Canakinumab Relieves Symptoms of Acute Flares and Improves Health-Related Quality Of Life (HRQoL) in Difficult-To-Treat Gouty Arthritis Patients by Suppressing Inflammation: Results of a Randomized, Dose-Ranging Study

RATIONALE:We investigated the impact of canakinumab, a fully human anti-interleukin-1b monoclonal antibody on inflammation and HRQoL in gouty arthritis patients.METHODS: In this 8-week, single-blind, dose-ranging study, patients with acute gouty arthritis flares, unresponsive/intolerant or contraindicated to NSAIDs and/or colchicine were randomized to single subcutaneous canakinumab (10, 25, 50, 90, or 150mg, N5143) or single intramuscular triamcinolone acetonide (TA, 40mg, N557). Patients assessed pain (Likert scale), physicians assessed clinical signs of joint inflammation, and HRQoL was recorded using SF-36.RESULTS: At baseline, 98% patients had moderate-to-extreme pain, 85% had moderate/severe joint swelling, 64-79% had elevated inflammatory markers and HRQoL scores indicated impaired physical function. Percentage of patients with no/mild pain was numerically greater in most canakinumab groups vs. TA, 24-72h post-dose; difference significant for 150mg group at these time-points (P<0.05). Canakinumab 150mg was associated with significantly lower Likert scores for tenderness [OR, 3.2; 95% CI, 1.27-7.89; P50.014] and swelling (OR, 2.7; 95% CI, 1.09-6.50, P50.032) at 72h vs. TA; erythema was not different. Median CRP and SAA levels normalized by 7 days post-dose in most canakinumab groups, but remained elevated in TA. Physical function improved at 7 days postdose in all groups, highest improvement for canakinumab 150mg. SF-36 scores for physical functioning and bodily pain with canakinumab 150mg approached US general population scores by 7 days post-dose and exceeded normal values by 8 weeks post-dose.CONCLUSION: Canakinumab 150mg produced significantly greater and rapid pain-relief and improvements in HRQoL vs. TAin acute gouty arthritis patients.

Early high-dose treatment: SCT results from the European High Risk Neuroblastoma Study

Aims: The HR-NBL1 Study of the European SIOP Neuroblastoma Group (SIOPEN) randomised two high dose regimens to learn about potential superiority and toxicity profiles.Patients and Methods: At interim analysis 1483 high risk neuroblastoma patients (893 males) were included since 2002 with either INSS stage 4 disease (1383 pts) above 1 year, or as infants (59 pts) and stage 2&3 of any age (145 pts) with MYCN amplification. The median age at diagnosis was 2.9 years (1 month-19.9 years) with a median follow up of 3 years. Response eligibility criteria prior randomisation after Rapid Cojec Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and at least partial response at skeletal sites with no more than 3, but improved mIBG positive spots and a PBSC harvest of at least 3x10E6 CD34/kgBW. The randomised regimens were BuMel [busulfan oral till 2006, 4x150mg/m² in 4 ED; or intravenous use according to body weight as licenced thereafter; melphalan 140mg/m²/day) and CEM [carboplatinum ctn. infusion (4x AUC 4.1mg/ml.min/day, etoposid ctn. infusion (4x 338mg/m²/day or [4x 200mg/m²/day]*, melphalan (3x70mg/m²/day; 3x60mg/m²/day*;*reduced dosis if GFR< 100ml/min/1.73m²). Supportive care followed institutional guidelines. VOD prophylaxis included ursadiol, but randomised patients were not eligible for the prophylactic defibrotide trial. Local control included surgery and radiotherapy of 21Gy.Results: Of 1483 patients, 584 were being randomised for the high dose question at data lock. A significant difference in event free survival (3-year EFS 49% vs. 33%, p<0.001) and overall survival (3-year OS 61% vs. 48%, p=0.003) favouring the BuMel regimen over the CEM regimen was demonstrated. The relapse/progression rate was significantly higher after CEM (0.60±0.03) than after BuMel (0.48±0.03)(p<0.001). Toxicity data had reached 80% completeness at last analysis. The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p= 0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute HDT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%).Conclusions: The Peto rule of P<0.001 at interim analysis on the primary endpoint, EFS was met. Hence randomization was stopped with BuMel as recommended standard treatment in the HR-NBl1/SIOPEN trial which is still accruing for the randomised immunotherapy question.

Neurotrophic activity of human adipose stem cells isolated from deep and superficial layers of abdominal fat.

New approaches to the clinical treatment of traumatic nerve injuries may one day utilize stem cells to enhance nerve regeneration. Adipose-derived stem cells (ASC) are found in abundant quantities and can be harvested by minimally invasive procedures that should facilitate their use in such regenerative applications. We have analyzed the properties of human ASC isolated from the deep and superficial layers of abdominal fat tissue obtained during abdominoplasty procedures. Cells from the superficial layer proliferate significantly faster than those from the deep layer. In both the deep and superficial layers, ASC express the pluripotent stem cell markers oct4 and nanog and also the stro-1 cell surface antigen. Superficial layer ASC induce the significantly enhanced outgrowth of neurite-like processes from neuronal cell lines when compared with that of deep layer cells. However, analysis by reverse transcription with the polymerase chain reaction and by enzyme-linked immunosorbent assay has revealed that ASC isolated from both layers express similar levels of the following neurotrophic factors: nerve growth factor, brain-derived neurotrophic factor and glial-derived neurotrophic factor. Thus, human ASC show promising potential for the treatment of traumatic nerve injuries. In particular, superficial layer ASC warrant further analysis of their neurotrophic molecules.

Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose.

In mice, vaccination with high peptide doses generates higher frequencies of specific CD8+ T cells, but with lower avidity compared to vaccination with lower peptide doses. To investigate the impact of peptide dose on CD8+ T cell responses in humans, melanoma patients were vaccinated with 0.1 or 0.5 mg Melan-A/MART-1 peptide, mixed with CpG 7909 and Incomplete Freund's adjuvant. Neither the kinetics nor the amplitude of the Melan-A-specific CD8+ T cell responses differed between the two vaccination groups. Also, CD8+ T cell differentiation and cytokine production ex vivo were similar in the two groups. Interestingly, after low peptide dose vaccination, Melan-A-specific CD8+ T cells showed enhanced degranulation upon peptide stimulation, as assessed by CD107a upregulation and perforin release ex vivo. In accordance, CD8+ T cell clones derived from low peptide dose-vaccinated patients showed significantly increased degranulation and stronger cytotoxicity. In parallel, Melan-A-specific CD8+ T cells and clones from low peptide dose-vaccinated patients expressed lower CD8 levels, despite similar or even stronger binding to tetramers. Furthermore, CD8+ T cell clones from low peptide dose-vaccinated patients bound CD8 binding-deficient tetramers more efficiently, suggesting that they may express higher affinity TCRs. We conclude that low peptide dose vaccination generated CD8+ T cell responses with stronger cytotoxicity and lower CD8 dependence.

Evolution of superficial lake water temperature profile under diurnal radiative forcing

In lentic water bodies, such as lakes, the water temperature near the surface typically increases during the day, and decreases during the night as a consequence of the diurnal radiative forcing (solar and infrared radiation). These temperature variations penetrate vertically into the water, transported mainly by heat conduction enhanced by eddy diffusion, which may vary due to atmospheric conditions, surface wave breaking, and internal dynamics of the water body. These two processes can be described in terms of an effective thermal diffusivity, which can be experimentally estimated. However, the transparency of the water (depending on turbidity) also allows solar radiation to penetrate below the surface into the water body, where it is locally absorbed (either by the water or by the deployed sensors). This process makes the estimation of effective thermal diffusivity from experimental water temperature profiles more difficult. In this study, we analyze water temperature profiles in a lake with the aim of showing that assessment of the role played by radiative forcing is necessary to estimate the effective thermal diffusivity. To this end we investigate diurnal water temperature fluctuations with depth. We try to quantify the effect of locally absorbed radiation and assess the impact of atmospheric conditions (wind speed, net radiation) on the estimation of the thermal diffusivity. The whole analysis is based on the results of fiber optic distributed temperature sensing, which allows unprecedented high spatial resolution measurements (∼4 mm) of the temperature profile in the water and near the water surface.

