Dermatitis herpetiformis (DH) is an autoimmunity-driven inflammatory blistering dermatosis associated with a gluten-dependent enteropathy. Tissue transglutaminase (tTG) and nonapeptides of gliadin (npG) are considered in its pathomechanism/diagnostics. Here, the diagnostic accuracy of anti-tTG/anti-npG IgA ELISAs in Slavic DH patients with active skin rash was assessed through creating receiver operating characteristic (ROC) curves, determining cutoff values, and calculating correlations between levels of anti-tTG/anti-npG IgA in DH, IgA/neutrophil-mediated non-DH patients and healthy persons. Altogether, sera from 80 Slavic individuals were examined. There were negligible differences between cutoff points obtained by the ELISAs manufacturer and those in this study. There were statistically significant correlations between levels of anti-tTG/anti-npG IgA in both DH group and the group of IgA/neutrophil-mediated non-DH dermatoses. There was no such correlation in healthy controls. It seems that IgA autoantibodies to tTG and npG in the IgA/neutrophil-mediated DH are produced in the coordinated way implying their causal relationship.

Cytokeratins (CKs) 8 and 18 are normally expressed in simple epithelia. This unique pair of CKs is believed to be involved in hepatic diseases and many human cancers. Little is known about the role of tissue expression of both CKs in patients with cholelithiasis (CH). The aim of the study was to analyse tissue expression of CK8 and 18 in the specimens of gallbladder mucosa in 35 young (up to 25 years of age) and 20 older patients (approximately 50 years of age) with CH. An immunocytochemical ABC method and the spatial visualization technique were conducted. Our study demonstrated significantly lower amounts of both CKs in young patients, as compared to older patients. The higher cellular expression of CK8 in older patients was linked to acute clinical course vs. chronic ones. Tissue expression of neither CK correlated with inflammatory activity (grading) of the gallbladder mucosa. A positive correlation between reciprocal expressions of the two CKs may confirm a cytoprotective role of the two proteins in both groups of patients with symptomatic CH. Significantly higher expression of CK18 than that of CK8 in younger patients suggests a different role of CK8 and 18 in lithogenesis in this group.

BACKGROUND: Transplant arteriosclerosis (TA) is the pathognomonic feature of chronic rejection, the primary cause of allograft failure. We have shown that the NF-κB inhibitory protein A20 exerts vasculoprotective effects in endothelial and smooth muscle cells (SMC), and hence is a candidate to prevent TA. We sought direct proof for this hypothesis. METHODS: Fully mismatched, C57BL/6 (H2) into BALB/c (H2), aorta to carotid allografts were preperfused with saline, recombinant A20 adenovirus (rAd.A20) or rAd.β-galactosidase (β-gal), implanted, harvested 4 weeks after transplantation, and analyzed by histology, immunohistochemistry, and immunofluorescence staining. We measured indoleamine 2,3-dioxygenase, interleukin-6, and transforming growth factor-β mRNA and protein levels in nontransduced, and rAd.A20 or rAd.β-gal-transduced human SMC cultures after cytokine treatment. RESULTS: Vascular overexpression of A20 significantly reduced TA lesions. This correlated with decreased graft inflammation and increased apoptosis of neointimal SMC. Paradoxically, T-cell infiltrates increased in A20-expressing allografts, including the immunoprivileged media, which related to A20 preventing indoleamine 2,3-dioxygenase upregulation in SMC. However, infiltrating T cells were predominantly T-regulatory cells (CD25+/Forkhead Box P3 [FoxP3+]). This agrees with A20 inhibiting interleukin-6 and promoting transforming growth factor-β production by medial SMC and in SMC cultures exposed to cytokines, which favors differentiation of regulatory over pathogenic T cells. CONCLUSIONS: In summary, A20 prevents immune-mediated remodeling of vascular allografts, therefore reduces TA lesions by affecting apoptotic and inflammatory signals and modifying the local cytokine milieu to promote an immunoregulatory response within the vessel wall. This highlights a novel function for A20 in local immunosurveillance, which added to its vasculoprotective effects, supports its therapeutic promise in TA.

