Bipolar Disorder (BD) is the 4
leading cause of disability worldwide among young people ages 10-24 years. Although the diagnosis is largely defined by the mood episodes associated with the illness, ...cognitive deficits are among the most persistent and disabling symptoms of illness and have a profound impact on clinical course and functional outcome. Specifically, trait-like impairment is common in the domains of attention, verbal learning, and executive function; these deficits contribute to functional disability and are targets for emerging treatments and preventions. Although considerable progress has been made over the past two decades, our understanding of the underlying causes of the cognitive deficits in BD remains surprisingly limited. As such, there are no approved treatments for this disabling symptom specific to BD. This article is protected by copyright. All rights reserved.
MMPI-2-RF over-reporting scales for physical, cognitive, or psychological symptoms were examined in 130 consecutive referrals to a first-episode psychosis (FEP) clinic. Although acutely ill upon ...presentation, consistent and responsive profiles were obtained in 79% of the sample. There was no indication of under-reporting on defensive scales, and anticipated elevations were observed on clinical scales sensitive to thought disorder, ideas of persecution, and aberrant experiences. The Infrequent Somatic (Fs), Symptom Validity Scale (FBS-r), and Response Bias (RBS) scales did not indicate somatic or cognitive over-reporting, but the Infrequent Psychopathology Scale (Fp-r) showed a moderate elevation that may suggest a propensity for over-reporting or an effect of clinical symptoms on the over-reporting scale. Clinician ratings of positive symptoms of psychosis were related to the Fp-r. Although the over-reporting classifications with the RBS were relatively low, RBS scores were directly related to positive and general symptoms of psychosis. The MMPI-2-RF appears to have clinical value in an acutely ill FEP sample. The sample was not prone to over-reporting pathology, but associations between both the Fp-r and the RBS with clinical symptoms will warrant further investigation.
S’inscrivant dans une communauté scientifique grandissante qui cherche et expérimente des solutions urbaines aux problèmes sociaux et écologiques, la Chaire de recherche UQAM sur la transition ...écologique a pour mission d’étudier et d’accompagner les transformations en cours en s’intéressant plus particulièrement aux expérimentations portées par les acteurs locaux et urbains de la transition sociale et écologique, ainsi qu’aux changements institutionnels inspirés de ces innovations. Cet article présente les travaux de ses membres selon une grille portant sur les questions centrales du programme de la Chaire, soit l’approfondissement des connaissances sur les transformations, la pérennisation des initiatives de transition et la structuration d’un champ institutionnel de la transition. Fondés sur des approches de recherche participative et partenariale, ces travaux menés dans la région montréalaise s’inscrivent dans trois « chantiers de la transition » : l’urgence climatique, les milieux de vie et les systèmes alimentaires. Cet article montre comment, en s’associant avec les acteurs de la transition sociale et écologique montréalaise, les chercheuses et chercheurs de la Chaire contribuent à clarifier et à mettre en place certains fondements de la transition sociale et écologique.
Environmental influences may affect carcinogen absorption and residency in the tissues of the aero-digestive tract. We quantified the effect of ethanol and menthol on the rates of ...4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzoapyrene (BaP) absorption using a fully validated in vitro diffusion system, capable of accurately and precisely quantifying tobacco carcinogen permeation and reservoir formation in porcine esophageal mucosa. Confocal microscopy was employed to visualize the location of BaP in the exposed membranes. Markedly different extents of permeation and reservoir formation for the tobacco carcinogens were recorded in the presence of ethanol and menthol. The water-soluble NNK permeated the membrane rapidly, while the lipophilic BaP did not appreciably diffuse through the tissue. Significantly different extents of reservoir formation were observed for the different carcinogens and in the presence of the different penetration-enhancer solvents. Alcohol (at 5% concentration) did not influence the permeation or reservoir formation of NNK. A mentholated donor solution (0.08%) both decreased the flux of NNK and significantly increased the tissue reservoir formation. The magnitude of the reservoir formed by BaP was relatively extensive (even though membrane permeation rates were negligible), being greatest in the presence of both ethanol and menthol. This suggests synergy between the two penetration-enhancer species acting on this carcinogen. Confocal microscopy studies confirmed that there was an appreciable intra-cellular, and specifically nuclear, association of the BaP species during the reservoir formation process. The aqueous solubility of the diffusing species and the presence of penetration enhancers appeared to be key factors in the absorption and cellular binding processes. The results presented support the hypothesis that the use of mentholated cigarettes, or the concomitant consumption of alcohol while smoking, may have marked effects on the fate of tobacco chemicals. This finding may help to explain elevated rates of esophageal squamous cell carcinoma in African Americans.
