Greg Reece, MD

• Professor of Plastic Surgery
• Department of Plastic Surgery
• University of Texas MD Anderson Cancer Center
• Houston, Texas

Vascular endothelial growth factor D is dispensable for development of the lymphatic system virus 7 life processes generic 400mg floxin with visa. Vascular endothelial growth factor-d modulates caliber and function of initial lymphatics in the dermis antibiotics for acne safe for pregnancy order floxin 200 mg otc. Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation antibiotics for dogs cough buy floxin 400 mg with mastercard. Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions antibiotic 3 days purchase floxin 200 mg fast delivery. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning antibiotic yellow teeth order 200mg floxin, and only the latter role is rescued by angiopoietin-1 antibiotics for acne while breastfeeding purchase floxin line. Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. An unexpected role of semaphorin3A/neuropilin-1 signaling in lymphatic vessel maturation and valve formation. Semaphorin3A, neuropilin-1, and plexinA1 are required for lymphatic valve formation. Prox1 is a marker of ectodermal placodes, endodermal compartments, lymphatic endothelium and lymphangioblasts. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. Endothelial cell plasticity: how to become and remain a lymphatic endothelial cell. Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice. Notch1 functions as a negative regulator of lymphatic endothelial cell differentiation in the venous endothelium. Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Time course of angiogenesis and lymphangiogenesis after brief corneal inflammation. Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. Ccbe1 regulates Vegfcmediated induction of Vegfr3 signaling during embryonic lymphangiogenesis. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax. Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Weinberg, and Robert Krams 13 Atherosclerosis: cellular mechanisms 181 Esther Lutgens, Marie-Luce Bochaton-Piallat, and Christian Weber 14 Molecular mechanisms 199 Claudia Monaco and Giuseppina Caligiuri Section introduction Imo Hoefer Atherosclerosis is the primary underlying process of arterial narrowing and occlusion and, therefore, one of the main factors accountable for the commonest cause of death worldwide. The search for therapeutic strategies and the fight against cardiovascular disease heavily relies on a well-founded understanding of the mechanisms that lead to initiation and progression of atherosclerosis. In the past decades, our growing knowledge on its asymptomatic instigation by lipids, and sustainment and fuelling by inflammation towards symptomatic disease has enabled prevention programmes and specific treatments that have significantly reduced cardiovascular disease mortality and increased life-expectancy in Western countries. Pathologists were the first to describe atherosclerotic lesions in the nineteenth century, but even 2,000-year-old Egyptian mummies show definite signs of atherosclerosis on computer tomography images. Based on pathological observations, two different schools of thinking initially evolved, the most popular being the lipid model, which described atherosclerosis as a disease of lipid accumulation in the vascular wall. This was modified to the response-to-injury model and later evolved into the currently valid inflammatory paradigm. Today, atherosclerosis is best summarized as a lipid-driven inflammatory disease, as outlined in Chapter 10. While the debate on the respective share of lipids and inflammation continues, there is broad consensus on the prime role of lipids in the onset of atherosclerosis. Blood transport of lipids occurs in the form of lipid-protein complexes of different composition, different characteristics, and varying functions. Chapter 11 deals with the various lipid fractions, their role as causal factors and biomarkers, and lipid metabolism aimed treatments. Nevertheless, it is not randomly distributed throughout the vasculature, but follows clear patterns. Some vessel segments are almost never affected, whereas other, biomechanically more exposed, parts are much more prone to atherosclerotic plaque formation. The prominent influence of biomechanical factors, such as flow and stress, in this context are detailed in Chapter 12. Biomechanical factors also form the basis for the increased inflammatory cell accumulation at these predilection sites. Macrophages were the first inflammatory cells to be observed in atherosclerotic plaques and were long considered the main cellular drivers. Their importance remains unquestioned, but there is much evidence for a complex interplay of resident vascular and circulating inflammatory cells that encompasses most blood cell fractions. The various cellular and molecular players in this multifaceted, multifactorial process are put in context in Chapters 13 and 14, respectively. Evolution of the hypothesis mirrored the progress of cellular and molecular biology, leading to progressive broadening of the understanding of cell types and molecules involved in atherogenesis. In this article, we first describe the current histopathological view on the pathogenesis of atherosclerosis. Subsequently, we touch on a historical perspective weaving in the fundamental discoveries that still influence our perception of this disease in humans. Histopathology Nowadays, atherosclerosis is considered as a lipid-driven inflammatory disease in which both lipids and immune cells play a major role (3). The disease is characterized by the presence of atherosclerotic plaques consisting of lipids, (immune) cells, and debris that form in the arterial intima. Plaques develop at predisposed regions characterized by disturbed blood flow dynamics, such as curvatures and branch points. Early plaques, called fatty streaks or intimal xanthomas, are typified by the presence of cholesterol-engorged macrophages and few T