HLA phenotypes in patients surviving a long time after immunotherapy with BCG for acute childhood lymphoblastic leukemia. Arguments in favor of the existance of a gene for immune response in human leukemia]

HLA phenotypes of 13 patients surviving in lasting first remission over 6 years after BCG immunotherapy for acute childhood lymphoblastic leukaemia (ALL) were compared to phenotypes of normal subjects and of surviving ALL patients treated exclusively with chemotherapy. Among the BCG-treated patients, the frequency of the antigen HLA-BW 17 was 46.1% vs 7.3% in healthy controls (p less than 0.001) and the frequency of the antigen HLA-AW 33 was 30.8% vs 1.2% (p less than 0.001). 9 patients possessed at least one of these two antigens (69.2% vs 8% in controls p less than 0.001). Phenotypes of the chemotherapy-treated patients did not differ significantly from controls. These results suggest the existence in humans of HLA-linked genes which are involved in the response to BCG immunotherapy in ALL.     

Cellular and molecular pathogenesis of type 1A diabetes

Type 1A diabetes is an organ-specific autoimmune disease resulting from destruction of insulin-producing pancreatic beta-cells. The main susceptibility genes code for polymorphic HLA molecules and in particular alleles of class II MHC genes (DR, DQ and DP). Polymorphisms of individual genes outside the MHC also contribute to diabetes risk but recent evidence suggests that there are additional non-HLA genes determining susceptibility linked to the MHC. It is now possible using genetic and autoantibody assays to predict the development of type 1A diabetes in the majority of individuals, and trials of diabetes prevention are underway.     

Polymorphism in the regulatory sequence of the human hsp70-1 gene does not affect heat shock factor binding or heat shock protein synthesis

A bi-allelic polymorphism found in the regulatory region of the human heat shock (HS) protein (HSP) hsp70-1 gene, which comprises an A-->C transversion, 3 bp upstream of the HS element (HSE), has been associated with extended HLA haplotypes. In view of the chaperoning and protective functions of Hsp70, we investigated whether this hsp70-1 bi-allelic polymorphism could modulate the stress response, which may relate to enhanced resistance or susceptibility to certain diseases. We compared the basal and HS-induced HS factor (HSF)-binding activity of the two polymorphic HSEs, hsp70-1 mRNA accumulation and HSP expression in two human Epstein Barr virus (EBV)-transformed B cell lines typed for hsp70-1 promoter alleles. Our results suggest that hsp70-1 promoter polymorphism does not influence HSF-binding activity, hsp70 mRNA accumulation or synthesis in human EBV-transformed B cell lines.     

Detection of a minor stimulating product involved in secondary allogenic proliferation of human lymphocytes in vitro]

In a family with a shared parental haplotype studied in MLR I and II we report that: 1) A secondary proliferation can be induced without a primary positive MLR; 2) In these conditions a minor determinant activating secondary proliferation is detected; 3) No significant association of this product with the available makers (HLA-A, B, C, D, Ly-Li) of the HLA region has been found so far; its localisation within or outside the MHC is under investigation.     

HLA groups in the infantile psychoses during development, and hypothesis for an enzyme defect]

The HLA typing (loci A and B) of a series of fifteen psychotic children has shown an increase of the frequency of both HLA-A9 and B5 antigens. These preliminary data and previous biochemical findings in psychotic patients lead the authors to postulate the hypothesis of a qualitative or quantitative anomaly of the superoxide dismutase (SOD-2), the gene of which is situated on the same chromosome (sixth) as the HLA complex.     

Complexed rheumatoid factor measurements in sera, synovial fluids and in immune complex fractions.

Mild acidic treatment increases the rheumatoid factor titre of some sera and synovial fluids (SF) in rheumatoid arthritis (RA), juvenile RA (JRA) and most frequently in rheumatoid vasculitis. This unmasking of 'hidden' RF in serum and SF samples correlated with the RF-immune complexes (RF-IC) and complexed C4 present in the 3% polyethylene glycol (PEG) precipitates, indicating that by means of 'hidden' RF measurements RF-ICs are possibly detected. This method seems to provide a diagnostic tool for detecting RF-ICs in RA and other related diseases.     

