Aberrant nuclear expression of AP-1 and NFkappaB in lymphocytes of women stressed by the experience of breast biopsy.

We have investigated the expression of AP-1 and NFkappaB in peripheral blood lymphocytes of women scheduled for breast biopsy. Samples were collected when women were informed of the need for biopsy (prebiopsy, T1, 5-7 days prior to the actual biopsy) and 7-10 days after they learned the result of their biopsy (postbiopsy, T2). At the time of blood collection, psychological stress was evaluated using Speilberger's State Trait Anxiety Inventory (STAI) and the Profile of Mood States (POMS). Women scheduled to undergo breast biopsy reported significant increases in anxiety (STAI) and mood disturbance (POMS). Gel shift mobility assays showed that mitogen stimulated peripheral blood lymphocytes of these women were less capable of the nuclear expression of AP-1 or NFkappaB at T1. Similar assessments, 7-10 days after the women learned of the results of their breast biopsy, showed these same women to have a marked reduction in anxiety and mood disturbance and an increased nuclear translocation of AP-1 and NFkappaB. These results show a significant decrease in nuclear AP-1 and NFkappaB expression during the period of emotional distress prior to biopsy with a return of nuclear transcription activity to normal levels when distress was relieved. Several studies have correlated increased psychological stress with decreased immune function. The results of this study suggest that psychological stress may mediate immunosuppression by altering the expression of the transcription factors, AP-1 and NFkappaB.

Stress reduction and HIV disease: a review of intervention studies using a psychoneuroimmunology framework.

The field of psychoneuroimmunology (PNI) posits that relationships exist between stress, immunological impairment, and health outcomes. Accumulating evidence suggests that stress may hasten HIV disease progression by increasing viral replication, suppressing immune response, and inducing deleterious health-related behaviors. Interventions that attenuate the effects of stress are postulated to operate by altering cognitive perception and/or modulating neuroendocrine and sympathetic reactivity. A review of HIV/PNI intervention studies is presented as a guide for the inclusion of stress reduction interventions in comprehensive plans of care for HIV-infected individuals. Although effect and sample sizes are small, the results of these studies provide support for a positive effect of various interventions on immunological and health-related indices in HIV-infected individuals.

Stress and HIV disease progression: psychoneuroimmunological framework.

Psychoneuroimmunology (PNI) is the study of the interrelationships among behavior, neural and endocrine function, and the immune system. PNI investigates the relationships among stress, physiological dysregulation, and health outcomes. Research has supported the theory that emotional distress and the resultant neuroendocrine activation can induce immune system suppression. This suppression has significant implications for disease susceptibility and progression. HIV disease and its extensive immunological consequences are explored within this framework. Potential physiological pathways that may mediate stress-induced dysregulation within the context of HIV disease are identified. Key HIV-related PNI research studies are reviewed and critically analyzed. Implications for nursing practice and research are discussed.

Differential effects of glucocorticoids on colony stimulating factors produced by neonatal mononuclear cells.

The purpose of this study was to examine the effect of dexamethasone (DEX) on the production of granulocyte and granulocyte-macrophage colony stimulating factors (G-CSF and GM-CSF) by neonatal mononuclear cells. Mononuclear cells were isolated from umbilical cord blood and cultured with either phorbol myristate acetate/phytohemagglutinin (PMA/PHA) or Candida albicans with or without DEX (10(-8)-10(-6) M) for 48 h. Cell supernatants were assayed for G-CSF and GM-CSF by ELISA. Mononuclear cells from term and preterm infants responded to PMA/PHA stimulation with a significant increase in G-CSF production over baseline levels. The PMA/PHA-induced increase in G-CSF production was markedly augmented by the addition of DEX to cell cultures. DEX augmented production of G-CSF was significantly less in mononuclear cells from preterm infants. Similarly, production of G-CSF was significantly less by mononuclear cells from infants with acute physiology scores of > or = 10, as judged by the Score for Acute Neonatal Physiology. In contrast, DEX significantly inhibited PMA/PHA-induced GM-CSF production. Although C. albicans induced mononuclear cells to produce G-CSF, DEX did not significantly augment this production. No significant effect of DEX on C. albicans induced GM-CSF production was observed. The data show DEX induced differential regulation of infant peripheral blood mononuclear cell production of G-CSF and GM-CSF. These results suggest that glucocorticoids may enhance certain aspects of host immune function in addition to their well-documented immunosuppressive effects. Further, the neutrophilia observed in DEX-treated infants may be due to enhanced G-CSF production.

