Determination of oseltamivir and oseltamivir carboxylate in human plasma by liquid chromatography-tandem mass spectrometry

Introduction: Oseltamivir phosphate (OP), the prodrug of oseltamivir carboxylate (OC; active metabolite), is marketed since 10 years for the treatment of seasonal influenza flu. It has recently received renewed attention because of the threat of avian flu H5N1 in 2006-7 and the 2009-10 A/H1N1 pandemic. However, relatively few studies have been published on OP and OC clinical pharmacokinetics. The disposition of OC and the dosage adaptation of OP in specific populations, such as young children or patients undergoing extrarenal epuration, have also received poor attention. An analytical method was thus developed to assess OP and OC plasma concentrations in patients receiving OP and presenting with comorbidities or requiring intensive care. Methods: A high performance liquid chromatography coupled to tandem mass spectrometry method (HPLC-MS/MS) requiring 100-µL aliquot of plasma for quantification within 6 min of OP and OC was developed. A combination of protein precipitation with acetonitrile, followed by dilution of supernant in suitable buffered solvent was used as an extraction procedure. After reverse phase chromatographic separation, quantification was performed by electro-spray ionization-triple quadrupole mass spectrometry. Deuterated isotopic compounds of OP and OC were used as internal standards. Results: The method is sensitive (lower limit of quantification: 5 ng/mL for OP and OC), accurate (intra-/inter-assay bias for OP and OC: 8.5%/5.5% and 3.7/0.7%, respectively) and precise (intra-/inter-assay CV%: 5.2%/6.5% and 6.3%/9.2%, respectively) over the clinically relevant concentration range (upper limits of quantification 5000 ng/mL). Of importance, OP, as in other previous reports, was found not to be stable ex vivo in plasma on standard anticoagulants (i.e. EDTA, heparin or citrate). This poor stability of OP has been prevented by collecting blood samples on commercial fluoride/oxalate tubes. Conclusions: This new simple, rapid and robust HPLC-MS/MS assay for quantification of OP and OC plasma concentrations offers an efficient tool for concentration monitoring of OC. Its exposure can probably be controlled with sufficient accuracy by thorough dosage adjustment according to patient characteristics (e.g. renal clearance). The usefulness of systematic therapeutic drug monitoring in patients appears therefore questionable. However, pharmacokinetic studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.

Etes-vous serein face à votre placement? Une étude pilote

Introduction: Des unités d'attente de placement ont vu le jour pour¦répondre à la pénurie de lits d'hébergement de long séjour dans le¦Canton de Vaud et désengorger les hôpitaux aigus. Pour les patients¦qui y sont admis, la décision de placement intervient au sortir d'une¦hospitalisation aiguë, laissant peu de temps à la personne pour¦cheminer face à cette décision. Cette étude pilote vise à investiguer¦le degré de sérénité de ces patients face à l'hébergement de longue¦durée et déterminer s'il existe une relation avec la durée d'attente ou¦le décès en unité d'attente.¦Population et méthode: Personnes âgées (N = 78) admises dans¦une structure d'attente et préparation à l'hébergement de longue¦durée après un séjour hospitalier aigu. Des données démographiques,¦fonctionnelles, cognitives et affectives ont été récoltées dans les 4¦semaines après l'admission. La sérénité ressentie face à l'hébergement¦longue durée a été évaluée à l'aide d'une échelle de type Likert à¦quatre niveaux (pas du tout/plutôt pas/plutôt/tout à fait serein).¦Résultats: Les patients étaient âgés de 85.6 ans en moyenne, 74%¦(58/78) étaient des femmes, 47% (37/78) avaient des troubles cognitifs¦et 35% (27/78) des troubles dépressifs. Globalement 24% (19/78)¦des patients se déclaraient peu ou pas du tout sereins face au¦placement. Comparés aux patients sereins, ces 19 patients étaient¦significativement (p <.05) moins âgés (83.2 ± 1.0 vs 86.8 ± 6.5 ans),¦plus dépendants dans les activités de la vie quotidienne (BAVQ 2.5 ±¦1.7 vs 3.5 ± 1.6), plus déprimés (GDS 15-items 7.0 ± 3.5 vs 4.4 ± 3.0),¦et avaient plus souvent des antécédents de chutes (95% vs 75%). En¦analyse multivariée, le manque de sérénité restait significativement¦associé à une dépendance plus élevée dans les BAVQ, à un score¦GDS plus élevé ainsi qu'aux antécédents de chute. Il n'y avait pas de¦différence significative en termes de durée moyenne de séjour avant le¦placement (90.0 ± 57.3j vs 87.8 ± 73.2, médianes 85 vs 57, P = .45), ni¦de mortalité dans l'unité d'attente (5% vs 5%) entre les deux groupes¦de patients.¦Conclusion: Près d'un quart des patients en unité d'attente se¦déclarent peu sereins face à la perspective du placement. Ces patients¦sont plus dépendants, ont des antécédents de chutes et sont plus¦déprimés, ce qui souligne l'importance d'une identification précoce de¦ces patients afin de leur offrir un soutien dans cette période difficile de¦transition dans leur parcours de vie.

