Cryoballoon Ablation for Atrial Fibrillation

Focal point-by-point radiofrequency catheter ablation has shown considerable success in the treatment of paroxysmal atrial fibrillation. However, it is not without limitations. Recent clinical and preclinical studies have demonstrated that cryothermal ablation using a balloon catheter (Artic Front©, Medtronic CryoCath LP) provides an effective alternative strategy to treating atrial fibrillation. The objective of this article is to review efficacy and safety data surrounding cryoballoon ablation for paroxysmal and persistent atrial fibrillation. In addition, a practical step-by-step approach to cryoballoon ablation is presented, while highlighting relevant literature regarding: 1) the rationale for adjunctive imaging, 2) selection of an appropriate cryoballoon size, 3) predictors of efficacy, 4) advanced trouble-shooting techniques, and 5) strategies to reduce procedural complications, such as phrenic nerve palsy

Evidence for a role of NTS2 receptors in the modulation of tonic pain sensitivity

<p>Abstract</p> <p>Background</p> <p>Central neurotensin (NT) administration results in a naloxone-insensitive antinociceptive response in animal models of acute and persistent pain. Both NTS1 and NTS2 receptors were shown to be required for different aspects of NT-induced analgesia. We recently demonstrated that NTS2 receptors were extensively associated with ascending nociceptive pathways, both at the level of the dorsal root ganglia and of the spinal dorsal horn. Then, we found that spinally administered NTS2-selective agonists induced dose-dependent antinociceptive responses in the acute tail-flick test. In the present study, we therefore investigated whether activation of spinal NTS2 receptors suppressed the persistent inflammatory pain symptoms observed after intraplantar injection of formalin.</p> <p>Results</p> <p>We first demonstrated that spinally administered NT and NT69L agonists, which bind to both NTS1 and NTS2 receptors, significantly reduced pain-evoked responses during the inflammatory phase of the formalin test. Accordingly, pretreatment with the NTS2-selective analogs JMV-431 and levocabastine was effective in inhibiting the aversive behaviors induced by formalin. With resolution at the single-cell level, we also found that activation of spinal NTS2 receptors reduced formalin-induced <it>c-fos </it>expression in dorsal horn neurons. However, our results also suggest that NTS2-selective agonists and NTS1/NTS2 mixed compounds differently modulated the early (21–39 min) and late (40–60 min) tonic phase 2 and recruited endogenous pain inhibitory mechanisms integrated at different levels of the central nervous system. Indeed, while non-selective drugs suppressed pain-related behaviors activity in both part of phase 2, intrathecal injection of NTS2-selective agonists was only efficient in reducing pain during the late phase 2. Furthermore, assessment of the stereotypic pain behaviors of lifting, shaking, licking and biting to formalin also revealed that unlike non-discriminative NTS1/NTS2 analogs reversing all nociceptive endpoint behaviors, pure NTS2 agonists specifically inhibited paw lifting, supporting a role of NTS2 in spinal modulation of persistent nociception.</p> <p>Conclusion</p> <p>The present study provides the first demonstration that activation of NTS2 receptors produces analgesia in the persistent inflammatory pain model of formalin. The dichotomy between these two classes of compounds also indicates that both NTS1 and NTS2 receptors are involved in tonic pain inhibition and implies that these two NT receptors modulate the pain-induced behavioral responses by acting on distinct spinal and/or supraspinal neural circuits. In conclusion, development of NT agonists targeting both NTS1 and NTS2 receptors could be useful for chronic pain management.</p

The RNA-Binding Protein Musashi1 Affects Medulloblastoma Growth via a Network of Cancer- Related Genes and Is an Indicator of Poor Prognosis

Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target

Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples

The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Cytogenetic Prognostication Within Medulloblastoma Subgroups

PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials

Compliance des suicidants par intoxication médicamenteuse volontaire au suivi proposé (à propos de 159 cas de patients pris en charge à l'unité d'hospitalisation de courte durée du service d'accueil des urgences de Grenoble entre le 1er février et le 31 mars 2006)

