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1.
Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre- IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine. 相似文献
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Kok Yvette J.M.de; Merkx Gerard F.M.; van der Maarel Silvere M.; Huber Irene; Malcolm Susan; Ropers Hans-Hilger; Cremers Frans P.M. 《Human molecular genetics》1995,4(11):2145-2150
X-linked deafness with stapes fixation (DFN3) is caused by mutationsin the POU3F4 gene at Xq21.1. By employing pulsed field gelelectrophoresis (PFGE) we identified a chromosomal aberrationin the DNA of a DFN3 patient who did not show alterations inthe open reading frame (ORF) of POU3F4. Southern blot analysisindicated that a DNA segment of 150 kb, located 170 kb proximalto the POU3F4 gene, was duplicated. Fluorescence in situ hybridization(FISH) analysis, PFGE, and detailed Southern analysis revealedthat this duplication is part of a more complex rearrangementincluding a paracentric inversion involving the Xq21.1 region,and presumably the Xq21.3 region. Since at least two DFN3-associatedminideletions are situated proximal to the duplicated segment,the inversion most likely disconnects the POU3F4 gene from aregulatory element which is located at a distance of at least400 kb upstream of the POU3F4 gene. 相似文献
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Background
Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population. 相似文献6.
Direct evidence for the involvement of carbohydrate sequences in human sperm-zona pellucida binding 总被引:2,自引:0,他引:2
Several lines of evidence indicate that mammalian fertilization is
initiated via a binding process that is dependent upon the recognition of
oligosaccharide sequences associated with zona pellucida (ZP)
glycoproteins. Here, specific chemical and enzymatic methods were employed
to modify human ZP and to test their effects on sperm binding in the
hemizona assay system (HZA). Periodate oxidation of human ZP under very
mild conditions (10 min, 0 degrees C, 1 mM sodium m- periodate) that
attacks only terminal sialic acid resulted in a 30% loss of human sperm
binding in the HZA [hemizona index (HZI) = 70.2 +/- 10.9, n = 22; P <
0.05]. Periodate oxidation under mild conditions (1 h, 23 degrees C, 10 mM
sodium m-periodate) caused a 40% decrease in binding (HZI = 60.8 +/- 10.3;
n = 24; P< 0.01). Treatment of human ZP with neuraminidase caused a
substantial increase in sperm binding to human ZP (HZI = 297 +/- 45, n =
22; P < 0.01). These findings indicate that there are sialic acid
dependent binding sites coexisting with binding sites that are obscured by
sialic acid. To determine the periodate sensitivity of these obscured
sites, hemizona were first digested with neuraminidase and subsequently
subjected to mild periodate oxidation. The combined enzymatic and chemical
treatments caused a 79% decrease in sperm binding compared to control
hemizona (HZI = 20.7 +/- 4.4, n = 16; P < 0.001). Human sperm-ZP
interaction was also increased by digestion of human ZP with
endo-beta-galactosidase (HZI = 710 +/- 232, n = 14; P < 0.01),
indicating that potential binding sites for spermatozoa are also obscured
by lactosaminoglycan sequences. These studies support a definitive role for
the involvement of ZP-associated glycans in the binding of human
spermatozoa to oocytes.
相似文献
7.
