ABSTRACT
OBJECTIVES: The aim of this study was to describe expression of parathyroid hormone-related peptide (PTHrP) in collagen-induced arthritis (CIA), a well-established animal model for rheumatoid arthritis. METHODS: CIA was induced in female dark agouti rats. Inguinal (ILNs) and popliteal (PLNs) lymph nodes and distal interphalangeal joints (DIP) were retrieved at different time points. Tissues were processed for detection of PTHrP and cell marker proteins by immunohistochemistry. Lymph node RNA was extracted, and PTHrP mRNA quantified using competitive reverse transcriptase polymerase chain reaction. RESULTS: Hyperplasia of ILNs was observed 2 days after injection, coinciding with the peak in PTHrP expression in ILNs (1240 +/- 373 gene copies/ng RNA vs normal 339 +/- 120, P < 0.05). Hyperplasia of PLNs was first seen at 1 day after onset of arthritis, coinciding with the peak in PTHrP expression in PLNs (2267 +/- 697 vs normal 781 +/- 136, P < 0.01). PTHrP expression in PLNs remained increased 5 days after onset (1361 +/- 302 vs normal 781 +/- 136, P < 0.05). In both PLNs and ILNs PTHrP protein was localized to high endothelial venules, lymphocytes and monocytes/macrophages. In DIP joint synovium PTHrP staining was first detected on day 10 after onset, and was most abundant at day 20 after onset, at sites of bone resorption and deposition, where it was localized to neutrophils, cells of monocyte lineage and osteoblasts. CONCLUSIONS: Changes in ILN and PLN PTHrP mRNA expression suggest that elevated levels of the cytokine are associated with aggravation of the inflammatory immune response. Changes in PTHrP in DIP joints indicate its involvement in late rather than early pathogenic events in CIA joints.
Subject(s)
Arthritis, Experimental/metabolism , Parathyroid Hormone-Related Protein/biosynthesis , Animals , Arthritis, Experimental/pathology , Disease Progression , Female , Gene Expression Regulation , Hyperplasia/metabolism , Lymph Nodes/metabolism , Lymph Nodes/pathology , Parathyroid Hormone-Related Protein/genetics , RNA, Messenger/genetics , Rats , Rats, Inbred Strains , Reverse Transcriptase Polymerase Chain Reaction/methods , Severity of Illness Index , Synovial Membrane/metabolism , Toe Joint/metabolismABSTRACT
The objective was to prospectively validate a method of increasing the sensitivity, specificity and negative predictive value of a normal ECG in the exclusion of left ventricular systolic dysfunction by the addition of clinical history. We performed a prospective three year study of all referrals to our direct access ECHO service for assessment of LV function. The ECG was reported blind of the result of the ECHO, history of MI or not was noted, and result of the ECHO predicted. Over three years 416 patients were assessed for the presence or absence of left ventricular systolic dysfunction and consequent changes in clinical management. A total of 320(77%) of patients referred with suspected left ventricular dysfunction were found to have normal left ventricular function. Of the 250(60%) patients treated prior to referral for assessment, 183(73%) were treated inappropriately. The combination of a normal ECG and a negative history of myocardial infarction had a sensitivity of 98% and a negative predictive value of 99% in the assessment of LV function. This was an improvement over a normal ECG alone. Our study shows that diagnosis and treatment of heart failure in the community remains sub-optimal. The combination of a normal ECG and no previous history of myocardial infarction is shown to be a sensitive and accurate predictor of normal left ventricular function. If adopted by general practitioners this would be a valuable method of optimising the use of echocardiography in patients with suspected left ventricular dysfunction.