The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal ...breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis.
Functional magnetic resonance imaging (fMRI) has become a powerful tool for studying the normal and diseased human brain. The application of fMRI in detecting neuronal signals in the trigeminal ...system, however, has been hindered by low detection sensitivity due to activation artifacts caused by cardiac pulse-induced brain and brainstem movement. A variety of cardiac gating techniques have been proposed to overcome this issue, typically by phase locking the sampling to a particular time point during each cardiac cycle. We sought to compare different cardiac gating strategies for trigeminal system fMRI. In the present study, we used tactile stimuli to elicit brainstem and thalamus activation and compared the fMRI results obtained without cardiac gating and with three different cardiac gating strategies: single-echo with TR of 3 or 9 heartbeats (HBs) and dual-echo T2*-mapping EPI (TR = 2 HBs, TE = 21/55 ms). The dual-echo T2* mapping and the single-echo with TR of 2 and 3 HBs cardiac-gated fMRI techniques both increased detection rate of fMRI activation in brainstem. Activation in the brainstem and the thalamus was best detected by cardiac-gated dual-echo EPI.
In this paper we review the assessment and measurement of normal unwanted intrusive thoughts, images, and impulses that are considered the basis of clinical obsessions. After highlighting some ...difficulties with how the definition of cognitive intrusion has been applied to the development of assessment measures, we evaluate the construct validity of a number of retrospective self-report instruments such as the Intrusive Thoughts Questionnaire, Cognitive Intrusions Questionnaire, and Obsessional Intrusions Inventory, as well as interview and diary procedures. Measures of personal responsibility and meta-cognitive beliefs, which are still in the developmental phase, are also discussed. We conclude with a number of recommendations and areas of further research which would strengthen the construct validity of measures of intrusive thoughts and related constructs.
Wegner's (1994,
Psychological Review,
101, 34–52)
research on the paradoxical effect of thought suppression has been incorporated into contemporary cognitive-behavioural models of ...obsessive-compulsive disorder. However, findings on the effects of thought suppression on thought frequency have been inconsistent and few studies have actually examined the suppression of thoughts that are obsessional in nature. In the present study 219 nonclinical participants were randomly assigned to suppress or not suppress a neutral, obsessional or positive thought during an initial monitoring interval. In a second thought monitoring interval, all participants received instructions not to suppress their target thought. No paradoxical effect of suppression on frequency was observed for any type of thought, although suppression of obsessional thoughts was associated with greater subsequent discomfort and a more negative mood state than suppression of positive or neutral target thoughts.
▪
Background: We have previously reported high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (CAR) targeting CD19 in adult patients with ...relapsed or refractory (R/R) ALL (Park et al. ASH 2014). Herein, we further report the long-term outcome of a larger cohort from our phase 1 clinical trial in adults with R/R ALL (NCT01044069) with a focused analysis on the role of post-treatment minimal residual disease (MRD) negativity as a predictive marker of survival as well as the effect of allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to or after CAR T cell infusion on safety and clinical outcome.
Patients and Methods: Adult patients with R/R B-cell ALL (B-ALL) were enrolled. Eligible patients underwent leukapheresis, and T cells were transduced with a retroviral vector encoding a CAR comprising a CD19-specific scFv and CD28 and CD3ζ signaling domains (19-28z). All patients received lymphodepleting chemotherapy followed 2 days later by 1x106 - 3x106 19-28z CAR T cells/kg. The primary objective of the study was to evaluate the safety and anti-tumor activity of 19-28z CAR T cells. Post-treatment MRD was assessed at day 14-28 by multiparameter flow cytometry in bone marrow (BM) samples.
Results: 44 patients have been treated to date. The median age was 45 years (range, 22-74). 14 patients (32%) had Philadelphia chromosome positive (Ph+) ALL (T315I mutation in 5 patients), 17 patients (39%) had prior allo-HSCT, and 24 patients (55%) had ≥ 3 prior lines of ALL therapy.
