Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Mudanças da fertilidade do solo e crescimento de um povoamento de Eucalyptus grandis fertilizado com biossólido

Antes da recomendação em larga escala de biossólido em plantações florestais, é preciso compreender seus efeitos no solo e na planta. Assim, a fertilidade do solo, o estado nutricional e o crescimento de um povoamento de Eucalyptus grandis fertilizado com biossólido foram avaliados em um experimento na Estação Experimental de Ciências Florestais de Itatinga (SP), ESALQ/USP. O delineamento experimental foi o de blocos casualizados, com quatro blocos e nove tratamentos: (1) Testemunha; (2) Adubação mineral; (3) 5 t ha-1 de bios. + K; (4) 10 t ha-1 de bios. + K; (5) 10 t ha-1 de bios.; (6) 10 t ha-1 de bios. + K + P; (7) 15 t ha-1 de bios. + K; (8) 20 t ha-1 de bios. + K, e (9) 40 t ha-1 de bios. + K. Foram analisadas quimicamente amostras de solo (camadas de 0-5, 5-10 e 10-20 cm) e de folhas. A produção de madeira foi avaliada por meio da colheita e pesagem de árvores. Até 32 meses após a aplicação do biossólido, 36 meses pós-plantio, constataram-se aumentos do pH, dos teores de C orgânico, de P-resina e de Ca trocável nas três camadas, diretamente associados às doses de biossólido aplicadas. Os teores de S-SO4(2-) e K trocável diminuíram 13 meses após a aplicação do biossólido e, 19 meses depois, os teores estavam aumentados. O Al trocável diminuiu com o aumento das doses de biossólido, nas três camadas amostradas. A aplicação de biossólido influiu positivamente na nutrição das plantas, proporcionando uma produção de madeira igual à obtida no tratamento que só recebeu adubação mineral (1,5 t ha-1 de calcário dolomítico e, em kg ha-1, 98 de N, 79,5 de P2O5, 165 de K2O, 1,3 de B e 1,2 de Zn), quando a dose de biossólido foi equivalente a 12 t ha-1.

Integrated Analysis of High-Resolution Gene Expression and Copy Number Profiling Identified Biallelic Deletion of CDKN2A/2B Tumor Suppressor Locus As the Most Frequent and Unique Genomic Abnormality in Diffuse Large B-Cell Lymphoma (DLBCL) with Strong Prognostic Value in Both GCB and ABC Subtypes and Not Overcome by a Dose-Intensive Immunochemotherapy Regimen Plus Rituximab. Results of a Prospective GELA Clinical Trial Program