Le pronostic des suicidants dépend pour une grande partie des soins ultérieurs. Ceux-ci sont limités par une faible compliance au suivi proposé. Dans le cadre de ce travail de thèse, la compliance primaire au suivi proposé a été étudiée de façon descriptive pour des suicidants accueillis aux urgences. Parmi 159 patients pris en charge entre le 1er février et le 31 mars 2006 à l'Unité d'Hospitalisation de Courte Durée du Service d'Accueil des Urgences de Grenoble pour intoxication médicamenteuse volontaire et évalués par un psychiatre, 89 sont sortis avec une proposition de suivi. La présentation ou non au premier entretien de suivi de ces patients a été recherchée par un contact téléphonique auprès de chaque intervenant (ou structure) qui devait revoir le patient. Cette prise de contact s'est faite soixante jours après la sortie de chaque patient non hospitalisé, délai estimé suffisamment long pour l'obtention d'un rendez-vous. Parallèlement les caractéristiques socio démographiques, les antécédents psychiatriques et les prises en charges antérieures de ces patients étaient aussi recueillis rétrospectivement. Aucune différence significative n'a été retrouvée entre le groupe des suicidants compliants (45) et celui des non compliants (28) concernant les données socio démographiques et les caractéristiques de prises en charge. En revanche le sous-groupe des suicidants compliants comportait plus de sujets suicidants récidivants et plus de sujets ayant déjà été pris en charge aux urgences. Une relative bonne compliance des patients pour lesquels un rendez-vous a été pris (82,6% des 23 rendez-vous pris ont été honorés) a été relevée et ce d'autant plus que ce rendez-vous a été pris avec leur psychiatre traitant (88%). En revanche les patients simplement orientés, sans rendez-vous, vers un psychiatre non connu au préalable (22 cas) présentaient une très mauvaise compliance (plus de 68% de telles orientations ne sont pas honorées). Le passage des suicidants aux urgences représente un moment clé pour favoriser l'adhésion à un suivi ultérieur. Cette étude confirme l'intérêt majeur de la prise d'un rendez-vous, à partir des urgences, auprès d'un intervenant si possible connu afin d'améliorer cette adhésion et ainsi mieux prévenir une récidive.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Compliance des suicidants par intoxication médicamenteuse volontaire au suivi proposé (à propos de 159 cas de patients pris en charge à l'unité d'hospitalisation de courte durée du service d'accueil des urgences de Grenoble entre le 1er février et le 31 mars 2006)

Le pronostic des suicidants dépend pour une grande partie des soins ultérieurs. Ceux-ci sont limités par une faible compliance au suivi proposé. Dans le cadre de ce travail de thèse, la compliance primaire au suivi proposé a été étudiée de façon descriptive pour des suicidants accueillis aux urgences. Parmi 159 patients pris en charge entre le 1er février et le 31 mars 2006 à l'Unité d'Hospitalisation de Courte Durée du Service d'Accueil des Urgences de Grenoble pour intoxication médicamenteuse volontaire et évalués par un psychiatre, 89 sont sortis avec une proposition de suivi. La présentation ou non au premier entretien de suivi de ces patients a été recherchée par un contact téléphonique auprès de chaque intervenant (ou structure) qui devait revoir le patient. Cette prise de contact s'est faite soixante jours après la sortie de chaque patient non hospitalisé, délai estimé suffisamment long pour l'obtention d'un rendez-vous. Parallèlement les caractéristiques socio démographiques, les antécédents psychiatriques et les prises en charges antérieures de ces patients étaient aussi recueillis rétrospectivement. Aucune différence significative n'a été retrouvée entre le groupe des suicidants compliants (45) et celui des non compliants (28) concernant les données socio démographiques et les caractéristiques de prises en charge. En revanche le sous-groupe des suicidants compliants comportait plus de sujets suicidants récidivants et plus de sujets ayant déjà été pris en charge aux urgences. Une relative bonne compliance des patients pour lesquels un rendez-vous a été pris (82,6% des 23 rendez-vous pris ont été honorés) a été relevée et ce d'autant plus que ce rendez-vous a été pris avec leur psychiatre traitant (88%). En revanche les patients simplement orientés, sans rendez-vous, vers un psychiatre non connu au préalable (22 cas) présentaient une très mauvaise compliance (plus de 68% de telles orientations ne sont pas honorées). Le passage des suicidants aux urgences représente un moment clé pour favoriser l'adhésion à un suivi ultérieur. Cette étude confirme l'intérêt majeur de la prise d'un rendez-vous, à partir des urgences, auprès d'un intervenant si possible connu afin d'améliorer cette adhésion et ainsi mieux prévenir une récidive.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF