Treatment-mediated changes in human immunodeficiency virus (HIV) type 1 RNA and CD4 cell counts as predictors of weight growth failure, cognitive decline, and survival in HIV-infected children.

This meta-analysis of 5 large studies of the Pediatric AIDS Clinical Trials Group was undertaken to evaluate the predictive value of antiretroviral treatment-mediated changes in 3 markers of human immunodeficiency virus (HIV) type 1 disease progression-HIV-1 RNA level, CD4 cell count, and CD4 percentage-for weight growth failure, cognitive decline, and survival in HIV-infected children. Proportional hazards models were used to assess the prognostic value of the markers at baseline and after 24 weeks of treatment, with data from 1089 children. Among children receiving nucleoside with or without nonnucleoside reverse-transcriptase inhibitors, higher immunologic and lower virologic markers at baseline and after 24 weeks were significant independent predictors of survival, whereas virologic markers were significant predictors of weight growth and cognitive failure in children >1 year old. The finding of differential age effects on pediatric-specific clinical outcomes emphasizes the need for continued investigation of treatment effects in children.

Constitutive properties of adult mammalian cardiac muscle cells.

BACKGROUND: The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction. METHODS AND RESULTS: Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (sigma), and resultant changes in cell strain (epsilon) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the sigma on the agarose gel at a constant rate to define the cardiocyte sigma-versus-epsilon relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte sigma-versus-epsilon relationship during an increase and then a decrease in sigma. In both protocols, myofilament activation was minimized by a reduction in [Ca2+]i. Myofilament activation effects were assessed in protocol C by defining cardiocyte sigma versus epsilon during an increase in sigma with physiological [Ca2+]i. In protocol A, the cardiocyte sigma-versus-epsilon relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the sigma-versus-epsilon relation in hypertrophied cardiocytes was shifted to the left compared with normal cells. CONCLUSIONS: Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction.

Gel stretch method: a new method to measure constitutive properties of cardiac muscle cells.

Diastolic dysfunction is an important cause of congestive heart failure; however, the basic mechanisms causing diastolic congestive heart failure are not fully understood, especially the role of the cardiac muscle cell, or cardiocyte, in this process. Before the role of the cardiocyte in this pathophysiology can be defined, methods for measuring cardiocyte constitutive properties must be developed and validated. Thus this study was designed to evaluate a new method to characterize cardiocyte constitutive properties, the gel stretch method. Cardiocytes were isolated enzymatically from normal feline hearts and embedded in a 2% agarose gel containing HEPES-Krebs buffer and laminin. This gel was cast in a shape that allowed it to be placed in a stretching device. The ends of the gel were held between a movable roller and fixed plates that acted as mandibles. Distance between the right and left mandibles was increased using a stepper motor system. The force applied to the gel was measured by a force transducer. The resultant cardiocyte strain was determined by imaging the cells with a microscope, capturing the images with a CCD camera, and measuring cardiocyte and sarcomere length changes. Cardiocyte stress was characterized with a finite-element method. These measurements of cardiocyte stress and strain were used to determine cardiocyte stiffness. Two variables affecting cardiocyte stiffness were measured, the passive elastic spring and viscous damping. The passive spring was assessed by increasing the force on the gel at 1 g/min, modeling the resultant stress vs. strain relationship as an exponential [sigma = A/k(ekepsilon - 1)]. In normal cardiocytes, A = 23.0 kN/m2 and k = 16. Viscous damping was assessed by examining the loop area between the stress vs. strain relationship during 1 g/min increases and decreases in force. Normal cardiocytes had a finite loop area = 1.39 kN/m2, indicating the presence of viscous damping. Thus the gel stretch method provided accurate measurements of cardiocyte constitutive properties. These measurements have allowed the first quantitative assessment of passive elastic spring properties and viscous damping in normal mammalian cardiocytes.

Perspective: human immunodeficiency virus type 1 (HIV-1) RNA end points in HIV clinical trials: issues in interim monitoring and early stopping.

Due to the desire to both shorten the length and reduce the size of clinical trials in human immunodeficiency virus (HIV) disease, the use of surrogate end points such as HIV-1 RNA is becoming increasingly standard. While these end points may be reasonable surrogates for the clinical effectiveness of drugs, a key point in their use as trial end points is the definition of a relevant duration of antiviral response. This definition is often complicated by the desire to perform interim reviews of ongoing laboratory end point trials. Unlike clinical end point trials, in which early clinical response is generally indicative of longer-term follow-up, it is yet to be determined whether short-term viral response adequately predicts the long-term durability of that response.

Analysis of the maternal components of the AIDS clinical trial group 076 zidovudine regimen in the prevention of mother-to-infant transmission of human immunodeficiency virus type 1.

To gain insight into the protective effects of the three components of the zidovudine regimen used in AIDS Clinical Trial Group (ACTG) 076 on mother-to-infant transmission of human immunodeficiency virus (HIV) type 1, 188 zidovudine-treated women and their untreated infants from five HIV-1 obstetric centers were retrospectively studied. The overall rate of mother-to-infant transmission was 12.3% (95% confidence interval [CI], 7.9%-18.0%). When the 38 women with <200 CD4 cells/microL were excluded, the mother-to-infant transmission rate was 8.8% (95% CI, 4.6%-14.8%). This rate compares favorably with the 8.3% transmission in the zidovudine arm of the ACTG 076 study. Apart from low (<200/microL) maternal CD4 cells (P = .016), no factors, including the duration of zidovudine therapy during gestation and intravenous administration of zidovudine during labor, affected the rate of mother-to-infant transmission. These findings suggest that antenatal oral zidovudine may be as effective as antenatal oral plus intravenous zidovudine during labor and the three-component ACTG 076 regimen in decreasing mother-to-infant HIV-1 transmission.

Hematopoietic growth factors after HLA-identical allogeneic bone marrow transplantation in patients treated with methotrexate-containing graft-vs.-host disease prophylaxis.

The use of hematopoietic growth factors (HGFs) in the allogeneic transplant setting has sometimes been avoided for fear of stimulating leukemic cell growth and intensifying graft-vs.-host disease (GVHD). However, neither an increase in relapse rate nor an aggravation of GVHD has been routinely described when HGFs are used after allogeneic bone marrow transplantation (allo-BMT). Early outcomes after HLA-matched allo-BMT in 26 patients with hematologic malignancies treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) or recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) from the day of transplantation were analyzed. Results were compared to those from a series of 38 patients treated earlier with an identical approach, but not scheduled to receive HGFs after transplantation. All patients received a preparative regimen consisting of etoposide, cyclophosphamide, and total-body irradiation and GVHD prophylaxis with cyclosporine and a short course of methotrexate (MTX). The analysis has shown that the duration of neutropenia was significantly decreased in the group of patients treated routinely with HGFs (median 17 vs. 20 days; p < 0.001). These patients also required fewer days of intravenous antibiotic therapy (median 20 vs. 34 days; p < 0.001), had fewer positive blood and tissue cultures (median 2 vs. 12 and 13 vs. 28; p = 0.02 and p = 0.05, respectively), needed fewer packed red blood cell transfusions (median 7 vs. 11; p < 0.03), and were discharged earlier from the hospital (median 33.5 vs. 39 days; p < 0.001). The use of HGFs was not associated with an increase in acute GVHD or early leukemic relapse. No side effects were attributable to the simultaneous administration of MTX and HGF during the neutropenic period. A trend toward better 100-day actuarial survival for patients treated with rhG-CSF or rhGM-CSF did not reach statistical significance. A decrease in the number of early deaths from fungal or bacterial infections was found in the cytokine-treated group (p = 0.05). These data suggest that the early use of rhG-CSF or rhGM-CSF after HLA-matched allo-BMT in hematologic malignancies accelerates engraftment, reduces hospitalization time, and improves outcome, without increasing acute GVHD or early relapse. Because MTX-based prophylaxis regimens are associated with prolonged neutropenia, the routine use of HGFs after transplantation may be particularly useful in regimens including MTX.

Long-term metered-dose inhaler adherence in a clinical trial. The Lung Health Study Research Group.

Poor adherence to medication regimens is a well-documented phenomenon in clinical practice and an ever-present concern in clinical trials. Little is known about adherence to inhaled medication regimens over extended periods. The present paper describes the 2-yr results of the Lung Health Study (LHS) program, which was developed to maintain long-term adherence to an inhaled medication regimen in 3,923 special intervention participants (as measured by self-report and medication canister weight). The LHS is a double-blind, multicenter, randomized controlled clinical trial of smoking intervention and bronchodilator therapy (ipratropium bromide or placebo) for early intervention in chronic obstructive pulmonary disease (COPD). At the first 4-mo follow-up visit, nearly 70% of participants reported satisfactory or better adherence. Over the next 18 mo, self-reported satisfactory or better adherence declined to about 60%. Canister weight classified adherence as satisfactory or better in 72% of participants returning all canisters at 1 yr, and in 70% of the participants returning all canisters at the 2-yr follow-up. Self-reporting confirmed by canister weight classified 48% of participants at 1 yr as showing satisfactory or better adherence. Overusers were 50% more likely than others to misrepresent their true smoking status, suggesting that canister weights indicating overuse may be deceptive. Results of multiple logistic regression analysis indicate that the best compliance was found in participants who were married, older, white, had more severe airways obstruction, less shortness of breath, and fewer hospitalizations, and who had not been confined to bed for respiratory illnesses.(ABSTRACT TRUNCATED AT 250 WORDS)