Regulation of endothelial cell activity and vascular inflammation by shear stress

This paper was presented at the 3rd Micro and Nano Flows Conference (MNF2011), which was held at the Makedonia Palace Hotel, Thessaloniki in Greece. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, Aristotle University of Thessaloniki, University of Thessaly, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute.Atherosclerosis, a chronic inflammatory disease of arteries, develops predominantly at branches, bends, and bifurcations in the arterial tree that are exposed to low or disturbed blood flow. The endothelium is in direct contact with flowing blood and hence is exposed to shear stress, a mechanical force that varies with time, magnitude, and direction, according to vascular pulsatility and anatomy. Bends and bifurcations of arteries that are susceptible to lesion formation are exposed to low/oscillatory shear stress, a mechanical environment that influences vascular physiology by enhancing inflammatory activation and promoting endothelial cell (EC) apoptosis. In contrast, relatively straight, unbranched regions of the arterial tree that are exposed to high shear stress are protected from inflammation, EC death and lesion development. Thus low shear stress may predispose arteries for lesion formation whereas high shear stress may prevent atherosclerosis by enhancing endothelial protection. In this paper, I will summarize some of the molecular mechanisms behind the spatial localization of vascular inflammation and atherosclerosis, emphasizing studies by my research group of two key proinflammatory signaling pathways, the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor-kappa-B (NF-κB) pathway.This study is funded by the British Heart Foundation

Menthol cigarette smoking and nicotine dependence

Since tobacco use is driven by dependence on nicotine, the primary addictive substance in tobacco, much research has focused on nicotine dependence. Less well understood, however, is the role that menthol plays in nicotine dependence. This review seeks to examine what role, if any, menthol plays in nicotine addiction in adults and youth. Based on research examining several indicators of heaviness of nicotine addiction, including time to first cigarette upon waking, night waking to smoke, as well as some other indications of dependence, it is suggested that menthol cigarette smokers are more heavily dependent on nicotine. Although other indicators of nicotine dependence, including number of cigarettes per day and the Fagerstrom Test of Nicotine Dependence, failed to consistently differentiate menthol and non-menthol smokers, these indicators are thought to be less robust than time to first cigarette. Therefore, though limited, the existing literature suggests that menthol smokers may be more dependence on nicotine

Multi-scale interaction of flow and the artery wall

We discuss, from the perspective of basic science, the physical and biological processes which underlie atherosclerotic (plaque) initiation at the vascular endothelium, identifying their widely separated spatial and temporal scales which participate. We draw on current, related models of vessel wall evolution, paying particular attention to the role of flow, and proceed to propose, then validate (in practical, qualitative terms, at least) a multiply coupled, multi-scale modeling strategy, which, eventually, aims at a quantitative, patient-specific understanding of the coupling between the flow and the endothelial state

Quorum Sensing Controls Adaptive Immunity through the Regulation of Multiple CRISPR-Cas Systems

Bacteria commonly exist in high cell density populations, making them prone to viral predation and horizontal gene transfer (HGT) through transformation and conjugation. To combat these invaders, bacteria possess an arsenal of defenses, such as CRISPR-Cas adaptive immunity. Many bacterial populations coordinate their behavior as cell density increases, using quorum sensing (QS) signaling. In this study, we demonstrate that QS regulation results in increased expression of the type I-E, I-F, and III-A CRISPR-Cas systems in $\textit{Serratia}$ cells in high-density populations. Strains unable to communicate via QS were less effective at defending against invaders targeted by any of the three CRISPR-Cas systems. Additionally, the acquisition of immunity by the type I-E and I-F systems was impaired in the absence of QS signaling. We propose that bacteria can use chemical communication to modulate the balance between community-level defense requirements in high cell density populations and host fitness costs of basal CRISPR-Cas activity.This work was supported by a Rutherford Discovery Fellowship (P.C.F.) from the Royal Society of New Zealand (RSNZ) and the Marsden Fund, RSNZ. A.G.P. was supported by a University of Otago Doctoral Scholarship. G.P.C.S. is funded by the Biotechnology and Biological Sciences Research Council, UK

