Cognitive errors assessed by observer ratings in bipolar affective disorder: relationship with symptoms and therapeutic alliance

The construct of cognitive errors is clinically relevant for cognitive therapy of mood disorders. Beck's universality hypothesis postulates the relevance of negative cognitions in all subtypes of mood disorders, as well as positive cognitions for manic states. This hypothesis has rarely been empirically addressed for patients presenting bipolar affective disorder (BD). In-patients (n = 30) presenting with BD were interviewed, as were 30 participants of a matched control group. Valid and reliable observer-rater methodology for cognitive errors was applied to the session transcripts. Overall, patients make more cognitive errors than controls. When manic and depressive patients were compared, parts of the universality hypothesis were confirmed. Manic symptoms are related to positive and negative cognitive errors. These results are discussed with regard to the main assumptions of the cognitive model for depression; thus adding an argument for extending it to the BD diagnostic group, taking into consideration specificities in terms of cognitive errors. Clinical implications for cognitive therapy of BD are suggeste

Metabolic and inflammatory profile in obese patients with chronic obstructive pulmonary disease

Background: Overweight and obesity have been associated with better survival in patients with chronic obstructive pulmonary disease (COPD). On the other hand, excess body weight is associated with abnormal metabolic and inflammatory profiles that define the metabolic syndrome and predispose to cardiovascular diseases. This study was undertaken to evaluate the impact of overweight and obesity on the prevalence of the metabolic syndrome and on the metabolic and inflammatory profiles in patients with COPD. Methods: Twenty-eight male patients with COPD were divided into an overweight/obese group [n 16, body mass index (BMI) 33.5 4.2 kg/m2] and normal weight group (n 12, BMI 21.1 2.6 kg/m2). Anthropometry, pulmonary function and body composition were assessed. The metabolic syndrome was diagnosed according to waist circumference, circulating levels of triglyceride and high-density lipoprotein cholesterol levels, fasting glycemia and blood pressure. C-reactive protein, tumor necrosis factor- (TNF-), interleukin-6 (IL-6), leptin and adiponectin plasma levels were measured. Results: Airflow obstruction was less severe in overweight/obese compared with normal weight patients (forced expiratory volume1: 51 19% versus 31 12% predicted, respectively, P 0.01). The metabolic syndrome was diagnosed in 50% of overweight/obese patients and in none of the normal weight patients. TNF-, IL-6 and leptin were significantly higher in overweight/obese patients whereas the adiponectin levels were reduced in the presence of excess weight. Conclusions: The metabolic syndrome was frequent in overweight/obese patients with COPD. Obesity in COPD was associated with a spectrum of metabolic and inflammatory abnormalities

Species and Chlorine Fertilisation Affect Dietary Cation-Anion Difference of Cool-Season Grasses

The Dietary Cation-Anion Difference [DCAD = (Na + K) - (Cl + S); Ender et al., 1971] is used in balancing rations for dry dairy cows. Low DCAD diets induce a mild, compensated metabolic acidosis that stimulates bone resorption, improves Ca homeostasis, and prevents milk fever. Dry cow rations contain a high proportion of forage and, therefore, forages fed two to four weeks prepartum should have a low or negative DCAD value. Our objectives were to evaluate the DCAD of five cool-season grass species grown in eastern Canada and to determine the effect of Cl fertilisation on the DCAD value of timothy (Phleum pratense L.)

Vascular smooth muscle contractility assays for inflammatory and immunological mediators

The blood vessels are one of the important target tissues for the mediators of inflammation and allergy; further cytokines affect them in a number of ways. We review the use of the isolated blood vessel mounted in organ baths as an important source of pharmacological information. While its use in the bioassay of vasoactive substances tends to be replaced with modern analytical techniques, contractility assays are effective to evaluate novel synthetic drugs, generating robust potency and selectivity data about agonists, partial agonists and competitive or insurmountable antagonists. For instance, the human umbilical vein has been used extensively to characterize ligands of the bradykinin B2 receptors. Isolated vascular segments are live tissues that are intensely reactive, notably with the regulated expression of gene products relevant for inflammation (e.g., the kinin B1 receptor and inducible nitric oxide synthase). Further, isolated vessels can be adapted as assays of unconventional proteins (cytokines such as interleukin-1, proteases of physiopathological importance, complement-derived anaphylatoxins and recombinant hemoglobin) and to the gene knockout technology. The well known cross-talks between different cell types, e.g., endothelium-muscle and nerve terminal-muscle, can be extended (smooth muscle cell interaction with resident or infiltrating leukocytes and tumor cells). Drug metabolism and distribution problems can be modeled in a useful manner using the organ bath technology, which, for all these reasons, opens a window on an intermediate level of complexity relative to cellular and molecular pharmacology on one hand, and in vivo studies on the other

Mutant TDP-43 and FUS Cause Age-Dependent Paralysis and Neurodegeneration in C. elegans

