The RSNA Image Sharing Network.

In the era of health information exchanges, there are trade-offs to consider when sharing a patient's medical record among all providers that a patient might choose. Exchange among in-network partners on the same electronic medical records (EMR) and other integrated information systems is trivial. The patient identifier is common, as are the relevant departmental systems, to all providers. Difficulties arise when patient records including images (and reports) must be shared among different networks and even with the patients themselves. The National Institutes of Health (NIH) challenged Radiological Society of North America (RSNA) to develop a transport method that could supersede the need for physical media (for patients or other providers), replace point-to-point private networks among providers, and enable image exchange on an ad hoc basis between arbitrary health networks without long legal delays. In concert with the evolving US health care paradigm, patient engagement was to be fundamental. With Integrating Healthcare Enterprise's (IHE's) help, the challenge has been met with an operational system.

Pathogenic obesity and nutraceuticals.

Over a decade of intense research in the field of obesity has led to the knowledge that chronic, excessive adipose tissue expansion leads to an increase in the risk for CVD, type 2 diabetes mellitus and cancer. This is primarily thought to stem from the low-grade, systemic inflammatory response syndrome that characterises adipose tissue in obesity, and this itself is thought to arise from the complex interplay of factors including metabolic endotoxaemia, increased plasma NEFA, hypertrophic adipocytes and localised hypoxia. Plasma concentrations of vitamins and antioxidants are lower in obese individuals than in the non-obese, which is hypothesised to negatively affect the development of inflammation and disease in obesity. This paper provides a review of the current literature investigating the potential of nutraceuticals to ameliorate the development of oxidative stress and inflammation in obesity, thereby limiting the onset of obesity complications. Research has found nutraceuticals able to positively modulate the activity of adipocyte cell lines and further positive effects have been found in other aspects of pathogenic obesity. While their ability to affect weight loss is still controversial, it is clear that they have a great potential to reverse the development of overweight and obesity-related comorbidities; this, however, still requires much research especially that utilising well-structured randomised controlled trials.

Thrombostatin FM compounds: direct thrombin inhibitors - mechanism of action in vitro and in vivo.

BACKGROUND: Novel pentapeptides called Thrombostatin FM compounds consisting mostly of D-isomers and unusual amino acids were prepared based upon the stable angiotensin converting enzyme breakdown product of bradykinin - RPPGF. METHODS AND RESULTS: These peptides are direct thrombin inhibitors prolonging the thrombin clotting time, activated partial thromboplastin time, and prothrombin time at >or=0.78, 1.6, and 1.6 microm, respectively. They competitively inhibit alpha-thrombin-induced cleavage of a chromogenic substrate at 4.4-8.2 microm. They do not significantly inhibit plasma kallikrein, factor (F) XIIa, FXIa, FIXa, FVIIa-TF, FXa, plasmin or cathepsin G. One form, FM19 [rOicPaF(p-Me)], blocks alpha-thrombin-induced calcium flux in fibroblasts with an IC(50) of 6.9 +/- 1.2 microm. FM19 achieved 100% inhibition of threshold alpha- or gamma-thrombin-induced platelet aggregation at 8.4 +/- 4.7 microm and 16 +/- 4 microm, respectively. The crystal structure of thrombin in complex with FM19 shows that the N-terminal D-Arg retrobinds into the S1 pocket, its second residue Oic interacts with His-57, Tyr-60a and Trp-60d, and its C-terminal p-methyl Phe engages thrombin's aryl binding site composed of Ile-174, Trp-215, and Leu-99. When administered intraperitoneal, intraduodenal, or orally to mice, FM19 prolongs thrombin clotting times and delays carotid artery thrombosis. CONCLUSION: FM19, a low affinity reversible direct thrombin inhibitor, might be useful as an add-on agent to address an unmet need in platelet inhibition in acute coronary syndromes in diabetics and others who with all current antiplatelet therapy still have reactive platelets.

Proactively monitoring departmental clinical IT systems with an open source availability system.

The goal of all radiology information technology (IT) support organizations is excellent customer service through the availability of critical clinical information services, such as picture archiving communication systems and radiology information systems. Despite these goals, IT support personnel often act like firefighters, reacting to each problem, but unable to prevent or predict other problems. Proactive support is always more desirable than reactive support. Warning signs may exist well before a technical issue becomes system wide or the user is affected. The objective for IT support organizations in health care should be to maximize system uptime by using proactive monitoring systems for failures and to automatically detect failures through systems management tools. We report on the implementation of Nagios, an open source monitoring tool, as an availability management system in a diagnostic imaging department and on customized applications and protocols specific to radiology needs.

Il-13 and IFN-gamma: interactions in lung inflammation.

