SPEEDPOST EMS SERVICE TO KOREA FACILITY SHEET NO. 13 _________________________________________________________________________________________ SERVICE TITLE In Singapore - known as “Speedpost EMS”In Korea DATE OF SERVICE INTRODUCED DELIVERY AREAS STANDARD OF DELIVERY FROM DAY OF POSTING Item addressed to rural areas may be subject to delay GUARANTEE Yes (Pleas
Australian people can buy antibiotics in Australia online here: http://buyantibioticsaustralia.com/ No prescription required and cheap price!
Pnas201118355 1.5Chronic stress, glucocorticoid receptor resistance,inﬂammation, and disease riskSheldon Cohena,1, Denise Janicki-Devertsa, William J. Doyleb, Gregory E. Millerc, Ellen Frankd, Bruce S. Rabine,and Ronald B. Turnerf aDepartment of Psychology, Carnegie Mellon University, Pittsburgh, PA 15213; bDepartment of Otolaryngology/ENT, Children’s Hospital of Pittsburgh,Pittsburgh, PA 15224; cDepartment of Psychology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4; Departments of dPsychiatry and ePathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and fDepartment of Pediatrics, University of Virginia Health SciencesCenter, Charlottesville, VA 22908 Edited* by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved February 27, 2012 (received for review November 7, 2011) We propose a model wherein chronic stress results in glucocorticoid of chronic inﬂammatory diseases such as CVD, and type II di- receptor resistance (GCR) that, in turn, results in failure to down- regulate inﬂammatory response. Here we test the model in two In the common cold, the typical signs and symptoms of illness viral-challenge studies. In study 1, we assessed stressful life events, are primarily caused by the release of the proinﬂammatory cyto- GCR, and control variables including baseline antibody to the chal- kines produced in response to infection (13). A series of studies lenge virus, age, body mass index (BMI), season, race, sex, educa- have shown that chronic stress is associated with increased sus- tion, and virus type in 276 healthy adult volunteers. The volunteers ceptibility to developing a common cold among persons experi- were subsequently quarantined, exposed to one of two rhinovi- mentally exposed to an upper respiratory virus (e.g., refs. 14–17).
ruses, and followed for 5 d with nasal washes for viral isolation This association has been replicated in cross-sectional and pro- and assessment of signs/symptoms of a common cold. In study 2, spective studies conducted in natural settings (18). Although we assessed the same control variables and GCR in 79 subjects who attempts to identify behavioral pathways linking stress to cold were subsequently exposed to a rhinovirus and monitored at base- susceptibility have not been especially successful (14, 15), there is line and for 5 d after viral challenge for the production of local (in evidence consistent with stress effects resulting in increased dis- nasal secretions) proinﬂammatory cytokines (IL-1β, TNF-α, and IL-6).
ease risk because of their association with exaggerated local (in Study 1: After covarying the control variables, those with recent the nose) release of inﬂammatory cytokines (16). The explanation exposure to a long-term threatening stressful experience demon- for this association has been that stress disrupts the HPA response strated GCR; and those with GCR were at higher risk of subsequently and that the regulation of inﬂammation is under HPA control.
developing a cold. Study 2: With the same controls used in study 1, However, cortisol levels based on 24-h urine (15) and waking di- greater GCR predicted the production of more local proinﬂamma- urnal assessments in saliva (19, 20) do not play a part in this tory cytokines among infected subjects. These data provide support process. Alternatively, what matters may be how the target tissue for a model suggesting that prolonged stressors result in GCR, responds to cortisol, rather than the levels of the hormone per se.
which, in turn, interferes with appropriate regulation of inﬂamma- To the extent that chronic stress results in GCR, one might expect tion. Because inﬂammation plays an important role in the onset and insufﬁcient control over the inﬂammatory response to the in- progression of a wide range of diseases, this model may have broad fection, and consequently a greater expression of the signs and implications for understanding the role of stress in health.
