Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

Un rosarino, médico voluntario en la Guerra del Chaco

En noviembre de 1932 el médico rosarino Carlos de Sanctis se trasladó a Asunción del Paraguay para incorporarse al Cuerpo de Sanidad paraguayo. La Guerra del Chaco todavía no se había declarado formalmente, pero para Carlos de Sanctis estaba claro que ese conflicto ya había ido tomando forma en los años previos, en especial a partir del fin de la Primera Guerra Mundial. Gracias a su condición de "periodista corresponsal" del periódico rosarino La Capital, prensa hoy día vigente, el Poder Ejecutivo paraguayo le permitió a Carlos de Sanctis fotografiar su entrada a la ciudad de Asunción, el viaje que hicieron por el río Paraguay para entrar al Chaco Paraguayo por el Puerto Casado (así llamado por el español Carlos Casado del Alisal), así como el traslado del ejército hacia la zona del Fortín Arze que era dirigido por el Coronel Carlos José Fernández. Este tema histórico que presentamos a los lectores y a las lectoras, tiene vigencia hoy día: en el año 2010, la presidenta argentina Cristina Fernández intervino en la firma del Tratado de Paz definitivo entre Bolivia y Paraguay. Los presidentes Evo Morales y Fernando Lugo sellaron "La paz de la eterna guerra del Chaco".

Preparation, spectroscopic and acidity properties of two hydrazones: an organic lab experiment

An undergraduate organic lab experiment is described based on the preparation of two readily accessible hydrazones. The UV-visible spectra of these N-H acids and of their conjugate bases are employed to illustrate the importance of through-conjugation in determining their acid strength and their internal charge-transfer-band transitions.

Las tierras chaqueñas de Genara, hija de Carlos Casado del Alisal. El Chaco Paraguayo en el periodo de entreguerras (1870-1932. Segunda parte.

Genara Casado de Sastre apeló el fallo en el juicio que seguía contra la Sociedad Rosarina de Campos y Bosques por el lote 69 del Chaco Paraguayo. Pero los camaristas concluyeron que el causante del error había sido José Monte, quien al adquirir los lotes 70 a79 a nombre de Casado, había invadido tierras que no le correspondían, y vendido a Casado inmuebles ajenos, es decir, del Estado. La Cámara afirmó que 'el comprador Casado tampoco pudo transmitir válidamente á sus herederos unos derechos que en realidad no adquirió' hasta Puerto Max, y que 'con toda temeridad' se hizo descender la propiedad chaqueña de los Casado 2 leguas más abajo del Río Paraguay. Sentenció también que los conflictos de tierras entre las diversas empresas y propietarios era 'consecuencia de la enojosa trasposición de los mojones oficiales y judiciales', situación originada en la diversidad de valores aplicados en la medición. En efecto, la legua paragtraya debió haber sido fijada en los lotes de Casado en un equivalente a 5.000 varas o a 4.330 metros, cuando en realidad tenía 4.370 metros de ancho frente al río.

Principals intercanvis de mercaderies entre València Port i la Xina en el període 1996-2014

La present memòria es planteja com una aportació a la comprensió de les últimes dos dècades de relacions comercials amb la Xina des del port de València, en fase d'integració amb el de Sagunt i Gandia, i el seu hinterland constituït a més de pel País Valencià per una àrea que abasta tota la zona est i central de la Península Ibèrica. La Xina és el país protagonista d'entre les economies emergents en l'actualitat, així l'estudi analitza, des d'una perspectiva eminentment valenciana, quins són els principals intercanvis de mercaderies entre València Port i els principals ports de la Xina.

Avaliação do potencial antioxidante de extratos ativos de plantas obtidos por extração com fluido supercrítico

The aim of this work was to evaluate the antioxidant properties of ginger and rosemary extracts, obtained by supercritical extraction. The extracts were characterized by HPLC, GC-MS, phenolic compounds content and antioxidant activity. The main active compounds were identified and high content of phenolic compounds was observed. The extracts presented high antioxidant activity against the free radicals ABTS•+ (350 and 200 mM Trolox/g, for ginger and rosemary, respectively) and DPPH•+ (145 and 80 mM Trolox/g, for ginger and rosemary, respectively). These results suggested that the attained extracts are potential substitutes of synthetic antioxidants used in chemical, food and pharmaceutical industries.

Variabilidad espacial de atributos físicos de un Typic Haplustox de los Llanos Orientales de Colômbia

O objetivo deste trabalho foi estudar o comportamento da variabilidade espacial da resistência mecânica à penetração (RP), da densidade do solo, da densidade de partículas do solo, da porosidade total e dos teores de areia, silte e argila, e as relações existentes entre as propriedades analisadas. O estudo foi desenvolvido em Puerto López (Meta-Colômbia). As amostras do solo foram coletadas em duas profundidades (0 - 0,10 e 0,10 - 0,20 m), em intervalos regulares de 25 m, em malha regular, compreendendo 42 pontos, sendo a RP medida até 0,42 m de profundidade. A RP não se correlacionou com nenhuma propriedade, na primeira profundidade. De 0,10 - 0,20 m de profundidade, a RP correlacionou-se com os teores de silte e areia. Os semivariogramas da RP não apresentaram correlação espacial nas duas profundidades, possivelmente devido ao sistema de preparo do solo, que modifica a dependência espacial na superfície, acarretando maior homogeneidade do solo. As propriedades ajustaram-se a modelos de semivariogramas exponenciais e esféricos. Para a profundidade de 0,10 - 0,20 m, as propriedades não se ajustaram a modelos de semivariogramas, apresentando efeito pepita puro, ou seja, não apresentaram dependência espacial, à exceção da densidade aparente.

Modelagem computacional do fluxo unidimensional de água em meio não saturado do solo

O estudo do fluxo de água em zonas não saturadas do solo é de grande importância para pesquisas relacionadas à disponibilidade hídrica para o desenvolvimento das plantas. Devido ao alto custo, ao tempo demandado e ao esforço humano nas investigações de campo, os modelos matemáticos, aliados às técnicas numéricas e avanços computacionais, constituem-se em uma ferramenta importante na previsão desses estudos. No presente trabalho, objetivou-se solucionar a equação diferencial parcial não linear de Richards mediante a aplicação do Método de Elementos Finitos. Na aproximação espacial, foi empregada a adaptatividade com refinamento "h" na malha de elementos finitos e, na derivada temporal, foi aplicado o esquema de Euler Explícito. A função interpolação polinomial utilizada foi de grau 2, e a que garantiu a conservação de massa da estratégia de adaptação. Para a validação do modelo, foram utilizados dados disponíveis em literatura. A utilização da função interpolação polinomial de grau 2 e o refinamento "h", com considerável redução do tempo de execução da rotina computacional, permitiram uma boa concordância do modelo em comparação a soluções disponíveis na literatura.

Pectus Excavatum / Pectus Carinatum: tratamento cirúrgico

OBJETIVO: Apresentar os resultados obtidos com técnica única para tratamento do Pectus Excavatum e Pectus Carinatum. MÉTODO: De 1976 a 2000 foram operados, 183 portadores de Deformidades da Parede Torácica Anterior sendo 98 Pectus Carinatum (70 P. Carinatum Simétrico, 18 P. Carinatum Lateral a Direita e 10 P. Carinatum Lateral a esquerda), 62 Pectus Excavatum (57 P. Excavatum Simétrico, 4 P. Excavatum Lateral a Direita e um P. Excavatum Lateral a Esquerda), 17 Pectus Carinatum Superior, um Pectus Combinado, quatro Protusões Costais Inferiores e uma Depressão Costal. A indicação foi exclusivamente estética em 182 (99,4%) dos pacientes. Foi utilizada técnica única para Pectus Carinatum e Pectus Excavatum: incisão transversal inframamária; ressecção subpericondral de todas as cartilagens envolvidas na deformidade; dissecção retroesternal mínima; osteotomia esternal anterior, fixação da osteotomia esternal com fios de aço;utilização da placa retroesternal em casos selecionados de Pectus Excavatum; pregueamento dos feixes pericondriais para dar maior rigidez a parede torácica e auxílio na manutenção do esterno na sua posição; drenagem do tecido celular subcutâneo e do plano submuscular, sutura intradérmica da pele. RESULTADOS: Bom ou excelente em 175 (95,6%) dos pacientes. Complicações ocorreram em 14 (7,6%) pacientes: oito casos (4,5%) de seroma; um (0,5%)hematoma de parede; dois (1,0%) caso de dor torácica intensa no pós-operatório; um(1,0%) caso de deiscência parcial da sutura da pele e dois casos (1,0%) de cicatriz hipertrófica que foram tratados com ressecção e betaterapia. CONCLUSÃO: Pelos resultados estéticos alcançados, a esternocondroplastia apresentada está indicada para correção de Pectus Excavatum/Carinatum.

