Imaging activated-T-lymphocytes in the salivary glands of patients with sjögren’s syndrome by 99mTc-interleukin-2. diagnostic and therapeutic implications

Background: Sjögren’s syndrome (SS) is a progressive autoimmune disease characterized by local mononuclear cell infiltration of the salivary and lachrymal glands. Labial biopsy demonstrates local infiltration by Th1 cells that produce pro-inflammatory cytokines, such as interleukin-2 (IL2). The aim of this study was to assess the utility of 99mTc-labelled-IL2 (99mTc-IL2) in evaluating in vivo the extent and severity of lympho-mononuclear cell infiltration in the salivary glands of patients with SS. Methods: We investigated 48 patients with primary SS and 27 control subjects using 99mTc-IL2 scintigraphy. Furthermore, in a subgroup of 30 patients, we also performed 99mTc-pertechnetate scintigraphy (99mTcO4−) for evaluation of the salivary gland function. Results: 99mTc-IL2 uptake in the salivary glands of SS patients was higher than in the control subjects (1.30 ± 0.16 vs. 0.83 ± 0.08 for parotids and 1.36 ± 0.15 vs. 1.16 ± 0.07 for submandibular glands; p < 0.0001). The salivary gland uptake of 99mTc-IL2 in patients with a longer history of disease was lower compared with the recently diagnosed patients. A significant direct correlation was found between the uptake of 99mTc-IL2 and histology. Conclusions: 99mTc-IL2 scintigraphy showed that the degree of lymphocytic infiltration of major salivary glands is variable in patients with different disease durations. Patients with a high 99mTc-IL2 uptake could be efficiently treated with immuno-modulatory drugs and the efficacy of treatment could be followed-up by 99mTc-IL2 scintigraphy

A Toolkit for Building Energy Consumption Data Quality Assurance/Quality Control

Radiolabelled cytokines and monoclonal antibodies are an emerging class of radiopharmaceuticals for imaging inflammation. These radiopharmaceuticals bind to their targets with high affinity and specificity and therefore have excellent diagnostic potential for imaging of patients with chronic inflammatory diseases. One of the key cytokines involved in the process of inflammation is tumor necrosis factor alpha (TNFα). With the introduction of anti-TNFα monoclonal antibodies over the past decade, treatment of inflammatory diseases has evolved, which allowed remarkable advances in controlling signs and symptoms of inflammation and in slowing destruction. However, drugs may lose efficacy over time in patients or induce adverse events. Using immediately the right medication tailored to the patient's molecular status avoids unnecessary costs and side effects. Significant differences in mechanisms of action and in therapy outcome, depending on the disease to be treated, exist among the different TNFα antagonists. Labelling these agents may help to find out if TNFα is present in the inflammatory process and will therefore help in therapy prediction and stratification in the individual patient. This review describes the role of cytokines and in particular of TNFα in the process of inflammation as well as the influence of TNFα in some well-known and common inflammatory diseases, such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, psoriasis and sarcoidosis. The main focus of this article is to review the role of molecular imaging with radiolabelled anti-TNFα monoclonal antibodies for diagnostic purposes, and in therapy precision, decision-making and evaluation

Somatostatin receptor scintigraphy in patients with rheumatoid arthritis and secondary Sjogren's syndrome treated with Infliximab:a pilot study

Background: Human T lymphocytes infiltrating tissues in autoimmune diseases are known to express somatostatin receptors amongst other activation markers. In this study, we evaluated whether somatostatin receptor scintigraphy (SRS) using a radiolabelled somatostatin analogue (Tc-99m-EDDA/tricine-HYNIC-tyr(3)-octreotide (Tc-99m-EDDA/HYNIC-TOC)) is able to detect the presence of immune-mediated processes in patients with rheumatoid arthritis and secondary Sjogren's syndrome. We also aimed to evaluate whether positivity to SRS was predictive of therapeutic response and if SRS could be used for monitoring the efficacy of immunomodulatory treatment. Methods: Eighteen patients with rheumatoid arthritis and secondary Sjogren's syndrome not responding to conventional treatment were recruited for treatment with infliximab, a monoclonal antibody against TNF-alpha. All patients had complete blood cell count, renal and liver function tests, measurements of ESR, CRP, ANA, ENA, and anti-dsDNA antibodies, functional salivary gland scintigraphy, labial biopsy, and ophthalmologic assessment with Schirmer's test and tear film break-up time (BUT). Diagnosis was made according to the revised criteria of the American-European Consensus Group. All patients underwent SRS at baseline and after 3-6 months of therapy with infliximab. Eleven out of 18 had repeat SRS images. Images of the salivary glands and major joints were acquired 3 h after injection of 370 MBq of 99mTc-EDDA/HYNIC-TOC. Image analysis was performed semi-quantitatively. Results: All patients showed uptake of Tc-99m-EDDA/HYNIC-TOC in the joints. Salivary glands also showed variable radiopharmaceutical uptake in 12 out of 18 patients, but all patients showed presence of lymphocytic infiltration at labial salivary gland biopsy. All patients, who repeated the study after treatment, showed significant reduction of somatostatin uptake in the joints but not in the salivary glands. Conclusions: SRS using Tc-99m-EDDA/HYNIC-TOC may be a useful imaging tool to assess disease activity and extent in patients with rheumatoid arthritis and may help to detect secondary Sjogren's syndrome. It may also aid therapy decision-making with anti-TNF alpha antibodies in the joints but not in salivary glands

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo

Abstract Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn 2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An A-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC 50 of 0.045 Mmol/L in the screening biochemical assay and an EC 50 of 0.025 Mmol/L in HeLa cell -based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classe

Investigation of Association between PFO Complicated by Cryptogenic Stroke and a Common Variant of the Cardiac Transcription Factor GATA4

Patent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke