Alloimmunization prevents the migration of transfused indium-111- labeled granulocytes to sites of infection

111In-labeled granulocytes were used to study the effects of histocompatibility factors on the migration of transfused granulocytes to infected sites. Fourteen alloimmunized and 20 nonalloimmunized patients received approximately 10(8) 111In-labeled granulocytes from ABO-compatible, non-HLA-matched donors, and scans were performed over known infected sites. All 14 alloimmunized patients had lymphocytotoxic antibody (LCTAb) and required HLA-matched platelet transfusions. Of the nonalloimmunized patients, 20/20 had positive scans at sites of infection. None of the 20 had LCTAb, 0/17 had a positive lymphocytotoxic crossmatch (LCTXM) with the donor, and 3/18 had a positive leukoagglutinin crossmatch (LAXM). Thus, histocompatibility testing was not found to be important in nonalloimmunized patients. In contrast, only 3/14 alloimmunized patients had positive scans at sites of infection (p = 0.00001 compared to nonalloimmunized patients). One of 3 had a positive LCTXM and 2/3 had a positive LAXM. Of the alloimmunized patients, 10/11 with negative scans had a positive LCTXM and 8/11 had a positive LAXM. Labeled granulocytes failed to reach sites of infection in 11/14 (78%) alloimmunized patients, demonstrating that histocompatibility factors can be of major importance in affecting the outcome of granulocyte transfusions. Granulocytes from random donors are unlikely to be effective in alloimmunized patients. The lack of an adequate crossmatching technique is a major problem limiting the ability to provide granulocyte transfusions for alloimmunized patients.     

Body mass index in middle age and health-related quality of life in older age: the Chicago heart association detection project in industry study

BACKGROUND: Overweight and obesity are associated with higher morbidity and shorter life expectancy, but the effect of body mass index (BMI) (calculated as weight in kilograms divided by the square of height in meters) ascertained during middle age on subsequent quality of life among older survivors is unknown. This study evaluates whether BMI in middle age is related to health-related quality of life in older age. METHODS: This prospective cohort of adults from the Chicago Heart Association Detection Project in Industry included 6766 middle-aged men and women, aged 36 to 64 years, without diabetes mellitus or myocardial infarction at baseline (November 7, 1967-January 8, 1973), who completed a 26-year follow-up questionnaire in 1996 when they were 65 years and older. Relationships of baseline BMI (categories: normal weight, overweight, and obese) to mean 26-year follow-up Health Status Questionnaire 12 scores (measuring physical, mental, and social well-being) were assessed. RESULTS: For men and women, BMI had significant inverse-graded associations with all Health Status Questionnaire 12 scores (P<.01 for trend for all). Scores (adjusted for baseline cardiovascular disease risk factors and 1996 age) were highest (best) in normal-weight individuals (BMI, 18.5-<25.0) and decreased significantly (P range,.006-<.001 for trend) with higher BMI, with worst outcomes for obese persons (BMI, >or=30.0). A higher multivariate-adjusted percentage of normal-weight persons reported excellent or very good health compared with overweight and obese persons: for women, 46.8% vs 37.9% and 24.3%; and for men, 53.8% vs 49.1% and 36.5% (P<.001 for trend). CONCLUSIONS: A higher BMI in middle age is associated with a poorer quality of life in older age. Preventive measures may lessen the burden of disease and impaired quality of life associated with excess weight.     

Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment

Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-alpha (IFNalpha) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.     

Factors affecting posttransfusion platelet increments, platelet refractoriness, and platelet transfusion intervals in thrombocytopenic patients

