A relevância das medidas individualizadas : ouvimos o paciente mas captamos a história?

Individualized measures are relevant for the assessment of therapeutic results and allow patients to identify the aspects that they value the most in assessing their clinical improvement. PSYCHLOPS, as an individualized measure, invite the patient to create their own items. The items created by the patients were compared with the contents of standardized measures. A sample composed by 107 patients admitted for psychological treatment in Hospital Espírito Santo (Évora), and three institutions for drug misuse fill in the PSYCHLOPS and two standardized measures presented in a random order: CORE-OM and PHQ-9. 279 items were created in PSYCHLOPS and later recoded, by thematic analysis, in 51 subthemes. Work-related problems was the most common subtheme identified by patients as relevant to the clinical improvement assessment. From the 51 subthemes, 17 (33.3%) were not represented in CORE-OM and 43 (84.3%) were not represented in PHQ-9. The majority of our sample indicated at least one subtheme that was not represented in CORE-OM and PHQ-9. These results show us the importance of individualized measures in identifying the patients’ most value concerns, which may have implications in the therapeutic process.

Interactions métaboliques entre le bisphénol A et le naproxène dans un modèle de foie de rat isolé et perfusé

L'exposition aux mélanges de contaminants (environnementaux, alimentaires ou thérapeutiques) soulève de nombreuses interrogations et inquiétudes vis-à-vis des probabilités d'interactions toxicocinétiques et toxicodynamiques. Une telle coexposition peut influencer le mode d’action des composants du cocktail et donc de leur toxicité, suite à un accroissement de leurs concentrations internes. Le bisphénol A (4 dihydroxy-2,2-diphenylpropane) est un contaminant chimique répandu de manière ubiquitaire dans notre environnement, largement utilisé dans la fabrication des plastiques avec l’un des plus grands volumes de production à l’échelle mondiale. Il est un perturbateur endocrinien par excellence de type œstrogèno-mimétique. Cette molécule est biotransformée en métabolites non toxiques par un processus de glucuronidation. L'exposition concomitante à plusieurs xénobiotiques peut induire à la baisse le taux de glucuronidation du polluant chimique d'intérêt, entre autres la co-exposition avec des médicaments. Puisque la consommation de produits thérapeutiques est un phénomène grandissant dans la population, la possibilité d’une exposition simultanée est d’autant plus grande et forte. Sachant que l'inhibition métabolique est le mécanisme d'interaction le plus plausible pouvant aboutir à une hausse des niveaux internes ainsi qu’à une modulation de la toxicité prévue, la présente étude visait d'abord à confirmer et caractériser ce type d'interactions métaboliques entre le bisphénol A et le naproxène, qui est un anti-inflammatoire non stéroïdiennes (AINS), sur l'ensemble d'un organe intact en utilisant le système de foie de rat isolé et perfusé (IPRL). Elle visait ensuite à déterminer la cinétique enzymatique de chacune de ces deux substances, seule puis en mélange binaire. Dans un second temps, nous avons évalué aussi l’influence de la présence d'albumine sur la cinétique métabolique et le comportement de ces deux substances étudiées en suivant le même modèle de perfusion in vivo au niveau du foie de rat. Les constantes métaboliques ont été déterminées par régression non linéaire. Les métabolismes du BPA et du NAP seuls ont montré une cinétique saturable avec une vélocité maximale (Vmax) de 8.9 nmol/min/ mg prot de foie et une constante d'affinité de l'enzyme pour le substrat (Km) de 51.6 μM pour le BPA et de 3 nmol/min/mg prot de foie et 149.2 μM pour le NAP. L'analyse des expositions combinées suggère une inhibition compétitive partielle du métabolisme du BPA par le NAP avec une valeur de Ki estimée à 0.3542 μM. Les résultats obtenus montrent que l’analyse de risque pour les polluants environnementaux doit donc prendre en considération la consommation des produits pharmaceutiques comme facteur pouvant accroitre le niveau interne lors d’une exposition donnée. Ces données in vivo sur les interactions métaboliques pourraient être intégrées dans un modèle pharmacocinétique à base physiologique (PBPK) pour prédire les conséquences toxicococinétique (TK) de l'exposition d'un individu à ces mélanges chimiques.

