Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period.

We recently reported that immune stimulation can be compromised if animals are simultaneously subjected to stressful conditions. To test the generalizability of these findings, and to elucidate neuroendocrine mediating mechanisms, we herein employed CpG-C, a novel TLR-9 immune-stimulating agent. Animals were subjected to ongoing stress (20-h of wet cage exposure) during CpG-C treatment, and antagonists to glucocorticoids, ß-adrenoceptor, COX2, or opioids were employed (RU486, nadolol, etodolac, naltrexone). In F344 rats, marginating-pulmonary NK cell numbers and cytotoxicity were studied, and the NK-sensitive MADB106 experimental metastasis model was used. In Balb/C mice, experimental hepatic metastases of the CT-26 colon tumor were studied; and in C57BL/6J mice, survival rates following excision of B16 melanoma was assessed - both mouse tumor models involved surgical stress. The findings indicated that simultaneous blockade of glucocorticoid and ß-adrenergic receptors improved CpG-C efficacy against MADB106 metastasis. In mice bearing B16 melanoma, long-term survival rate was improved by CpG-C only when employed simultaneously with blockers of glucocorticoids, catecholamines, and prostaglandins. Prolonged stress impaired CpG-C efficacy in potentiating NK activity, and in resisting MADB106 metastasis in both sexes, as also supported by in vitro studies. This latter effect was not blocked by any of the antagonists or by adrenalectomy. In the CT26 model, prolonged stress only partially reduced the efficacy of CpG-C. Overall, our findings indicate that ongoing behavioral stress and surgery can jeopardize immune-stimulatory interventions and abolish their beneficial metastasis-reducing impacts. These findings have implications for the clinical setting, which often involve psychological and physiological stress responses during immune-stimulation.

In vivo suppression of plasma IL-12 levels by acute and chronic stress paradigms: potential mediating mechanisms and sex differences.

Interleukin-12 (IL-12) is a major pro-inflammatory cytokine, which promotes cell-mediated immunity and T(H)1 differentiation. In vitro studies indicated suppression of IL-12 production by several stress-related factors, but no effects of behavioral stress were shown on plasma IL-12 levels. Therefore, in the current study we (i) examined the in vivo effects of various behavioral and pharmacological stress paradigms on baseline plasma IL-12 levels; (ii) compared these in vivo findings to those obtained following in vitro stimulation of leukocytes from the same rats; and (iii) assessed potential sexual dimorphism in these outcomes. The findings indicated that plasma IL-12 levels were significantly reduced by social confrontation, wet-cage exposure, surgery, and the administration of corticosterone, epinephrine, or prostaglandin-E(2). Notably, most in vivo impacts on plasma levels were not evident when assessed in vitro. The IL-12-reducing effects of wet-cage exposure, and of corticosterone and epinephrine administration, were significantly greater in males than in females, although females exhibited greater total corticosterone levels following stress. The duration of acute stressors predicted the degree of IL-12 reduction, but more prolonged stressors did not. Furthermore, seven days of alternating behavioral stressors reduced plasma IL-12 levels more than 14 days. These findings suggest animals' behavioral habituation to stress conditions, or a specific immune mechanism restricting the duration of IL-12 reduction. Overall, our findings indicate a generic and robust stress-induced reduction in plasma IL-12 levels, and suggest epinephrine, corticosterone, and prostaglandin-E(2), as potential mediators that should be scrutinized in vivo in the context of natural physiological stress responses.

Acute alcohol intoxication suppresses natural killer cell activity and promotes tumor metastasis.

Alcohol consumption is associated with increased morbidity and mortality related to infectious diseases and malignancy (1-5), although immune mediation of these relationships is controversial. Specifically, the activity of natural killer (NK) cells, which are involved in the resistance to infections and metastasis, can be suppressed in the presence of ethanol in vitro. However, acute consumption or infusion of ethanol in vivo exerts no effects on NK activity assessed in vitro thereafter. Therefore, we have developed and used a method to study the effects of ethanol on NK activity in living rats by using an NK-sensitive metastatic process and selective depletion of NK cells in vivo. Acute ethanol intoxication caused a marked suppression of NK activity in vivo and a tenfold increase in the number of MADB106 tumor metastases. Ethanol had no effect in rats selectively depleted of NK cells or when an NK-insensitive tumor (C4047) was used. These findings suggest that even acute ethanol intoxication markedly suppresses NK activity in the living organism. This suppression may underlie some aspects of the association between alcoholism, infectious disease and malignancies.

Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats.

We have previously shown in rats that the provision of analgesic doses of morphine significantly reduces the tumor-promoting effects of undergoing and recovering from surgery. Because morphine had no effect in non-operated animals, and because a single preoperative dose given hours before tumor inoculation was effective, we have suggested that it is the pain-relieving effects of the drug that underlies its beneficial impact. To support and strengthen this suggestion, two different regimens of analgesia were employed, the systemic administration of the more selective mu-agonist, fentanyl, and the intrathecal (i.t.) administration of bupivacaine plus morphine. To assess host resistance against metastasis, we used a lung clearance assay of the MADB106 mammary adenocarcinoma, a natural killer (NK)-sensitive syngeneic cell line that metastasizes only to the lungs. Female and male Fischer 344 rats were randomly assigned to one of four groups using a 2x2 experimental design: experimental laparotomy under halothane anesthesia versus anesthesia alone, by drug treatment versus vehicle. In the first in vivo experiment, fentanyl was administered 20 min before surgery (40 microg/kg subcutaneously (s.c.)), and at the end of surgery in a slow-release suspension (20 microg/kg s.c.). In the second in vivo experiment, bupivacaine (10 microg) plus morphine (20 microg) in 50 microl was administered i.t. before surgery. Surgery resulted in a 3- to 4-fold increase in the lung retention of MADB106 cells in both males and females, and the observed surgery-induced increase in lung tumor retention was reduced by more than 65% in the fentanyl-treated animals and more than 45% in the animals receiving i.t. bupivacaine plus morphine. Neither drug regimen exerted effects in the anesthesia only animals. Surgery also resulted in a significant suppression of whole blood NK activity assessed at 5 h postoperatively, the same time point at which MADB106 tumor cells were inoculated in the in vivo studies. Unlike the in vivo study, fentanyl suppressed NK activity at this time point in non-operated rats, but had no effect in operated rats. Taken together, these findings strengthen the suggestion that the management of perioperative pain is a critical factor in preventing surgery-induced decreases in host resistance against metastasis. If similar relationships between pain and metastasis occur in humans, then pain control must become a priority in the postoperative care of individuals with cancer.

The development of sexual dimorphism in natural killer cell activity and resistance to tumor metastasis in the Fischer 344 rat.

The development of sexual dimorphism in the number and activity level of natural killer (NK) cells was studied in the inbred Fischer 344 rat from prepubescence to maturity. Additionally, in view of the biological significance of NK cells in controlling cancer, especially the metastatic process, we used a syngeneic mammary tumor (MADB106) to assess the host anti-metastatic activity. This tumor model was used because NK cells control the lung clearance of i.v.-injected MADB106 tumor cells, a process that critically affects the metastatic colonization of these tumor cells in the lungs. The results indicated that although prepubescent (36 days of age) males and females exhibited greater NK cytotoxicity (assessed in vitro) and higher anti-metastatic activity, evidenced by fewer tumor cells retained in the lungs. On the other hand, the mature males (140-170 days of age) displayed greater LGL/NK number and activity per ml blood, retained fewer tumor cells, and developed fewer lung tumor colonies compared to the females. During early postpubescence (63 days of age), a transitional stage between prepubescence and maturity, females and males exhibited equivalent numbers of circulating LGL/NK cells, and females displayed slightly greater NK cytotoxicity per ml blood yet retained somewhat greater numbers of tumor cells compared to the males. Overall, whereas the males exhibited increasing levels of NK number and activity throughout the age span tested, the females, despite displaying greater NK function compared to the males at prepubescence and slight improvement at postpubescence, fell behind the males in these indices of NK function at maturity.

