Cytochrome P450 2D6 genotype and methadone steady-state concentrations

A genetic polymorphism of cytochrome P450 2D6 has been described with the existence of poor (zero functional genes), extensive (one or two functional genes), and ultrarapid metabolizers (three or more functional genes). The authors measured the steady-state trough (R)- (i.e., the active enantiomer), (S)-, and (R,S)-methadone plasma levels in opiate-dependent patients receiving methadone maintenance treatment (MMT) and genotyped them for cytochrome P4502D6. The patients' medical records were reviewed to assess the outcome of the MMT with regard to the absence of illicit opiate consumption and to the absence of withdrawal complaints in ultrarapid and poor metabolizers. Of 256 patients included, 18 were found to be poor metabolizers, 228 to be extensive metabolizers, and 10 to be ultrarapid metabolizers. Significant differences were found between genotypes for (R)- (p = 0.024), (S)- (p = 0.033), and (R,S)-methadone (p = 0.026) concentrations to dose-to-weight ratios. For (R)-methadone, a significant difference was found between ultrarapid metabolizers and poor metabolizers (p = 0.009), with the median value in the former group being only 54% of the median value in the latter group. These results confirm the involvement of cytochrome P450 2D6 in methadone metabolism. Although the difference was nonsignificant (p = 0.103), 13 (72%) of the 18 poor metabolizers and only 4 (40%) of the 10 ultrarapid metabolizers were considered successful in their treatment. More studies are needed to examine the influence of the ultrarapid metabolizer status on the outcome of the MMT.

Radiopuhe 10.7.1953

Puhe

Alexithymia in patients recently diagnosed with cancer

Background: Contrary to the frequent assumption that alexithymia is a rather static personality trait hampering psychotherapeutic approaches, we have observed that cancer patients who qualify for the criteria of alexithymia may benefit from psychotherapy. Therefore, in patients facing a cancer diagnosis, alexithymia can often be considered as a state due to the threat of the disease (secondary alexithymia).Aims: To identify prevalence of alexithymia in newly diagnosed cancer patients and to document its evolution with and without psychotherapeutic interventions.Methods: Between 2006 and summer 2009, every newpatient of the Oncology Service of the University Hospital Lausanne was invited to benefit from psychotherapeutic support. Accepting patients were randomly assigned to a psychotherapeutic intervention or to a 4-month waiting list. Psychotherapies were formalized as psychodynamic-oriented short interventions (1-4 sessions) or brief psychodynamic psychotherapies (16 sessions). Patients who declined psychotherapeutic support were asked to participate in an observational group. Socio-demographic and medical data, alexithymia (TAS), anxiety and depression (SCL-90, HADS) and quality of life (EORTC) of participants of all groups were recorded at base line and at 1, 4, 8 and 12-months follow-up. Results: Of the 419 patients included, 190 desired psychotherapeutic support (94 were assigned to an immediate and 96 to a delayed intervention) and 229 patients accepted to be followed in the observational group. A very high proportion, almost 2/3 of the patients in all groups, qualified for alexithymia. With regard to the evolution of alexithymia, no significant changes were observed within and between groups and psychological symptoms also remained almost stable.Conclusions: Secondary alexithymia seems to be highly prevalent in newly diagnosed cancer patients. This raises important clinical and scientific questions: are these patients deprived from psychological support? How should interventions be conceptualized? Are interventions necessary and beneficial? Does alexithymia neutralize the effect of interventions on symptoms of anxiety and depression? Which outcome should be chosen for patients with secondary alexithymia?Keywords: Alexithymia, cancer, psycho-oncology, psychotherapy, secondary alexithymia