Transatlantic MRAs: Lessons for TTIP? CEPS Special Report No. 101/March 2015

It is striking that there is little or no mention in the TTIP debate so far of the US-EU Mutual Recognition Agreement (MRA) concluded in 1998. At the time, expectations of the gains from the MRA were high. One should expect the MRA to be instructive for TTIP and entail some lessons to be learned for today’s attempt to lower technical barriers to trade (TBTs) across the North Atlantic. We offer an analysis of the 1998 MRA, the difficulties in the prior negotiations and those during the implementation phase, the subsequent and present status of sectoral approaches. The MRA experience revealed clearly how difficult it is to accomplish the acceptance of all relevant aspects of conformity assessment of the trading partner for the mere purpose of testing and certifying export goods on the requirements of the importing economy. The MRA has succeeded only in a few sectors. However, the ambition in TTIP with respect to TBTs is said to go so much further. It is therefore important for all those involved or interested in TTIP to learn the lessons of this early exercise in lowering TBT costs. This paper reaches two main conclusions: i) the US-EU MRA was only partially successful and only for some one-fifth of the export flows at the time: a disappointing outcome and a far cry from the expectations of business and political leaders; and ii) the EU’s attempt to ‘balance’ the negotiations in 1995 by bringing in three relatively competitive sectors did not work out – it was precisely there that problems accumulated. It is critical that domestic regulators must be satisfied during and after the negotiations that their pursuit of health, safety, environment and consumer protection objectives will not be watered down in any way. Lessons drawn include, among others: MRAs are not about regulatory change (by definition), but if initial regulatory cleavages between trading partners are too wide, conditions become so restrictive that parties may regard them as a denial of the very purpose of the MRA. There are incentives to opt for alternatives in the market for the formalised designation of conformity assessment bodies in the MRA and these are often cheaper and faster, while equally qualified. Even in heavily regulated sectors such as medicines and medical devices, the narrow MRA has been superseded by near-global forms of effective cost-reducing cooperative (i.e. not treaty-based) regulatory alignment, a confirmation of the OECD approach that governments should think in terms of an entire spectrum of forms of regulatory cooperation.

A intervenção do exercício físico funcional em idosos hipertensos do sexo feminino

Introdução - A abordagem da intervenção promotora da atividade física funcional em um grupo de idosas hipertensas consiste em considerar a pessoa na sua integridade física, psíquica e social. Objetivo – Avaliar o efeito da implementação de um programa de treinamento funcional sobre a pressão arterial em repouso em mulheres idosas hipertensas, submetidas ao treinamento de exercício físico durante um período de 24 meses. Métodos - Pesquisa de caráter exploratório, com orientação analítico-descritiva com a finalidade de analisar a ação da atividade física direcionada e implementada três vezes por semana no prognóstico da hipertensão arterial. Esta pesquisa foi suportada na recolha de dados da pressão arterial em repouso numa amostra de idosas brasileiras na faixa etária de 60 a 90 anos, em condições de excelente motivação por parte do grupo. Para as análises estatísticas foi utilizado o programa IBM SPSS 20, onde os dados foram tratados de forma descritiva e inferencial. Verificou-se o pressuposto de parametria quanto à normalidade dos resíduos para PAS e PAD ao longo das avaliações pressóricas na amostra pelo teste K-S, onde o mesmo não foi detectado (p<0,05). Assim, foram utilizados o teste de X2 e de Comparações Múltiplas para observações acerca de quais diferenças estatísticas eram significativas (p<0,05), além da Análise de Correlação de Pearson (rho) para apontar as devidas associações entre os níveis de PAS e PAD durante o estudo. Resultados – A maioria (100%) das idosas estavam hipertensas, constatando-se que durante o período de treino apresentaram pressão arterial sistólica e diastólica muito abaixo do padrão da normalidade para essa faixa etária. Tal decréscimo foi altamente significativo (p<00,1) e foi detectado tanto nas estatísticas comparativas quanto nas de associação. Conclusões - Após a intervenção do Projeto Prevenção de Saúde Estádio Vivo, as idosas apresentaram redução e maior controle dos valores da sua pressão arterial. Considera-se assim, que o treinamento físico ao exercer um efeito fisiológico especifica ao nível muscular e cardiocirculatório é protetor do estado de saúde global pelo que deve ser incentivado ao longo de todo o ciclo vital. Infere-se também que o Programa implementado pode ser replicado como medida de educação terapêutica, de avaliação e de auditoria de boas práticas em saúde. Palavra-chave: Idosos. Atividade Física. Hipertensão.

Problemas éticos identificados por enfermeiros na relação com usuários em situação crítica

O artigo apresenta os resultados da análise das questões éticas identificadas por enfermeiros perante usuários em situação crítica, de risco iminente de morte, e cuja sobrevivência depende de métodos avançados de vigilância, monitorização e terapêutica. As principais preocupações éticas dizem respeito à informação ao cliente, ao acompanhamento em fim de vida, à responsabilidade profissional em intervenções interdependentes; as temáticas reportam à decisão da pessoa (consentimento/recusa de proposta terapêutica), dilemas na informação, atuação nos processos de morrer e decisão de não tentar reanimar, respeito pelos direitos humanos em contextos desfavoráveis. Destacamos as dimensões do sentido de responsabilidade, da influência da consciência moral nas decisões, da deliberação de proteger o Outro em risco e da vivência de episódios profissionais de superação; finalmente, identificamos fatores mediadores na gestão das dificuldades éticas.