Biological markers of alcohol consumption in alcoholised drivers: Comparison of capillary electrophoresis (CZE CDT) and a direct immunoassay (N Latex CDT) with the traditional method of anion-exchange chromatography-immunoturbidimetry (%CDT TIA).

Objectives: The aim of this study was to compare specificity and sensitivity of different biological markers that can be used in a forensic field to identify potentially dangerous drivers because of their alcohol habits. Methods: We studied 280 Swiss drivers after driving while under the alcohol influence. 33 were excluded for not having CDT N results, 247 were included (218 men (88%) and 29 women (12%). Mean age was 42,4 (SD:12, min: 20 max: 76). The evaluation of the alcohol consumption concerned the month before the CDT test and was considered as such after the interview: Heavy drinkers (>3 drinks per day): 60 (32.7%), < 3 drinks per day and moderate: 127 (51.4%) 114 (46.5%), abstinent: 60 (24.3%) 51 (21%). Alcohol intake was monitored by structured interviews, self-reported drinking habits and the C-Audit questionnaire as well as information provided by their family and general practitioner. Consumption was quantified in terms of standard drinks, which contain approximately 10 grams of pure alcohol (Ref. WHO). Results: comparison between moderate (less or equal to 3 drinks per day) and excessive drinkers (more than 3 drinks) Marker ROC area 95% CI cut-off sensitivity specificity CDT TIA 0.852 0.786-0917 2.6* 0.93 LR+1.43 0.35 LR-0.192 CDT N latex 0.875 0.821-0.930 2.5* 0.66 LR+ 6.93 0.90 LR- 0.369 Asialo+disialo-tf 0.881 0.826-0.936 1.2* 0.78 LR+4.07 0.80 LR-0.268 1.7° 0.66 LR+8.9 0.93 LR-0.360 GGT 0.659 0.580-0.737 85* 0.37 LR+2.14 0.83 LR-0.764 * cut-off point suggested by the manufacturer ° cut-off point suggested by our laboratory Conclusion: With the cut-off point established by the manufacturer, CDT TIA performed poorly in term of specificity. N latex CDT and CZE CDT were better, especially if a 1.7 cut-off is used with CZE

Eficiência no Mercado Ibérico de Títulos: Evidência na Forma Fraca

A forma fraca da Hipótese de Eficiência de Mercado (HEM) é das três formas de eficiência propostas por Fama (1970) aquela que tem sido mais testada ao longo do tempo, em grande parte devido à disponibilidade de informação relativa aos dados históricos dos títulos. De acordo com esta hipótese, é impossível obter ganhos anormais através de estratégias de investimento com base em padrões dos preços passados. O objectivo deste trabalho é o de testar a hipótese de eficiência de mercado, na sua forma fraca, tendo por base os dois principais índices de acções do mercado de capitais ibérico ˗˗ o índice de acções português (Portuguese Stock Index, PSI-20) e o índice de acções espanhol (Spanish Stock Index, IBEX-35) ˗˗ no período compreendido entre Janeiro de 1997 a Dezembro de 2010. Para tal, recorre-se a uma metodologia baseada em quatro testes para analisar a hipótese de passeio aleatório: teste de correlação linear, teste de sequências, teste de raiz unitária e teste do rácio de variância. Todos estes testes foram realizados através dos softwares estatísticos EVIEWS 7.0 e SPSS 17.0. Os testes efectuados reportam resultados empíricos mistos. Apesar da hipótese de passeio aleatório ser suportada pelo teste de correlação linear, para as rendibilidades diárias dos dois índices de acções, e pelo teste de sequências para as rendibilidades diárias em relação ao IBEX-35, verifica-se que existem fortes evidências que conduzem à rejeição desta hipótese. Por conseguinte, a hipótese de eficiência na forma fraca também é rejeitada para os dois mercados bolsistas.

Impact and cost of a 2-week community-based screening and awareness program for diabetes and cardiovascular risk factors in a Swiss canton.

