Pharmacogenetics of OATP Transporters Reveals That SLCO1B1 c.388A > G Variant Is Determinant of Increased Atorvastatin Response

Aims: The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated. Material and Methods: One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot (R) and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (-71T>C) gene polymorphisms were identified by TaqMan (R) Real-time PCR. Results: Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%: 1.3-8.0, p < 0.05). Conclusion: SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy.

Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women

Objectives: To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/ S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status. Subjects/ Methods: Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism ( RFLP). Results: Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios. Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms. In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l. Conclusions: Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.

Loxosceles venom-induced cytokine activation, hemolysis, and acute kidney injury

Herein, we describe a confirmed case of Loxosceles spider bite that illustrates the critical complications seen in loxoscelism, including skin necrosis, rhabdomyolysis, hemolysis, coagulopathy, acute kidney failure, and electrolyte disorders. Upon initial assessment, laboratory studies revealed the following: the white blood cell count was 29 400 WBCs/mm(3), hemoglobin was 9.2g/dL, and the platelet count was 218000cells/mm(3). Coagulation studies revealed the following: international normalized ratio, 1.83; activated partial-thromboplastin time, 62s; D-dimer, 600 ng/mL (normal range < 500 ng/mL); free protein S, 37% (normal range = 64-114%); protein C, negative; and antithrombin III, negative. Various serum levels were abnormal: urea, 110mg/dL; creatinine, 3.1 mg/dL; indirect bilirubin, 3.8 mg/dL; creatine kinase, 1631 U/L, lactate dehydrogenase, 6591 U/L; potassium 6.2mmol/L. Urine tests were positive for hemoglobin and bilirubin. In addition, concentrations of interleukin-6 and tumor necrosis factor-alpha were notably elevated in the serum. In conclusion, physicians must be alert to the possibility of loxoscelism when a patient presents with the clinical and laboratory findings described above, especially if the patient resides in an endemic area. Advances in our understanding of multiple pathways and mediators that orchestrate the response to Loxosceles venom might reveal new possibilities for the management of loxoscelism. (C) 2007 Elsevier Ltd. All rights reserved.

The H63D genetic variant of the HFE gene is independently associated with the virological response to interferon and ribavirin therapy in chronic hepatitis C

Background Conflicting results have been reported in studies evaluating the relationship between serum markers of iron overload, liver iron deposits, and HFE mutations (C282Y and H63D) in chronic hepatitis C patients, and also their impact on the response to therapy in these patients. Aim To evaluate the role of HFE mutations in the severity of liver disease and in the response to therapy in chronic hepatitis C. Methods Two hundred and sixty-four hepatitis C patients treated with standard interferon and ribavirin were divided into two groups according to type of antiviral response: sustained virological response (SVR) and nonresponse or relapse. We evaluated the relationship between HFE mutation and the type of antiviral response, clinical data, biochemical tests, liver histopathology, virological data, and HFE mutations. Results Of the 264 patients, 88 (32.1%) had SVR whereas 67.9% had nonresponse or relapse. Liver iron deposits were observed in 49.2% of the patients. The factors associated with SVR were hepatitis C virus genotype 2 or 3, transferrin saturation value of 45% or less, and detection of the H63D mutation. HFE mutation was more frequent in patients with iron deposits, but without association with serum iron biochemistry or severity of liver disease. Steatosis was more frequent in patients with liver iron deposits. Conclusion The H63D mutation was an independent factor associated with SVR in chronic hepatitis C patients, as also were hepatitis C virus genotype 2 or 3 and transferrin saturation value of 45% or less. Moreover, the H63D mutation was associated with liver iron deposits. Eur J Gastroenterol Hepatol 22: 1204-1210 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Influência da migração na prevalência de marcadores sorológicos de hepatite B em comunidade rural: 2 - Análise comparativa de algumas características das populações estudadas

A associação entre prevalência de marcadores sorológicos de hepatite B e local de nascimento, verificado em estudo realizado num município de características rurais do Estado de São Paulo, Cássia dos Coqueiros, sugere existirem diferenças entre migrantes e não-migrantes no que diz respeito a fatores de risco para hepatite B. Esses dois grupos foram analisados segundo as variáveis escolaridade, ocupação profissional, número de hospitalizações, antecedente de transfusões sangüíneas e tipo de tratamento dentário prévio. A comparação entre os grupos mostra que migrantes, particularmente de outros Estados do País, apresentam baixos níveis de escolaridade, elevadas proporções de lavradores empregados, maior número de internações prévias e maiores exposições a transfusões sangüíneas e a procedimentos odontológicos mais agressivos. Observaram-se ainda associações entre a prevalência de marcadores de hepatite B e as variáveis escolaridade, ocupação profissional, número de hospitalizações e tipo de tratamento odontológico, muito embora as duas últimas não justifiquem as maiores prevalências entre os migrantes. A distribuição diferenciada de marcadores de hepatite B parece ser resultado da pior condição socioeconômica dos migrantes, refletida pelo seu nível inferior de escolaridade e pela predominância de ocupações secundárias.

Optical nonlinearity in Tandem SI-C photodetectors

The behavior of tandem pin heterojunctions based on a-SiC: H alloys is investigated under different optical and electrical bias conditions. The devices are optimized to act as optically selective wavelength filters. Depending on the device configuration (optical gaps, thickness, sequence of cells in the stack structure) and on the applied voltage (positive or negative) and optical bias (wavelength, intensity, frequency) it is possible to combine the wavelength discrimination function with the self amplification of the signal. This wavelength nonlinearity allows the amplification or the rejection of a weak signal-impulse. The device works as an active tunable optical filter for wavelength selection and can be used as an add/drop multiplexer (ADM) which enables data to enter and leave an optical network bit stream without having to demultiplex the stream. Results show that, even under weak transient input signals, the background wavelength controls the output signal. This nonlinearity, due to the transient asymmetrical light penetration of the input channels across the device together with the modification on the electrical field profile due to the optical bias, allows tuning an input channel without demultiplexing the stream. This high optical nonlinearity makes the optimized devices attractive for the amplification of all optical signals. Transfer characteristics effects due to changes in steady state light, control d.c. voltage and applied light pulses are presented. Based on the experimental results and device configuration an optoelectronic model is developed. The transfer characteristics effects due to changes in steady state light, dc control voltage or applied light pulses are simulated and compared with the experimental data. A good agreement was achieved.

Arte romana e pedreiras de mármore na Lusitânia: novos caminhos de investigação

Legar à posteridade em mármore uma cidade que recebeu constraída em tijolo foi uma das alegrias do Imperador Augusto ao fazer um balanço da sua vida, segundo Suetônio'. As propostas urbanísdcas do Princeps transformam-se em modelos para todas as novas cidades e capitais de colônia, incrementando-se deste modo o uso do mármore logo a pardr dos inícios do Império, perdurando ainda bem vivo nos finais do séc. IV, já numa sociedade em grande parte cristianizada. Séneca diz-nos, nos meados do séc. I d. C, que existia o ideal de que as paredes reluzissem com mármores importados da outra banda do mar, que se olhavam com admiração as crustae marmoriae que as revestiam e que era sinal do melhor estatuto caminhar sobre mármores. E Paciano de Barcelona, nos finais do séc. IV, encontra na renúncia ao marmoribus tegi, ao habitar em casas de mármore, uma forma de fazer penitência.

CARACTERIZAÇÃO FÍSICA E QUÍMICA DOS FRUTOS DE ARAÇÁ-PERA (Psidium acutangulumD.C.)

