Health care reform: lessons from Canada

Although Canadian health care seems to be perennially in crisis, access, quality, and satisfaction in Canada are relatively high, and spending is relatively well controlled. The Canadian model is built on a recognition of the limits of markets in distributing medically necessary care. Current issues in financing and delivering health care in Canada deserve attention. Key dilemmas include intergovernmental disputes between the federal and provincial levels of government and determining how to organize care, what to pay for (comprehensiveness), and what incentive structures to put in place for payment. Lessons for the United States include the importance of universal coverage, the advantages of a single payer, and the fact that systems can be organized on a subnational basis.     

Sequential analysis of adhesion molecules and their ligands in rat renal allografts during the development of chronic rejection

Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are important in endothelial cell-leukocyte interactions. In this sequential study, the expression of ICAM-1 and VCAM-1 and their ligands LFA-1 and VLA-4 as well as major histocompatibility complex class II antigens (MHC class II), and interleukin-2-receptor (IL-2R) were investigated during the development of chronic renal allograft rejection in a rat model. The time-related expression of adhesion molecules and their ligands in the graft was correlated to the chronic allograft damage index (CADI). In association with an initial short immune activation, there was a significant ICAM-1 and VCAM-1 induction in the vascular endothelium and the tubular epithelium. In the interstitium, there was infiltration of lymphocytes expressing ligand molecules VLA-4 and LFA-1, as well as activation markers MHC class II and IL-2R. Thereafter, the expression declined together with the increase of CADI-values. In end-stage chronic rejection, there was practically no expression of ICAM-1 and VCAM-1. In the interstitium, there were only few ligand-expressing leukocytes. In conclusion, adhesion molecules and their ligands are involved in the induction phase of the process but no longer in the later stages of chronic rejection. Received: 12 July 1999 Revised: 7 December 1999 Accepted: 27 April 2000     

Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)-mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA-treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA(-/-) Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA-treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA-treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID.     

Phosphorylation of GATA4 at serine 105 is required for left ventricular remodelling process in angiotensin II‐induced hypertension in rats

In this study, we investigated whether local intramyocardial GATA4 overexpression affects the left ventricular (LV) remodelling process and the importance of phosphorylation at serine 105 (S105) for the actions of GATA4 in an angiotensin II (AngII)‐induced hypertension rat model. Adenoviral constructs overexpressing wild‐type GATA4 or GATA4 mutated at S105 were delivered into the anterior LV free wall. AngII (33.3 µg/kg/h) was administered via subcutaneously implanted minipumps. Cardiac function and structure were examined by echocardiography, followed by histological immunostainings of LV sections and gene expression measurements by RT‐qPCR. The effects of GATA4 on cultured neonatal rat ventricular fibroblasts were evaluated. In AngII‐induced hypertension, GATA4 overexpression repressed fibrotic gene expression, reversed the hypertrophic adult‐to‐foetal isoform switch of myofibrillar genes and prevented apoptosis, whereas histological fibrosis was not affected. Overexpression of GATA4 mutated at S105 resulted in LV chamber dilatation, cardiac dysfunction and had minor effects on expression of myocardial remodelling genes. Fibrotic gene expression in cardiac fibroblasts was differently affected by overexpression of wild‐type or mutated GATA4. Our results indicate that GATA4 reduces AngII‐induced responses by interfering with pro‐fibrotic and hypertrophic gene expressions. GATA4 actions on LV remodelling and fibroblasts are dependent on phosphorylation site S105.     

Development and content validation of an assessment tool for medicine compounding on hospital wards

Background Medicines should be compounded by using an aseptic technique to assure patient safety. The parenteral administration of microbiologically contaminated doses can result in bacteriaemia, other morbidity and even death. Objective The purpose was to develop and content validate an assessment tool for medicine compounding on hospital wards suitable for self-assessment and external audit to ensure the safety of medicine compounding on wards. Setting Finland as setting. Method The first draft of the tool was based on ISMP “Guidelines for safe preparation of sterile compounds” and a systematic literature search. The tool was validated by using a two-rounded Delphi-method with a panel of 19 experts. Suitability and feasibility of each item was evaluated. Main outcome measure An agreement of ≥70% on each item was required. Results The final tool comprises of 64 items under the following topics: (1) general principles of good compounding practices (23 items), (2) recording and confirming medicine orders on the wards (5 items), (3) storage of medicines on the wards (7), (4) aseptic compounding of intravenous medicines (25 items) and (5) quality assurance (4 items). Most items related to General principles of good compounding practices and Compounding of IV medicines (36 and 38% of the items, respectively). Conclusion It was possible to develop and content validate, by the Delphi method, an assessment tool for safe aseptic compounding on hospital wards. A two-round Delphi process yielded consensus on 64 items for this purpose.