Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team.

BACKGROUND: Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. METHODS: The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS: At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. CONCLUSIONS: In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.

Reduction in T cell apoptosis in patients with HIV disease following antiretroviral therapy.

Patients with HIV infection manifest increased T lymphocyte apoptosis. This study investigated the influence of antiretroviral therapy (ART) upon lymphocyte apoptosis in 23 HIV-infected adults naive to protease inhibitors. Patients were enrolled in a treatment trial consisting of Nelfinavir (NFV), d4T, or NFV + d4T for 24 weeks, followed by triple therapy (NFV + reverse transcriptase inhibitors) for an additional 24 weeks. Spontaneous T cell apoptosis in cultured PBMC decreased by 23.67 +/- 18.2% (P < 0.006) at 48 weeks and plasma HIV RNA decreased by 1.79 +/- 0.59 log(10) RNA copies/ml (P < 0.001). The absolute decrease and slope of T cell apoptosis correlated with plasma virus load and with activated CD8 T cells and was inversely correlated with CD4 T cells. We conclude that reduction in chronic antigenic stimulation and the absence of cellular signals elicited by viral products contribute to the rescue of T lymphocytes from apoptosis, which facilitates immunologic recovery in ART-treated patients.

Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate.

An open-label study was conducted of nelfinavir mesylate, given with reverse transcriptase inhibitors to human immunodeficiency virus 1 (HIV-1)-infected infants and children 3 months to 13 years of age. Doses of nelfinavir mesylate of 20-30 mg/kg yielded drug exposures comparable to those seen in adults. The drug was well tolerated; mild diarrhea was the primary toxic effect observed. Seventy-one percent (39) of the 55 evaluable subjects had an initial decrease in plasma HIV-1 RNA, of at least 0.7 log10 copies/mL; suppression of plasma HIV-1 RNA levels to < 400 copies/mL was observed in 15. Children who began taking at least one new reverse transcriptase inhibitor near the time when nelfinavir mesylate was started, and those with a > or = 24% proportion of CD4 lymphocytes, had a greater chance of achieving and maintaining a decline in plasma HIV-1 RNA to < 400 copies/mL. Suppression of viremia was achieved in children as young as 3 months of age.

Mechanisms of autoimmunity and AIDS: prospects for therapeutic intervention.

The network theory of autoimmunity is presented with recent experimental data relevant to the understanding of the pathogenesis of AIDS. Schematically, effector T cells specific for self-antigens exist normally, but their activity is modulated and prevented by networks of regulatory T cells. As a result of mimicry between molecular components of microorganisms and self-antigens, autoimmune disease can be triggered by specific foreign pathogens which alter the state of activity of the network from suppression to activation. Conversely, by a procedure known as T-cell vaccination, autologous effector T cells re-injected after in vitro stimulation and attenuation may alter the state of the network from an activation to a suppression. Numerous observations are reviewed that support the concept of autoimmune activity in the destruction of non-infected T4 cells. Such activity is presumed to be triggered by an antigen of viral origin, the most likely, but not the only one, being the envelope protein gp 120. Based on this hypothesis, a T-cell vaccination procedure against effector T cells responsible for autoimmunopathic activity in HIV-seropositive patients is proposed, similar to the one known from experimental study of autoimmunity and presently being tested in human autoimmune diseases. Its purpose would be to prevent T-cell loss and the onset of immunodeficiency disease in HIV-seropositive patients. Apart from its potential therapeutic value, this procedure will have use as a therapeutic test from which insight will be gained about the immunopathogenesis of AIDS.

Can AIDS be prevented by T-cell vaccination?

T-cell vaccination as a specific prophylactic and therapeutic procedure has been shown to be effective in animal models of autoimmune disease. As autoimmunopathogenic components have been implicated in HIV infection, the authors propose a therapeutic test utilizing T-cell vaccination and suggest that AIDS could be prevented by such a procedure.

3-D corneal modeling system.

New surgical procedures have been introduced recently that provide refractive correction to replace the use of eyeglasses or contact lenses. The procedures involve reshaping the cornea to compensate for the optical anomalies of astigmatism and nearsightedness. Although thousands of operations are currently performed in the U.S., there are no instruments available for monitoring the results. Thus, a critical need has arisen to inspect and measure the cornea's surface both before and after surgery. In this paper an instrument is presented which provides a detailed topographical model of an individual's cornea. The method uses a novel structured light source. The cornea is modeled as a convex mirror which forms a virtual image of the structured light source. A single image is recorded from the patient's cornea. The depth is obtained from triangulation between the acquired image and a reference image of a sphere. The reconstruction of the depth map is complicated by the fact that the magnification used in recording the image varies with the radius of curvature of the cornea. An iterative method is presented which solves for the radius of curvature despite the variation in magnification. The virtual image is digitized and the instantaneous curvature of the cornea is obtained. The instantaneous curvature is displayed in units of optical power (diopters). This display provides the ophthalmologist or optometrist with the essential optical properties of the cornea.

Psychiatric correlates of behavioral inhibition in young children of parents with and without psychiatric disorders.

Behavioral inhibition is a laboratory-based temperamental category by the tendency to constrict behavior in unfamiliar situations and assumed to reflect low thresholds of limbic arousal. We previously found behavioral inhibition prevalent in the offspring of parents with panic disorder and agoraphobia. In this report, we examined the psychiatric correlates of behavioral inhibition by evaluating the sample of offspring of parents with panic disorder and agoraphobia, previously dichotomized as inhibited and not inhibited, and an existing epidemiologically derived sample of children, followed by Kagan and colleagues and originally identified at 21 months of age as inhibited or uninhibited. A third group of healthy children was added for comparison. Our findings indicate that inhibited children had increased risk for multiple anxiety, overanxious, and phobic disorders. It is suggested that behavioral inhibition may be associated with risk for anxiety disorders in children.

Behavioral inhibition in children of parents with panic disorder and agoraphobia. A controlled study.

To investigate the role of "behavioral inhibition to the unfamiliar" as an early temperamental characteristic of children at risk for adult panic disorder and agoraphobia (PDAG), we compared children of parents with PDAG with those from psychiatric comparison groups. Fifty-six children aged 2 to 7 years, matched for age, socioeconomic status, ethnic background, and ordinal position, were blindly evaluated at the Harvard Infant Study laboratory, Cambridge, Mass. The rates of behavioral inhibition in children of probands with PDAG, with or without comorbid major depressive disorder (MDD), were significantly higher than for our comparison group without PDAG. Further, the data suggest a progression of increasing rates of inhibition from the comparison group without MDD (15.4%), to MDD (50.0%), and to comorbid PDAG and MDD (70%) and PDAG (84.6%). In contrast, the rate of behavioral inhibition in children of probands with MDD did not meaningfully differ from the comparison group without MDD. Behavioral inhibition to the unfamiliar, as defined and measured in the previous work of the Harvard Infant Study program, is highly prevalent in the offspring of adults in treatment for PDAG. These children appear to be at risk for distress and disability in childhood and also perhaps for development of psychiatric disorder in later childhood and aulthood.

Corneal modeling.

The Corneal Modeling System is presented as an integrated instrument system designed to give the corneal surgeon the capability of measuring and designing alterations of corneal shape that are comparable to the computer-aided design (CAD) capability used in aerospace design and other industries. The system provides realtime digital video image acquisition using a high-resolution, cylindrical photokeratoscope and scanning laser slit lamp. From these digitized images, the system's computer derives topographic and pachymetric information in sufficient density to produce a continuous mathematical function that represents both the front and the back surface of the cornea. The mathematical model may then be sampled in as many points as the clinical application requires, in the form of either computer graphics or a numerical data stream to control precision machinery to make contact lenses or tissue lenses. Representative computer graphics of normal and pathologic corneal conditions are presented.

Calmodulin-stimulated plasma membrane (Ca2+ + Mg2+)-ATPase: inhibition by calcium channel entry blockers.

Calcium channel entry blockers representing different structural classes were studied for their effects on human erythrocyte basal and calmodulin-stimulated (Ca2+ + Mg2+)-ATPase. Effects on the activity of (Mg2+)-ATPase and (Na+ + K+)-ATPase were also assessed. Of the four Ca2+ entry blockers tested, only verapamil and diltiazem specifically inhibited the calmodulin-stimulated (Ca2+ + Mg2+)-ATPase activity, the basal enzyme activity being unaltered by these drugs. Other membrane-associated ATPases were not affected. Calmodulin concentration effect curves showed the inhibition by verapamil (10(-3) M) and diltiazem (10(-3) M) to be non-competitive. This concentration inhibited the calmodulin-dependent increment (5.1 nM calmodulin) of the ATPase activity by 35 and 36% respectively. Similarly, both drugs inhibited the Ca2+-activation process of calmodulin-stimulated activity in a non-competitive manner, decreasing Vmax by 23 and 17% respectively. Basal (Ca2+ + Mg2+)-ATPase activity was not affected by verapamil or diltiazem at any calcium concentration. In contrast, cinnarizine non-specifically inhibited all four membrane ATPases including calmodulin-stimulated (Ca2+ + Mg2+)-ATPase activity at concentrations above 3 X 10(-6) M. Nifedipine was without effect on any of the four membrane ATPases. From this we conclude that certain calcium channel entry blockers can inhibit calmodulin-regulated plasma membrane Ca2+-pump ATPase. Therefore, this identifies an additional functional low affinity receptor in the plasma membrane for some of the calcium channel entry blockers.

The effect of verapamil on pancreatic exocrine secretion.

This study set out to examine the effects of a Ca++ channel blocker, verapamil, on pancreatic exocrine secretion because of the known relationship between amylase secretion and intracellular Ca++. Pancreatic secretion was stimulated in dogs by infusing secretin and cholecystokinin. Verapamil was found to inhibit the secretion of amylase but to have no effect on lipase, trypsin, or total protein. There was no effect on the secretion of water and bicarbonate. To determine the possible physiologic significance of these findings, the pancreas was stimulated by a meat meal, and verapamil was found to inhibit amylase secretion again and in addition to inhibit the secretion of water and bicarbonate. The results suggest that verapamil has an inhibitory effect on amylase secretion by blocking the influx of Ca++ into the acinar cell and has an indirect effect leading to inhibition of water and bicarbonate secretion from the duct cells.

A defined basal medium for study of in vitro T-cell responses.

A basal serum-free medium has been devised which supports short-term murine T-cell proliferative and functional assays in the absence of added lipids or serum albumin. Immune responses obtained with this medium are totally dependent on cell-cell interactions known to generate the lymphokines and monokines essential for replication and differentiation. Background activity is minimal, allowing better control of the specificity of response than is possible with serum-containing media. This medium is also suitable for the identification of added agents which modulate immune responses, and may facilitate the purification of secreted factors.

Failure of inhibitor assay to determine isoamylase distribution.

Isoamylase distribution in the urine of normal individuals and patients admitted to the hospital with hyperamylasemia was determined by a wheat inhibitor mmethod and compared to results obtained by cellulose-acetate electrophoresis. We report two cases where the inhibitor ethod failed to give accurate results in urine, as well as serum, when compared to both electrophoresis and column chromatography. The discrepant results were due to the unexpected inhibition of P isoamylase.