Sepsis: from bench to bedside

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.     

微型膜式氧合器在大鼠体外循环中的应用

目的建立大鼠体外循环（cardiopulmonary bypass，CPB动物模型）。方法选用雄性SD大鼠，经右颈静脉、股静脉插管引流，股动脉插管灌注建立CPB。CPB使用微型膜式氧合器，运转1h，期间监测血流动力学指标、心电图、血气及电解质的变化。结果8只大鼠CPB中血流动力学稳定，血气结果满意，完全符合满意CPB标准，停机后心血管和呼吸功能恢复。结论利用微型动物膜式氧合器建立的大鼠CPB模型，具有安全、稳定、简单、实用的特点，是进行与CPB相关脏器损伤研究可靠的实验平台。     

Refractory celiac disease: from bench to bedside

Refractory celiac disease is defined by the persistence of symptoms of malnutrition and intestinal villous atrophy for more than 6-12?months despite strict gluten-free diet in celiac patients. Diagnosis of this rare condition is made after excluding other causes of chronic small intestinal inflammation and villous atrophy and inadvertent intake of gluten. Over the past 15?years, multidisciplinary approaches have been developed to assess the mechanism of resistance to the diet, and two distinct entities have been delineated. Type II refractory celiac disease (RCD) can be defined as a low-grade intraepithelial lymphoma. RCD II is characterised by a massive accumulation of abnormal IEL that display an aberrant hybrid NK/T cell phenotype, contain clonal T cell rearrangement(s) and can mediate a cytolytic attack of the gut epithelium. This condition has a severe prognosis, largely due to the frequent transformation of RCDII IEL into overt aggressive enteropathy-type-associated T cell lymphoma. In contrast, in type I RCD, intestinal lymphocytes have a normal phenotype, and this generally milder condition remains often difficult to differentiate from uncomplicated CD except for the resistance to gluten-free diet (GFD). Several mechanisms may underlie resistance to gluten. Herein, we review the distinctive characteristics of RCD I and RCD II, the mechanisms underlying the onset of resistance to GFD, the risk of developing high grade lymphoma and possible clues to improve their treatment.     

Heat shock protein vaccines: from bench to bedside

Heat shock proteins (HSPs) are immunogenic, with the specificity of the immune response provided by the peptides that they chaperone. Binding of cell surface receptors by HSPs is central to the elicitation of the innate and adaptive immune responses obtained after vaccination and also plays a physiologic role in cross-priming. These effects of HSPs have been exploited in prophylaxis and therapy of cancer and infectious disease. The data obtained from murine studies have been translated into ongoing clinical trials of cancer of which the most recent results are provided here.     

Rheumatoid arthritis therapy: Advances from bench to bedside

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with significant functional disability and morbidity. Treatment with conventional disease-modifying anti-rheumatic drugs has substantial limitations including partial efficacy and poor tolerability. Advances in our understanding of the pathogenesis of RA over the past decade have fostered development of targeted therapies and greatly expanded the available treatment options. Several of the therapeutic targets identified by recent studies have been translated into effective therapeutic agents, and many additional agents are currently under active development. In this article, we review the biologic agents that have made successful transitions from bench to bedside as well as the biologic and small molecule agents that are at various stages of development in human trials.     

Rapamycine and mTOR inhibitors: from bench to bedside

Rapamycin is a macrocyclic lactone with antifungal and antibiotic properties isolated from Streptomyces hygroscopicus during the 70's. Studies of rapamycin properties in yeast led to the discovery of TOR (Target Of Rapamycin) and its mammalian analogue, mTOR. mTOR is a central regulator of cell growth and proliferation in response to environmental stimuli such as growth factors or nutrients. There are two proteins that have been shown to be regulated by mTOR in response to a broad range of mitogenic stimuli. The translation regulation induced by mTOR is mediated by the p70 S6 kinase activation and the 4E-BP1 inhibition. Both proteins participate in the regulation of translation process and growth in cells stimulated by either mitogens or hormones. Antiproliferative effects of rapamycin and analogues have been demonstrated on numerous cell types, explaining the development of these drugs in clinical practice: as immunosuppressive drugs in solid organ transplantation, in oncology for the treatment of various types of cancer, and for the prevention of restenosis after coronary angioplasty. Rapamycin is a potent immunosuppressive drug used in solid organ transplantation for the prevention of acute rejection. In oncology these antiproliferative effects are evaluated in several types of cancers. Rapamycin is now widely used for coating stents to reduce post-stenting restenosis phenomenon after coronary angioplasty. Finally, rapamycin is now evaluated in various diseases characterized by proliferative disorders.     

From bench to bedside: a diagnostics framework for pharmacogenetics research

Although many genetic variants have been associated with differential drug responses, a very limited number of pharmacogenetic tests have entered common clinical practice. Pharmacogenetic tests that are successful address unmet medical needs, are clinically relevant, and have sufficient sensitivity, and specificity. In this respect, pharmacogenetics is no different from other diagnostics fields. Unmet medical need, clinical relevance, sensitivity, and specificity are discussed in the context of specific pharmacogenetic associations. These parameters are useful guides for researchers interested in translating pharmacogenetic findings from the bench to the bedside.     

Exhaled nitric oxide in asthma: from bench to bedside

With more than 600 publications, exhaled nitric oxide (NO) has been extensively investigated as a noninvasive marker of airway inflammation in a research setting. This clinical rostrum presents a synopsis of the latest research about this novel marker in asthma and suggests how it might move from bench to bedside. Specifically, we review the evidence citing the applicability of exhaled NO in diagnosing asthma, monitoring the response to therapy, evaluating current symptom control, and predicting exacerbations of asthma. These studies support a role for exhaled NO in the evaluation and treatment of asthma in the clinical arena.     

Optical coherence tomography: a review of clinical development from bench to bedside

Since its introduction, optical coherence tomography (OCT) technology has advanced from the laboratory bench to the clinic and back again. Arising from the fields of low coherence interferometry and optical time- and frequency-domain reflectometry, OCT was initially demonstrated for retinal imaging and followed a unique path to commercialization for clinical use. Concurrently, significant technological advances were brought about from within the research community, including improved laser sources, beam delivery instruments, and detection schemes. While many of these technologies improved retinal imaging, they also allowed for the application of OCT to many new clinical areas. As a result, OCT has been clinically demonstrated in a diverse set of medical and surgical specialties, including gastroenterology, dermatology, cardiology, and oncology, among others. The lessons learned in the clinic are currently spurring a new set of advances in the laboratory that will again expand the clinical use of OCT by adding molecular sensitivity, improving image quality, and increasing acquisition speeds. This continuous cycle of laboratory development and clinical application has allowed the OCT technology to grow at a rapid rate and represents a unique model for the translation of biomedical optics to the patient bedside. This work presents a brief history of OCT development, reviews current clinical applications, discusses some clinical translation challenges, and reviews laboratory developments poised for future clinical application.     

Interleukin-6 and its receptor: from bench to bedside

Interleukin-6 (IL-6) is an inflammatory cytokine with a well-documented role in inflammation and cancer. The cytokine binds to a membrane bound IL-6 receptor (IL-6R) and this complex associates with two molecules of the signal transducing protein gp130 thereby initiating intracellular signaling. While gp130 is present on most if not all cells of the body, the IL-6R is only present on some cells, mainly hepatocytes and several leukocytes. Cells, which only express gp130 and no IL-6R are refractory to IL-6 signals. We have shown earlier that the IL-6R can exist as a soluble protein generated by limited proteolysis of the membrane bound receptor or by translation from an alternatively spliced mRNA. This soluble IL-6R (sIL-6R) can bind the ligand IL-6 and the soluble complex of sIL-6R and IL-6 can bind to gp130 on cells which lack the membrane bound IL-6R and trigger gp130 signaling. We have named this process ‘trans-signaling’. We will review data, which clearly show that IL-6 uses classical signaling via the membrane bound receptor and trans-signaling via the soluble receptor in various physiological and pathophysiological situations. Furthermore, we have developed designer cytokines, which can specifically enhance or inhibit IL-6 trans-signaling. These designer cytokines have been shown to be extremely useful to in therapeutic applications ranging from the long-term culture of stem cells and enhancing liver regeneration up to the blockade of chronic inflammation and cancer.There are inclusions in this text from a number of different articles, which are cited in the reference section.     

Fetal and neonatal alloimmune thrombocytopenia: from bench to bedside

During the recent years considerable advances in the clinical and laboratory diagnosis of alloimmune thrombocytopenia have been done. Feto-maternal alloimmunization is the commonest cause of cause of severe isolated fetal and neonatal thrombocytopenia. The condition results from maternal immunization against specific fetal platelet antigens (HPA). HPA-1a is mostly implicated in Caucasians. The diagnosis is usually made at birth when an otherwise “well” term infant exhibits bleeding at delivery or few hours afterwards. The most feared complication of this disorder is the occurrence of intracranial hemorrhage (ICH) as a result of severe thrombocytopenia leading to death or neurological sequels. The diagnosis of alloimmune thrombocytopenia enables appropriate management of the index case and future pregnancies. Due to the recurrence and increasing severity of this condition in subsequent pregnancies with incompatible fetuses, antenatal management has been proposed. Predictive maternal parameters for severe fetal thrombocytopenia and therapy effectiveness are important for the development of non- invasive strategy.     

Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside

Central nervous system toxicity following administration of beta-lactam antibiotics, of which penicillin is the prototype, is a potential cause of morbidity and mortality. In recent years, important advances have been made in the pathogenesis of antibiotic-related neurotoxicity. This review focuses on the experimental and clinical aspects of neurotoxicity caused by beta-lactam antibiotics. The purpose is to provide an update on the pathogenesis, mechanism, and clinical manifestations of the neurotoxicity, along with an overview of the relationship between antibiotic structure and convulsive action. In particular, some of the prevailing ideas about pathogenesis are highlighted, including theories of the mechanism of pathogencity. A better understanding of antibiotic-related neurotoxicity, as derived from animal models and human clinical experience, would be of value in facilitating more efficient and safer use of antimicrobial compounds.