Chronic inflammatory diseases of the lungs, such as asthma, are frequently associated with mixed (Th2 and Th1) T cell responses. We examined the impact of critical Th1 and Th2 cytokines, IFN-gamma and IL-13, on the responses in the lungs. In a mouse model of airway inflammation induced by mixed T cell responses, the number of Th1 (IFN-gamma-positive) cells was found to be negatively correlated with airway hyperreactivity. In these mice, blockade of IL-13 partially inhibited airway hyperreactivity and goblet cell hyperplasia but not inflammation. In contrast, in mice that responded with a polarized Th2 response to the same Ag, blockade of IL-13 inhibited airway hyperreactivity, goblet cell hyperplasia, and airway inflammation. These results indicated that the presence of IFN-gamma would modulate the effects of IL-13 in the lungs. To test this hypothesis, wild-type mice were given recombinant cytokines intranasally. IFN-gamma inhibited IL-13-induced goblet cell hyperplasia and airway eosinophilia. At the same time, IFN-gamma and IL-13 potentiated each other's effects. In the airways of mice given IL-13 and IFN-gamma, levels of IL-6 were increased as well as numbers of NK cells and of CD11c-positive cells expressing MHC class II and high levels of CD86. In conclusion, IFN-gamma has double-sided effects (inhibiting some, potentiating others) on IL-13-induced changes in the lungs. This may be the reason for the ambiguous role of Th1 responses on Th2 response-induced lung injury.

Thrombostatin inhibits cyclic flow variations in stenosed canine coronary arteries.

Thrombostatins are a group of compounds based upon a breakdown product of bradykinin, RPPGF. They inhibit alpha-thrombin-induced platelet activation by binding to protease activated receptor 1 and, at a lower affinity, by interacting with thrombin's active site. After a single intravenous infusion of MAP4-RPPGF (11.58 mg/kg), its t1/2alpha was 4.5 min with a clearance of 2.0 ml/min. MAP4-RPPGF administration had a sustained antiplatelet effect, preventing gamma-thrombin-induced (12.5 nM) platelet activation for 4 h. Its antiplatelet effect summated with that of aspirin and/or clopidogrel. MAP4-RPPGF was compared with aspirin and clopidogrel in the Folts model of coronary artery thrombosis. Dogs were randomized to 3 treatment groups: aspirin 1.14 mg/kg i.v., clopidogrel 0.5 mg/kg i.v., or MAP4-RPPGF 0.77 mg/kg i.v. Cyclic flow variations (CFV) were recorded in 5 untreated dogs hourly for 3 successive hours and for 1 h before (all groups >11 CFV/h), and for 2 h after drug infusion in each of the 3 treatment groups. After 1 h drug treatment, all groups of animals had <6 CFV/h; after 2 h treatment, all had <1 CFV/h. All agents significantly reduced CFV from control at each hour, but none was significantly better than any other. Thrombostatin was as effective as aspirin or clopidogrel in inhibiting coronary artery thrombosis in this canine model.

Developing peptide inhibitors to thrombin activation of platelets from bradykinin analogs.

Investigations identified peptide, platelet-selective thrombin inhibitors. Three peptides (MAP4-RPPGF, RGKWC and RGDWC) were relatively selective inhibitors of thrombin-induced platelet activation and calcium mobilization. MAP4-RPPGF at 35.5+/-0.03 microM inhibits gamma-thrombin-induced platelet aggregation 100% and alpha-thrombin-induced calcium mobilization in fibroblasts 84%. RGKWC at 800+/-400 microM inhibits gamma-thrombin-induced platelet aggregation 100% and calcium mobilization 63%. RGDWC at 140+/-100 microM inhibits gamma-thrombin-induced platelet aggregation 100% and calcium mobilization 32%. RGDWC also inhibits ADP-induced platelet aggregation, whereas MAP4-RPPGF and RGKWC do not. RGKWC prolongs the activated partial thromboplastin time (APTT) but not the prothrombin time (PT) or thrombin clotting time (TCT). RGKWC uniquely inhibits alpha-thrombin activation of human factor XI. Single amino acid substitutions in peptide pentamers result in differences in potency and mechanism(s) of inhibition of platelet and fibroblast activation by thrombin.

Variable extrathoracic airflow obstruction and chronic laryngotracheitis in Gulf War veterans.

STUDY OBJECTIVES: To study the flow-volume loop for evidence of variable extrathoracic airflow obstruction in Persian Gulf War veterans. DESIGN: Retrospective case-control, single-center study. SETTING: The pulmonary division of an academic health-care center. SUBJECTS: A convenience sample of the Persian Gulf Registry. MEASUREMENTS AND INTERVENTIONS: (1) Midvital capacity ratio (ratio of maximum forced midexpiratory to maximum forced midinspiratory flow). This ratio is the criterion standard for the diagnosis of variable extrathoracic airflow obstruction. (2) Evaluation of the anatomy and function of the extrathoracic airway by fiberoptic bronchoscopy. (3) Further investigation into the airway abnormality by histologic evaluation of tracheal biopsy samples in Gulf War veterans only. RESULTS: Midvital capacity was > 1.0 in 32 of 37 Gulf War veterans compared with only 11 of 38 control subjects. The mean (+/-SD) value was 1.37+/-0.4 among Gulf War veterans and 0.88+/-0.3 among control subjects (p=0.0000005). FVC and its ratio to FEV1 were normal in all these subjects. Bronchoscopy showed inflamed larynx and trachea in all (n=17) Gulf War veterans. Histologic study showed chronic inflammation of the trachea in everyone (n=12) who had an adequate biopsy sample. CONCLUSION: Physicians should be made aware of the presence of chronic inflammation of the upper airways and inspiratory airflow limitation in a number of Gulf War veterans.