Reduced capacity of neonatal lymphocytes to inhibit the growth of Candida albicans.

Opportunistic microorganisms produce significant morbidity and mortality in preterm and term infants. Because of the heightened susceptibility of infants to opportunistic fungal infections, neonatal lymphocytes were assessed for their capacity to inhibit the growth of Candida albicans. Lymphocytes from both preterm and term cord blood demonstrated significantly less effect upon C. albicans than did lymphocytes from adults. Neonatal lymphocytes of infants <32 weeks of gestation showed a marked reduction in growth inhibitory capacity compared to infants >32 weeks of gestation. Lymphocytes from female infants had a significantly greater fungal growth inhibitory capacity than did lymphocytes from male infants. These results show that neonatal lymphocytes have a reduced capacity to inhibit the growth of C. albicans. This reduced antifungal capacity may underlie the increased susceptibility of such infants to opportunistic microorganisms, like C. albicans.

Antifungal activity of interleukin-2-activated natural killer (NK1.1+) lymphocytes against Candida albicans.

Interleukin-2 (IL-2)-activated lymphocytes interact directly with, and inhibit, the growth of Candida albicans hyphae. C. albicans-stimulated natural killer (NK1.1+) lymphocytes were demonstrated to secrete a soluble product capable of directly affecting C. albicans yeast forms. Antibodies specific for interferon-gamma completely eliminated the antifungal activity of the NK1.1+ lymphocyte product and diminished the antifungal activity of NK1.1+ lymphocytes against C. albicans. Antibodies specific for other cytokines had no such effect. These data demonstrate that C. albicans-stimulated NK1.1+ lymphocytes have antifungal activity against C. albicans yeast cells via the release of interferon-gamma. This antifungal activity was demonstrable only against the yeast form of the fungus, with no effect on C. albicans hyphae.

Effect of Pichia anomala killer toxin on Candida albicans.

The effect of a Pichia anomala killer toxin upon a Candida albicans-sensitive strain was studied. Yeast and hyphae, after treatment with the toxin, were less capable of uptaking either [3H]-uridine or [35S]-methionine. In addition, the hyphal form of the fungus appeared to be less capable of DNA synthesis after toxin treatment. No effect of the killer toxin was shown upon a natural resistant mutant of the source strain. These data suggest that, similar to other killer yeast toxins, the toxin of P. anomala can produce a number of quantifiable effects upon sensitive C. albicans cells.

Trauma-induced immune dysfunction: a challenge for critical care.

Multiply injured trauma patients present a major challenge for the critical care nurse. Should the patient survive the initial injuries, the third phase of mortality (five to seven days following injury) is sepsis. Research findings document a strong link between trauma and immune dysfunction. This article highlights the main immunological defects and underlying mechanisms for trauma-induced immune dysfunction. It provides the theoretical foundation that underlies the rationale for current and future immune-based therapy for trauma patients. Because of the complexity of caring for and preventing septic complications in the trauma patient, advanced practice nurses and nurse educators can use this material to update the knowledge and skills of critical care nurses.

Candida albicans: an opportunistic threat to critically ill low birth weight infants.

Major advances in the management of critically ill low birth weight (LBW) infants have increased their survival. Yet the clinical course of these infants is complicated by the emergence of opportunistic microbial pathogens. Most importantly, serious infections from opportunistic fungi, such as Candida albicans, have produced systemic disease in vulnerable LBW infants. Invasive C. albicans infection is generally difficult to manage and is associated with high morbidity and mortality. Because the infection has an insidious and rapid course, the critical care nurse and advanced practice nurse need to provide key prevention and early treatment measures.

