Enantioselective analysis of mirtazapine and its two major metabolites in human plasma by liquid chromatography-mass spectrometry after three-phase liquid-phase microextraction

A three-phase liquid-phase microextraction (LPME) method using porous polypropylene hollow fibre membrane with a sealed end was developed for the extraction of mirtazapine (MRT) and its two major metabolites, 8-hydroxymirtazapine (8-OHM) and demethylmirtazapine (DMR), from human plasma. The analytes were extracted from 1.0 mL of plasma, previously diluted and alkalinized with 3.0 mL 0.5 mol L-1 pH 8 phosphate buffer solution and supplemented with 15% sodium chloride (NaCl), using n-hexyl ether as organic solvent and 0.01 moL L-1 acetic acid solution as the acceptor phase. Haloperidol was used as internal standard. The chromatographic analyses were carried out on a chiral column, using acetonitrile-methanol-ethanol (98:1:1, v/v/v) plus 0.2% diethylamine as mobile phase, at a flow rate of 1.0 mL min(-1). Multi-reaction monitoring (MRM) detection was performed by mass spectrometry (MS-MS) using a triple-stage quadrupole and electrospray ionization interface operating in the positive ion mode. The mean recoveries were in 18.3-45.5% range with linear responses over the 1.25-125 ng mL(-1) concentration range for all enantiomers evaluated. The quantification limit (LOQ) was 1.25 ng mL(-1). Within-day and between-day assay precision and accuracy (2.5, 50 and 100 ng mL(-1)) showed relative standard deviation and the relative error lower than 11.9% for all enantiomers evaluated. Finally, the method was successfully used for the determination of mirtazapine and its metabolite enantiomers in plasma samples obtained after single drug administration of mirtazapine to a healthy volunteer. (c) 2007 Elsevier B.V. All rights reserved.

Forward-looking versus recursive-dynamic modeling in climate policy analysis: A comparison

This paper develops a multi-regional general equilibrium model for climate policy analysis based on the latest version of the MIT Emissions Prediction and Policy Analysis (EPPA) model. We develop two versions so that we can solve the model either as a fully inter-temporal optimization problem (forward-looking, perfect foresight) or recursively. The standard EPPA model on which these models are based is solved recursively, and it is necessary to simplify some aspects of it to make inter-temporal solution possible. The forward-looking capability allows one to better address economic and policy issues such as borrowing and banking of GHG allowances, efficiency implications of environmental tax recycling, endogenous depletion of fossil resources, international capital flows, and optimal emissions abatement paths among others. To evaluate the solution approaches, we benchmark each version to the same macroeconomic path, and then compare the behavior of the two versions under a climate policy that restricts greenhouse gas emissions. We find that the energy sector and CO(2) price behavior are similar in both versions (in the recursive version of the model we force the inter-temporal theoretical efficiency result that abatement through time should be allocated such that the CO(2) price rises at the interest rate.) The main difference that arises is that the macroeconomic costs are substantially lower in the forward-looking version of the model, since it allows consumption shifting as an additional avenue of adjustment to the policy. On the other hand, the simplifications required for solving the model as an optimization problem, such as dropping the full vintaging of the capital stock and fewer explicit technological options, likely have effects on the results. Moreover, inter-temporal optimization with perfect foresight poorly represents the real economy where agents face high levels of uncertainty that likely lead to higher costs than if they knew the future with certainty. We conclude that while the forward-looking model has value for some problems, the recursive model produces similar behavior in the energy sector and provides greater flexibility in the details of the system that can be represented. (C) 2009 Elsevier B.V. All rights reserved.

