Feasibility of and delay in obtaining pulse oximetry during neonatal resuscitation

Application of the sensor to newly born infants before connection to a pulse oximeter increases the reliability and speed with which data are displayed. Data are available in most infants within 90 seconds of birth. Oximetry may be useful in guiding interventions during resuscitation.     

Characterization of HLA-DR- and TCR-binding residues of an immunodominant and genetically permissive peptide of the 16-kDa protein of Mycobacterium tuberculosis

The 16-kDa protein of Mycobacterium tuberculosis represents an important antigenic target during bacillary latency and, consequently, should be considered as candidate subunit vaccine component. In this study, we have used CD4 T cell clones that recognize the peptide p91-110, an immunodominant and genetically permissive epitope, in the context of five different HLA-DR molecules and truncated and substituted variants of this peptide, to identify the minimal binding sequence (HLA-DR-binding core) and the minimal stimulatory sequence (TCR-binding core), as well as the residues that contact HLA-DR molecules and the TCR. We have found a common 9-mer sequence, spanning amino acids 93-101, as the binding core for HLA-DR1, -DR11, -DR13 and -DR7, but a longer (13-mer) sequence spanning amino acids 92-104 was required for binding to the HLA-DR15 molecules. F(93) was required for binding to all the tested HLA-DR molecules, hence allowing us to identify it as the N-terminal primary anchor residue (P1). Additionally, the binding requirements for other residues varied considerably between the tested alleles: A(94) for HLA-DR15, V(99) for HLA-DR1, -DR15, -DR11 and -DR7, R(100) for HLA-DR11 and -DR13, and L(104) for HLA-DR15. Concerning the residues of p91-110 peptide required for binding to the TCR, the pepscan analysis results would support the contention that P(-1) E(92), P6 F(98) would be important TCR contact sites because their substitutions led to full loss of T cell activation. Moreover, P8 R(100) is found to be critical residue in binding to HLA-DR11- and -DR13-restricted T cell clones, without influencing binding to the relevant HLA-DR molecule. Our results could be useful to design peptides with altered HLA anchor residues or TCR interaction sites to achieve remarkable increase in activity and to study their vaccine potential.     

Significant NK cell activation associated with decreased cytolytic function in peripheral blood of HIV-1-infected patients

One of the hallmarks of HIV-1 infection is represented by the finding of massive T cell activation in peripheral blood lymphocytes of infected patients. An impairment of NK cell function during HIV-1 infection is also detected, and is associated with decreased expression of natural cytotoxicity receptors (NCR). In this study we tried to determine whether also NK cells are affected by relevant activation and whether this could be associated with decreased NK cell function. In 18 viremic HIV-1-infected patients, freshly drawn purified peripheral NK cells displayed significant levels of activation with an incomplete pattern (HLA-DR(+)CD69(+)CD25(-)NKp44(-)). Activated (HLA-DR(+)CD69(+)) peripheral NK cells expressed an NCR(dull) phenotype as determined by cytofluorometric analysis in all the patients, and did not derive from a homogeneous/oligoclonal expansion in vivo as analyzed by expression of HLA-specific inhibitory NK cell receptors. As determined by cytotoxicity assays, activated NK cells showed a decreased cytolytic function in HIV-1-infected patients. Thus, the decrease in NK cell function observed during HIV-1 infection is associated not only with decreased NCR expression, but also with significant and incomplete NK cell activation in vivo. These results suggest a consistent continuous involvement of the innate immune response in the failure to control viral replication.     

Monocyte derived dendritic cell responses in common variable immunodeficiency

The phenotype and function of monocyte derived dendritic cells (MdDC) were investigated in 25 patients with common variable immunodeficiency (CVID) to test for abnormalities that might help explain the failure of antibody production. Using MHC class II DR and CD86 as markers of maturation, DCs from the majority of CVID patients were normal. However 5 patients, the majority of whom had affected family members who had previously been shown to have a susceptibility genetic locus in the MHC region, expressed abnormally low levels of DR on repeated testing, in some cases associated with a reduced capacity to support antigen stimulated T cell proliferation; nevertheless costimulatory molecules for production of IL-13, IL-10 and IFN-gamma from T cells were intact. In contrast to DCs from healthy donors, DCs from many CVID patients had high spontaneous production of IL-8 and lipopolysaccharide stimulation often caused a reduction in DR expression. Expression of other cytokines (IL-1a, IL-6 and IL-12), either before or after LPS stimulation, was normal. The data suggests there is a fundamental defect in the maturation of MdDCs in a subset of CVID patients that may compromise antigen presentation and subsequent antibody production.     

The feasibility of low-dose CT for pulmonary metastasis in patients with primary gynecologic malignancy

PURPOSE: To assess the feasibility of low-dose CT (LDCT) in the detection of pulmonary metastases in patients with primary gynecologic malignancies and also to compare the performance of chest digital radiography (DR) and LDCT for their delectability of pulmonary metastases, with use of standard-dose CT (SDCT) as the reference standard. MATERIALS AND METHODS: Thirty female patients with primary gynecologic malignancies (age range, 20-76 years; mean age, 50 years) underwent DR, noncontrast LDCT and contrast-enhanced SDCT, which were performed within an interval of 2 weeks. We used lung nodule, mediastinal lymphadenopathy (>10 mm in the short axis) and pleural changes (including effusion, irregular thickening, or nodularity) as the cardinal imaging findings of lung metastases. A five-point scoring system was designed to indicate the probability of lung metastasis from primary gynecologic malignancies. The five-point scores of DR, LDCT, and SDCT were analyzed by receiver operating characteristic (ROC) curve. RESULTS: SDCT probability scores of +2 and -2 were set to indicate true positive and true negative for pulmonary nodule, mediastinal lymphadenopathy, and pleural effusion, respectively. All the areas under the ROC curve of LDCT appeared to be larger than those of DR[pulmonary nodule: 0.96 [95% confidence interval (CI): 0.92-1.01] vs. 0.74 [95% CI: 0.57-0.91], 0.82 [95% CI: 0.70-0.95] vs. 0.61 [95% CI: 0.50-0.77]; mediastinal lymphadenopathy: 0.98 [95% CI: 0.93-1.03] vs. 0.90 [95% CI: 0.79-1.01], 0.94 [95% CI: 0.82-1.06] vs. 0.66 [95% CI: 0.44-0.88]; and pleural effusion: 0.98 [95% CI: 0.93-1.03] vs. 0.56 [95% CI: 0.29-0.82], 0.90 [95% CI: 0.74-1.05] vs. 0.46 [95% CI: 0.23-0.68]]. CONCLUSION: The performance of LDCT were comparable to those of SDCT and superior to those of DR for detection of pulmonary nodule, mediastinal lymphadenopathy, and pleural effusion. By using LDCT, there was no need of intravenous contrast injection and less radiation exposure. We propose a protocol including standard-dose abdominal CT and low-dose chest CT for the initial and follow-up stagings of primary gynecologic malignancy. The use of chest DR is unnecessary.     

HLA-DRB alleles are differentially expressed by tumor cells in breast carcinoma

The biologic and prognostic significance of HLA-DR expression and T-cell infiltration in breast carcinoma are presently controversial. To test the hypothesis that these factors are influenced by particular HLA-DRB alleles, 52 breast tumor samples, composed of 26 DRB1*04 and 26 non-DRB1*04 tumors, were assessed using immunohistochemistry for expression of DR and its associated invariant chain (Ii) and for infiltrating CD3+ T cells. While DR expression by tumor cells was significantly associated with T-cell infiltration, DRB1*04 tumors were more frequently DR+ Ii+ and contained smaller CD3+ infiltrates than non-DRB1*04 tumors. This difference was largely attributable to DRB1*07 tumors, which were typically DR- Ii-, although they contained similar numbers of T cells to DR+ Ii+ tumors. Further analysis of DR+ tumors using allotype discriminating antibodies revealed that DRB1*04 alleles were always expressed, while non-DRB1*04 alleles were inconsistently expressed. The results of this study provide the first reported evidence that DRB alleles influence DR expression and T-cell infiltration in breast carcinoma and suggest that multiple factors contribute to DR expression. Ongoing studies aimed at elucidating the molecular and immunologic mechanisms controlling differential DR expression and implications for prognosis and outcome should further our understanding of the antitumor immune response and evasion strategies employed by tumor cells.     

人类白细胞抗原DRB基因型及其与妊娠期糖尿病的相关性研究

目的：探讨人类白细胞抗原（human leukocyte antigen,HLA)DRB各基因型在妊娠期糖尿病（GDM）孕妇中的分布,及其与GDM发病的相关性。方法：采用序列特异性引物聚合酶链反应技术,对GDM孕妇30例（GDM组）及同期入院的正常健康孕妇40例（对照组0的HLA－DRB各基因型的分布进行检测,并对HLA－DRB各基因型与GDM的相关性进行研究。结果（1）GDM组HLA－DR6（13）等位基因频率（12％）明显高于对照组（％,P＜0．05）,GDM组HLA－DR3（8％）及HLA－DR9（23％）等位基因频率与对照组（4％,16％）比较,均有增高趋势,但差异均无显著性（P＞0．05）,GDM组HLA－DR2（15）和HLA－DR51等位基因频率均为10％,较对照组（24％,38％）明显降低（P＜0．05）,（2）孕妇为HLA－DR3基因型或HLA－DR16（13）／DR9基因杂合型时,其GDM病情较重风险比（RR）分别为27．1和8．5,且产后血糖多未恢复正常,结论：（1）HLA－DR6（13）基因型可能与GDM易感性相关,HLA－DR2（15）,HLA－DR51基因型可能与GDM保护性相关,（2）DLA－DR3,HLA－DR6（13）／DR9基因型与GDM病情严重程度有相关性,并可能影响GDM孕妇产后血糖的恢复。     

Regulation of proliferation, survival and apoptosis by members of the TNF superfamily

Tumor necrosis factor (TNF) was first identified in 1984 as a cytokine with anti-tumor effects in vitro and in vivo. Extensive research since then has shown that there are at least 18 distinct members of the TNF super family and they exhibit 15-25% amino acid sequence homology with each other. These family members bind to distinct receptors, which are homologous in their extracellular domain. These cytokines have been implicated in a wide variety of diseases including tumorigenesis, septic shock, viral replication, bone resorption, rheumatoid arthritis, diabetes, and other inflammatory diseases. TNF blockers have been approved for human use in treating some of these conditions in the United States and other countries. Various members of the TNF super family mediate either proliferation, survival, or apoptosis of cells. Although distinct receptors, all members share a common cell signaling pathway that mediates the activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (e.g. c-jun N-terminal kinase). Regulation of cell growth and activation of NF-kappaB and of c-jun N-terminal kinase by the TNF super family is mediated through sequential activation/association of a set of cell signaling proteins named TNF receptor-associated factors, Fas-associated death domain and FADD-like ICE, caspases, receptor-interacting protein, NF-kappaB-inducing kinases, and IkappaBalpha kinases. Both apoptotic and antiapoptotic signals are activated simultaneously by the same cytokine in the same cell. Together these cytokines regulate cell growth/survival/apoptosis in a complex dance of changing partners and overlapping steps.     

Humanization and characterization of the anti-HLA-DR antibody 1D10

1D10 is a previously described antibody that binds to cells from a majority of B-cell malignancies. The current studies were designed to further evaluate the antigen specificity of 1D10 and its potential as an immunotherapeutic agent. Studies with transfectants and immunoprecipitation demonstrated that 1D10 recognizes some, but not all, of the human HLA-DR beta chains. Both normal and malignant B cells can express the 1D10 antigen. A humanized version of 1D10 was produced using CDR grafting. The resulting antibody has an affinity that is similar to that of the parental murine antibody. In addition, the humanized antibody is capable of inducing complement-mediated cytotoxicity, antibody-dependent cell cytotoxicity, and direct apoptosis of 1D10-expressing B cells. Based on these in vitro anti-tumor activities, we conclude humanized 1D10 deserves further evaluation as an immunotherapeutic agent.     

糖尿病动物模型及其在DR的应用

糖尿病动物模型(DM模型)是糖尿病研究的基础。DM模型基础上建立的DR模型为糖尿病性视网膜病变提供很好的病理模型,在糖尿病性视网膜病变研究中起很重要的作用。DM模型主要可分为化学物质诱导性模型、自发性遗传性动物模型、胰腺部分切除模型和转基因模型等4种。其建立方法各有优缺点.实验性糖尿病动物模型价格低廉,可操作性强,并且在一定程度上符合人类糖尿病形成的病理过程,成为目前研究糖尿病的最主要动物模型,特别是STZ注射模型最为普遍;而基因敲除复制模型随着技术的发展,将有广阔的发展前景。