Effect of Antigen Valency on Autoreactive B-Cell Targeting.

Many autoimmune diseases are characterized by B cells that mistakenly recognize autoantigens and produce antibodies toward self-proteins. Current therapies aim to suppress the immune system, which is associated with adverse effects. An attractive and more specific approach is to target the autoreactive B cells selectively through their unique B-cell receptor (BCR) using an autoantigen coupled to an effector molecule able to modulate the B-cell activity. The cellular response upon antigen binding, such as receptor internalization, impacts the choice of effector molecule. In this study, we systematically investigated how a panel of well-defined mono-, di-, tetra-, and octavalent peptide antigens affects the binding, activation, and internalization of the BCR. To test our constructs, we used a B-cell line expressing a BCR against citrullinated antigens, the main autoimmune epitope in rheumatoid arthritis. We found that the dimeric antigen construct has superior targeting properties compared to those of its monomeric and multimeric counterparts, indicating that it can serve as a basis for future antigen-specific targeting studies for the treatment of RA.

Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Gastro-Intestinal Therapeutic System.

AIMS: To present the design of ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS), an ongoing multicentre clinical outcome trial with nifedipine GITS (Gastro-Intestinal Therapeutic System) in patients with stable angina pectoris. METHODS: At least 6000 patients with optimally treated stable angina without depressed left ventricular function are randomized in equal proportions to either nifedipine GITS or matching placebo (starting dose 30 mg, maintenance dose 60 mg once daily). Patients are followed for at least four years. The primary end-point, to be analyzed by assigned treatment, includes all-cause mortality, acute myocardial infarction, emergency coronary angiography for refractory angina, overt heart failure, debilitating stroke and peripheral revascularization. For this end-point, the trial has a power of 95% to detect a relative risk reduction of 18% at the 5%, level of significance, and is large enough to exclude an excess mortality caused by nifedipine GITS of 3.1 deaths per 1000 years of treatment or greater. The pre-specified early termination rule is more conservative in the case of a beneficial effect than in the case of an adverse effect of nifedipine GITS. The first patient was randomized on 29 November, 1996. By the end of April 1998, about 5200 patients had been started on study medication. CONCLUSIONS: Results will be available in the autumn of 2003.

Comparison of costs of percutaneous transluminal coronary angioplasty and coronary bypass surgery for patients with angina pectoris.

To determine the costs of a procedure, the total costs of the department that provides the service must be considered and, in addition, the direct cost of the specific procedure. Applying this principle to the cost accounting of angioplasty and bypass surgery results in a direct, i.e. procedural, cost, including the initial hospital stay, of respectively 8694 Dfl and 20,987 Dfl. A review of the follow-up data for the first year after the original intervention revealed a 2% reintervention rate for bypass surgery, while this percentage was 29% for angioplasty. Adding the first year costs involved with reinterventions to the procedural costs results in a 1-year cost of angioplasty and bypass operation of 13,625 Dfl and 21,363 Dfl, respectively. It is concluded that because of reinterventions in the first year, a mark up of 57% on the procedural cost of angioplasty must be added to cover 1-year costs, while for bypass surgery this is only 1%. Nevertheless, the 1-year cost for angioplasty is still 36% less than for bypass surgery. As reinterventions after PTCA may stay considerably higher than for CABG for several years, the mark-up percentages will be substantially higher for longer time spans. This may tend to equalize the total costs of PTCA and CABG over time spans of perhaps 5-8 years. Sufficient data are not available to verify this statement. Clinicians must realize that choosing the most appropriate procedure is not only a matter of medical assessment but also a matter of cost effectiveness. CABG can be seen as an 'investment decision' while PTCA tends to become a decision with characteristics of 'maintenance planning'!

Cost benefit analysis of early thrombolytic treatment with intracoronary streptokinase. Twelve month follow up report of the randomised multicentre trial conducted by the Interuniversity Cardiology Institute of The Netherlands.

The costs and benefits of early thrombolytic treatment with intracoronary streptokinase in acute myocardial infarction were compared in a randomised trial. All hospital admissions were recorded and the functional class was assessed at visits to the outpatient clinic during a 12 month follow up of 269 patients allocated to thrombolytic treatment and of 264 allocated to conventional treatment. Mean survival during the first year was calculated for patients with inferior and with anterior infarction and adjusted for impaired quality of life in cases where there were symptoms or hospital admission. In patients with inferior infarction mean survival was 337 days (out of a total follow up of 365 days) for patients allocated to thrombolytic treatment and 327 days for controls. Quality adjusted survival was seven days longer in the thrombolysis group (307 vs 300 days in controls). In patients with anterior infarction mean survival was significantly longer (35 days) in the thrombolysis group than in the control group as was quality adjusted survival (38 days) (304 vs 266 days in controls). The gain in life expectancy with thrombolytic treatment was 0.7 years for patients with inferior infarction, 2.4 years for patients with anterior infarction, and 3.6 years for the subset of patients with large anterior infarction who were admitted within two hours of the onset of symptoms. The costs of medical treatment, including medication, hospital stay, cardiac catheterisation, coronary angioplasty, and bypass surgery, in the first year follow up were higher inpatients allocated to thrombolytic treatment (an additional cost ofDfl 7000 in inferior and Dfl 9000in anterior infarction (1 pounds sterling approximately Dfl 3.3.)) than in conventionally treated patients. The additional costs per year of life gained were Dfl 10 000 in inferior infarction, Dfl 3 800 in anterior infarction, and only Dfl 1 900 in patients with large anterior infarction admitted within two hours of onset of symptoms. Intracoronary thrombolysis can be recommended as a cost effective treatment in patients with extensive anteroseptal infarction.

Usefulness of pimobendan in the treatment of heart failure.

The effects of the benzimidazole-pyridazinone pimobendan (UD-CG 115 BS) on systemic haemodynamics, myocardial performance and the distribution of cardiac output were studied in open-chest anaesthetized pigs. After intravenous bolus injections (0.1-0.5 mg X kg-1, n = 7) increases in heart rate (up to 37%), LVdP/dtmax (up to 54%) and decreases in systemic vascular resistance (up to 33%) and left ventricular filling pressure (up to 50%) were observed, while cardiac output was unchanged. Vasodilation occurred in nearly all regional vascular beds, but was most pronounced in the adrenals (200%), followed by stomach (150%), small intestines (130%), heart (125%) and brain (110%). O2-consumption was not affected in spite of the increases in heart rate and myocardial inotropy. To evaluate the direct effects on the myocardial, pimobendan was also infused (1-5 micrograms X kg-1 X min-1, n = 7) directly into the left anterior descending coronary artery. In addition to a marked vasodilation of the coronary bed (140%), also a lowering of the left ventricular filling pressure (up to 20%) and cardiac output (15%) was observed, but no changes in regional myocardial function, LVdP/dtmax and systemic vascular resistance occurred. Immediately after intracoronary bolus injections (1 mg X kg-1, n = 4), vasodilation of the coronary vessels was apparent, but myocardial contractility was not affected. This may explain that cyclic AMP content, determined in biopsies excised 30 s after injection, was unaltered. It may be concluded that pimobendan exerts actions on the cardiovascular system which may be useful in the treatment of heart failure.