Genetic Mutation Carriers: Special Considerations for Their Influence on a Modern Breast Reconstruction Practice

With medical advancement, increasing numbers of genetic variations and mutations are being uncovered that offer greater insight into which patients have a predisposition for the development of breast cancer. Reasonable management for these patients includes high-risk surveillance, medical prophylaxis, or bilateral prophylactic mastectomy with immediate reconstruction which is becoming increasingly popular. However, this cohort of patients differs from the average breast cancer patient in that they are typically younger and may have distinct reconstructive objectives for their outcomes. This chapter considers this unique and expanding population, as well as their expectations for surgical outcomes both aesthetically and oncologically. We will discuss the evolving role of social media in this population, with patient to patient virtual information sharing and how this may impact patient referrals in a manner diverging from traditional hospital-based patterns. Furthermore, we discuss how practices in which cutting-edge and novel surgical treatments are available, such as pre-pectoral and single stage reconstruction, and that incorporate team collaboration with the surgical oncologist to deliver aesthetically pleasing results with nipple sparing mastectomy and concealed scars may ultimately be attractive to genetic mutation carriers concerned not only with risk reduction but also post-operative aesthetics

Sexual dimorphisms in leukocyte trafficking in a mouse peritonitis model

E.K was funded by the British Heart Foundation Grant # FS113028789 and JRW was funded by Arthritis Research-UK Grant #19207

Leukotriene B-4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo

This work was supported by generous funds from the Wellcome Trust (098291/Z/12/Z to S.N.). T.C. was supported by the ERC (ENDHORET). The work was also supported in part by funds from the William Harvey Research Foundation

Neutrophil elastase plays a non-redundant role in remodeling the venular basement membrane and neutrophil diapedesis post ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury is a severe inflammatory insult associated with numerous pathologies such as myocardial infarction, stroke and acute kidney injury. I/R injury is characterized by a rapid influx of activated neutrophils secreting toxic free radical species and degrading enzymes that can irreversibly damage the tissue, thus impairing organ functions. Significant efforts have been invested in identifying therapeutic targets to suppress neutrophil recruitment and activation post I/R injury. In this context, pharmacological targeting of neutrophil elastase (NE) has shown promising anti‐inflammatory efficacy in a number of experimental and clinical settings of I/R injury, and is considered a plausible clinical strategy for organ care. However, the mechanisms of action of NE, and hence its inhibitors, in this process is not fully understood. Here we conducted a comprehensive analysis of the impact of NE genetic deletion on neutrophil infiltration in four murine models of I/R injury as induced in the heart, kidneys, intestine and cremaster muscle. In all models, neutrophil migration into ischemic regions was significantly suppressed in NE‐/‐ mice as compared to wild‐type controls. Analysis of inflamed cremaster muscle and mesenteric microvessels by intravital and confocal microscopy revealed a selective entrapment of neutrophils within venular walls, most notably at the level of the venular basement membrane (BM) following NE‐deletion/pharmacological blockade. This effect was associated with the suppression of NE‐mediated remodeling of the low matrix protein expressing regions within the venular BM used by transmigrating neutrophils as exit portals. Furthermore, whilst NE deficiency led to reduced neutrophil activation and vascular leakage, levels of monocytes and pro‐healing M2 macrophages were reduced in tissues of NE‐/‐ mice subjected to I/R. Collectively our results identify a vital and non‐redundant role for NE in supporting neutrophil breaching of the venular BM post I/R injury but also suggest a protective role for NE in promoting tissue repai

Foot and ankle injuries during the Athens 2004 Olympic Games

<p>Abstract</p> <p>Background</p> <p>Major, rare and complex incidents can occur at any mass-gathering sporting event and team medical staff should be appropriately prepared for these. One such event, the Athens Olympic Games in 2004, presented a significant sporting and medical challenge. This study concerns an epidemiological analysis of foot and ankle injuries during the Games.</p> <p>Methods</p> <p>An observational, epidemiological survey was used to analyse injuries in all sport tournaments (men's and women's) over the period of the Games.</p> <p>Results</p> <p>A total of 624 injuries (525 soft tissue injuries and 99 bony injuries) were reported. The most frequent diagnoses were contusions, sprains, fractures, dislocations and lacerations. Significantly more injuries in male (58%) versus female athletes (42%) were recorded. The incidence, diagnosis and cause of injuries differed substantially between the team sports.</p> <p>Conclusion</p> <p>Our experience from the Athens Olympic Games will inform the development of public health surveillance systems for future Olympic Games, as well as other similar mass events.</p