Role of the adrenal cortex and medulla in the young rats' glucoregulatory response to endotoxin.

The importance of the adrenal gland in the 10 day old (10 d) rats' glucoregulatory response to endotoxin (ETX) was investigated. Plasma glucose, lactate, and liver glycogen were measured at 0, 2, 3, and 4 h after ETX to 10 d adrenalectomized (ADRNX), adrenal demedullated (MEDX), and sham-operated (SHAM) rats. At 24 h after ETX, mortality in the ADRNX group was a striking 86% compared with 34% and 36% in intact and SHAM groups, respectively. Mortality in MEDX rats (47%) did not differ from control groups. Although MEDX exacerbated hypoglycemia at 3 and 4 h after ETX (p < or = .05), ADRNX produced severe hypoglycemia by 2 h after ETX. Lactacidemia occurred earlier and was greater in ADRNX rats than in MEDX and SHAM rats. Unlike MEDX, ADRNX significantly decreased liver glycogen and ETX rapidly depleted the remaining glycogen by 2 h after injection. These results demonstrate the greater importance of the adrenal cortex relative to the adrenal medulla in the 10 d rats' defense against ETX-induced hypoglycemia, hyperlactacidemia, and lethality.

Glucose, lactate, insulin, and somatostatin responses to endotoxin in developing rats.

The purpose of this study was to examine the temporal plasma glucose, lactate, insulin, and somatostatin responses of 10-day-old (10 d) and 28-day-old (28 d) rats to the effects of an LD90 dose of endotoxin for a 4 h period. Salmonella enteritidis endotoxin was administered to 10 d and 28 d rats at .2 and 30.0 mg/kg, respectively. Hyperglycemia was the initial response to endotoxin, followed by hypoglycemia; this was similar for 10 d and 28 d rats. Lactate levels were significantly elevated in 10 d rats, but only mild hyperlactacidemia was observed in 28 d rats. Hyperinsulinemia was observed in both 10 d and 28 d rats in response to elevated glucose levels; in 10 d rats, decreased insulin levels preceded the hyperinsulinemia. Plasma somatostatin levels were elevated in both 10 d and 28 d rats in response to endotoxin, but the endotoxin-induced somatostatin levels were greater and occurred earlier in 28 d rats than in 10 d rats. The magnitude of the somatostatin response to endotoxin in the developing rats was markedly less than that previously reported in adult rats. Since previous reports indicated that somatostatin supported the glucoregulatory adaptive response to endotoxin in adult rats, the present results suggested that the diminished somatostatin response to endotoxin in developing rats may partially underlie their increased sensitivity to endotoxin and the profound glucose dyshomeostasis that results subsequently.

Neonatal sepsis: confronting the challenge.

The challenge of neonatal sepsis is reviewed and updated, and the incidence and importance of microbial pathogens are addressed. Important maternal, neonatal, and environmental risk factors responsible for increasing the incidence of neonatal sepsis are reviewed. Underlying the neonate's susceptibility to sepsis is the markedly limited immunologic defense of the neonate. The neonate's humoral, cellular, and barrier defense limitations are analyzed with respect to how each alters host susceptibility. The clinical manifestations and progression of sepsis in the neonate are reviewed and the status of new therapeutic approaches is examined. Ways that nurses can assist in the prevention and limitation of disability from neonatal sepsis are provided.

Advances in immunotherapy of sepsis.

Septic shock, with its associated high morbidity and mortality, has long been a challenge to the critical care nurse. A promising new development in the treatment of this condition is the use of monoclonal antibodies to inactivate two prime mediators that induce the cascade of events that culminate in septic shock and multiple organ failure: bacterial endotoxin and tumor necrosis factor (TNF). The effectiveness of this immunotherapy depends on its timely administration, which necessitates the early identification of sepsis.

Mortality, temporal substrate and insulin responses to endotoxic shock in zero, ten and twenty-eight day old rats.