A role for NK cells in greater susceptibility of young rats to metastatic formation.

Cancer is the second leading cause of death in children (after accidents) and is more prevalent in the first 5 years of life than in the subsequent 10 years. Very young animals have been shown to be more susceptible to malignant growth and whether such increased susceptibility is attributable to reduced resistance of the host to tumor development or to increased incidence of cancerous cells is, as yet, unclear. In the current study, we used 36 day old male and female rats and adult rats to specifically study the role of natural killer (NK) cell activity, as well as hormones known to regulate their activity, in mediating reduced resistance to tumor metastasis at prepubescence. A mammary adenocarcinoma cell line (MADB106) syngeneic to the Fischer 344 rat was used. Following i.v. injection, MADB106 tumor cells seed and colonize only in the lungs, a process shown in adult rats to be controlled by NK cells during the first 24 hours after tumor inoculation. As was found in our previous studies, young rats demonstrated a 10-fold higher percentage of lung tumor cell retention compared to adult rats. Importantly, this higher percentage of tumor cell retention was evident using the same number of tumor cells per kg of body weight in young and adult rats, and maintained even when young rats were challenged with 10- and 100-fold fewer MADB106 cells per kg than adults. Selective depletion of NK cells markedly increased tumor cell retention in all rats, indicating that NK cells play a crucial role in resistance against MADB106 retention in both young and adult rats. Employing in vitro assessment of whole blood NK cytotoxicity. young animals exhibited markedly less specific killing compared to the mature animals. Taken together, these findings indicate a reduced resistance of the young rats against MADB106 retention that is mediated by diminished NK activity in these rats. Factors other than NK cells appear to play a minor role determining age differences in this model. Age- and sex-related differences in plasma beta-endorphin and corticosterone levels were also found, suggesting different activation levels of the HPA axis. These differences, however, seen unlikely to underlie the reduced NK activity in young rats.

N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 blocks non-opioid stress-induced analgesia. I. Comparison of opiate receptor-deficient and opiate receptor-rich strains of mice.

The effects of the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 (0.075 mg/kg), and the specific opiate receptor antagonist naloxone (10 mg/kg), on swim stress-induced analgesia (SSIA) were studied in opiate receptor-deficient (CXBK) and opiate receptor-rich (CXBH) mice. Animals were subjected to forced swimming, and analgesia was assessed using the hot-plate test. In CXBK mice SSIA was blocked by MK-801 but was completely insensitive to naloxone. In CXBH mice SSIA was partially attenuated both by naloxone and MK-801, and it was nearly abolished by a combination of these drugs. Morphine analgesia (10 mg/kg) was abolished by naloxone but completely unaffected by MK-801 in CXBH mice. These findings suggest that the NMDA receptor is critically involved in the non-opioid component of SSIA.

Psychological influences on surgical recovery. Perspectives from psychoneuroimmunology.

Greater fear or distress prior to surgery is associated with a slower and more complicated postoperative recovery. Although anxiety presumably interferes with recuperation through both behavioral and physiological mechanisms, the pathways have been unclear. Recent work in psychoneuroimmunology (PNI) has demonstrated that stress delays wound healing. In addition, a second line of research has illustrated the adverse effects of pain on endocrine and immune function. A biobehavioral model is described that is based on these and other data; it suggests a number of routes through which psychological and behavioral responses can influence surgery and post-surgical outcomes. Clinical and research implications are highlighted.

Cost of clinical instructors' time in clinical education--physical therapy students.

The purpose of this study was to estimate the total clinical instructor time required to conduct the clinical education program of our physical therapy school. Clinical instructors in 12 of the 29 regional health care facilities providing clinical education programs described, through questionnaires and interviews, the instructional activities in their programs and the number of hours a week required for each activity. For each activity, the instructors indicated whether it served educational purposes only (a single purpose activity) or patient care and research purposes as well (a joint purpose activity), and they estimated the time that they spent with the student (direct contact time). The sample data were used to estimate the annual requirement for clinical instructor time for the physical therapy clinical program, totaling 10,264 hours. The methodology and the findings of this study can assist governmental agencies, educational institutions, and clinical facilities to define policy and funding agreements for clinical training purposes.

Patent ductus arteriosus in the premature neonate.

This article has reviewed current thought on the pathophysiology, medical management, and nursing implications of PDA in the premature newborn. The ductus arteriosus is a normal vascular channel that provides a route for blood flow to the descending aorta in the fetus; and it is an abnormal channel in the newborn that allows additional pulmonary blood flow to be shunted from the higher pressured aorta. Left heart volume overload and additional insults in connection with concurrent RDS and BPD were discussed. Current management for closure advocates indomethacin administration, and ligation, should indomethacin fail or be contraindicated. Continued patency with prostaglandin administration is the objective in cyanotic neonates with congenital heart disease and diminished pulmonary blood flow and in acyanotic neonates with aortic arch abnormalities that lead to decreased descending aortic flow. Nursing responsibilities encompass the well-being of the newborn as well as the family. The neonate must be assessed frequently for signs of cardiopulmonary deterioration. The neonate's responses to drug administration must be monitored for their effect on the ductus and the minimization of side effects. Care of the parents regarding support and information was discussed.

Tetralogy of Fallot.

This article has discussed TOF, its occurrence, physiology, medical interventions and nursing implications. In its classic form, TOF consists of four anatomical aberrations: a large VSD, pulmonic stenosis, dextroposition of the aorta, and right ventricular hypertrophy. Surgical palliation versus primary intracardiac repair is a continuing discussion in medical literature. Children who have undergone intracardiac repair for TOF have an excellent prognosis for late survival, near 90% 10 years after repair. Nursing responsibilities in the care of the newborn diagnosed as having TOF encompass the well-being of the newborn as well as the family. Palliation increases pulmonary arterial flow, thus decreasing cyanosis and promoting measurable clinical improvement in the infant. Preparation of the family and child for surgery involves completing a baseline assessment of family dynamics, diagnosing stressors, composing objectives, carrying out interventions focused on developmental ability, and evaluating the effectiveness of the nursing process. Maintaining the physical and emotional integrity of a child just out of the operating room is a challenge. Parental support is important to the young child's feelings of security while hospitalized.

The immune-suppressive nature of pain.

OBJECTIVES: To review evidence that the immune system plays a role in controlling the spread of cancer and findings that perioperative pain relief improves immune status and health outcomes. DATA SOURCES: Research studies and review articles pertaining to immunity, immune function, stress, and immune-suppressive nature of pain. CONCLUSIONS: Pain not only results in suffering but is a pathogen itself, capable of facilitating the progression of metastatic disease. Adequate pain relief decreases these risks. IMPLICATIONS FOR NURSING PRACTICE: Adequate pain relief is not only a primary concern in caring for individuals in pain but may be a matter of physiologic necessity as further studies reveal the immune-suppressive nature of pain.

Chronic pain and the child with juvenile rheumatoid arthritis.

This article presents a summary of nursing issues concerning the assessment and management of pain in children with juvenile rheumatoid arthritis (JRA). Following a brief description of the difference between acute and chronic pain and a description of JRA, the developmental issues relating to pain assessment in this population are discussed. Three pain assessment tool alternatives are presented. Finally, current strategies for pain relief and treatment of children with JRA are presented.

An analysis and comparison of the educational costs of clinical placements for occupational therapy, physical therapy, and speech pathology and audiology students.