Carla M van Herpen Maaike Looman Marijke Zonneveld Nicole Scharenborg Peter C de Wilde Louis van de Locht Matthias A W Merkx Gosse J Adema Pieter H de Mulder 《Clinical cancer research》2004,10(8):2626-2635
The objective of this Phase II study was to evaluate the pharmacodynamic and immune effects of intratumorally administered recombinant human interleukin-12 (IL-12) on regional lymph nodes, primary tumor, and peripheral blood. Ten previously untreated patients with head and neck squamous cell carcinoma were injected in the primary tumor two to three times, once/week, at two dose levels of 100 or 300 ng/kg, before surgery. We compared these patients with 20 control (non-IL-12-treated) patients. Toxicity was high, with unexpected dose-limiting toxicities at the 300 ng/kg dose level. Dose-dependent plasma IFN-gamma and IL-10 increments were detected. These cytokine levels were higher after the first injection than after the subsequent injections. A rapid, transient reduction in lymphocytes, monocytes, and all lymphocyte subsets, especially natural killer cells, was observed, due to a redistribution to the lymph nodes. In the enlarged lymph nodes of the IL-12-treated patients, a higher percentage of natural killer cells and a lower percentage of T-helper cells were found compared with control patients. The same pattern was detected in the infiltrate in the primary tumor. Real-time semiquantitative PCR analysis of peripheral blood mononuclear cells in the peripheral blood showed a transient decrease of T-bet mRNA. Interestingly, the peripheral blood mononuclear cells in the lymph nodes showed a 128-fold (mean) increase of IFN-gamma mRNA. A switch from the Th2 to a Th1 profile in the lymph nodes compared with the peripheral blood occurred in the IL-12-treated patients. In conclusion, in previously untreated head and neck squamous cell carcinoma patients, recombinant human IL-12 intratumorally showed dose-limiting toxicities at the dose level of 300 ng/kg and resulted in measurable immunological responses locoregionally at both dose levels. 相似文献
8.
Raymond C.W. Wong Henk Tideman Matthias A.W. Merkx John Jansen Suk Meng Goh 《Journal of cranio-maxillo-facial surgery》2012,40(8):e479-e486
IntroductionIn this paper we present the results of the mechanical testing of a new generation modular endoprosthesis, which has been designed to improve the results of mandibular reconstruction.Materials and methodsThe new cementless endoprosthesis consists of a male part, a female part (both with screws on the stems), connected via a dove-tailed connection and secured with a coronal screw.The endoprosthesis was fitted into standardized blocks of synthetic bone (Synbone AG, Malans, Switzerland). The set-up was fixed to an ElectroPuls testing machine at one end and loaded at the other end 25 mm away. Three specimens were loaded continuously until failure to determine the average load to failure of the construct. Five specimens were then loaded cyclically between 10 and 150 N until either failure or 500,000 cycles. A finite element analysis was also performed on the set-up.ResultsOf the five specimens in the fatigue testing, only one survived while the other four either were bent or fractured at the stem of the clamped portion. The specimen that survived had very good bony contact with the prosthesis at the lower border. The connection of the modules via the dove-tailed design did not show any loosening. Finite element analysis showed areas of stress concentration at the superior surface of the stems to 188.8 MPa. This was well below the yield strength of titanium alloy of 897 MPa. Statistical analysis performed for specimens 1 to 4 to calculated lower tolerance bounds on cycles to failure, representing the estimated minimum achievable cycles to failure at 90, 95, and 99% of the population at 90 and 95% confidence levels, showed that the estimated mean cycles to failure was 10,132 cycles at the mean, minimum and maximum loads of 120 N and 18.4 N respectively.ConclusionGood bony contact seems to be essential at the lower border for long-term survival of the reconstruction. Small gaps increase the bending forces and thus shear stresses at the stem. The new design of the modular endoprosthesis is prone to stress concentrations at the superior surface of the stems. This is accentuated by the sharp screw threads of the stems. The loosening of the module connection seemed to have been stopped with the dove-tailed design. 相似文献
9.
Chi DX Yan GZ Wang WX Lin LM Zhang GF Shi Y 《Journal of medical engineering & technology》2013,37(5):233-237
Manometry of the alimentary tract is a valuable and widely used means to evaluate and diagnose the function of the alimentary tract. However, the measurement can be inconvenient due to the invasive method used, and the many factors affecting results. Research on colonic pressure data is even more insufficient. This paper deals with colonic pressure data via an improved method ensuring that pressure data of the whole colon is available. The data is analysed based on the learning vector quantization (LVQ) method. Testing results show that this method distinguishes the normal data and the abnormal data, consistently with the original diagnoses. This method can serve as an assistant diagnosis of colonic motility and contributes to further research on colonic motility based on pressure data. 相似文献
10.
Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate 总被引:1,自引:0,他引:1
We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A. 相似文献