The endothelial nitric oxide synthase (eNOS) has been implicated in the rapid (Frank–Starling) and slow (Anrep) cardiac response to stretch. Our work and that of others have demonstrated that a neuronal nitric oxide synthase (nNOS) localized to the myocardium plays an important role in the regulation of cardiac function and calcium handling. However, the effect of nNOS on the myocardial response to stretch has yet to be investigated. Recent evidence suggests that the stretch-induced release of angiotensin II (Ang II) and endothelin 1 (ET-1) stimulates myocardial superoxide production from NADPH oxidases which, in turn, contributes to the Anrep effect. nNOS has also been shown to regulate the production of myocardial superoxide, suggesting that this isoform may influence the cardiac response to stretch or ET-1 by altering the NO-redox balance in the myocardium. Here we show that the increase in left ventricular (LV) myocyte shortening in response to the application of ET-1 (10 nM, 5 min) did not differ between nNOS−/− mice and their wild type littermates (nNOS+/+). Pre-incubating LV myocytes with the NADPH oxidase inhibitor, apocynin (100 μM, 30 min), reduced cell shortening in nNOS−/− myocytes only but prevented the positive inotropic effects of ET-1 in both groups. Superoxide production (O2−) was enhanced in nNOS−/− myocytes compared to nNOS+/+; however, this difference was abolished by pre-incubation with apocynin. There was no detectable increase in O2− production in ET-1 pre-treated LV myocytes. Inhibition of protein kinase C (chelerythrine, 1 μM) did not affect cell shortening in either group, however, protein kinase A inhibitor, PKI (2 μM), significantly reduced the positive inotropic effects of ET-1 in both nNOS+/+ and nNOS−/− myocytes. Taken together, our findings show that the positive inotropic effect of ET-1 in murine LV myocytes is independent of nNOS but requires NADPH oxidases and protein kinase A (PKA)-dependent signaling. These results may further our understanding of the signaling pathways involved in the myocardial inotropic response to stretch.

Usual Interstitial Pneumonia (UIP) is a histological pattern characteristic of Idiopathic Pulmonary Fibrosis (IPF). The UIP pattern is patchy with histologically normal lung adjacent to dense fibrotic tissue. At this interface, fibroblastic foci (FF) are present and are sites where myofibroblasts and extracellular matrix (ECM) accumulate. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the FF, adjacent mature scar, and adjacent alveoli in 6 fibrotic (UIP/IPF) specimens plus 6 nonfibrotic alveolar specimens as controls. The data were subject to qualitative and quantitative analysis, and histologically validated. We found that the fibrotic alveoli protein signature is defined by immune deregulation as the strongest category. The fibrotic mature scar classified as end-stage fibrosis whereas the FF contained an overabundance of a distinctive ECM compared to non-fibrotic control. Furthermore, the FF is positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of the FF is predominantly positive for TGFB2. In conclusion, spatial proteomics demonstrated distinct protein compositions in the histologically defined regions of UIP/IPF tissue. These data revealed that the FF is the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This new and essential information will inform future mechanistic studies on fibrosis progression.

Fracture-dislocations of the carpometacarpal joint (CMCJ) of the little ray involve dorsal subluxation of the metacarpal base and they may be associated with injury of neighbouring CMCJs. Different treatment options are described, with no clear consensus on their management. This study presents a systematic review of comparative studies describing the management of these injuries. A bespoke search strategy was applied across multiple databases. Results were screened against specified stepwise inclusion criteria and data were extracted independently by two authors with discrepancy resolution by a third. Of 437 search results, six comparative studies were identified. Comparisons included non-operative or early mobilization versus fixation K-wires or open reduction and internal fixation. Conclusions were mixed; all studies had critical or significant risks of bias (using the ROBINS-I tool) and there was heterogeneity between studies.