Release of miR-29 Target Laminin C2 Improves Skin Repair.

miRNAs are small noncoding RNAs that regulate mRNA targets in a cell-specific manner. miR-29 is expressed in murine and human skin, where it may regulate functions in skin repair. Cutaneous wound healing model in miR-29a/b1 gene knockout mice was used to identify miR-29 targets in the wound matrix, where angiogenesis and maturation of provisional granulation tissue was enhanced in response to genetic deletion of miR-29. Consistently, antisense-mediated inhibition of miR-29 promoted angiogenesis in vitro by autocrine and paracrine mechanisms. These processes are likely mediated by miR-29 target mRNAs released upon removal of miR-29 to improve cell-matrix adhesion. One of these, laminin (Lam)-c2 (also known as laminin γ2), was strongly up-regulated during skin repair in the wound matrix of knockout mice. Unexpectedly, Lamc2 was deposited in the basal membrane of endothelial cells in blood vessels forming in the granulation tissue of knockout mice. New blood vessels showed punctate interactions between Lamc2 and integrin α6 (Itga6) along the length of the proto-vessels, suggesting that greater levels of Lamc2 may contribute to the adhesion of endothelial cells, thus assisting angiogenesis within the wound. These findings may be of translational relevance, as LAMC2 was deposited at the leading edge in human wounds, where it formed a basal membrane for endothelial cells and assisted neovascularization. These results suggest a link between LAMC2, improved angiogenesis, and re-epithelialization.

Atypical late presentation of muscular metastasis of melanoma in the contralateral limb.

A man in his 50s presented to plastic surgery again with a lesion on his left upper arm. He had previously been treated for a malignant melanoma (MM) on his right arm over 5 years earlier. Sentinel lymph node biopsy (SLNB) had been negative, and he had completed the recommended 5 years follow-up period. Imaging was suspicious for an intramuscular soft tissue malignancy within the triceps muscle. After discussion with the regional sarcoma service, a core biopsy was performed. Histopathology suggested a diagnosis of metastatic MM, which was confirmed after surgical excision. This case highlights a rare example of an isolated muscular metastasis of MM, which presented at a distant site, over 5 years from the original treatment. This case highlights the unpredictable nature of MM, reminding clinicians of the need for a low threshold for investigation of soft tissue masses in patients with a history of cutaneous malignancy.

Morphologically intact airways in lung fibrosis have an abnormal proteome.

Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.

Return to sport or work following surgical management of scapholunate ligament injury: a systematic review.

INTRODUCTION: This systematic review aims to compare the rate and time to return to sport or work following surgical interventions for isolated scapholunate ligament (SLL) injury. SOURCES OF DATA: A PRISMA-compliant systematic search of Medline, EMBASE, Cochrane, AMED, CINAHL Plus and SPORTDiscus was performed using keywords 'scapholunate', 'scapholunate ligament', 'scaphoid lunate', 'sport', 'sport injury', 'athlete', 'athletic performance', 'elite', 'return to sport', 'training', 'work', 'activity', 'return to activity'. Adult patients with isolated SLL injury, without osteoarthritis, were included. AREAS OF AGREEMENT: Fourteen papers, including six different surgical interventions, met the criteria for the final analysis. All surgical techniques demonstrated acceptable rates of return to work or sport (>80%). AREAS OF CONTROVERSY: The optimal surgical intervention for isolated SLL injury remains undetermined due to heterogeneity and limited sample sizes of published studies. GROWING POINTS: This systematic review has provided clarification on the available literature on treatment modalities for isolated SLL injuries in the absence of osteoarthritis. AREAS TIMELY FOR DEVELOPING RESEARCH: Prospective, randomized, primary studies are needed to establish optimal treatment for acute isolated SLL injuries.

The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix.

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, 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 subjected 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 with the nonfibrotic control. Furthermore, FF were positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of FF was 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 FF are the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This essential information will inform future mechanistic studies on fibrosis progression.

Management of fracture-dislocations of the little finger carpometacarpal joint: a systematic review.

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.

The role of nitric oxide and reactive oxygen species in the positive inotropic response to mechanical stretch in the mammalian myocardium.

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 microM, 30 min), reduced cell shortening in nNOS(-/-) myocytes only but prevented the positive inotropic effects of ET-1 in both groups. Superoxide production (O(2)(-)) was enhanced in nNOS(-/-) myocytes compared to nNOS(+/+); however, this difference was abolished by pre-incubation with apocynin. There was no detectable increase in O(2)(-) production in ET-1 pre-treated LV myocytes. Inhibition of protein kinase C (chelerythrine, 1 microM) did not affect cell shortening in either group, however, protein kinase A inhibitor, PKI (2 microM), 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.