Background and aim of the study: Genomic gains and losses play a crucial role in the development and progression of DLBCL and are closely related to gene expression profiles (GEP), including the germinal center B-cell like (GCB) and activated B-cell like (ABC) cell of origin (COO) molecular signatures. To identify new oncogenes or tumor suppressor genes (TSG) involved in DLBCL pathogenesis and to determine their prognostic values, an integrated analysis of high-resolution gene expression and copy number profiling was performed. Patients and methods: Two hundred and eight adult patients with de novo CD20+ DLBCL enrolled in the prospective multicentric randomized LNH-03 GELA trials (LNH03-1B, -2B, -3B, 39B, -5B, -6B, -7B) with available frozen tumour samples, centralized reviewing and adequate DNA/RNA quality were selected. 116 patients were treated by Rituximab(R)-CHOP/R-miniCHOP and 92 patients were treated by the high dose (R)-ACVBP regimen dedicated to patients younger than 60 years (y) in frontline. Tumour samples were simultaneously analysed by high resolution comparative genomic hybridization (CGH, Agilent, 144K) and gene expression arrays (Affymetrix, U133+2). Minimal common regions (MCR), as defined by segments that affect the same chromosomal region in different cases, were delineated. Gene expression and MCR data sets were merged using Gene expression and dosage integrator algorithm (GEDI, Lenz et al. PNAS 2008) to identify new potential driver genes. Results: A total of 1363 recurrent (defined by a penetrance > 5%) MCRs within the DLBCL data set, ranging in size from 386 bp, affecting a single gene, to more than 24 Mb were identified by CGH. Of these MCRs, 756 (55%) showed a significant association with gene expression: 396 (59%) gains, 354 (52%) single-copy deletions, and 6 (67%) homozygous deletions. By this integrated approach, in addition to previously reported genes (CDKN2A/2B, PTEN, DLEU2, TNFAIP3, B2M, CD58, TNFRSF14, FOXP1, REL...), several genes targeted by gene copy abnormalities with a dosage effect and potential physiopathological impact were identified, including genes with TSG activity involved in cell cycle (HACE1, CDKN2C) immune response (CD68, CD177, CD70, TNFSF9, IRAK2), DNA integrity (XRCC2, BRCA1, NCOR1, NF1, FHIT) or oncogenic functions (CD79b, PTPRT, MALT1, AUTS2, MCL1, PTTG1...) with distinct distribution according to COO signature. The CDKN2A/2B tumor suppressor locus (9p21) was deleted homozygously in 27% of cases and hemizygously in 9% of cases. Biallelic loss was observed in 49% of ABC DLBCL and in 10% of GCB DLBCL. This deletion was strongly correlated to age and associated to a limited number of additional genetic abnormalities including trisomy 3, 18 and short gains/losses of Chr. 1, 2, 19 regions (FDR < 0.01), allowing to identify genes that may have synergistic effects with CDKN2A/2B inactivation. With a median follow-up of 42.9 months, only CDKN2A/2B biallelic deletion strongly correlates (FDR p.value < 0.01) to a poor outcome in the entire cohort (4y PFS = 44% [32-61] respectively vs. 74% [66-82] for patients in germline configuration; 4y OS = 53% [39-72] vs 83% [76-90]). In a Cox proportional hazard prediction of the PFS, CDKN2A/2B deletion remains predictive (HR = 1.9 [1.1-3.2], p = 0.02) when combined with IPI (HR = 2.4 [1.4-4.1], p = 0.001) and GCB status (HR = 1.3 [0.8-2.3], p = 0.31). This difference remains predictive in the subgroup of patients treated by R-CHOP (4y PFS = 43% [29-63] vs. 66% [55-78], p=0.02), in patients treated by R-ACVBP (4y PFS = 49% [28-84] vs. 83% [74-92], p=0.003), and in GCB (4y PFS = 50% [27-93] vs. 81% [73-90], p=0.02), or ABC/unclassified (5y PFS = 42% [28-61] vs. 67% [55-82] p = 0.009) molecular subtypes (Figure 1). Conclusion: We report for the first time an integrated genetic analysis of a large cohort of DLBCL patients included in a prospective multicentric clinical trial program allowing identifying new potential driver genes with pathogenic impact. However CDKN2A/2B deletion constitutes the strongest and unique prognostic factor of chemoresistance to R-CHOP, regardless the COO signature, which is not overcome by a more intensified immunochemotherapy. Patients displaying this frequent genomic abnormality warrant new and dedicated therapeutic approaches.

Conversant amb Ignasi Terradas i Saborit. Antropologia, universitat i societat: la necessitat d'una lectura crítica de l'actualitat

A través d'aquesta entrevista, Ignasi Terradas i Saborit, catedràtic d'antropologia social de la Universitat de Barcelona, ens transmet la seva visió sobre la nostre disciplina, ens explica per què creu que actualment ja no la defineix el famós mètode del treball de camp i per què en canvi s'ha de definir pels seus objectius i continguts, si volem que conservi la seva capacitat crítica. Ens parla també del realisme etnogràfic com a la forma més fiable d¿encarar la comparació intercultural i intersocietal i el coneixement antropològic en general i de l¿àmbit de l'antropologia jurídica, al qual s¿ha dedicat en els darrers anys. Tot en el marc d'una reflexió crítica d'ampli abast sobre la seva pròpia trajectòria acadèmica, sobre la situació actual de la universitat, sotmesa a importants reformes, i sobre el que creu que ha de ser el compromís èticosocial del professor-investigador. Veurem com hi té un paper important la resistència davant el que anomena liberalisme vulgar o groller.