The cellular response to an inflammatory stressor requires a proinflammatory cellular activation followed by a controlled resolution of the response to restore homeostasis. We hypothesized that biliverdin reductase (BVR) by binding biliverdin (BV) quells the cellular response to endotoxin-induced inflammation through phosphorylation of endothelial nitric oxide synthase (eNOS). The generated NO, in turn, nitrosylates BVR, leading to nuclear translocation where BVR binds to the Toll-like receptor-4 (TLR4) promoter at the Ap-1 sites to block transcription. We show in macrophages that BV-induced eNOS phosphorylation (Ser-1177) and NO production are mediated in part by Ca(2+)/calmodulin-dependent kinase kinase. Furthermore, we show that BVR is S-nitrosylated on one of three cysteines and that this posttranslational modification is required for BVR-mediated signaling. BV-induced nuclear translocation of BVR and inhibition of TLR4 expression is lost in macrophages derived from Enos(-/-) mice. In vivo in mice, BV provides protection from acute liver damage and is dependent on the availability of NO. Collectively, we elucidate a mechanism for BVR in regulating the inflammatory response to endotoxin that requires eNOS-derived NO and TLR4 signaling in macrophages.

Pattern recognition receptors (PRRs) constitute a pivotal arm of innate immunity. Their distribution is widespread and not limited to cells of the immune system. Following our previous findings concerning the expression of Toll-like receptors (TLRs) 2, 3 and 4 in chronic viral hepatitis C of children, we wished to search for other PRRs, including other TLRs, NOD-like receptors (NLRs) and RIG-1-like helicase receptors (RLR) in infected hepatocytes. Liver biopsy fragments from ten children with chronic hepatitis B and C were used and two others in which hepatotropic virus infection was excluded. Frozen sections of liver samples were subjected to ABC immunohistochemistry (IHC) following incubation with a set of antibodies. Results of IHC findings were screened for correlation with clinical/laboratory data of patients. It was found that several PRRs could be shown in affected hepatocytes, but the incidence was higher in hepatitis C than in B. In hepatitis C, TLR1, 2, 4, NALP and RIG-1 helicase showed the most marked expression. In hepatitis B, TLR1, 3, 9, NOD1 and NALP expression were the most conspicuous. Expression PRRs in liver from hepatitis of unknown origin was much lower. It was also the case in cytospins from human hepatoma cell line. Several correlations between PRRs expression and clinical findings in patients could be shown by statistical exploration. In conclusion, this data suggests some role for PRRs in the pathogenesis of chronic viral hepatitis.(Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 3, pp. 410-416).

BACKGROUND We aimed to examine the role of age and premorbid intelligence (IQ) in suppressing the relationship between subjective memory complaints (SMCs) and raw score memory performance. METHODS We used a community sample of older adults aged 66-90 years (N = 121) to test whether the inclusion of age and a premorbid IQ measure in multiple regression analyses increased semipartial correlations of raw score memory performance in predicting SMCs. Rank contrast correlations were also carried out to observe how age and premorbid IQ are related to complaint-performance congruency. Measures utilized in the study included the Memory Functioning Questionnaire (for SMCs), Visual Reproduction and Logical Memory Subtests (memory performance), and the National Adult Reading Test (premorbid IQ). RESULTS Inclusion of age and premorbid IQ in the multiple regression analyses increased semipartial correlations for all raw score measures of memory. Both age and premorbid IQ were significantly related to complaint-performance congruency, whereby older participants and those with lower premorbid IQ scores rated their memory abilities more leniently than younger and higher premorbid IQ participants. CONCLUSION The results suggest differences in age and premorbid IQ play a small role in suppressing the relationship between SMCs and memory performance when utilizing raw score measures of memory.