A variety of patient and product-related factors influenced the outcome of 6379 transfusions given to 533 patients in the Trial to Reduce Alloimmunization to Platelets (TRAP). Responses measured were platelet increments, interval between platelet transfusions, and platelet refractoriness. Patient factors that improved platelet responses were splenectomy and increasing patient age. In contrast, at least 2 prior pregnancies, male gender, splenomegaly, bleeding, fever, infection, disseminated intravascular coagulation, increasing height and weight, lymphocytotoxic antibody positivity, an increasing number of platelet transfusions, or receiving heparin or amphotericin were associated with decreased posttransfusion platelet responses. Platelet factors that were associated with improved platelet responses were giving ABO-compatible platelets, platelets stored for 48 hours or less, and giving large doses of platelets while ultraviolet B (UV-B) or gamma irradiation decreased platelet responses. However, in alloimmunized lymphocytoxic antibody-positive patients, the immediate increment to UV-B-irradiated platelets was well maintained, whereas all other products showed substantial reductions. Refractoriness to platelet transfusions developed in 27% of the patients. Platelet refractoriness was associated with lymphocytotoxic antibody positivity, heparin administration, fever, bleeding, increasing number of platelet transfusions, increasing weight, at least 2 pregnancies, and male gender. The only factors that reduced platelet refractoriness rates were increasing the dose of platelets transfused or transfusing filtered apheresis platelets.     

High frequency of immunophenotype changes in acute myeloid leukemia at relapse: implications for residual disease detection (Cancer and Leukemia Group B Study 8361)

Multiparameter flow cytometry (MFC) has the potential to allow for sensitive and specific monitoring of residual disease (RD) in acute myeloid leukemia (AML). The use of MFC for RD monitoring assumes that AML cells identified by their immunophenotype at diagnosis can be detected during remission and at relapse. AML cells from 136 patients were immunophenotyped by MFC at diagnosis and at first relapse using 9 panels of 3 monoclonal antibodies. Immunophenotype changes occurred in 124 patients (91%); they consisted of gains or losses of discrete leukemia cell populations resolved by MFC (42 patients) and gains or losses of antigens on leukemia cell populations present at both time points (108 patients). Antigen expression defining unusual phenotypes changed frequently: CD13, CD33, and CD34, absent at diagnosis in 3, 33, and 47 cases, respectively, were gained at relapse in 2 (67%), 15 (45%), and 17 (36%); CD56, CD19, and CD14, present at diagnosis in 5, 16, and 20 cases, were lost at relapse in 2 (40%), 6 (38%), and 8 (40%). Leukemia cell gates created in pretreatment samples using each 3-antibody panel allowed identification of relapse AML cells in only 68% to 91% of cases, but use of 8 3-antibody panels, which included antibodies to a total of 16 antigens, allowed identification of relapse AML cells in all cases. Thus, the immunophenotype of AML cells is markedly unstable; nevertheless, despite this instability, MFC has the potential to identify RD in AML if multiple antibody panels are used at all time points. (Blood. 2001;97:3574-3580)     

Modeling the World Health Organization Disability Assessment Schedule II using non‐parametric item response models

The World Health Organization Disability Assessment Schedule II (WHO‐DAS II) is a multidimensional instrument developed for measuring disability. It comprises six domains (getting around, self‐care, getting along with others, life activities and participation in society). The main purpose of this paper is the evaluation of the psychometric properties for each domain of the WHO‐DAS II with parametric and non‐parametric Item Response Theory (IRT) models. A secondary objective is to assess whether the WHO‐DAS II items within each domain form a hierarchy of invariantly ordered severity indicators of disability. A sample of 352 patients with a schizophrenia spectrum disorder is used in this study. The 36 items WHO‐DAS II was administered during the consultation. Partial Credit and Mokken scale models are used to study the psychometric properties of the questionnaire. The psychometric properties of the WHO‐DAS II scale are satisfactory for all the domains. However, we identify a few items that do not discriminate satisfactorily between different levels of disability and cannot be invariantly ordered in the scale. In conclusion the WHO‐DAS II can be used to assess overall disability in patients with schizophrenia, but some domains are too general to assess functionality in these patients because they contain items that are not applicable to this pathology. Copyright © 2014 John Wiley & Sons, Ltd.     

Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart

Zinc-α2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombinant AZGP1. Exposure of AZGP1-deficient mice to cardiac stress by thoracic aortic constriction revealed that antifibrotic effects were not restricted to the kidney but were cardioprotective. In vitro, recombinant AZGP1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-β signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-β signaling in fibroblasts. Taken together, these findings indicate a novel role for AZGP1 as a negative regulator of fibrosis progression, suggesting that recombinant AZGP1 may have translational effect for treating fibrotic disease.