Interactions métaboliques entre le bisphénol A et le naproxène dans un modèle de foie de rat isolé et perfusé

L'exposition aux mélanges de contaminants (environnementaux, alimentaires ou thérapeutiques) soulève de nombreuses interrogations et inquiétudes vis-à-vis des probabilités d'interactions toxicocinétiques et toxicodynamiques. Une telle coexposition peut influencer le mode d’action des composants du cocktail et donc de leur toxicité, suite à un accroissement de leurs concentrations internes. Le bisphénol A (4 dihydroxy-2,2-diphenylpropane) est un contaminant chimique répandu de manière ubiquitaire dans notre environnement, largement utilisé dans la fabrication des plastiques avec l’un des plus grands volumes de production à l’échelle mondiale. Il est un perturbateur endocrinien par excellence de type œstrogèno-mimétique. Cette molécule est biotransformée en métabolites non toxiques par un processus de glucuronidation. L'exposition concomitante à plusieurs xénobiotiques peut induire à la baisse le taux de glucuronidation du polluant chimique d'intérêt, entre autres la co-exposition avec des médicaments. Puisque la consommation de produits thérapeutiques est un phénomène grandissant dans la population, la possibilité d’une exposition simultanée est d’autant plus grande et forte. Sachant que l'inhibition métabolique est le mécanisme d'interaction le plus plausible pouvant aboutir à une hausse des niveaux internes ainsi qu’à une modulation de la toxicité prévue, la présente étude visait d'abord à confirmer et caractériser ce type d'interactions métaboliques entre le bisphénol A et le naproxène, qui est un anti-inflammatoire non stéroïdiennes (AINS), sur l'ensemble d'un organe intact en utilisant le système de foie de rat isolé et perfusé (IPRL). Elle visait ensuite à déterminer la cinétique enzymatique de chacune de ces deux substances, seule puis en mélange binaire. Dans un second temps, nous avons évalué aussi l’influence de la présence d'albumine sur la cinétique métabolique et le comportement de ces deux substances étudiées en suivant le même modèle de perfusion in vivo au niveau du foie de rat. Les constantes métaboliques ont été déterminées par régression non linéaire. Les métabolismes du BPA et du NAP seuls ont montré une cinétique saturable avec une vélocité maximale (Vmax) de 8.9 nmol/min/ mg prot de foie et une constante d'affinité de l'enzyme pour le substrat (Km) de 51.6 μM pour le BPA et de 3 nmol/min/mg prot de foie et 149.2 μM pour le NAP. L'analyse des expositions combinées suggère une inhibition compétitive partielle du métabolisme du BPA par le NAP avec une valeur de Ki estimée à 0.3542 μM. Les résultats obtenus montrent que l’analyse de risque pour les polluants environnementaux doit donc prendre en considération la consommation des produits pharmaceutiques comme facteur pouvant accroitre le niveau interne lors d’une exposition donnée. Ces données in vivo sur les interactions métaboliques pourraient être intégrées dans un modèle pharmacocinétique à base physiologique (PBPK) pour prédire les conséquences toxicococinétique (TK) de l'exposition d'un individu à ces mélanges chimiques.

Tables for statisticians.

The first two tables are lithoprinted from the author's Generalizations of the normal curve of error. [1930]

Willie Heston, UM Football, 1903 Minnesota game

Attached caption: "Willie Heston (top center of picture) gains fifteen yards in the historic 1903 "Little Brown Jug" game." Played at Minnesota.

New and nonofficial drugs.

Descriptions of therapeutic, prophylactic and diagnostic agents evaluated by the Council on Drugs.

In vivo gene expression: DNA electrotransfer

The use of electric pulses to deliver therapeutic molecules to tissues and organs in vivo is a rapidly growing field of research. Electrotransfer can be used to deliver a wide range of potentially therapeutic agents, including drugs, proteins, oligonucleotides, RNA and DNA. Optimization of this approach depends upon a number of parameters such as target organ accessibility, cell turnover, microelectrode design, electric pulsing protocols and the physiological response to the therapeutic agent. Many organs have been successfully transfected by electroporation, including skin, liver, skeletal and cardiac muscle, male and female germ cells, artery, gut, kidney, retinal ganglion cells, cornea, spinal cord, joint synovium and brain. Electrotransfer technology is relevant in a variety of research and clinical settings including cancer therapy, modulation of pathogenic immune reactions, delivery of therapeutic proteins and drugs, and the identification of drug targets by the modulation of normal gene expression. This, together with the capacity to deliver very large DNA constructs, greatly expands the research and clinical applications of in vivo DNA electrotransfer.

Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine

Advanced metastatic melanoma is incurable by standard treatments, but occasionally responds to immunotherapy. Recent trials using dendritic cells (DC) as a cellular adjuvant have concentrated on defined peptides as the source of antigens, and rely on foreign proteins as a source of help to generate a cell-mediated immune response. This approach limits patient accrual, because currently defined, non-mutated epitopes are restricted by a small number of human leucocyte antigens. It also fails to take advantage of mutated epitopes peculiar to the patient's own tumour, and of CD4(+) T lymphocytes as potential effectors of anti-tumour immunity. We therefore sought to determine whether a fully autologous DC vaccine is feasible, and of therapeutic benefit. Patients with American Joint Cancer Committee stage IV melanoma were treated with a fully autologous immunotherapy consisting of monocyte-derived DC, matured after culture with irradiated tumour cells. Of 19 patients enrolled into the trial, sufficient tumour was available to make treatments for 17. Of these, 12 received a complete priming phase of six cycles of either 0.9X10(6) or 5X10(6) DC/intradermal injection, at 2-weekly intervals. Where possible, treatment continued with the lower dose at 6-weekly intervals. The remaining five patients could not complete priming, due to progressive disease. Three of the 12 patients who completed priming have durable complete responses (average duration 3 5 months +), three had partial responses, and the remaining six had progressive disease (WHO criteria). Disease regression was not correlated with dose or with the development of delayed type hypersensitivity responses to intradermal challenge with irradiated, autologous tumour. However, plasma S-100B levels prior to the commencement of treatment correlated with objective clinical response (P = 0.05) and survival (log rank P < 0.001). The treatment had minimal side-effects and was well tolerated by all patients. Mature, monocyte-derived DC preparations exposed to appropriate tumour antigen sources can be reliably produced for patients with advanced metastatic melanoma, and in a subset of those patients with lower volume disease their repeated administration results in durable complete responses.

Neck flexor muscle fatigue is side specific in patients with unilateral neck pain

Despite the evidence of greater fatigability of the cervical flexor muscles in neck pain patients, the effect of unilaterality of neck pain on muscle fatigue has not been investigated. This study compared myoelectric manifestations of sternocleidomastoid (SCM) and anterior scalene (AS) muscle fatigue between the painful and non-painful sides in patients with chronic unilateral neck pain. Myoelectric signals were recorded from the sternal head of SCM and the AS muscles bilaterally during sub-maximal isometric cervical flexion contractions at 25% and 50% of the maximum voluntary contraction (MVC). The time course of the mean power frequency, average rectified value and conduction velocity of the electromyographic signals were calculated to quantify myoelectric manifestations of muscle fatigue. Results revealed greater estimates of the initial value and slope of the mean frequency for both the SCM and AS muscles on the side of the patient's neck pain at 25% and 50% of MVC. These results indicate greater myoelectric manifestations of muscle fatigue of the superficial cervical flexor muscles ipsilateral to the side of pain. This suggests a specificity of the effect of pain on muscle function and hence the need for specificity of therapeutic exercise in the management of neck pain patients. (C) 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.

Functional memory CD8+ T cells can be generated in vivo without evident T help

Synthetic cytotoxic T cell (CTL) epitope peptides provide an effective and safe means of vaccination against cancers and viruses, as these peptides can induce specific CD8+ effector T cells in vivo. However, the effector CD8+ T cells induced by the minimal CTL epitope peptides do not last past about 3 weeks after the induction and no functional memory CD8+ T cells are generated. It is held that simultaneous induction of CD4+ T cells by incorporating peptides containing T-helper epitopes in the vaccine at the time of primary vaccination are necessary for the induction of long-lived functional memory CD8+ T cells. We now report that, surprisingly, incorporation of medium length (>20 AA) peptides devoid of detectable T-helper epitopes in a minimal CTL epitope-based vaccine can also induce long-lasting! functional rumour antigen specific memory CD8+ T cells that are capable of promoting protection against tumour challenge. This observation may have implications for the formulation of therapeutic anti-cancer and anti-virus peptide vaccines where a strong induction of CD4 T help would be undesirable. (C) 2004 Elsevier Ltd. All rights reserved.

Macroscopic quantum Schrdinger and Einstein-Podolsky-Rosen paradoxes

We propose macroscopic generalizations of the Einstein-Podolsky-Rosen paradox in which the completeness of quantum mechanics is contrasted with forms of macroscopic reality and macroscopic local reality defined in relation to Schrodinger's original 'cat' paradox.

Continuous variable tripartite entanglement and Einstein-Podolsky-Rosen correlations from triple nonlinearities

We compare theoretically the tripartite entanglement available from the use of three concurrent x(2) nonlinearities and three independent squeezed states mixed on beamsplitters, using an appropriate version of the van Loock-Furusawa inequalities. We also define three-mode generalizations of the Einstein-Podolsky-Rosen paradox which are an alternative for demonstrating the inseparability of the density matrix.