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Mesenchymal stem cells: From bench to bedside  [cached]
Teng Ma
World Journal of Stem Cells , 2010,
Abstract: Human mesenchymal stem cells (hMSCs) have tremendous promise for use in a variety of clinical applications. The ability of these cells to self-renew and differentiate into multiple tissues makes them an attractive cell source for a new generation of cell-based regenerative therapies. Encouraging results from clinical trials have also generated growing enthusiasm regarding MSC therapy and related treatment, but gaps remain in understanding MSC tissue repair mechanisms and in clinical strategies for efficient cell delivery and consistent therapeutic outcomes. For these reasons, discoveries from basic research and their implementation in clinical trials are essential to advance MSC therapy from the laboratory bench to the patient’s bedside.
Sepsis: from bench to bedside
Silva, Eliézer;Passos, Rogério Da Hora;Ferri, Maurício Beller;Figueiredo, Luiz Francisco Poli de;
Clinics , 2008, DOI: 10.1590/S1807-59322008000100019
Abstract: sepsis is a syndrome related to severe infections. it is defined as the systemic host response to microorganisms in previously sterile tissues and is characterized by end-organ dysfunction away from the primary site of infection. the normal host response to infection is complex and aims to identify and control pathogen invasion, as well as to start immediate tissue repair. both the cellular and humoral immune systems are activated, giving rise to both anti-inflammatory and proinflammatory responses. the chain of events that leads to sepsis is derived from the exacerbation of these mechanisms, promoting massive liberation of mediators and the progression of multiple organ dysfunction. despite increasing knowledge about the pathophysiological pathways and processes involved in sepsis, morbidity and mortality remain unacceptably high. a large number of immunomodulatory agents have been studied in experimental and clinical settings in an attempt to find an efficacious anti-inflammatory drug that reduces mortality. even though preclinical results had been promising, the vast majority of these trials actually showed little success in reducing the overwhelmingly high mortality rate of septic shock patients as compared with that of other critically ill intensive care unit patients. clinical management usually begins with prompt recognition, determination of the probable infection site, early administration of antibiotics, and resuscitation protocols based on "early-goal" directed therapy. in this review, we address the research efforts that have been targeting risk factor identification, including genetics, pathophysiological mechanisms and strategies to recognize and treat these patients as early as possible.
Mechanisms of Inflammation in Proliferative Vitreoretinopathy: From Bench to Bedside  [PDF]
Stavros N. Moysidis,Aristomenis Thanos,Demetrios G. Vavvas
Mediators of Inflammation , 2012, DOI: 10.1155/2012/815937
Abstract: Proliferative vitreoretinopathy (PVR) is a vision-threatening disease and a common complication of surgery to correct rhegmatogenous retinal detachment (RRD). Several models of the pathogenesis of this disease have been described with some of these models focusing on the role of inflammatory cells and other models focusing on the role of growth factors and cytokines in the vitreous which come into contact with intraretinal and retinal pigment epithelial cells. New experiments have shed light on the pathogenesis of PVR and offer promising avenues for clinical intervention before PVR develops. One such target is the indirect pathway of activation of platelet-derived growth factor receptor alpha (PDGRα), which plays an important role in PVR. Clinical trials assessing the efficacy of 5-fluorouracil (5-FU) and low-molecular-weight heparin (LMWH), daunorubicin, and 13-cis-retinoic acid, among other therapies, have yielded mixed results. Here we review inflammatory and other mechanisms involved in the pathogenesis of PVR, we highlight important clinical trials, and we discuss how findings at the bench have the potential to be translated to the bedside. 1. Introduction Proliferative vitreoretinopathy (PVR) is a vision-threatening disease that can occur secondary to retinal detachment (RD). RD allows macrophages, retinal pigment epithelial (RPE) cells, glial cells, and fibroblasts to migrate to the vitreous, where they proliferate, survive, form extracellular matrix proteins and assemble into a membrane [1]. This membrane can attach to the retina and subsequently contract, which can cause a new retinal detachment or failure of a surgically corrected detachment [2]. PVR occurs most commonly as a complication of surgery to correct rhegmatogenous retinal detachment (RRD) and is the most common reason for the failure of this operation [3, 4]. In one study of 119 patients with RRD and no previous vitreoretinal surgery, there was a 52.9% prevalence of PVR and 26.9% prevalence of severe PVR with mean retinal detachment duration of days [5]. Visual outcomes and the anatomical success of surgery are worse for RD that is complicated by PVR and may require twice as many resources to care for as those cases of RD without PVR [6]. Here we review inflammatory and other mechanisms involved in the pathogenesis of PVR, we highlight important clinical trials, and we discuss how findings at the bench have the potential to be translated to the bedside. 2. The Macrophage Hypothesis for Development of PVR Some of the hypotheses regarding the pathogenesis of PVR have focused on the
Bench-to-bedside review: Significance and interpretation of elevated troponin in septic patients
Raphael Favory, Remi Neviere
Critical Care , 2006, DOI: 10.1186/cc4991
Abstract: In 2000, the Joint European Society of Cardiology/American College of Cardiology Committee proposed a new definition of myocardial infarction based predominantly on the detection of the cardiospecific biomarkers troponin T and troponin I in the appropriate clinical setting [1]. Given that cardiac troponin is highly sensitive for detecting even minimal myocardial-cell necrosis, these markers may become 'positive' even in the absence of thrombotic acute coronary syndromes [2]. This may occasionally be related to a spurious troponin elevation but may also be due to several non-thrombotic cardiac and systemic diseases [2-4]. Sepsis and other systemic inflammatory processes may lead to myocardial depression and cellular injury, greatly increased oxygen consumption, reduced microvascular circulation, and decreased oxygen delivery to the heart, ultimately resulting in the release of troponin into the systemic circulation [5]. The aim of this review is to go from bench to bedside to determine what evidence and interests are able to incite intensivists to evaluate the cardiac troponin plasma marker in the context of sepsis.Abnormalities of cardiac function are frequent in patients with sepsis. Approximately 50% of patients with severe sepsis and septic shock may develop impairment of ventricular performance. Whereas evaluation of myocardial performance during septic shock is of critical importance to select the best therapeutic options, several factors complicate the diagnosis of sepsis-induced myocardial dysfunction in humans. Making accurate measurements of cardiac function is difficult and this is confounded by the inherent difficulty of excluding patients with true coronary insufficiency with sepsis. The available evaluation methods have their strengths and limitations, leading to an absence of consensus regarding the gold standard technique to assess cardiac function. In addition, most of the contractility indexes are affected by peripheral vasodilatation and changes in
Telomerase immunity from bench to bedside: round one
Xochtil Cortez-Gonzalez, Maurizio Zanetti
Journal of Translational Medicine , 2007, DOI: 10.1186/1479-5876-5-12
Abstract: Active immunization (vaccination) offers the greatest advantages to prevent or control disease. Applied to the control of cancer, this concept is referred to as therapeutic vaccination. In the past decade great effort was placed exerted to identify tumor associated and tumor specific antigens [1,2] and to develop efficient methods to vaccinate cancer patients [3-6]. By and large, efforts have been directed at inducing T cell mediated responses, and particularly major histocompatibility complex (MHC) Class I-restricted cytotoxic CD8 T lymphocytes. Tumor associated antigens can be clustered in major categories. Traditionally, they were regarded as onco-developmental antigens mainly carbohydrate in nature [7]. Subsequently, new families of antigens were identified. These include tissues specific antigens, i.e., antigens found principally in one type of tumor cells, e.g., melanoma cells, prostate cancer cells, pancreatic tumor cells etc. A second group of is antigens is shared by a variety of tumors such as certain oncogenes (e.g., p53 NY-ESO1, MUC.1, and Her2-neu). These shared antigens cover a larger segment of the tumor population. A third family comprises antigens that are common to most or all tumor cells irrespective of their origin and histological type. These are molecules intimately associated with cellular processes common to all tumor cells such as immortalization or survival. Finally, there are viral antigens in tumor cells that viral antigens in those cases where a viral pathogenesis is at play (e.g., HPV, HBV and EBV).In this review article we will recapitulate the history of one such effort as it relates to the discovery and immunological characterization of the first bona fide common tumor antigen, telomerase reverse transcriptase [8]. More importantly, the emphasis will be to demonstrate in how little time a handful of laboratories around the world interested in this new antigen converted their bench studies into bedside therapeutic vaccination interven