BACKGROUND: Community-based diabetes screening programs can help sensitize the population and identify new cases. However, the impact of such programs is rarely assessed in high-income countries, where concurrent health information and screening opportunities are common place. INTERVENTION AND METHODS: A 2-week screening and awareness campaign was organized as part of a new diabetes program in the canton of Vaud (population of 697,000) in Switzerland. Screening was performed without appointment in 190 out of 244 pharmacies in the canton at the subsidized cost of 10 Swiss Francs per participant. Screening included questions on risk behaviors, measurement of body mass index, blood pressure, blood cholesterol, random blood glucose (RBG), and A1c if RBG was >/=7.0 mmol/L. A mass media campaign promoting physical activity and a healthy diet was channeled through several media, eg, 165 spots on radio, billboards in 250 public places, flyers in 360 public transport vehicles, and a dozen articles in several newspapers. A telephone survey in a representative sample of the population of the canton was performed after the campaign to evaluate the program. RESULTS: A total of 4222 participants (0.76% of all persons aged >/=18 years) underwent the screening program (median age: 53 years, 63% females). Among participants not treated for diabetes, 3.7% had RBG >/= 7.8 mmol/L and 1.8% had both RBG >/= 7.0 mmol/L and A1c >/= 6.5. Untreated blood pressure >/=140/90 mmHg and/or untreated cholesterol >/=5.2 mmol/L were found in 50.5% of participants. One or several treated or untreated modifiable risk factors were found in 78% of participants. The telephone survey showed that 53% of all adults in the canton were sensitized by the campaign. Excluding fees paid by the participants, the program incurred a cost of CHF 330,600. CONCLUSION: A community-based screening program had low efficiency for detecting new cases of diabetes, but it identified large numbers of persons with elevated other cardiovascular risk factors. Our findings suggest the convenience of A1c for mass screening of diabetes, the usefulness of extending diabetes screening to other cardiovascular risk factors, and the importance of a robust background communication campaign.

The size and burden of mental disorders and other disorders of the brain in Europe 2010.

Aims: To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU. Method: Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY). Results: Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8 million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165 m vs. 2005: 82 m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (>4%), ADHD (5%) in the young, and dementia (1-30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment. Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke. Conclusion: In every year over a third of the total EU population suffers from mental disorders. The true size of "disorders of the brain" including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past.Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for isorders of the brain as the core health challenge of the 21st century. (C) 2011 Published by Elsevier B.V.

Increasing prevalence of gastroschisis in Europe 1980-2002: a phenomenon restricted to younger mothers?

Gastroschisis is an abdominal wall defect more prevalent in offspring of young mothers. It is known to be increasing in prevalence despite the general decrease in the proportion of births to young European women. We investigated whether the increase in prevalence was restricted to the high-risk younger mothers. We analysed 936 cases of gastroschisis from 25 population-based registries in 15 European countries, 1980-2002. We fitted a Bayesian Hierarchical Model which allowed us to estimate trend, to estimate which registries were significantly different from the common distribution, and to adjust simultaneously for maternal age, time (in grouped years) and the random variation between registries. The maternal age-standardised prevalence (standardised to the year 2000 European maternal age structure) increased almost fourfold from 0.54 [95% Credible Interval (CrI) 0.37, 0.75] per 10,000 births in 1980-84 to 2.12 [95% CrI 1.85, 2.40] per 10,000 births in 2000-02. The relative risk of gastroschisis for mothers <20 years of age in 1995-2002 was 7.0 [95% CrI 5.6, 8.7]. There were geographical differences within Europe, with higher rates of gastroschisis in the UK, and lower rates in Italy after adjusting for maternal age. After standardising for regional variation, our results showed that the increase in risk over time was the same for mothers of all ages--the increase for mothers <20 years was 3.96-fold compared with an increase of 3.95-fold for mothers in the other age groups. These findings indicate that the phenomenon of increasing gastroschisis prevalence is not restricted to younger mothers only.

Condiciones hidroquímicas del mar peruano de Tambo de Mora a Paita, durante agosto y setiembre 1995

Reportan los valores de las condiciones hidroquímicas del agua de mar observadas durante el Crucero de Evaluación de la Biomasa Desovante de Anchoveta y Sardina, BIC Humboldt y BIC SNP-1 9508-09. Se trata de la evaluación y cuantificación de los valores de las principales sales nutritivas y (fosfatos, nitratos, nitritos y silicatos) del oxígeno disuelto y la clorofila "A", En su distribución superficial y vertical. Frente a Salaverry, entre las 20 y 50 millas náuticas se halló concentraciones altas de clorofila "a" (30-50 ug/L) como producto de una intensa actividad fitoplanctónica, asociada con valores de 7,0 mL/L de oxígeno disuelto.