Cigarette smoke induces β2-integrin-dependent neutrophil migration across human endothelium

<p>Abstract</p> <p>Background</p> <p>Cigarette smoking induces peripheral inflammatory responses in all smokers and is the major risk factor for neutrophilic lung disease such as chronic obstructive pulmonary disease. The aim of this study was to investigate the effect of cigarette smoke on neutrophil migration and on β₂-integrin activation and function in neutrophilic transmigration through endothelium.</p> <p>Methods and results</p> <p>Utilizing freshly isolated human PMNs, the effect of cigarette smoke on migration and β₂-integrin activation and function in neutrophilic transmigration was studied. In this report, we demonstrated that cigarette smoke extract (CSE) dose dependently induced migration of neutrophils <it>in vitro</it>. Moreover, CSE promoted neutrophil adherence to fibrinogen. Using functional blocking antibodies against CD11b and CD18, it was demonstrated that Mac-1 (CD11b/CD18) is responsible for the cigarette smoke-induced firm adhesion of neutrophils to fibrinogen. Furthermore, neutrophils transmigrated through endothelium by cigarette smoke due to the activation of β₂-integrins, since pre-incubation of neutrophils with functional blocking antibodies against CD11b and CD18 attenuated this transmigration.</p> <p>Conclusion</p> <p>This is the first study to describe that cigarette smoke extract induces a direct migratory effect on neutrophils and that CSE is an activator of β₂-integrins on the cell surface. Blocking this activation of β₂-integrins might be an important target in cigarette smoke induced neutrophilic diseases.</p

Mesenchymal Stem Cells Exhibit Firm Adhesion, Crawling, Spreading and Transmigration across Aortic Endothelial Cells: Effects of Chemokines and Shear

Mesenchymal stem cells (MSCs) have anti-inflammatory and immunosuppressive properties and may be useful in the therapy of diseases such as arteriosclerosis. MSCs have some ability to traffic into inflamed tissues, however to exploit this therapeutically their migratory mechanisms need to be elucidated. This study examines the interaction of murine MSCs (mMSCs) with, and their migration across, murine aortic endothelial cells (MAECs), and the effects of chemokines and shear stress. The interaction of mMSCs with MAECs was examined under physiological flow conditions. mMSCs showed lack of interaction with MAECs under continuous flow. However, when the flow was stopped (for 10min) and then started, mMSCs adhered and crawled on the endothelial surface, extending fine microvillous processes (filopodia). They then spread extending pseudopodia in multiple directions. CXCL9 significantly enhanced the percentage of mMSCs adhering, crawling and spreading and shear forces markedly stimulated crawling and spreading. CXCL9, CXCL16, CCL20 and CCL25 significantly enhanced transendothelial migration across MAECs. The transmigrated mMSCs had down-regulated receptors CXCR3, CXCR6, CCR6 and CCR9. This study furthers the knowledge of MSC transendothelial migration and the effects of chemokines and shear stress which is of relevance to inflammatory diseases such as arteriosclerosis

Endogenous TNF alpha orchestrates the trafficking of neutrophils into and within lymphatic vessels during acute inflammation

This work was supported by funds from Arthritis Research UK (19913 to M.-B.V.) and the Wellcome Trust (098291/Z/12/Z to S.N.). S. A. was supported by a QMUL Principal’s Award PhD Studentship

Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo

Neutrophilic inflammation is tightly regulated and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent kinase (CDK) inhibitor drugs induce neutrophil apoptosis in vitro and promote resolution of inflammation in rodent models. Here we present the first in vivo evidence, using pharmacological and genetic approaches, that CDK9 is involved in the resolution of neutrophil-dependent inflammation. Using live cell imaging in zebrafish with labelled neutrophils and macrophages, we show that pharmacological inhibition, morpholino-mediated knockdown and CRISPR/cas9-mediated knockout of CDK9 enhances inflammation resolution by reducing neutrophil numbers via induction of apoptosis after tailfin injury. Importantly, knockdown of the negative regulator La-related protein 7 (LaRP7) increased neutrophilic inflammation. Our data show that CDK9 is a possible target for controlling resolution of inflammation

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues

This work was supported by the National Institutes of Health (NIH) grant AI112521 and the John and Virginia Kaneb Fellowship