Desmosomal cadherins in humans involve three isoforms, each in two splicing variants, of desmocollin (DSC1-3) and four isoforms of desmoglein (DSG1-4). DSGs are transmembranous desmosomal adhesive glycoproteins, which are generally expressed in a differentiation-specific manner. The aim of this study was to measure intensities of expression of both DSG2 and DSG3 in basal cell carcinoma (BCC) and to compare them with those in normal epidermis. Using immunoperoxidase staining on frozen tissue with monoclonal antibodies against human DSG2 and DSG3, DSG2 and DSG3 expression was assessed in specimens from 26 BCC patients. There was a significant overexpression of DSG2 and a significantly lower expression of DSG3 in BCC tumor nests (BCCpos) compared to non-BCC-affected epidermis (BCCneg). There was no significant correlation between the intensities of DSG2 and DSG3 expression in BCCpos, but there was a significant correlation (r=+0.6092) between these markers in BCCneg. That loss of coordination of DSG2 and DSG3 expression in BCC, revealed with quantitative digital morphometry, might explain in part the BCC behavior as a locally invasive tumor. Our study further suggests that in human skin, DSG2-mediated adhesion appears to be more proliferation-associated, whereas DSG3-mediated adhesion seemingly is more differentiation-associated.

Vascular remodeling plays a pivotal role in a variety of pathophysiological conditions where hypoxia and inflammation are prominent features. Intravascular ATP, ADP and adenosine are known as important regulators of vascular tone, permeability and homeostasis, however contribution of purinergic signalling to endothelial cell growth and angiogenesis remains poorly understood. By using vasa vasorum endothelial cells (VVEC) isolated from pulmonary artery adventitia of control and chronically hypoxic neonatal calves, these studies were aimed to evaluate the effect of hypoxia on biochemical and functional properties of microvascular endothelial network at the sites of angiogenesis. In comparison with normoxic controls, VVEC from hypoxic animals are characterized by (1) drastically impaired nucleoside triphosphate diphosphohydrolase-1 (NTPDase-1/CD39) and ecto-5'-nucleotidase/CD73 activities with respective increases in basal extracellular ATP and ADP levels (2) higher proliferative responses to low micromolar concentrations of ATP and ADP; and (3) enhanced permeability and disordered adenosinergic control of vascular barrier function (measured as a paracellular flux of 70 kDa fluorescein isothiocyanate-dextran). Together, these results suggest that unique pattern of purine-mediated angiogenic activation and enhanced leakiness of VVEC from chronically hypoxic vessels may be defined by disordered endothelial nucleotide homeostasis at sites of active neovascularization.

Well-established evidence links extracellular nucleotides to numerous vascular pathologies, including restenosis associated with angioplasty, atherosclerosis and transplant arteriosclerosis. Through activation of purinergic P2 receptors, extracellular nucleotides contribute to the pathogenesis of occlusive vascular diseases by mediating thrombosis, and vascular smooth muscle proliferation and migration. Therefore, there is a growing interest in the enzymes that hydrolyze nucleotides for their capability to modulate nucleotide-triggered pathologies. In this review, we present the current data addressing the therapeutic potential of nucleoside triphosphate diphosphohydrolases (NTPDases) to prevent intimal hyperplasia and treat vascular intimal disease. In addition, we discuss the mechanisms by which NTPDases exert protective effects in vascular function.

Aim  Dysplasia of the pouch mucosa after restorative proctocolectomy is rare. The aim of this study was to establish whether there is a correlation between pouchitis and dysplasia. Method  A group of 276 patients treated for ulcerative colitis by restorative proctocolectomy between 1984 and 2009 was analysed. The presence or absence of pouchitis and dysplasia within the pouch was evaluated. Results  Inflammation was diagnosed in 66 (23.9%) patients, low-grade dysplasia in five (1.8%), high-grade dysplasia in three (1.1%), and cancer in one patient (0.4%). The prevalence of low-grade dysplasia was significantly higher in patients with inflammation than in those without (P < 0.04). High-grade dysplasia was significantly more frequent in pouchitis than in non-inflamed pouches (P < 0.01). Logistic regression analysis suggested that the occurrence of mucosal inflammation increased the risk of low grade dysplasia. Conclusion  Patients with chronic pouchitis are at risk of dysplasia and require surveillance of the pouch.