Neural circuits associated with positive and negative self-appraisal.

Self-worth is particularly influenced by self-appraisal, which is negatively biased in many psychiatric disorders. Positive and negative self-appraisals also shape current emotional states or even evoke defensive reactions, when they are incongruent with a subject's current state. Prior studies have mainly used externally given evaluative appraisals. In this study, 30 subjects used individual negative and positive self-appraisals during functional magnetic resonance imaging. We additionally investigated the effects of such self-appraisals onto the subsequent perception of photos of the individual subjects. Both self-appraisal conditions activated dorsomedial and dorsolateral prefrontal cortex compared to the neutral condition. Positive self-appraisal evoked stronger activity than negative self-appraisal in the amygdala, ventral striatum and anterior cingulate cortex, whereas negative self-appraisal was associated with increased activity in the occipital regions. Positive self-appraisal had no effect on the perception of a photo of oneself, whereas negative appraisal increased activity in the anterior insula and parietal regions. Overall, positive self-appraisal activated more emotion-related brain regions, whereas negative self-appraisal had a relatively stronger influence on perception-related brain activity. These findings could on the one hand explain the effect of negative self-appraisal on the behavior in the real world and on the other hand support a stronger focus of psychotherapy on enhancing positive self-appraisals.

Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development.

Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in tumor than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expressions were lower in PDAC and CP compared with normal tissues both in patients and mouse models. Overexpression of WNK2 led to reduced cell growth, and WNK2 expression in tissues correlated negatively with pERK1/2 expression, a downstream target of WNK2 responsible for cell proliferation. Downregulation of WNK2 by promoter hypermethylation occurs early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway.

Neural correlates of 'pessimistic' attitude in depression.

BACKGROUND: Preparing for potentially threatening events in the future is essential for survival. Anticipating the future to be unpleasant is also a cognitive key feature of depression. We hypothesized that 'pessimism'-related emotion processing would characterize brain activity in major depression.MethodDuring functional magnetic resonance imaging, depressed patients and a healthy control group were cued to expect and then perceive pictures of known emotional valences--pleasant, unpleasant and neutral--and stimuli of unknown valence that could have been either pleasant or unpleasant. Brain activation associated with the 'unknown' expectation was compared with the 'known' expectation conditions. RESULTS: While anticipating pictures of unknown valence, activation patterns in depressed patients within the medial and dorsolateral prefrontal areas, inferior frontal gyrus, insula and medial thalamus were similar to activations associated with expecting unpleasant pictures, but not with expecting positive pictures. The activity within a majority of these areas correlated with the depression scores. Differences between healthy and depressed persons were found particularly for medial and dorsolateral prefrontal and insular activations. CONCLUSIONS: Brain activation in depression during expecting events of unknown emotional valence was comparable with activation while expecting certainly negative, but not positive events. This neurobiological finding is consistent with cognitive models supposing that depressed patients develop a 'pessimistic' attitude towards events with an unknown emotional meaning. Thereby, particularly the role of brain areas associated with the processing of cognitive and executive control and of the internal state is emphasized in contributing to major depression.

A case of late onset leukoencephalopathy with cerebral calcifications and cysts in a 59-year-old woman.

BACKGROUND: Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a recently described, very rare entity, clinically characterized by progressive neurological deficits such as cognitive decline, epileptic seizures, pyramidal, extrapyramidal and cerebellar symptoms/signs. With the exception of two patients with adult onset, in all previously described cases symptoms onset occurred between early infancy and adolescence. RESULTS: We report a case of late onset LCC in a 59-year-old woman presenting with urinary and fecal incontinence and behavioural changes, then rapid progression with hemianopia, hemiparesis, ataxia and cognitive decline. Extensive work-up was performed, including brain magnetic resonance imaging, magnetic resonance spectroscopy, cyst fluid analysis and brain biopsy, confirming the final diagnosis of LCC. CONCLUSION: Our case supports the existence of a late onset adult form of LCC.