The purpose of this paper is to describe the methodology and summarize the results of a study of the educational costs of clinical placement for students in occupational therapy, physical therapy, and speech pathology and audiology at The University of British Columbia. The sample represented 42.9% of the facilities offering occupational therapy placements, 41.4% of those offering physical therapy placements, and 52.4% of those offering speech pathology and audiology placements. During a 12-month period, these facilities provided 77.3% of the total clinical hours for the occupational therapy students, 65.1% for the physical therapy students, and 66.1% for the speech pathology and audiology students. Estimates of the number of hours of single-purpose and joint-purpose instructional activities and percentage estimates of direct-contact time were used as a basis for calculating the costs to facilities of accepting students for clinical placement. The methodology permitted comparisons of these costs across health disciplines. Both the methodology and the findings of this study can help government, educational institutions, and clinical facilities in defining policies and funding mechanisms for clinical training programs.

Physician-assessment and physician-enhancement programs in Canada.

In the mid-1980s, the licensing authorities in Quebec, Ontario and Manitoba have introduced programs to conduct in-depth assessments of the clinical skills and abilities of physicians with suspected deficiencies. These assessments are intended to supplement the provincial licensing authorities' existing peer review or patient-complaint mechanisms by confirming the physicians' overall level of competence and identifying specific clinical strengths and weaknesses. An "educational prescription", based on the results of the assessment, focuses on aspects of clinical practice in which the physicians need or wish to enhance their skills. In some situations, licensure decisions are based on the assessment information. This article describes the programs in Quebec, Ontario and Manitoba. Each program comprises a different process of personal assessment and individualized continuing medical education to help physicians improve their clinical competence, and each is built on sound principles of clinical competence assessment and educational planning.

Perceived control moderates the influence of active coping on salivary cortisol response to acute pain among women but not men.

It is generally established that active-coping strategies and greater perceived control over pain are associated with improved pain-related outcomes; however, it remains unclear whether these factors independently or interactively influence adrenocortical function in reaction to a painful stimulus. The present study examined whether active coping predicted magnitude cortisol response to acute pain, whether perceived control over pain moderated this association, and whether effects differed as a function of sex. Our findings suggest that perceived control moderates the active coping-adrenocortical relation among women but not men, such that active coping may augment the release of cortisol in response to a painful stimulus only in the presence of greater perceived control over pain. Taken together, active coping and perceived control may potentiate an adaptive neuroendocrine response to an acute painful stressor.

The association of the cortisol awakening response with experimental pain ratings.

Cortisol is a key stress hormone that is implicated in a variety of physiological responses. Attenuated Cortisol Awakening Response (CAR) is associated with many negative health outcomes, but little research has investigated CAR and pain. The current study examines the association of CAR with experimental acute-pain ratings in healthy men and women. Attenuated CAR was related to greater pain intensity and unpleasantness ratings. Future research should examine this association across various pain populations.

Medical conditions and symptoms associated with posttraumatic stress disorder in low-income urban women.

BACKGROUND: Epidemiological studies have consistently reported rates of posttraumatic stress disorder (PTSD) in women that are twice that of men. In men and women, PTSD has been associated with comorbid medical conditions, medical symptoms and lower self-rating of health. In low-income urban women, rates of PTSD are even more elevated than in suburban women and may be related to observed health disparities. METHODS: In this study, 250 women seeking healthcare at an urban clinic were interviewed for a PTSD diagnosis, major depressive disorder (MDD), the experience of traumatic events, the experience of current and past common medical conditions and symptoms, and subjective rating of health. A chart review was used to assess healthcare use in the past year. RESULTS: More current (5.2 vs. 3.8, p < 0.05) and past medical conditions (4.6 vs. 3.3, p < 0.05) were reported by women with a lifetime history of PTSD than by women without this history, after controlling for demographics and current depression. Women with lifetime PTSD also had more annual clinic appointments (5.9 vs. 3.8 p < 0.03) and were 2.4 times (p < 0.05) more likely to report lower appraisal of their physical health. CONCLUSIONS: These findings suggest that urban health-seeking women with PTSD experience health impairments that may cause increased morbidity and that healthcare providers should consider the health ramifications of PTSD when providing medical care to women.