The viral-challenge paradigm provides an ideal context to study lymphocytes | receptor sensitivity | psychological stress | cortisol | the general model of stress leading to disease via effects on the hypothalamic–pituitary–adrenocortical axis HPA and inﬂammatory regulation. In these studies, stress andGCR are assessed before subjects are exposed to a virus and fol- Chronic psychological stress is associated with a greater risk of lowed in quarantine to determine whether they develop a clinical depression, cardiovascular disease (CVD), diabetes, autoim- illness (infection plus signs of illness). Here we conduct secondary mune diseases, upper respiratory infections (URIs), and poorer analyses of two independent studies (15, 21), each using a different wound healing (1). Although these associations are often attrib- means of assessing GCR, to address the potential role of target uted to stress-induced dysregulation of the hypothalamic–pitui- tissue sensitivity to cortisol in linking stress to disease. In study 1, tary–adrenocortical axis (HPA) (e.g., refs. 2, 3), few human studies we attempt to replicate earlier evidence that stress exposure is include assessments of stressful events, HPA response, and a dis- associated with increased GCR (5, 6, 9–11) and test whether GCR ease outcome in the same subjects. The lack of such studies is partly prospectively predicts who will develop a cold when exposed to attributable to the as yet incomplete understanding of the effects of a rhinovirus. In study 2, we address whether GCR is prospectively prolonged stress on the HPA in human subjects (4) and on de- associated with the magnitude of the local inﬂammatory cytokine termining which stress-induced changes in HPA play a downstream response to being infected by a cold virus. We predict that GCR role in disease risk. The simple notion that chronic stress acts will be associated with experiencing a long-term threateningstressful experience, will interfere with the down-regulation of through the direct effects of elevated circulating cortisol is be- proinﬂammatory cytokine response, and will increase illness ex- coming less likely (5, 6). What may matter more is how target tis- pression among persons infected with a cold virus.
sues respond to cortisol, rather than levels of the hormone per se.
GCR refers to a decrease in the sensitivity of immune cells to glucocorticoid hormones that normally terminate the inﬂammatory Author contributions: S.C., W.J.D., and G.E.M. designed research; S.C., W.J.D., E.F., B.S.R., response (6–9). Evidence for GCR in response to chronic stress and R.B.T. performed research; E.F. and R.B.T. contributed new reagents/analytic tools; has been found in parents of children with cancer (10), spouses of S.C. and D.J.-D. analyzed data; and S.C., D.J.-D., W.J.D., G.E.M., E.F., B.S.R., and R.B.T.
brain-cancer patients (11) and in persons reporting high levels of loneliness (5). Without sufﬁcient glucocorticoid regulation, the The authors declare no conﬂict of interest.
duration and/or intensity of the inﬂammatory response increases, *This Direct Submission article had a prearranged editor.
heightening risk for acute exacerbations such as occur in asthma Freely available online through the PNAS open access option.
and autoimmune diseases, as well as for the onset and progression 1To whom correspondence should be addressed. E-mail: GCR and colds. Similarly we ﬁnd the expected associations between All analyses include seven covariates: prechallenge viral-speciﬁc cortisol and leukocyte counts for persons who did not develop antibody titers, age, body mass index [BMI: weight (kg)/height a cold following viral challenge (n = 167). In contrast, and con- (m)2], season (spring or fall), race (white or not), sex, and edu- sistent with GCR putting people at greater risk for illness, there cation (study 1: less than high school, high school graduate, some were no associations between cortisol and leukocyte counts college, bachelor’s degree or greater; study 2: years of educa- among those who did develop a cold (n = 109). (Fig. 2, N/L ratio.) tion). In study 1, where subjects receive one of two viruses, Here linear regressions indicate stress-by-cortisol interactions for analyses also control for virus type [rhinovirus (RV)21 or RV39].
lymphocytes (P = 0.02), neutrophils (marginal at P = 0.08), andN/L ratio (P = 0.02). For all three analyses, simple slopes among Study 1. Stress and colds. As reported in similar analyses of these those who did not develop a cold were signiﬁcantly different from data (14), in a multiple logistic regression, exposure to a recent 0, whereas slopes for those who did develop a cold were not major stressful life event was associated with an increased risk (Table 2). As expected, plasma cortisol levels did not predict who for developing a cold following exposure to RV (OR = 1.99, developed a cold (OR = 1.27, CI = 0.20, 7.94). Together, results CI = 1.04, 3.08). This association was similar across the two from these prospective analyses support the hypothesis that GCR viruses (P > 0.16 for stress-by-virus interaction).