Coronary CT angiography using 64 detector rows: methods and design of the multi-centre trial CORE-64

Multislice computed tomography (MSCT) for the noninvasive detection of coronary artery stenoses is a promising candidate for widespread clinical application because of its non-invasive nature and high sensitivity and negative predictive value as found in several previous studies using 16 to 64 simultaneous detector rows. A multi-centre study of CT coronary angiography using 16 simultaneous detector rows has shown that 16-slice CT is limited by a high number of nondiagnostic cases and a high false-positive rate. A recent meta-analysis indicated a significant interaction between the size of the study sample and the diagnostic odds ratios suggestive of small study bias, highlighting the importance of evaluating MSCT using 64 simultaneous detector rows in a multi-centre approach with a larger sample size. In this manuscript we detail the objectives and methods of the prospective ""CORE-64"" trial (""Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography using 64 Detectors""). This multi-centre trial was unique in that it assessed the diagnostic performance of 64-slice CT coronary angiography in nine centres worldwide in comparison to conventional coronary angiography. In conclusion, the multi-centre, multi-institutional and multi-continental trial CORE-64 has great potential to ultimately assess the per-patient diagnostic performance of coronary CT angiography using 64 simultaneous detector rows.

Biomechanical analysis of sutures used for mesh fixation in the donor area after removal of the rectus abdominis muscle

Background: The use of synthetic mesh for abdominal wall closure after removal of the rectus abdominis is established but not standardised. This study compares two forms of mesh fixation: a simple suture, which fixes the mesh to the edges of the defect on the anterior rectus abdominis fascia; and total fixation, which incorporates the fasciae of the internal oblique, external oblique and transverse muscles in the suture, anchoring the mesh in the position of the removed muscle. Method: A total of 16 fresh cadavers were dissected. Two sutures were compared: simple and total. Three different sites were analysed: 5 cm above, 5 cm below and at the level of the umbilicus. The two sutures compared were tested in each region using a standardised technique. All sutures were performed with nylon 0, perpendicular to the linea alba. Each suture was secured to a dynamometer, which was pulled perpendicularly towards the midline until the rupture of the aponeurosis. `Rupture resistance` was measured in kilogram force. The mean among the groups was compared using the paired Student`s t-test to a significance level of 1% (p < 0.01). Results: The mean rupture resistance of the total suture was 160% higher than that of the simple suture. Conclusion: The total suture includes the external oblique, internal oblique and transverse fasciae, which are multi-directional, and creates a much higher resistance when compared with the simple suture. Total suture may reduce the incidence of bulging and hernias of the abdominal wall after harvesting the rectus abdominis muscle, but comparative clinical studies are necessary. (C) 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Is PHEEM a multi-dimensional instrument? An international perspective

Aim: To look at the characteristics of Postgraduate Hospital Educational Environment Measure (PHEEM) using data from the UK, Brazil, Chile and the Netherlands, and to examine the reliability and characteristics of PHEEM, especially how the three PHEEM subscales fitted with factors derived statistically from the data sets. Methods: Statistical analysis of PHEEM scores from 1563 sets of data, using reliability analysis, exploratory factor analysis and correlations of factors derived with the three defined PHEEM subscales. Results: PHEEM was very reliable with an overall Cronbach`s alpha of 0.928. Three factors were derived by exploratory factor analysis. Factor One correlated most strongly with the teaching subscale (R=0.802), Factor Two correlated most strongly with the role autonomy subscale (R=0.623) and Factor Three correlated most strongly with the social support subscale (R=0.538). Conclusions: PHEEM is a multi-dimensional instrument. Overall, it is very reliable. There is a good fit of the three defined subscales, derived by qualitative methods, with the three principal factors derived from the data by exploratory factor analysis.

Strategies for genetic model specification in the screening of genome-wide meta-analysis signals for further replication