Biologia e tabela de vida de fertilidade de Frankliniella occidentalis (Pergande) (Thysanoptera, Thripidae) em morangueiro

O objetivo deste trabalho foi estudar aspectos biológicos de Frankliniella occidentalis (Pergande) (Thysanoptera, Thripidae), considerando que no Brasil quase nada se sabe sobre a fauna de tripes associada à cultura do morangueiro. Larvas recém-eclodidas foram individualizadas em placas de Petri contendo uma flor ou um folíolo de morangueiro, mantidas em câmaras climatizadas (25 ± 1 ºC; 60 ± 10% U.R.; fotofase de 12 horas) e observadas diariamente até a morte. A duração média do período de larva-adulto e a viabilidade não diferiram entre os insetos mantidos em flores (8,49 ± 0,18 e 68,52%) e folíolos (8,85 ± 0,15 e 75,47%). A fecundidade média diária e a total foram mais elevadas quando flores foram fornecidas como alimento (7,4 ± 0,69 e 70,0 ± 9,18 ovos/fêmea respectivamente), em comparação com folíolos (2,4 ± 0,35 e 8,5 ± 1,13 ovos/fêmea, respectivamente). A duração média, em dias, do período embrionário foi distinta entre os indivíduos mantidos em flores (3,7 ± 0,03) e em folíolos (4,4 ± 0,09). A viabilidade dos ovos depositados sobre flores e folíolos foi de 65,5 ± 0,01 e 74,3 ± 0,03%, respectivamente. Com base na tabela de vida de fertilidade, o desempenho dos indivíduos de F. occidentalis que se desenvolveram em flores foi melhor, com uma geração (ovo-adulto) completada a cada 20,92 dias, a 25 °C.

Tubular Dysfunction in Idiopathic Nephrotic Syndrome

Objectives: To evaluate the degree of tubular involvement in INS at various stage of the disease. Methods: 19 patients with INS were studied. 13 were steroid responders (group 1). 5 of them had biopsy which showed MCD. 6 patients were non responder to steroid or were steroid dependant with frequent relapses (group 2). Biopsies showed 3 FSGS and 3 MCD. They were treated with prednisone, ciclosporin and/ or mycofenolate mofetil. Protein, microalbumin (ALB), alpha-microglobulin (AMG), N-acetyl-beta-D-glucosaminidase (NAG) and creatinine (cr) were measured in each urine sample. Patients were considered in remission if prot/ cr ratio (g/mol) was < 20 (group 1a and 2a), and in relapse if the ratio was > 200 (group 1c and 2c). Some patients in group 1 had non nephrotic proteinuria (group 1b). Tubular dysfunction was defi ned by NAG/cr ratio (mg/mmol) > 0.86 or by AMG/cr ratio (mg/mmol) > 1.58. Results: Prot/cr ALB/cr NAG/cr AMG/cr Group 1a 10.3 ± 4.1 1.1 ± 1.0 0.19 ± 0.12 1.40 ± 0.97 Group 1b 60.4 ± 63.4 42.8 ± 66.7 0.39 ± 0.21 1.20 ± 0.56 Group 1c 713.3 ± 276.8 799.8 ± 534.9 2.25 ± 1.86* 4.25 ± 2.09* Group 2a 11.3 ± 6.1 4.7 ± 5.7 0.26 ± 0.19 1.18 ± 0.60 Group 2c 914.9 ± 718.6 682.9 ± 589.3 3.00 ± 2.72* 5.47 ± 4.30* Results are mean ± SD, p < 0.001 compared to group 1a and 2a No difference was observed between group 1 and group 2 neither in remission nor in relapse. Conclusions: These data indicate that tubular dysfunction occurs in INS but only in patients in relapse. In this population, tubular dysfunction was independent of the severity of the nephrotic syndrome, the treatment protocol and the histopathology.

Condición reproductiva y fecundidad de Vinciguerria lucetia pecific durante el crucero BIC Humboldt 9808-09

Describe el estado reproductivo de Vinciguerria lucetia pacifici a través del análisis histológico de ovarios por grados latitudinales. Se elabora una escala de madurez sexual de cinco estadíos. Durante la ejecución del Crucero 9808-09, efectuado entre el 20 de agosto y el 18 de setiembre de 1998 la Vinciguerria lucetia pacifici se encontró en plena etapa de desove. La talla de los individuos estuvo comprendida entre 3,5 y 7,0 cm de longitud total. Esta especie tiene un desarrollo ovocitario asincrónico y un tipo de desove parcial. Se estimó la fecundidad parcial promedio en 309 ovocitos por hembra (DS=164).