Subatomic and atomic crystallographic studies of aldose reductase: implications for inhibitor binding

The determination of several of aldose reductase-inhibitor complexes at subatomic resolution has revealed new structural details, including the specific interatomic contacts involved in inhibitor binding. In this article, we review the structures of the complexes of ALR2 with IDD 594 (resolution: 0.66 Å, IC50 (concentration of the inhibitor that produced half-maximal effect): 30 nM, space group: P2¹), IDD 393 (resolution: 0.90 Å, IC50: 6 nM, space group: P1), fidarestat (resolution: 0.92 Å, IC50: 9 nM, space group: P2¹) and minalrestat (resolution: 1.10 Å, IC50: 73 nM, space group: P1). The structures are compared and found to be highly reproductible within the same space group (root mean square (RMS) deviations: 0.15 0.3 Å). The mode of binding of the carboxylate inhibitors IDD 594 and IDD 393 is analysed. The binding of the carboxylate head can be accurately determined by the subatomic resolution structures, since both the protonation states and the positions of the atoms are very precisely known. The differences appear in the binding in the specificity pocket. The high-resolution structures explain the differences in IC50, which are confirmed both experimentally by mass spectrometry measures of VC50 and theoretically by free energy perturbation calculations. The binding of the cyclic imide inhibitors fidarestat and minalrestat is also described, focusing on the observation of a Cl^- ion which binds simultaneously with fidarestat. The presence of this anion, binding also to the active site residue His110, leads to a mechanism in which the inhibitor can bind in a neutral state and then become charged inside the active site pocket. This mechanism can explain the excellent in vivo properties of cyclic imide inhibitors. In summary, the complete and detailed information supplied by the subatomic resolution structures can explain the differences in binding energy of the different inhibitors.     

Babylonian solar theory on the Antikythera mechanism

This article analyzes the angular spacing of the degree marks on the zodiac scale of the Antikythera mechanism and demonstrates that over the entire preserved 88° of the zodiac, the marks are systematically placed too close together to be consistent with a uniform distribution over 360°. Thus, in some other part of the zodiac scale (not preserved), the degree marks have been spaced farther apart. By contrast, the day marks on the Egyptian calendar scale are spaced uniformly, apart from minor errors. A solar equation of center is apparent which rises by nearly 2.7° over the preserved portion of the zodiac. The placement of the degree marks indicates that, in the preserved portion of the zodiac, the Sun was considered to run at a uniform pace of about 30° per synodic month, which is consistent with the Sun’s speed in the fast zone of the Babylonian solar theory of System A.

     

Immunology and functional genomics of Behçet's disease

Behçet's disease (BD) is a multisystemic inflammatory disorder. Although the cause and pathogenesis of BD are still unclear, there is evidence for genetic, immunologic and infectious factors at the onset or in the course of BD. This review focusses on the functional genomics and immunology of BD. HLA-B51 is the major disease susceptibility gene locus in BD. An increased number of T cells in the peripheral blood and in the involved tissues have been reported. However, the T cells at the sites of inflammation appear to be a phenotypically distinct subset. There is also a significant T cell proliferative response to mycobacterial 65-kDa heat shock protein peptides. Homologous peptides derived from the human 60-kDa heat shock protein were observed in BD patients. There is evidence that natural killer T cells may also play a role in BD.Received 27 November 2002; accepted 4 March 2003     

Common features between diabetes mellitus and Alzheimer’s disease

Epidemiological studies establish a link between Type 2 diabetes (T2DM) and Alzheimer’s disease (AD), both leading causes of morbidity and mortality in the elderly. These diseases also share clinical and biochemical features suggesting common pathogenic mechanisms. Specifically, both are amyloidoses as they are characterized by fibrillar protein aggregates – amylin in T2DM pancreatic islets, and β-amyloid (Aβ) and neurofibrillary tangles (NFTs) in AD brain. Amylin aggregation is associated with pancreatic β-cell loss, and Aβ and NFT formation with neuronal cell loss. We discuss the possibility that amylin and Aβ exert their toxicity by similar mechanisms, with components of the pathocascades shared, and that therapies based on amyloidogenic properties are beneficial for both T2DM and AD. Received 27 January 2009; received after revision 17 February 2009; accepted 23 February 2009     

Platelet insulin receptor determination in non-insulin dependent diabetes mellitus

Summary The platelet membrane insulin receptors of healthy and non-insulin dependent (type 2) diabetic patients were studied. Receptor number and affinity proved to be decreased in type 2 diabetes mellitus. The changes in platelet insulin receptor characteristics are in good correlation with the alterations reported in other tissues or cells. The possible role of these phenomena in the pathogenesis of disturbed platelet function in diabetics needs further investigation.     