Is Less Chemotherapy Detrimental in Adults with Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with High-Dose Imatinib? Results of the Prospective Randomized Graaph-2005 Study

Aim: To compare a less intensive regimen based on high-dose imatinib (IM) to an intensive IM/HyperCVAD regimen in adults with Ph+ ALL, in terms of early response and outcome after stem cell transplantation (SCT). Methods: Patients aged 18-60 years with previously untreated Ph+ ALL not evolving from chronic myeloid leukemia were eligible if no contra-indication to chemotherapy and SCT (ClinicalTrials.gov ID, NCT00327678). After a steroid prephase allowing Ph and/or BCR-ABL diagnosis, cycle 1 differed between randomization arms. In arm A (IM-based), IM was given at 800 mg on day 1-28, combined with vincristine (2 mg, day 1, 8, 15, 22) and dexamethasone (40 mg, day 1-2, 8-9, 15-16, and 22-23) only. In arm B (IM/HyperCVAD), IM was given at 800 mg on day 1-14, combined with adriamycin (50 mg/m2, day 4), cyclophosphamide (300 mg/m2/12h, day 1, 2, 3), vincristine (2 mg, day 4 and 11), and dexamethasone (40 mg, day 1-4 and 11-14). All patients received a cycle 2 combining high-dose methotrexate (1 g/m2, day 1) and AraC (3 g/m2/12h, day 2 and 3) with IM at 800 mg on day 1-14, whatever their response. Four intrathecal infusions were given during this induction/consolidation period. Minimal residual disease (MRD) was centrally evaluated by quantitative RQ-PCR after cycle 1 (MRD1) and cycle 2 (MRD2). Major MRD response was defined as BCR-ABL/ABL ratio <0.1%. Then, all patients were to receive allogeneic SCT using related or unrelated matched donor stem cells or autologous SCT if no donor and a major MRD2 response. IM/chemotherapy maintenance was planned after autologous SCT. In the absence of SCT, patients received alternating cycles 1 (as in arm B) and cycles 2 followed by maintenance, like in the published IM/HyperCVAD regimen. The primary objective was non-inferiority of arm A in term of major MRD2 response. Secondary objectives were CR rate, SCT rate, treatment- and transplant-related mortality, relapse-free (RFS), event-free (EFS) and overall (OS) survival. Results: Among the 270 patients randomized between May 2006 and August 2011, 265 patients were evaluable for this analysis (133 arm A, 132 arm B; median age, 47 years; median follow-up, 40 months). Main patient characteristics were well-balanced between both arms. Due to higher induction mortality in arm B (9 versus 1 deaths; P=0.01), CR rate was higher in the less intensive arm A (98% versus 89% after cycle 1 and 98% versus 91% after cycle 2; P= 0.003 and 0.006, respectively). A total of 213 and 205 patients were evaluated for bone marrow MRD1 and MRD2. The rates of patients reaching major MRD response and undetectable MRD were 45% (44% arm A, 46% arm B; P=0.79) and 10% (in both arms) at MRD1 and 66% (68% arm A, 63.5% arm B; P=0.56) and 25% (28% arm A, 22% arm B; P=0.33) at MRD2, respectively. The non-inferiority primary endpoint was thus demonstrated (P= 0.002). Overall, EFS was estimated at 42% (95% CI, 35-49) and OS at 51% (95% CI, 44-57) at 3 years, with no difference between arm A and B (46% versus 38% and 53% versus 49%; P=0.25 and 0.61, respectively). Of the 251 CR patients, 157 (80 arm A, 77 arm B) and 34 (17 in both arms) received allogeneic and autologous SCT in first CR, respectively. Allogeneic transplant-related mortality was similar in both arms (31.5% versus 22% at 3 years; P=0.51). Of the 157 allografted patients, 133 had MRD2 evaluation and 89 had MRD2 <0.1%. In these patients, MRD2 did not significantly influence post-transplant RFS and OS, either when tested with the 0.1% cutoff or as a continuous log covariate. Of the 34 autografted patients, 31 had MRD2 evaluation and, according to the protocol, 28 had MRD2 <0.1%. When restricting the comparison to patients achieving major MRD2 response and with the current follow-up, a trend for better results was observed after autologous as compared to allogeneic SCT (RFS, 63% versus 49.5% and OS, 69% versus 58% at 3 years; P=0.35 and P=0.08, respectively). Conclusions: In adults, the use of TK inhibitors (TKI) has markedly improved the results of Ph+ ALL therapy, now close to those observed in Ph-negative ALL. We demonstrated here that chemotherapy intensity may be safely reduced when associated with high-dose IM. We will further explore this TKI-based strategy using nilotinib prior to SCT in our next GRAAPH-2013 trial. The trend towards a better outcome after autologous compared to allogeneic SCT observed in MRD responders validates MRD as an important early surrogate endpoint for treatment stratification and new drug investigation in this disease.