Reduced keratin expression in colorectal neoplasia and associated fields is reversible by diet and resection

Abstract Background Patients with adenomatous colonic polyps are at increased risk of developing further polyps suggesting field-wide alterations in cancer predisposition. The current study aimed to identify molecular alterations in the normal mucosa in the proximity of adenomatous polyps and to assess the modulating effect of butyrate, a chemopreventive compound produced by fermentation of dietary residues. Methods A cross-sectional study was undertaken in patients with adenomatous polyps: biopsy samples were taken from the adenoma, and from macroscopically normal mucosa on the contralateral wall to the adenoma and from the mid-sigmoid colon. In normal subjects biopsies were taken from the mid-sigmoid colon. Biopsies were frozen for proteomic analysis or formalin-fixed for immunohistochemistry. Proteomic analysis was undertaken using iTRAQ workflows followed by bioinformatics analyses. A second dietary fibre intervention study arm used the same endpoints and sampling strategy at the beginning and end of a high-fibre intervention. Results Key findings were that keratins 8, 18 and 19 were reduced in expression level with progressive proximity to the lesion. Lesional tissue exhibited multiple K8 immunoreactive bands and overall reduced levels of keratin. Biopsies from normal subjects with low faecal butyrate also showed depressed keratin expression. Resection of the lesion and elevation of dietary fibre intake both appeared to restore keratin expression level. Conclusion Changes in keratin expression associate with progression towards neoplasia, but remain modifiable risk factors. Dietary strategies may improve secondary chemoprevention. Trial registration number ISRCTN90852168. Keywords: ADENOMA, BUTYRATE, CYTOKERATINS, DIETARY FIBR

The effect of absent blood flow on the zebrafish cerebral and trunk vasculature

The role of blood flow in vascular development is complex and context-dependent. In this study, we quantify the effect of the lack of blood flow on embryonic vascular development on two vascular beds, namely the cerebral and trunk vasculature in zebrafish. We perform this by analysing vascular topology, endothelial cell (EC) number, EC distribution, apoptosis, and inflammatory response in animals with normal blood flow or absent blood flow. We find that absent blood flow reduced vascular area and EC number significantly in both examined vascular beds, but the effect is more severe in the cerebral vasculature, and severity increases over time. Absent blood flow leads to an increase in non-EC-specific apoptosis without increasing tissue inflammation, as quantified by cerebral immune cell numbers and nitric oxide. Similarly, while stereotypic vascular patterning in the trunk is maintained, intra-cerebral vessels show altered patterning, which is likely to be due to vessels failing to initiate effective fusion and anastomosis rather than sprouting or path-seeking. In conclusion, blood flow is essential for cellular survival in both the trunk and cerebral vasculature, but particularly intra-cerebral vessels are affected by the lack of blood flow, suggesting that responses to blood flow differ between these two vascular beds

Requirement of JNK1 for endothelial cell injury in atherogenesis

AbstractObjectiveThe c-Jun N-terminal kinase (JNK) family regulates fundamental physiological processes including apoptosis and metabolism. Although JNK2 is known to promote foam cell formation during atherosclerosis, the potential role of JNK1 is uncertain. We examined the potential influence of JNK1 and its negative regulator, MAP kinase phosphatase-1 (MKP-1), on endothelial cell (EC) injury and early lesion formation using hypercholesterolemic LDLR−/− mice.Methods and resultsTo assess the function of JNK1 in early atherogenesis, we measured EC apoptosis and lesion formation in LDLR−/− or LDLR−/−/JNK1−/− mice exposed to a high fat diet for 6 weeks. En face staining using antibodies that recognise active, cleaved caspase-3 (apoptosis) or using Sudan IV (lipid deposition) revealed that genetic deletion of JNK1 reduced EC apoptosis and lesion formation in hypercholesterolemic mice. By contrast, although EC apoptosis was enhanced in LDLR−/−/MKP-1−/− mice compared to LDLR−/− mice, lesion formation was unaltered.ConclusionWe conclude that JNK1 is required for EC apoptosis and lipid deposition during early atherogenesis. Thus pharmacological inhibitors of JNK may reduce atherosclerosis by preventing EC injury as well as by influencing foam cell formation

