An ultra performance liquid chromatography-tandem MS assay for tamoxifen metabolites profiling in plasma: first evidence of 4'-hydroxylated metabolites in breast cancer patients.

There is increasing evidence that the clinical efficacy of tamoxifen, the first and most widely used targeted therapy for estrogen-sensitive breast cancer, depends on the formation of the active metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Large inter-individual variability in endoxifen plasma concentrations has been observed and related both to genetic and environmental (i.e. drug-induced) factors altering CYP450s metabolizing enzymes activity. In this context, we have developed an ultra performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) requiring 100 μL of plasma for the quantification of tamoxifen and three of its major metabolites in breast cancer patients. Plasma is purified by a combination of protein precipitation, evaporation at room temperature under nitrogen, and reconstitution in methanol/20 mM ammonium formate 1:1 (v/v), adjusted to pH 2.9 with formic acid. Reverse-phase chromatographic separation of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen is performed within 13 min using elution with a gradient of 10 mM ammonium formate and acetonitrile, both containing 0.1% formic acid. Analytes quantification, using matrix-matched calibration samples spiked with their respective deuterated internal standards, is performed by electrospray ionization-triple quadrupole mass spectrometry using selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of relative matrix effects variability, as well as tamoxifen and metabolites short-term stability in plasma and whole blood. The method is precise (inter-day CV%: 2.5-7.8%), accurate (-1.4 to +5.8%) and sensitive (lower limits of quantification comprised between 0.4 and 2.0 ng/mL). Application of this method to patients' samples has made possible the identification of two further metabolites, 4'-hydroxy-tamoxifen and 4'-hydroxy-N-desmethyl-tamoxifen, described for the first time in breast cancer patients. This UPLC-MS/MS assay is currently applied for monitoring plasma levels of tamoxifen and its metabolites in breast cancer patients within the frame of a clinical trial aiming to assess the impact of dose increase on tamoxifen and endoxifen exposure.

Multiple sclerosis-related trigeminal neuralgia: a prospective series of 43 patients treated with gamma knife surgery with more than one year of follow-up.

BACKGROUND: Trigeminal neuralgia (TN) related to multiple sclerosis (MS) is more difficult to manage pharmacologically and surgically. OBJECTIVE: This article aims to evaluate the safety and efficacy of Gamma Knife surgery (GKS) in this special group of patients. METHODS: Between July 1992 and November 2010, 43 cases with more than 1 year of follow-up were operated with GKS for TN related to MS and prospectively evaluated in the Timone University Hospital, Marseille, France. Radiosurgery using the Gamma Knife (model B or C or Perfexion) was performed. A single 4-mm isocenter was positioned at a median distance of 8 mm (range 5.7-14.7) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 75-90) was delivered. RESULTS: The median follow-up period was 53.8 months (12-157.1). Thirty-nine patients (90.7%) were initially pain free. Their actuarial probability of remaining pain free without medication at 6 months, 1, 3, 5 and 10 years was 87.2, 71.8, 43.1, 38.3 and 20.5%, respectively, and remained stable till 12 years. The hypoesthesia actuarial rate at 6 months, 1 and 2 years was 11.5, 11.5 and 16%, and remained stable till 12 years. CONCLUSIONS: GKS proved safe and effective in this special group of patients.

First description of reproductive behavior of the Amazonian damselfly Chalcopteryx rutilans (Rambur) (Odonata, Polythoridae)

Polythoridae comprise a widespread group of species in the New World tropics, but little is known about their behavior or life history. Here, we described the reproductive behavior of Amazonian Chalchopteryx rutilans, using mark-recapture techniques. Males were resident and territorial, though we found disputes (complex flight manoeuvres) to be rare. Trunks (rotting wood) were important to male persistence in sites, as these are the locations preferred by females for oviposition. The mating system of C. rutilans may be comparable to the resource limitation category, described by Conrad & Pritchard (1992), where males cannot control female access to oviposition sites. So, female choice becomes important and apparently, the observed displays (in which males flash the coppery coloration of their hind wings) may be related to attraction of females to territories, as in a lek system.

First record of species of Liogenys (Coleoptera, Melolonthidae) associated with winter grain crops in Rio Grande do Sul (Brazil)

First record of species of Liogenys (Coleoptera, Melolonthidae) associated with winter crops in Rio Grande do Sul (Brazil). Some species of Liogenys Guerín-Meneville, 1831 are known to cause damage to soybean, corn and other summer crops in the Brazilian "Cerrado" region. This work aimed to identify melolontid larvae associated with winter crops in Rio Grande do Sul state. Larvae and adults of Liogenys species were collected from the municipalities of Ijuí, Cruz Alta, Manoel Viana, São Luiz Gonzaga and São Francisco de Assis. The specimens were identified as L. bidenticeps Moser, 1919; L. fusca Blanchard, 1851, L. obesa Burmeister, 1855, and L. sinuaticeps Moser, 1918. This is the first record of these species associated with winter grain crops, for Rio Grande do Sul State. Biological and behavioral studies are necessary to confirm their association with host plants.

First record of larvae of Chironomidae (Insecta, Diptera) as prey of Temnocephala sp. (Platyhelminthes, Temnocephalidae), an ectosymbiont on larvae of Corydalidae (Megaloptera)

First record of larvae of Chironomidae (Insecta, Diptera) as prey of Temnocephala sp. (Platyhelminthes, Temnocephalidae), an ectosymbiont on larvae of Corydalidae (Megaloptera). This study constitutes the first record of Temnocephala Blanchard, an ectosymbiont on Corydalidae, as a possible predator of chironomid larvae. Twenty-eight Corydalidae larvae (Corydalus and Protochauliodes) were examined under stereomicroscopic in search for Temnocephala and Chironomidae larvae, of which five megalopteran larvae had 24 Temnocephala sp. associated. Furthermore, eight of these Temnocephala worms had chironomid larvae in their gut contents, an interaction previously unknown. Gut content analyses revealed Corynoneura as the commonest chironomid, but larvae of Larsia, Rheotanytarsus and Tanytarsus were recorded as well. This study included Corydalus and Protochauliodes as hosts for Temnocephala, which might be important for this worm dispersion and population dynamics.

Transaortic transcatheter aortic valve replacement with the Sapien? valve and the first generations of Ascendra?.

Traditionally, the transcatheter aortic valve replacement is performed through a transapical, a transfemoral or a trans-subclavian approach. Recently, the transaortic approach for transcatheter aortic valve replacement through the distal part of the ascending aorta was successfully implemented in order to avoid peripheral vascular access-related complications and apical life-threatening haemorrhage. The Sapien? stent valve has great transaortic potential because it can be loaded 'upside down' in different generations of delivery systems. However, because of their health regulatory systems and despite the launch, in 2012, of the latest generation of the Ascendra? delivery system, the Ascendra+?, specifically designed for transapical and transaortic valve placements, several countries are still using the first generations of Ascendra? (Ascendra? 1 and 2). This device was specifically designed for transapical procedures, and retrograde stent-valve positioning through the stenotic aortic valve may be very challenging and risk the integrity of the aorta. We describe the manoeuvre required in order to pass the stenotic aortic valve safely in a retrograde direction using the Sapien? stent valve and the first generations of Ascendra?.

Decreased Probability of Initial Pain Cessation in Classic Trigeminal Neuralgia Treated With Gamma Knife Surgery in Case of Previous Microvascular Decompression: A Prospective Series of 45 Patients With >1 Year of Follow-up.

BACKGROUND: Microvascular decompression (MVD) is the reference technique for pharmacoresistant trigeminal neuralgia (TN). OBJECTIVE: To establish whether the safety and efficacy of Gamma Knife surgery for recurrent TN are influenced by prior MVD. METHODS: Between July 1992 and November 2010, 54 of 737 patients (45 of 497 with >1 year of follow-up) had a history of MVD (approximately half also with previous ablative procedure) and were operated on with Gamma Knife surgery for TN in the Timone University Hospital. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.6 mm (range, 3.9-11.9 mm) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range, 70-90 Gy) was delivered. RESULTS: The median follow-up time was 39.5 months (range, 14.1-144.6 months). Thirty-five patients (77.8%) were initially pain free in a median time of 14 days (range, 0-180 days), much lower compared with our global population of classic TN (P = .01). Their actuarial probabilities of remaining pain-free without medication at 3, 5, 7, and 10 years were 66.5%, 59.1%, 59.1%, and 44.3%. The hypoesthesia actuarial rate at 1 year was 9.1% and remained stable until 12 years (median, 8 months). CONCLUSION: Patients with previous MVD showed a significantly lower probability of initial pain cessation compared with our global population with classic TN (P = .01). The toxicity was low (only 9.1% hypoesthesia); furthermore, no patient reported bothersome hypoesthesia. However, the probability of maintaining pain relief without medication was 44.3% at 10 years, similar to our global series of classic TN (P = .85). ABBREVIATIONS: BNI, Barrow Neurological InstituteCI, confidence intervalCTN, classic trigeminal neuralgiaGKS, Gamma Knife surgeryHR, hazard ratioMVD, microvascular decompressionTN, trigeminal neuralgia.

