Steven E. Keller

HIV-relevant sexual behavior among a healthy inner-city heterosexual adolescent population in an endemic area of HIV

The AIDS crisis has devastated segments of the population including the gay community and those who use intravenous drugs. HIV has spread to other groups including prostitutes and those with other sexually transmitted diseases. We have been studying adolescents in a major Northeast city where there is a major HIV/AIDS epidemic. Despite high levels of AIDS related knowledge, these adolescents reported high levels of sex risk behaviors. In addition, our data suggests that even moderate alcohol or marijuana use predicts high risk sexual behaviors. These data indicate the urgent need to develop prevention strategies for the spread of HIV among inner-city youth based upon relevant predictors of risk behaviors. The coupling of HIV in inner-city populations with a high frequency of risk behaviors in adolescents demands an immediate public health response.

Enhancement of the Therapeutic Efficacy of Taxol by the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 in Nude Mice Bearing Human Heterotransplants

Taxol may contribute to intrinsic chemoresistance by activating the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) cytoprotective pathway in human cancer cell lines and tumors. We have previously shown additivity between Taxol and the MEK inhibitor, U0126 in human cancer cell lines. Here, the combination of Taxol with an orally bioavailable MEK inhibitor, CI-1040, was evaluated in human lung tumors heterotransplanted into nude mice. Unlike xenograft models that are derived from cells with multiple genetic alterations due to prolonged passage, heterotransplanted tumor models are more clinically relevant. Combined treatment with both drugs resulted in inhibition of tumor growth in all models and tumor regressions in three of four models tested, supporting our previous observation that Taxols efficacy is potentiated by MEK inhibition. Concurrent administration was superior to intermittent dosing. Pharmacodynamic assessments of tumors indicated that suppression of MEK was associated with induction of S473 phosphorylated Akt and reduced proliferation in the combination groups relative to single agents, in addition to suppression of fibroblast growth factor-mediated angiogenesis and reduced expression of vascular endothelial growth factor. These findings are significant and indicate that this combination may have broad therapeutic applications in a diverse range of lung tumors with different intrinsic chemosensitivities.

Psychosocial and immune effects of self-hypnosis training for stress management throughout the first semester of medical school.

This study was a 19-week prospective conducted to determine the effectiveness of a self-hypnosis/relaxation intervention to relieve symptoms of psychological distress and moderate immune system reactivity to examination stress in 35 first-year medical students. Twenty-one subjects were randomly selected for training in the use of self-hypnosis as a coping skill and were encouraged to practice regularly and to maintain daily diary records related to mood, sleep, physical symptoms, and frequency of relaxation practice. An additional 14 subjects received no explicit training in stress-reduction strategies, but completed similar daily diaries. Self-report psychosocial and symptom measures, as well as blood draws, were obtained at four time points: orientation, late semester, examination period, and postsemester recovery. It was found that significant increases in stress and fatigue occurred during the examination period, paralleled by increases in counts of B lymphocytes and activated T lymphocytes, PHA-induced and PWM-induced blastogenesis, and natural killer cell (NK) cytotoxicity. No immune decreases were observed. Subjects in the self-hypnosis condition reported significantly less distress and anxiety than their nonintervention counterparts, but the two groups did not differ with respect to immune function. Nevertheless, within the self-hypnosis group, the quality of the exercises (ie, relaxation ratings) predicted both the number of NK cells and NK activity. It was concluded that stress associated with academic demands affects immune function, but immune suppression is not inevitable. Practice of self-hypnosis reduces distress, without differential immune effects. However, individual responses to the self-hypnosis intervention appear to predict immune outcomes.

Suppression of lymphocyte stimulation by anterior hypothalamic lesions in the guinea pig.

Abstract Anterior hypothalamic lesions in the guinea pig inhibited lymphocyte stimulation in whole blood cultures with the antigen tuberculin and with the mitogen phytohemagglutinin (PHA) and suppressed the delayed cutaneous hypersensitivity response to tuberculin. The lesions did not affect the stimulation of purified lymphocytes with either tuberculin or PHA. The anterior hypothalamic lesions had no effect on the absolute number of T and B lymphocytes.

Depression and immunity: clinical factors and therapeutic course ☆

While many reports describe associations between depressive disorders and altered immunity, findings have not been fully consistent. Diagnostic subtype, demographic factors such as age and gender, medical characteristics, and the immune measures selected for assessment may have contributed to the heterogeneous findings. In a study of 21 medically healthy young adults with major depression, we found, consistent with previous reports, evidence of increased lymphocyte activation to mitogen challenge and decreased natural killer (NK) cell numbers and function during acute depression. Fifteen subjects were followed longitudinally. T, CD4+, CD29+, and CD45RA+ lymphocytes and T-cell mitogen responses decreased significantly (P<0.05) during 6 weeks of pharmacotherapy and concurrent clinical improvement. There was no change in NK activity or CD56+ cells. The longitudinal effects appeared unrelated to tricyclic antidepressant levels. Changes in the immune system with short-term clinical improvement in depressed patients are not uniform providing further evidence that several mechanisms are involved in the altered immunity associated with clinical depression.