Of the 44 patients, 43 patients were evaluable for response. At the time of 19-28z CAR T cell infusion, 22 of the 43 patients (51%) had morphologic disease (≥5% blasts in BM or measurable extramedullary disease) and the remaining 21 patients had minimal disease (<5% blasts in BM). 36 patients (84%) were in complete remission (CR) after 19-28z CAR T-cell infusion. MRD analysis was performed in 35 of 36 CR patients, and 29 of these 35 patients (83%) achieved an MRD-negative CR (MRD-CR).
As of July 13, 2015, the median follow-up was 4.2 months (range 1-45), with 16 patients having at least 6 months of follow-up. Responses appear durable with 7 patients remaining disease-free beyond 1 year up to 45 months. A median overall survival (OS) of all patients and patients who achieved MRD-CR is 8.5 months and 10.8 months, respectively. Post-treatment MRD status emerged as a strong predictive marker of OS: OS at 6 months was 76% (95% CI: 51-89) in the MRD-CR cohort vs. 14% (95% CI: 8-45) in the MRD+CR cohort. In contrast, allo-HSCT after achieving CR with CAR T cell infusion did not affect the survival rate. Of the 36 patients in CR following the T cell infusion, 12 patients underwent allo-HSCT. OS at 6 months was 70% (95% CI: 33-89) in patients who underwent post-CAR allo-HSCT vs. 64% (95% CI: 36-82) in patients who did not get allo-HSCT after CAR T cells.
Comparing baseline disease characteristics of patients who had prior allo-HSCT before the CAR T cell treatment vs. no prior allo-HSCT, patients who had prior allo-HSCT (n=17) were similar in age (median age 45 vs. 46), but had higher disease burden (65% with morphologic disease vs. 44%), were more heavily pretreated (59% of patients with ≥4 lines of therapy vs. 15%), and included more high-risk disease (41% with Ph+ ALL vs. 26%). However, there was no statistically significant difference in CR rates (75%, CI: 48-93 vs. 89%, CI: 71-98), incidences of severe cytokine release syndrome (24% vs. 22%), and OS at 6 months (57% vs. 60%) between these two cohorts. Fewer patients who had prior allo-HSCT underwent another allo-HSCT following CAR T cell infusion: 2 patients vs. 10 patients with no prior all-HSCT. Although no obvious case of graft-versus-host disease (GvHD) was noted, one patient experienced a grade 3 gastrointestinal toxicity that may have been related to GvHD.
Conclusions: These data confirm the potent anti-tumor efficacy of 19-28z CAR T cells (JCAR015) in adult patients with R/R ALL. MRD negativity following the 19-28z CAR T cell treatment is highly predictive of survival, and allo-HSCT post-CAR T cell infusion had no significant impact on survival. Furthermore, 19-28z CAR T cells appear to be safe in patients who had prior allo-HSCT, and may represent an attractive alternative option to second allo-HSCT. These findings are being confirmed in an ongoing multi-center, pivotal phase 2 trial evaluating JCAR015 in adult patients with R/R ALL.
Park:Amgen: Consultancy; Genentech: Research Funding; Juno Therapeutics: Other: Advisory Board, Research Funding. Riviere:Juno Therapeutics: Other: Co-founder, stockholder and consultant. Curran:Juno Therapeutics: Consultancy. Sadelain:Juno Therapeutics: Consultancy, Equity Ownership, Other: Co-Founder, stockholder, Patents & Royalties: Licensed patents on CARs. Brentjens:Juno Therapeutics: Other: Co-founder, stockholder and consultant.
This thesis project explores landowner experiences of wind energy development through an inductive qualitative case study in Huron County, Ontario. The research included in-depth interviews with ...landowners focused on landscape and community change, participant observation of Environmental Review Tribunals (ERT), the gathering of participant photos, as well as relevant government and industry documents and media reports. The iterative data gathering and analysis were supported by my observations and reflections while living in affected communities and talking to participants. The study demonstrates how the health debate over wind can inform divisions between neighbours, that local politics have been given a token role as a place for resistance to wind energy development that fails to meaningfully influence projects, and that appeals are legalistic and do not provide an outlet, or place for appellants to be heard. Furthermore, the felt experience of tight knit and fragile communities were disrupted through land leases, as well as changes to the landscape. These disruptions impacted connections to, and associations with place, and are shown to have had negative emotional and physical impacts on some individuals. Supporters of wind development tied their mostly positive views of landscape change to a sense of disruption generally throughout the community. Insights from the research lead to a set of suggested actions that might improve the current situation at the levels of provincial policy, planning, local governance and industry practice. Keywords: wind energy policy, planning, landscape, Ontario, rural communities
PDF
