Gold complex research in medical science. Difficulties with experimental design

Despite the use of gold complexes in modern medicine for over 100 years and the use of gold complexes in the management of rheumatoid disease for more than 60 years, the definitive mechanisms of action for efficacy and for toxicity have not been established. Gold is a group 1b metal in the periodic table with several oxidation states but it is only Au(I) which is active in the biological milieu. Gold sodium thiomalate is not only a polymeric structure, but also has the chiral ligand, thiomalic acid. Gold sodium thiomalate thus can exist in several different physical states which may have different biological activity. In addition the pharmacokinetic profile of gold complexes has been of little value in the understanding of either the mechanism of action, efficacy or toxicity for both the injectable and the oral gold complexes. Many authors have misinterpreted research data on the activities of gold complexes because they compared gold complexes of different structures, and gold complexes which exist at different pH. Experimental work in our laboratory has identified that gold sodium thiomalate is a mixture and can exist as either a yellow or a colourless solution. These have some similar but several different biological activities. Many factors contribute to the lack of understanding of the action of gold complexes. Some of these factors are related to the wide variation in physical structure and biological activities exhibited by these compounds.     

Ankylosing spondylitis antirheumatic drug trials. III. Setting the delta for clinical trials of antirheumatic drugs--results of a consensus development (Delphi) exercise.

Defining the minimum clinically important difference or delta to be detected in a clinical trial depends on a number of factors including the research hypothesis, patient characteristics, the nature of the intervention and the trial design. In 2 previous studies, we have developed standardized procedures for conducting outcome measurement based on current Food and Drug Administration and European League Against Rheumatism guidelines for clinical trials in ankylosing spondylitis, and thereafter, determined the standard deviation for these outcome measures. In the final component of this series of studies, we have employed a Delphi technique to establish estimates for delta, and calculated the sample size requirements under 2 different conditions of Type I and Type II error probabilities.     

Transplant Tolerance in Non-Human Primates: Progress, Current Challenges and Unmet Needs

Given the significant morbidity associated with current post-transplant immunosuppressive regimens, induction of immune tolerance continues to be an important goal of clinical organ transplantation. While many strategies for inducing tolerance have been successfully applied in murine models, significant barriers are faced when translating these approaches to the clinic. This has necessitated pre-clinical studies in the more closely related model system, the non-human primates (NHP). In this review, we will discuss the four most prominent strategies for inducing transplantation tolerance and highlight their relative success and shortcomings in NHP. These strategies are: (1) T-cell costimulation blockade (2) mixed chimerism induction (3) T-cell depletion and (4) tolerance induction through regulatory T-cells. After discussing the progress that has been made with each of these strategies, we will identify this field's most pressing unmet needs and discuss how we may best overcome the resulting barriers to tolerance induction.     

Treatment of atrial fibrillation in a district general hospital.

OBJECTIVE--To assess current strategies used to investigate and manage acute atrial fibrillation in hospital. DESIGN--Prospective survey of all acute admissions over 6 months. SETTING--District general hospital serving a population of 230,000 in north east Glasgow. SUBJECTS--2686 patients admitted as emergency cases over 6 months. RESULTS--Of the 2686 patients, 170 (age range 38-95, mean (SD) 73.5 (10.6) years; 70 men (41%) and 100 women (59%)) were admitted with atrial fibrillation. The principal underlying medical conditions were ischaemic heart disease in 79 (46.5%), rheumatic heart disease in 26 (15.3%), and thyroid disease in six (3.5%). Cardiac failure was present on admission in 61 (36%), cerebrovascular events in 23 (14%), and myocardial infarction in 17 (10%). Of those with a history of atrial fibrillation (102 (60%) including 10 with paroxysmal atrial fibrillation) treatment on admission included digoxin in 71 (70%), warfarin in 20 (20%), and aspirin in 17 (17%); the aspirin was predominantly given for concomitant vascular disease. The mean (SD) inpatient stay was 16 days (19.7) (range 1-154) largely due to the patients with stroke. Thyroid function tests were performed in only 63% and echocardiography in 33%. Overall, the rate of introduction of anticoagulation (seven patients) and attempted cardioversion (21 patient: 19 pharmacological and two electrical) was surprisingly low. Only 49 patients (34% of those not on warfarin) had contraindications to anticoagulation: these included peptic ulcer or gastrointestinal bleeding in 18 (12%), dementia in eight (6%), chronic renal failure or dialysis in eight (6%), and alcohol excess in four (3%). CONCLUSION--Standard investigations were inadequately used in patients with atrial fibrillation and there was a reluctance to perform cardioversion or to start anticoagulant treatment.     

NK Cells Rapidly Reject Allogeneic Bone Marrow in the Spleen Through a Perforin- and Ly49D-Dependent, but NKG2D-Independent Mechanism

We have used a sensitive and specific in vivo killing assay to monitor the kinetics, anatomic location and mechanisms controlling NK-mediated rejection of Balb/c bone marrow by C57BL/6 natural killer (NK) cells. We find that NK killing of fully allogeneic bone marrow is a rapid, highly efficient process, leading to substantial rejection of transplanted marrow within 6 h of transplant and elimination of 85% of the transplanted cells within 2 days. NK-mediated rejection occurred predominantly in the spleen, with sparing of rejection in the bone marrow and lymph nodes. Rejection was dependent on Perforin gene function, but was independent of interferon-gamma. Finally, rejection of Balb/c bone marrow by B6 NK cells required signaling through the Ly49D receptor, but occurred despite blockade of NKG2D, which distinguishes these results from previous studies using semiallogeneic transplant pairs. These results identify NK cells as highly active mediators of bone marrow rejection, and suggest that inhibiting NK function early during transplantation may increase the efficiency of engraftment and allow successful engraftment of limiting doses of donor bone marrow.