Analysis of antiviral immunity in primary and chronic infections

Several evidences in humans underscored the contribution of CD4 and CD8 T-cell responses in controlling viral and bacterial infections. However, CD4 and CD8 Τ cells have distinct and specific effector functions leading to a hierarchical importance in responding to different types of pathogens. In this context, the present work aimed to investigate distinct CD8 T-cell features potentially influencing T-cell efficacy against viral infection. To achieve this-objective, CD8 Τ cells derived from HIV-infected patients and healthy donors harbouring virus-specific immune responses or immunized with an HTV vaccine candidate were studied. In particular, we performed a comprehensive cross-sectional and longitudinal analysis to characterize the function, the phenotype and the functional avidity of HIV-specific CD8 Τ cells during acute (PHI) and chronic infection and, in particular, we investigated immunological parameters potentially associated with the functional avidity of HIV-specific CD8 Τ cells. In addition, we studied the expression pattern of co-inhibitory molecules and the influence of CD 160 on the functions of CD8 Τ cells in absence of chronic infections. From these analyses we observed that the functional avidity of HIV-specific CD8 T- cell responses was significantly lower in acute than in chronic infection, but was not different between chronic progressive and non-progressive patients. Functional avidity remained low after several years of antiretroviral therapy in PHI patients, but increased in patients experiencing a virus rebound following treatment interruption in association with a massive renewal of the global CD8 complementarity-determining region 3 of the TCR. The functional avidity was also directly associated to T-cell exhaustion. In individuals with no sign of HIV or Hepatitis A, Β or C virus infection, CD8 Τ cells expressed higher levels of co-inhibitory molecules than CD4 Τ cells and this was dependent on the stage of T-cell differentiation and activation. The expression of CD 160 impaired the proliferation capacity and IL-2 production of CD8 Τ cells and was reduced upon CD8 T-cell activation, entitling CD 160 as unique marker of CD8 T-cell exhaustion. The CD 160 blockade restored the proliferation capacity of virus-specific CD8 Τ cells providing a potential new target for immunotherapy. All together, these results expand our knowledge regarding the interplay between the immune system and the viruses. - De nombreuses études chez l'Homme ont mis en évidence la contribution des réponses cellulaires Τ CD4 et CD8 dans le contrôle des infections virales et bactériennes. En particulier, les lymphocytes Τ ont différentes fonctions effectrices spécifiques qui leur confèrent un rôle clé lors d'infections par différents pathogènes. Ce travail vise à étudier différentes caractéristiques des cellules Τ CD8 affectant l'efficacité des réponses cellulaires contre les virus. Pour atteindre cet objectif nous avons étudié les cellules Τ CD8 provenant de patients infectés par le VIH et de donneurs sains avec des réponses immunitaires naturelles ou vaccinales contre des virus. Nous avons effectué plusieurs analyses transversales et longitudinales des fonctions, du phénotype et de l'avidité fonctionnelle des lymphocytes Τ CD8 spécifiques au VIH au cours d'infections aiguës et chroniques; en particulier, nous avons étudié les paramètres immunologiques qui pourraient être associés à l'avidité fonctionnelle. De plus, nous avons investigué le profil d'expression des principales molécules co-inhibitrices et en particulier le rôle du CD 160 dans les fonctions des lymphocytes Τ CD8. Sur la base de ces analyses, nous avons constaté que l'avidité fonctionnelle des cellules Τ CD8 spécifiques au VIH était significativement plus faible lors infections aiguës que lors d'infections chroniques, mais n'était, par contre, pas différente entre les patients avec des infections chroniques progressives et non progressives. L'avidité fonctionnelle reste faible après plusieurs années de traitement antirétroviral, mais augmente chez les patients subissant un rebond viral, et donc exposés à des hautes virémies, suite à l'interruption du traitement. Cette augmentation d'avidité des lymphocytes Τ CD8, liée à un épuisement fonctionnel accru, était quantitativement directement associée à un renouvellement massif du TCR. Indépendamment de l'infection par le VIH, les cellules Τ CD8 expriment des niveaux plus élevés de molécules co-inhibitrices (PD-1, 2B4 et CD 160) par rapport aux cellules Τ CD4 et ceci dépend de leur stade de différenciation et d'activation. En particulier, CD 160 semble être un marqueur clé d'épuisement cellulaire des cellules Τ CD8, et donc une nouvelle cible potentielle pour l'immunothérapie, car a) son expression réduit la capacité proliférative et la production d'IL-2 b) CD 160 diminue suite à 1'activation et c) le blocage de CD 160 redonne la capacité proliférative aux cellules Τ CD8 spécifiques aux virus. - Le système immunitaire est un ensemble de cellules, tissus et organes indispensables pour limiter l'entrée des pathogènes à travers la peau et les muqueuses. Parmi les différentes cellules composant le système immunitaire, les cellules Τ CD4 et CD8 sont fondamentales pour le contrôle des infections virales et bactériennes. Les moyens pour combattre les différents pathogènes peuvent être cependant très variables. Les cellules Τ CD8, qui sont indispensables pour la lutte contre les virus, peuvent avoir différents niveaux de sensibilité; les cellules qui répondent à de faibles quantités d'antigène ont une forte sensibilité. Suite à une première infection virale, les cellules Τ CD8 ont une sensibilité plus faible que lors d'expositions répétées au même virus. En effet, la réexposition au pathogène induit une augmentation de sensibilité, grâce au recrutement et/ou à l'expansion de cellules Τ dotées d'une sensibilité plus élevée. Les cellules Τ CD8 avec une plus haute sensibilité semblent être caractérisées par une perte de fonctionnalité (épuisement fonctionnel associé à une haute expression de molécules dites inhibitrices). En absence d'infection, la fonction des molécules inhibitrices n'est pas encore clairement définie. Les cellules Τ CD8 montrent un niveau d'expression plus élevé de ces molécules par rapport aux cellules Τ CD4. Ceci dépend de l'état des cellules. Parmi ces molécules, le CD160 est associé à l'incapacité des cellules à proliférer et à produire de l'IL-2, une protéine importante pour la prolifération et la survie cellulaire. L'incapacité des cellules exprimant le CD 160 à proliférer en réponse à des virus peut être restaurée par le blocage fonctionnel du récepteur CD 160. Cette étude étoffe notre connaissance du rôle des cellules Τ CD8 ainsi que des conséquences induites par leur épuisement fonctionnel. Ces informations sont fondamentales pour le développement de nouvelles stratégies thérapeutiques et vaccinales.

Kansanedustaja Raimo Ilaskivi 21/4 1975

Kirje 21.4.1975

Pohjoismaiden yhteinen puolueettomuus (28.11.1954 Helsingissä)

Puhe

Synthesis of a radioiodinated photoreactive MAGE-1 peptide derivative and photoaffinity labeling of cell-associated human leukocyte antigen-A1 molecules.

The synthesis of a photoreactive derivative of the human leukocyte antigen-A1 (HLA-A1)-restricted MAGE-1 peptide 161-169 (EADPTGHSY) is described. Using conventional automated solid-phase peptide synthesis, a photoreactive derivative of this peptide was synthesized by replacing histidine-167 with photo-reactive N-beta-4-azidosalicyloyl-L-2,3-diaminopropionic acid. The C-terminal tyrosine was incorporated as phosphotyrosine. This peptide derivative was radioiodinated in the presence of chloramine T. This iodination took place selectively at the photoreactive group, because the phosphate ester prevented tyrosine iodination. Following dephosphorylation with alkaline phosphatase and chromatographic purification, the radiolabeled peptide derivative was incubated with cells expressing HLA-A1 or other HLA molecules. Photoactivation resulted in efficient photoaffinity labeling of HLA-A1. Other HLA molecules or other cellular components were not detectably labeled. This labeling was inhibited by HLA-A1 but not by HLA-A2-binding peptides. This synthesis is generally applicable and can also be adapted to the synthesis of well-defined radiolabeled nonphotoreactive peptide derivatives.

Quantitative estimation of foot-flat and stance phase of gait using foot-worn inertial sensors.

Time periods composing stance phase of gait can be clinically meaningful parameters to reveal differences between normal and pathological gait. This study aimed, first, to describe a novel method for detecting stance and inner-stance temporal events based on foot-worn inertial sensors; second, to extract and validate relevant metrics from those events; and third, to investigate their suitability as clinical outcome for gait evaluations. 42 subjects including healthy subjects and patients before and after surgical treatments for ankle osteoarthritis performed 50-m walking trials while wearing foot-worn inertial sensors and pressure insoles as a reference system. Several hypotheses were evaluated to detect heel-strike, toe-strike, heel-off, and toe-off based on kinematic features. Detected events were compared with the reference system on 3193 gait cycles and showed good accuracy and precision. Absolute and relative stance periods, namely loading response, foot-flat, and push-off were then estimated, validated, and compared statistically between populations. Besides significant differences observed in stance duration, the analysis revealed differing tendencies with notably a shorter foot-flat in healthy subjects. The result indicated which features in inertial sensors' signals should be preferred for detecting precisely and accurately temporal events against a reference standard. The system is suitable for clinical evaluations and provides temporal analysis of gait beyond the common swing/stance decomposition, through a quantitative estimation of inner-stance phases such as foot-flat.

Que temáticas? Pensamento crítico, Ciência e Sociedade

Como pudemos ver no capítulo anterior, foi traçado o perfil do Seminário complementar oferecido no 1º ano de todos os cursos de graduação da UniPiaget. Para além do historial e dos fundamentos que justificam e ditam a inserção deste seminário nestes cursos, foi descrita e apresentada a sua organização (todas as suas fases e etapas, incluindo a da Avaliação) tal como o preconizado para o ano lectivo de 2005/2006.