Canine distemper virus detection in asymptomatic and non vaccinated dogs

A quantitative real time polymerase chain reaction (PCR) revealed canine distemper virus presence in peripheral blood samples from asymptomatic and non vaccinated dogs. Samples from eleven domestic dogs with no signs of canine distemper and not vaccinated at the month of collection were used. Canine distemper virus vaccine samples in VERO cells were used as positive controls. RNA was isolated with Trizol®, and treated with a TURBO DNA-free kit. Primers were designed for canine distemper virus nucleocapsid protein coding region fragment amplification (84 bp). Canine b-actin (93 bp) was utilized as the endogenous control for normalization. Quantitative results of real time PCR generated by ABI Prism 7000 SDS Software showed that 54.5% of dogs with asymptomatic canine distemper were positive for canine distemper virus. Dissociation curves confirmed the specificity of the real time PCR fragments. This technique could detect even a few copies of viral RNA and identificate subclinically infected dogs providing accurate diagnosis of this disease at an early stage.

Apoptose na maturação placentária de vacas em diferentes estágios de gestação: evidenciação imuno-histoquímica e bioquímica

Apoptose tem um papel importante na manutenção da homeostase placentária, e o desequilíbrio desse processo pode comprometer a gestação. O objetivo do presente estudo foi avaliar a ocorrencia de apoptose em amostras de placenta de vacas em diferentes fases de gestação. Amostras de placentomos de 15 vacas saudáveis com 4 (n=5), 6 (n=5) e 9 (n=5) meses de gestação foram colhidas e processadas rotineiramente para a histologia, imuno-histoquímica e isolamento de DNA. As lâminas obtidas foram coradas em HE, ou submetidas à análise imuno-histoquímica das proteínas pró-apoptóticas caspase-3 e Bax, e da proteína anti-apoptótica Bcl-2. O DNA isolado foi submetido à eletroforese em gel de agarose para detecção da fragmentação internucleossômica do genoma. Os resultados de histomorfometria revelaram que as células apoptóticas aumentaram progressivamente com o avanço da gestação. Confirmou-se a apoptose pela fragmentação característica do DNA genômico, visualizada pelo clássico "padrão em escada" na eletroforese em gel de agarose. Adcionalmente, a imunoexpressão de caspase-3, Bax e Bcl-2 foram observadas em todas as amostras. Entretanto, a proteína caspase-3 apresentou marcação mais intensa em todos os tempos gestacionais, quando comparada com a marcação das proteínas Bcl-2 e Bax. Esses resultados confirmam e reforçam a importância da apoptose na maturação placentária. Além disto, indica que caspase-3, Bax e Bcl-2 estão envolvidas nos mecanismos de ativação da apoptose pela via intrínseca mitocondrial ao longo da gestação, contribuindo para o equilíbrio fisiológico da celularidade e renovação celular na placenta bovina.

Rock outcrop habitats in the Venezuelan Guayana lowlands: their main vegetation types and floristic components

The Guayana Shield, located in north-eastern South America, consists of a highly complex and composite mosaic of landscape elements. Amongst these, inselbergs are very conspicuous, because of their peculiar shape and their unusual associated vegetation. Geologically, these rock outcrops are part of the underlying ancient igneous-metamorphic basement and occur mainly in the lowlands of the periphery of the shield. As azonal habitats, inselbergs harbour a highly specialized flora. The characteristic vegetation is composed of lithophytic and savanna-like plant communities, as well as low dry forests. As a whole, the vegetation of an inselberg may be interpreted as a mosaic of marginal habitats. Therefore a large number of taxa find suitable niches in a quite condensed space. Gradients of soil depth and water availability are the main factors determining the floristic composition. A preliminary floristic inventory of the Venezuelan inselberg flora comprises 614 vascular plant species. 24% of them are endemic to the Guayana region, 15% are endemic to inselbergs of the Guayana region. The distribution patterns of these latter, eco-endemic species allows to distinguish a northern and a southern inselberg district. The two districts overlap in the Átures area, in the surroundings of Puerto Ayacucho, where a true centre of endemism is located. The distinction into two districts is emphasised by different phytogeographic relations. The southern inselberg district shows connections to the "tepui" flora, whereas the northern district reveals phytogeographic relations to the Caribbean region as well as to the Brazilian Shield. Possible explanations for the floristic interchange across the equator are discussed.

Pituitary glycoprotein hormone a-subunit secretion by cirrhotic patients

Secretion of the a-subunit of pituitary glycoprotein hormones usually follows the secretion of intact gonadotropins and is increased in gonadal failure and decreased in isolated gonadotropin deficiency. The aim of the present study was to determine the levels of the a-subunit in the serum of patients with cirrhosis of the liver and to compare the results obtained for eugonadal cirrhotic patients with those obtained for cirrhotic patients with hypogonadotropic hypogonadism. Forty-seven of 63 patients with cirrhosis (74.6%) presented hypogonadism (which was central in 45 cases and primary in 2), 7 were eugonadal, and 9 women were in normal menopause. The serum a-subunit was measured by the fluorimetric method using monoclonal antibodies. Cross-reactivity with LH, TSH, FSH and hCG was 6.5, 1.2, 4.3 and 1.1%, respectively, with an intra-assay coefficient of variation (CV) of less than 5% and an interassay CV of 5%, and sensitivity limit of 4 ng/l. The serum a-subunit concentration ranged from 36 to 6253 ng/l, with a median of 273 ng/l. The median was 251 ng/l for patients with central hypogonadism and 198 ng/l for eugonadal patients. The correlation between the a-subunit and basal LH levels was significant both in the total sample (r = 0.48, P<0.01) and in the cirrhotic patients with central hypogonadism (r = 0.33, P = 0.02). Among men with central hypogonadism there was a negative correlation between a-subunit levels and total testosterone levels (r = 0.54, P<0.01) as well as free testosterone levels (r = -0.53, P<0.01). In conclusion, although the a-subunit levels are correlated with LH levels, at present they cannot be used as markers for hypogonadism in patients with cirrhosis of the liver.

Expression of p53 protein in pituitary adenomas

Inactivating mutations of TP53, a tumor suppressor gene, are associated with abnormal cell proliferation. Although p53 expression is common in many human malignancies, p53 protein has seldom been evaluated in pituitary tumors. When detected, the percentage of p53-positive cells is low, and, in general, it is exclusive for invasive lesions. The aim of the present study was to use immunohistochemistry to determine the presence of p53 protein in pituitary adenomas from tumor samples of 163 surgeries performed in 148 patients (40% male, 60% female). In 35% of the cases the adenoma was nonfunctional, while in the others it was associated with PRL, GH and/or ACTH endocrine hypersecretion syndrome. Macroadenomas were observed in 83.2% of the cases with available neuroimage evaluation, of which 28% invaded the cavernous, sphenoid and/or ethmoidal sinus, bone, third ventricle or subfrontal lobe. p53 protein was detected in 2/148 patients (1.3%). Immunohistochemistry was positive for PRL and GH in these cases. Due to the high percentage of invasive pituitary adenomas found in our study, the low frequency of p53 detection suggests that it is inadequate as a routine marker for aggressiveness and as a predictive factor of tumor behavior.

Measurement of Ki-67 antigen in 159 pituitary adenomas using the MIB-1 monoclonal antibody

Pituitary adenomas sometimes show rapid growth and recurrence, and about one third invade the structures surrounding the sella turcica. In an attempt to determine aggressive behavior at an early stage, we used the MIB-1 antibody to identify the Ki-67 antigen. The present study was designed to evaluate pituitary adenomatous tissue in terms of secretion and proliferation and to correlate the Ki-67 index with hormone phenotype and invasive behavior. Material from 159 patients submitted to one or more resections of pituitary adenomas was evaluated. Forty-two non-secretory adenomas and 43 adenomas immunoreactive for growth hormone, 19 for prolactin, 18 for growth hormone and prolactin, 16 for adrenocorticotropic hormone (ACTH), and 21 cases of plurihormonal/gonadotropin adenomas were detected by immunohistochemistry. The MIB-1 antibody was positive in 139 samples and the Ki-67 index ranged from 0.16 to 15.48% (mean = 1.22 ± 2.09%), with no significant difference between genders, age groups, or secretory and non-secretory status. The Ki-67 index was higher in ACTH-secreting adenomas. Invasive pituitary adenomas had a significantly higher Ki-67 index (2.01 ± 3.15%) than macroadenomas with or without supra-sellar extension (1.12 ± 1.87%; P = 0.02). The index was not significantly different in the subgroup of adenomas with invasion of the cavernous sinus compared to groups with other types of invasion. We conclude that tumoral proliferative activity evaluated by the detection of the Ki-67 antigen is significantly higher in invasive than noninvasive adenomas, information which can be useful in therapeutic postoperative management since index cut-off values associated with aggressive behavior can be established.