Influence of Neurological Level on Immune Function Following Spinal Cord Injury: A Review

Abstract Due to the high incidence of lifelong infections in persons with spinal cord injury (SCI), the authors examined level of injury-relateifimmune characteristics in a cohort of subjects with chronic SCI. Since the sympathetic nervous system and the endocrine system are known to be modulators of immune function, one possible explanation for heightened incidence of infections includes dysregulation of sympathetic outflow tracts in individuals with tetraplegia or high paraplegia. Natural killer cell cytotoxicity (NKCC) and bactericidal function of circulating neutrophils were assayed in a group of 10 individuals with chronic complete cervical SCI, a group of 8 individuals with paraplegia with injuries below the main sympathetic outflow (T-1 0 and below) and a group of 18 age- and sex-matched controls. In addition, a psychiatric assessment of depression was performed as well as assays of pituitary and adrenal functions. Analyses revealed no significant differences in immune function between all subjects with SCI combined and their matched controls. Further analyses stratifying based on presence or absence of sympathetic dysregulation revealed significantly impaired phagocytic ability and a trend toward reduced NKCC in the group with tetraplegia compared with their controls. Hormonal assays showed that dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DS) were higher in individuals with tetraplegia than controls, but no such differences were observed in individuals with paraplegia compared with their controls. The results of this study suggest that individuals sustaining complete cervical SCI experience alterations in immune function, while those with lesions at or below T-10 do not. These findings of level of injury related immune alteration could not be explained by mood differences. This paper is a review of previously published work and the authorsș current thinking regarding increased acquisition of infections in this population.

Immunity, major depression, and panic disorder comorbidity

Because recent research reports indicated clinical and biological differences in major depression with and without comorbid Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) panic disorder, and as altered immune measures were reported in selected subgroups of depressive patients, we investigated 51 pairs of major depressive episode (MDE) subjects, and gender- and age-matched healthy controls in order to determine if T lymphocytes number and function abnormalities were associated with Panic Disorder comorbidty. We found that those MDE subjects with DSM-III-R panic disorder (PD) had greater numbers of T cells (p less than 0.05) and PHA mitogen (p less than 0.05) responses than depressive patients without PD, as well as increased phytohemagglutinin (PHA) (p less than 0.05) concanavalin A (ConA) (p less than 0.02) mitogen responses compared to their controls. These data suggest that panic disorder comorbidity significantly contributes to the variance of immunologic parameters in major depression and has to be carefully assessed within psychoimmunological studies of psychiatric patients with affective disorders.

Alteration of immune system function in tetraplegics. A pilot study

ABSTRACT Over the past 20 yr, evidence has accumulated that implicates the autonomic nervous system as a central modulator of immune function. We hypothesized that injury to the cervical spinal cord would affect immune function by dysregulation of the sympathetic outflow tract. To test this hypothesis, peripheral blood lymphocytes were obtained from five individuals with complete cervical spinal cord injury (SCI) and from five age- and sex-matched neurologically intact controls. Immunologic parameters studied included cell counts by flow cytometry, lymphocyte proliferation response to three mitogens and a natural killer cell cytotoxicity assay. In addition the Ilfeld Psychiatric Symptom Index was completed by all subjects and controls. Repeated measures analysis of variance revealed an impaired lymphocyte proliferation response in the SCI group. Our results suggest that individuals who have sustained complete cervical SCI have alteration in immune function as compared with neurologically intact controls. This may contribute to infections after spinal cord injury. The mechanism may involve dysregulation of the sympathetic arm of the autonomic nervous system.

Stress-Induced Changes in Immune Function in Animals: Hypothalamo–Pituitary–Adrenal Influences

This chapter discusses stress-induced changes in immune function in animals. Traditional hypotheses assert that stress effects on the immune system are primarily mediated by adrenal mechanisms. Studies of stress effects on mitogen responses and on natural-killer cell activity provide important basic information about the effects of stress on nonspecific lymphoid responses. The consequences of stress effects on immune responses can best be assessed in relation to the development of a specific immune response following antigen challenge. Parametric considerations in such studies are crucial and complicate interpretation of the findings because effects on the immune response depend on the specific sequence and timing of the stressor, antigen exposure, and immune assessment. The complex findings in the various studies concerned with stress effects on in vivo immune response emphasize the need to specify the type and schedule of stress exposure and the specific aspect of immune function assessed.

Impaired phagocytosis of Staphylococcus aureus in complete tetraplegics

Accumulating evidence implicates the sympathetic nervous system as a modulator of immune function. Immune alteration has been observed in survivors of cervical level spinal cord injury, possibly because of dysregulation of the sympathetic outflow tracts. The majority of immune studies in the spinal cord-injured population have focused on lymphocytes. Because of the high incidence of infections in this population, we hypothesized that the immune alteration would extend to the cells of the myeloid lineage. This hypothesis was tested by analyzing the phagocytic and bactericidal function of circulating neutrophils in response to Staphylococcus aureus. A group of ten individuals with complete cervical spinal cord injury, a group of eight paraplegics with injuries below the majority of sympathetic outflow (T-10 and below), and age- and gender-matched controls for each subject were studied. In addition, a psychiatric screening for depression was completed by all subjects and controls. Paired t test revealed significantly impaired phagocytic ability in the tetraplegic group compared with their controls. The paraplegic group did not demonstrate these findings. Our results suggest that individuals who have sustained complete cervical spinal cord injury have alteration in immune function compared with neurologically intact controls, whereas those with lesions at or below T-10 do not. This in vitro finding may be related to infection after cervical spinal cord injury. The mechanism may involve dysregulation of the sympathetic arm of the autonomic nervous system.