Case management for frequent users of the emergency department: study protocol of a randomised controlled trial.

BACKGROUND: We devised a randomised controlled trial to evaluate the effectiveness and efficiency of an intervention based on case management care for frequent emergency department users. The aim of the intervention is to reduce such patients' emergency department use, to improve their quality of life, and to reduce costs consequent on frequent use. The intervention consists of a combination of comprehensive case management care and standard emergency care. It uses a clinical case management model that is patient-identified, patient-directed, and developed to provide high intensity services. It provides a continuum of hospital- and community-based patient services, which include clinical assessment, outreach referral, and coordination and communication with other service providers. METHODS/DESIGN: We aim to recruit, during the first year of the study, 250 patients who visit the emergency department of the University Hospital of Lausanne, Switzerland. Eligible patients will have visited the emergency department 5 or more times during the previous 12 months. Randomisation of the participants to the intervention or control groups will be computer generated and concealed. The statistician and each patient will be blinded to the patient's allocation. Participants in the intervention group (N = 125), additionally to standard emergency care, will receive case management from a team, 1 (ambulatory care) to 3 (hospitalization) times during their stay and after 1, 3, and 5 months, at their residence, in the hospital or in the ambulatory care setting. In between the consultations provided, the patients will have the opportunity to contact, at any moment, the case management team. Participants in the control group (N = 125) will receive standard emergency care only. Data will be collected at baseline and 2, 5.5, 9, and 12 months later, including: number of emergency department visits, quality of life (EuroQOL and WHOQOL), health services use, and relevant costs. Data on feelings of discrimination and patient's satisfaction will also be collected at the baseline and 12 months later. DISCUSSION: Our study will help to clarify knowledge gaps regarding the positive outcomes (emergency department visits, quality of life, efficiency, and cost-utility) of an intervention based on case management care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01934322.

The Amish Mennonites: A sketch of Their Origin, and of Their Settlement in Iowa, with Their Creed in an Appendix,1894.

Traces the origin and growth of the Mennonite movement from its first summation into a creed in Holland and its story as it has been recorded in American, and in later years in Iowa.

Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study.

BACKGROUND: Poor tolerance and adverse drug reactions are main reasons for discontinuation of antiretroviral therapy (ART). Identifying predictors of ART discontinuation is a priority in HIV care. METHODS: A genetic association study in an observational cohort to evaluate the association of pharmacogenetic markers with time to treatment discontinuation during the first year of ART. Analysis included 577 treatment-naive individuals initiating tenofovir (n = 500) or abacavir (n = 77), with efavirenz (n = 272), lopinavir/ritonavir (n = 184), or atazanavir/ritonavir (n = 121). Genotyping included 23 genetic markers in 15 genes associated with toxicity or pharmacokinetics of the study medication. Rates of ART discontinuation between groups with and without genetic risk markers were assessed by survival analysis using Cox regression models. RESULTS: During the first year of ART, 190 individuals (33%) stopped 1 or more drugs. For efavirenz and atazanavir, individuals with genetic risk markers experienced higher discontinuation rates than individuals without (71.15% vs 28.10%, and 62.5% vs 14.6%, respectively). The efavirenz discontinuation hazard ratio (HR) was 3.14 (95% confidence interval (CI): 1.35-7.33, P = .008). The atazanavir discontinuation HR was 9.13 (95% CI: 3.38-24.69, P < .0001). CONCLUSIONS: Several pharmacogenetic markers identify individuals at risk for early treatment discontinuation. These markers should be considered for validation in the clinical setting.

