Donor interleukin-4 promoter gene polymorphism influences allograft rejection after heart transplantation.

BACKGROUND: The cytokine interleukin-4 (IL-4) is secreted mainly by activated T lymphocytes and characterizes the T-helper 2 (Th2) sub-type. In transplantation Th2 cells are believed to induce graft tolerance. Previous studies revealed that patients with a relatively high frequency of IL-4 producing helper T lymphocytes (HTL) before heart transplantation (HTX) had no or less rejection episodes compared with patients with a low frequency of IL-4 producing HTL. Three single nucleotide polymorphisms (SNPs) have been identified in the promoter region of the IL-4 gene, which influence promoter strength. We investigated whether there was a correlation between SNP genotypes in the IL-4 promoter and heart failure, and rejection after HTX. METHODS: Seventy HTX patients, 61 donors, and 36 controls were genotyped for the 3 SNPs by sequencing. RESULTS: Of the SNPs at -285 and -81, only the C and A alleles, respectively, were found in this study. Both alleles were found for the -590 SNP. No relation between patient genotype of the SNP at -590 and heart failure and rejection was found. However, incidence of rejection was significantly lower in patients that received a donor heart with the T-positive genotype compared with patients that received a heart from a T-negative donor. Patients who had the T-negative genotype and received a heart from a T-positive donor, suffered significantly less from rejection than T-negative patients that received a T-negative donor heart. This was not significant in the T-positive patient group. CONCLUSIONS: This indicates that IL-4 production within the donor heart and by cells from the donor is important for reducing incidence of episodes of rejection.     

Characterization of P-glycoprotein and multidrug resistance proteins in rat kidney and intestinal cell lines.

The activity of P-glycoprotein (Pgp/MDR1/ABCB1) and multidrug resistance proteins (MRP/ABCC) influence the pharmacokinetics and bioavailability of many drugs. Few suitable cell lines for the study of drug transport exist. Additional non-human cell lines may help clarify species differences and contribute to the current knowledge of drug transport. The aim of the present study was to characterize three rat epithelial cell lines for transporter expression and activity. Transporter expression was assessed in intestinal IEC-6 and renal GERP and NRK-52E cells using RT-PCR and Western blot analysis. Pgp and Mrp transport activity were analyzed by measuring calcein accumulation and glutathione-S-bimane efflux, respectively. The three cell lines showed Pgp expression and Pgp-dependent transport, both decreasing with culture time after reaching confluency. Besides Pgp, cells expressed Mrp1, Mrp3, Mrp4, and Mrp5, while Mrp2 and Mrp6 were absent. In addition, they showed temperature- and Mrp-dependent efflux of glutathione-S-bimane. Exposure to a panel of different inhibitors showed that this efflux was probably mediated by Mrp4. In conclusion, the three rat epithelial cell lines investigated showed Pgp and Mrp expression and transport. Mrp dependent transport was most likely mediated by Mrp4. In future, these cell lines may be used as in vitro models to study drug transport.     

Stress proteins as inducers and targets of regulatory T cells in arthritis

Immunization with microbial or mammalian stress proteins or heat-shock proteins in models of experimental autoimmunity has been observed to lead to increased disease resistance. Furthermore, such immunization has been proposed to result in the induction and expansion of T cells that suppress disease upon transfer. Comparisons of microbial heat-shock proteins with other conserved immunogenic proteins of bacterial origin have indicated a unique capacity for heat-shock proteins to induce a regulatory phenotype in T cells, such as reflected by the production of IL10. Also, studies in children with chronic arthritis have indicated that T-cell responses to heat-shock proteins are associated with a benign course of the disease and with remission. Furthermore, in patients, heat-shock-protein-(HSP-) activated T cells were shown to display regulatory phenotypes consistent with CD4+ CD25+ T regulatory cells.     