Background Meta-analysis is increasingly being employed as a screening procedure in large-scale association studies to select promising variants for follow-up studies. However, standard methods for meta-analysis require the assumption of an underlying genetic model, which is typically unknown a priori. This drawback can introduce model misspecifications, causing power to be suboptimal, or the evaluation of multiple genetic models, which augments the number of false-positive associations, ultimately leading to waste of resources with fruitless replication studies. We used simulated meta-analyses of large genetic association studies to investigate naive strategies of genetic model specification to optimize screenings of genome-wide meta-analysis signals for further replication. Methods Different methods, meta-analytical models and strategies were compared in terms of power and type-I error. Simulations were carried out for a binary trait in a wide range of true genetic models, genome-wide thresholds, minor allele frequencies (MAFs), odds ratios and between-study heterogeneity (tau(2)). Results Among the investigated strategies, a simple Bonferroni-corrected approach that fits both multiplicative and recessive models was found to be optimal in most examined scenarios, reducing the likelihood of false discoveries and enhancing power in scenarios with small MAFs either in the presence or in absence of heterogeneity. Nonetheless, this strategy is sensitive to tau(2) whenever the susceptibility allele is common (MAF epsilon 30%), resulting in an increased number of false-positive associations compared with an analysis that considers only the multiplicative model. Conclusion Invoking a simple Bonferroni adjustment and testing for both multiplicative and recessive models is fast and an optimal strategy in large meta-analysis-based screenings. However, care must be taken when examined variants are common, where specification of a multiplicative model alone may be preferable.

Prevalence of, and risk factors for Kaposi`s sarcoma-associated herpesvirus infection among blood donors in Brazil: A multi-center serosurvey

Kaposi`s sarcoma-associated herpesvirus (KSHV) is endemic in the Amazon and rare in southern regions of Brazil. However, geographical distribution and epidemiological correlates of infection in this large country are still poorly defined. To estimate the seroprevalence of, and risk factors for, KSHV infection in Brazil, a multi-center study was conducted among 3,493 first-time voluntary unpaid blood donors from Salvador, Sao Paulo and Manaus. Antibodies against KSHV were detected using a whole-virus ELISA validated prior to the serosurvey. Antibodies against the latency-associated nuclear antigen (LANA) were detected by immuno-fluorescence assay (IFA) among ELISA-positive sera and a random sample of ELISA-negative sera. Overall, seroprevalence of KSHV by whole-virus ELISA was 21.7% (95% confidence interval (Cl): 20-23.4%) in men and 31.7% (95% Cl: 29-34.3%) in women (P<0.0001). KSHV antibodies were detected by IFA-LANA in 3% (95% Cl: 2-4.3%) of 867 ELISA-positive samples and in none of 365 randomly selected ELISA-negative samples. In multivariate analysis, KSHV seroprevalence by whole-virus ELISA was independently associated with female sex (odds ratio [OR] = 1.6, 95% Cl: 1.4-1.9); residence in the Amazon (OR = 1.4, 95% Cl: 1.2-1.8; compared to Salvador); Caucasian ethnicity (OR = 1.3, 95% Cl: 1.1-1.6) and herpes simplex virus type 2 (HSV-2) infection (OR = 1.3, 95% Cl: 1.1-1.6). KSHV seroprevalence did not significantly increase with age, nor was it associated with self-reported sexual behavior. KSHV seroprevalence is high among Brazilian blood donors, particularly from the Amazon region. This study supports the co-existence of sexual and non-sexual routes of KSHV transmission in this population.

Reduced medial prefrontal N-Acetyl-Aspartate levels in pediatric major depressive disorder: A multi-voxel in vivo (1)H spectroscopy study

There is increasing evidence of a reciprocal fronto-limbic network in the pathogenesis of mood disorders. Prior in vivo proton ((1)H) spectroscopy studies provide evidence of abnormal neurochemical levels in the cingulate and dorsolateral prefrontal cortex (DLPFC) of adult subjects with major depressive disorder (MOD). We examined whether similar abnormalities occur in children and adolescents with MDD. We collected two-dimensional multi-voxel in vivo 1H spectroscopy data at 1.5 Tesla to quantify levels of N-acetyl-aspartate (NAA), glycerolphosphocholine plus phosphocholine (GPC + PC), and phosphocreatine plus creatine (PCr + Cr) in the DLPFC, medial prefrontal cortex (MPFC), and anterior cingulate (AC) of children and adolescents aged 8-17 years with MDD (n = 16) compared with healthy control subjects (n = 38). Analysis of covariance with age and gender as covariates was performed. MDD subjects showed significantly lower levels of NAA in the right MPFC and right AC than controls. MDD subjects also had significantly lower levels of GPC + PC in the right AC than control subjects. There were no significant differences in other metabolites in the studied regions. Pediatric patients with MDD exhibit neurochemical alterations in prefrontal cortex regions that are important in the monitoring and regulation of emotional states. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Salvage Radical Prostatectomy for Radiation-recurrent Prostate Cancer: A Multi-institutional Collaboration

Background: Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined. Objective: To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP. Design, setting, and participants: This is a retrospective, international, multi-institutional cohort analysis. There was amedian follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers. Intervention: Open SRP. Measurements: BCR after SRP was defined as a serum prostate-specific antigen (PSA) >= 0.1 or >= 0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancerspecific death. Results and limitations: Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31-43), 77% (95% CI, 71-82), and 83% (95% CI, 76-88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period. Conclusions: In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in > 75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Genetic Analysis of Age-at-Onset for Cardiovascular Risk Factors in a Brazilian Family Study

Background/Aims: Statistical analysis of age-at-onset involving family data is particularly complicated because there is a correlation pattern that needs to be modeled and also because there are measurements that are censored. In this paper, our main purpose was to evaluate the effect of genetic and shared family environmental factors on age-at-onset of three cardiovascular risk factors: hypertension, diabetes and high cholesterol. Methods: The mixed-effects Cox model proposed by Pankratz et al. [2005] was used to analyze the data from 81 families, involving 1,675 individuals from the village of Baependi, in the state of Minas Gerais, Brazil. Results: The analyses performed showed that the polygenic effect plays a greater role than the shared family environmental effect in explaining the variability of the age-at-onset of hypertension, diabetes and high cholesterol. The model which simultaneously evaluated both effects indicated that there are individuals which may have risk of hypertension due to polygenic effects 130% higher than the overall average risk for the entire sample. For diabetes and high cholesterol the risks of some individuals were 115 and 45%, respectively, higher than the overall average risk for the entire population. Conclusions: Results showed evidence of significant polygenic effects indicating that age-at-onset is a useful trait for gene mapping of the common complex diseases analyzed. In addition, we found that the polygenic random component might absorb the effects of some covariates usually considered in the risk evaluation, such as gender, age and BMI. Copyright (C) 2008 S. Karger AG, Basel

Clinical Validity of the Protocol for Multi-Professional Centers for the Determination of Signs and Symptoms of Temporomandibular Disorders. Part II

The aims of this study were to analyze the criterion and construct validity of Part II of the protocol for multi-professional centers for the determination of signs and symptoms of temporomandibular disorders (ProTMDMulti) as a measure of TMD severity. The study was conducted on eight asymptomatic subjects (CG) and 30 subjects with articular TMD (TMDG), according to the Research Diagnostic Criteria for TMD (RDC/TMD). The ProTMDMulti-Part II was validated using the Helkimo Clinical Dysfunction Index (Di). The construct validity was tested using the analysis of the ability of ProTMDMulti-part II to differentiate the CG from the TMDG and to measure the changes that occurred in the TMDG between the period before and after TMD treatment. Correlations between the Di and the ProTMDMulti-Part II scores were calculated using the Spearman test. Inter- and intragroup comparisons were made (p<0.05). There was a statistically significant correlation between the Helkimo Clinical Dysfunction Index (Di) and the severity scores of the ProTMDMulti-Part II. There was a significant difference between TMDG and CG regarding the severity of signs and symptoms. The present study provides statistical evidence of the clinical validity of the ProTMDmulti-Part II as a measure of the severity of TMD symptoms.

A FOSSIL BULGE GLOBULAR CLUSTER REVEALED BY VERY LARGE TELESCOPE MULTI-CONJUGATE ADAPTIVE OPTICS

The globular cluster HP 1 is projected on the bulge, very close to the Galactic center. The Multi-Conjugate Adaptive Optics Demonstrator on the Very Large Telescope allowed us to acquire high-resolution deep images that, combined with first epoch New Technology Telescope data, enabled us to derive accurate proper motions. The cluster and bulge fields` stellar contents were disentangled through this process and produced an unprecedented definition in color-magnitude diagrams of this cluster. The metallicity of [Fe/H] approximate to -1.0 from previous spectroscopic analysis is confirmed, which together with an extended blue horizontal branch imply an age older than the halo average. Orbit reconstruction results suggest that HP 1 is spatially confined within the bulge.

An analysis of the composite stellar population in M32

We obtained long-slit spectra of high signal-to-noise ratio of the galaxy M32 with the Gemini Multi-Object Spectrograph at the Gemini-North telescope. We analysed the integrated spectra by means of full spectral fitting in order to extract the mixture of stellar populations that best represents its composite nature. Three different galactic radii were analysed, from the nuclear region out to 2 arcmin from the centre. This allows us to compare, for the first time, the results of integrated light spectroscopy with those of resolved colour-magnitude diagrams from the literature. As a main result we propose that an ancient and an intermediate-age population co-exist in M32, and that the balance between these two populations change between the nucleus and outside one effective radius (1r(eff)) in the sense that the contribution from the intermediate population is larger at the nuclear region. We retrieve a smaller signal of a young population at all radii whose origin is unclear and may be a contamination from horizontal branch stars, such as the ones identified by Brown et al. in the nuclear region. We compare our metallicity distribution function for a region 1 to 2 arcmin from the centre to the one obtained with photometric data by Grillmair et al. Both distributions are broad, but our spectroscopically derived distribution has a significant component with [Z/Z(circle dot)] <= -1, which is not found by Grillmair et al.

Analysis of a hyper-diverse seed dispersal network: modularity and underlying mechanisms

Mutualistic interactions involving pollination and ant-plant mutualistic networks typically feature tightly linked species grouped in modules. However, such modularity is infrequent in seed dispersal networks, presumably because research on those networks predominantly includes a single taxonomic animal group (e.g. birds). Herein, for the first time, we examine the pattern of interaction in a network that includes multiple taxonomic groups of seed dispersers, and the mechanisms underlying modularity. We found that the network was nested and modular, with five distinguishable modules. Our examination of the mechanisms underlying such modularity showed that plant and animal trait values were associated with specific modules but phylogenetic effect was limited. Thus, the pattern of interaction in this network is only partially explained by shared evolutionary history. We conclude that the observed modularity emerged by a combination of phylogenetic history and trait convergence of phylogenetically unrelated species, shaped by interactions with particular types of dispersal agents.

Cladistic analysis of continuous modularized traits provides phylogenetic signals in Homo evolution

Evolutionary novelties in the skeleton are usually expressed as changes in the timing of growth of features intrinsically integrated at different hierarchical levels of development(1). As a consequence, most of the shape- traits observed across species do vary quantitatively rather than qualitatively(2), in a multivariate space(3) and in a modularized way(4,5). Because most phylogenetic analyses normally use discrete, hypothetically independent characters(6), previous attempts have disregarded the phylogenetic signals potentially enclosed in the shape of morphological structures. When analysing low taxonomic levels, where most variation is quantitative in nature, solving basic requirements like the choice of characters and the capacity of using continuous, integrated traits is of crucial importance in recovering wider phylogenetic information. This is particularly relevant when analysing extinct lineages, where available data are limited to fossilized structures. Here we show that when continuous, multivariant and modularized characters are treated as such, cladistic analysis successfully solves relationships among main Homo taxa. Our attempt is based on a combination of cladistics, evolutionary- development- derived selection of characters, and geometric morphometrics methods. In contrast with previous cladistic analyses of hominid phylogeny, our method accounts for the quantitative nature of the traits, and respects their morphological integration patterns. Because complex phenotypes are observable across different taxonomic groups and are potentially informative about phylogenetic relationships, future analyses should point strongly to the incorporation of these types of trait.