Primary care management of women with breast cancer-related concerns-a dynamic cohort study using a network database.

The aim of this study was to determine the incidence, management and diagnostic outcomes of breast cancer-related concerns presented in primary care. A dynamic cohort study was performed in the anonymised routine electronic medical records (EMRs) extracted from 49 General Practices in the Netherlands (163,471 person-years, women aged 18-75). Main Outcome Measures were: (1) incidence rates for breast cancer-related concerns in Primary Care, (2) proportions of these women with and without symptoms of the breast referred for further investigation, (3) proportions of referrals (not) according to the guideline and (4) proportions of women with breast cancer-related concerns diagnosed with breast cancer during follow-up. Breast cancer-related concerns are presented frequently in Primary Care (incidence rate 25.9 per 1,000 women annually). About half these women are referred for further investigation. There is room to improve General Practitioner management, mainly for women with an increased lifetime risk of developing breast cancer. Information concerning family history of cancer is often missing in the EMR. Since cancer is rarely diagnosed during follow-up, particularly when symptoms are absent, reduction of unnecessary concerns is plausible if identification of those without an increased risk is improved.

Heart rate, neuroendocrine, and immunological reactivity in response to an acute laboratory stressor.

OBJECTIVE: The primary objective of the present study was to identify neuroendocrine and immunological correlates of cardiovascular reactivity to an acute laboratory stressor. METHODS: Subjects were 56 healthy volunteers. Heart rate and blood pressure were assessed at regular intervals during a 30-minute adaptation period and a 6-minute videotaped speech task. Blood was drawn before and after the task and was assayed for natural killer cell activity (NKCA), cortisol production, in vitro interferon gamma (IFN-gamma) and interleukin 10 production by peripheral blood mononuclear cells (PBMC), and antibody titers to the Epstein-Barr virus. Psychological measures were also administered. RESULTS: NKCA increased significantly in response to the task, and this increase was significantly and positively correlated with heart rate reactivity. IFN-gamma production by PBMC also increased in response to the task, but these increases were unrelated to heart rate reactivity. In addition, baseline cortisol levels were found to be predictive of heart rate reactivity. Finally, questionnaire data were modestly related to various aspects of stress-induced reactivity. CONCLUSIONS: Consistent with the task-related increases in NKCA and IFN-gamma, acute stress may signal an increase in at least some aspects of the cell-mediated, or TH1-driven, immune response. Furthermore, the finding that heart rate reactivity was related in part to baseline individual differences in cortisol production suggests that short-term cardiovascular responses to stress may be directly related to longer-term neuroendocrine modulation. Finally, the present results also help to highlight the influence of both sympathetic and nonsympathetic pathways in the response to acute stressors and suggest tentative links between certain psychological traits and various aspects of stress-induced reactivity.

One-trial conditioning of the antibody response to hen egg lysozyme in rats.

In Wistar rats, reexposure to a novel conditioned stimulus (CS) previously paired with a protein antigen, hen egg lysozyme (HEL) on a single conditioning trial increased anti-HEL IgG levels relative to conditioned rats that were not reexposed to the CS, conditioned rats that were preexposed to the CS, and nonconditioned rats. These results confirm previous findings that a single exposure to a CS associated with immunization is sufficient to elicit an antibody response upon subsequent reexposure to the CS in the absence of exogenous antigen.

Classical conditioning in the treatment of psoriasis.

It has been argued that the placebo effect represents a learned response. Research is suggested to address the utility of applying principles derived from classical (Pavlovian) conditioning to the design of drug treatment protocols. In the present instance, it is hypothesized that, by capitalizing on conditioned pharmacotherapeutic responses, it may be possible to reduce the cumulative amount of corticosteroid medication used in the treatment of psoriasis.

On the development of psychoneuroimmunology.

Psychoneuroimmunology, the study of interactions among behavioral, neural and endocrine, and immune processes, coalesced as an interdisciplinary field of study in the late 1970s. Some of the early research that was critical in establishing neuroanatomical, neurochemical and neuroendocrine pathways and functional relationships between the brain and the immune system is outlined here. These and subsequent studies have led to the general acknowledgment that the nervous and immune systems are components of an integrated system of adaptive processes, and that immunoregulatory processes can no longer be studied as the independent activity of an autonomous immune system. This paradigm shift in the study of immunoregulatory processes and the elaboration of the mechanisms underlying behaviorally induced alterations of immune function promise a better understanding and a new appreciation of the multi-determined etiology of pathophysiological states.