A Dose-Response Strategy Reveals Differences between Normal-Weight and Obese Men in Their Metabolic and Inflammatory Responses to a High-Fat Meal.

A dose-response strategy may not only allow investigation of the impact of foods and nutrients on human health but may also reveal differences in the response of individuals to food ingestion based on their metabolic health status. In a randomized crossover study, we challenged 19 normal-weight (BMI: 20-25 kg/m(2)) and 18 obese (BMI: >30 kg/m(2)) men with 500, 1000, and 1500 kcal of a high-fat (HF) meal (60.5% energy from fat). Blood was taken at baseline and up to 6 h postprandially and analyzed for a range of metabolic, inflammatory, and hormonal variables, including plasma glucose, lipids, and C-reactive protein and serum insulin, glucagon-like peptide-1, interleukin-6 (IL-6), and endotoxin. Insulin was the only variable that could differentiate the postprandial response of normal-weight and obese participants at each of the 3 caloric doses. A significant response of the inflammatory marker IL-6 was only observed in the obese group after ingestion of the HF meal containing 1500 kcal [net incremental AUC (iAUC) = 22.9 ± 6.8 pg/mL × 6 h, P = 0.002]. Furthermore, the net iAUC for triglycerides significantly increased from the 1000 to the 1500 kcal meal in the obese group (5.0 ± 0.5 mmol/L × 6 h vs. 6.0 ± 0.5 mmol/L × 6 h; P = 0.015) but not in the normal-weight group (4.3 ± 0.5 mmol/L × 6 h vs. 4.8 ± 0.5 mmol/L × 6 h; P = 0.31). We propose that caloric dose-response studies may contribute to a better understanding of the metabolic impact of food on the human organism. This study was registered at clinicaltrials.gov as NCT01446068.

Época de aplicação da primeira dose de nitrogênio em cobertura em milho e espécies antecessoras de cobertura de inverno

