, p = 0.252). More intensive NRT at week 4 increased the probability not to relapse at the end of the programme. Conclusions: Over 9 weeks, medical and pharmacological costs of stopping smoking are low. Good medical and social support as well as adequate NRT seem to play a role in successful quitting.

Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer.

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205.