T cell response of I-Aq mice to self type II collagen: meshing of the binding motif of the I-Aq molecule with repetitive sequences results in autoreactivity to multiple epitopes

Type II collagen (CII) is of immunological interest because of its repetitive structure and properties as an autoantigen. The mouse gene has recently been cloned, thus enabling T cell-defined epitopes to be identified. Multiple novel epitopes on mouse CII are here detected in the autoreactive T cell response. The major response is directed to an epitope with residues 707-721 located on the CB10 fragment. Some 25 other epitopes are also recognized, including the autologous homologue of the 256-270 epitope which dominates in the response to foreign collagen. The cells reactive with mouse collagen peptides were of Th1 type, as judged by release of IFN-gamma. No significant reactivity was detected to mouse CII peptides during ongoing disease. Alignment of the mouse epitopes revealed a sequence motif with characteristic side chains at residues P1, P4 and P7, and to a lesser extent at P5, within a nonamer core sequence. Binding of these epitopes was simulated in a computer model of the I-Aq molecule, where peptides with anchor residues at P1, P4 and P7 were indeed found to fit the binding groove best. The spacing of pockets and the fine structure of the binding surface of the I-Aq molecule meshes with the repetitive structure of the collagen (X-Y-Gly), thus providing a likely explanation for the occurrence of multiple epitopes. Comparison with human DR binding motifs showed that the I-Aq motif resembles most closely that of the DR4 subtypes which predispose for rheumatoid arthritis.      

PJA-BP expression and TCR delta deletion during human T cell differentiation

Recombination of deltaRec to psiJalpha will delete the TCR delta gene, which is thought to play an important role in the bifurcation of the TCR alphabeta versus TCR gammadelta differentiation lineages. We recently detected a DNA-binding protein in human thymocytes, the so- called PJA-BP, which recognizes the psiJalpha gene segment and might be one of the factors involved in the regulation of preferential deltaRec- psiJalpha rearrangements. We now investigate PJA-BP expression and its correlation with TCR delta gene deletion in thymocytes. Our electrophoretic mobility shift assay experiments showed that the PJA-BP is evolutionary conserved in human, murine and simian thymocytes. Using a large series of human hematopoietic malignancies (n = 30), we conclude that PJA-BP expression is thymocyte specific and seems to be restricted to thymocytes committed to the TCR alphabeta lineage. Analysis of seven well-defined human thymocyte subpopulations showed that preferential deltaRec-psiJalpha rearrangements as well as PJA-BP expression can be detected from the immature CD34-/CD1+/CD3- /CD4+/CD8alpha+beta- thymocyte differentiation stage onwards. These experiments indicate that expression of PJA-BP in human thymocytes starts simultaneously with preferential deltaRec-psiJalpha rearrangements, which supports our hypothesis that PJA-BP is one of the factors involved in the preferential recombination of deltaRec to psiJalpha.      

Morphology of cells and hemagglutinogens of Bordetella species: resolution of substructural units in fimbriae of Bordetella pertussis.

The morphology of cells and the hemagglutinogens isolated from cultures of Bordetella pertussis, Bordetella bronchiseptica, and Bordetella parapertussis were studied by electron microscopy with the negative-staining technique. Cells of all three species had long, thin (3 nm thick), peritrichously arranged fimbriae on the cell surface. Similar structures were found in purified hemagglutinogen preparations together with shorter fimbrial structures 3 nm thick and from 40 to 100 nm long. In one experiment, long, thin fimbriae isolated from B. pertussis were found to be arranged in a crystalline structure on the specimen grid after negative staining. Optical diffraction analysis with a filtering technique performed on micrographs of these structures revealed 12.5-nm-long substructures within individual fimbriae. Further analysis resolved each of these structures into three globules, a central globule 3.5 nm in diameter and two diametrically opposed globules 2.5 nm in diameter. Based on this substructural composition, it is suggested that subunits of the individual fimbriae are connected by fragile regions. The presence of such regions would explain the size heterogeneity of the filamentous structures observed in preparations of hemagglutinogens isolated from cultures of B. pertussis and B. bronchiseptica. The concept that the short filamentous structures present in purified preparations of hemagglutinogens originate from the surface fimbriae present on the cells is supported.     

The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

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.      

p53 immunoreactivity in hepatocellular adenoma, focal nodular hyperplasia, cirrhosis and hepatocellular carcinoma

The prolonged half-life of mutant p53 makes feasible its immunocytochemical detection. In order to assess the pathogenetic role of mutant p53 in regenerative and neoplastc liver disease we studied its immunohistochemical expression in cases of hepatic cirrhosis, hepatocellular carcinoma (HCC), cirrhosis with areas of HCC, hepatocellular adenoma and focal nodular hyperplasia. The study included needle and wedge biopsies of 50 cirrhotic livers, 59 HCCs (36 of them with associated cirrhosis), six adenomas and two focal nodular hyperplasias. Sixty-five HCC fineneedle cytology specimens were also included in the study. There was no immunohistochemical evidence of mutant p53 expression in any of the cases of cirrhotic liver (except for one instance associated with HCC) adenoma or focal nodular hyperplasia. In contrast p53 was detected in 8.5% of HCC cases in the biopsy series and 24% of HCC cases in the fine needle aspiration series. In addition, mutant p53 expression in HCC was positively correlated with tumour grade. According to grade, the distribution of p53 positive immunoreactivity among HCCs was as follows: Grade I-II, 0% of cases in the biopsy series and 9% in the fine needle aspirates; Grade III, 18% in the biopsy series and 55% in the fine needle aspirates; and Grade IV, 40% in the biopsy series. Therefore, mutant p53 expression does not seem to be associated with benign liver lesions but seems to correlate with the progression of HCC through various grades of increasing malignancy.     

Patients Receiving a Primary Unicompartmental Knee Replacement Have a Higher Risk of Revision but a Lower Risk of Mortality Than Predicted Had They Received a Total Knee Replacement: Data From the National Joint Registry for England,Wales, Northern Ireland,and the Isle of Man

BackgroundTo determine unicompartmental (UKR) and total knee replacement (TKR) revision rates, compare UKR revision rates with what they would have been had they received TKR instead, and assess subsequent re-revision and 90-day mortality rates.MethodsUsing National Joint Registry data, we estimated UKR and TKR revision and mortality rates. Flexible parametric survival modeling (FPM) was used to model failure in TKR and make estimates for UKR. Kaplan-Meier estimates were used to compare cumulative re-revision for revised UKRs and TKRs.ResultsTen-year UKR revision rates were 2.5 times higher than expected from TKR, equivalent to 70 excess revisions/1000 cases within 10 years (5861 excess revisions in this cohort). Revision rates were 2.5 times higher for the highest quartile volume UKR surgeons compared to the same quartile for TKR and 3.9 times higher for the lowest quartiles respectively. Re-revision rates of revised TKRs (10 years = 17.5%, 95% confidence interval [CI] 16.4-18.7) were similar to revised UKRs (15.2%, 95% CI 13.4-17.1) and higher than revision rates following primary TKR (3.3%, 95% CI 3.1-3.5). Ninety-day mortality rates were lower after UKR compared with TKR (0.08% vs 0.33%) and lower than predicted had UKR patients received a TKR (0.18%), equivalent to 1 fewer death per 1000 cases.ConclusionUKR revision rates were substantially higher than TKR even when demographics and caseload differences were accounted for; however, fewer deaths occur after UKR. This should be considered when forming treatment guidelines and commissioning services. Re-revision rates were similar between revised UKRs and TKRs, but considerably higher than for primary TKR, therefore UKR cannot be considered an intermediate procedure.     

电离辐射对放射工作者职业健康的影响

目的 分析放射工作者外周血象、淋巴细胞微核及染色体畸变情况,为放射工作者职业防护和健康监测提供依据。方法 对2015年、2017年和2019年连续3次接受健康检查的127名放射工作者进行淋巴细胞微核、染色体及血象分析,将其设为放射组。另外选取133名无射线接触史的医务人员设为对照组;结果 放射组中淋巴细胞微核率和染色体畸变率高于对照组,白细胞和血小板计数低于对照组,均具有统计学意义（P < 0.05）。127名放射工作者外周血白细胞总数随着接触电离辐射时间的增长逐渐降低,染色体畸变率逐渐增加,均具有统计学意义（P < 0.05）。损害工龄大于20年的放射工作者染色体畸变率高于低工龄组,不同损害工龄之间比较无统计学意义（P > 0.05）。核医学与介入治疗工种染色体畸变率高于其他工种,具有统计学意义（P < 0.05）。结论 长时间接触低剂量电离辐射可使放射工作者白细胞总数降低和淋巴细胞染色体畸变率增加,应加强放射工作者防护措施以备降低电离辐射损伤程度,特别要加强核医学和介入治疗放射工作人员的职业防护。     

Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group

OBJECTIVE: The authors present demographic and surgical data from a randomized phase III trial, instituted by the EORTC Genitourinary Group in 1988, the aim of which was to assess whether complete lymph node dissection in conjunction with radical nephrectomy for renal cell cancer is more effective than radical nephrectomy alone. METHODS: Before surgery, the renal cell carcinoma was staged and judged to be nonmetastatic and resectable. The patients were randomized prior to surgery into those having radical nephrectomy combined with complete lymph node dissection or into those having radical nephrectomy alone. Postoperatively all patients were followed until progression of disease or death. RESULTS: Of the 772 randomized patients, 41 were not eligible. 383 had a complete lymph node dissection together with a radical nephrectomy. 389 had a radical nephrectomy alone. The complication rate did not differ significantly between the two groups. A complete lymph node dissection in 336 patients revealed absence of lymph node metastases in 325 of them. CONCLUSIONS: The present study shows that complete lymph node dissection does not add morbidity to the radical nephrectomy. After proper preoperative staging, the incidence of unsuspected lymph node metastases is low (3.3%).     

Optimal detection of the alpha state in a model of the human electroencephalogram

A mole of the EEG with waxing, waning and blocking alpha rhythm is described. One parameter is time dependent and simulates the "physiological alpha state' of the EEG generating network. A theoretically optimal detector of this state appears to be prescribed by the model and the statistics of the alpha state parameter. It minimizes the expected false decision rate.     

Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial

BACKGROUND: An elevated plasma homocysteine concentration is a putative risk factor for cardiovascular disease. Observational studies have reported an association between coffee consumption and plasma homocysteine concentrations. OBJECTIVE: We studied the effect of coffee consumption on plasma homocysteine in a crossover trial. We used unfiltered coffee so as to include the possible effects of coffee diterpenes, which are removed by filtering. DESIGN: Sixty-four healthy volunteers (31 men and 33 women) with a mean (+/-SD) age of 43 +/- 11 y were randomly assigned to 2 groups. One group (n = 30) drank 1 L unfiltered cafetière (French press) coffee daily for 2 wk. Such coffee is rich in the cholesterol-raising diterpenes kahweol and cafestol. The other group (n = 34) received water, milk, broth, tea, and chocolate drinks instead of coffee. After a washout period of 8 wk, both groups received the alternate intervention for another 2 wk. RESULTS: Consumption of 1 L unfiltered coffee/d for 2 wk significantly raised fasting plasma homocysteine concentrations by 10%, from 12.8 to 14.0 micromol/L. CONCLUSIONS: Unfiltered coffee increases plasma homocysteine concentrations in volunteers with normal initial concentrations. It is unclear whether the effect is caused by the cholesterol-raising diterpenes present exclusively in unfiltered coffee or by factors that are also present in filtered coffee.