Glucocorticoid-resistant asthma: more than meets the eye

Abstract

Introduction: For decades glucocorticoids have been considered as the gold standard for the treatment of asthma. We present a case report of typical glucocorticoid-resistant asthma and current consensus in definitions of “severe refractory”, “difficult” and “glucocorticoid-resistant” asthma. Methods: Full-text papers and abstracts were identified on the basis of a comprehensive literature search primarily in MEDLINE (1966 to June 2012) but also in the Cochrane Central Register of Controlled Trials database. Results: Glucocorticoid-resistant asthmatics are a small subset of patients who pose noteworthy diagnostic challenges while contributing disproportionately to health care costs. Recognition of various asthma phenotypes has aided in characterizing groups with severe asthma and given a better understanding of its pathophysiological process. The molecular mechanism of glucocorticoid action is complicated and several pathways have been identified to explain drug resistance, which in turn is crucial for drug development. Tobacco smoking appears to be the single most important contributor of glucocorticoid resistance. We present the emerging and promising concepts in the management of glucocorticoid-resistant asthma, which mainly include drugs targeting specific molecules, receptors, inflammatory cells or immune processes. Conclusion: The challenges in making a diagnosis of glucocorticoid-resistant asthma may contribute to underestimating its prevalence and impact on patient care. Considerable progress has been made in identifying distinct phenotypes and mechanisms of glucocorticoid resistance; therefore the future of new drug development in management of asthma is promising.     

Hypertensive retinopathy: there's more than meets the eye

Hypertension is associated with increased cardiovascular risk, leading to systemic end-organ damage, including retinopathy. However, the recent European Society of Hypertension-European Society of Cardiology and World Health Organization-International Society of Hypertension 2003 guidelines propose new prognostic indications for the classification of hypertensive retinopathy. In particular, grades I and II are no longer included among signs of end-organ damage, and only grades III and IV are retained as associated clinical conditions for the stratification of global cardiovascular risk. This review article will focus on the wider implications of clinical markers of microvascular damage in the retina, with specific reference to hypertension and end-organ damage. Early recognition of retinal changes remains an important step in the risk stratification of hypertensive patients.     

Hematopoiesis in the yolk sac: more than meets the eye

The first blood cells observed in the embryo are large nucleated erythroblasts generated in blood islands of the extraembryonic yolk sac. These unique red cells have been termed primitive because of their resemblance to nucleated erythroblasts of nonmammalian species. It is now widely assumed that hematopoiesis in the yolk sac is "primitive" and that "definitive" hematopoiesis has its origins in the aorta/gonad/mesonephros (AGM) region. Recent studies of yolk sac hematopoiesis have challenged several aspects of this paradigm. First, primitive erythropoiesis in mammals shares many features with definitive erythropoiesis, including progressive erythroblast maturation leading to the circulation of enucleated erythrocytes. Second, the emergence of primitive erythroid progenitors in the yolk sac prior to somitogenesis may be associated with the macrophage and megakaryocyte lineages, raising the possibility that "primitive" hematopoiesis may be multilineage in nature. Third, a second wave of hematopoietic progenitors emerge from the yolk sac during early somitogenesis that consists of multiple myeloid lineages that are temporally and spatially associated with definitive erythroid progenitors. These "definitive" hematopoietic progenitors expand in numbers in the yolk sac and are thought to seed the fetal liver and generate the first definitive blood cells that rapidly emerge from the liver. Recent findings support a model of hematopoietic ontogeny in which the conceptus' first maturing blood cells and committed progenitors are provided by the yolk sac, allowing survival until AGM-derived hematopoietic stem cells can emerge, seed the liver and differentiate into mature blood cells.     

The neovasculature homing motif NGR: more than meets the eye

A growing body of evidence suggests that peptides containing the Asn-Gly-Arg (NGR) motif can selectively recognize tumor neovasculature and can be used, therefore, for ligand-directed targeted delivery of various drugs and particles to tumors or to other tissues with an angiogenesis component. The neovasculature binding properties of these peptides rely on the interaction with an endothelium-associated form of aminopeptidase N (CD13), an enzyme that has been implicated in angiogenesis and tumor growth. Recent studies have shown that NGR can rapidly convert to isoaspartate-glycine-arginine (isoDGR) by asparagine deamidation, generating alpha(v)beta(3) ligands capable of affecting endothelial cell functions and tumor growth. This review focuses on structural and functional properties of the NGR motif and its application in drug development for angiogenesis-dependent diseases. Furthermore, we discuss the time-dependent transition of NGR to isoDGR in natural proteins, such as fibronectins, and its potential role of as a "molecular timer" for generating new binding sites for integrins impli-cated in angiogenesis.     

Proteomics in liver fibrosis is more than meets the eye

Liver fibrosis is a serious health issue for many liver patients and is currently diagnosed using liver biopsy. The erroneous nature of this technique urges the search for better, noninvasive alternatives. In this regard, proteomics has been described as a useful biomarker discovery tool and has become increasingly applied in the study of liver fibrosis. Experimental and clinical studies have already provided deeper insights in the molecular pathways of liver fibrosis and even confirmed previous findings. Recent advances in proteomic strategies and tools enable multiple fractionation, multiple protein identifications and parallel analyses of multiple samples. Despite its increasing popularity, proteomics still faces certain pitfalls concerning preanalytical variability, protein coverage and statistic reliability. Proteomics is still evolving, but will undoubtedly contribute to a better understanding of the basics of the pathology and certainly offer opportunities in liver fibrosis diagnostics and therapeutics.     

Intraluminal filling defects on coronary angiography: more than meets the eye

Intraluminal filling defects are occasionally encountered on coronary angiography and often related with coronary thrombi. However, other conditions affecting the coronary arteries may present with similar angiographic findings causing diagnostic uncertainty. Accurate characterization of the angiographic filling defect is critical, particularly in patients planned for a percutaneous coronary intervention (PCI), as diagnosis of a coronary thrombus not only increases the risk of post procedural adverse events but also requires a specific therapeutic approach. In this paper, we report three patients in whom coronary angiography revealed intraluminal filling defects mimicking coronary thrombi. When further investigated with intravascular ultrasound (IVUS) as a part of the planned PCI, the thrombus was excluded and alternate etiology of the filling defect was confirmed in all patients. The angiographic "pseudothrombi" were produced by coronary dissection in one and by heavy calcification within the atherosclerotic plaque in two patients. The use of IVUS allowed accurate characterization of the angiographic filling defect and provided important information to guide management and optimize therapeutic approach.     

Anal fistula,there is more than meets the eye!

Techniques in Coloproctology -     

Editorial: hepatocellular carcinoma in type 2 diabetes: more than meets the eye

Hepatocellular carcinoma (HCC), a disease with poor survival rates unless recognized and treated early, ranks as the fifth most common cancer worldwide and has a rising incidence in the United States. Recent data indicate that the growing epidemic of type 2 diabetes mellitus may contribute to this alarming trend. In this issue, Lai et al. utilize a large Taiwanese insurance claims database to demonstrate that diabetes is associated with an increased risk of HCC. Moreover, this risk escalates if diabetes coincides with chronic hepatitis C and cirrhosis. Lai et al. also show that treatment with metformin or thiazolidinediones may reduce the risk of HCC. The findings may prompt risk stratification for HCC surveillance and improved disease control in diabetes as measures of cancer prevention.