Microbiome,probiotics and neurodegenerative diseases: deciphering the gut brain axis

The gut microbiota is essential to health and has recently become a target for live bacterial cell biotherapies for various chronic diseases including metabolic syndrome, diabetes, obesity and neurodegenerative disease. Probiotic biotherapies are known to create a healthy gut environment by balancing bacterial populations and promoting their favorable metabolic action. The microbiota and its respective metabolites communicate to the host through a series of biochemical and functional links thereby affecting host homeostasis and health. In particular, the gastrointestinal tract communicates with the central nervous system through the gut–brain axis to support neuronal development and maintenance while gut dysbiosis manifests in neurological disease. There are three basic mechanisms that mediate the communication between the gut and the brain: direct neuronal communication, endocrine signaling mediators and the immune system. Together, these systems create a highly integrated molecular communication network that link systemic imbalances with the development of neurodegeneration including insulin regulation, fat metabolism, oxidative markers and immune signaling. Age is a common factor in the development of neurodegenerative disease and probiotics prevent many harmful effects of aging such as decreased neurotransmitter levels, chronic inflammation, oxidative stress and apoptosis—all factors that are proven aggravators of neurodegenerative disease. Indeed patients with Parkinson’s and Alzheimer’s diseases have a high rate of gastrointestinal comorbidities and it has be proposed by some the management of the gut microbiota may prevent or alleviate the symptoms of these chronic diseases.     

Platelet insulin receptor determination in non-insulin dependent diabetes mellitus

The platelet membrane insulin receptors of healthy and non-insulin dependent (type 2) diabetic patients were studied. Receptor number and affinity proved to be decreased in type 2 diabetes mellitus. The changes in platelet insulin receptor characteristics are in good correlation with the alterations reported in other tissues or cells. The possible role of these phenomena in the pathogenesis of disturbed platelet function in diabetics needs further investigation.     

Serological study of Ia antigens determined at the I-A and I-E sub-regions of the H-E complex in the H-2 complex of mice

Immune serum B10.S (7R) anti-B10.S (9R)(anti I-JEkCd) contained as expected an anti-Ia7 antibody. A series of weaker but reproducible extra-reactions might recognize Ia3 specificity coded at the I-A subregion of the H-2 complex. Results with recombinant haplotypes confirmed this mapping. Such a reactivity could be interpreted as an interlocus cross-reaction (I-E/I-A) since the immunization was induced against an I-E subregion product. Another interpretation was possible: the immune serum would thus contain an antibody recognizing Ia7 (on the E alpha k Ia chain) and another antibody recognizing an antigenic determinant carried by the E beta k Ia chain. The latter antibody might recognize by cross-reaction as specificity carried by the A beta chain of various haplotypes (H-2b,k,q).     

Death receptor 3 mediates necroptotic cell death

Death receptor 3 (DR3) was initially identified as a T cell co-stimulatory and pro-inflammatory molecule, but further studies revealed a more complex role of DR3 and its ligand TL1A. Although being a death receptor, DR3 gained to date predominantly attention as a contributor to inflammation-driven diseases. In our study, we investigated the cell death pathways associated with DR3. We show that in addition to apoptosis, DR3 can robustly trigger necroptotic cell death and provide evidence for TL1A-induced, DR3-mediated necrosome assembly. DR3-mediated necroptosis critically depends on receptor-interacting protein 1 (RIP1) and RIP3, the core components of the necroptotic machinery, which activate the pseudo-kinase mixed lineage kinase domain-like, the prototypic downstream effector molecule of necroptosis. Moreover, we demonstrate that DR3-mediated necroptotic cell death is accompanied by, but does not depend on generation of reactive oxygen species. In sum, we identify DR3 as a novel necroptosis-inducing death receptor and thereby lay ground for elucidating the (patho-) physiological relevance of DR3-mediated necroptotic cell death in vitro and in vivo.     

A simple test using restricted PCR-amplified mitochondrial DNA to study the genetic structure ofApis mellifera L

The COI-COII intergenic region ofApis mellifera mitochondrial DNA contains an important length polymorphism based on a variable number of copies of a 192–196 bp sequence (Q) and the completer or partial deletion of 67 pb sequence (Po). This length variability has been combined with a restriction site polymorphism to produce a rapid and simple test for the characterization of mtDNA haplotypes. This test included the amplification by the polymerase chain reaction of the COI-COII region followed by aDraI restriction of the amplified fragment. In a survey of 302 colonies belonging to 12 subspecies, 21 different haplotypes have been found which have been unambiguously allocated to one of the 3 mtDNA lineages of the species. Although all colonies of lineage C exhibit the same pattern (C1), each one of lineages A and M presents up to 10 different haplotypes, opening the way to studies on the genetic structure and the evolution of a large fraction of the species. This test also differentiates southern Spanish and South African colonies, which can be of great interest for the Africanized bee problem.     

Resting energy expenditure in patients with cirrhosis of the liver measured by indirect calorimetry,anthropometry and bioelectrical impedance analysis

Energy expenditure was investigated in 15 patients with liver cirrhosis and 20 healthy controls by three methods: indirect calorimetry, anthropometry using the Harris-Benedict equation and bioelectrical impedance analysis. The energy expenditure was expressed in kcal/day, kcal/kg BW/day (BW — body weight), kcal/kg LBM/day (LBM — lean body mass, derived by bioelectrical impedance analysis) or in kcal/m²/day. We did not find statistical differences between values of resting energy expenditure obtained in patients with cirrhosis of the liver and healthy controls whichever method we used. We also did not find statistical differences between values obtained by indirect calorimetry, anthropometry and bioelectrical impedance analysis. There was a significant correlation between indirect calorimetry and anthropometry in both groups. We found significant correlations between indirect calorimetry and anthropometry, and between indirect calorimetry and bioelectrical impedance analysis, in the control group only. We can conclude that (1) resting energy expenditure of patients with cirrhosis of the liver is not changed when compared with healthy controls, and (2) bioelectrical impedance is a useful method to calculate body composition from which energy expenditure is derived; however, it gives an appropriate result only in healthy people, and only approximate values in patients with cirrhosis.     

链脲佐菌素诱导的1型糖尿病小鼠对视网膜神经节细胞及眼压的影响

目的 研究糖尿病小鼠视网膜神经无细胞及眼压的变化.方法 5周龄的C57BL/6小鼠腹腔注射链脲佐菌素(STZ)建立糖尿病模型.模型建立后3周和6周,行眼压测量与视网膜神经节细胞计数.结果 与对照鼠相比较,糖尿病小鼠的眼压升高(P＜0.01),视网膜神经节细胞比值减少(P＜0.01).结论 糖尿病会导致小鼠视网膜神经节细胞的减少和眼压升高,这些病理改变可能是糖尿病视网膜病变的重要组成部分.     

TSH-receptor antibodies, HLA B8 and thyroid autoantibodies in patients with Graves' disease in therapeutically induced euthyroidism.

The prevalence of TSH-receptor antibodies and of thyroid autoantibodies was studied in 48 HLA-typed patients with Graves' disease, who were in an euthyroid state after antithyroid therapy with methimazole. TSH-receptor antibodies, which were found in 35% of the patients, did not correlate with the positivity of HLA B8. By contrast the persistence of thyroid microsomal antibodies was significantly associated with HLA B8.     

TSH-Receptor antibodies,HLA B8 and thyroid autoantibodies in patients with Graves' disease in therapeutically induced euthyroidism

Summary The prevalence of TSH-receptor antibodies and of thyroid autoantibodies was studied in 48 HLA-typed patients with Graves' disease, who were in an euthyroid state after antithyroid therapy with methimazole. TSH-receptor antibodies, which were found in 35% of the patients, did not correlate with the positivity of HLA B8. By contrast the persistence of thyroid microsomal antibodies was significantly associated with HLA B8.