Neonatal sepsis is a significant health problem. However, to our knowledge, the temporal substrates and insulin response to endotoxin have not been characterized in the young animal to guide the investigations of glucoregulation in septic shock in the newborn. We characterized the temporal response to endotoxin in the developing rat. Sprague-Dawley rats were given intraperitoneal Salmonella enteritidis endotoxin in high and low lethal doses to zero, ten and 28 day old rats. Mortality, temporal glucose, lactate, hepatic glycogen and insulin were monitored. Mortality experiments show the ten day old rat is 300 times as sensitive to endotoxin as the 28 day old rat. Plasma glucose concentration increased in the high mortality groups by 120 minutes in the zero and ten day old rats (102 +/- 4 milligrams per deciliter, 119 +/- 6 milligrams per deciliter, respectively, and by 60 minutes in the 28 day old rats (223 +/- 12 milligrams per deciliter). The plasma glucose level decreased to 52 +/- 3 milligrams per deciliter by 240 minutes in the ten day old and by 180 minutes to 99 +/- 8 milligrams per deciliter in the 28 day high mortality groups. Peak lactic acid levels in the high lethality groups were zero day 2.8 +/- 0.2 millimoles per liter in zero day old rats, 3.3 +/- 0.2 millimoles per liter in 28 day old rats. Glycogen in the liver decreased rapidly by 120 minutes in all age groups. Plasma insulin concentration did not elevate significantly in zero and ten day old rats. In the 28 day old rat, insulin concentration increased by 120 minutes to 52 +/- 17 microunits per milliliter. Insulin glucose ratios were also elevated in the 28 day old endotoxin treated rat, indicating hyperinsulinemia. Thus, temporal substrates and insulin responses to endotoxin differ with animal age.

Sepsis in the young rat: maternal milk protects during cecal ligation and puncture sepsis but not during endotoxemia.

Cecal ligation and puncture (CLP) sepsis and the impact of maternal milk were studied in young rats from 10 to 28 days of age. Ten- and 14-day-old rats were highly resistant to CLP; 24 hr survival was 90% and 97%, respectively. However, survival decreased to 55% and 30%, respectively, in 21- and 28-day-old rats. No differences in plasma glucose and lactate were seen in rats from 10 to 18 days of age, but 21-day-old rats became significantly hypoglycemic and hyperlacticacidemic after CLP. In rats maintained on an exclusive maternal milk diet from 14 to 21 days of age, survival after CLP was improved (55% versus 94%); P less than .05), hypoglycemia did not occur, and hyperlacticacidemia was blunted. But this protective effect of maternal milk was not observed during endotoxemia in the young rat. These results suggest important differences between the models of CLP sepsis and endotoxemia in the young rat.

Pituitary-adrenal response to bacterial endotoxin in developing rats.

The neonatal rat is very sensitive to the lethal effects of bacterial endotoxin. Because of the adaptive importance of pituitary-adrenal secretions to stress, this study examined the ontogeny of the plasma corticosterone and adrenocorticotropic hormone (ACTH) responses to endotoxin. The lethal sensitivity of young rats to endotoxin ranged from 0.5 to 30 mg/kg (ip) in the 1- to 21-day-old rat. After endotoxin treatment, the 1- and 2-day-old rat showed marked elevations of corticosterone similar in magnitude to that seen in 21-day-old and adult rats; however, significantly depressed corticosterone increments were observed in the 5-, 10-, and 14-day-old rats. This age-related pattern of adrenocortical secretion was correlated with the developing rat's corticosterone response to exogenous ACTH. In contrast, endotoxin administered to 5-, 10-, and 14-day-old rats resulted in increments of plasma ACTH similar to those observed in the 21-day-old and adult rats. Although plasma ACTH levels increased by 84-127% in the 1- and 2-day-old rats, these increases were significantly less than those of rats at all other ages tested. Thus the newborn rat mounts an effective corticosterone response to endotoxin, loses this ability between ages 5-14 days, and regains this response at 21 days of age. Because the hyporesponsive ages exhibit a marked increase in ACTH secretion, the loss of the adrenocortical response to endotoxin appears to be a result of a depressed responsiveness of the adrenal cortex to ACTH.