Atualmente, os critérios utilizados no Sul do Brasil para definição da dose de nitrogênio (N) a ser aplicada no milho são o teor de matéria orgânica no solo, a expectativa de rendimento da cultura e as características da cultura antecessora. Embora apresente alta relação carbono:nitrogênio (C/N), a aveia preta é a espécie de cobertura de solo de inverno mais utilizada como antecessora às culturas comerciais de verão. Essa característica pode resultar em imobilização do N do solo, deficiência de N na planta de milho e redução no rendimento de grãos. Embora na determinação da dose a ser aplicada sejam consideradas as espécies antecessoras, os avanços quanto à melhor época para aplicar N em cobertura em milho foram pequenos. Com o objetivo de avaliar a época mais adequada para aplicação da primeira dose de N em cobertura no milho cultivado em sucessão a espécies de inverno com distintas relações C/N, um experimento foi realizado em vasos em casa de vegetação em Porto Alegre-RS. Utilizaram-se colunas de solo não deformado, classificado como Argissolo Vermelho distrófico típico. Os tratamentos constaram de quatro sistemas de coberturas de solo de inverno (aveia preta, ervilhaca comum, nabo forrageiro e pousio) e três formas de manejo de N em cobertura (com aplicação de N nos estádios V3 ou V5 e sem aplicação de N em cobertura). O delineamento experimental foi o completamente casualizado, em esquema fatorial 4 x 3, com três repetições. Procedeu-se à análise de variância pelo teste F e à comparação de médias pelo teste de Tukey (p < 0,05). A aveia, que tem alta relação C/N, apresentou baixa taxa de mineralização e de liberação de N de seus resíduos, enquanto as culturas de ervilhaca comum e nabo forrageiro mostraram relação C/N mais estreita, estimulando esses processos. Com o uso de aveia como cultura antecessora ao milho, verificou-se diminuição dos teores de N mineral no solo e de N total na planta de milho, independentemente da época de aplicação de N em cobertura, diminuindo o desenvolvimento inicial da planta. Em sucessão à ervilhaca comum e ao nabo forrageiro, o teor relativo de clorofila na folha e a produção de massa seca de milho, avaliados no estádio V7, foram maiores em relação aos obtidos em sucessão à aveia preta, independentemente da época de aplicação da primeira dose de N em cobertura. Os dados obtidos evidenciaram ser possível retardar a época de aplicação da primeira dose de N em cobertura em milho do estádio V3 para V5, quando o milho for cultivado em sucessão a espécies de inverno com baixa relação C/N.

Fluxo difusivo de micronutrientes catiônicos afetado pelo tipo, dose e época de incorporação de adubos verdes ao solo

Os solos brasileiros, principalmente os do cerrado, são bastante intemperizados e pobres em alguns micronutrientes catiônicos na solução do solo. A utilização de técnicas de manejo, como a adubação verde, pode favorecer o fluxo difusivo (FD) e a disponibilidade desses nutrientes para as plantas. O presente trabalho visou avaliar se a incorporação de adubos verdes ao solo, em diferentes doses e épocas, modifica o FD e a forma iônica de transporte dos micronutrientes Zn, Cu, Fe e Mn no solo. Para tanto, foram incorporados dois resíduos vegetais largamente cultivados como adubo verde: o feijão guandu (Cajanus cajan) ou o milheto (Pennisetum americanum) por diferentes períodos (0, 15, 25, 35, 45 e 55 dias) e doses (0, 9, 18 e 36 t ha-1) num Latossolo Vermelho, argiloso, em condições de laboratório. Para avaliar o FD, utilizaram-se resinas de troca aniônica (positivamente carregada) e de troca catiônica (negativamente carregada) na forma de lâmina, incubadas junto ao solo em câmaras de difusão durante 15 dias. Os resultados obtidos demonstraram que houve aumento do FD do Cu e do Fe com o aumento das doses de material vegetal, principalmente no início do período de incubação, e maior fluxo desses dois micronutrientes para a resina aniônica em relação à catiônica, possivelmente por ser o seu transporte no solo mais dependente da formação de complexos organometálicos com carga líquida negativa. Já para Zn e Mn, o fluxo difusivo foi maior para a resina catiônica. O aumento do tempo de incubação favoreceu o fluxo difusivo de Mn e Zn e reduziu o do Cu e Fe.

When "enough" is not enough: new perspectives on optimal methadone maintenance dose.

