Redirecting anti-viral CTL against cancer cells by surface targeting of monomeric MHC class I-viral peptide conjugated to antibody fragments.

To combine the advantage of both the tumor targeting capacity of high affinity monoclonal antibodies (mAbs) and the potent killing properties of cytotoxic T lymphocytes (CTL), we investigated the activity of conjugates made by coupling single Fab' fragments, from mAbs specific for tumor cell surface antigens, to monomeric HLA-A2 complexes containing the immunodominant influenza-matrix peptide 58-66. In solution, the monovalent 95 kDa Fab-HLA-A2/Flu conjugates did not activate influenza-specific CTL. However, when targeted to tumor cells expressing the relevant tumor-associated antigen, the conjugates induced CTL activation and efficient tumor cell lysis, as a result of MHC/peptide surface oligomerization. The highly specific and sensitive in vitro cytotoxicity results presented suggest that injection of Fab-MHC/peptide conjugates could represent a new form of immunotherapy, bridging antibody and T lymphocyte attack on cancer cells.

Off-label utilization of antipsychotics

Résumé Ce travail s'inscrit dans un programme de recherche centré sur la pharmacovigilance en psychiatrie. Buts de l'étude Les nouveaux antipsychotiques atypiques sont prescrits avec beaucoup de succès, parce qu'ils présentent une sécurité dans leur emploi bien supérieure à celle des antipsychotiques classiques. Cette situation a conduit à une large prescription «off-label» (hors indication admise). Le but de ce travail a été d'étudier la pratique en matière de prescription des psychiatres hospitaliers en ce qui concerne les antipsychotiques en comparant des patients traités pour des psychoses ou d'autres indications officielles aux patients recevant un traitement antipsychotique «off-label». Méthode Dans le cadre d'un programme de pharmacovigilance - pharmacoépidemiologie, tous les médicaments prescrits à 5 jours de référence (entre 1999 et 2001) à l'hôpital psychiatrique universitaire de Lausanne (98 lits) ont été enregistrés, avec des données sur l'âge, le sexe et le diagnostic des patients. Les prescriptions de 202 patients ont été évaluées. Les patients ont été classés dans 3 groupes diagnostiques : (1) patient présentant des troubles psychotiques, (2) patient présentant des épisodes maniaques et des épisodes dépressifs avec des symptômes psychotiques, et (3) patient présentant d'autres troubles. Les groupes (1) et (2) forment une classe de patients recevant un antipsychotique pour une indication officielle, et les prescriptions dans le groupe (3) ont été considérées comme «off-label». Résultats principaux Moins de patients psychotiques ont reçu un antidépresseur (p<0.05) ou des hypnotiques non-benzodiazepine (p<0.001) comparés aux patients des deux autres groupes. Les patients présentant des troubles affectifs recevaient seulement exceptionnellement une combinaison d'un antipsychotique atypique et conventionnel, tandis qu'un nombre inférieur de patients avec des indications « off-label » ont reçu moins .souvent des antipsychotiques atypiques que ceux des deux groupes de comparaison (p<0.05). L'analyse statistique (stepwise logistic regression) a révélé que les patients présentant des troubles psychotiques avaient un risque plus élevé de recevoir un médicament antipsychotique d'une dose moyenne ou élevée, (p<0.001) en comparaison aux deux autres groupes. Conclusion Les nouveaux médicaments antipsychotiques semblent être prescrits avec moins d'hésitation principalement pour des indications admises. Les médecins prescrivent de nouveaux médicaments « off-label » seulement après avoir acquis une certaine expérience dans le domaine des indications approuvées, et ils étaient plus prudents en ce qui concerne la dose en traitant sur la base «off-label». Abstract Objective The new brands of atypical antipsychotics are very successfully prescribed because of their enhanced safety profiles and their larger pharmacological profile in comparison to the conventional antipsychotic. This has led to broad off-label utilisation. The aim of the present survey was to study the prescription practice of hospital psychiatrists with regard to antipsychotic drugs, comparing patients treated for psychoses or other registered indications to patients receiving an off-label antipsychotic treatment. Method As part of a pharmacovigilance/pharmacoepidemiology program, all drugs given on 5 reference days (1999 - 2001) in the 98-bed psychiatric hospital of the University of Lausanne, Switzerland, were recorded along with age, sex and diagnosis. The prescriptions of 202 patients were assessed. Patients were classified in 3 diagnostic groups: (1) patient with psychotic disorders, (2) patients with manic episodes and depressive episodes with psychotic symptoms, and (3) patients with other disorders. Group (1) and (2) formed the class of patients receiving an antipsychotic for a registered indication, and the prescriptions in group (3) were considered as off-label. Main results A lesser number of psychotic patients received antidepressant (p<0.05) and nonbenzodiazepine hypnotics (p<0.001) compared to the patients of the other two groups. The patients with affective disorders received only exceptionally a combination of an atypical and a conventional antipsychotic, whereas a lesser number of patients with off-label indications received less often atypical antipsychotics than those of the two comparison groups (p<0.05). Stepwise logistic regression revealed that patients with psychotic disorder were at higher risk of receiving an antipsychotic medication in medium or high dose (p<0.001), in comparison to the two other groups. Conclusions The new antipsychotic drugs seem to be prescribed with less hesitation mainly for approved indications. Physicians prescribe new drugs on off-label application only after having gained some experience in the field of the approved indications, and were more cautious with regard to dose when treating on an off-label basis.