Safety of artemether-lumefantrine exposure in first trimester of pregnancy: an observational cohort.

BACKGROUND: There is limited data available regarding safety profile of artemisinins in early pregnancy. They are, therefore, not recommended by WHO as a first-line treatment for malaria in first trimester due to associated embryo-foetal toxicity in animal studies. The study assessed birth outcome among pregnant women inadvertently exposed to artemether-lumefantrine (AL) during first trimester in comparison to those of women exposed to other anti-malarial drugs or no drug at all during the same period of pregnancy. METHODS: Pregnant women with gestational age <20 weeks were recruited from Maternal Health clinics or from monthly house visits (demographic surveillance), and followed prospectively until delivery. RESULTS: 2167 pregnant women were recruited and 1783 (82.3%) completed the study until delivery. 319 (17.9%) used anti-malarials in first trimester, of whom 172 (53.9%) used (AL), 78 (24.4%) quinine, 66 (20.7%) sulphadoxine-pyrimethamine (SP) and 11 (3.4%) amodiaquine. Quinine exposure in first trimester was associated with an increased risk of miscarriage/stillbirth (OR 2.5; 1.3-5.1) and premature birth (OR 2.6; 1.3-5.3) as opposed to AL with (OR 1.4; 0.8-2.5) for miscarriage/stillbirth and (OR 0.9; 0.5-1.8) for preterm birth. Congenital anomalies were identified in 4 exposure groups namely AL only (1/164[0.6%]), quinine only (1/70[1.4%]), SP (2/66[3.0%]), and non-anti-malarial exposure group (19/1464[1.3%]). CONCLUSION: Exposure to AL in first trimester was more common than to any other anti-malarial drugs. Quinine exposure was associated with adverse pregnancy outcomes which was not the case following other anti-malarial intake. Since AL and quinine were used according to their availability rather than to disease severity, it is likely that the effect observed was related to the drug and not to the disease itself. Even with this caveat, a change of policy from quinine to AL for the treatment of uncomplicated malaria during the whole pregnancy period could be already envisaged.

Introducción a la farmacia galénica: un reto en primer año de farmacia

[spa] Este curso académico 2009-2010 se implanta el nuevo plan de estudios de Farmacia en la Universidad de Barcelona, diseñado según los planteamientos del EEES. Como consecuencia, y por primera vez en la historia de la Facultad de Farmacia de la UB, se imparte una asignatura troncal de cariz galénico en el primer año de la carrera. Esto constituye un nuevo reto para el Grupo de Innovación Docente de Tecnología Farmacéutica (GIDTF), dado que la asignatura Introducción a la Farmacia Galénica se ha de impartir a grandes grupos de estudiantes, al inicio de su carrera, mediante sesiones teóricas de 1,5 h. Excepcionalmente en este curso académico, la asignatura se imparte en el primer semestre y se repite en el segundo. En este trabajo se presenta el planteamiento metodológico presencial diseñado para esta asignatura, apoyado en estrategias no presenciales como foro de debate, recursos on-line, cuestionarios y tareas de autoevaluación a través de la plataforma Moodle del Campus Virtual de la UB, puesto que el equipo docente considera prioritario iniciar al estudiante en el uso de la misma en el primer año de carrera. Se han efectuado encuestas de satisfacción a los estudiantes que se han evaluado, así también como los resultados académicos obtenidos. En el análisis de los puntos fuertes y débiles de la metodología empleada, se han detectado evaluaciones positivas y también aspectos que podrían mejorarse, estableciendo las medidas correctoras adecuadas. En cuanto a los resultados académicos, han sido muy satisfactorios. [eng] This academic year 2009-2010, the new curriculum of Pharmacy according to the premises of the EHEA is started at the University of Barcelona. As a result, for the first time in the history of the Faculty of Pharmacy of UB, an obligatory galenic subject will be given during the first year of the career. This is a new challenge for Teaching Innovation Group of Pharmaceutical Technology (GIDTF), as the subject Introduction to Galenic Pharmacy is given by a team of teachers to large groups of students who began its career, through theoretical sessions of 1.5 h. The subject will be taught exceptionally this academic year in the first semester and repeated in the second. In this paper we present the methodological approach designed to face this subject, supported by virtual strategies as discussion forum, online resources, self-assessment test and work through the platform Moodle of the Virtual Campus UB, as the team considers it a priority to initiate the student in using it in the first year of pharmacy study. Were carried out satisfaction surveys to students and we have evaluated them, as well as academic performance. Through the analysis of the methodology, we detected positive evaluations and areas for improvement that have been used to establish appropriate corrective measures. Academic results have been very satisfactory.

