Muscle protein waste in tumor-bearing rats is effectively antagonized by a beta 2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway.

Tissue protein hypercatabolism (TPH) is a most important feature in cancer cachexia, particularly with regard to the skeletal muscle. The rat ascites hepatoma Yoshida AH-130 is a very suitable model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle waste mainly due to TPH (Tessitore, L., G. Bonelli, and F. M. Baccino. 1987. Biochem. J. 241:153-159). Detectable plasma levels of tumor necrosis factor-alpha associated with marked perturbations in the hormonal homeostasis have been shown to concur in forcing metabolism into a catabolic setting (Tessitore, L., P. Costelli, and F. M. Baccino. 1993. Br. J. Cancer. 67:15-23). The present study was directed to investigate if beta 2-adrenergic agonists, which are known to favor skeletal muscle hypertrophy, could effectively antagonize the enhanced muscle protein breakdown in this cancer cachexia model. One such agent, i.e., clenbuterol, indeed largely prevented skeletal muscle waste in AH-130-bearing rats by restoring protein degradative rates close to control values. This normalization of protein breakdown rates was achieved through a decrease of the hyperactivation of the ATP-ubiquitin-dependent proteolytic pathway, as previously demonstrated in our laboratory (Llovera, M., C. García-Martínez, N. Agell, M. Marzábal, F. J. López-Soriano, and J. M. Argilés. 1994. FEBS (Fed. Eur. Biochem. Soc.) Lett. 338:311-318). By contrast, the drug did not exert any measurable effect on various parenchymal organs, nor did it modify the plasma level of corticosterone and insulin, which were increased and decreased, respectively, in the tumor hosts. The present data give new insights into the mechanisms by which clenbuterol exerts its preventive effect on muscle protein waste and seem to warrant the implementation of experimental protocols involving the use of clenbuterol or alike drugs in the treatment of pathological states involving TPH, particularly in skeletal muscle and heart, such as in the present model of cancer cachexia.

Volatilização de amônia, lixiviação de nitrogênio e produtividade de milho em resposta à aplicação de misturas de uréia com sulfato de amônio ou com gesso agrícola

A adubação em cobertura na cultura de milho, assim como de outras culturas anuais, deve incluir N e S para acrescentar qualidade protéica à produção de grãos. Este trabalho foi desenvolvido na safra 2004/2005, na cultura de milho, na Fazenda Floresta do Lobo - Pinusplan, BR 050, km 93, município de Uberlândia (MG). O estudo foi realizado em Latossolo Vermelho ácrico típico fase Cerrado subcaducifólio muito argiloso (720 g kg-1), objetivando: quantificar as perdas por volatilização de N-NH3 provenientes de algumas das misturas de grânulos utilizadas em cobertura nitrogenada na cultura de milho; determinar a distribuição, até 60 cm de profundidade de solo, do N-mineral (NH4+ e NO3-) e S-SO4(2-) após 37 e 51 dias da aplicação dos adubos em cobertura; e avaliar o efeito na produtividade de milho da aplicação de misturas de grânulos, com diferentes granulometrias e relações N:S, em relação à aplicação exclusiva, em cobertura nitrogenada, de uréia (U) e sulfato de amônio (SA). Foram instalados 11 tratamentos de adubação N:S:K em cobertura, no estádio de 5-6 folhas, em dose de 90 kg ha-1 de N, nas formas exclusivas de U e SA, em misturas físicas de U+SA granulado (U+SAgr), U+SA farelado (U+SAfa), U+Gesso granulado (U+Gesso gr) e U+Gesso em pó (U+Gesso pó), em delineamento de blocos casualizados. As perdas gasosas de N-NH3 foram em ordem decrescente, em relação ao N aplicado: U 76,8 %; U+SA Gr 37,9 %; U+SAfa 27,7 % e SAfa 7,8 %. Os teores de N-amônio e N-nitrato no solo, após 37 dias da aplicação das misturas, mostraram-se similares à testemunha (menos N), evidenciando que o N fornecido via fertilizante foi em parte absorvido pela cultura, nitrificado, lixiviado e, ou, adsorvido em maior profundidade. Aos 51 dias após a aplicação das misturas, o teor de N-mineral total do solo, estava mais evidente nas camadas de 20 a 40 cm de profundidade, indicando lixiviação de N das camadas mais superficiais. Nos tratamentos com aplicação de apenas U ou SA, essa tendência foi mais atenuada. Quanto ao S-sulfato, a camada mais superficial apresentou os menores teores em todos os tratamentos, diminuindo ainda mais na camada de 0 a 10 cm, após os 37 e 51 dias da aplicação dos fertilizantes. Os teores de S-sulfato continuaram expressivos nas camadas mais profundas. No estádio de florescimento, a análise de nutrientes na folha oposta à espiga não mostrou diferença significativa na relação N:S, assim como na parte aérea da planta. As maiores produtividades foram alcançadas pelos tratamentos de U+SAfa e U+Gesso gr, respectivamente: 10.285 kg ha-1 e 10.241 kg ha-1 de grãos. Os tratamentos com maiores produtividades ocorreram com a aplicação da U em mistura com SAfa, SAgr e Gesso gr, nas relações N:S entre 2,75 e 4,0. Esses resultados permitem concluir que a aplicação de S em cobertura pode ser realizada misturando-se U com SA ou U com Gesso gr, embora esta última tenha apresentado perdas de NH3 mais significativas.

