COMPETITION AMONG HOSPITALS AND ITS MEASUREMENT: THEORY AND A CASE STUDY

Our paper provides several insights on the characteristics of the concept of “Poles d’Excellence Rurale” (PER) through bilateral comparisons with that of Competitive Pole (CP) and cluster. The concept of PER is a French government’ initiative designed for the development of rural areas similar to that of the Competitive Pole. We emphasize important particularities of these concepts by analyzing some of their similarities and major differences.Pole d’Excellence Rurale, Competitive Pole, cluster, rural development

Angiotensin AT(2) Receptor Stimulation Alleviates Collagen-Induced Arthritis by Upregulation of Regulatory T Cell Numbers

The angiotensin AT(2) receptor (AT(2)R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT(2)R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT(2)R-stimulation with the selective non-peptide AT(2)R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4(+)FoxP3(+) cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4(+)IL-17A(+) and CD4(+)IFN-gamma(+) T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT(2)R-stimulation promotes the expansion of CD4(+) regulatory T cells and suppresses IL-17A production. Thus, AT(2)R-stimulation may represent an attractive treatment strategy for arthritis

Angiotensin AT(2) Receptor Stimulation Alleviates Collagen-Induced Arthritis by Upregulation of Regulatory T Cell Numbers

The angiotensin AT(2) receptor (AT(2)R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT(2)R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT(2)R-stimulation with the selective non-peptide AT(2)R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4(+)FoxP3(+) cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4(+)IL-17A(+) and CD4(+)IFN-gamma(+) T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT(2)R-stimulation promotes the expansion of CD4(+) regulatory T cells and suppresses IL-17A production. Thus, AT(2)R-stimulation may represent an attractive treatment strategy for arthritis

Misregulation of mitotic chromosome segregation in a new type of autosomal recessive primary microcephaly

Primary autosomal recessive microcephaly (MCPH) is a congenital disorder characterized by a pronounced reduction of brain size and mental retardation. We present here a consanguineous Turkish family clinically diagnosed with MCPH and without linkage to any of the known loci (MCPH1-MCPH7). Autozygosity mapping identified a homozygous region of 15.8 Mb on chromosome 10q11.23-21.3, most likely representing a new locus for MCPH. Although we were unable to identify the underlying genetic defect after extensive molecular screening, we could delineate a possible molecular function in chromosome segregation by the characterization of mitosis in the patients' cells. Analyses of chromosome nondisjunction in T-lymphocytes and fibroblasts revealed a significantly elevated rate of nondisjunction in the patients' cells as compared to controls. Mitotic progression was further explored by immunofluorescence analyses of several chromosome and spindle associated proteins. We detected a remarkable alteration in the anaphase distribution of Aurora B and INCENP, which are key regulators of chromosome segregation. In particular, a fraction of both proteins remained abnormally loaded on chromosomes during anaphase in MCPH patients' cells while in cells of normal control subjects both proteins are completely transferred to the spindle midzone. We did not observe any other alterations regarding cell cycle progression, chromosome structure, or response to DNA damage. Our observations point towards a molecular role of the underlying gene product in the regulation of anaphase/telophase progression possibly through interaction with chromosomal passenger proteins. In addition, our findings represent further evidence for the proposed role of MCPH genes in the regulation of mitotic progression

Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice.

In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis