Management of pediatric pontine gliomas

We present 36 consecutive patients with intrinsic glioma of the pons. Tumors with exophytic expansion were excluded. There were 16 females and 20 males, ranging in age from 2 to 13 years, median 6 years. The most common presenting symptoms were cranial nerve dysfunction. unsteadiness of gait, and hemiparesis. Computed tomography (CT) showed a hypodense (17/21) or isodense (4/21) expansion of the pons. Five tumors had areas of contrast enhancement. Following information about prognosis and possible types of management, parents decided for or against radiation therapy: twentyfour children underwent irradiation and 12 did not. Median survival among children receiving a full course of irradiation was 280 days, compared to 140 days in an equivalent group of non-irradiated children. Hemiparesis presenting without cranial nerve symptoms and contrast enhancement on CT scan were poor prognostic factors, whereas sex, age, and duration of symptoms at diagnosis were unrelated to prognosis.     

β2-glycoprotein I, anti-β2-glycoprotein I, and fibrinolysis

β₂-glycoprotein-I (β₂GPI) is a phospholipid-binding plasma protein that consists of five homologous domains. Domain V is distinguished from others by bearing a positively charged lysine cluster and hydrophobic extra C-terminal loop. β₂GPI has been known as a natural anticoagulant regulator. β₂GPI exerts anticoagulant activity by inhibition of phospholipid-dependent coagulation reactions such as prothrombinase, tenase, and factor XII activation. It also binds factor XI and inhibits its activation. On the other hand, β₂GPI inhibits anticoagulant activity of activated protein C. According to the data from knockout mice, β₂GPI may contribute to thrombin generation in vivo. Phospholipid-bound β₂GPI is one of the major target antigens for antiphospholipid antibodies present in patients with antiphospholipid syndrome (APS). Binding of pathogenic anti-β₂GPI antibodies increases the affinity of β₂GPI to the cell surface and disrupts the coagulation/fibrinolysis balance on the cell surface. These pathogenic antibodies activate endothelial cells via signal transduction events in the presence of β₂GPI. Impaired fibrinolysis has been reported in patients with APS. Using a newly developed chromogenic assay, we demonstrated lower activity of intrinsic fibrinolysis in euglobulin fractions from APS patients. Addition of monoclonal anti-β₂GPI antibodies with β₂GPI also decreased fibrinolytic activity in this assay system. β₂GPI is proteolytically cleaved by plasmin in domain V (nicked β₂GPI) and becomes unable to bind to phospholipids, reducing antigenicity against antiphospholipid antibodies. This cleavage occurs in patients with increased fibrinolysis turnover. Nicked β₂GPI binds to plasminogen and suppresses plasmin generation in the presence of fibrin, plasminogen, and tissue plasminogen activator (tPA). Thus, nicked β₂GPI plays a role in the extrinsic fibrinolysis via a negative feedback pathway loop.     

Detecting possible vaccine adverse events in clinical notes of the electronic medical record

The Vaccine Safety Datalink (VSD) is a collaboration between the CDC and eight large HMOs to investigate adverse events following immunization through analyses of clinical data. We modified an existing system, called MediClass, that uses natural language processing to identify clinical events recorded in electronic medical records (EMRs). We customized MediClass so it could detect possible vaccine adverse events (VAEs) generally, and gastrointestinal-related VAEs in particular, in the text clinical notes of encounters recorded in the EMR of a large HMO. Compared to methods that use diagnosis and utilization codes assigned to encounters by clinicians and administrators, the MediClass system can both find more adverse events and improve the positive predictive value for detecting possible VAEs.     

The molecular basis of Natural Killer (NK) cell recognition and function

Natural Killer cells are likely to play an important role in the host defenses because they kill virally infected or tumor cells but spare normal self-cells. The molecular mechanism that explains why NK cells do not kill indiscriminately has recently been elucidated. It is due to several specialized receptors that recognize major histocompatibility complex (MHC) class I molecules expressed on normal cells. The lack of expression of one or more HLA class I alleles leads to NK-mediated target cell lysis. Different types of receptors specific for groups of HLA-C, HLA-B, and, very recently, HLA-A alleles have been identified. While in most instances, they function as inhibitory receptors, an activatory form of the HLA-C-specific receptors has been identified in some donors. Molecular cloning of HLA-C-, HLA-B- or HLA-A-specific receptors has revealed new members of the immunoglobulin superfamily with two or three Ig-like domains, respectively, in their extracellular portion. While the inhibitory form is characterized by a long cytoplasmic tail associated with a non-polar transmembrane portion, the activatory one has a short tail asociated with a Lys-containing transmembrane portion. Thus, these human NK receptors are different from the murine Ly49, that is a type II transmembrane protein characterized by a C-type lectin domain. A subset of activated T lymphocytes expresses NK-type class I-specific receptors. These receptors exert an inhibiting activity on T cell receptor-mediated functions and may provide an important mechanism of downregulation of T cell responses.     

Cryopreservation of human mononuclear cells for quality control in clinical immunology. I. Correlations in recovery of K- and NK-cell functions,surface markers,and morphology

Cryopreserved human peripheral blood mononuclear cells (PBMC) were tested for natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) and for high-affinity (29°C) and total (4°C) rosette formation with sheep erythrocytes. PBMC produced variable NK activity following freezing and thawing, but consistently reacted well in ADCC. A significant correlation was found between low NK activity and a decreased percentage of low-affinity rosette-forming cells. On the contrary, the number of large granular lymphocytes (LGL), among which NK cells are restricted, and the reactivity with the monoclonal antibody OKT10, which recognizes the majority of LGL in the peripheral blood, were not significantly altered by cryopreservation. Cryopreserved cells proved to be excellent controls for determining the day-to-day variability of the NK assay and for selecting optimum conditions for this test in the clinical immunology laboratory.     

Natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) activities can be differentiated by their different sensitivities to interferon and prostaglandin E1

Though purported to be identical cells (or in identical populations of cells), the natural killer (NK) cell mediating spontaneous natural cytotoxicity and the killer (K) cell mediating antibody-dependent cellular cytotoxicity (ADCC) may not be totally identical, at least in susceptibility to regulation by the immunomodulators prostaglandin E₁ (PGE₁) and interferon (IFN). We demonstrate here that NK cells are always enhanced by IFN, while K cells are inhibited from binding targets, resulting in fewer effectors at optimal concentrations of antibody. Only at 10- to 100-fold suboptimal concentrations of antibody is ADCC activity enhanced. As measured by magnitude of inhibition and dose-response titration, ADCC activity is less sensitive to the effects of PGE₁ than is NK activity in the⁵¹Cr release assay and single-cell assay. After overnight incubation with or without PGE₁, whatever sensitivity ADCC activity had to PGE₁ is lost. However, NK cells incubated in the presence of PGE₁ overnight are still sensitive to inhibition. Indomethacin boosts NK activity without having any effect on ADCC activity. Finally, NK activity is substantially reduced by overnight incubation of cells at room temperature, which has no effect on K cells.     

Changes of Lymphocyte Subsets in Normal Pregnant and Postpartum Women: Postpartum Increase of NK/K (Leu 7) Cells

ABSTRACT: Changes in lymphocyte subsets in whole blood of normal pregnant and postpartum women were examined by flow cytometry with an automated leukocyte differential system. From the first trimester and throughout pregnancy, the absolute counts of T(CD3) and B(CD20) and T-cell subsets (CD4, CD8) decreased with a decrease in the absolute lymphocyte count, although the proportions of these cells remained unchanged except for a decrease in the percentage of T helper-inducer (CD4) cells in the first trimester. On the contrary, the percentage of NK/K (Leu 7) cells, but not of NK/K (CD16) cells, increased in the first trimester and then both gradually decreased in the second and third trimesters. In the postpartum period, the percentages and absolute counts of T(CD3) and NK/K (Leu 7) cells, but not of other cells, increased transiently. These changes of lymphocyte subsets may indicate suppression of immunological activity during pregnancy and its “increase” in the postpartum period.     

慢性乙肝患者杀伤性免疫细胞功能的研究

通过对４４例病毒性肝炎患者Ｔ细胞亚群，ＮＫ细胞活性与ＬＡＫ细胞活性的观察，探讨了在慢性乙型肝炎病毒复制与非复制状态下的杀伤性细胞活性。结果表明：在乙肝病毒的高复制状态下，ＣＤ８＾＋细胞数增加，ＣＤ４＾＋／ＣＤ８＾＋比例显著下降；ＮＫ细胞活性与ＬＡＫ细胞活性也明显低下，且在ＨＢｅＡｇ与ＨＢＶＤＮＡ阳性组中，ＮＫ活性与ＬＡＫ活性的改变与ＨＢｅＡｇ的Ｐ／Ｎ值变化呈显著负相关，而ＮＫ活性与ＬＡＫ活性变化则