Serum soluble CD8 molecule is a marker of CD8 T-cell activation in HIV-1 disease

To characterize CD8 T-cell activation during HIV-1 infection we measured serum soluble CD8 (sCD8) levels longitudinally in seroconverters and in individuals with established HIV infection who were in different stages of illness. CD8 T-cell activation occurs very early in HIV infection. Serum sCD8 levels were elevated in 91.5% of the first seropositive samples in seroconverters. Furthermore, CD8 T-cell activation persists throughout HIV infection. sCD8 predicted the occurrence of AIDS in HIV-seropositive individuals and so the addition of serum sCD8 levels to CD4 T-cell measurements increased the power in predicting the onset of AIDS. The serum level of sCD8 was particularly relevant to the prediction of subsequent CD4 T-cell fall relatively early in infection, for example, in the 3 years after seroconversion. However, later in HIV infection, for example within 2 years prior to development of AIDS, sCD8 levels were less predictive. sCD8 correlated with levels of beta 2-microglobulin and neopterin, which reflect activation of cell types other than CD8. Thus, serum sCD8 level can be a useful marker of specific CD8 T-cell activation, and is an independent predictor of prognosis in HIV infection.     

Preparation of factor IX deficient human plasma by immunoaffinity chromatography using a monoclonal antibody

A murine hybridoma clone is described that grows continuously in culture and produces a monoclonal antibody we have called Royal Free Monoclonal Antibody to factor IX No. 1 (RFF-IX/1). This has high affinity for a coagulation site on factor IX. RFF-IX/1 immobilised on sepharose can be used to deplete factor IX from normal human plasma. This immunoaffinity depleted plasma is indistinguishable from severe Christmas disease plasma and can be used as the substrate in a one stage coagulation assay for factor IX. The affinity column has high capacity and can be regenerated so that large scale production from normal plasma of factor IX deficient plasma as a diagnostic reagent is now feasible.     

Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces

Using ellipsometry, anodized tantalum interference color, and Coomassie blue staining in conjunction with immunologic identification of proteins adsorbed at interfaces, we have previously found that fibrinogen is the main constituent deposited by plasma onto many man- made surfaces. However, the fibrinogen deposited from normal plasma onto glass and similar wettable materials is rapidly modified during contact activation until it can no longer be identified antigenically. In earlier publications, we have called this modification of the fibrinogen layer "conversion," to indicate a process of unknown nature. Conversion of adsorbed fibrinogen by the plasma was not accompanied by marked change in film thickness, so that we presumed that this fibrinogen was not covered but replaced by other protein. Conversion is now showen to be markedly delayed in plasma lacking high molecular weight kininogen, slightly delayed in plasma lacking factor XII, and normal in plasma that lack factor XI or prekallikrein. We conclude that intact plasma will quickly replace the fibrinogen it has deposited on glass-like surfaces by high molecular weight kininogen and, to a smaller extent, by factor XII. Platelets adhere preferentially to fibrinogen-coated surfaces; human platelets adhere to hydrophobic nonactivating surfaces, since on these, adsorbed firbinogen is not exchanged by the plasma. The adsorbed fibrinogen will be replaced on glass-like surfaces during surface activation of clotting, and platelets failing to find fibrinogen will not adhere.     

Immunotherapy and human tumor immunology.

Present knowledge about the immune response to tumors in man is briefly reviewed, and the effects of cancer on immune-system functions are noted. The concepts that human tumors elicit cell-mediated immune responses to tumor antigens are re-examined and modified; for example, cell-mediated immunity may be detectable only at certain stages of tumor growth. Introduction of more sensitive methods for detecting antibodies is providing additional evidence for humoral immune responses to tumor-associated antigens. The present proliminary approaches to immunotherapy, particularly the use of adjuvants such as BCG and Corynebacterium parvum, are assessed, and initial pharmacoimmunologic findings with these agents are reported. The field of tumor immunology is in a dynamic state of development, with input from many areas of immunology and oncology. Carefully controlled clinical trials of these therapeutic regimens will be required to establish the value and indications for the use of such procedures.     

Prevention of graft rejection following bone marrow transplantation

Bone marrow transplantation from an HLA-identical sibling is increasingly used in the treatment of severe aplastic anemia. One major problem with this approach is graft rejection that occurs in 25%-60% of patients conditioned for transplantation with cyclophosphamide. At most transplant centers it has been difficult to accurately identify patients at high risk for graft rejection. We studied a conditioning regimen of cyclophosphamide (200 mg per kg) and low-dose total body irradiation (3 Gy; equivalent to 300 rad) in 23 consecutive unselected patients with aplastic anemia followed for a minimum of 6 mo. There was only one episode of graft rejection. Graft-versus-host disease and interstitial pneumonitis were not increased by the more intensive conditioning regimen. Actuarial survival was 61% at 1 yr and 49% at 2.5 yr. Cyclophosphamide and low-dose total body irradiation is an effective conditioning regimen in patients with aplastic anemia. It may be particularly useful when accurate predictive tests of graft rejection are not available as is the case in most transplant centers.     

Stability of plasma levels of cytokines and soluble activation markers in patients with human immunodeficiency virus infection

Cytokine and immune activation marker levels in plasma are valuable measurements of immune status and treatment effects in human immunodeficiency virus (HIV) infection and AIDS. Five populations representing various stages of disease were studied: controls, 2 AIDS groups with <50/mm3 CD4 cells, and 2 groups of HIV-positive subjects-1 with stable CD4 T cells (median, 545/mm3) and 1 with >100/mm3 CD4 cell decline in 1 year. Relatively stable levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor (R)II, soluble interleukin-2R, neopterin, and beta2-microglobulin (beta2M) were documented over 5-8 weeks in patients with AIDS and for 1-4 years in the other groups. beta2M was generally the most stable marker. Interferon-gamma levels, however, fluctuated substantially. Individuals, whether normal or HIV-positive, maintain characteristic plasma levels of cytokines and immune activation markers. Thus, documented changes, in excess of the variability observed in this study, are likely to be significant indicators of change in disease status or effects of therapy.     

Bone marrow transplantation for patients with Philadelphia chromosome- positive acute lymphoblastic leukemia

We report the treatment outcome of allogeneic bone marrow transplantation in ten patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Six patients are alive and well for 6 to 30 months (median 19 months) after transplantation. Four patients died with transplant related complications. In view of the poor prognosis associated with this disease, marrow ablation followed by allogeneic or syngeneic marrow grafting may be the preferred treatment modality if a suitable marrow donor is available.     

Absence of alternative splicing in bcr-abl mRNA in chronic myeloid leukemia cell lines

The major consequence of the Philadelphia (Ph) translocation in chronic myeloid leukemia (CML) is the formation of a bcr-abl hybrid oncogene encoding a tumor cell-specific protein P210bcr-abl. In contrast to this, in Ph chromosome-positive acute lymphoblastic leukemia (Ph + ALL), a P190bcr-abl can be observed. This P190bcr-abl has been implicated in acute rather than chronic leukemogenesis. Therefore, it can be hypothesized that the transition from chronic to blast phase in CML is accompanied by an alternative splice in the bcr-abl mRNA, which results in a switch of the production of P210bcr-abl into P190bcr-abl. Initial S1 nuclease protection mapping supported this theory. However, this result appears to be based on an artifact in the S1 analysis. By using the polymerase chain reaction we provide evidence for the absence of alternative splicing in bcr-abl mRNA in two CML blast crisis cell lines.     

How can we improve adherence to blood pressure-lowering medication in ambulatory care? Systematic review of randomized controlled trials

BACKGROUND: Lack of adherence to blood pressure-lowering medication is a major reason for poor control of hypertension worldwide. The objective of this study was to determine the effectiveness of interventions to increase adherence to blood pressure-lowering medication. METHODS: We performed a systematic review of randomized controlled trials and searched for all-language publications in the Cochrane Controlled Trials Register, MEDLINE, EMBASE, and CINAHL in April 2002. RESULTS: We included 38 studies testing 58 different interventions and containing data on 15 519 patients. The studies were conducted in 9 countries between 1975 and 2000. The duration of follow-up ranged from 2 to 60 months. Because of heterogeneity between studies in terms of interventions and the methods used to measure adherence, we did not pool the results. Simplifying dosing regimens increased adherence in 7 of 9 studies, with a relative increase in adherence of 8% to 19.6%. Motivational strategies were partly successful in 10 of 24 studies with generally small increases in adherence up to a maximum of 23%. Complex interventions comparing more than 1 technique increased adherence in 8 of 18 studies, ranging from 5% to a maximum of 41%. Patient education alone seemed largely unsuccessful. CONCLUSIONS: Reducing the number of daily doses appears to be effective in increasing adherence to blood pressure-lowering medication and should be tried as a first-line strategy, although there is so far less evidence of an effect on blood pressure reduction. Some motivational strategies and complex interventions appear promising, but we need more evidence on their effect through carefully designed randomized controlled trials.