[Lettre autographe signée de Giuseppe Verdi adressée à Du Locle (sans date)]

Comprend aussi une enveloppe. - En français

Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t½) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t½ of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t½ of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t½ of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.

Expression of intercellular adhesion molecule-1 in UVA-irradiated human skin cells in vitro and in vivo.

Ultraviolet A (UVA) radiation represents an important oxidative stress to human skin and certain forms of oxidative stress have been shown to modulate intercellular adhesion molecule-1 (ICAM-1) expression. ICAM-1 has been shown to play an important part in many immune reactions and the perturbations of this molecule by ultraviolet radiation could have implications in many inflammatory responses. An enhancement immunohistochemical method with avidin/biotin was used for analysing the early effects of UVA radiation on human cell cultures and human skin (340-400 nm). Both in vitro and in vivo data show that ICAM-1 staining in epidermal keratinocytes, which was expressed constitutively, decreased in a UVA dose-dependent manner. The decrease was most noted at 3-6 h following UVA radiation with some ICAM-1 staining returning by 48 h post-UVA. ICAM-1 positive staining in the dermis was specific for vascular structures and was increased 24 h after UVA radiation. Cultured dermal fibroblasts exhibited ICAM-1 staining which increased slightly within 6-48 h post-UVA radiation. As epidermal ICAM-1 expression is depleted following UVA radiation and dermal expression increases due to an increase in the vascular structures, ICAM-1 provides a valuable marker following UVA radiation in human skin that can be readily measured in situ.

Muscle protein waste in tumor-bearing rats is effectively antagonized by a beta 2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway.

Tissue protein hypercatabolism (TPH) is a most important feature in cancer cachexia, particularly with regard to the skeletal muscle. The rat ascites hepatoma Yoshida AH-130 is a very suitable model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle waste mainly due to TPH (Tessitore, L., G. Bonelli, and F. M. Baccino. 1987. Biochem. J. 241:153-159). Detectable plasma levels of tumor necrosis factor-alpha associated with marked perturbations in the hormonal homeostasis have been shown to concur in forcing metabolism into a catabolic setting (Tessitore, L., P. Costelli, and F. M. Baccino. 1993. Br. J. Cancer. 67:15-23). The present study was directed to investigate if beta 2-adrenergic agonists, which are known to favor skeletal muscle hypertrophy, could effectively antagonize the enhanced muscle protein breakdown in this cancer cachexia model. One such agent, i.e., clenbuterol, indeed largely prevented skeletal muscle waste in AH-130-bearing rats by restoring protein degradative rates close to control values. This normalization of protein breakdown rates was achieved through a decrease of the hyperactivation of the ATP-ubiquitin-dependent proteolytic pathway, as previously demonstrated in our laboratory (Llovera, M., C. García-Martínez, N. Agell, M. Marzábal, F. J. López-Soriano, and J. M. Argilés. 1994. FEBS (Fed. Eur. Biochem. Soc.) Lett. 338:311-318). By contrast, the drug did not exert any measurable effect on various parenchymal organs, nor did it modify the plasma level of corticosterone and insulin, which were increased and decreased, respectively, in the tumor hosts. The present data give new insights into the mechanisms by which clenbuterol exerts its preventive effect on muscle protein waste and seem to warrant the implementation of experimental protocols involving the use of clenbuterol or alike drugs in the treatment of pathological states involving TPH, particularly in skeletal muscle and heart, such as in the present model of cancer cachexia.

Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme.

