The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

Background

Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin‐dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE).

Material and methods

To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family‐based SLE collections, containing more than 2000 samples.

Result

A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3′ part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non‐terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5–6 times, p<0.0001 for all tests).

Conclusion

Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.     

CD83 is a regulator of murine B cell function in vivo

The transmembrane glycoprotein CD83 has been described as a specific maturation marker for dendritic cells and several lines of evidence suggest that CD83 regulates thymic T cell maturation as well as peripheral T cell activation. Here we show for the first time that CD83 is involved also in the regulation of B cell function. CD83 is up-regulated on activated B cells in vivo, specifically in the draining lymph nodes of Leishmania major-infected mice. The ubiquitous transgenic (Tg) expression of CD83 interferes with Leishmania-specific T cell-dependent and with T cell-independent antibody production. This defect is restricted to the B cell population since the antigen-specific T cell response of CD83Tg mice to L. major infection is unchanged. The defective immunoglobulin (Ig) response is due to Tg expression of CD83 on the B cells because wild-type B cells display normal antigen-specific responses in CD83Tg hosts and CD83Tg B cells do not respond to immunization in a mixed wild-type/CD83Tg bone marrow chimera. Finally, the treatment of non-Tg C57BL/6 mice with anti-CD83 mAb induces a dramatic increase in the antigen-specific IgG response to immunization, thus demonstrating a regulatory role for naturally induced CD83 on wild-type B cells.     

Der BGF-Monitor

Background

Surveys on employee health are of significant importance in order to develop target group specific interventions in operational health management. The aim of the present study was to assess the psychometric quality of a screening questionnaire on employee health and to identify and assess the factorial structure of the questionnaire.

Materials and methods

The screening questionnaire was answered by 1855 employees from nine companies. Internal consistency was tested by Cronbach’s alpha (α) using the split-half method. Discriminatory power (part-whole correction) of the items and item severity were assessed for the 25 items. An exploratory factor analysis as well as comparative confirmatory factor analysis was computed and model fitting was assessed (Root Mean Square Error of Approximation, RMSEA; Standardized Root Mean Square Residual, SRMR).

Results

The questionnaire (Cronbach’s α 0.948) and the scales (Cronbach’s α 0.802–0.912) had good reliabilities. Discriminatory power (part-whole correction) and item severity of the 25 items was good. The exploratory factor analysis identified a four-factor model that was confirmed by the confirmatory factor analysis. Model fit showed a RMSEA of 0.081 and SRMR of 0.067.

Conclusions

As the results indicated good psychometric properties, the BGF Monitor was verified as a short and reliable instrument applicable to research and practice in operational health management. The reliability of the instrument was good and the items showed good discriminatory power as well as a well-balanced item severity. The model structure showed a reasonably close fit.

     

Wie häufig werden Patienten mit depressiven Störungen in der hausärztlichen Praxis erkannt?

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Hausärzte sind als Primärversorger für Patienten mit depressiven Störungen entscheidende Weichensteller...     

How should hospital reimbursement be refined to support concentration of complex care services?

The English National Health Service is promoting concentration of the treatment of patients with relatively rare and complex conditions into a limited number of specialist centres. If these patients are more costly to treat, the prospective payment system based on Healthcare Resource Groups (HRGs) may need refinement because these centres will be financially disadvantaged. To assess the funding implications of this concentration policy, we estimate the cost differentials associated with caring for patients that receive complex care and examine the extent to which complex care services are concentrated across hospitals and HRGs. We estimate random effects models using patient‐level activity and cost data for all patients admitted to English hospitals during the 2013/14 financial year and construct measures of the concentration of complex services. Payments for complex care services need to be adjusted if they have large cost differentials and if provision is concentrated within a few hospitals. Payments can be adjusted either by refining HRGs or making top‐up payments to HRG prices. HRG refinement is preferred to top‐payments the greater the concentration of services among HRGs.     

Psychodramatiker*innen und ihr sehr persönlicher Umgang mit ihrem Handwerkszeug

Zeitschrift für Psychodrama und Soziometrie - In diesem Artikel der Zeitschrift für Psychodrama und Soziometrie geben fünf Psychodramatiker*innen Einblick in ihren Praxisalltag und...     

Toward acellular xenogeneic heart valve prostheses: Histological and biomechanical characterization of decellularized and enzymatically deglycosylated porcine pulmonary heart valve matrices

The use of decellularized xenogeneic heart valves might offer a solution to overcome the issue of human valve shortage. The aim of this study was to revise decellularization protocols in combination with enzymatic deglycosylation, in order to reduce the immunogenicity of porcine pulmonary heart valves, in means of cells, carbohydrates, and, primarily, Galα1-3Gal (α-Gal) epitope removal. In particular, the valves were decellularized with sodium dodecylsulfate/sodium deoxycholate (SDS/SD), Triton X-100 + SDS (Tx + SDS), or Trypsin + Triton X-100 (Tryp + Tx) followed by enzymatic digestion with PNGaseF, Endoglycosidase H, or O-glycosidase combined with Neuraminidase. Results showed that decellularization alone reduced carbohydrate structures only to a limited extent, and it did not result in an α-Gal free scaffold. Nevertheless, decellularization with Tryp + Tx represented the most effective decellularization protocol in means of carbohydrates reduction. Overall, carbohydrates and α-Gal removal could strongly be improved by applying PNGaseF, in particular in combination with Tryp + Tx treatment, contrary to Endoglycosidase H and O-glycosidase treatments. Furthermore, decellularization with PNGaseF did not affect biomechanical stability, in comparison with decellularization alone, as shown by burst pressure and uniaxial tensile tests. In conclusion, valves decellularized with Tryp + Tx and PNGaseF resulted in prostheses with potentially reduced immunogenicity and maintained mechanical stability.     

Bioengineered kidneys: new sights on a distant horizon

The need for renal replacement therapy is currently rising at an annually increasing rate. Current treatment options for patients with end-stage kidney disease include dialysis or organ transplantation. Yet, even though transplant survival has increased due to refined immunosuppressive therapy, morbidity remains high because of organ shortage. Here we discuss a recent publication that describes the transplantation of a bioengineered biocompatible kidney from a decellularized organ scaffold, thus possibly providing a solution to both transplant organ shortage and morbidity associated with long-term immunosuppression.