Requirement for IL-13 independently of IL-4 in experimental asthma.

The pathogenesis of asthma reflects, in part, the activity of T cell cytokines. Murine models support participation of interleukin-4 (IL-4) and the IL-4 receptor in asthma. Selective neutralization of IL-13, a cytokine related to IL-4 that also binds to the alpha chain of the IL-4 receptor, ameliorated the asthma phenotype, including airway hyperresponsiveness, eosinophil recruitment, and mucus overproduction. Administration of either IL-13 or IL-4 conferred an asthma-like phenotype to nonimmunized T cell-deficient mice by an IL-4 receptor alpha chain-dependent pathway. This pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL-4 receptor.

Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice.

BACKGROUND: The pathogenesis of asthma is believed to reflect antigen-induced airway inflammation leading to the recruitment of eosinophils and activation of mast cells through cell-associated IgE. Controversies persist however, regarding the relative importance of different pathogenic cells and effector molecules. MATERIALS AND METHODS: A variety of gene-targeted mice were examined for the induction of cholinergic airway hyperresponsiveness (AH), allergic airway inflammation, mucus production, and serum IgE reactivity following intratracheal challenge with a potent allergen. AH was determined using whole-body plethysmography following acetylcholine challenge. Where possible, results were confirmed using neutralizing antibodies and cell-specific reconstitution of immune deficient mice. RESULTS: T and B cell-deficient, recombinase-activating-gene-deficient mice (RAG -/-) failed to develop significant allergic inflammation and AH following allergen challenge. Reconstitution of RAG -/- mice with CD4+ T cells alone was sufficient to restore allergen-induced AH, allergic inflammation, and goblet cell hyperplasia, but not IgE reactivity. Sensitized B cell-deficient mice also developed airway hyperreactivity and lung inflammation comparable to that of wild-type animals, confirming that antibodies were dispensable. Treatment with neutralizing anti-IL-4 antibody or sensitization of IL-4-deficient mice resulted in loss of airway hyperreactivity, whereas treatment with anti-IL-5 antibody or sensitization of IL-5-deficient mice had no effect. CONCLUSIONS: In mice, CD4+ T cells are alone sufficient to mediate many of the pathognomonic changes that occur in human asthma by a mechanism dependent upon IL-4, but independent of IL-5, IgE, or both. Clarification of the role played by CD4+ T cells is likely to stimulate important therapeutic advances in treatment of asthma.

Cryptic T-cell epitopes and their role in the pathogenesis of autoimmune diseases.

Immune recognition of self-proteins features prominently in the early pathogenesis of autoimmune rheumatic diseases such as rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and systemic sclerosis. The mechanisms which provide lymphocytes with access to such autoantigens are therefore fundamental in creating the opportunity for autoimmune responses to develop. It has long been thought that the tissue or cellular location of some self-proteins may determine that they are normally 'hidden' from immune recognition, thereby reducing their potential for autoantigenicity. Recently, this concept has been extended to apply even to different epitopes within the same protein. Many studies, encompassing a wide variety of antigens, have shown that some epitopes are not presented for recognition by T lymphocytes unless they are produced in unusually large concentrations or unless they are freed from the configuration of their native antigen. Epitopes for which this phenomenon occurs are described as cryptic. There is increasing interest in the possibility that crypticity may be an important characteristic of epitopes which are recognized by T lymphocytes in autoimmune pathogenesis. The evidence which has led to this theory and its significance are reviewed.

Alteration of cartilage metabolism by cells from osteoarthritic bone.

OBJECTIVE: To determine whether bone cells alter cartilage metabolism. METHODS: Bone cell cultures were established using explants obtained from the hip and knee joints of 9 patients with osteoarthritis (OA) and 6 subjects without arthritis (nonarthritic [NA]). NA human cartilage biopsy samples were incubated in the presence or absence of bone-derived cells, and the effects on glycosaminoglycan (GAG) release from cartilage were measured. RESULTS: Bone cell cultures secreted osteocalcin (OC) and did not contain cells expressing leukocyte common antigen. None of the 8 cultures established from NA bone, compared with 17 of 32 from OA bone, significantly altered GAG release from cartilage (P = 0.006). In knees with medial joint damage, 38% of the cultures derived from the medial side of the joint increased GAG release from cartilage. In contrast, 77% of the cultures derived from the lateral side of the joint had an effect on GAG, with 38% increasing and 38% decreasing GAG release. Seven cytokines were measured in OA bone cell supernatants. No significant difference was apparent in the concentration of any one cytokine when supernatants were compared according to their effects on GAG release. CONCLUSION: Bone cells from OA patients can influence cartilage metabolism. This might explain why increased subchondral bone activity can predict cartilage loss.