Frutos de araçá-pera (Psidium acutanguium D.C.) em estádio de amadurecimento comercial foram avaliados quanto às características físicas, fisico-químicas e químicas. Houve grande variação no peso dos frutos (47,89 a 138,34 g) e no rendimento em polpa (55,01 a 75,98%). O araçá-pera é um fruto suculento (85,85% de umidade), com baixa relação Brix/ acidez (5,88), baixo pH (3,0) e acidez elevada (1,87% de ácido citrico). Destaca-se como excelente fonte de vitamina C total (389,34 mg l00g-1 de polpa integral). O baixo grau de doçura é fator limitante para o consumo "in natura". Apresenta potencial para industrialização, e para esta finalidade, seus atributos de qualidade são a uniformidade de formato,(levemente arredondado), alto rendimento em polpa, baixo pH e elevadas concentrações de acidez e vitamina C total.

Óleo de andiroba: processo tradicional da extração, uso e aspectos sociais no estado do Amazonas, Brasil

O processo tradicional de extração do óleo das sementes de andiroba foi levantado em três municípios (Anamã, Manacapuru e Silves) no Estado do Amazonas. Em 1992 e 2004, foi aplicado um questionário a 38 extratoras. Sementes das duas espécies de andiroba (Carapa procera D.C. e Carapa guianensis Aubl.) foram utilizadas como matéria prima. O processo tradicional é complexo, demora cerca de dois meses e pode ser dividido em três etapas: 1. A coleta, seleção de sementes boas e um primeiro armazenamento (3-15 dias). 2. O preparo da massa pelo cozimento das sementes em água (1-3 horas), um segundo período de armazenamento (até 20 dias) e finalizada pela retirada da casca e o amassamento das amêndoas. 3. A extração do óleo (até 30 dias), pelo gotejamento colocando a massa sobre uma superfície inclinada. Óleo extraído na sombra foi considerado de melhor qualidade do que no sol, porém o processo é mais demorado. Uma segunda extração com a prensa ("tipiti"), usada na fabricação de farinha, foi raramente empregada. Verificaram-se pequenas variações entre os procedimentos das extratoras, aparentemente com conseqüências na rentabilidade e na qualidade do óleo. Na primeira e segunda etapa da extração participaram membros da família e/ou vizinhos, ao contrário da etapa final, realizada por uma única mulher. Enquanto, transmissão do conhecimento tradicional, em geral, costuma passar de geração por geração pela oralidade e observação, este estudo revelou, que os jovens não participam mais da extração. Fato, que no futuro próximo, pode causar a perda de conhecimento em relação à extração do óleo de andiroba pelo método tradicional.

Inventory of seeds and plants imported / U.S. Department of Agriculture, Bureau of Plant Industry.

62-73, 1923-1924

Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.

BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts. METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications. RESULTS: Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR,1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95%CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03). CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

Recurrence pattern after [(18)F]fluoroethyltyrosine-positron emission tomography-guided radiotherapy for high-grade glioma: a prospective study.

PURPOSE: To assess the failure pattern observed after (18)F fluoroethyltyrosine (FET) planning after chemo- and radiotherapy (RT) for high-grade glioma. METHODS: All patients underwent prospectively RT planning using morphological gross tumour volumes (GTVs) and biological tumour volumes (BTVs). The post-treatment recurrence tumour volumes (RTVs) of 10 patients were transferred on their CT planning. First, failure patterns were defined in terms of percentage of RTV located outside the GTV and BTV. Second, the location of the RTV with respect to the delivered dose distribution was assessed using the RTV's DVHs. Recurrences with >95% of their volume within 95% isodose line were considered as central recurrences. Finally, the relationship between survival and GTV/BTV mismatches was assessed. RESULTS: The median percentages of RTV outside the GTV and BTV were 41.8% (range, 10.5-92.4) and 62.8% (range, 34.2-81.1), respectively. The majority of recurrences (90%) were centrally located. Using a composite target volume planning formalism, the degree of GTV and BTV mismatch did not correlate with survivorship. CONCLUSIONS: The observed failure pattern after FET-PET planning and chemo-RT is primarily central. The target mismatch-survival data suggest that using FET-PET planning may counteract the possibility of BTV-related progression, which may have a detrimental effect on survival.