cells (6). These plaques are clinically silent and can either disappear or evolve into mature lesions over time. Via intertwined immunological interactions between immune cell subsets, endothelial cells, platelets, and smooth muscle cells, but also via extracellular matrix production, remodelling, and degradation, an advanced, clinically relevant plaque stage develops: the fibrous cap atheroma (6). Fibrous cap atheromas are characterized by the presence of a necrotic core surrounded by a fibrous cap. Immune cell interactions in the fibrous cap atheroma typically occur at the shoulder regions, and can finally weaken the extracellular matrix, resulting in intraplaque haemorrhage. In the histopathological setting, thrombi-containing plaques are classified according to the thrombus-causing process: rupture, erosion, or, more rarely, a calcified nodule (6). These processes can occur in the setting of a fibrous cap atheroma or, in the case of erosion, a pathological intimal thickening. Plaque rupture is defined by an area of fibrous cap disruption whereby the overlying thrombus is in continuity with the necrotic core. Plaque erosion is identified when a thrombosed artery fails to show fibrous cap rupture. A rare form of plaque thrombosis is the calcified nodule, a lesion with fibrous cap disruption and thrombi associated with eruptive, dense calcified nodules. Plaque thrombosis can lead to growth of the atherosclerotic plaque (upon healing) and/or occlusion of the artery, resulting in severe clinical complications such as myocardial infarction, stroke, peripheral arterial disease, or intestinal ischaemia (6). Evolving insights the thrombosis model Two centuries ago, in 1852 in Austria, von Rokitansky described the presence of mural thrombi in human lesions (7). Later, it was postulated that an encrustation of small mural thrombi existed at the sites of arterial injury. Michael Davies substantiated this model as an important mechanism of coronary plaque progression in 1990 (8). In 1856, Virchow, who was also based in Austria, observed lipid deposits in the atherosclerotic plaque (1). Also in Russia, Anitschkov and Chalatov reproduced experimental atherosclerosis by adding pure cholesterol to rabbit food (10). This gave rise to the lipid theory of atherosclerosis that remained the dominant theory on the origin of atherosclerosis until the 1990s. Animal models of hypercholesterolaemia have contributed invaluably to the understanding of the sequence of events in atherosclerotic lesions. Rabbits and nonhuman primates were first used, since they develop atherosclerosis after being fed a fat and cholesterol-containing diet. In the following sections, we will touch upon past and current theories that have contributed to our current view on the pathogenesis of atherosclerosis. The monocytes attach to the endothelial cells in clusters that appear to be randomly located throughout the arterial tree in all large- and medium-sized arteries. Within <1 month, large numbers of foam cells are found beneath the endothelial lining, leading to the formation of fatty streaks, i. These advanced lesions initially formed at branches and bifurcations in the iliac arteries and subsequently at higher regions in the arterial tree. Changes towards fibrous cap atheroma formation occurred at the iliac bifurcation after approximately 7 months, in the abdominal aorta after 9 months, in the thoracic aorta after 11 months, and in the coronary arteries after a year. The pioneering studies performed in the mouse were aimed at finding the most susceptible mouse strain. The most susceptible strain was found to be the C57Bl/6 strain, which was thus used for the development of transgenic atherosclerosis strains (17). The most used atherosclerotic mouse is the ApoE knockout mouse, which is deficient in apolipoprotein E, an important ligand for lipoprotein clearance. As a consequence of this deficiency, mice develop severe hypercholesterolaemia and intimal xanthomas, pathological intimal thickenings, and fibrous cap atheromas, resembling those observed in humans (18, 19). These lesions are exacerbated when mice are fed a highcholesterol, high-fat, Western-type diet. They proposed a broader theory (24, 25) that took into account the micro- and macro-thrombotic aspects, which are much more prevalent in human disease than in hypercholesterolaemic animal models. They proposed that the extent of platelet deposition and the size of the thrombus are proportional to the severity of the vessel wall injury. Although the process begins as a physiological repair of the insult, it subsequently evolves towards a pathological alteration because of the severity of the insult and its persistence or recurrence (23). This most recent version emphasized endothelial dysfunction and/or endothelial activation rather than denudation. These findings provided the basis for an hypothesis of entirely new pathogenic mechanisms. Furthermore, even the earliest type of lesion, the fatty streak, was shown to contain T lymphocytes (34). It would be a mistake to surmise that the different models on the pathogenesis of atherosclerosis that have been proposed are mutually exclusive. Modern biology, through the definition of the molecular mechanisms of disease, has reconciled the different interpretations of atherosclerosis. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Compensatory adjustments in the structure of coronary arteries of the heart with stenotic atherosclerosis. Heterozygous familial hypercholesterolemia: failure of normal allele to compensate for mutant allele at a regulated genetic locus. Atherosclerosis susceptibility differences among progenitors of recombinant inbred strains of mice. ApoE-deficient mice develop lesions of all phases of references 147 atherosclerosis throughout the arterial tree. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehydelysine in serum. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein(a) retention and macrophage foam cell formation.

