Dominant negative DISC1 mutant mice display specific social behaviour deficits and aberration in BDNF and cannabinoid receptor expression

Objectives. Disrupted in schizophrenia 1 (DISC1) is considered the most prominent candidate gene for schizophrenia. In this study, we aimed to characterize behavioural and brain biochemical traits in a mouse expressing a dominant negative DISC1mutant (DN-DISC1). Methods. DN-DISC1 mice underwent behavioural tests to evaluate object recognition, social preference and social novelty seeking. ELISA was conducted on brain tissue to evaluate BDNF levels. Western blot was employed to measure BDNF receptor (TrkB) and cannabinoid receptor CB1. Results. The mutant DISC1 mice displayed deficits in preference to social novelty while both social preference and object recognition were intact. Biochemical analysis of prefrontal cortex and hippocampus revealed a modest reduction in cortical TrkB protein levels of male mice while no differences in BDNF levels were observed. We found sex dependent differences in the expression of cannabinoid-1 receptors. Conclusions. We describe novel behavioural and biochemical abnormalities in the DN-DISC1 mouse model of schizophrenia. The data shows for the first time a possible link between DISC1 mutation and the cannabinoid system.     

Multicompartmental Analysis of Cholesterol Metabolism in Man: CHARACTERIZATION OF THE HEPATIC BILE ACID AND BILIARY CHOLESTEROL PRECURSOR SITES

The present report has presented the first clear evidence in man for the existence of specific hepatic cholesterol precursor sites associated with the formation and secretion of bile acids and biliary cholesterol. These hepatic compartments derive virtually all their cholesterol from newly synthesized and lipoprotein free cholesterol. The model which is presented was formulated on current concepts of cholesterol metabolism in man and is concerned, at this initial stage, with the elucidation of the bile acid and biliary cholesterol compartments. The complexity of cholesterol metabolism in man necessitated an initial approach that would minimize the number of inputs of cholesterol into the system, allow for the sampling of several cholesterol compartments, and permit the simultaneous labeling of newly synthesized cholesterol and preformed cholesterol. To achieve these objectives, we studied the patient with a total bile fistula. Six patients were administered simultaneously pulse injections of labeled mevalonic acid and [(14)C]cholesterol. The qualitative features of the specific activity time course curves after labeled mevalonic acid revealed no precursor-product relationship between bile acid, biliary cholesterol, and plasma free cholesterol. The peak specific activity of the bile acids was reached in approximately 100 min and was higher than the biliary cholesterol, which was higher than the plasma free cholesterol. The plasma free cholesterol specific activity became higher than the other lipids after 12 h and remained higher throughout the period of study. Similar related observations were made with [(14)C]cholesterol. The data were then subjected to simulation analysis and modeling using the SAAM-27 computer program. Computer least-square fits of the data were obtained after the model was evolved. During the model development, the least number of compartments and transport pathways were introduced consistent with a good fit of the data. Of particular importance was the constraint that the model fit the data obtained from both [(14)C]cholesterol and labeled mevalonic acid. The same parameter values were used to fit the data from both tracers. The fluxes arrived at in the model indicate that 31% and 20%, respectively, of the cholesterol input into the bile acid and biliary cholesterol precursor sites were derived directly from the newly synthesized hepatic cholesterol. The remainder had its origin predominantly from lipoprotein free cholesterol. Plasma esterified cholesterol (as free) made a small contribution (11%) to the bile acid compartment. Similarly, 10% of the biliary cholesterol arose from an unknown hepatic site.The present report has provided the basis for a new procedure for studying in vivo cholesterol metabolism in man. Examination of the derived cholesterol flux rates between the compartments suggests the presence of an important mechanism regulating the partitioning of lipoprotein free cholesterol between the bile acid and biliary cholesterol precursor sites. Aberrations in the proportioning of precursor cholesterol between these sites could be a causative factor precipitating the excessive secretion of biliary cholesterol and the production of lithogenic bile.     

