Methadone blood concentrations are decreased by the administration of abacavir plus amprenavir.

Abacavir and amprenavir, a nucleoside reverse transcription inhibitor and a protease inhibitor, respectively, are new drugs used for the treatment of HIV. Methadone blood concentrations were measured in five addict patients receiving methadone maintenance therapy before and after introduction of abacavir plus amprenavir. The administration of these two drugs for a median period of 14 days resulted in a significant reduction (P = 0.043) of methadone concentration, with a median decrease to 35% of the original concentration (range 28-87%). Two patients reported on several occasions nausea in the morning before the intake of the daily methadone dose, which is compatible with withdrawal reaction to opioids. Because amprenavir is a cytochrome P4503A4 substrate and is involved in the metabolism of methadone, reduction of methadone concentrations could be explained by an induction of cytochrome P4503A4.

Sediment penetration depths of epi- and infaunal ostracods from Lake Geneva (Switzerland)

Many (palaeo-)environmental parameters can be deduced from ecological and chemical analyses of ostracods. However, the specific ecology of each taxon has a great impact on its reaction to changing environmental conditions. As a consequence, each taxon records these changes differently. The mean penetration depth (MPD) and relative individual abundances have been documented along sediment depth profiles for the dominant sub-littoral to profundal species of ostracods in western Lake Geneva, Switzerland, and this data can be used to estimate their preferential habitat in terms of sediment depths. Isocypris beauchampi, Limnocytherina sanctipatricii, Cypria ophtalmica forma lacustris at 13-m water depths, Limnocythere inopinata, and a winter generation of Herpetocypris reptans have the shallowest habitat preferences at the study sites (MPDs of 0.45, 0.48, 0.49, 0.60, and 0.81 cm, respectively). These results suggest that these populations may be regarded as being preferentially epifaunal forms. Populations of Cytherissa lacustris (MPDs of 0.61, 0.73, and 0.82 cm at 13-, 33-, and 70-m water depths, respectively), Cypria ophtalmica forma lacustris at 70 m (MPD = 0.96 cm), Fabaeformiscandona caudata (MPD = 0.99 cm), and a summer generation of Herpetocypris reptans (MPD = 1.03 cm) were identified as being infaunal. Candona neglecta is the species that was found the deepest in the sediment of Lake Geneva, with MPDs of 0.65, 1.22, and 1.30 cm at 13-, 33-, and 70-m water depths, respectively. Information on the sediment texture and oxygen concentrations inferred from the analyses of sediment pore water suggest that the oxygen content of the sediment pore water is not the only dominant parameter controlling the differences in ostracod sediment penetration depths observed among the different sites, but that they might also be influenced by the sediment 'softness,' which itself depends on grain size, water content, and the abundance of organic matter in sediment.

A novel Th cell epitope of Candida albicans mediates protection from fungal infection.

Fungal pathogens are a frequent cause of opportunistic infections. They live as commensals in healthy individuals but can cause disease when the immune status of the host is altered. T lymphocytes play a critical role in pathogen control. However, specific Ags determining the activation and function of antifungal T cells remain largely unknown. By using an immunoproteomic approach, we have identified for the first time, to our knowledge, a natural T cell epitope from Candida albicans. Isolation and sequencing of MHC class II-bound ligands from infected dendritic cells revealed a peptide that was recognized by a major population of all Candida-specific Th cells isolated from infected mice. Importantly, human Th cells also responded to stimulation with the peptide in an HLA-dependent manner but without restriction to any particular HLA class II allele. Immunization of mice with the peptide resulted in a population of epitope-specific Th cells that reacted not only with C. albicans but also with other clinically highly relevant species of Candida including the distantly related Candida glabrata. The extent of the reaction to different Candida species correlated with their degree of phylogenetic relationship to C. albicans. Finally, we show that the newly identified peptide acts as an efficient vaccine when used in combination with an adjuvant inducing IL-17A secretion from peptide-specific T cells. Immunized mice were protected from fatal candidiasis. Together, these results uncover a new immune determinant of the host response against Candida ssp. that could be exploited for the development of antifungal vaccines and immunotherapies.

Increased connexin43 expression in human sphenous veins in culture is associated with intimal hyperplasia

Résumé Objectif : L'hyperplasie intimale est un processus de remodelage vasculaire qui apparaît après une lésion vasculaire. Les mécanismes impliqués dans l'hyperplasie intimale sont la prolifération, la dédifférentiation et la migration des cellules musculaires lisses depuis la média vers l'espace sous-intimal. Nous avons émis l'hypothèse que les jonctions communicantes de type gap, qui coordonnent certains processus physiologiques tels que la croissance et la différentiation cellulaire, pouvaient participer au développement de l'hyperplasie intimale. Méthodes : Des segments de veines saphènes humaines prélevées chirurgicalement lors de pontages, ont été ouverts longitudinalement avec la surface luminale placée vers le haut et maintenus en culture pendant 14 jours. Des fragments veineux ont été préparés pour une évaluation histologique, pour des mesures de l'épaisseur de la néointima, et pour des analyses immunocytochimiques de l'ARN messager ainsi que des protéines. Résultats : Parmi les 4 connexines (Cxs 37, 40, 43 et 45) qui forment les jonctions communicantes dans les veines, nous avons focalisé notre étude sur l'expression des Cxs 43 et 40; nous avons démontré que la Cx43 est exprimée dans les cellules musculaires lisses et les cellules endothéliales alors que la Cx40 est uniquement présente dans l'endothélium. Après 14 jours en culture, des analyses histomorphométriques ont montré une augmentation significative de l'épaisseur de l'intima démontrant la présence d'hyperplasie intimale. Une analyse temporelle a révélé une augmentation progressive de la Cx43 jusqu'à une augmentation maximale de six à huit fois au niveau de l'ARN messager et des protéines après 14 jours en culture. Au contraire, l'expression de la Cx40 n'était pas modifiée. Des analyses par immunofluorescence ont montré également une augmentation de la Cx43 dans les membranes des cellules musculaires lisses de la média. Le développement de l'hyperplasie intimale in vitro est diminué en présence de fluvastatin et cette diminution est associée à une réduction de l'expression de la Cx43. Conclusions : Ces données démontrent que la Cx43 est augmentée in vitro pendant le processus d'hyperplasie intimale et que la fluvastatin prévient cette induction. Ces résultats suggèrent un rôle crucial joué par la communication intercellulaire impliquant la Cx43 dans la veine humaine durant le développement de l'hyperplasie intimale. Abstract Objective: Intimal hyperplasia is a vascular remodelling process that occurs after a vascular injury. The mechanisms involved in intimal hyperplasia are proliferation, dedifferentiation, and migration of medial smooth muscle cells towards the subintimal space. We postulated that gap junctions, which coordinate physiologic processes such as cell growth and differentiation, might participate in the development of intimal hyperplasia. connexin43 (Cx43) expression levels may be altered in intimal hyperplasia, and we therefore evaluated the regulated expression of Cx43 in human saphenous veins in culture in the presence or not of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity. Methods: Segments of harvested human saphenous veins, obtained at the time of bypass graft, were opened longitudinally with the luminal surface uppermost and maintained in culture for 14 days. Vein fragments were then processed for histologic examination, neointimal thickness measurements, immunocytochemistry, RNA, and proteins analysis. Results: Of the four connexins (Cx37, 40, 43, and 45), we focused on Cx43 and Cx40, which we found by real-time polymerase chain reaction to be expressed in the saphenous vein because they are the predominant connexins expressed by smooth muscle cells and endothelial cells. Afrer 14 days of culture, histomorphometric analysis showed a significant increase in the intimal thickness as observed during the process of intimal hyperplasia. Atime-course analysis revealed a progressive upregulation of Cx43 to reach a maximal increase of sixfold to eightfold at both transcript and protein levels after 14 days in culture. In contrast, the expression of Cx40, abundantly expressed in the endothelial cells, was not altered. Immunofluorescence showed a large increase in Cx43 within smooth muscle cell membranes of the media layer. The development of intimal hyperplasia in vitro was decreased in presence of fluvastatin and was associated with reduced Cx43 expression. Conclusions: These data show that Cx43 is increased in vitro during the process of intimal hyperplasia and that fluvastatin could prevent this induction, supporting a critical role for Cx43-mediated gap-junctional communication in the human vein during the development of intimal hyperplasia. (J Vasc Surg 2005;41:1043-52.)

Postoperative delirium. Part 1: pathophysiology and risk factors.