Various studies antibiotics publix purchase floxin in india, however virus 2014 september buy floxin 200 mg fast delivery, have highlighted a correlation between fluoroquinolone use and C antibiotic for lyme disease order 200mg floxin fast delivery. Antimicrobial resistance can cause delays in the onset of an adequate therapy and is associated with increased mortality infection high blood pressure generic 200mg floxin with visa, length of hospital stay and healthcare costs [80] antibiotic resistance for dummies buy floxin 400 mg without a prescription. Recommended empirical therapy for pulmonary infections in adults according to the setting and severity of presentation [73 antimicrobial keyboard covers purchase floxin 200mg on-line, 74]. Studies have reported concentrations of 41% in lung tissue and 52% in the epithelial lining fluid [82, 88]. In critically ill patients, penetration of vancomycin into the epithelial lining fluid ranged from 0 to 8. Other adverse effects associated with vancomycin use include aminotransferase elevations, neutropenia and infusion reactions [94, 95]. Oxazolidinones: linezolid Linezolid binds to the bacterial ribosome 50S subunit and interferes with protein synthesis [96]. Although no drug adjustments are necessary for patients with renal impairment or mild to moderate liver disease [100], it is recommended that linezolid is used with caution in patients with severe renal insufficiency. Initial studies confirmed excellent concentrations of linezolid in the epithelial lining fluid [101]. Use of linezolid, however, has been associated with the onset of various adverse effects including nausea, headache, peripheral and optic neuropathy, lactic acidosis and myelosuppression (especially thrombocytopenia). The majority of the effects were reported during prolonged regimens (>14 days) and in patients with renal impairment [103, 104]. Linezolid is also a reversible monoamine oxidase inhibitor and can interact with selective serotonin reuptake inhibitors [105]. Limitations in the use of colistin, however, include unclear pharmacokinetic/pharmacodynamic parameters and dosing regimen, poor lung penetration and renal toxicity [109]. Other antimicrobials used in the treatment of pneumonia include aztreonam, characterised by excellent tolerability but limited by a narrow antimicrobial spectrum including only Gram-negative bacteria, and aminoglycosides. Although the efficacy of many new compounds still needs to be confirmed, promising features include a broad spectrum of activity, limited risk of antimicrobial resistance, availability of i. Table 2 summarises the characteristics and current approval status of new antimicrobials that have been studied for the treatment of pulmonary infections. Ceftolozane possesses a potent antipseudomonal activity and is not affected by mechanisms of resistance that are typical of P. Fluoroketolides Solithromycin is a fourth-generation macrolide antibiotic and the first fluoroketolide within the macrolide class. Multiple interacting sites are involved in its low resistance rates and improved activity against macrolide-resistant isolates of S. Solithromycin has activity against the most common respiratory pathogens and atypical bacterial pathogens, including Legionella pneumophila, shows bactericidal activity against most isolates of S. When administered as 400 mg once daily, solithromycin had a bioavailability of 67% and a plasma half-life of 10 h [128]. Solithromycin is excreted primarily by the liver and no dose adjustment is needed in patients with hepatic impairment. Although a higher incidence of infusion site reactions was demonstrated in the solithromycin arm compared with moxifloxacin, other adverse effects were similar in the two arms. Telavancin acts by disrupting the bacterial membrane function and inhibiting bacterial wall synthesis via transglycosylation and transpeptidation, using a unique dual mechanism of action [133]. Oxazolidinones Among oxazolidinones, tedizolid is currently approved for the treatment of acute bacterial skin and soft tissue infections. Recent pharmacokinetic/pharmacodynamic studies confirmed high epithelial lining fluid concentrations of tedizolid in healthy volunteers after 200 mg of tedizolid administered orally, supporting its potential role in the treatment of pneumonia [141]. Fluorocyclines Eravacycline is a novel fluorocycline that is not influenced by the mechanisms that usually confer resistance to tetracyclines, such as efflux pumps and ribosomal protection proteins [144]. These data, together with the availability of an oral formulation, make eravacycline an attractive option for the treatment of respiratory infections. Characteristics of antimicrobials that are currently commonly used in the treatment of respiratory infections Class Spectrum Lung penetration Sequential therapy. Challenges in the treatment of respiratory infections encountered in clinical practice are the frequent absence of microbial diagnosis to guide antimicrobial choice and, in some areas, an increased rate of antimicrobial resistance among pathogens that are usually involved in these infections, especially in the nosocomial setting. A short course of antimicrobials should be favoured, where possible, to reduce resistance selection; de-escalation therapy should also be pursued to reduce length of hospital stay and healthcare costs. Limitations in the use of antimicrobials, however, include variable penetration in the lung tissue, availability only as an i. To overcome these issues and to face the emerging increase in resistance to antimicrobials, new molecules have been developed. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Microbiological profile of community-acquired pneumonia in adults over the last 20 years. Antibiotic therapy for adults hospitalized with community-acquired pneumonia: a systematic review. Effectiveness of early switch from intravenous to oral antibiotics in severe community acquired pneumonia: multicentre randomised trial. Executive summary: management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. The etiology of community acquired pneumonia in Australia: why penicillin plus doxycyline or a macrolide is the most appropriate therapy. Bactericidal activity, post antibiotic effect and modified controlled effective regrowth time of meropenem at high concentrations. Continuous versus intermittent intravenous administration of antibacterials with time-dependent action: a systemic review of pharmacokinetic and pharmacodynamic parameters. Comparison of the clinical and bacteriological efficacy of clarithromycin and erythromycin in the treatment of streptococcal pharyngitis. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Comparison of azithromycin and erythromycin in the treatment of atypical pneumonias. Simplified treatment of acute lower respiratory tract infection with azithromycin: a comparison with erythromycin and amoxicillin. Clarithromycin in the treatment of community-acquired lower respiratory tract infections. Three-day azithromycin compared with ten-day roxithromycin treatment of atypical pneumonia. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. Fluoroquinolone resistance: overuse of fluoroquinolones in human and veterinary medicine can breed resistance. Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections. Antacid interaction with new quinolones: dose regimen recommendations based on pharmacokinetic modeling of clinical data for ciprofloxacin, gatifloxacin and norfloxacin and metal cations. Gatifloxacin, gemifloxacin, and moxifloxacin: the role of 3 newer fluoroquinolones. In vitro activity of levofloxacin against contemporary clinical isolates of Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae from North America and Europe. Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers. Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers. Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects. Levofloxacin penetration into epithelial lining fluid as determined by population pharmacokinetic modeling and Monte Carlo simulation. Efficacy of 750-mg, 5-day levofloxacin in the treatment of community-acquired pneumonia caused by atypical pathogens. Comparison of the adverse event profiles of levofloxacin 500 mg and 750 mg in clinical trials for the treatment of respiratory infections. Evidence of tendinitis provoked by fluoroquinolone treatment: a case-control study. A review of new fluoroquinolones: focus on their use in respiratory tract infections. Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12-8039), a new enantiomerically pure 8-methoxy quinolone. Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Safety profile of oral and intravenous moxifloxacin: cumulative data from clinical trials and postmarketing studies. Epidemiology and predictors of multidrug-resistant community-acquired and healthcare-associated pneumonia. The impact of multidrug resistance on the outcomes of critically ill patients with Gram-negative bacterial pneumonia. Epidemiology of methicillin-resistant Staphylococcus aureus pneumonia in community hospitals. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Vancomycin pharmacokinetics, renal handling, and nonrenal clearances in normal human subjects. Plasma and intrapulmonary concentrations of oritavancin and vancomycin in normal healthy adults. Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. Pharmacokinetics, metabolism and excretion of linezolid following an oral dose of [14C]linezolid to healthy human subjects. Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency. Linezolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. Current and future treatment options for infections caused by multidrug-resistant Gram-negative pathogens. Prolonged use of carbapenems and colistin predisposes to ventilator-associated pneumonia by pandrug-resistant Pseudomonas aeruginosa. Penetration of gentamicin into the alveolar lining fluid of critically ill patients with ventilator-associated pneumonia. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Activity of ceftaroline and comparator agents tested against contemporary Gram-positive and -negative (2011) isolates collected in Europe, Turkey, and Israel. Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more -lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skinstructure infections in patients with normal and impaired renal function. A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation.

