Differential expression of the TL1A/DcR3 system of TNF/TNFR-like proteins in large vs. small intestinal Crohn's disease

Background

TNF-like cytokine 1A provides co-stimulatory signals to activated lymphocytes through binding to death-domain receptor-3. Decoy receptor-3 inhibits death-domain receptor-3 signalling, rendering immunocytes resistant to apoptosis. These functions may be important for the pathogenesis of Crohn's disease.

Aims

To study the mucosal and systemic expression of Decoy receptor-3 and TNF-like cytokine 1A in Crohn's disease, in relation to disease activity, localization, and response to treatment.

Methods

Soluble Decoy receptor-3 and TNF-like cytokine 1A were measured by ELISA in active or quiescent Crohn's disease. Relative mRNA expression in non-affected and inflamed intestinal mucosa was determined by real-time RT-PCR.

Results

We found significant upregulation of Decoy receptor-3 and its ligands TNF-like cytokine 1A and FasL in inflamed intestinal mucosa of Crohn's disease patients. During active disease, Decoy receptor-3 and TNF-like cytokine 1A were detected in the serum in the majority of patients. Intestinal inflammation was strongly associated with these elevations as they were absent during remission and significantly reduced with anti-inflammatory treatment. Regional diversity was observed as Decoy receptor-3 was upregulated in colonic and ileal sites, whereas TNF-like cytokine 1A was preferentially induced in the large bowel mucosa and systemic circulation of patients with colonic involvement.

Conclusions

TNF-like cytokine 1A and Decoy receptor-3 are upregulated during active Crohn's disease and may participate in disease pathogenesis and offer novel therapeutic opportunities.     

Homologous recombinational repair vis-à-vis chlorambucil resistance in chronic lymphocytic leukemia

The objective of this study was to further define the role of homologous recombinational repair (HRR) in resistance to the nitrogen mustards in B-cell chronic lymphocytic leukemia (B-CLL). We have demonstrated previously that increased chlorambucil (CLB)-induced HsRad51 nuclear foci formation correlated with a CLB-resistant phenotype in B-CLL lymphocytes. In this report, we measured the protein levels of HsRad51 and Xrcc3 (an HsRad51 paralog) and correlated them with the in vitro CLB cytotoxicity (LD(50)) in lymphocytes from seventeen B-CLL patients. Both HsRad51 (r=0.75, P=0.0005) and Xrcc3 (r=0.52, P=0.03) protein levels correlated with the in vitro CLB LD(50). In addition, multiple linear regression analysis showed a significant correlation between Xrcc3 and Rad51 protein levels versus the CLB LD(50) (r=0.78, P=0.0014), suggesting that both proteins influence CLB cytotoxicity. Moreover, since HsRad51 expression varies in cell lines during the cell cycle, we determined proliferating cell nuclear antigen (PCNA) protein levels to assess possible differences in cell cycle progression. There was no correlation between PCNA protein levels and the CLB LD(50) (r=0.042, P=0.87) or with HsRad51/Xrcc3 protein levels. Our data suggest that HsRad51 and Xrcc3 protein expression may be predictive of the response in B-CLL patients to treatment with nitrogen mustards.     

Newborn primary congenital glaucoma: 2005 update

BACKGROUND: Newborn primary congenital glaucoma is an unusual and important subtype of primary congenital glaucoma. Affected patients typically manifest specific signs that facilitate its recognition at birth and become important in the assessment and determination of appropriate treatment for this severe expression of primary congenital glaucoma. PATIENTS AND METHODS: The medical records of 35 patients with newborn primary congenital glaucoma were reviewed to determine its clinical manifestations and response to therapy. The published literature related to newborn primary congenital glaucoma was reviewed and referenced. RESULTS: Newborn primary congenital glaucoma is recognized at birth because of the associated corneal opacification. Ocular examination reveals anterior segment abnormalities of the cornea, iris, and filtration angle as well as related elevated intraocular pressure. Genetic analysis of a subset of patients with newborn primary congenital glaucoma confirmed its relationship with the less severe infantile form of primary congenital glaucoma, which is characterized by favorable results after goniosurgery. In contrast, goniosurgery was found to have unfavorable results and be less successful compared with trabeculectomy and glaucoma drainage tube shunts as initial therapy for newborn primary congenital glaucoma. CONCLUSIONS: Newborn primary congenital glaucoma is an important subtype of primary congenital glaucoma. It can be differentiated from the more frequent and familiar infantile type by history and careful anterior segment examinations to enable and support appropriate choices for its successful surgical treatment.     

Primary nephrotic syndrome in the black African child]

Idiopathic nephrotic syndrome (INS) in black African children differs from that of children in temperate areas. The main differences are the high rate of corticosteroid non-responders and the low rate of minimal change glomerulopathy in black African children, possibly related to a racial factor. The identification of a high corticosensibility in certain African regions (Togo and Ghana) can lead to the identification of an ethnic factor. Further genetic studies should be carried out in order to provide a better approach to INS in Africa.     

Cytotoxicity of a New Calcium Silicate Endodontic Sealer

Introduction

Resin sealers with biocompatible and bioactive additives have been used in clinical practice. Recently, a calcium silicate root canal sealer was introduced under the name BioRoot RCS (Septodont, Saint Maur-des-Fossés, France). The aim of this study was to evaluate the effects of BioRoot RCS on cell survival and proliferation of cultured cells in parallel with an epoxy resin sealer with calcium phosphate and calcium oxide and a salicylate resin sealer with mineral trioxide aggregate filler. The tested hypothesis was that BioRoot RCS is significantly less cytotoxic than the other tested sealers.

TREM2-dependent lipid droplet biogenesis in phagocytes is required for remyelination

Upon demyelinating injury, microglia orchestrate a regenerative response that promotes myelin repair, thereby restoring rapid signal propagation and protecting axons from further damage. Whereas the essential phagocytic function of microglia for remyelination is well known, the underlying metabolic pathways required for myelin debris clearance are poorly understood. Here, we show that cholesterol esterification in male mouse microglia/macrophages is a necessary adaptive response to myelin debris uptake and required for the generation of lipid droplets upon demyelinating injury. When lipid droplet biogenesis is defective, innate immune cells do not resolve, and the regenerative response fails. We found that triggering receptor expressed on myeloid cells 2 (TREM2)–deficient mice are unable to adapt to excess cholesterol exposure, form fewer lipid droplets, and build up endoplasmic reticulum (ER) stress. Alleviating ER stress in TREM2-deficient mice restores lipid droplet biogenesis and resolves the innate immune response. Thus, we conclude that TREM2-dependent formation of lipid droplets constitute a protective response required for remyelination to occur.