Delirium presents clinically with differing subtypes ranging from hyperactive to hypoactive. The clinical presentation is not clearly linked to specific pathophysiological mechanisms. Nevertheless, there seem to be different mechanisms that lead to delirium; for example the mechanisms leading to alcohol-withdrawal delirium are different from those responsible for postoperative delirium. In many forms of delirium, the brain's reaction to a peripheral inflammatory process is considered to be a pathophysiological key element and the aged brain seems to react more markedly to a peripheral inflammatory stimulus than a younger brain. The effects of inflammatory mediators on the brain include changes in neurotransmission and apoptosis. On a neurotransmitter level, impaired cholinergic transmission and disturbances of the intricate interactions between dopamine, serotonin and acetylcholine seem to play an important role in the development of delirium. The risk factors for delirium are categorised as predisposing or precipitating factors. In the presence of many predisposing factors, even trivial precipitating factors may trigger delirium, whereas in patients without or with only a few predisposing factors, a major precipitating insult is necessary to trigger delirium. Well documented predisposing factors are age, medical comorbidities, cognitive, functional, visual and hearing impairment and institutional residence. Important precipitating factors apart from surgery are admission to an ICU, anticholinergic drugs, alcohol or drug withdrawal, infections, iatrogenic complications, metabolic derangements and pain. Scores to predict the risk of delirium based on four or five risk factors have been validated in surgical patients.

Three essays on organizations and their external environment

Abstract: The literature on the various links between organizations and their external environment is very extensive and fragmented. This thesis is comprised of three separate essays, each examining specific research questions related to these links. The first essay deals with the notion of industry life cycle and how the geographical concentration of an industry is linked to the particular life cycle stage in which the industry finds itself. The aim of this first essay is firstly to verify if the evolution of the Swiss hotel industry fits some of the stylized facts of the industry life cycle. The second aim is to verify if there is evidence of geographical clustering of the hotel industry, and by extension of tourism. The third aim is to verify a hypothesis that industry decline manifests itself mainly by company closures in decentralized locations. The importance for organizational survival and performance of adapting and reacting to environmental changes has long been ascertained. This adaptation requires managers, under conditions of uncertainty, to identify relevant changes in their external environment and to interpret the possible effects of those changes on their organization. Furthermore, it requires finding and adopting organizational responses in reaction to the environmental changes. The second essay explores how managers perceive their environment by reporting the results of two workshops held with managers from the European hotel industry. In the third essay we examine in more detail the role of uncertainty in the interpretation by executives of environmental changes. We integrate existing theories of interpretation and uncertainty into one framework, which we then test using national survey data from the hotel industry. In all three essays we are able to provide some evidence to support our main hypotheses, but.also make suggestions far further research into the topics examined.

Réponses de la musaraigne musette Crocidura russula, aux marquages odorants d'individus de son espèce (Insectivota, Soricidae)

In order to evaluate the reaction to conspecifics scent tracks of Crocidura russula, a shrew with poorly developped territorial behaviour, simple choice tests in a Y-shaped systems were used. C. russula prefers a marked path to an unmarked one, the tracks of an unknown individual to its own, the tracks of an individual of the opposite sex to those of an individual of the same sex, and the tracks of its sexual partner to those of another individual of the same sex. The choices between two tracks gave a less obvious result than the choices between a marked path and an unmarked one. Ecological and social implications of these results are discussed.

Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development.

We have demonstrated that cortical cell autografts might be a useful therapy in two monkey models of neurological disease: motor cortex lesion and Parkinson's disease. However, the origin of the useful transplanted cells obtained from cortical biopsies is not clear. In this report we describe the expression of doublecortin (DCX) in these cells based on reverse-transcription polymerase chain reaction (RT-PCR) and immunodetection in the adult primate cortex and cell cultures. The results showed that DCX-positive cells were present in the whole primate cerebral cortex and also expressed glial and/or neuronal markers such as glial fibrillary protein (GFAP) or neuronal nuclei (NeuN). We also demonstrated that only DCX/GFAP positive cells were able to proliferate and originate progenitor cells in vitro. We hypothesize that these DCX-positive cells in vivo have a role in cortical plasticity and brain reaction to injury. Moreover, in vitro these DCX-positive cells have the potential to reacquire progenitor characteristics that confirm their potential for brain repair.

Leishmania RNA virus: when the host pays the toll.

The presence of an RNA virus in a South American subgenus of the Leishmania parasite, L. (Viannia), was detected several decades ago but its role in leishmanial virulence and metastasis was only recently described. In Leishmania guyanensis, the nucleic acid of Leishmania RNA virus (LRV1) acts as a potent innate immunogen, eliciting a hyper-inflammatory immune response through toll-like receptor 3 (TLR3). The resultant inflammatory cascade has been shown to increase disease severity, parasite persistence, and perhaps even resistance to anti-leishmanial drugs. Curiously, LRVs were found mostly in clinical isolates prone to infectious metastasis in both their human source and experimental animal model, suggesting an association between the viral hyperpathogen and metastatic complications such as mucocutaneous leishmaniasis (MCL). MCL presents as chronic secondary lesions in the mucosa of the mouth and nose, debilitatingly inflamed and notoriously refractory to treatment. Immunologically, this outcome has many of the same hallmarks associated with the reaction to LRV: production of type 1 interferons, bias toward a chronic Th1 inflammatory state and an impaired ability of host cells to eliminate parasites through oxidative stress. More intriguing, is that the risk of developing MCL is found almost exclusively in infections of the L. (Viannia) subtype, further indication that leishmanial metastasis is caused, at least in part, by a parasitic component. LRV present in this subgenus may contribute to the destructive inflammation of metastatic disease either by acting in concert with other intrinsic "metastatic factors" or by independently preying on host TLR3 hypersensitivity. Because LRV amplifies parasite virulence, its presence may provide a unique target for diagnostic and clinical intervention of metastatic leishmaniasis. Taking examples from other members of the Totiviridae virus family, this paper reviews the benefits and costs of endosymbiosis, specifically for the maintenance of LRV infection in Leishmania parasites, which is often at the expense of its human host.

Que cache l'agenda caché [What is behind the hidden agenda?]

The physicians often forget to ask their patients if they would like to discuss other complaints or topics. It is sometimes quite difficult to explore the patient's complaints; while the physicians tend to focus on the immediate problem, the patients may have not only one, but several hidden agendas during a visit. In a caring relation there is a clear advantage to clarify the implicit. The search for the hidden agenda is to improve the care of i) biomedical problems ii) the social quest presented to the physicians. The sentence "Oh, by the way, doctor..." should not be only understood as an information but also as a relational expression and a reaction to the imminent separation from the physician.

Accurate memory for object location by individuals with intellectual disability: Absolute spatial tagging instead of configural processing?

Using head-mounted eye tracker material, we assessed spatial recognition abilities (e.g., reaction to object permutation, removal or replacement with a new object) in participants with intellectual disabilities. The "Intellectual Disabilities (ID)" group (n=40) obtained a score totalling a 93.7% success rate, whereas the "Normal Control" group (n=40) scored 55.6% and took longer to fix their attention on the displaced object. The participants with an intellectual disability thus had a more accurate perception of spatial changes than controls. Interestingly, the ID participants were more reactive to object displacement than to removal of the object. In the specific test of novelty detection, however, the scores were similar, the two groups approaching 100% detection. Analysis of the strategies expressed by the ID group revealed that they engaged in more systematic object checking and were more sensitive than the control group to changes in the structure of the environment. Indeed, during the familiarisation phase, the "ID" group explored the collection of objects more slowly, and fixed their gaze for a longer time upon a significantly lower number of fixation points during visual sweeping.

Increased connexin43 expression in human saphenous veins in culture is associated with intimal hyperplasia.

OBJECTIVE: Intimal hyperplasia is a vascular remodelling process that occurs after a vascular injury. The mechanisms involved in intimal hyperplasia are proliferation, dedifferentiation, and migration of medial smooth muscle cells towards the subintimal space. We postulated that gap junctions, which coordinate physiologic processes such as cell growth and differentiation, might participate in the development of intimal hyperplasia. Connexin43 (Cx43) expression levels may be altered in intimal hyperplasia, and we therefore evaluated the regulated expression of Cx43 in human saphenous veins in culture in the presence or not of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity. METHODS: Segments of harvested human saphenous veins, obtained at the time of bypass graft, were opened longitudinally with the luminal surface uppermost and maintained in culture for 14 days. Vein fragments were then processed for histologic examination, neointimal thickness measurements, immunocytochemistry, RNA, and proteins analysis. RESULTS: Of the four connexins (Cx37, 40, 43, and 45), we focused on Cx43 and Cx40, which we found by real-time polymerase chain reaction to be expressed in the saphenous vein because they are the predominant connexins expressed by smooth muscle cells and endothelial cells. After 14 days of culture, histomorphometric analysis showed a significant increase in the intimal thickness as observed during the process of intimal hyperplasia. A time-course analysis revealed a progressive upregulation of Cx43 to reach a maximal increase of sixfold to eightfold at both transcript and protein levels after 14 days in culture. In contrast, the expression of Cx40, abundantly expressed in the endothelial cells, was not altered. Immunofluorescence showed a large increase in Cx43 within smooth muscle cell membranes of the media layer. The development of intimal hyperplasia in vitro was decreased in presence of fluvastatin and was associated with reduced Cx43 expression. CONCLUSIONS: These data show that Cx43 is increased in vitro during the process of intimal hyperplasia and that fluvastatin could prevent this induction, supporting a critical role for Cx43-mediated gap-junctional communication in the human vein during the development of intimal hyperplasia. CLINICAL RELEVANCE: Stenosis due to intimal hyperplasia is the most common cause of failure of venous bypass grafts. To better understand the development of intimal hyperplasia, we used an ex vivo organ culture model to study saphenous veins harvested from patients undergoing a lower limb bypass surgery. In this model, the morphologic and functional integrity of the vessel wall is maintained and significant intimal hyperplasia development occurs after 14 days in culture. We have postulated that gap junctions, which coordinate physiologic processes such as cell growth and differentiation, may participate in the development of intimal hyperplasia. Indeed, intimal hyperplasia consists of proliferation and migration of smooth muscle cells into the subendothelial space. Intercellular communication is responsible for the direct transfer of ions and small molecules from one cell to the other through gap-junction channels found at cell-cell appositions. No study to date has evaluated whether gap junctional communication is involved in the process of intimal hyperplasia in humans. This assertion was investigated by using the aforementioned organ culture model of intimal hyperplasia in human saphenous veins, and our data support a critical role for Cx43-mediated gap junctional communication in human vein during the development of intimal hyperplasia.

Philemon and Baucis deaths: case reports and postmortem biochemistry contribution.

The death of a person as a reaction to the death of another is known as Philemon and Baucis death and may represent a difficult challenge for pathologists, especially due to the decompositional changes that often characterized these situations. In this article, we describe two cases of Philemon and Baucis deaths, the first concerning a married couple and the second concerning a father and son. Postmortem investigations including radiology and biochemistry were performed. Based on the results of all investigations, deaths were attributed to natural causes. Third-party involvement could be excluded in both situations. In one case, biochemical analysis results revealed potentially contributing causes of death. The reported cases emphasize the importance of correlating findings from different postmortem investigations to identify causes of death, precipitating conditions and predisposing disorders, thus allowing the conclusion of natural death to be reached and third-party involvement to be excluded.

Pharmacovigilance et teratovigilance 2008 [Pharmacovigilance and teratovigilance 2008]

Various signals and alerts of pharmacovigilance were issued in 2008. Frequent neuropsychiatric adverse events are reported with varenicline and rimonabant and the marketing authorization of the latter has been suspended. Ezetimibe/simvastatin combination is suspected of causing cancer while it's clinical utility remains to be proved. Neuroleptics, typical and atypical, are associated with an increased risk of death in elderly with dementia. Safety is a concern with various biological drugs. Rituximab, natalizumab and efalizumab are involved in rare cases of progressive multifocal leukoencephalopathy with fatal issue. Screening of HLA-B*5701, a good predictor of hypersensitivity reaction to abacavir, is recommended prior to starting therapy. Mycophenolate turns out to be a human teratogen.

Inflammatory myofibroblastic tumor of the trachea with concomitant granulomatous lymph node lesions.

We report herein the case of a 57-year-old lady who had two concomittant lesions, an inflammatory myofibroblastic tumor in the trachea, and severe granulomatous lesions in the adjacent hilar lymph nodes. While these two lesions shared histological and some immunohistochemical features lesions. They differed in terms of ALK-1 expression, which was positive in the tracheal tumor and negative in the lymph nodes. The discussion of the case circles around putative pathophysiological links between the lesions. The authors favor the idea that the lymph nodes present a sarcoid-like granulomatous reaction to the inflammatory myofibroblastic tumor in the trachea over a coexistence of two independent entities. However, no conclusive evidence for this interpretation can be presented based on the existing literature.