Deficiency of cathepsin C ameliorates severity of acute pancreatitis by reduction of neutrophil elastase activation and cleavage of E-cadherin.

Acute pancreatitis is characterized by premature intracellular protease activation and infiltration of inflammatory cells, mainly neutrophil granulocytes and macrophages, into the organ. The lysosomal proteases cathepsin B, D, and L have been identified as regulators of early zymogen activation and thus modulators of the severity of pancreatitis. Cathepsin C (CTSC, syn. dipeptidly-peptidase I) is a widely expressed, exo-cystein-protease involved in the proteolytic processing of various other lysosomal enzymes. We have studied its role in pancreatitis. We used CTSC-deleted mice and their WT littermates in two experimental models of pancreatitis. The mild model involved eight hourly caerulein injections and the severe model partial duct ligation. Isolated pancreatic acini and spleen-derived leukocytes were used for ex vivo experiments. CTSC is expressed in the pancreas and in inflammatory cells. CTSC deletion reduced the severity of pancreatitis (more prominently in the milder model) without directly affecting intra-acinar cell trypsin activation in vitro The absence of CTSC reduced infiltration of neutrophil granulocytes impaired their capacity for cleaving E-cadherin in adherens junctions between acinar cells and reduced the activity of neutrophil serine proteases polymorphonuclear (neutrophil) elastase, cathepsin G, and proteinase 3, but not neutrophil motility. Macrophage invasion was not dependent on the presence of CTSC. CTSC is a regulator and activator of various lysosomal enzymes such as cathepsin B, D, and L. Its loss mitigates the severity of pancreatitis not by reducing intra-acinar cell zymogen activation but by reducing infiltration of neutrophil granulocytes into the pancreas. In this context one of its key roles is that of an activator of neutrophil elastase.

Effects of inhibitory theta burst TMS to different brain sites involved in visuospatial attention - a combined neuronavigated cTBS and behavioural study.

PURPOSE AND METHODS: The study sought to alter visual spatial attention in young healthy subjects by a neuronavigated inhibitory rTMS protocol (cTBS-600) to right brain areas thought to be involved in visual attentional processes, i.e. the temporoparietal junction (TPJ) and the posterior middle frontal gyrus (pMFG), and to test the reversibility of effects by an additional consecutive cTBS to the homologue left brain cortical areas. RESULTS: Healthy subjects showed a leftward bias of the egocentric perspective for both visual-perceptive and visual-exploratory tasks specifically for items presented in the left hemifield. cTBS to the right TPJ, and less systematically to the right pMFG reduced this bias for visuo-spatial and exploratory visuo-motor behaviour. Further, a consecutive cTBS to the left TPJ changed the bias again towards the left for a visual-perceptive task. CONCLUSIONS: The evidence supports the notion of an involvement of the right TPJ (and pMFG) in spatial visual attention. The observations further indicate that inhibitory non-invasive brain stimulation (cTBS) to the left TPJ has a potential for reversing a rightward bias of spatial attention when the right TPJ is dysfunctional. Accordingly, the findings could have implications for therapeutic rTMS development for right brain damaged patients with visual neglect.