Suppressed clinical experimental autoimmune myasthenia gravis in bm12 mice is linked to reduced intracellular calcium mobilization and IL-10 and IFN-gamma release by acetylcholine receptor-specific T cells

Class II MHC mutant bm12 mice have an increased resistance to experimental autoimmune myasthenia gravis (EAMG) compared to C57BL/6 mice. In vitro, this relative resistance was mainly associated with a reduced cytokine response to acetylcholine receptor (AChR) and its dominant pathogenic peptide alpha 146-162, whereas the response to the epitope alpha 111-126 remained intact. Calcium mobilization after stimulation of AChR-immune T cells with AChR or alpha 146-162 peptide, but not alpha 111-126 peptide, was decreased in bm12 compared to C57BL/6. Thus, the reduced incidence of clinical EAMG in bm12 is linked to lower IFN-gamma and IL-10 release, and intracellular calcium mobilization by alpha 146-162-specific T cells.     

Contribution of interleukin 2 and interleukin 12 receptors in signal transduction during cell activation of the immune system

Interleukin-2 (IL-2) and interleukin-12 (IL-12) belong to lympho-hematopoietic cytokines and play a critical role in the promotion and enhancement of cellular response. IL-2 as the second signal of antigenic stimulation facilitates the transition of the cell cycle from phase G1 to phase S and is responsible for the regulation of T lymphocytes proliferation and the activation of cytotoxic T cells, natural killers, macrophages and granulocytes. IL-12 is the dominant factor in T helper cells polarization leading to the secretion of IFN-gamma. Receptors for both of the cytokines (IL-2R or IL-12R) represent class I cytokine receptors composed of multiple subunits. Generally, they contain a similar extracellular conserved motif of four cysteines, and amino acid sequence--WSXWS (interacting directly with ligand) but possess no catalytic domens in the intrinsic tail of the chains. For this reason, to transfer the impact, the association with number of signaling molecules, allowing the activation of the signaling pathways is required. The connections of IL-2R or IL-12R with their ligands recruit receptor-associated cytoplasmic proteins from the JAK family (JAK1/JAK3 or JAK2/TYK2, respectively), which catalyze the phosphorylation of themselves and intrinsic tyrosine residues on the receptor, creating STAT docking sites. This phosphorylated and subsequent dimerised proteins bind rapidly to DNA and activate it. This review, presents the differences and similarities between the signaling pathways triggered by IL-2R or IL-12R ligation.     

N-methyl-d-aspartate receptor-mediated processing of beta-amyloid precursor protein in rat hippocampal slices: in vitro--superfusion study

Abnormal proteolytic degradation of the beta amyloid precursor protein (beta-APP) may result in accumulation of potentially neurotoxic beta amyloid (betaA). The role of various receptors in the regulation of beta-APP processing has been suggested. This study aimed to determine how NMDA receptors and Ca2+ ions regulate proteolysis of beta-APP in rat hippocampus in vitro. Adult rat hippocampal slices were superfused with NMDA-containing media, and immunoreactivity of soluble beta-APP derivatives was detected in dialysates. Application of 100 microM and 250 microM NMDA for 20 min in Ca2+-containing medium induced dose-dependent release of aminoterminal beta-APP derivatives, and a fragment of Abeta sequence, whereas carboxy-terminal fragments of beta-APP were only slightly detected. This indicates activation of beta-APP processing, and release of its soluble cleavage products. This effect was inhibited by NMDA receptor antagonist 1 microM MK-801 and 100 microM CPP in Ca2+-free medium, thus indicating that NMDA receptors and calcium ions mediate proteolytic non-amyloidogenic degradation of the beta-APP.     

The role of platelet activating factor (PAF) in physiology and pathology of the central nervous system

This review describes the role of platelet activating factor (PAF) in the central nervous system injury. Cerebral ischaemia, traumatic injury of central nervous system, metabolic, toxic and degenerative neuropathy, and also the increase in Ca2+ concentration in the cell, are strong stimulators of PAF synthesis and its release from cell membranes. Neurons, glial and microglial cells, monocyte cell populations, macrophages and endothelial cells of blood vessels are the targets of platelet activating factor. The release of PAF leads to ischaemia of nervous tissue, acute traumatic or nontraumatic injuries, degenerative and metabolic nervous system disorders in adults. The use of PAF receptor antagonists prevents partially cell injury in central nervous system and leukocyte adhesion to endothelial cells.     

Vertebral canal abscess as a complication of congenital sacral sinus in a two year old girl

Vertebral canal abscess is rather an uncommon disease. Since 1830, when the first report that spinal of abscess was published. Till to 2000, no more than 20 cases as a result of dermal sinus infection were reported. Dermal sinus results from an incomplete separation of the cutaneus ectoderm from the neural ectoderm between the 4 and 6 weeks of fetal development. Surgical excision of the sinus is the treatment of choice for prevention of infection. The authors describes a 2-year-old girl with that abscess secondary to dorsal dermal sinus in sacral region. The patient presented with fever, since two weeks, flaccid paraparesis mainly in the right lower extremity, urinary and bowel incontinence. The child was initially treated conservatively, and after limitation of inflammatory process the dermal sinus and dermoid cyst containing a large quantity of pus were excised. The authors reviewed the literature of spinal cord abscesses secondary to congenital dermal sinus. The diagnostic and therapeutic methods presented in the literature are discussed in comparison with our case.     

Effect of trimetazidine on the nucleotide profile in rat kidney with ischemia-reperfusion injury.

Ischemia-reperfusion injury is often responsible for delayed graft function after transplantation. Trimetazidine (TMZ) is an antioxidant agent used to protect grafts from ischemia-reperfusion injury. The aim of the study was to examine the effect of TMZ on nucleotide profile in rat kidney with ischemia-reperfusion injury. The study was carried out on Wistar rats divided into two groups: animals treated with TMZ and control group receiving placebo. TMZ 10mg/kg/day was administrated for 30 days. Concentrations of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine (Ado), guanosine triphosphate (GTP), guanosine diphosphate (GDP), guanosine monophosphate (GMP), guanosine (Guo), inosine monophosphate (IMP), inosine (Ino), hypoxanthine (Hyp), xanthine (Xan), uric acid (UA), uridine (Urd), nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) were determined in kidney tissues after ischemia-reperfusion using HPLC. The total adenine nucleotide concentration (TAN) and adenylate energy charge (AEC) were also determined. Moreover the kidneys were evaluated histologically. Tissue concentrations of ATP, ADP, AMP, TAN and AEC were significantly increased in kidneys from rats treated with TMZ in comparison with rats receiving placebo. Concentrations of products of nucleotide degradation: inosine (Ino), guanosine (Guo) and uridine (Urd), as well as oxypurines: Hyp and Xan, were significantly decreased in rats treated with trimetazidine. Moreover, significantly less pronounced acute tubular necrosis was observed in kidneys of rats treated with TMZ. These results suggest that trimetazidine protects against dephosphorylation of nucleotides and ischemic damage.     

CHEK2-positive breast cancers in young Polish women.

PURPOSE: To investigate the contribution of CHEK2 mutations to early-onset breast cancer in Poland and to establish the characteristic features of these cancers. EXPERIMENTAL DESIGN: We studied 3,228 women diagnosed with breast cancer under the age of 51 years and 5,496 population controls. CHEK2 mutations were detected by RFLP-PCR or allele-specific oligonucleotide-PCR assays. Clinical and pathologic features of CHEK2-positive cases and CHEK2-negative cases were compared. RESULTS: A truncating CHEK2 mutation (1100delC or IVS2+1G>A) was seen in 47 of 3,228 cases and in 34 of 5,496 controls (odds ratio, 2.4; P = 0.0001). The CHEK2 I157T missense mutation was present in 207 of 3,228 cases, compared with 264 of 5,496 controls (odds ratio, 1.4; P = 0.002). Breast cancers in women with a CHEK2 mutation were more commonly of lobular histology (21.5% versus 15.8%; P = 0.05), of size >2 cm (54.8% versus 43.5%; P = 0.01), or of multicentric origin (28.7% versus 19.5%; P = 0.01) than were cancers from women without a CHEK2 mutation. Bilateral cancers were equally common in both subgroups. CONCLUSION: Three founder alleles in CHEK2 contribute to early-onset breast cancer in Poland. Breast tumors which arise in carriers of CHEK2 mutations seem to be similar to those of breast cancers in the population at large.     

Th1/Th2 balance and CD45-positive T cell subsets in primary nephrotic syndrome

T cells are involved in the pathogenesis of nephrotic syndrome (NS). The aim of the study was to determine whether the activity of T-helper-1 (Th1) and T-helper-2 (Th2) cells and the distribution of the lymphocyte subsets, namely CD45RA+CD4+ (”naive” helper T cells, suppressor-inducer), CD45RA+CD8+ (”naive” suppressor T cells, suppressor-effector), CD45RO+CD4+ (”memory” helper T cells), are predictive for steroid sensitivity in children with primary NS. These parameters were assessed at the onset of disease, before initiation of steroid therapy. Two groups of NS children were retrospectively formed according to steroid sensitivity (SS) or resistance (SR). The activity of Th1 and Th2 cells was defined by the production of interleukin-2 (IL-2), interferon-γ, IL-4, and IL-10 in the supernatants of CD4+ T cell cultures activated with autologous monocytes presenting tetanus toxoid (TT). Peripheral lymphocyte subsets were determined using double- or triple-color flow cytometry. In SS children with NS we found a decreased proliferative response of CD4+ T cells to TT stimulation, cytokine synthesis indicating the predominance of Th2 activity, and an increased percentage of activated suppressor-inducer (CD45RA+ CD4+CD25+, 5.18±0.8, P<0.001) and suppressor-effector (CD45RA+CD8+CD25+, 2.05±0.6, P<0.01) cells, with the concomitant reduction of activated memory cells (CD45RO+CD4+CD25+, 0.2±0.1, P<0.001). In children with SRNS we found an increased proliferative response of CD4+ T cells to TT, a rise in activated memory (CD45RO+CD4+CD25+, 3.82±0.7, P<0.01) and suppressor-inducer peripheral T cells (CD45RA+ CD4+CD25+, 3.85±0.6, P<0.01), but a low percentage of activated suppressor-effector (CD45RA+CD8+ CD25+, 0.5±0.2, P<0.05) T cells. We conclude that prior to treatment the distribution of lymphocyte subpopulations in peripheral blood together with Th1 and Th2 cell activity provides a useful tool for evaluating the likelihood of steroid sensitivity in patients with primary NS. Received: 3 November 1998 / Revised: 1 September 1999 / Accepted: 8 September 1999