Biomedical subjects

Edmond O'Riordan

Publications and source records attributed to Edmond O'Riordan.

8 recordsLinked to original sources

PubMed2006

Chronic NOS inhibition actuates endothelial-mesenchymal transformation.

Chronic kidney diseases are accompanied by the accumulation of substances like asymmetric dimethylarginine, phenylacetic acid, homocysteine, and advanced glycation end products, known to either inhibit endothelial nitric oxide synthase (eNOS) or uncouple it, consequently limiting the amount of available nitric oxide (NO). Reduced bioavailability of NO induces endothelial dysfunction. An early loss of peritubular capillaries in tubulointerstitial fibrotic areas and injury to endothelial cells have been linked to progressive renal disease. Screening endothelial genes in cells treated with NOS inhibitors showed upregulation of collagen XVIII, a precursor of a potent antiangiogenic substance, endostatin. This finding was confirmed at the level of mRNA and protein expression. Tie-2 promoter-driven green fluorescent protein mice treated with nonhypertensinogenic doses of a NOS inhibitor exhibited upregulation of collagen XVIII/endostatin and rarefaction of capillary profiles. This was accompanied by the increased expression of transforming growth factor-beta and connective tissue growth factor in the kidney. Occasional endothelial cells expressed both the marker of endothelial lineage (green fluorescent protein) and mesenchymal marker (alpha-smooth muscle actin or calponin). In vitro studies of endothelial cells treated with asymmetric dimethylarginine showed decreased expression of eNOS and Flk-1 and enhanced expression of calponin and fibronectin, additional markers of smooth muscle and mesenchymal cells. These cells overexpressed transforming growth factor-beta and connective tissue growth factor, as well as endostatin. In conclusion, data presented here 1) ascribe to NO deficiency in endothelial cells the function of a profibrotic stimulus associated with the expression of an antiangiogenic fragment of collagen XVIII (endostatin) and 2) provide evidence of endothelial-mesenchymal transdifferentiation in the course of inhibition of NOS by a pathophysiologically important antagonist, asymmetric dimethylarginine. Both mechanisms may account for microvascular rarefaction.

Animals↗

PubMed2006

Urinary proteome of steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome of childhood.

The response to steroid therapy is used to characterize the idiopathic nephrotic syndrome (INS) of childhood as either steroid-sensitive (SSNS) or steroid-resistant (SRNS), a classification with a better prognostic capability than renal biopsy. The majority (approximately 80%) of INS is due to minimal change disease but the percentage of focal and segmental glomerulosclerosis is increasing. We applied a new technological platform to examine the urine proteome to determine if different urinary protein excretion profiles could differentiate patients with SSNS from those with SRNS. Twenty-five patients with INS and 17 control patients were studied. Mid-stream urines were analyzed using surface enhanced laser desorption and ionization mass spectrometry(SELDI-MS). Data were analyzed using multiple bioinformatic techniques. Patient classification was performed using Biomarker Pattern Software and a generalized form of Adaboost and predictive models were generated using a supervised algorithm with cross-validation. Urinary proteomic data distinguished INS patients from control patients, irrespective of steroid response, with a sensitivity of 92.3%, specificity of 93.7%, positive predictive value of 96% and a negative predictive value of 88.2%. Classification of patients as SSNS or SRNS was 100%. A protein of mass 4,144 daltons was identified as the single most important classifier in distinguishing SSNS from SRNS. SELDI-MS combined with bioinformatics can identify different proteomic patterns in INS. Characterization of the proteins of interest identified by this proteomic approach with prospective clinical validation may yield a valuable clinical tool for the non-invasive prediction of treatment response and prognosis.

Adolescent↗

PubMed2006

Technology Insight: renal proteomics--at the crossroads between promise and problems.

Knowledge of the human genome has fertilized research in the embryonic field of proteomics. The aim of this Review is to examine the recent application of emerging proteomic technologies to diagnosis of renal disease. We discuss the roles, efficacy and diagnostic potential of different proteomic approaches, focusing on current difficulties and potential solutions. Our rudimentary knowledge of the healthy human urine proteome is described, as are studies that have sought to use the urinary proteome as a tool for diagnosis of renal disease. Vignettes of renal proteome are also presented. The integral role of bioinformatics, and the need for standardized sample preservation and reporting of results, are discussed.

Humans↗

PubMed2005

Endothelial microparticles affect angiogenesis in vitro: role of oxidative stress.

Endothelium-derived microparticles have recently been described as a new marker of endothelial cell dysfunction. Increased levels of circulating microparticles have been documented in inflammatory disorders, diabetes mellitus, and many cardiovascular diseases. Perturbations of angiogenesis play an important role in the pathogenesis of these disorders. We demonstrated previously that isolated endothelial microparticles (EMPs) impair endothelial function in vitro, diminishing acetylcholine-induced vasorelaxation and nitric oxide production by rat aortic rings and simultaneously increasing superoxide production. Herein, using the Matrigel assay of angiogenesis in vitro and a topological analysis of the capillary-like network by human umbilical vein endothelial cells (HUVECs), we investigated the effects of EMPs on formation of the vascular network. All parameters of angiogenesis were affected by treatment for 48 h with isolated EMPs in a concentration of 10(5) but not 10(3) or 10(4) EMPs/ml. The effects included decreases in total capillary length (24%), number of meshes (45%), and branching points (36%) and an increase in mesh area (38%). The positional and topological order indicated that EMPs affect angiogenic parameters uniformly over the capillary network. Treatment with the cell-permeable SOD mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (Mn-TBAP) partially or completely restored all parameters of angiogenesis affected by EMPs. EMPs reduced cell proliferation rate and increased apoptosis rate in time- and dose-dependent manners, and this phenomenon was also prevented by Mn-TBAP treatment. Our data demonstrate that EMPs have considerable impact on angiogenesis in vitro and may be an important contributor to the pathogenesis of diseases that are accompanied by impaired angiogenesis.

Apoptosis↗

PubMed2005

Emerging studies of the urinary proteome: the end of the beginning?

PURPOSE OF REVIEW: Urinary proteomics is a rapidly growing field, holding the promise of discovery of biomarkers of various disease processes and elucidation of pathophysiologic mechanisms of disease states. This may be true not only for renal disease but for diseases of other organs and systemic disorders. RECENT FINDINGS: Recent advances in separation technologies and rapid, high-throughput, and accurate protein detection and identification now permit rigorous examination of complex biological fluids. This review sketches the progress achieved in recent years and the existing hurdles in describing a normal urinary proteome, its aberrations in pathological conditions, and the search for biomarkers of several renal and non-renal diseases. SUMMARY: The first wave of urinary proteomic studies has now arrived and their results are summarized. Future lines of investigation are delineated.

Acute Disease↗

PubMed2005

Endothelial cell dysfunction: the syndrome in making.

Endothelial cell dysfunction is emerging as the ultimate culprit for diverse cardiovascular diseases and cardiovascular complications in patients with chronic renal diseases, yet the definition of this new syndrome, its pathophysiology and therapy remain poorly defined. Here, we summarize some molecular mechanisms leading from hyperhomocysteinemia, elevated asymmetric dimethylarginine (ADMA) and advanced glycation end products (AGEs)-modified proteins to atherogenic endothelial phenotype and offer a model of endothelial dysfunction based on the interconnectedness of diverse functions.

Animals↗

PubMed2004

Bioinformatic analysis of the urine proteome of acute allograft rejection.

The urinary proteome in health and disease attracts increasing attention because of the potential diagnostic and pathophysiologic biomarker information carried by specific excreted proteins or their constellations. This cross-sectional study aimed to analyze the urinary proteome in patients with biopsy-proven acute rejection (n = 23) compared with transplant recipients with stable graft function (n = 22) and healthy volunteers (n = 20) and to correlate this with clinical, morphologic, and laboratory data. Urine samples were preadsorbed on four different protein chip surfaces, and the protein composition was analyzed using a surface-enhanced laser desorption/ionization time-of-flight mass spectrometer platform. The data were analyzed using two independent approaches to sample classification. Patients who experienced acute rejection could be distinguished from stable patients with a sensitivity of 90.5 to 91.3% and a specificity of 77.2 to 83.3%, depending on the classifier used. Protein masses that were important in constructing the classification algorithms included those of mass 2003.0, 2802.6, 4756.3, 5872.4, 6990.6, 19,018.8, and 25,665.7 Da. Normal urine was distinguished from transplant urine using a protein marker of mass 78,531.2 Da with both a sensitivity and a specificity of 100%. In conclusion, (1) urine proteome in transplant recipients with stable graft function was significantly different from healthy control subjects, and (2) acute rejections were characterized by a constellation of excreted proteins. Analysis of the urinary proteome may expedite the noninvasive prediction of acute graft rejection, thus importantly assisting in establishing the diagnosis.

Acute Disease↗

PubMed2002

Madura foot in the U.K.: fungal osteomyelitis after renal transplantation.

We report the case of an ethnic Asian patient who attended the renal transplant follow-up clinic complaining of pain in the right great toe. He had undergone transplantation nine months earlier and was maintained on triple immunosuppression. Initially, a clinical diagnosis of gout was made and the patient treated with analgesia. Two weeks later he remained symptomatic and developed a discharging sinus on his toe. A plain X-ray revealed a lytic lesion with minimal periosteal reaction. Aspiration of his first right metatarsal phalangeal joint was performed and fungal hyphae were observed in the fluid. Subsequently, despite surgical debridement and treatment with Itraconozaole amputation of the toe was required. Microbiological analysis revealed the organism to be Madurella grisea,which was resistant to both Itraconazole and Amphotericin B. He has remained well since amputation. We believe this to be the first case of Madurella infection to be described in a transplant patient.

Amputation, Surgical↗