Bench to bedside: A role for erythropoietin in sepsis
Andrew P Walden, J Duncan Young, Edward Sharples
Critical Care , 2010, DOI: 10.1186/cc9049
Abstract: Sepsis is the systemic inflammatory response to infection. The clinical syndrome can range from mild constitutional upset to overt septic shock with the failure of multiple organ systems, reflecting the complex pathogenesis of sepsis involving immunological and coagulation pathways [1,2]. The burden from sepsis remains high with worldwide incidence ranging from 0.5 to 1.5 per 1,000 population, a mortality rate at 1 month of 30% from recent randomised trials, and costs of between $11,500 and $22,000 per hospital episode [3,4]. The modulation of single inflammatory pathways (for example, TNFα [5]) and generalised immune suppression with steroids [6,7] has proved unsuccessful in the past, reflecting the complex pathogenesis of sepsis and leading to a reevaluation of the mechanisms that may underlie it. Several laboratory and observational studies have shown that accelerated apoptosis occurs in sepsis and may explain both the organ failure that is a feature of it and secondary infections that can intervene [8-10].The haematopoietic growth factor erythropoietin (EPO) reduces apoptotic cell death and attenuates inflammation, with cytoprotective effects in both animal and human models of ischaemic injury. EPO also has putative vasopressor actions. A complete summary of the extra-haemopoietic effects of EPO in specific organs is beyond the scope of the present discussion so readers are referred to reviews [11-13]. The present communication seeks to explain the role of apoptosis in sepsis and to summarise the available data on EPO and its extra-haemopoietic effects in sepsis and critical illness.Apoptosis is programmed cell death, distinct from necrosis, limiting damage around the penumbra of an injury. This process is important in the homeostasis of the inflammatory response, and delayed neutrophil apoptosis has been implicated in mediating tissue damage in acute respiratory distress syndrome and systemic inflammatory response syndrome [14-16]. That said, accelerated apopto
Coagulation cascade in sepsis: getting from bench to bedside?
Glen Brown
Critical Care , 2002, DOI: 10.1186/cc1842
Abstract: The relationship between the clotting cascade and the promotion or inhibition of the anti-inflammatory response continues to be defined through basic research. The potential key role of proteins that were originally believed to be exclusively involved in coagulation in the inflammatory response provides an exciting potential mechanism(s) for modification through the application of new therapies. The accompanying review by Riewald and Ruf [1] outlines the available information on the possible steps involving some of the various proteins that are common to both coagulation and inflammation. The complexity of the multiple actions of the proteins in both inflammation and coagulation should excite the clinician with regard to potential new therapies that may be beneficial via activation of one or both of the concurrent pathways [2]. However, before clinicians can administer new therapies that utilize new knowledge on the actions of coagulation cascade components, and hence improve the outcomes of their patients, several gaps in our current understanding must be addressed. This information is imperative if the clinician is to take basic knowledge 'to the bedside', where individual patients can benefit.Administration of intrinsic or synthetic analogues of coagulation cascade components (e.g. protein C, thrombin, and factor VIIa or Xa), coagulation inhibitors (e.g. heparin or analogues), or agonists or antagonists of the protease-activated receptors, in an attempt to alter the individual patient's coagulation/inflammation balance, could theoretically produce responses ranging from beneficial to detrimental. Knowledge of the 'most beneficial' balance between augmenting or inhibiting the contribution of the clotting cascade components to inflammation would be required for determining the selection and dosing of potential new therapies.A safe assumption is that any new therapies that alter the intrinsic response to coagulation and inflammatory stimulants would also potentially
Molecular engineering of an orthopaedic implant: from bench to bedside  [PDF]
IM Shapiro,NJ Hickok,J Parvizi,S Stewart
European Cells and Materials (ECM) , 2012,
Abstract: The use of metallic implants has revolutionised the practice of orthopaedic surgery. While the safety and biocompatibility of these devices are excellent, a small percentage becomes infected. These infections are due to the formation of a biofilm that harbours bacteria encased in a complex extracellular matrix. The matrix serves as a barrier to immune surveillance as well as limiting the biocidal effects of systemic and local antibiotics. The objective of the review is to describe a novel approach to controlling implant infection using an antibiotic that is linked to titanium through a self-assembled monolayer of siloxy amines. We show that the hybrid-engineered surface is stable, biocompatible and resists colonisation by bacterial species most commonly associated with implant-related infections. Studies with rodent bone infection models suggest that the engineered titanium surface prevents bone infection. Results of a very recent investigation utilising a sheep model of infection indicate that the titanium-tethered antibiotic controls infection without compromising bone formation and remodelling. From all of these perspectives, the tethered antibiotic holds promise of providing a novel and practical approach to reducing implant-associated infections.
CXCR2: From Bench to Bedside  [PDF]
Anika Stadtmann,Alexander Zarbock
Frontiers in Immunology , 2012, DOI: 10.3389/fimmu.2012.00263
Abstract: Leukocyte recruitment to sites of infection or tissue damage plays a crucial role for the innate immune response. Chemokine-dependent signaling in immune cells is a very important mechanism leading to integrin activation and leukocyte recruitment. CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils. During the last years, several studies were performed investigating the role of CXCR2 in different diseases. Until now, many CXCR2 inhibitors are tested in animal models and clinical trials and promising results were obtained. This review gives an overview of the structure of CXCR2 and the signaling pathways that are activated following CXCR2 stimulation. We discuss in detail the role of this chemokine receptor in different disease models including acute lung injury, COPD, sepsis, and ischemia-reperfusion-injury. Furthermore, this review summarizes the results of clinical trials which used CXCR2 inhibitors.
From bench to bedside: bacterial growth and cytokines
Claudia C dos Santos, Haibo Zhang, Arthur S Slutsky
Critical Care , 2002, DOI: 10.1186/cc1443
Abstract: On page 24 of this issue of Critical Care, Meduri introduces a new layer of complexity to our understanding of the inflammatory response in acute respiratory distress syndrome (ARDS). He postulates that cytokines secreted by the host during ARDS may favor the growth of some strains of bacteria and consequently explain the association between exaggerated and protracted systemic inflammation and the development of nosocomial infections [1]. Evidence for this novel theory comes from in vitro studies evaluating the extracellular and intracellular responses of clinically relevant bacterial species to graded concentrations of pro-inflammatory cytokines [2]. These studies demonstrate a U-shaped bacterial growth response curve. Bacterial growth was enhanced at both extremes of this curve, suggesting that insufficient or dysregulated inflammation may play an active role in stimulating bacterial growth and/or impairment of bacterial clearance, with the subsequent development of nosocomial infections. This new finding has important implications for our understanding and management of patients with ARDS.Over the past two decades, the recognition that neutrophils, macrophages, and other components of the inflammatory cascade participate in the generation and progression of acute lung injury (ALI) and ARDS has resulted in the use of anti-inflammatory agents as pharmacological probes to define this syndrome. Furthermore, preclinical models of endotoxin-induced sepsis demonstrated a survival benefit if pro-inflammatory cytokines were neutralized [3], leading to a number of studies in which this therapy was used in patients with ARDS. The U-shaped bacterial growth curve may be a partial explanation for the lack of efficacy of these trials as decreasing cytokine activity may be beneficial, or may be harmful, depending on the specific location on the dose response curve.For an effective host response to be mounted against infection, the cellular components of the innate and acquired i
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