Frontal mucocele with an accompanying orbital abscess mimicking a fronto-orbital mucocele: case report

BACKGROUND: Mucoceles are slowly expanding cystic lesions with respiratory epithelium containing mucus most commonly affecting the frontal and ethmoidal sinuses. They are caused by obstruction of sinus ostium. Mucoceles exert pressure on the bony boundaries and due to the proximity to the brain and orbit extension to these areas are common. CASE PRESENTATION: A case of a frontal mucocele with an accompanying orbital abscess mimicking a fronto-orbital mucocele is reported. A 77 year old female patient suffering from left sided proptosis and pain around the left eye was admitted to our department. She had a history of left frontal sinus mucocele one year ago that was offered an osteoplastic frontal sinus surgery that the patient refused. Patient had limitation of eye movements. Fundoscopic examination revealed a minimal papilledema. Coronal computerized tomography and orbital magnetic resonance imaging showed a frontal mucocele with suspicious erosion of the orbital roof and a superiorly localized extraconal mass displacing the orbit lateroinferiorly. Frontal and orbital masses had similar intensities. Thus surgery was planned for a fronto-orbital mucocele. During surgery no defect was found on the orbital roof. Frontal mucocele and orbital cystic mass was removed separately. Pathological examination showed a frontal mucocele and an orbital abscess wall. Postoperatively eye movements returned to normal and papilledema resolved. CONCLUSION: Fronto-orbital mucoceles are commonly encountered pathologies, but frontal mucocele with an orbital abscess is a rarely seen and should be kept in mind because their treatments differ

Robot-assisted pancreatoduodenectomy with preservation of the vascular supply for autologous islet cell isolation and transplantation: a case report

<p>Abstract</p> <p>Introduction</p> <p>For patients with chronic pancreatitis presenting with medically intractable abdominal pain, surgical intervention may be the only treatment option. However, extensive pancreatic resections are typically performed open and are associated with a substantial amount of postoperative pain, wound complications and long recovery time. Minimally invasive surgery offers an avenue to improve results; however, current limitations of laparoscopic surgery render its application in the setting of chronic pancreatitis technically demanding. Additionally, pancreatic resections are associated with a high incidence of diabetes. Transplantation of islets isolated from the resected pancreas portion offers a way to prevent post-surgical diabetes; however, preservation of the vascular supply during pancreatic resection, which determines islet cell viability, is technically difficult using current laparoscopic approaches. With recent advances in the surgical field, robotic surgery now provides a means to overcome these obstacles to achieve the end goals of pain relief and preserved endocrine function. We present the first report of a novel, minimally invasive robotic approach for resection of the pancreatic head that preserves vascular supply and enables the isolation of a high yield of viable islets for transplantation.</p> <p>Case presentation</p> <p>A 35-year old Caucasian woman presented with intractable chronic abdominal pain secondary to chronic pancreatitis, with a stricture of her main pancreatic duct at the level of the ampulla of Vater and distal dilatation. She was offered a robotic-assisted pylorus-preserving pancreatoduodenectomy and subsequent islet transplantation, to both provide pain relief and preserve insulin-secretory reserves.</p> <p>Conclusion</p> <p>We present a novel, minimally invasive robotic approach for resection of the pancreatic head with complete preservation of the vascular supply, minimal warm ischemia time (less than three minutes) and excellent islet recovery (134,727 islet equivalent). Our patient is currently pain-free with normal glycemic control. Robot-assisted pylorus-preserving pancreatoduodenectomy and autologous islet transplantation can be safely performed and has the potential to minimize operative traumas as well as to partially preserve endocrine function. Results from this case report suggest that this dual procedure should be considered as a treatment option for patients with chronic pancreatitis at earlier stages of the disease, before irreversible islet loss occurs.</p