Immune deviation following stress odor exposure: role of endogenous opioids.

Olfactory cues can alter immune function. BALB/c mice exposed to odors produced by footshock stressed donor mice have increased antibody responses and increased splenic interleukin (IL)-4 production following immunization relative to recipients of odors from unstressed animals. Here we document that exposure to stress odors results in analgesia that is blocked by the non-selective opioid receptor antagonist naltrexone. The stress odor-induced increase in antigen-driven IL-4 and antibody is also blocked by oral administration of naltrexone. Thus, we provide evidence that immune deviation can occur following a psychosocial stressor, and that the deviation appears to be mediated by endogenous opioid production.

The differential impact of training stress and final examination stress on herpesvirus latency at the United States Military Academy at West Point.

In this study, we searched for evidence for reactivation of three latent herpesviruses, Epstein-Barr virus (EBV), herpes simplex virus type-1 (HSV-1), and human herpesvirus 6 (HHV-6), in West Point cadets experiencing two different stressors. Blood samples were obtained from cadets before and after a 6-week training period known as "Cadet Basic Training" (CBT), at a baseline prior to final examinations, and then once again during the week of final examinations. Antibody titers to latent HSV-1, EBV, and HHV-6 were determined as a measure of the steady-state expression of latent virus. EBV virus capsid antigen (VCA) IgG antibody titers were unchanged in blood samples obtained prior to and immediately after CBT. However, EBV antibody titers were significantly higher in the blood sample obtained during examination week than in the baseline period before examination; they were also higher than antibody titers before/after CBT. None of the serum samples were positive for EBV VCA IgM antibodies, indicating that the changes in antibody titers to EBV were not associated with recent EBV infections in the class. No significant changes in antibody titers to HSV-1 or HSV-6 were found over the identical time periods, including examination week. Academic stress but not CBT modulated the steady-state expression of latent EBV, resulting in the reactivation of latent virus. The same stressors, however, did not affect the steady-state expression of latent HSV-1 or HSV-6, at least as measured by changes in antibody titers. The data provide additional evidence of the impact of different psychological stressors on the steady-state expression of latent herpesviruses.

Psychosocial influences on immune responses to HSV-1 infection in BALB/c mice.

The effects of differential housing (one or four mice/cage) on T-helper (Th) cell markers of cellular and humoral immune responses were examined. Differentially housed male BALB/cJ mice were infected with herpes simplex virus (HSV)-1 (Patton strain), and in vitro cytokine production [interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-gamma] by splenocytes and popliteal lymph node cells and serum antibody titers (IgM and IgG) were evaluated. Differential housing of male BALB/c mice influenced the magnitude, but not the kinetics, of some, but not all, immune responses to HSV-1. Splenocytes from individually housed mice produced more IL-2, IFN-gamma, IL-4, and IL-10 than splenocytes from group-housed mice; in popliteal lymph node cells, only IFN-gamma and IL-10 production was influenced by housing. Although the social environment influenced cytokine production, there were no concomitant changes in circulating IgM or IgG antibody titers. These results do not support the hypothesis that dominant Th cell responses are the primary targets of this psychosocial manipulation, or that a reciprocal relationship exists between Th1 and Th2 cell-derived cytokines.

Psychoneuroimmunology: animal models of disease.

OBJECTIVE: Psychoneuroimmunology, which investigates the bidirectional communication between the central nervous system and the immune system, has been greatly advanced by the use of animal models. The objective of this paper is to describe animal models of disease that can or might be utilized to elucidate neural-immune interactions that alter pathogenesis. METHODS: This paper reviews animal studies that have demonstrated a link among the brain, behavior, immunity, and disease, highlighting models in which the potential contribution of CNS-immune interactions has not yet been explored. RESULTS: Animal studies allow for careful control of environmental stimuli, genetic background, and immunological challenge. As such, they are an important component of psychoneuroimmunology research. Models in which one might study the role of psychosocial factors in immunologically mediated disease processes, as in the case of other pathophysiologic processes, profit from an ability to manipulate both stressful events and the magnitude of the challenge to the immune system. CONCLUSIONS: Animal studies in psychoneuroimmunology highlight the complexity of the interactions among behavior, the brain, the immune system, and pathogen. The genetic background of the animal (both in terms of central nervous and immune system responses), its previous history, the nature of the stressor, the nature of the pathogen and the type of immune response generated are some of the interacting factors that determine the magnitude and direction of stress-induced changes in disease outcome.