Maternal ethanol ingestion: effect on maternal and neonatal glucose balance.

Liver glycogen availability in the newborn is of major importance for the maintenance of postnatal blood glucose levels. This study examined the effect of maternal ethanol ingestion on maternal and neonatal glucose balance in the rat. Female rats were placed on the Lieber-DeCarli liquid ethanol diet, an isocaloric liquid pair-fed diet, or an ad libitum rat chow diet at 3 wk before mating and throughout gestation. Blood and livers were obtained from dams and rat pups on gestational days 21 and 22. The pups were studied up to 6 h in the fasted state and up to 24 h in the fed state. Maternal ethanol ingestion significantly decreased litter size, birth weight, and growth. A significantly higher mortality during the early postnatal period was seen in the prenatal ethanol exposed pups. Ethanol significantly decreased fed maternal liver glycogen stores but not maternal plasma glucose levels. The newborn rats from ethanol ingesting dams also had significantly decreased liver glycogen stores. Despite mobilizing their available glycogen, these prenatal ethanol exposed pups became hypoglycemic by 6 h postnatal. This was more marked in the fasted pups. Ethanol did not affect maternal nor neonatal plasma insulin levels. Thus maternal ethanol ingestion reduces maternal and neonatal liver glycogen stores and leads to postnatal hypoglycemia in the newborn rat.

Hypoxic and nycthemeral responses by the adrenal cortex of partially hepatectomized rats.

Adrenocortical nycthemeral (day-night alteration) and hypoxic stress responses of rats were evaluated 48 h following 70% hepatectomy. Morning plasma and adrenal corticosterone concentrations of hepatectomized (H) rats at 0800 hours were significantly higher than those of sham (S) operated animals. Although both groups showed significant nocturnal elevations in these parameters at 2000 hours, the nocturnal rises in plasma corticosterone levels were 75% and 223% in H and S rats, respectively, yet the absolute steroid levels did not differ between the groups. The hypothalamic-pituitary-adrenocortical (HPA) response of H animals to hypoxia was assessed by measuring plasma corticosterone levels at various times before, during and after exposure to 10% O2 at ground level. Curvilinear analysis of the plasma steroid levels revealed a significantly slower corticosterone rise during the hypoxic phase in H than S animals, as well as a much slower return to baseline levels after the hypoxic stimulus was terminated. The latter indicates a decreased hepatic capacity to inactivate steroids in H animals, while the sluggish activation of the HPA system by hypoxia may be due to altered neuroendocrine control resulting from prior exposure of feedback sites to elevated basal plasma corticosterone levels.

Relation of endotoxin structure to hypoglycemic and insulinlike actions.

Various endotoxin preparations were used to determine which portion of endotoxin, lipid A, polysaccharide, or lipid-associated protein (LAP), mediates the hypoglycemic and insulinlike action in rats. Salmonella enteriditis Boivin (SEB), complete endotoxin, and S enteriditis Westphal (SEW), lacking LAP, were equally lethal to endotoxin-sensitized rats; however, S minnesota (SM) glycolipid (lipid A plus 16% polysaccharide) was comparatively more toxic. Toxic effects were prevented by alteration of lipid A through alkaline hydrolysis or polymixin B treatment. SM-lipid A (0.02% polysaccharide) was less toxic than SM-glycolipid. Similar hypoglycemic effects were produced by SEB and SEW; however, SM-glycolipid produced a significantly greater hypoglycemia. Although SEB, SEW, and SM-glycolipid all produced significant increases in adipose tissue glucose oxidation a decreasing trend in effectiveness was observed, while the SM-lipid A was without effect. However, adding detoxified hydrolysates of endotoxin to SM-lipid A produced a significant increase in glucose oxidation. In conclusion, lipid A is the primary endotoxin moiety mediating both the lethal effects of endotoxin and its hypoglycemic action. However, maximal expression of insulinlike action requires the presence of all three portions of endotoxin.