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These receptors are membranespanning and thus either survey the extracellular space or the lumen of intracellular vesicles infections after surgery floxin 400 mg amex, including endosomes and lysosomes infection low temperature 200mg floxin with mastercard. In an ex vivo model of human atheroma based on the short-term culture of live cells from surgical carotid endarterectomies antibiotic 825 order floxin 400 mg online, comprising a mixed population representing the major cell types resident in human atherosclerotic plaques antibiotic resistance of helicobacter pylori in u.s. veterans discount floxin 200 mg fast delivery. The identity of hyperlipidaemia-derived endogenous ligands in human pathology is unknown but some hints as to their nature have been recently generated antibiotics alcohol buy floxin 200mg online. Pattern recognition is often achieved via signalling complexes rather than single receptors in isolation antibiotic 141 klx discount 400 mg floxin mastercard. Intravenous administration of Poly(I:C) can augment endothelial dysfunction and impair rendothelialization (71). Finally, increased lesion development in high-fat fed ApoE-/- mice was observed after Poly(I:C) stimulation (71). These mice displayed increased lesion development and increased macrophages and lipids, with reduced smooth muscle cell content within the lesions. Caspase-1 mediates the cleavage of the pro-form of these cytokines into mature forms, which results in the secretion of bioactive cytokines. This leads to the induction of chemokines, cytokines, and defensins, which mediate the antimicrobial responses (for a review see (82)). Usually thought to be a rather late occurrence in the disease, their identification in murine lesions has been more elusive. Small cholesterol Bioactive lipids and atherosclerosis Bioactive lipids are produced from fatty acids, mainly from pre-existing membrane phospholipids, through specific biosynthetic pathways in response to extracellular stimuli. Their action is spatially restricted, because they are rapidly sequestered by dedicated processes on local cells. A growing body of evidence links the action of several such lipid mediators in atherosclerosis. The local generation of bioactive lipids is prompted by the dense clustering of different cell types in atherosclerotic plaques, which presents a unique situation for lipid handling. Similar to their protein counterparts, bioactive lipids are also a means of cross-talk between cells of different origin at the blood/vessel interface. In particular, the production of bioactive lipids is orchestrated by enzyme pathways that involve multiple cells (transcellular biosynthesis). Unlike proteins, the information of bioactive lipids acting in the atherosclerotic plaque cannot be obtained from the genome since they are not genome-encoded. However, we can manipulate the genes encoding the set of enzymes and receptors that are essential for their actions. Most of the bioactive lipids involved in atherosclerosis derive from the hydrolysis of the phospholipids from cellular membranes and lipoproteins, but some (resolvins) are synthetized from dietary -3 fatty acids. This in turn favours foam-cell formation by promoting lipoprotein oxidation and internalization by tissue macrophages and stromal cells. Similarly, the eicosanoids generated from the oxidation of arachidonic acid, a free fatty acid produced by the hydrolysis of phospholipids, act as signalling lipids by binding to specific cell surface receptors on various cell types. On the other hand, experimental studies show that S1P can have both pro- and anti-atherosclerotic effects, depending on the targeted cell-specific S1P receptors. Whereas S1P1 agonism reduces atherosclerosis (99), S1P2 and S1P3 receptors appear to have a pro-atherosclerotic role (100, 101). Biaoctive lipids deriving from arachidonic acid Arachidonic acid is the precursor of potent bioactive lipids comprising the prostaglandins, thromboxanes, leukotrienes, lipoxins, resolvins, and protectins. Two main pathways are involved in the biosynthesis of eicosanoids: the prostaglandins and thromboxanes are synthesized by the cyclic pathway; the leukotrienes by the linear pathway. Interestingly, aspirin-triggered lipoxin are significantly lower in patients with atherosclerosis (110). The role of thromboxane A2, another product of arachidonic acid by the cyclic pathway, is more complex. It is a chemoattractant and a proinflammatory mediator able to trigger the activation of all types of leukocytes and the upregulation of proinflammatory genes in the target cells. However, inhibitors of leukotriene synthesis or of leukotriene receptor in experimental atherosclerosis have generated contradictory results so far (for a review see (108)). Conclusions the induction of signalling in host defence is tightly regulated in physiological conditions to achieve the maximum effect on pathogens with minimal tissue destruction. In chronic inflammatory conditions, including atherosclerosis, the inflammatory processes are chronically engaged, even in the absence of pathogens, either due to persistence of the proinflammatory stimuli (such as modified lipoproteins) or due to the failure of regulatory mechanisms. This chronic activation enhances pathogenic cellular cross-talks, enhancing cell recruitment within the vessel wall, as well as the production of adhesion molecules and proinflammatory mediators such as cytokines and leukotrienes. The activation of inflammatory signalling in the references 209 context of metabolic diseases such as atherosclerosis differs from inflammation induced by canonical pathogen recognition during host defence. This is accomplished by the selective use of specific innate immune receptors and the participation of scavenger receptors, as highlighted in this chapter. The challenge for the future is to devise therapeutics that are able to target atherogenic events leaving the host response unimpaired. Moreover, the most studied pathways in atherogenesis are hyperlipidaemia-dependent, while human disease is multifactorial, posing the challenge of understanding in detail how signalling is initiated and maintained in human disease. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions. Abnormal High-Density Lipoprotein Induces Endothelial Dysfunction via Activation of Toll-like Receptor-2. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function. Modulation of expression of endothelial intercellular adhesion molecule-1, platelet-endothelial cell adhesion molecule-1, and vascular cell 22. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice. Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of toll-like receptor-2. Lipopolysaccharide binding protein binds to triacylated and diacylated lipopeptides and mediates innate immune responses. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha. Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. Sphingosine-1-phosphate receptor-2 function in myeloid cells regulates vascular inflammation and atherosclerosis. Sphingosine-1phosphate receptor 3 promotes recruitment of monocyte/ macrophages in inflammation and atherosclerosis. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Placental Toll-like receptor 3 and Toll-like receptor 7/8 activation contributes to preeclampsia in humans and mice. Toll-like receptor 3 activation during pregnancy elicits preeclampsia-like symptoms in rats. Viral Toll Like Receptor activation of pulmonary vascular smooth muscle cells results in endothelin-1 generation; relevance to pathogenesis of pulmonary arterial hypertension. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Blocking toll-like receptors 7 and 9 reduces postinterventional remodeling via reduced macrophage activation, foam cell formation, and migration. Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques. Critical role of bone marrow apoptosis-associated speck-like protein, an inflammasome adaptor molecule, in neointimal formation after vascular injury in mice. Cyclooxygenases, thromboxane, and atherosclerosis: plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. Resolvin E1 (RvE1) Attenuates Atherosclerotic Plaque Formation in Diet and Inflammation-Induced Atherogenesis. Mason Section introduction Esther Lutgens In the previous sections of this text book, the structure, physiology, and biology of the normal vasculature, as well as the changes that occur during the most prevalent disease of the vasculature, atherosclerosis, have been discussed in detail. However, although the most prevalent, atherosclerosis is not the only disease of the vasculature. This section of the book reports on the other important, prevalent diseases of the vasculature. In Chapter 16, Dr Michel provides us with all the ins and outs on the pathophysiology of aneurysm formation and arterial dissection. Lastly, in Chapter 17, Drs Masson and Tombetti have minutely outlined the different vasculitides and their pathophysiology. This important section of the textbook will provide great knowledge on the other diseases of the vasculature. After reading this section, I hope there will be an increased awareness that the vasculature can be affected by a plethora of diseases, and that recognition and understanding of the pathophysiology of these vascular maladies is of the utmost importance in developing proper treatment regimens for patients suffering from vascular disease. The atrioventricular valves are referred to as the tricuspid and mitral valves, situated between the right atrium and ventricle, and the left atrium and ventricle, respectively. The pulmonary valve ensures the right ventricular outflow, whereas the ejection from the left ventricle into the aorta is maintained through the aortic valve. The aortic valve consists of three leaflets (called cusps), corresponding to the physiological dilatations of the aortic root, which are referred to as the sinuses of Valsalva. The left and right cusps correspond to the aortic departure of the left and right coronary artery, whereas the posterior aortic valve leaflet is referred to as the non-coronary cusp. In addition to this common tricuspid anatomy of the aortic valve, a congenital bicuspid valve is found in approximately 0. The mitral valve is made up of an anterior and a posterior leaflet, the edges of which are attached to the cardiac papillary muscles by thread-like bands called chordae tendineae. Valvular heart disease Valvular heart disease refers to valvular dysfunction due to congenital and/or acquired causes and can be divided into either stenotic or regurgitant lesions. In stenosis, there is a narrowing of the valve opening causing an obstruction of the valvular flow, whereas regurgitation refers to a back-flow through the valve. Valvular regurgitation may occur as a result of either changes to the structure to which the valve leaflets are inserted (secondary or functional regurgitation), or as a result of a malfunctioning of one or more valve leaflets (primary or organic regurgitation). The displacement of part of the valve leaflet below the level of coaptation is a referred to as valve prolapse, and is one cause of, for example, mitral regurgitation. Of note, valve stenosis and regurgitation may co-exist in the same valve and in addition, more than one heart valve may be affected at the same time. This article will specifically address the pathophysiology of aortic stenosis, and also provide a brief outline of the pathogenesis of mitral valve prolapse. A haemodynamically severe aortic stenosis is present when the mean pressure gradient is above 40 mmHg and the maximal velocity is above 4. Top panels show echocardiographic images of a normal aortic valve: (a) short axis, (b) long axis; and of a stenotic valve with calcification and reduced opening (c) short axis, (d) long axis. The pressure difference between the left ventricle and the aorta (the transvalvular gradient) can be calculated using the Bernoulli equation in which the pressure difference equals four times the velocity squared (4*v2). Middle panels show normal (f) and stenotic (g) human aortic valve derived from cardiac surgery (courtesy of Professor Anders Franco-Cereceda, Department of Thoracic Surgery, Karolinska University Hospital).

While antibiotic-modifying enzymes and target modification have been considered the main principles of resistance antibiotic joint spacer floxin 200 mg otc, the role of increased efflux and decreased influx that usually confer lower level resistance may have been underestimated infection control certification 400mg floxin with amex. In particular infection under crown order cheap floxin line, the combination of several resistance mechanisms in a single isolate treatment for sinus infection in child 400mg floxin fast delivery, which seems to occur increasingly frequently antibiotic eye drops for stye buy floxin now, is a challenge antibiotic spacer floxin 200mg free shipping. Antibiotic tolerance due to biofilm formation additionally complicates both diagnostics and treatment. Therefore, these mechanisms of resistance and tolerance are currently being specifically addressed in many major research initiatives. Bacterial yield from quantitative cultures of bronchoalveolar lavage fluid in patients with pneumonia on antimicrobial therapy. High frequency of hotspot mutations in core genes of Escherichia coli due to short-term positive selection. Mutation frequency in antibiotic-resistant and -susceptible isolates of Streptococcus pneumoniae. The diversity of antimicrobial resistance genes among staphylococci of animal origin. Clinically feasible biofilm susceptibility assay for isolates of Pseudomonas aeruginosa from patients with cystic fibrosis. Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. Low prevalence of Chlamydia pneumoniae in adults with community-acquired pneumonia. Coxiella burnetii (Q fever) as a cause of community-acquired pneumonia during the warm season in Germany. 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Macrolide efflux in Streptococcus pneumoniae is mediated by a dual efflux pump (mel and mef) and is erythromycin inducible. Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance. LmrS is a multidrug efflux pump of the major facilitator superfamily from Staphylococcus aureus. Mutational analysis of class A and class B penicillin-binding proteins in Streptococcus gordonii. Vaccine escape recombinants emerge after pneumococcal vaccination in the United States. Genetics of high level penicillin resistance in clinical isolates of Streptococcus pneumoniae. Genetics of resistance to third-generation cephalosporins in clinical isolates of Streptococcus pneumoniae. Molecular basis and phenotype of methicillin resistance in Staphylococcus aureus and insights into new beta-lactams that meet the challenge. Beta-lactam resistance in Staphylococcus aureus: the adaptive resistance of a plastic genome. 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Rapid, adequate and appropriate individualised antibiotic therapy can help improve outcomes in these patients, and in this chapter we discuss how to optimise this treatment. In order to deliver this kind of therapy, rapid and accurate diagnosis of infection and identification of infecting pathogens and their antibiotic susceptibilities is necessary. As the pharmacokinetics of drugs is unpredictable in infected, critically ill patients, routine therapeutic drug monitoring of antibiotics should be considered whenever possible to optimise therapeutic efficacy and reduce risk of toxicity. In order to improve therapeutic efficacy, antibiotics may be given with higher loading doses, in continuous perfusion or by inhalation. Antibiotics in critical care: dosing, therapeutic drug monitoring and continuous infusions. To begin with, we discuss why the critically ill patient is so different from other patients. We then discuss the importance of: 1) rapid diagnosis of infection with rapid identification of causative organisms and their antibiotic susceptibilities, and 2) appropriate and adequate antibiotic therapy. Correspondence: Fabio Silvio Taccone, Erasme Hospital, Route de Lennik 808, 1070 Brussels, Belgium. Early, appropriate and adequate antibiotic therapy is necessary to treat these infections in order to improve outcomes (figure 1). However, a recent meta-analysis has challenged these observations, as no significant mortality benefit was observed when antibiotics were administered within 1 h of shock recognition [15]. Differences in observations may be due to the fact that the authors of the meta-analysis did not evaluate whether patients had received effective or "appropriate" antibiotic therapy. Diagnosing and treating infections in the critically ill patient can nevertheless be very challenging for the clinician. Typical signs of infection are not sensitive, as they may be lacking in the critically ill patient. Schematic representation of the characteristics of antibiotic therapy during critical illness that might increase the likelihood of therapeutic success. Moreover, results from microbiology tests may take several days and may remain negative if the patient has received recent previous antibiotic therapy. Furthermore, the worldwide increase in antimicrobial resistance makes it difficult to administer appropriate and adequate empiric antibiotic therapy. There has been a general and significant increase in the number of pathogens resistant to antibiotics worldwide ever since the utilisation of the first antibiotics (sulfamides) in humans in the early 1900s. Many different classes of antibiotics (with different modes of action) were developed and commercialised from the 1940s until the late 1990s. However, the previously flowing pipeline of new antibiotics has currently floundered to a trickle [23], leaving clinicians with few therapeutic choices for certain infections. To illustrate this phenomenon, we can take a closer look at antibiotic resistance in Europe. For Klebsiella pneumoniae, resistance to fluoroquinolones, third-generation cephalosporins and aminoglycosides, but also combined resistance to all three antibiotic groups, significantly increased from 2006 until 2014. For Escherichia coli, population-weighted (European Union and Economic Area) mean percentage of resistance to third-generation cephalosporins increased from 9. To further complicate matters, the critically ill patient presents many physiological changes responsible for changes in volume of distribution and drug clearance, and thus of their pharmacokinetics (figure 2). The volume of distribution of a drug is the theoretical volume in which the drug distributes. Effects of changes in antibiotic pharmacokinetics during critical illness on drug concentrations. In the case of an increased volume of distribution, the maximum concentration after drug injection will be reduced. Increased cardiac output, interstitial fluid shifts associated with increased capillary leakage, fluid resuscitation, hypoalbuminaemia and drains are responsible for an increased volume of distribution of hydrophilic antibiotics, and thus decreased antibiotic plasma levels (figure 3). The volume of distribution of lipophilic drugs is hardly modified by these physiological changes. Also, as hydrophilic drugs are essentially eliminated by the kidneys, changes in renal function will affect drug clearance; as such, hyperdynamic status and increased renal blood flow could result in lower than expected plasma concentrations than in patients who are not critically ill. Lipophilic drugs are essentially eliminated from the body by hepatic metabolism; drug clearance may be slower when patients present hepatic insufficiency [28]. These potential pharmacokinetics variations in the critically ill patient are highly unpredictable. How to improve empiric antibiotic treatment There are several ways to try to improve empiric antibiotic therapy: 1) the diagnosis of sepsis and its causative pathogens must be done more rapidly, and with more precision, and 2) the spectrum of empiric antibiotic therapy can be broadened by administering combination therapy. Diagnosis the diagnosis of infection and then the administration of the appropriate antibiotic to treat the infection in the critically ill patient rely heavily on results from the microbiology laboratory. It can take several days to obtain positive results as most tests currently depend on culture-based techniques. However, new techniques are being developed to shorten the laboratory turnaround time for providing results. However, these techniques do not differentiate infecting pathogens from colonisation, and they may underdiagnose infections when they are not accompanied by bloodstream infection.