CDKN2BAS is associated with periodontitis in different European populations and is activated by bacterial infection

Epidemiological studies have indicated a relationship between coronary heart disease (CHD) and periodontitis. Recently, CDKN2BAS was reported as a shared genetic risk factor of CHD and aggressive periodontitis (AgP), but the causative variant has remained unknown. To identify and validate risk variants in different European populations, we first explored 150 kb of the genetic region of CDKN2BAS including the adjacent genes CDKN2A and CDKN2B, covering 51 tagging single nucleotide polymorphisms (tagSNPs) in AgP and chronic periodontitis (CP) in individuals of Dutch origin (n=313). In a second step, we tested the significant SNP associations in an independent AgP and CP population of German origin (n=1264). For the tagSNPs rs1360590, rs3217992, and rs518394, we could validate the associations with AgP before and after adjustment for the covariates smoking, gender and diabetes, with SNP rs3217992 being the most significant (OR 1.48, 95% CI 1.19 to 1.85; p=0.0004). We further showed in vivo gene expression of CDKN2BAS, CDKN2A, CDKN2B, and CDK4 in healthy and inflamed gingival epithelium (GE) and connective tissue (CT), and detected a significantly higher expression of CDKN2BAS in healthy CT compared to GE (p=0.004). After 24 h of stimulation with Porphyromonas gingivalis in Streptococcus gordonii pre-treated gingival fibroblast (HGF) and cultured gingival epithelial cells (GECs), we observed a 25-fold and fourfold increase of CDKN2BAS gene expression in HGFs (p=0.003) and GECs (p=0.004), respectively. Considering the global importance of CDKN2BAS in the disease risk of CHD, this observation supports the theory of inflammatory components in the disease physiology of CHD.     

Activated T cells induce rapid CD83 expression on B cells by engagement of CD40

The conserved transmembrane glycoprotein CD83 was originally described as highly specific marker for mature dendritic cells in the peripheral circulation. Besides its regulatory role in thymic T cell maturation and peripheral T cell activation, recent studies suggest, that CD83 is also involved in the regulation of B cell maturation, homeostasis and function. Here we show, that antigen-specific T cell stimulation leads to CD83 induction predominantly on B cells. In vivo activation of T cells by injection of cognate antigenic peptide into T cell receptor transgenic mice induced strong expression of the early activation marker CD69 but only low levels of surface CD83 on T cells. In contrast CD83 was induced on 80% of B cells in the draining lymph node. This T cell mediated induction of CD83 expression on B cells was not mediated by soluble factors but was contact dependent because separation of B cells from an ongoing T cell stimulation in a transwell system abrogated CD83 expression. Since CD83 expression was induced on both MHC-matched and MHC-mismatched B cells present in cultures of activated T cells, cell contact via TCR/MHC binding was not essential. The application of an antibody to the CD40 ligand of T cells, however, strongly interfered with the induction of CD83 expression on bystander B cells. Taken together we provide evidence that activated T cells induce CD83 on B cells via CD40 engagement but independent of TCR/MHC binding and thus independent of antigen-specificity of B cells.     

Structural brain correlates of sensorimotor gating in antipsychotic-naive men with first-episode schizophrenia

Background: Prepulse inhibition (PPI) of the startle reflex is modulated by a complex neural network. Prepulse inhibition impairments are found at all stages of schizophrenia. Previous magnetic resonance imaging (MRI) studies suggest that brain correlates of PPI differ between patients with schizophrenia and healthy controls; however, these studies included only patients with chronic illness and medicated patients. Our aim was to examine the structural brain correlates of PPI in antipsychotic-naive patients with first-episode schizophrenia. Methods: We performed acoustic PPI assessment and structural MRI (1.5 and 3 T) in men with first-episode schizophrenia and age-matched controls. Voxel-based morphometry was used to investigate the association between PPI and grey matter volumes. Results: We included 27 patients and 38 controls in the study. Patients had lower PPI than controls. The brain areas in which PPI and grey matter volume correlated did not differ between the groups. Independent of group, PPI was significantly and positively associated with regional grey matter volume in the right superior parietal cortex. Prepulse inhibition and grey matter volume associations were also observed in the left rostral dorsal premotor cortex, the right presupplementary motor area and the anterior medial superior frontal gyrus bilaterally. Follow-up analyses suggested that the rostral dorsal premotor cortex and presupplementary motor area correlations were driven predominantly by the controls. Limitations: We used 2 different MRI scanners, which might have limited our ability to find subcortical associations since interscanner consistency is low for subcortical regions. Conclusion: The superior parietal cortex seems to be involved in the regulation of PPI in controls and antipsychotic-naive men with first-episode schizophrenia. Our observation that PPI deficits in schizophrenia may be related to the rostral dorsal premotor cortex and presupplementary motor area, brain areas involved in maintaining relevant sensory information and voluntary inhibition, warrants further study.     

Impact of Preoperative Physiological Risk Profile on Postoperative Morbidity and Mortality After Emergency Operation of Complicated Peptic Ulcer Disease

Aim The aim of this study was to evaluate the preoperative physiological risk profile for postoperative morbidity and mortality after emergency treatment of complicated peptic ulcer disease (PUD). Methods Operative notes and hospital files of 261 patients—111 female, 150 male; median age 67 years (range 17–100 years)—undergoing an emergency operation from 1993 to 2005 were analyzed retrospectively. The physiologic subscore of the POSSUM score (POSSUM-phys) was analyzed with regard to predicting postoperative complications. Follow-up was obtained from questionnaires sent to family practitioners or by patient interviews. Results The overall complication rate was 44%, and mortality was 24%. Among risk factors studied (e.g., sex, patient’s age, duration of symptoms, type of surgery), a high POSSUM-phys score was the strongest predictor for postoperative sepsis, anastomotic/suture dehiscence, postoperative bleeding, and mortality. Cut points for patients at risk could be calculated. Surgical procedures (organ-preserving versus resection) had no influence when matched for POSSUM-phys score. Nevertheless, organ resections were associated with higher scores. Recurrent PUD was a rare event (7.6%). Conclusion The preoperative physiologic POSSUM score is a promising instrument for identifying patients at increased risk to develop major postoperative complications after emergency surgery for complicated PUD. Prospective studies are needed to prove its applicability for adjusting treatment to individual patients.     

Evaluation of a neurodevelopmental model of schizophrenia--early postnatal PCP treatment in attentional set-shifting

Phencyclidine (PCP) was administered to male and female Lister hooded rats on postnatal days (PND) 7, 9 and 11. All PCP animals tested in adulthood (PND 53-93) showed deficits in cognitive flexibility, specifically in their ability to shift attentional set, compared to controls. This novel finding is reminiscent of the impairment observed in schizophrenia patients, and supports the validity of the early postnatal PCP regimen as a disease-like model.