"Michael's Game," a card game for the treatment of psychotic symptoms.

Objective: "Michael's Game" is a card game which aims at familiarizing healthcare professionals and patients with cognitive therapy of psychotic symptoms. The present study tests the feasibility and the impact of the intervention in naturalistic settings.Methods: 135 patients were recruited in 11 centres. They were assessed pre- and post-tests with the Beck Cognitive Insight Scale (BCIS) and the Peters Delusion Inventory-21 items (PDI-21).Results: Data about 107 patients were included in the entire analyses. Significant improvements were observed on BCIS subscales as well as a reduction of severity of conviction and preoccupation scores on the PDI-21. The intervention has a moderate effect on the PDI-21 preoccupation and conviction as well as the BCIS subscales. Patients who benefit the most from the program are patients who have a low degree of self-reflectiveness and patients who are concomitantly preoccupied by their symptoms.Conclusion: The present study supports the feasibility and effectiveness of "Michael's Game" in naturalistic settings.Practical implications: The game seems to be a useful tool for patients with psychotic disorders. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.

In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor-β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.

Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation.

Bcl10, a caspase recruitment domain (CARD)-containing protein identified from a breakpoint in mucosa-associated lymphoid tissue (MALT) B lymphomas, is essential for antigen-receptor-mediated nuclear factor kappaB (NF-kappaB) activation in lymphocytes. We have identified a novel CARD-containing protein and interaction partner of Bcl10, named Carma1. Carma1 is predominantly expressed in lymphocytes and represents a new member of the membrane-associated guanylate kinase family. Carma1 binds Bcl10 via its CARD motif and induces translocation of Bcl10 from the cytoplasm into perinuclear structures. Moreover, expression of Carma1 induces phosphorylation of Bcl10 and activation of the transcription factor NF-kappaB. We propose that Carma1 is a crucial component of a novel Bcl10-dependent signaling pathway in T-cells that leads to the activation of NF-kappaB.

Injury pattern of the Flash-Ball, a less-lethal weapon used for law enforcement: report of two cases and review of the literature.

Less-lethal weapons are used in law enforcement to neutralize combative individuals and to disperse riot crowds. Local police recently used such an impact weapon, the Flash-Ball, in two different situations. This gun fires large rubber bullets with kinetic energies around 200 J. Although it is designed to avoid skin penetration, impacts at such energies may still create major trauma with associated severe injuries to internal organs. This is a report of 2 patients shot with the Flash-Ball who required medical attention. One could be discharged quickly, but the other required hospitalization for heart and lung contusion. Both patients required advanced investigations including computed tomography (CT) scan. The medical literature on injuries induced by less-lethal impact weapons is reviewed. Impacts from the Flash-Ball can cause significant injury to internal organs, even without penetration. Investigations as for other high-energy blunt traumas are called for in these cases.

Jumping Jack Flash.

A 38-year-old woman presented with blurred vision and "jumping" of the right eye for 7 months. Magnetic resonance imaging of the head was normal. Intermittent intorsion of the right eye was noted on examination, consistent with superior oblique myokymia. She was initially treated with carbamazepine but stopped after becoming light-headed. The diagnosis and treatment of superior oblique myokymia are discussed.

Radiothérapie « flash » à très haut débit de dose : un moyen d'augmenter l'indice thérapeutique par minimisation des dommages aux tissus sains [Ultrahigh dose-rate, "flash" irradiation minimizes the side-effects of radiotherapy].

PURPOSE: Pencil beam scanning and filter free techniques may involve dose-rates considerably higher than those used in conventional external-beam radiotherapy. Our purpose was to investigate normal tissue and tumour responses in vivo to short pulses of radiation. MATERIAL AND METHODS: C57BL/6J mice were exposed to bilateral thorax irradiation using pulsed (at least 40Gy/s, flash) or conventional dose-rate irradiation (0.03Gy/s or less) in single dose. Immunohistochemical and histological methods were used to compare early radio-induced apoptosis and the development of lung fibrosis in the two situations. The response of two human (HBCx-12A, HEp-2) tumour xenografts in nude mice and one syngeneic, orthotopic lung carcinoma in C57BL/6J mice (TC-1 Luc+), was monitored in both radiation modes. RESULTS: A 17Gy conventional irradiation induced pulmonary fibrosis and activation of the TGF-beta cascade in 100% of the animals 24-36 weeks post-treatment, as expected, whereas no animal developed complications below 23Gy flash irradiation, and a 30Gy flash irradiation was required to induce the same extent of fibrosis as 17Gy conventional irradiation. Cutaneous lesions were also reduced in severity. Flash irradiation protected vascular and bronchial smooth muscle cells as well as epithelial cells of bronchi against acute apoptosis as shown by analysis of caspase-3 activation and TUNEL staining. In contrast, the antitumour effectiveness of flash irradiation was maintained and not different from that of conventional irradiation. CONCLUSION: Flash irradiation shifted by a large factor the threshold dose required to initiate lung fibrosis without loss of the antitumour efficiency, suggesting that the method might be used to advantage to minimize the complications of radiotherapy.

Prognostic importance of hyponatremia in patients with acute pulmonary embolism

Rapport de synthèse Enjeux et contexte: L'hyponatrémie est un trouble électrolytique fréquent et associé à un pronostic défavorable dans de nombreuses affections card iovascu lai res (1-5), pour lesquelles il est un marqueur de l'activation neurohumorale (6). Sa valeur pronostique chez les patients se présentant avec une emboîie pulmonaire était jusque là inconnue ; elle fait l'objet de la présente étude.Objectifs: Examiner chez les patients hospitalisés pour une embolie pulmonaire, les associations entre hyponatrémie et mortalité ainsi qu'avec le taux de réhospitalisation. Méthodes: Nous avons étudié les données de 13728 patients avec un diagnostic principal d'embolie pulmonaire provenant de 185 hôpitaux en Pennsylvanie (janvier 2000 à novembre 2002.) Nous avons utilisé un modèle de régression logistique afin d'établir l'association indépendante entre le niveau de sodium lors de la présentation aux urgences et la mortalité ainsi que le taux de ^hospitalisation durant 30 jours. Nous avons ajusté pour les caractéristiques du patient (race, assurance, sévérité de la maladie, usage de la thrombolyse) et de l'hôpital (région, taille, avec ou sans médecins en formation.)Résultats principaux: Une hyponatrémie (sodium £ 135 mmol/l) était présente chez 2907 patients (21.1%). Les patients avec un sodium >135, 130-135, et <130 mmol/l avaient une mortalité cumulée à 30 jours de 8.0%, 13.6%, et 28.5% (P <0.001), et un taux de réadmission de 11.8%, 15.6%, et 19.3% (P <0.001), respectivement. Comparés aux patients avec un sodium >135 mmol/l, les odd ratios ajustés concernant la mortalité étaient significativement plus important pour les patients avec un sodium compris entre 130 et 135 mmol/l (OR 1.53, 95% Cl: 1.33-1.76) ou <130 mmol/l (OR 3.26, 95% Cl: 2.48-4.29). Les odd ratios ajustés concernant la réhospitalisation étaient également augmentés pour les patients présentant un sodium entre 130 et 135 mmol/l (OR 1.28, 95% Cl: 1.12-1.46) ou <130 mmol/l (OR 1.44, 95% Cl: 1.02-2.02). Conclusions et perspectives: L'hyponatrémie est fréquente chez les patients se présentant avec une embolie pulmonaire, de plus elle est un prédicateur indépendant de la mortalité à court terme, ainsi que du taux de réhospitalisation. La natrémie est une information généralement disponible lors de l'établissement d'un pronostic. Bien que cette association soit compatible avec une activation neurohumorale, nous ne pouvons pas attester des mécanismes impliqués, du fait que notre étude ne donne pas d'informations sur d'autres étapes de la physiologie de cette association.

Post-translational modifications regulate distinct functions of CARMA1 and BCL10.

Activation of the transcription factor nuclear factor (NF)-kappaB is essential for the normal functioning of the immune system. Deregulated NF-kappaB signalling in lymphocytes can lead to immunodeficiency, but also to autoimmunity or lymphomas. Many of the signalling components controlling NF-kappaB activation in lymphocytes are now known, but it is less clear how distinct molecular components of this pathway are regulated. Here, we summarize recent findings on post-translational modifications of intracellular components of this pathway. Phosphorylation of the CARMA1 and BCL10 proteins and ubiquitylation of BCL10 affect the formation and stability of the CARMA1-BCL10-MALT1 (CBM) complex, and also control negative feedback regulation of the NF-kappaB signalling pathway. Moreover, the study of BCL10 phosphorylation isoforms has revealed a new mechanism controlling BCL10 nuclear translocation and an unexpected role for BCL10 in the regulation of the actin cytoskeleton.

Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation.

Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-kappaB activation. The current findings define a link among TCR, caspases, and the NF-kappaB pathway that occurs in a sequestered lipid raft environment in T cells.

Role of disease activity for decision making ability in early multiple sclerosis

Background and purpose: Decision making (DM) has been defined as the process through which a person forms preferences, selects and executes actions, and evaluates the outcome related to a selected choice. This ability represents an important factor for adequate behaviour in everyday life. DM impairment in multiple sclerosis (MS) has been previously reported. The purpose of the present study was to assess DM in patients with MS at the earliest clinically detectable time point of the disease. Methods: Patients with definite (n=109) or possible (clinically isolated syndrome, CIS; n=56) MS, a short disease duration (mean 2.3 years) and a minor neurological disability (mean EDSS 1.8) were compared to 50 healthy controls aged 18 to 60 years (mean age 32.2) using the Iowa Gambling Task (IGT). Subjects had to select a card from any of 4 decks (A/B [disadvantageous]; C/D [advantageous]). The game consisted of 100 trials then grouped in blocks of 20 cards for data analysis. Skill in DM was assessed by means of a learning index (LI) defined as the difference between the averaged last three block indexes and first two block indexes (LI=[(BI-3+BI-4+BI-5)/3-(BI-1+B2)/2]). Non parametric tests were used for statistical analysis. Results: LI was higher in the control group (0.24, SD 0.44) than in the MS group (0.21, SD 0.38), however without reaching statistical significance (p=0.7). Interesting differences were detected when MS patients were grouped according to phenotype. A trend to a difference between MS subgroups and controls was observed for LI (p=0.06), which became significant between MS subgroups (p=0.03). CIS patients who confirmed MS diagnosis by presenting a second relapse after study entry showed a dysfunction in the IGT in comparison to the other CIS (p=0.01) and definite MS (p=0.04) patients. In the opposite, CIS patients characterised by not entirely fulfilled McDonald criteria at inclusion and absence of relapse during the study showed an normal learning pattern on the IGT. Finally, comparing MS patients who developed relapses after study entry, those who remained clinically stable and controls, we observed impaired performances only in relapsing patients in comparison to stable patients (p=0.008) and controls (p=0.03). Discussion: These results raise the assumption of a sustained role for both MS relapsing activity and disease heterogeneity (i.e. infra-clinical severity or activity of MS) in the impaired process of decision making.