Condición reproductiva de la anchoveta durante la primavera 2005

Durante el crucero BIC Olaya 0511-12, el rango de LT de la anchoveta fue de 7,0 a 18,0 cm. La mayor actividad desovante se registró en la franja cercana a la costa. Se observó una alta variabilidad por grados latitudinales con algunas zonas importantes de desove (6 - 10°S y 12°S).

Avaliação de critérios para calagem de arroz inundado em casa de vegetação

O presente trabalho foi desenvolvido, no período de maio a setembro de 1995, com o objetivo de avaliar critérios para a recomendação de calcário para o arroz em solos inundados de Minas Gerais. Foram avaliados os efeitos de doses crescentes de carbonatos de cálcio e de magnésio sobre a produção de matéria seca de plantas de arroz em casa de vegetação. O experimento constou de um fatorial completo com dez solos de várzeas e cinco níveis de calagem. Verificou-se que a acidez potencial (H + Al) a pH 7,0, a saturação por bases (V), o teor de carbono orgânico (C) e o teor de cálcio mais magnésio (Ca + Mg) foram as características dos solos que mais influenciaram as doses recomendáveis de calcário. Por outro lado, os teores de Fe e de Mn redutíveis do solo não tiveram influência significativa na recomendação de calagem. O método que visa elevar V a 40% foi mais eficiente na definição das doses recomendáveis para obtenção da matéria seca equivalente a 90% da máxima eficiência física.

Characterization of Human Late Outgrowth Endothelial Progenitor-Derived Cells under Various Flow Conditions.

Background: Endothelial progenitor-derived cells (EPC) are a cell therapy tool in peripheral arterial disease and for re-endothelialization of bypasses and stents. Objective: To assess EPC behavior under flow conditions normally found in vivo. Results: EPC were isolated from human cord blood, cultured on compliant tubes and exposed in an in vitro flow system mimicking hemodynamic environments normally found in medium and large arteries. EPC exposed for 24 h to unidirectional (0.3 ± 0.1 or 6 ± 3 dynes/cm(2)) shear stress oriented along flow direction, while those exposed to bidirectional shear stress (0.3 ± 3 dynes/cm(2)) or static conditions had random orientation. Under bidirectional flow, tissue factor (TF) activity and mRNA expression were significantly increased (2.5- and 7.0-fold) compared to static conditions. Under low shear unidirectional flow TF mRNA increased 4.9 ± 0.5-fold. Similar flow-induced increases were observed for TF in mature umbilical vein-derived endothelial cells. Expression of tissue-type plasminogen activator (t-PA), urokinase (u-PA) and monocyte chemotactic protein 1 (MCP1) were reduced by 40-60% in late outgrowth endothelial progenitor-derived cells (LO-EPC) exposed to any flow environment, while MCP1, but not t-PA or u-PA, was decreased in HUVEC. Conclusions: Flow, in particular bidirectional, modifies the hemostatic balance in LO-EPC with increased TF and decreased plasminogen activator expression.

Modificações em atributos químicos de solo arenoso sob sistema plantio direto

O manejo do solo sem as operações de lavração e gradagem não incorpora os resíduos culturais, fertilizantes e corretivos, alterando a distribuição e disponibilidade dos nutrientes. Este trabalho teve por objetivo avaliar as modificações químicas decorrentes da adoção do sistema plantio direto (SPD) comparativamente ao cultivo convencional (SCC) e ao campo nativo (CN). Em 1995, coletaram-se amostras de um Podzólico Vermelho-Amarelo textura arenosa/argilosa, em quatro profundidades (0-5, 5-10, 10-20 e 20-40 cm), num experimento instalado, em 1989, na Universidade Federal de Santa Maria (RS). Foi utilizado o delineamento em blocos ao acaso com parcelas subdivididas e quatro repetições. Determinaram-se o ponto de efeito salino nulo (PESN), as cargas permanentes, as substâncias húmicas, o pH em água, Al e Ca + Mg trocáveis, H + Al, N total e mineral, K da solução do solo, trocável e não-trocável, e P disponível, total e orgânico. Calcularam-se a CTC efetiva e a pH 7,0, a saturação por Al e por bases e a percentagem de P orgânico. Não houve variação no PESN em decorrência dos diferentes sistemas de manejo do solo. A adoção do SPD aumentou o teor de carbono orgânico, de ácidos fúlvicos e húmicos, CTC, disponibilidade de P e K e acidez potencial, especialmente na camada de 0-5 cm, comparativamente ao SCC.