LILRB2 interaction with HLA class I correlates with control of HIV-1 infection.

Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10(-2)). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10(-11)-10(-9)) and African (p = 10(-5)-10(-3)) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.

The degradation of HFR1, a putative bHLH class transcription factor involved in light signaling, is regulated by phosphorylation and requires COP1.

All developmental transitions throughout the life cycle of a plant are influenced by light. In Arabidopsis, multiple photoreceptors including the UV-A/blue-sensing cryptochromes (cry1-2) and the red/far-red responsive phytochromes (phyA-E) monitor the ambient light conditions. Light-regulated protein stability is a major control point of photomorphogenesis. The ubiquitin E3 ligase COP1 (constitutively photomorphogenic 1) regulates the stability of several light-signaling components. HFR1 (long hypocotyl in far-red light) is a putative transcription factor with a bHLH domain acting downstream of both phyA and the cryptochromes. HFR1 is closely related to PIF1, PIF3, and PIF4 (phytochrome interacting factor 1, 3 and 4), but in contrast to the latter three, there is no evidence for a direct interaction between HFR1 and the phytochromes. Here, we show that the protein abundance of HFR1 is tightly controlled by light. HFR1 is an unstable phosphoprotein, particularly in the dark. The proteasome and COP1 are required in vivo to degrade phosphorylated HFR1. In addition, HFR1 can interact with COP1, consistent with the idea of COP1 directly mediating HFR1 degradation. We identify a domain, conserved among several bHLH class proteins involved in light signaling , as a determinant of HFR1 stability. Our physiological experiments indicate that the control of HFR1 protein abundance is important for a normal de-etiolation response.

Breath acetone to monitor life style interventions in field conditions: An exploratory study.

OBJECTIVE: To assess whether breath acetone concentration can be used to monitor the effects of a prolonged physical activity on whole body lipolysis and hepatic ketogenesis in field conditions. METHODS: Twenty-three non-diabetic, 11 type 1 diabetic, and 17 type 2 diabetic subjects provided breath and blood samples for this study. Samples were collected during the International Four Days Marches, in the Netherlands. For each participant, breath acetone concentration was measured using proton transfer reaction ion trap mass spectrometry, before and after a 30-50 km walk on four consecutive days. Blood non-esterified free fatty acid (NEFA), beta-hydroxybutyrate (BOHB), and glucose concentrations were measured after walking. RESULTS: Breath acetone concentration was significantly higher after than before walking, and was positively correlated with blood NEFA and BOHB concentrations. The effect of walking on breath acetone concentration was repeatedly observed on all four consecutive days. Breath acetone concentrations were higher in type 1 diabetic subjects and lower in type 2 diabetic subjects than in control subjects. CONCLUSIONS: Breath acetone can be used to monitor hepatic ketogenesis during walking under field conditions. It may, therefore, provide real-time information on fat burning, which may be of use for monitoring the lifestyle interventions.

Suivi du patient après transplantation cardiaque: monitoring et adaptation de l'immunosuppression [Monitoring and adjustment of immunosuppression after heart transplantation].

Heart transplantation remains the best therapeutic option for the treatment of end-stage heart failure. However, good survival rates can be obtained only if patients are closely monitored, particularly for their immunosuppressive regimens. Currently, a triple-drug regimen usually based on calcineurin-inhibitors (cyclosporin A or tacrolimus), anti-proliferative agents and steroids is used in most recipients. New agents such as the mTOR inhibitors, a more recently developed class of immunosuppressive drugs, can also be used in some patients. The aim of this article is to review currently used immunosuppressive regimens after heart transplantation, and to propose some individualized options depending on specific patient characteristics and recent pharmacological developments in the field.

Sex-related and non-sex-related comorbidity subtypes of tic disorders: a latent class approach.

BACKGROUND AND PURPOSE: Recent evidence suggests that there may be more than one Gilles de la Tourette syndrome (GTS)/tic disorder phenotype. However, little is known about the common patterns of these GTS/tic disorder-related comorbidities. In addition, sex-specific phenomenological data of GTS/tic disorder-affected adults are rare. Therefore, this community-based study used latent class analyses (LCA) to investigate sex-related and non-sex-related subtypes of GTS/tic disorders and their most common comorbidities. METHODS: The data were drawn from the PsyCoLaus study (n = 3691), a population-based survey conducted in Lausanne, Switzerland. LCA were performed on the data of 80 subjects manifesting motor/vocal tics during their childhood/adolescence. Comorbid attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, depressive, phobia and panic symptoms/syndromes comprised the selected indicators. The resultant classes were characterized by psychosocial correlates. RESULTS: In LCA, four latent classes provided the best fit to the data. We identified two male-related classes. The first class exhibited both ADHD and depression. The second class comprised males with only depression. Class three was a female-related class depicting obsessive thoughts/compulsive acts, phobias and panic attacks. This class manifested high psychosocial impairment. Class four had a balanced sex proportion and comorbid symptoms/syndromes such as phobias and panic attacks. The complementary occurrence of comorbid obsessive thoughts/compulsive acts and ADHD impulsivity was remarkable. CONCLUSIONS: To the best of our knowledge, this is the first study applying LCA to community data of GTS symptoms/tic disorder-affected persons. Our findings support the utility of differentiating GTS/tic disorder subphenotypes on the basis of comorbid syndromes.

Navigator-gated free-breathing three-dimensional balanced fast field echo (TrueFISP) coronary magnetic resonance angiography.

RATIONALE AND OBJECTIVES: Recent developments of MR imaging equipment enabled high-quality steady state-free-precession (Balanced FFE, True-FISP) MR-imaging with a substantial 'T2 like' contrast, resulting in a high signal intensity of the blood-pool without the application of exogenous contrast agents. It is hypothesized that Balanced-FFE may be valuable for contrast enhancement in 3D free-breathing coronary MRA. MATERIALS AND METHODS: Navigator-gated free-breathing cardiac triggered coronary MRA was performed in 10 healthy adult subjects and three patients with radiograph defined coronary artery disease using a segmented k-space 3D Balanced FFE imaging sequence. RESULTS: High contrast-to-noise ratio between the blood-pool and the myocardium (29 +/- 8) and long segment visualization of both coronary arteries could be obtained in about 5 minutes during free breathing using the present navigator-gated Balanced-FFE coronary MRA approach. First patient results demonstrated successful display of coronary artery stenoses. CONCLUSION: Balanced FFE offers a potential alternative for endogenous contrast enhancement in navigator-gated free-breathing 3D coronary MRA. The obtained results together with the relatively short scanning time warrant further studies in larger patient collectives.

MP2RAGE, a self bias-field corrected sequence for improved segmentation and T-1-mapping at high field

The large spatial inhomogeneity in transmit B, field (B-1(+)) observable in human MR images at hi h static magnetic fields (B-0) severely impairs image quality. To overcome this effect in brain T-1-weighted images the, MPRAGE sequence was modified to generate two different images at different inversion times MP2RAGE By combining the two images in a novel fashion, it was possible to create T-1-weigthed images where the result image was free of proton density contrast, T-2* contrast, reception bias field, and, to first order transmit field inhomogeneity. MP2RAGE sequence parameters were optimized using Bloch equations to maximize contrast-to-noise ratio per unit of time between brain tissues and minimize the effect of B-1(+) variations through space. Images of high anatomical quality and excellent brain tissue differentiation suitable for applications such as segmentation and voxel-based morphometry were obtained at 3 and 7 T. From such T-1-weighted images, acquired within 12 min, high-resolution 3D T-1 maps were routinely calculated at 7 T with sub-millimeter voxel resolution (0.65-0.85 mm isotropic). T-1 maps were validated in phantom experiments. In humans, the T, values obtained at 7 T were 1.15 +/- 0.06 s for white matter (WM) and 1.92 +/- 0.16 s for grey matter (GM), in good agreement with literature values obtained at lower spatial resolution. At 3 T, where whole-brain acquisitions with 1 mm isotropic voxels were acquired in 8 min the T-1 values obtained (0.81 +/- 0.03 S for WM and 1.35 +/- 0.05 for GM) were once again found to be in very good agreement with values in the literature. (C) 2009 Elsevier Inc. All rights reserved.

Swiss clinical practice guidelines on field cancerization of the skin.

Actinic keratosis (AK) affects millions of people worldwide, and its prevalence continues to increase. AK lesions are caused by chronic ultraviolet radiation exposure, and the presence of two or more AK lesions along with photodamage should raise the consideration of a diagnosis of field cancerization. Effective treatment of individual lesions as well as field cancerization is essential for good long-term outcomes. The Swiss Registry of Actinic Keratosis Treatment (REAKT) Working Group has developed clinical practice guidelines for the treatment of field cancerization in patients who present with AK. These guidelines are intended to serve as a resource for physicians as to the most appropriate treatment and management of AK and field cancerization based on current evidence and the combined practical experience of the authors. Treatment of AK and field cancerization should be driven by consideration of relevant patient, disease, and treatment factors, and appropriate treatment decisions will differ from patient to patient. Prevention measures and screening recommendations are discussed, and special considerations related to management of immunocompromised patients are provided.