Mutations in the DNA/RNA binding proteins TDP-43 and FUS are associated with Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration. Intracellular accumulations of wild type TDP-43 and FUS are observed in a growing number of late-onset diseases suggesting that TDP-43 and FUS proteinopathies may contribute to multiple neurodegenerative diseases. To better understand the mechanisms of TDP-43 and FUS toxicity we have created transgenic Caenorhabditis elegans strains that express full-length, untagged human TDP-43 and FUS in the worm's GABAergic motor neurons. Transgenic worms expressing mutant TDP-43 and FUS display adult-onset, age-dependent loss of motility, progressive paralysis and neuronal degeneration that is distinct from wild type alleles. Additionally, mutant TDP-43 and FUS proteins are highly insoluble while wild type proteins remain soluble suggesting that protein misfolding may contribute to toxicity. Populations of mutant TDP-43 and FUS transgenics grown on solid media become paralyzed over 7 to 12 days. We have developed a liquid culture assay where the paralysis phenotype evolves over several hours. We introduce C. elegans transgenics for mutant TDP-43 and FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening

FUS and TARDBP but Not SOD1 Interact in Genetic Models of Amyotrophic Lateral Sclerosis

Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS–related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS–related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Substance P et neurokinines : synthèse et étude de certains effets biologiques et du métabolisme de la substance P dans le plasma

Dans la présente étude nous avons préparé par synthèse en phase solide et purifié par chromatographie à haute performance en phase liquide, la substance P, les neurokinines A et B, des analogues de la substance P contenant une Tyr en N-terminal et des antagonistes. Les activités biologiques des peptides mentionnés ont été mesurées sur des organes isolés, principalement l'iléon de cobaye et la trachée de cobaye et elles ont été reconnues semblables à celles des peptides obtenus du commerce. Sur la base des activités relatives des neurokinines A et B et de la substance P, nous avons émis l'hypothèse de l'existence de trois types différents de récepteurs des neurokinines dans les tissus étudiés. L'iléon de cobaye contient un récepteur de type SP-P, la trachée de cobaye un récepteur de type NK-A et la vessie de hamster un récepteur de type NK-B. L'existence de trois types de récepteurs pour les neurokinines a été confirmée avec des antagonistes, certains ont une meilleure affinité envers la SP sur l'iléon de cobaye alors que d'autres montrent une meilleure affinité envers NKA et NKB sur les autres préparations. Les peptides contenant une Tyr en N-terminal ont été marqués à l'iode-125 et utilisés pour mesurer le métabolisme de la substance P et de ses fragments dans le plasma et dans un homogénat de cerveau de rat. La substance P est dégradée par une dipeptidyl peptidase et certains fragments par une aminopeptidase. Le plasma ne contient pas d'endopeptidase, alors que ces enzymes sont présents et actifs dans l'homogénat de cerveau. La dégradation de la substance P dans le plasma est prévenue par le captopril, un inhibiteur de l'enzyme de conversion qui est aussi actif contre la dipeptidyl peptidase. L'action du captopril semble être limité au plasma, car à des doses efficaces chez le rat anesthésié, cet inhibiteur ne modifie pas l'effet hypotenseur de la substance P. Dans l'ensemble les résultats présentés dans ce mémoire contiennent des données originales sur la chimie, la pharmacologie et la biochimie (métabolisme) d'un groupe de neuropeptides, les neurokinines, qui seraient impliquées dans la transmission des stimulations sensorielles (douleur) au niveau central et dans la régulation du tonus de divers muscles lisses (vasculaires, intestinaux, trachéo-bronchiques, ect.) au niveau des organes périphériques

Développement d'agonistes sélectifs pour les récepteurs de la substance P et des neurokinines A et B

Une série d'analogues de la substance P (SP), de la neurokinine A (NKA), de la neurokinine B (NKB) et de leurs fragments ont été synthétisés par la méthode de synthèse peptidique en phase solide. Les composés ont été purifiés par chromatographie HPLC (chromatographie à haute performance en phase liquide) et leurs structures caractérisées par analyse d'acides aminés, HPLC analytique, chromatographie sur couche mince et, pour certains peptides, analyse de spectrométrie de masse. L'activité biologique des composés a été évaluée sur trois préparations pharmacologiques monoréceptorielles représentatives de chacun des trois récepteurs des neurokinines. Ces préparations sont: l'artère carotide de chien pour le récepteur NK-1, l'artère pulmonaire de lapin pour le récepteur NK-2 et la veine porte de rat pour le récepteur NK-3. L'analyse d'une série de modifications conformationnelles en positions 9 de SP et 7 de NKB et de modifications structurelles en position C-terminale des trois neurokinines nous a permis de développer des composés sélectifs pour chacun des récepteurs des neurokinines. Les composés [Sar9,Met(02)11]SP et Ac[Arg6,Sar9,Met(02)11]SP(6-11) sont des analogues sélectifs pour le récepteur NK-1. L'analogue [Nie10 ]NKA(4-10) est sélectif pour le récepteur NK-2 et [MePhe ]NKB(4-10) ainsi que [MePhe ]NKB sont des composés sélectifs pour le récepteur NK-3. L'hypothèse des trois récepteurs des neurokinines est confirmée par l'activité des agonistes sélectifs. Ces derniers ont été testés sur la vessie de hamster et l'iléon de cobaye, des préparations reconnues comme étant multiréceptorielles, et ont permis de différencier les récepteurs impliqués dans la réponse de ces tissus aux neurokinines. Les composés sélectifs que nous avons développés sont proposés comme outils pharmacologiques dans la caractérisation des récepteurs des neurokinines