AIM: To perform a systematic review on the costs and cost-effectiveness of concomitant and adjuvant temozolomide with radiotherapy for the treatment of newly diagnosed glioblastoma compared with initial radiotherapy alone. METHODS: Electronic databases were searched for relevant publications on costs and cost-effectiveness until October 2008. RESULTS: We found four relevant clinical trials, one cost study and two economic models. The mean survival benefit in the radiotherapy plus temozolomide group varied between 0.21 and 0.25 life-years. Treatment costs were between 27,365 euros and 39,092 euros. The costs of temozolomide amounted to approximately 40% of the total treatment costs. The incremental cost-effectiveness ratios found in the literature were 37,361 euros per life-year gained and 42,912 euros per quality-adjusted life-year gained. However, the models are not comparable because different outcomes are used (i.e., life-years and quality-adjusted life-years). CONCLUSION: Although the models are not comparable according to outcome, the incremental cost-effectiveness ratios found are within acceptable ranges. We concluded that despite the high temozolomide acquisition costs, the costs per life-year gained and the costs per quality-adjusted life-year gained are comparable with other accepted first-line treatments with chemotherapy in patients with cancer.

Conditions de travail et santé dans les centres d'appels téléphoniques

A la demande d'une quarantaine de médecins du travail préoccupés par les conditions de travail dans les centres d'appels téléphoniques (CT) et la santé des téléopérateurs (TO), une enquête épidémiologique a été conduite par l'INRS.Il s'agit d'étudier, chez des TO, les relations entre, d'une part des contraintes de travail perçues et des marqueurs de santé et d'autre part, des facteurs organisationnels (FO) déclarés par les responsables de plateaux et des contraintes au travail perçues par les TO. Il s'agissait donc de mettre en évidence les caractéristiques organisationnelles qui ont des conséquences, via les contraintes, sur la santé en tenant compte des principaux facteurs de confusion.Quatorze FO ont été identifiés comme étant les plus souvent associés aux contraintes. Par ailleurs cette étude met en évidence que les relations entre FO et marqueurs de santé ne sont pas directes et passent le plus souvent par la perception des contraintes.Malgré son caractère transversal, cette étude permet de conclure sur le rôle de certains FO et l'implication de certaines contraintes dans l'apparition de problèmes de santé ouvrant des perspectives de prévention primaire et secondaire tant individuelle (dépistage, surveillance...) que collective (évaluation des conditions de travail et de la santé).Le questionnaire sur les caractéristiques organisationnelles, spécialement élaboré, sera bientôt accessible, et pourra être un instrument utile pour les évaluations de terrain. [Auteurs]

Fables et poésies diverses / par M. Étienne Azéma (de l'île Bourbon)

Comprend : Les pastorales...

Muscle protein waste in tumor-bearing rats is effectively antagonized by a beta 2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway.

Tissue protein hypercatabolism (TPH) is a most important feature in cancer cachexia, particularly with regard to the skeletal muscle. The rat ascites hepatoma Yoshida AH-130 is a very suitable model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle waste mainly due to TPH (Tessitore, L., G. Bonelli, and F. M. Baccino. 1987. Biochem. J. 241:153-159). Detectable plasma levels of tumor necrosis factor-alpha associated with marked perturbations in the hormonal homeostasis have been shown to concur in forcing metabolism into a catabolic setting (Tessitore, L., P. Costelli, and F. M. Baccino. 1993. Br. J. Cancer. 67:15-23). The present study was directed to investigate if beta 2-adrenergic agonists, which are known to favor skeletal muscle hypertrophy, could effectively antagonize the enhanced muscle protein breakdown in this cancer cachexia model. One such agent, i.e., clenbuterol, indeed largely prevented skeletal muscle waste in AH-130-bearing rats by restoring protein degradative rates close to control values. This normalization of protein breakdown rates was achieved through a decrease of the hyperactivation of the ATP-ubiquitin-dependent proteolytic pathway, as previously demonstrated in our laboratory (Llovera, M., C. García-Martínez, N. Agell, M. Marzábal, F. J. López-Soriano, and J. M. Argilés. 1994. FEBS (Fed. Eur. Biochem. Soc.) Lett. 338:311-318). By contrast, the drug did not exert any measurable effect on various parenchymal organs, nor did it modify the plasma level of corticosterone and insulin, which were increased and decreased, respectively, in the tumor hosts. The present data give new insights into the mechanisms by which clenbuterol exerts its preventive effect on muscle protein waste and seem to warrant the implementation of experimental protocols involving the use of clenbuterol or alike drugs in the treatment of pathological states involving TPH, particularly in skeletal muscle and heart, such as in the present model of cancer cachexia.