Inhibition of in vivo neutrophil transmigration by a novel humanized anti-CD11/CD18 monoclonal antibody.

Leukocyte adhesion receptors, including the beta-integrin (CD11/CD18) family, play an important role in inflammation via their regulatory effects on leukocyte adhesion, transmigration, and function. A randomized, placebo-controlled, double-blind study was conducted in healthy volunteers to evaluate the in vivo effects of a humanized anti-CD11/CD18 monoclonal antibody, Hu23F2G, on leukocyte activation and transmigration. Neutrophil migration to a site of cutaneous inflammation in vivo, as measured by the skin chamber technique, was significantly reduced in subjects 24 hours after Hu23F2G administration. At 96 hours, neutrophil migration was not significantly different in subjects who received Hu23F2G or placebo. In contrast, delayed-type hypersensitivity (DTH) testing, which involves activation and migration of T lymphocytes and macrophages, was unaffected by the Hu23F2G treatment. These responses to Hu23F2G in vivo are similar to the clinical phenotype of leukocyte adhesion deficiency (LAD) type 1, a congenital disorder of CD18 deficiency. The in vivo properties of Hu23F2G suggest therapeutic potential for use in the treatment of acute non-infectious inflammatory disorders mediated predominantly by neutrophils.

Role of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the treatment of patients with HIV infection.

The recombinant human colony-stimulating factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are hematopoietic cytokines that increase neutrophil number and enhance their function. In patients with HIV infection, G-CSF and GM-CSF have reversed or prevented neutropenia even during periods of full-dose myelotoxic therapy. Both colony-stimulating factors (CSFs) also have improved defects in neutrophil function in the setting of HIV infection. In non-neutropenic animal models of opportunistic bacterial or fungal infections, use of CSFs has increased survival. Future clinical applications of CSFs may include the adjunctive treatment of specific HIV-related opportunistic infections in addition to an expanding role in the treatment of HIV-associated neutropenia and defects in neutrophil function.

Infection of Macaca nemestrina brain with human immunodeficiency virus type 1.

We previously reported that pigtailed macaques (Macaca nemestrina) became infected after intravenous inoculation with the LAI strain of human immunodeficiency virus type 1 (HIV-1), an isolate that replicates in both M. nemestrina lymphocytes and blood-derived monocyte/macrophages. In the current study we investigated the presence of HIV-1 and pathology in the postmortem brains of four of these macaques. Histopathological findings revealed focal lesions in white matter in the frontal and occipital lobes of one macaque, with myelin loss, nerve fibre loss, and gliosis within these lesions. Semi-quantitative, solution-based PCR revealed HIV-1 DNA in the brains of two of the other macaques. Using slide-based PCR-driven in situ hybridization, we studied these two macaques further and detected intranuclear, circular HIV-1 DNA in vascular endothelia and other non-neuronal brain cells. These findings indicate that M. nemestrina brain can be infected with HIV-1 in vivo and may provide a useful animal model for understanding early HIV-1 brain infection in humans.

Acute infection of Macaca nemestrina by human immunodeficiency virus type 1.

The pigtail macaque (Macaca nemestrina) has a marked sensitivity to infection by simian immunodeficiency virus and human immunodeficiency virus type 2 (HIV-2). On this basis, we previously studied this species' susceptibility to HIV-1 and demonstrated infection in six macaques inoculated with either cell-associated HIV-1 or cell-free virus alone. This report expands upon our initial in vitro and in vivo findings. Five laboratory-adapted and one primary clinical strain of HIV-1 replicated in vitro in human and M. nemestrina peripheral blood mononuclear cells (PBMCs). Replication was enhanced when CD4+ purified PBMCs were infected and inhibited when PBMC cultures were treated with zidovudine. All six macaques demonstrated HIV-1 infection of PBMCs from 2 to 8 weeks after inoculation but nearly all PBMC cultures were negative from weeks 10 to 40. Polymerase chain reaction showed HIV-1 gag DNA in the PBMCs of all infected macaques, including times when the macaques were culture negative. All macaques developed and maintained antibodies to gag and envelope HIV-1 proteins from week 4 after inoculation through the period of observation. Five macaques showed neutralizing antibody. These findings suggest that M. nemestrina can be infected by cell-free and cell-associated HIV-1. This model of acute HIV-1 infection may help in evaluating the pathogenesis of HIV-1 replication and candidate vaccines and therapies.

Infection of Macaca nemestrina by human immunodeficiency virus type-1.

After observations that Macaca nemestrina were exceptionally susceptible to simian immunodeficiency virus and human immunodeficiency virus type-2 (HIV-2), studies of HIV-1 replication were initiated. Several strains of HIV-1, including a recent patient isolate, replicated in vitro in peripheral blood mononuclear cells (PBMCs) and in CD4-positive M. nemestrina lymphocytes in a CD4-dependent fashion. Eight animals were subsequently inoculated with either cell-associated or cell-free suspensions of HIV-1. All animals had HIV-1 isolated by cocultivation, had HIV-1 DNA in their PBMCs as shown by polymerase chain reaction, and experienced sustained seroconversion to a broad spectrum of HIV-1 proteins. Macaca nemestrina is an animal model of HIV-1 infections that provides opportunities for evaluating the pathogenesis of acute HIV-1 replication and candidate vaccines and therapies.

Wallenberg's syndrome following neck manipulation.

We describe 4 patients ages 28 to 41 with lateral medullary infarction (Wallenberg's syndrome) following chiropractic neck manipulation. In 3 patients, angiography documented dissection of the extracranial 3rd segment of the vertebral artery near the atlantoaxial joint. The onset of neurologic symptoms following manipulation varied from immediate to 4 days. All had good recovery with minor residual deficits. Although the association between chiropractic neck manipulation and vertebral-basilar artery distribution infarction is well known, we emphasize its occurrence in young healthy individuals without commonly regarded predisposing factors.

Change in auditory asymmetry with amobarbital: evidence of cerebral pharmacological asymmetry?

Eleven right-handed subjects were administered a dichotic listening test to assess cerebral hemispheric dominance, both under a drug-free condition and following systemic injection of the barbiturate, amobarbital. The finding of increased right ear advantage during the drug period reflects increased left cerebral dominance, and suggests that amobarbital may have an asymmetric, pharmacological effect on the two cerebral hemispheres.

Effects of meditation on brainstem auditory evoked potentials.

Brainstem auditory evoked potentials (BAEPs) were measured in five advanced practitioners of Transcendental Meditation (TM) to determine whether such responses would reflect reported increases in perceptual acuity to auditory stimuli following meditation. The BAEP provides an objective physiological index of auditory function at a subcortical level. Repeated measures of the BAEPs of TM practitioners were taken before and after a period of meditation and were compared with those of age-matched controls. Peak latencies as well as interwave latencies between major BAEP components were evaluated. No pre-postmeditation differences for experimental subjects were observed at low stimulus intensities (0--35 dB). At moderate intensities (40--50 dB), latency of the inferior collicular wave (wave V) increased following meditation, but at higher stimulus intensities (55--70 dB), latency of this wave was slightly decreased. Comparison of slopes and intercepts of stimulus intensity-latency functions indicates a possible effect of meditation on brainstem activity.

A dichotic index of laterality that scores linguistic errors.

The measure of cerebral laterality most commonly used in dichotic listening to detect ear advantages does not take errors into consideration. Experimental data were used to compare the laterality coefficient measure commonly used with a new method which scores error responses using linguistic rules. This new method produced significant results when applied to data for which the traditional measure found no significant effects. This suggests that on dichotic tasks where only one response is required, the traditional method of computing ear asymmetry by excluding errors may overlook a significant amount of information in these responses, information which is recoverable with the linguistically based scoring system.

The effect of transcendental meditation on iconic memory.

Three experiments investigated the effects of transcendental meditation (TM) on iconic memory. The task involved reporting of digits shown tachistoscopically, using Sperling's partial-report technique. Experiment 1 was a pilot study involving a meditation group and a nonmeditation gropu. All subjects were run in a pretest/treatment/posttest design. During the treatment phase the meditation group practiced TM for a 20-minute period and the nonmeditation group relaxed with eyes closed. The results showed that the treatment increased performance in meditators, but not in nonmeditators. In this experiment important controls such as individual administration of the task, extrinsic rewards, subject pacing, and adequate practice were lacking. Experiment 2 was a replication of the first, with these controls added. The results no longer showed a superiority for the meditation treatment. In fact, the meditation group performed worse on each day of running. Experiment 3 was a replication of Experiment 1, to assess whether the meditation effect of Experiment 1 was due to (a) differential increased attention of the meditators (minimized in subject-paced Experiment 2), (b) a gain early in learning for the meditators that was eliminated due to practice in Experiment 2, or (c) a lack of proper control procedures in Experiment 1. The performance of the meditators was, again, significantly lower. This research illustrates the importance of careful control when investigating the effects of meditation on behavior. It also suggests that the effects of meditation may depend on which hemisphere is dominant in performing the task.

Changes in cerebral hemispheric lateralization with hypnosis.

Cerebral hemisphere dominance was measured in 20 subjects before, during, and after hypnotic suggestion. During hypnosis, subjects demonstrated lower right ear/left hemisphere laterality scores on a dichotic listening task compared to pre- and posthypnosis periods. These results support the view that hypnosis facilitates greater participation of the right cerebral hemisphere in cognition and may partially account for several well known hypnotic effects.

The effect of transcendental meditation on right hemispheric functioning.

This study reports two experiments investigating the effects of transcendental meditation on right hemispheric functioning. The task used in both experiments was the Seashore Tonal Memory Test. In the first experiment a non-meditator group and an experienced meditator group were run. The design involved three periods: a pretest, a meditation or rest period, and then a posttest. The results showed the experienced meditators were significantly better in both pretest and posttest performance. There were no pretest-posttest differences. The second experiment was done to replicate the first experiment and to control for possible selection bias. The design was the same as the first experiment, except that an additional group of inexperienced meditators was included. The results again showed significantly superior performance for the experienced meditators compared to the non-meditators. In addition, the experienced meditators were superior to the inexperienced meditators. There were no significant differences between the non-meditators and the inexperienced meditators. These results support the hypothesis that meditation facilitates right hemispheric functioning. Alternative explanations, such as selection bias, are also discussed.