Self-Referential Thinking, Suicide, and Function of the Cortical Midline Structures and Striatum in Mood Disorders: Possible Implications for Treatment Studies of Mindfulness-Based Interventions for Bipolar Depression

Bipolar depression is often refractory to treatment and is frequently associated with anxiety symptoms and elevated suicide risk. There is a great need for adjunctive psychotherapeutic interventions. Treatments with effectiveness for depressive and anxiety symptoms as well as suicide-related thoughts and behaviors would be particularly beneficial. Mindfulness-based interventions hold promise, and studies of these approaches for bipolar disorder are warranted. The aim of this paper is to provide a conceptual background for such studies by reviewing key findings from diverse lines of investigation. Results of that review indicate that cortical midline structures (CMS) appear to link abnormal self-referential thinking to emotional dysregulation in mood disorders. Furthermore, CMS and striatal dysfunction may play a role in the neuropathology underlying suicide-related thoughts and behaviors. Thus, combining studies of mindfulness interventions targeting abnormal self-referential thinking with functional imaging of CMS and striatal function may help delineate the neurobiological mechanisms of action of these treatments

Aberrant functional connectivity of cortico-basal ganglia circuits in major depression

ManuscriptThere is considerable evidence of functional abnormalities of the cortico-basal ganglia circuitry in affective disorders. However, it has been unknown whether this represented primary pathology within these circuits or altered activation as a result of aberrant input from other brain regions. The aim of this study was to test the hypothesis that cortico-basal ganglia circuit dysfunction represents primary pathology in unipolar depression. Eighteen male subjects with recurrent unipolar depression and eighteen controls without psychiatric illness were studied using functional MRI and functional connectivity analyses. All unipolar subjects were unmedicated and without current psychiatric comorbidity. Compared to controls, unipolar subjects exhibited altered connectivity between bilateral subcortical components of the circuitry (putamen-thalamus) and left hemisphere input and output components. Results provided evidence that functional abnormalities of these circuits represent primary pathology. Further, we found that age of onset but not duration of illness impacts circuit function. These findings suggest that the cortico-basal ganglia circuitry is likely one of several loci of primary pathology in major depression. Additionally, early age of onset is associated with greater circuit abnormality and as such may impact clinical characteristics and/or treatment response through a mechanism of decreasing functional connectivity of some circuit segments. Finally, altered cortico-basal ganglia circuit connectivity with cortical regions (anterior cingulate, inferior frontal gyrus and sensorimotor) may contribute to the emotional dysregulation, impaired emotional recognition and psychomotor symptoms associated with unipolar illness

Discovery and Mechanistic Characterization of Novel SARS Coronavirus Inhibitors that Block Viral Entry [abstract]

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionSevere acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS-associated coronavirus (SARS-CoV). Viral entry is a key target step for therapies because it can prevent the propagation of virus at early stages of the disease. We used a cell-based assay to identify inhibitors of SARS-CoV entry. We prepared a pseudotyped virus in which the core is from HIV and envelop is from the SARS-CoV (HIV-luc/SARS env). This pseudotyped virus was used to infect, 293T cells expressing the receptor for SARS-CoV, Aangiotensin-converting enzyme-2 (ACE2). Using this assay we screened a chemical library of more than 2000 compounds and identified three compounds that specifically inhibit entry of the HIV-luc/SARS env. These compounds did not inhibit another pseudotyped virus which had same core from HIV but envelop was from Vesicular Stomatitis Virus. The compounds had strong potencies (EC50s were 2.9, 4.8 and 5.8 µM) and low cytotoxicities (high CC50s) resulting in promising Selectivity Indices (CC50/EC50 were >175, >65, and >86, respectively). Importantly, the compounds were found to have excellent antiviral activities, blocking SARS-CoV replication at low nM concentrations. Only one of the compounds was a moderate inhibitor of cathepsin L, a cellular protease whose activity is required to process the SARS-CoV env glycoprotein (Spike) and allow viral entry. Moreover, none of the compounds affects the cleavage activity of furin, another host protease, which may also be involved in SARS-CoV entry. Using a flow cytometry binding assay, we found that all three compounds decrease binding of the SARS-CoV Spike receptor binding domain to ACE2 receptor expressed on the surface of 293Tcells. Hence, we have discovered three promising compounds as the first small molecule inhibitors that can block receptor-dependent entry of SARS-CoV

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated. © 2012 Cicek et al

Getting shot of elves: healing, witchcraft and fairies in the Scottish witchcraft trials

This paper re-examines the evidence of the Scottish witchcraft trials for beliefs associated by scholars with "elf-shot." Some supposed evidence for elf-shot is dismissed, but other material illuminates the interplay between illness, healing and fairy-lore in early modern Scotland, and the relationship of these beliefs to witchcraft itself

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function