Efeitos de dose de nitrogênio, fósforo e potássio sobre os componentes da produção e a qualidade de bananas 'Prata Anã' no distrito agroindustrial de Jaíba

Com o objetivo de verificar os efeitos da adubação nitrogenada, fosfatada e potássica sobre os componentes da produção e a qualidade de bananas 'Prata Anã', no Distrito Agroindustrial de Jaíba, em Matias Cardoso-MG, foi conduzido um experimento com dez tratamentos constituídos pela combinação de doses (g/touceira) de N, P e K de acordo com uma matriz baconiana, sendo 1: 250-45-700, 2: 250-25-700, 3: 250-70-700, 4: 250-100-700, 5: 250-45-300, 6: 250-45-500, 7: 250-45-1000, 8: 150-45-700, 9: 400-45-700, 10: 600-45-700. O tratamento um é o de referência, correspondendo às doses adotadas pelos bananicultores da região. O delineamento foi de blocos ao acaso com quatro repetições. Avaliou-se a produção do primeiro ciclo. Os cachos foram colhidos, despencados e avaliados quanto ao número de pencas, número de frutos e massa do cacho, massa média das pencas e massa média, diâmetro e comprimentos total e comercial do fruto. Os resultados indicaram que as doses de nitrogênio ou fósforo utilizadas pelos produtores de banana do Distrito Agroindustrial de Jaíba podem ser reduzidas para 150 ou 25 g/touceira, respectivamente, sem prejuízo para a produção e qualidade dos frutos. Por outro lado, as doses de potássio até 1000 g/touceira, parceladas semanalmente, proporcionaram aumentos significativos na massa, comprimento total e comercial do fruto.

Crescimento e produtividade do mamoeiro fertirrigado com fósforo por gotejamento superficial e subsuperficial

O presente trabalho teve como objetivo determinar o efeito da freqüência de aplicação de fósforo via água de irrigação por gotejamento superficial e subsuperficial no crescimento e na produtividade do mamoeiro (Carica papaya L.), do grupo Formosa, cultivar Tainung nº 1. As variáveis de crescimento avaliadas foram: índice de área foliar, altura da planta e diâmetro do caule, mediante amostragens aos 39; 69; 182 e 317 dias após o plantio (DAP). O experimento seguiu um delineamento em blocos casualizados, num esquema fatorial 2 x 4 + 1, com três repetições e doze plantas por parcela. Foram avaliados dois sistemas de microirrigação (gotejamento subsuperficial e superficial) e quatro freqüências de fertirrigação com fósforo (30; 60; 90 e 120 dias) via água de irrigação, utilizando como fonte o fosfato monoamônico (MAP), mais um tratamento com adubação convencional via sólida, utilizando o superfosfato simples. As análises de variância indicaram que houve efeito significativo do sistema de irrigação aos 317 DAP na variável de crescimento altura da planta e efeito da interação sistema x freqüência de fertirrigação no diâmetro do caule aos 69 DAP e índice de área foliar aos 182 DAP. O fósforo, quando aplicado via fertirrigação nas freqüências de 30 e 60 dias, nos sistemas superficial e subsuperficial, proporcionou melhores resultados nas variáveis de crescimento e na produtividade. Em todas as variáveis de crescimento analisadas, bem como na produtividade, os tratamentos fertirrigados foram, em média, superiores ao tratamento com adubação convencional.

Aplicação superficial de calcário em pomar de laranjeira pêra em produção

A citricultura paulista é a maior do mundo, sendo de extrema importância manejos que visem a aumentar e melhorar a produção de frutos. Com vistas a isso, foi instalado na EECB (Bebedouro-SP), em um Latossolo Vermelho distrófico típico, um experimento com a aplicação de cinco doses de calcário calcinado, em julho/99. Os efeitos no solo foram avaliados através de amostragens nas camadas de 0-10; 10-20; 20-40 e 40-60 cm, aos 6; 12; 18; 24; 30 e 36 meses. Através da utilização de modelos lineares, constatou-se que os efeitos da aplicação superficial de calcário no solo podem atingir até a camada de 20-40 cm, sendo a saturação por bases uma ótima característica indicadora da ação do corretivo. A máxima reação do calcário ocorreu entre 12 e 18 meses após a aplicação. O estado nutricional das plantas e a produção foram alterados, significativamente em função da aplicação superficial de calcário, sendo que melhores respostas da planta foram obtidas com saturação por bases de aproximadamente 50%.

Ultra-low dose - new approaches in menopausal hormone therapy.

Despite increasing life expectancy, the age of onset of natural menopause has not significantly changed in recent decades. Thus, women spend about one-third of their lives in an estrogen-deficient state if untreated. There is a need for appropriate treatment of acute symptoms and prevention of the sequelae of chronic estrogen deficiency. International guidelines call for the use of the lowest effective hormone dosage for vasomotor symptom relief, the major indication for menopausal hormone therapy (MHT). In 2011, an oral continuous combined ultra-low-dose MHT was approved in Switzerland. This publication was elaborated by eight national menopause specialists and intends to review the advantages and disadvantages of ultra-low-dose MHT after the first years of its general use in Switzerland. It concludes that, for many women, ultra-low-dose MHT may be sufficient to decrease vasomotor symptoms, but not necessarily to guarantee fracture prevention.

Captación de escorrentía superficial en redes de drenaje urbano

Els sistema de captación superficial en redes alcantarillado, imbornales y rejas, es el encargo de que la escorrentía se introduzca en los colectores, por lo que su papel en el drenaje es fundamental. A pesar de lo obvio de la consideración que antecede, en la práctica no se presta la suficiente atención al cálculo de dicho sistema de captación. Diversos son los motivos, entre ellos, la falta de información sobre la capacidad hidráulica de las estructuras comercializadas. El presente artículo pretende contribuir a que se tome en consideración la necesidad de optimizar el diseño de los sistemas de captación, para evitar funcionamientos ineficaces de la red de colectores de nuestras poblaciones.

Distribuição da biomassa e minerais em "família" de bananeira 'prata-anã' adubada com zinco via broto desbastado

O Norte de Minas Gerais cultiva basicamente bananeira 'Prata-Anã', cultivar especialmente exigente em zinco. A possibilidade de fornecimento de Zn, sem que esse entre em contato com o solo, é importante para a região, uma vez que vários fatores levam à baixa disponibilidade do elemento fornecido via solo, como: elevado teor de matéria orgânica na camada superficial (resultante de resíduos culturais); manutenção de elevado pH do solo - acima de 6,00 - como estratégia contrária à proliferação do agente causal do mal- do-panamá; adubações frequentes com potássio e magnésio, que além de basificar o meio, diminuem a participação do Zn no equilíbrio cátion-ânion do solo, dificultando a absorção deste micronutriente pela planta. Para determinar a distribuição de biomassa e minerais na bananeira Prata-Anã, cultivada sob irrigação no norte de Minas Gerais, quando o zinco é fornecido via broto desbastado, foi conduzido um experimento no Perímetro Irrigado de Jaíba. As plantas foram adubadas com 0,00; 1,66 e 3,33 g.família-1 de Zn (0; 25 e 50 g.família-1.ano-1 de sulfato de Zn), via muda desbastada. Um mês após as adubações de outubro de 2007 e junho de 2008, avaliaram-se a produção de massa fresca (MF) e massa seca (MS), os teores e conteúdos de minerais em todos os órgãos de uma ''família'' de bananeira composta por planta-mãe com cacho + planta-filha alta + planta-neta. As doses de Zn não influíram na produção de MF e MS das plantas na primeira avaliação, enquanto na segunda avaliação observou-se efeito positivo do tratamento apenas para MF acumulada nas folhas inferiores, nas porções do terço médio e inferior do pseudocaule, e no rizoma da planta-mãe. Tanto o teor quanto o acúmulo de nutrientes nas plantas-mãe apresentaram a seguinte ordem decrescente: K > N > Ca > Mg > P > S > Fe > Zn > B > Cu. Os teores de Zn foram afetados pela dose desse micronutriente na maioria das situações estudadas. O Zn fornecido via broto desbastado ascendeu na planta-mãe, e daí se redistribuiu na ''família'' da bananeira.

Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Mephedrone is a drug of abuse marketed as 'bath salts'. There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings.