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31.
Familial hyperinsulinemia due to a structurally abnormal insulin. Definition of an emerging new clinical syndrome 总被引:7,自引:0,他引:7
M Haneda K S Polonsky R M Bergenstal J B Jaspan S E Shoelson P M Blix S J Chan S C Kwok W B Wishner A Zeidler 《The New England journal of medicine》1984,310(20):1288-1294
We have identified a patient with mild diabetes, marked fasting hyperinsulinemia (89 to 130 microU of insulin per milliliter), and a reduced fasting C-peptide: insulin molar ratio of 1.11 to 1.50 (normal, greater than 4). The patient responded normally to exogenous insulin. However, her endogenous immunoreactive insulin showed reduced biologic activity during a glucose-clamp study with hyperglycemia and a reduced ability to bind to the insulin receptor and stimulate glucose transport in vitro. Family studies showed that five additional relatives in three generations had variable degrees of glucose intolerance, marked hyperinsulinemia, and a reduced peripheral C-peptide:insulin molar ratio. Restriction-endonuclease cleavage of DNA isolated from circulating leukocytes in the patient and in family members with hyperinsulinemia revealed loss of the MboII recognition site in one allele of the insulin gene--consistent with a point mutation at position 24 or 25 in the insulin B chain. Other studies using high-pressure liquid chromatography and detailed gene analysis have identified the defect as a serine for phenylalanine substitution at position 24 of the insulin B chain. The secretion of a structurally abnormal insulin should be considered in patients with hyperinsulinemia who respond normally to exogenous insulin and have a reduced C-peptide:insulin molar ratio. Glucose tolerance may range from relatively normal to overtly diabetic. 相似文献
32.
Comparison of different metrics, using three large samples of haplotypes from different populations, demonstrates that rho is the most efficient measure of association between pairs of single nucleotide polymorphisms (SNPs). Pairwise data can be modeled, using composite likelihood, to describe the decline in linkage disequilibrium with distance (the Malecot model). The evidence from more isolated populations (Finland, Sardinia) suggests that linkage disequilibrium extends to 427-893 kb but, even in samples representative of large heterogeneous populations, such as CEPH, the extent is 385 kb or greater. This suggests that isolated populations are not essential for linkage disequilibrium mapping of common diseases with SNPs. The in parameter of the Malecot model (recombination and time), evaluated at each SNP, indicates regions of the genome with extensive and less extensive disequilibrium (low and high values of in respectively). When plotted against the physical map, the regions with extensive and less extensive linkage disequilibrium may correspond to recombination cold and hot spots. This is discussed in relation to the Xq25 cytogenetic band and the HFE gene region. 相似文献
33.
Dal Zotto L; Quaderi NA; Elliott R; Lingerfelter PA; Carrel L; Valsecchi V; Montini E; Yen CH; Chapman V; Kalcheva I; Arrigo G; Zuffardi O; Thomas S; Willard HF; Ballabio A; Disteche CM; Rugarli EI 《Human molecular genetics》1998,7(3):489-499
We have recently reported isolation of the gene responsible for X- linked
Opitz G/BBB syndrome, a defect of midline development. MID1 is located on
the distal short arm of the human X chromosome (Xp22. 3) and encodes a
novel member of the B box family of zinc finger proteins. We have now
cloned the murine homolog of MID1 and performed preliminary expression
studies during development. Mid1 expression in undifferentiated cells in
the central nervous, gastrointestinal and urogenital systems suggests that
abnormal cell proliferation may underlie the defect in midline development
characteristic of Opitz syndrome. We have also found that Mid1 is located
within the mouse pseudoautosomal region (PAR) in Mus musculus , while it
seems to be X- specific in Mus spretus. Therefore, Mid1 is likely to be a
recent acquisition of the M. musculus PAR. Genetic and FISH analyses also
demonstrated a high frequency of unequal crossovers in the murine PAR,
creating spontaneous deletion/duplication events involving Mid1. These data
provide evidence for the first time that genetic instability of the PAR may
affect functionally important genes. In addition, we show that MID1 is the
first example of a gene subject to X-inactivation in man while escaping it
in mouse. These data contribute to a better understanding of the molecular
content and evolution of the rodent PAR.
相似文献
34.
The localisation of the principal blood group antigens has been studied in human liver. These blood group antigens included the erythrocyte antigens and the antigen of the major histocompatibility complex. This study was performed by the indirect immunofluorescence technique using polyclonal antibodies of human or animal origin and monoclonal antibodies from hybridomas. This study has shown that the normal hepatocyte is lacking in blood group antigens. On the contrary, the biliary cell was rich in antigenic markers: the main antigens expressed were Lewis, Pr, HLA-A and B antigens. In Kupffer cells, only i and HLA-DR antigens were clearly expressed. The endothelial cells of blood vessels mainly show A, B, H, HLA-A and B antigens; HLA-DR and Pr are slightly expressed. HLA-DR antigens were more strongly expressed on veins than on arteries. Dendritic cells have been identified in the portal space of human liver. They bore i and HLA-DR antigens. 相似文献
35.
Evaluation and Validation of an Enzyme-Linked Immunosorbent Assay and an Immunochromatographic Test for Serological Diagnosis of Severe Acute Respiratory Syndrome
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Ming Guan Kwok Hung Chan J. S. Malik Peiris See Wai Kwan Siu Yan Lam Chiu Mei Pang Ka Wing Chu Kit Man Chan Hsiao Ying Chen Ewe Beng Phuah Caiqin Jane Wong 《Clinical and Vaccine Immunology : CVI》2004,11(4):699-703
A newly developed severe acute respiratory syndrome (SARS)-specific enzyme-linked immunosorbent assay (ELISA) was further validated to confirm cutoff values and evaluate its diagnostic performance with clinical samples. In parallel, an immunochromatographic test was also evaluated. A total of 227 clinical serum specimens collected from SARS patients were used in the study, together with 385 samples from healthy donors. By use of an immunofluorescent (IF) test as the “gold standard, ” both the ELISA and the immunochromatographic test were able to detect immunoglobulin G antibodies to SARS not only from late-convalescent-stage samples (>21 days from the onset of clinical symptoms), as previously established, but also from early-acute-phase samples (1 to 10 days from onset). The ELISA, using an optical density (OD) of 0.25 as its cutoff value, produced the best sensitivity while maintaining high specificity. It detected SARS-specific antibodies in 58, 70, 75, and 95%, respectively, of the four groups of samples collected from patients 1 to 10 days, 11 to 20 days, 21 to 30 days, and more than 30 days after the onset of clinical symptoms. Similarly, the immunochromatographic test detected SARS-specific antibodies in 55, 68, 81, and 79% of the four groups, respectively. The overall specificities for the ELISA and the rapid test were 99.5 and 97.7%, respectively. Although the positive correlation observed between the ELISA OD values and the IF titers was moderate (r = 0.6915; P < 0.001), the detection rates of both the ELISA and the rapid test were found well in agreement with the IF titers. 相似文献
36.
David M. Koelle Matthew L. Johnson Aimee N. Ekstrom Patricia Byers William W. Kwok 《Human immunology》1997,53(2):195-205
The HLA DQA1 locus is polymorphic. Haplotypes containing HLA DQA1*0501, but not HLA DQA1*0201, together with HLA DQB1*0201 are associated with Grave's disease and celiac sprue. In this report, we demonstrate a functional correlate of DQA1 polymorphism. T cells infiltrating a herpes simplex virus (HSV) lesion from a HLA DQ 2,7 individual yielded a virusspecific CD4+ clone restricted by DQ2. Presentation of viral peptide and protein segregated with DQA1 allele, because cell lines bearing DQA1*0501/DQB1*0201 heterodimers presented antigen in proliferation and cytotoxicity assays much more efficiently than cell lines bearing DQA1*0201/DQB1*0201. Binding of viral peptide to cell lines bearing DQA1*0201, in comparison to DQA1*0501, was only moderately reduced and may not explain this effect. Truncation and substitution analyses of peptide binding and T-cell activation were performed to determine which viral peptide residues contacting TCR might therefore be presented in an altered conformation by DQA1*0201/DQB1*0201. Residues 432, 435, 437, 438, and 440 (position P1, P4, P6, P7, and P9) contributed to DQ2 binding, whereas residues 431, 433, 434, and 436 (positions P-1, P2, P3, and P5) contributed to TCR contact. Differential presentation of peptide by HLA DQ2 heterodimers varying at the DQA1 locus may have relevance to host defense and the pathogenesis of HLA DQ2-associated autoimmune diseases. Human Immunology 53, 195-205 (1997). 相似文献
37.
The fetal porcine pancreas under experimental conditions can be transplanted in the form of explants or islet-like cell clusters (ICCs) to normalize blood glucose levels in diabetic recipients. ICCs are released from the collagenase-digested pancreas and require a 4- to 5-day culture period for their complete formation. In order to maximize insulin producing beta cell differentiation following transplantation, an understanding of ICC development is essential to utilize this alternative treatment for type 1 diabetes. In this study a role is proposed for exocrine cells in the generation of the multipotent pancreatic precursor cells during the culture period. Acinar cells undergo dedifferentiation during the initial stages of the culture period into multipotent pancreatic precursor cells, previously called protodifferentiated cells. The progressive loss of exocrine differentiation appears to involve rapid degranulation of zymogen granules by exocytosis and loss of the prominent secretory apparatus. These processes occur in parallel with a significant reduction in the expression of lipase in the period from day 0 to day 5 and simultaneously there is an increase in the epithelioid/ductal cell marker, cytokeratin 20. Using proliferating cell nuclear antigen, cell proliferation during the culture period does not appear to account for the increase in epithelioid/ductal cells. Further the rates of apoptosis and necrosis which were identified using the TUNEL technique and propidium iodide, respectively, do not appear to account for the reduction in exocrine cell numbers. Exocrine cell dedifferentiation appears to increase the pool of protodifferentiated cells which have the potential to develop into the insulin-producing beta-cell population following transplantation into the diabetic recipient 相似文献
38.
39.
The antiflammatory drug indomethacin, an inhibitor of prostaglandin synthesis, prevents the generalized Shwartzman reaction produced in rabbits by two intravenous injections of bacterial endotoxin. Indomethacin has this effect if given before the first but not the second injection of endotoxin. Measurements of circulating white blood cells, platelets, partial thromboplastin time, prothrombin time, fibrinogen, plasminogen, and soluble fibrin were made at several times after either the first or second injection of endotoxin treated and nontreated rabbits. Four hours after the first injection of endotoxin, leukopenia and thrombocytopenia were somewhat greater in treated rabbits and the prolongation of the activated partial thromboplastin time was shortened. Twenty-one hours after injection of endotoxin, leukocytosis and elevation of plasma fibrinogen were not as great in treated animals. Four hours following the second injection of endotoxin a decrease in fibrinogen, prolongation of the prothrombin time, and the elaboration of soluble fibrin were consistently found in rabbits with the generalized Shwartzman reaction. In treated rabbits, none of these changes occurred. Indomethacin prevents the generalized Shwartzman reaction by preventing the development of the prepared state in this endotoxin model. 相似文献
40.
Hematopoietic cytokines such as interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF) play a fundamental role in eosinophil functions in allergic asthma. The intracellular signal transduction mechanisms of these cytokines regulating the activation of eosinophils have been potential therapeutic targets. We investigated the roles of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-kappaB) in IL-3, IL-5, and GM-CSF-induced adhesion, morphological changes, and subsequence transmigration of human eosinophils. IL-3, IL-5, and GM-CSF could augment the phosphorylation of p38 MAPK and nucleus translocation of NF-kappaB in eosinophils. cDNA expression arrays demonstrated that the gene expression levels of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), alpha6, beta2 integrin (CD18), and CD44 were upregulated by these cytokines. Results from functional assays showed that adhesion of eosinophils onto airway epithelial cells was enhanced after IL-3 and IL-5 but not GM-CSF stimulation. These cytokines could markedly induce shape change and augment the transmigration of eosinophils. Moreover, administration of either p38 MAPK inhibitor, SB 203580, or proteasome inhibitor, N-cbz-Leu-Leu-leucinal (MG-132), could inhibit the cytokine-induced adhesion, shape change, and transmigration of eosinophils. Together, our findings suggest that IL-3, IL-5, and GM-CSF regulated the adhesion and chemotaxis of human eosinophils through shared signaling pathways involving both p38 MAPK and NF-kappaB. Our results therefore shed light on the further development of more effective agents for allergic and inflammatory diseases. 相似文献