Increased pain sensitivity in fibromyalgia: effects of stimulus type and mode of presentation

Fibromyalgia (FM) is defined in part by sensitivity to blunt pressure. Pressure pain sensitivity in FM is evaluated typically by the use of 'ascending' testing methods such as tender point counts or dolorimetry, which can be influenced by response bias of both the subject and examiner. Methods that present stimuli in a random, unpredictable fashion might minimize the influence of these factors. In this study, we compared the results of ascending and random assessments of both pressure and thermal pain sensitivities in 43 FM patients and 28 age- and gender-matched controls. Even though FM is defined on the basis of pressure sensitivity, this group was also more sensitive to heat stimuli, presented in either ascending or random paradigms. In both the patient and control groups, the pain ratings to painful sensations evoked by both thermal and pressure stimuli were significantly greater in the random, compared with the ascending method. The number of subjects classified as 'expectant' because they rated pain higher in ascending than random paradigms was similar for FM and control groups. Both patients and controls exhibited a similar degree of sensitization to pressure and thermal stimuli. The increased sensitivity to both pressure and thermal stimuli for threshold and suprathreshold stimuli in FM patients is consistent with central augmentation of pain processing.     

Childhood Verbal Abuse: A Risk Factor for Depression in Pre-Bariatric Surgery Psychological Evaluations

The present study evaluated the importance of multimodal assessment of childhood verbal abuse (CVA) in pre-bariatric surgery psychological evaluations, and the role of CVA as a predictor of depression. Data from the psychological evaluations of 184 pre-bariatric surgery patients were retrospectively examined. Using two self-report measures and an interview-based screen, 52.2 % of participants reported experiencing some form of CVA; conversely, assessments of CVA based on only one measure yielded significantly lower prevalence rates. Endorsement of CVA on multiple measures was associated with more severe depressive symptomatology and greater likelihood of mood disorder diagnosis. Based on these data, a self-report measure and interview-based screen for CVA should be included in pre-bariatric psychological evaluations; either of these assessments may be conducted via a single-item screen. Lastly, patients who endorse CVA on multiple measures should be monitored closely for symptoms of depression post-surgery.     

Pubic ramus convexity or ballooning: a sentinel sign for severe periacetabular osteolysis in total hip arthroplasty

Osteolysis is a significant long-term problem in hip arthroplasty. Plain radiographs are the routine investigation of choice for monitoring hip arthroplasty patients; however, the recognition of clinically significant osteolysis can be challenging. We present two case reports of arthroplasty patients with ballooning and expansion of the superior pubic ramus with loss of the normal concavity of the ilio-pectineal line. Both patients subsequently displayed massive pubic osteolysis at the time of revision surgery. We suggest that the presence of convexity of the ilio-pectineal line/superior pubic ramus indicates established pelvic osteolysis.     

Amotivation in Schizophrenia: Integrated Assessment With Behavioral,Clinical, and Imaging Measures

Motivational deficits play a central role in disability caused by schizophrenia and constitute a major unmet therapeutic need. Negative symptoms have previously been linked to hypofunction in ventral striatum (VS), a core component of brain motivation circuitry. However, it remains unclear to what extent this relationship holds for specific negative symptoms such as amotivation, and this question has not been addressed with integrated behavioral, clinical, and imaging measures. Here, 41 individuals with schizophrenia and 37 controls performed a brief, computerized progressive ratio task (PRT) that quantifies effort exerted in pursuit of monetary reward. Clinical amotivation was assessed using the recently validated Clinical Assessment Interview for Negative Symptoms (CAINS). VS function was probed during functional magnetic resonance imaging using a monetary guessing paradigm. We found that individuals with schizophrenia had diminished motivation as measured by the PRT, which significantly and selectively related to clinical amotivation as measured by the CAINS. Critically, lower PRT motivation in schizophrenia was also dimensionally related to VS hypofunction. Our results demonstrate robust dimensional associations between behavioral amotivation, clinical amotivation, and VS hypofunction in schizophrenia. Integrating behavioral measures such as the PRT will facilitate translational efforts to identify biomarkers of amotivation and to assess response to novel therapeutic interventions.Key words: motivation, progressive ratio, ventral striatum, fMRI, negative symptoms