Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study.

OBJECTIVE: To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, for the treatment of acute gouty arthritis. METHODS: In this 8-week, single-blind, double-dummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n = 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n = 57). Patients assessed pain using a 100-mm visual analog scale. RESULTS: Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of -11.5 mm [P = 0.04], -18.2 mm [P = 0.002], and -19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P ≤ 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity. CONCLUSION: Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.

Fósforo da biomassa microbiana e atividade de fosfatase ácida após aplicação de fosfato em solo no sistema plantio direto

A atividade de fosfatases e a biomassa microbiana são fundamentais no ciclo do fósforo no solo e no seu fornecimento às plantas. Este trabalho analisa os reflexos da aplicação de fósforo na atividade de fosfatase ácida e no acúmulo de fósforo na biomassa microbiana em solo no sistema plantio direto. Em janeiro de 2000, coletaram-se amostras da camada de 0-10 cm nos tratamentos de doses acumuladas de 0, 130, 180, 260, 360, 540, 720, 980 e 1.240 kg ha-1 de P2O5 em seis anos de cultivo de um experimento em Latossolo Vermelho distroférrico típico muito argiloso. Coletaram-se também amostras do solo sob mata nativa, em área próxima ao experimento. Determinaram-se os teores de fósforo na biomasssa microbiana, a atividade de fosfatase ácida, o fósforo total, orgânico e disponível, e o carbono orgânico total. O solo sob mata nativa apresentou os maiores valores de fósforo microbiano, de atividade de fosfatase ácida e de fósforo orgânico. A atividade de fosfatase ácida não foi influenciada pela adição de fosfato. O fósforo contido na biomassa microbiana aumentou com a aplicação recente de fosfato e não foi influenciado pelo fósforo do solo de aplicações anteriores.

Sorção de fósforo em função do teor inicial e de sistemas de manejo de solos

A relação entre o P sorvido/P solução do solo pode ser influenciada pelo teor de P previamente sorvido e pelos sistemas de manejo. Este trabalho teve o objetivo de avaliar as modificações na capacidade de sorção máxima (Pmax) e na constante relacionada com a energia de ligação de P com os colóides (k) da isoterma de Langmuir, provocadas (a) pela inclusão do teor de P previamente sorvido (Ppre) e (b) por sistemas de manejo de solos. Coletaram-se, em maio de 1997, amostras de solo (Latossolo Vermelho distroférrico típico, Latossolo Vermelho distrófico típico e Argissolo Vermelho distrófico típico), em três camadas (0-2,5, 2,5-7,5 e 7,5-17,5 cm), de três experimentos instalados a partir de 1979, envolvendo os sistemas plantio direto e cultivo convencional com diferentes sucessões de cultura. O solo foi equilibrado com oito concentrações de P em solução de CaCl2 0,001 mol L-1. Após a agitação por 16 h, avaliou-se a concentração de P no sobrenadante. Os dados de P-sorvido e P-solução foram ajustados à equação de Langmuir, obtendo-se a Pmax e a k, considerando ou não o Ppre. A inclusão do Ppre no modelo de Langmuir aumenta, em média, 2,9 vezes o valor da k e não afeta a Pmax, no LVdf, e aumenta em todas as camadas, no LVd, e na camada superficial, no PVd. A Pmax é pouco influenciada pelos métodos de preparo do solo, sucessões de culturas e camadas amostradas.

Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex.

Cytotoxic T cell (CTL) activation by antigen requires the specific detection of peptide-major histocompatibility class I (pMHC) molecules on the target-cell surface by the T cell receptor (TCR). We examined the effect of mutations in the antigen-binding site of a Kb-restricted TCR on T cell activation, antigen binding and dissociation from antigen.These parameters were also examined for variants derived from a Kd-restricted peptide that was recognized by a CTL clone. Using these two independent systems, we show that T cell activation can be impaired by mutations that either decrease or increase the binding half-life of the TCR-pMHC interaction. Our data indicate that efficient T cell activation occurs within an optimal dwell-time range of TCR-pMHC interaction. This restricted dwell-time range is consistent with the exclusion of either extremely low or high affinity T cells from the expanded population during immune responses.

p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.

BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.

Frações de fósforo acumuladas em Latossolo argiloso pela aplicação de fosfato no sistema plantio direto

O aumento da disponibilidade de P na camada superficial do solo no sistema plantio direto pode resultar em maior transformação de P inorgânico em frações orgânicas de P de diferentes labilidades. Este trabalho teve como objetivo determinar as frações preferenciais de acumulação de P pela adição de doses de fosfato solúvel ao solo no sistema plantio direto. Após cinco anos e meio da instalação do experimento em um Latossolo Vermelho distroférrico típico argiloso, coletaram-se amostras da camada de 0-10 cm de tratamentos com diferentes doses acumuladas de fosfato solúvel: 0, 130, 180, 260, 360, 540 e 720, 980 e 1.240 kg ha-1 P2O5, aplicadas no inverno e, ou, no verão ao longo do tempo. Determinaram-se o P orgânico, inorgânico, total microbiano e seis frações inorgânicas e três orgânicas de P, em extração seqüencial com labilidade decrescente. As modificações observadas no P total, com a adição de fosfato ficaram restritas às frações inorgânicas. A fração moderadamente lábil foi o maior dreno do P adicionado. A contribuição das frações mais lábeis de P aumentou numa relação direta com as doses aplicadas. As frações orgânicas lábeis e moderadamente lábeis de P foram constituintes tão importantes como as respectivas frações inorgânicas, especialmente nas baixas adições de fosfato.

Understanding informal payments in health care: motivation of health workers in Tanzania

BACKGROUND: There is growing evidence that informal payments for health care are fairly common in many low- and middle-income countries. Informal payments are reported to have a negative consequence on equity and quality of care; it has been suggested, however, that they may contribute to health worker motivation and retention. Given the significance of motivation and retention issues in human resources for health, a better understanding of the relationships between the two phenomena is needed. This study attempts to assess whether and in what ways informal payments occur in Kibaha, Tanzania. Moreover, it aims to assess how informal earnings might help boost health worker motivation and retention. METHODS: Nine focus groups were conducted in three health facilities of different levels in the health system. In total, 64 health workers participated in the focus group discussions (81% female, 19% male) and where possible, focus groups were divided by cadre. All data were processed and analysed by means of the NVivo software package. RESULTS: The use of informal payments in the study area was confirmed by this study. Furthermore, a negative relationship between informal payments and job satisfaction and better motivation is suggested. Participants mentioned that they felt enslaved by patients as a result of being bribed and this resulted in loss of self-esteem. Furthermore, fear of detection was a main demotivating factor. These factors seem to counterbalance the positive effect of financial incentives. Moreover, informal payments were not found to be related to retention of health workers in the public health system. Other factors such as job security seemed to be more relevant for retention. CONCLUSION: This study suggests that the practice of informal payments contributes to the general demotivation of health workers and negatively affects access to health care services and quality of the health system. Policy action is needed that not only provides better financial incentives for individuals but also tackles an environment in which corruption is endemic.

Role of the glyoxalase system in astrocyte-mediated neuroprotection.

The glyoxalase system is the most important pathway for the detoxification of methylglyoxal (MG), a highly reactive dicarbonyl compound mainly formed as a by-product of glycolysis. MG is a major precursor of advanced glycation end products (AGEs), which are associated with several neurodegenerative disorders. Although the neurotoxic effects of MG and AGEs are well characterized, little is known about the glyoxalase system in the brain, in particular with regards to its activity in different neural cell types. Results of the present study reveal that both enzymes composing the glyoxalase system [glyoxalase-1 (Glo-1) and Glo-2] were highly expressed in primary mouse astrocytes compared with neurons, which translated into higher enzymatic activity rates in astrocytes (9.9- and 2.5-fold, respectively). The presence of a highly efficient glyoxalase system in astrocytes was associated with lower accumulation of AGEs compared with neurons (as assessed by Western blotting), a sixfold greater resistance to MG toxicity, and the capacity to protect neurons against MG in a coculture system. In addition, Glo-1 downregulation using RNA interference strategies resulted in a loss of viability in neurons, but not in astrocytes. Finally, stimulation of neuronal glycolysis via lentiviral-mediated overexpression of 6-phosphofructose-2-kinase/fructose-2,6-bisphosphatase-3 resulted in increased MG levels and MG-modified proteins. Since MG is largely produced through glycolysis, this suggests that the poor capacity of neurons to upregulate their glycolytic flux as compared with astrocytes may be related to weaker defense mechanisms against MG toxicity. Accordingly, the neuroenergetic specialization taking place between these two cell types may serve as a protective mechanism against MG-induced neurotoxicity.

Efeito do composto de lixo urbano na nutrição e produção de gladíolo

Tem havido uma preocupação crescente da sociedade com o aumento exponencial da produção de resíduos orgânicos em diversas atividades humanas. Assim, muitas pesquisas têm sido realizadas, visando ao aproveitamento desses resíduos na agricultura. Dentre as alternativas, destaca-se sua utilização como substrato para o cultivo de flores. Estudaram-se efeitos da aplicação de composto de lixo urbano em um Latossolo Vermelho eutroférrico sobre a nutrição do gladíolo (Gladiolus grandiflorus). As plantas da variedade Red Beauty foram cultivadas em campo entre agosto de 1999 e janeiro de 2000. Utilizou-se delineamento em blocos inteiramente causalizados com seis tratamentos e quatro repetições. Os tratamentos foram: T1 - adubação química (AQ); T2 - 10,0 t ha-1 de composto de lixo urbano (CLU); T3 - 20,0 t ha-1 de CLU; T4 - AQ + 15,0 t ha-1 de CLU; T5 - AQ + 10,0 t ha-1 de CLU e T6 - AQ + 5, 0 t ha-1 de CLU, aplicados no plantio. As características avaliadas foram: altura e diâmetro médio de planta; número de flores; matéria seca da inflorescência; diâmetro de bulbos novos; matéria seca dos bulbos novos e bulbilhos; teores de nutrientes na planta e no solo. O CLU promoveu discreto incremento no pH CaCl2 e manteve teores adequados de P e K no solo. Sua aplicação, associada à adubação química com P e K, incrementou o teor de P e K no solo, e a dose de 10,0 t ha-1 de CLU proporcionou condições suficientes para adequada nutrição, desenvolvimento e produção da cultura do gladíolo.

Produtividade da soja em resposta à aplicação de Molibdênio e inoculação com Bradyrhizobium japonicum

A soja em simbiose com Bradyrhizobium japonicum é capaz de ter a sua exigência de N satisfeita com a fixação biológica de N2 (FBN). Entretanto, a FBN é afetada pela deficiência Mo, visto que este nutriente faz parte da enzima nitrogenase responsável pelo processo. Foi realizado um experimento, em condição de campo, em Latossolo Vermelho eutroférrico, no município de Palotina, PR, com o objetivo de avaliar o tratamento de sementes com Mo, inoculação de B. japonicum e adubação foliar de Mo na produtividade da soja. Os tratamentos foram quatro doses de Mo (0, 40, 80 e 160 g ha-1) aplicadas em adubação foliar e tratamento com aplicação nas sementes de 40 g ha-1 de Mo, combinados com e sem inoculação com B. japonicum. Não foram observados efeitos estatísticos significativos do tratamento de sementes com Mo, inoculação de B. japonicum e adubação foliar de Mo na produtividade da soja. Não foram obtidas diferenças significativas entre os tratamentos, obtendo-se tendência apra ganho de produtividade apenas com aplicação foliar de 80 g ha-1 de Mo e tratamento de sementes com 40 g ha-1.

Brain dynamics underlying training-induced improvement in suppressing inappropriate action.

Inhibitory control, a core component of executive functions, refers to our ability to suppress intended or ongoing cognitive or motor processes. Mostly based on Go/NoGo paradigms, a considerable amount of literature reports that inhibitory control of responses to "NoGo" stimuli is mediated by top-down mechanisms manifesting ∼200 ms after stimulus onset within frontoparietal networks. However, whether inhibitory functions in humans can be trained and the supporting neurophysiological mechanisms remain unresolved. We addressed these issues by contrasting auditory evoked potentials (AEPs) to left-lateralized "Go" and right NoGo stimuli recorded at the beginning versus the end of 30 min of active auditory spatial Go/NoGo training, as well as during passive listening of the same stimuli before versus after the training session, generating two separate 2 × 2 within-subject designs. Training improved Go/NoGo proficiency. Response times to Go stimuli decreased. During active training, AEPs to NoGo, but not Go, stimuli modulated topographically with training 61-104 ms after stimulus onset, indicative of changes in the underlying brain network. Source estimations revealed that this modulation followed from decreased activity within left parietal cortices, which in turn predicted the extent of behavioral improvement. During passive listening, in contrast, effects were limited to topographic modulations of AEPs in response to Go stimuli over the 31-81 ms interval, mediated by decreased right anterior temporoparietal activity. We discuss our results in terms of the development of an automatic and bottom-up form of inhibitory control with training and a differential effect of Go/NoGo training during active executive control versus passive listening conditions.

Les commentaires paratextuels des Kinder- und Hausmärchen, gesammelt durch die Brüder Grimm

Il y a deux cents ans, en 1812, parut le premier volume des Contes pour les enfants et la maison collectés par les Frères Grimm. Un second lui succéda en 1815. Depuis lors, l'ouvrage a constamment été réédité et traduit. Les auteurs eux-mêmes l'ont profondément remanié, l'augmentant d'une édition à l'autre, et finalement, d'un troisième volume contenant des annotations, des « Témoignages » (Zeugnisse) et une section « Littérature » (Literatur). L'intérêt de cet apparat paratextuel pour la recherche sur le conte est inestimable. Le but de cette contribution est de rendre plus accessible une partie de ces paratextes : les « Témoignages » et la section « Littérature ». La première partie de cette étude, consacrée aux « Témoignages », s'intéresse à leur emplacement au sein de l'oeuvre et à leur présentation chronologique. Une attention particulière est prêtée à la sélection des sphères linguistiques et culturelles que les Grimm ont effectuée ainsi qu'au vocabulaire étranger choisi pour définir par équivalence leur concept de Märchen. On analyse aussi les mises en scène narratives que les Grimm ont élaborées, leur maniement des citations et des sources des « Témoignages ». On montre comment ils ont utilisé et fonctionnalisé ces derniers pour légitimer la « scénographie » et le projet des Kinder- und Hausmärchen gesammelt durch die Brüder Grimm. La deuxième partie propose une traduction française inédite du début de la section « Littérature ». Les Grimm y ont traité des recueils de contes italiens (Straparola, Basile), des Gesta Romanorum, et de l'Espagne, ainsi que des auteurs de contes français, dont Perrault et Madame d'Aulnoy. Cette section offre donc un intérêt particulier pour la recherche sur les littératures et cultures européennes.

Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93.

To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.