Some methadone maintenance treatment (MMT) programs prescribe inadequate daily methadone doses. Patients complain of withdrawal symptoms and continue illicit opioid use, yet practitioners are reluctant to increase doses above certain arbitrary thresholds. Serum methadone levels (SMLs) may guide practitioners dosing decisions, especially for those patients who have low SMLs despite higher methadone doses. Such variation is due in part to the complexities of methadone metabolism. The medication itself is a racemic (50:50) mixture of 2 enantiomers: an active "R" form and an essentially inactive "S" form. Methadone is metabolized primarily in the liver, by up to five cytochrome P450 isoforms, and individual differences in enzyme activity help explain wide ranges of active R-enantiomer concentrations in patients given identical doses of racemic methadone. Most clinical research studies have used methadone doses of less than 100 mg/day [d] and have not reported corresponding SMLs. New research suggests that doses ranging from 120 mg/d to more than 700 mg/d, with correspondingly higher SMLs, may be optimal for many patients. Each patient presents a unique clinical challenge, and there is no way of prescribing a single best methadone dose to achieve a specific blood level as a "gold standard" for all patients. Clinical signs and patient-reported symptoms of abstinence syndrome, and continuing illicit opioid use, are effective indicators of dose inadequacy. There does not appear to be a maximum daily dose limit when determining what is adequately "enough" methadone in MMT.

Curva de crescimento e marcha de absorção de macronutrientes em mudas de goiabeira

A utilização de mudas de goiabeira com adequado estado nutricional determina o sucesso da implantação de um pomar. O objetivo deste trabalho foi determinar crescimento e acúmulo de macronutrientes em mudas de duas cultivares de goiabeira obtidas por estaquia herbácea. O delineamento utilizado foi o inteiramente casualizado, com parcelas subdivididas, com três repetições. Assim, foram utilizadas como parcelas duas cultivares de goiabeira (Paluma e Século XXI) e, como subparcelas, sete coletas de plantas ao longo do período experimental (120 dias), em solução nutritiva. As plantas foram avaliadas quinzenalmente quanto a: altura, número de folhas, diâmetro do caule, área foliar e massa de matéria seca (folhas, caule e raízes). Nos diferentes órgãos das mudas, determinou-se o acúmulo de macronutrientes. Houve acúmulo quadrático de matéria seca das mudas de goiabeira com o tempo de cultivo. A muda de goiabeira da cultivar Século XXI tem maior exigência de macronutrientes que a da cultivar Paluma, e o período de maior exigência é a partir dos 75 e 45 dias, para ambas as cultivares. O acúmulo de macronutrientes pelas mudas de goiabeira das cultivares Paluma e Século XXI foi de: K (726 e 696), N (552 e 585), Ca (293 e 302), S (73 e 66), P (64 e 66) e Mg (39 e 41) mg por planta, respectivamente.

"Las normas de la casa de la sidra": una crítica de la heteronomía

Las normas de la bioética han de ser nuestras propias normas y, por lo tanto, las normasjurídicas que regulan cuestiones bioéticas han de dejar el mayor margen posible para la toma de decisiones autónomas...

Cultivo de cana-de-açúcar em argissolo tratado com lodo de esgoto: II - Fertilidade do solo e nutrição da planta

A reciclagem do lodo de esgoto em solos agrícolas é uma das formas mais racionais de utilização desse material. Este trabalho teve por objetivo estudar o efeito da aplicação de lodo de esgoto em alguns atributos químicos de um Argissolo cultivado com cana-de-açúcar por dois anos. O experimento foi instalado em um Argissolo Vermelho distrófico cultivado com a variedade RB855536. O ensaio foi realizado durante dois períodos (outubro de 2002 a agosto de 2003 - ano agrícola 2003/04 e outubro de 2003 a outubro de 2004 - ano agrícola 2004/05). Os tratamentos testados foram oito: (a) Controle; (b) Fertilização Mineral (120 kg ha-1 N + 150 kg ha-1 K2O); c) LE + 0N, incorporado no solo após a aplicação (ISA); (d) LE + 0N, incorporado no solo 60 dias após a aplicação (IS60A); (e) LE + 60 kg ha-1 N (ISA); (f) LE + 60 kg ha-1 N (IS60A); (g) LE + 120 kg ha-1 N (ISA); e (h) LE + 120 kg ha-1 N (IS60A). O lodo de esgoto foi resultante de tratamento biológico e aeróbio, e a dose aplicada foi calculada em função da mineralização do N e suficiente para fornecer 120 kg ha-1 de N. Os resultados mostram que a aplicação do lodo causou incrementos nos teores de C do solo, sendo aqueles verificados no segundo ano maiores dos que os do primeiro. A incorporação do LE 60 dias após sua aplicação resultou nos maiores teores de C, provavelmente em função da desidratação do resíduo e do menor contato deste com as partículas do solo. Os demais atributos avaliados (pH, P, K, Ca e Mg) não foram alterados com a aplicação do resíduo. Apesar disso, nas folhas, os tratamentos com lodo apresentaram os maiores teores de P, indicando que o LE pode ter atuado como fonte do nutriente. Verificou-se aumento nos teores de Cu e Zn disponíveis no solo com a aplicação do LE. Os teores de metais, nutrientes e não-nutrientes de plantas, estiveram dentro das faixas consideradas adequadas, tanto no solo quanto nas folhas de cana-de-açúcar, mesmo com a reaplicação do lodo. Apesar de esses metais terem sido adicionados no solo, via LE, não foi observado aumento nos teores de Cd, Cr, Ni e Pb no solo com a aplicação do resíduo. De maneira similar, os teores desses elementos nas folhas não foram alterados pela adição de lodo no solo.

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Influence of the timing of low-dose aspirin on tolerability of prolonged-release nicotinic acid in patients at elevated cardiovascular risk

OBJECTIVES: To investigate the effect of low-dose aspirin administered in the morning or evening on the rate of discontinuation of prolonged-release nicotinic acid (Niaspan) due to flushing in patients at elevated cardiovascular risk. RESEARCH DESIGN AND METHODS: This was an observational, non-interventional study in patients at elevated cardiovascular risk due to cardiovascular disease or type 2 diabetes. Patients received prolonged-release nicotinic acid and aspirin under the usual care of their physician for 15 weeks. MAIN OUTCOME MEASURES: The main outcome measure was the rate of treatment discontinuation for flushing. Other adverse drug reactions (ADRs) were also recorded. Lipid parameters were also measured. RESULTS: The patient population included 539 subjects (70% male); 36% had type 2 diabetes, 80% had prior cardiovascular disease, and 37% had a family history of cardiovascular disease. The rate of treatment discontinuation due to flushing did not differ (p = 0.3375) between the morning aspirin group (10.6%) and the evening aspirin group (13.8%). The overall incidence of flushing was 57%. Most flushes were of mild or moderate severity and decreases occurred over time in both frequency and intensity. ADRs unrelated to flushing occurred in 6.6% of the morning aspirin group and 7.4% of the evening aspirin group. HDL-cholesterol increased by +21.3% in the overall population, together with moderate improvements in other lipid parameters. CONCLUSIONS: Flushing was the most common ADR with prolonged-release nicotinic acid treatment, as expected. The timing of aspirin administration did not influence the rate of treatment discontinuations for flushing. Marked increases in HDL-cholesterol were observed.

Memòria crítica de tres debats escolars

Com reflexió sobre l'ensenyament a l'Escola Elisava i de l'ensenyament del disseny en general, la intervenció pretén tractar els debats que durant molts anys s'havien donat tàcitament entre els diversos estaments acadèmics, mostrant la situació crítica que suposa -especialment per al fràgil disseny- que un qualsevol d'aquests estaments influeixi sobre els altres. A partir de mitjans dels anys 90, la progressiva adopció generalitzada a l'ensenyament superior del model anglosaxó -amb clar predomini del fet institucional- ha mostrat el caràcter premonitori de la crítica que aquí s'exposa.