The podocyte: from bench to bedside

The understanding of the molecular structure of the podocyte has increased considerabely in recent 5 years by genetic research in inherited glomerulopathies. Injury to the podocyte often leads to a reorganisation of the slit diaphragm and to foot process effacement, which can be noted in all forms of the nephrotic syndrome. Since the recent progress in our understanding of the molecular biology of the podocyte, it has become obvious that the podocyte is crucial in the pathogenesis of not only genetic but also of many acquired glomerulopathies such as focal segmental glomerulosclerosis, membranous glomerulopathy and diabetic nephropathy. In this review we provide a summary of the recent physiological and molecular insights into the podocyte and of its significance in different glomerulopathies.     

Interleukin 6: from bench to bedside

Interleukin (IL)-6 is a pleiotropic cytokine that has important roles in the regulation of the immune response, inflammation, and hematopoiesis. Disruption of IL-6 regulation might, however, affect the immune response and consequently induce immune-mediated inflammatory diseases such as rheumatoid arthritis, systemic juvenile idiopathic arthritis, Castleman disease, and Crohn's disease. Overproduction of IL-6 also contributes, through its roles as a growth factor or an antiapoptotic factor, to the development of malignant diseases such as multiple myeloma and renal cancer. Progress in the study of IL-6 has increased our understanding of the pathological roles of this cytokine in these diseases and provided key evidence that antagonizing its activities can be used as a therapeutic strategy. The application of molecular biology techniques to design monoclonal antibodies as therapeutic agents has made it possible to regulate the IL-6 signal to successfully treat diseases that have so far proved refractory to conventional therapies. Blocking IL-6 actions by use of a humanized antibody, tocilizumab, which targets the IL-6 receptor, has been proven to be therapeutically effective for rheumatoid arthritis, systemic juvenile idiopathic arthritis, Castleman disease and Crohn's disease. In this review, we discuss a paradigm of IL-6 from basic science to clinical use.     

Hepatic fibrosis: from bench to bedside

Antifibrotic therapies are preferentially targeted to the activated mesenchymal cells in the liver that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent hepatic stellate cells and (myo-) fibroblasts. Their activation is triggered and maintained by several fibrogenic modulators and cytokines, but also by mechanical stress. Whereas many agents inhibit stellate cell/myofibroblast proliferation and collagen synthesis in vitro, only few of them are tolerable or effective in suitable animal models in vivo. An antifibrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, sho-saiko-to which contains the related compound baicalein, for halofuginone, another plant-derived agent, for the phosphodiesterase inhibitor pentoxifylline and for LU135252, an oral inhibitor of the endothelin-A-receptor. The retrospective finding that interferon-alpha therapy for hepatitis C may halt or even reverse fibrosis, has to be confirmed in prospective randomized trials. Strategies to inhibit the profibrogenic cytokines transforming growth factor (TGF)-beta or connective tissue growth factor (e.g. by soluble decoy receptors) are evolving, but have not been convincing yet. Drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically up-regulated on activated stellate cells, for example those for platelet-derived growth factors or collagen type VI. In addition, blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a fibrolytic, collagen degrading phenotype. Combined with the evolving validation of serological markers of fibrogenesis and fibrolysis an effective and individualized treatment of liver fibrosis can be anticipated.     

Primary aldosteronism: from bench to bedside

Primary aldosteronism is now thought to be the commonest potentially curable and specifically treatable form of hypertension. The detection of primary aldosteronism is of utmost importance not only because it provides an opportunity for a targeted treatment, but also because it has been demonstrated that patients with primary aldosteronism are more prone to cardiovascular events and target organ damage than essential hypertensives. Normalization of blood pressure and hypokalemia should not be the only goal of treatment. Normalization of circulating aldosterone or mineralocorticoid blockade is necessary to prevent aldosterone-induced tissue damage that occurs independent of blood pressure. This review will focus on the current understanding and comprehensive management review of primary aldosteronism, highlighting the new evidence that has become recently available.     

Intravascular elastography: from bench to bedside

An unstable lesion may rupture and cause an acute thrombotic reaction. These lesions contain a large lipid pool covered by a thin fibrous cap. The stress in the cap increased with decreasing thickness and increasing macrophage infiltration. Intravascular ultrasound (IVUS) elastography might be an ideal technique to assess the presence of lipid pools and identify high stress regions. Elastography assesses the local mechanical properties of tissue using its deformation caused by the intraluminal pressure. The technique was validated in vitro using diseased human coronary and femoral arteries. These experiments demonstrated that the strain in the three plaque types is different (P < 0.001). Especially between fibrous and fatty tissue, a highly significant difference (P = 0.0012) was found. Additionally, the predictive value for identifying the vulnerable plaque was investigated. A high strain region at the lumen vessel wall boundary has 88% sensitivity and 89% specificity for identifying these plaques. In vivo, the technique is validated in an atherosclerotic Yucatan mini-pig animal model. This study also revealed higher strain values in fatty than fibrous plaques (P < 0.001). The presence of a high strain region at the lumen plaque interface has a high predictive value for identifying macrophages. Patient studies revealed high strain values (1-2%) in soft plaques. Calcified material shows low strain values (0-0.2%). With the development of three-dimensional elastography, identification of weak spots over the full length of a coronary artery becomes possible. In conclusion, intravascular elastography is a unique tool to assess lesion composition and vulnerability. The development of three-dimensional elastography provides a technique that may develop into a clinical available tool for identifying the rupture-prone plaque.     

HIV-associated immune activation: from bench to bedside

HIV infection is associated with a state of chronic, generalized immune activation that has been shown in many studies to be a key predictor of progression to AIDS. Consistent with this model, nonpathogenic SIV infections of natural hosts, such as the sooty mangabeys, are characterized by low levels of immune activation during the chronic phase of infection. The molecular, cellular, and pathophysiological mechanisms underlying the HIV-associated immune activation are complex and still poorly understood. There is, however, growing consensus that both viral and host factors contribute to this phenotype, with emphasis on the role played by the mucosal immune dysfunction (and consequent microbial translocation) as well as the pattern of in vivo-infected CD4(+) T cells. The observation that antiretroviral therapy (ART)-induced suppression of HIV replication does not fully resolve immune activation provided the rationale for a number of exploratory studies of potential immune modulatory treatments to be used in HIV-infected individuals in addition to standard ART. This review provides an update on the causes and consequences of the HIV-associated immune activation, and a summary of the immune modulatory approaches that are currently under clinical investigation.     

Heme oxygenase-1: from bench to bedside

As aspects of basic science come to play an increasingly prominent role in clinical medicine, heme oxygenase-1 is one of several molecules emerging as a central player in diseases of the lung and intensive care unit. Although the apparent raison d'être of this enzyme is to dispose of heme, its activity results in cytoprotection against oxidative injury and cellular stresses. As the lung interfaces directly with an oxidizing environment, it is expected that heme oxygenase-1 would be involved in many aspects of lung health and disease. The protective effects of heme oxygenase-1 and products of its enzymatic activity, including carbon monoxide, biliverdin and bilirubin, and ferritin, have opened the door to potential therapeutic and disease-monitoring possibilities that one day may be applicable to pulmonary medicine. This article introduces readers to the history of heme oxygenase research, the role of this enzyme in the lung, and related new developments to look forward to in the fields of pulmonary and critical care medicine.     

Heart rate variability: from bench to bedside

Power spectrum analysis of cardiovascular signal variability, and in particular of the RR period (heart rate variability, HRV), is a widely used methodology for investigating autonomic neural regulation in health and disease that can quantify the sympathovagal balance modulating the sinus node pacemaker. In some cases, it can also quantify the neural regulation of other organs or apparatuses. However, use of the correct methodology is crucial to extract the information embedded in the frequency domain. In numerous abnormal conditions, such as essential arterial hypertension, acute myocardial infarction and heart failure, the sympathovagal balance may be altered in basal conditions. However, a reduced responsiveness to an excitatory stimulus is the most common feature that characterizes numerous pathophysiological states. The attenuation of an oscillatory pattern can also reflect an altered target function, thus providing important prognostic markers. The general features of this approach correspond well to the needs of an internist attempting to envisage the involvement of the whole organism in a disease process.     

缺血再灌注损伤的防治——从实验室到临床

缺血性心、脑及外周血管疾病是严重危害人类健康的常见病,预计2020年冠心病将成为世界范围内的头号死亡原因。医学界一直在探索有效的保护缺血组织的方法,缩短组织缺血时间、尽早恢复血流是防治缺血损伤最有效的措施。溶栓、经皮穿刺冠状动脉腔内血管成型术（PTCA）和冠状动脉旁路移植术（CABG）等再灌注疗法通过恢复缺血组织的供血有效地挽救缺血组织,是治疗心肌缺血和梗死的最主要措施。但是再灌注疗法受缺血组织血管再通时间的限制并存在再灌注损伤等问题,因此,随着新的再灌注技术的长足进展,防治再灌注损伤成为了冠心病治疗亟待解决的关键问题之一。血运重建应用于临床30多年来,针对再灌注期心脏保护的研究取得了令人鼓舞的成果,但距临床应用仍有一定的距离,今后应当注重缺血心脏保护的实验研究向临床应用研究的转换和过渡。     

Myocardial fibrosis: biomedical research from bench to bedside

Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways. The European Commission funded the FIBROTARGETS consortium as a multinational academic and industrial consortium with the primary aim of performing a systematic and collaborative search of targets of myocardial fibrosis, and then translating these mechanisms into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. This review focuses on those methodological and technological aspects considered and developed by the consortium to facilitate the transfer of the new mechanistic knowledge on myocardial fibrosis into potential biomedical applications.     

GLP-1 and cardioprotection: from bench to bedside

During myocardial infarction (MI), a variety of mechanisms contribute to the activation of cell death processes in cardiomyocytes, determining the final MI size, subsequent mortality, and post-MI remodelling. The deleterious mechanisms accompanying the ischaemic and reperfusion phases in MI include deprivation of oxygen, nutrients, and survival factors, accumulation of waste products, generation of oxygen free radicals, calcium overload, neutrophil infiltration of the ischaemic area, depletion of energy stores, and opening of the mitochondrial permeability transition pore, all of which contribute to the activation of apoptosis and necrosis in cardiomyocytes. During the last few years, glucagon-like peptide-1 (GLP-1) (7-36)-based therapeutic strategies have been incorporated into the treatment of patients with type 2 diabetes mellitus. Cytoprotection is among the pleiotropic actions described for GLP-1 in different cell types, including cardiomyocytes. This paper reviews the most relevant experimental and clinical studies that have contributed to a better understanding of the molecular mechanisms and intracellular pathways involved in the cardioprotection induced by GLP-1, analysing in depth its potential role as a therapeutic target in the ischaemic and reperfused myocardium as well as in other pathologies that are associated with myocardial remodelling and heart failure.     

Airway remodeling from bench to bedside: current perspectives

Bronchospasm and airway inflammation can lead to a constellation of irreversible changes in airway structure termed remodeling. Remodeling theory offers insight into the permanent biomechanical and pathologic alterations of asthmatic airways. Structural changes seen in asthmatic patients can include thickening of the airway wall reticular basement membrane (RBM), the presence of an abnormal elastic fiber network, and alterations in airway cartilage structure. Although steroid therapy is helpful in symptomatic control, it does not remedy structural alterations or many aspects of the inflammatory milieu. This article discusses several studies and supports the need for further investigation.     

The novel antioxidant edaravone: from bench to bedside

Over the last decade, important advances have been made to support the fact that reactive oxygen species (ROS) are generated and play a harmful role during the acute and late stages of cerebral ischemia. Several drugs, such as radical scavengers and antioxidants, have been evaluated in preclinical and clinical studies. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut, Mitsubishi Tanabe Pharma Corporation) is a novel antioxidant that is currently used in Japan for the treatment of patients in the acute stage of cerebral infarction. Edaravone scavenges ROS and inhibits proinflammatory responses after brain ischemia in animals and humans. In particular, postischemic inflammation, leading to brain edema and infarction due to neuronal damage and endothelial cell death, can be ameliorated by edaravone. In addition to these antistroke effects, edaravone has also been shown to prevent oxidative damage to various extracerebral organs. Therefore, in addition to its usefulness in the treatment of stroke, edaravone is expected to play an integral role in the treatment of many oxidative stress-related diseases.