Modulation of osteopontin in proteinuria-induced renal interstitial fibrosis

Proteinuria is associated with macrophage-dependent interstitial fibrosis (IF). Osteopontin (OPN), a macrophage chemoattractant, may be involved in the transition of proteinuria to IF but protective properties have also been reported. To elucidate whether OPN may be involved in the proteinuria-induced cascade of tubulointerstitial damage, renal expression of OPN was studied during the development of proteinuria-induced renal damage and during anti-proteinuric intervention with ACE inhibition (ACEi). First, the temporal relationships between proteinuria, interstitial OPN induction, and IF in adriamycin nephrosis (AN), a model of chronic proteinuria-induced renal damage, were studied. Second, the effect of anti-proteinuric treatment on OPN expression was investigated. The time course of OPN induction and markers of renal damage was studied in rats with unilateral AN at 6-week intervals until week 30. In a second study, a renal biopsy was taken 6 weeks after induction of bilateral AN; subsequently, rats were treated with ACEi until termination (week 12). In unilateral AN, proteinuria developed gradually and stabilized at week 10. In proteinuric kidneys, OPN expression was induced from week 12 onwards. Simultaneously, a progressive increase in interstitial macrophages, alpha-smooth muscle actin (alpha-SMA), collagen type III, and focal glomerulosclerosis (FGS) was observed. In bilateral AN, ACEi reduced proteinuria and OPN protein and stabilized fibrosis. In untreated animals, OPN mRNA increased, with stable OPN protein and fibrosis and increased FGS. Thus, in AN, development of proteinuria is followed by up-regulation of OPN along with markers of renal damage. The up-regulation of OPN is reversible by anti-proteinuric treatment without a corresponding reduction in fibrosis. Whereas these data are consistent with a role for OPN in the cascade of transition from proteinuria to fibrosis, intervention with ACEi showed that reduction of OPN does not attenuate established fibrosis.     

Inability to Work Fulltime,Prevalence and Associated Factors Among Applicants for Work Disability Benefit

Journal of Occupational Rehabilitation - Purpose Inability to work fulltime is an important outcome in the assessment of workers applying for a disability benefit. However, limited knowledge is...     

Person misfit on the Inventory of Depressive Symptomatology: Low quality self‐report or true atypical symptom profile?

Person misfit on a self‐report measure refers to a response pattern that is unlikely given a theoretical measurement model. Person misfit may reflect low quality self‐report data, for example due to random responding or misunderstanding of items. However, recent research in the context of psychopathology suggests that person misfit may reflect atypical symptom profiles that have implications for diagnosis or treatment. We followed‐up on Wanders et al. (Journal of Affective Disorders, 180, 36–43, 2015) who investigated person misfit on the Inventory of Depressive Symptomatology (IDS) in the Netherlands Study of Depression and Anxiety (n = 2,981). Our goal was to investigate the extent to which misfit on the IDS reflects low‐quality self‐report patterns and the extent to which it reflects true atypical symptom profiles. Regression analysis showed that person misfit related more strongly to self‐report quality indicators than to variables quantifying theoretically‐derived atypical symptom profiles. A data‐driven atypical symptom profile explained most variance in person misfit, suggesting that person misfit on the IDS mainly reflects a sample‐ and questionnaire‐specific atypical symptom profile. We concluded that person‐fit statistics are useful for detecting IDS scores that may not be valid. Further research is necessary to support the interpretation of person misfit as reflecting a meaningful atypical symptom combination.     

Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies

We present the nature of pathogenic SNP array findings in pregnancies without ultrasound (US) abnormalities and show the additional diagnostic value of SNP array as compared with rapid aneuploidy detection and karyotyping. 1,330 prenatal samples were investigated with a 0.5‐Mb SNP array after the exclusion of the most common aneuploidies. In 2.7% (36/1,330) of the cases, pathogenic chromosome aberrations were found; a microscopically detectable abnormality in 0.7% and a submicroscopic aberration in 2%. Our results show that in addition to the age‐ or screening‐related aneuploidy risk, in pregnancies without US abnormalities, there is a risk of 1:148 (9/1,330) for a (sub)microscopic abnormality associated with an early‐onset often severe disease, 1:222 (6/1,330) for a submicroscopic aberration causing an early‐onset disease, 1:74 (18/1,330) for carrying a susceptibility locus for a neurodevelopmental disorder, and 1:443 (3/1,330) for a late‐onset disorder (hereditary neuropathy with liability to pressure palsies in all three cases). These risk figures are important for adequate pretest counseling so that prospective parents can make informed individualized choices between targeted prenatal testing and broad testing with SNP array. Based on our results, we believe if invasive testing is performed, SNP array should be the preferred cytogenetic technique irrespective of the indication.