Objective results at 1 year of a new ultracongruent postero-stabilized total knee arthroplasty

Introduction: A new ultra congruent, postero-stabilized total knee arthroplasty (TKA) with a mobile bearing, the FIRST knee prosthesis (Free Insert in Rotation Stabilized in Translation, Symbios SA), was designed and expected to significantly reduce polyethylene wear, to improve the range of motion and the overall stability of the knee while ensuring a physiological ligament balance. Gait analysis has proven to give really objective outcome parameters after lower limb surgery. The goal of our study was to compare the subjective and really objective results of this new TKA with two other widespread models of TKA. Methods: A clinical prospective monocentric cohort study of 100 consecutive patients (47-88 yrs) undergoing a FIRST TKA for primary osteoarthritis is currently being done. Pre- and post-operative follow-ups (6 weeks, 4 months and 1 year) were done with well-recognized subjective evaluations (EQ-5D and WOMAC scores) and semi-objective questionnaires (KSS score and radiography evaluation) as well as with a really objective evaluation using gait parameters from 6 walking trials, performed at different speeds (slow, normal and fast) with an ambulatory gait analysis system (Physilog®, BioAGM CH). The outcomes of the first 32 new TKA after one year of follow-up were compared to the results after 1 year of a randomized controlled clinical trial comparing 29 NexGen® postero-stabilized TKA (Zimmer Inc) with a fixed bearing and 26 NexGen® TKA with a mobile bearing using the same methods. Results: Subjective and semi-objective results were similar for the three types of TKA. As for the really objective parameters, the gait cycle time of the FIRST TKA was statistically significantly shorter at normal speed of walk, as well as double-support periods, as compared to both standard models. The extension (in terms of range of motion when walking) of the operated knee was significantly improved for all three types of walk in favour of the FIRST TKAs compared to both NexGen TKAs. The normal walking speed was significantly higher with faster swing speed and stride lengths for the new TKA. Significantly better coordination scores were observed at normal walking speed for the FIRST TKA as compared to the fixed-bearing TKAs. Conclusion: The FIRST TKAs showed statistically significantly better objective outcomes in terms of gait after one year of follow-up with similar subjective and semi-objective results in comparison with widespread TKA designs. These encouraging short-terms results will have to be confirmed at a 5 years follow-up of the FIRST TKAs.

Symmetric periodic orbits near a heteroclinic loop formed by two singular points and their invariant manifolds of dimension 1 and 2

In this paper we consider vector fields in R3 that are invariant under a suitable symmetry and that posses a “generalized heteroclinic loop” L formed by two singular points (e+ and e −) and their invariant manifolds: one of dimension 2 (a sphere minus the points e+ and e −) and one of dimension 1 (the open diameter of the sphere having endpoints e+ and e −). In particular, we analyze the dynamics of the vector field near the heteroclinic loop L by means of a convenient Poincar´e map, and we prove the existence of infinitely many symmetric periodic orbits near L. We also study two families of vector fields satisfying this dynamics. The first one is a class of quadratic polynomial vector fields in R3, and the second one is the charged rhomboidal four body problem.

Premier cas de néphropathie epidémique endémique en Suisse [First case of nephropathia epidemica acquired in Switzerland]

A 43 year healthy old man complains of fever with abdominal pain, vomiting, diarrhoea, followed by the development of thrombocytopenia and acute renal failure. The laboratory tests show the presence of Hantavirus specific IgM and IgG which is confirmed by a specific test revealing Puumala serotype as responsible. The patient received a symptomatic treatment with a favourable evolution allowing discharge about ten days after the beginning of symptoms. Hantavirus are transmitted by rodents, and this patient has certainly been infected in Switzerland in the absence of travel abroad during the incubation period. This means that when confronted in Switzerland with an acute nephritis of unknown origin, a diagnosis of nephropathia epidemica must be taken into account.