Conditioned increase in peripheral blood mononuclear cell (PBMC) number and corticosterone secretion in the rat.

Femoral artery catheters were surgically implanted into male Lewis/N rats to allow blood sampling and drug infusion in the freely moving animal. After recovery, conditioned animals received four pairings of a peppermint odor, the conditioned stimulus (CS), and an infusion of 0.1 mg/kg nicotine bitartrate, an unconditioned stimulus (US) for an increase in the number of peripheral blood mononuclear cells (PBMC) and an increase in corticosterone concentration. When reexposed to the peppermint odor, conditioned animals showed a significant increase in PBMC number and corticosterone secretion when compared to saline and unpaired control groups and previously conditioned animals that were not reexposed to the CS. Increased PBMCs were found on the fifth unreinforced CS trial. Conditioned CORT responses were lost after the initial test trial. The data indicate that the distribution of immune cells can be influenced by learning processes and support the role of learning in the regulation of corticosterone secretion.

Conditioning of cyclophosphamide-induced leukopenia in humans.

This study evaluated whether decrements in peripheral leukocyte counts induced by cyclophosphamide can be conditioned in humans. Ten subjects being treated for multiple sclerosis received four intravenous treatments with cyclophosphamide (unconditioned stimulus) paired with a conditioned stimulus. Subjects received conditioned stimulus plus 10 mg of cyclophosphamide during one of the next two treatments in a double-blind manner. Eight of 10 subjects (P = 0.044) displayed decreased peripheral leukocyte counts following conditioned stimulus. This change may have resulted from classical conditioning processes.

Pavlovian conditioning of the immune system.

In the classical Pavlovian conditioning paradigm, a stimulus that unconditionally elicits a physiological response is repeatedly paired with a neutral stimulus that does not elicit that same response. Eventually, the neutral stimulus becomes a conditioned stimulus in that it elicits the physiological response in the absence of an unconditioned stimulus. Here we summarize experiments in which Pavlovian conditioning has revealed an intimate relationship between the central nervous system and the immune system.

Effects of differential housing on the primary and secondary antibody responses of male C57BL/6 and BALB/c mice.

The influence of the number of animals housed together in a cage on antibody production in response to keyhole limpet hemocyanin (KLH) was evaluated among male C57Bl/6 and BALB/c mice. In Experiment 1, male C57Bl/6 mice were housed 1, 6, or 12 animals per cage and primary and secondary responses were evaluated. The secondary, but not the primary, antibody responses of male C57Bl/6 mice were higher among mice housed alone compared to mice housed in groups; differences were observed for both IgM and IgG anti-KLH antibodies. The differential housing effects on secondary IgM antibody responses interacted with the priming dose of KLH. In Experiment 2, the primary and secondary responses to KLH of male C57Bl/6 and BALB/c mice were compared among mice housed alone or 4 per cage. Among both strains, the secondary, not the primary, response was influenced by the number of mice housed in a cage; both secondary IgM and IgG titers were higher among the C57Bl/6 mice housed alone but only secondary IgM titers were higher among the BALB/c mice housed alone. These experiments confirm previous observations that the primary antibody responses of C57Bl/6 mice are not influenced by the number of animals housed in a cage and extend these findings by demonstrating that the secondary antibody responses of C57Bl/6 and BALB/c are influenced by housing condition.

Conditioned enhancement of antibody production using antigen as the unconditioned stimulus.

Antigen is the most salient stimulus for an unconditional activation of the immune system. BALB/c mice were given repeated immunizations with keyhole limpet hemocyanin (KLH) paired with a gustatory conditioned stimulus (CS). A classically conditioned enhancement of anti-KLH antibody titers was observed when conditioned mice were reexposed to the CS in the context of reexposure to a minimally immunogenic dose of that same antigen. An interaction between signals derived from the neuroendocrine and immune systems is hypothesized to mediate this conditioned immune response.