predicts an increased risk for colds following viral exposure, Stress, GCR, and colds. Greater levels of glucocorticoid are associated whereas levels of circulating cortisol do not.
with higher numbers of circulating neutrophils, lower numbers Consideration of alternative explanations. To evaluate the possibility of circulating lymphocytes, and a lower neutrophil-to-lymphocyte that sympathetic nervous system hormones that often increase (N/L) ratio—an overall marker of the trafﬁcking of these cells (e.g., with cortisol may be driving the redistribution of cells, we con- refs. 22, 23). Cole and his colleagues (5, 24) showed that this as- ducted all of the same analyses described earlier replacing cor- sociation can be used to indirectly assess GCR. The logic of the tisol with epinephrine (E) and with norepinephrine (NE). These measure is that there is a strong physiologic correlation between hormones were not associated with numbers of any of the cell cortisol levels and the number of circulating leukocytes only if types in relevant subgroups of subjects deﬁned by either stress leukocyte glucocorticoid receptors are sensitive (i.e., signaling cells to redistribute).
Stress and GCR. We found the expected associations between Study 2. GCR and nasal cytokines. We suggest that the association of leukocyte numbers and cortisol among those who did not expe- GCR with colds reﬂects inadequate control of local inﬂammatory rience a major stressor (n = 83). In contrast, consistent with the responses to the virus. To test this hypothesis, we examine hypothesis that stress results in GCR, there were no associations whether GCR predicts the production of local proinﬂammatory between cortisol and leukocytes among those who did experience cytokines when subjects are exposed to a rhinovirus. Data for this a stressor (n = 193). Fig. 1 displays these ﬁndings graphically study were collected from a subsample of subjects in a larger viral- using the relation of cortisol to N/L ratio as an example. That the challenge trial (15). Here GCR was assessed before viral chal- slopes of the stressed and nonstressed subjects were different lenge using a standard ex vivo model (6), wherein leukocytes were from each other is supported by stress-by-cortisol level inter- coincubated with lipopolysaccharide and dexamethasone, and actions found in linear regressions predicting lymphocytes (P = proinﬂammatory cytokine production measured in supernatants.
0.03), neutrophils (P = 0.03) and the N/L ratio (P = 0.03). For The logic behind this assay is that dexamethasone should inhibit all three analyses, simple slopes for those without stress were cytokine production only to the extent that leukocytes are sensi- signiﬁcantly different from 0, whereas slopes for those with stress tive to its effects. This study had enough subjects with the required were not (Table 1). These analyses support GCR emergence data to examine cytokine response (a continuous variable) but not among those experiencing major stressors.
Association between plasma cortisol and the ratio of neutrophils to lymphocytes for subjects experiencing and not experiencing a signiﬁcant stressful life event during the last year. Lack of correlation is a marker of GCR. Filled circles/solid line, major stressful life event; open circles/dashed line, no stressful event.
Simple effect associations of stress status with developing a cold following exposure to a rhinovirus (also reported in ref. 15). New analyses indicate that this same stress measurewas also associated with GCR, with stressed persons showing less sensitivity of lymphocyte and neutrophil counts to distributional changes associated with greater circulating levels of cortisol. In turn, GCR was prospectively associated with increased risk of developing a common cold following experimental inoculation with a cold virus. These data are consistent with a model whereinstress leads to GCR, which in turn results in greater risk for de- Analyses control for age, sex, race, body mass index, education, prechal- veloping a cold. In study 2, GCR predicted how much local ﬁc antibody titers, season, and virus type. **P < 0.01.
proinﬂammatory cytokine was produced in response to infection.
Because the analyses in both studies were prospective, we can Table 3 presents the partial correlations between GCR and eliminate reverse causation (colds did not cause stress, colds did proinﬂammatory cytokine levels in the nasal cavity during the 5 d not cause GCR, and cytokine release did not cause GCR) as an following viral challenge. For both IL-6 and TNF-α, increases in alternative explanation. The use of multiple control variables also the resistance curve were associated with increased production of eliminates many potential spurious explanations.
the matching local inﬂammatory cytokine. Greater IL-1β GCR The GCR measure used in study 1 is indirect. However, exper- was also associated with greater local IL-6 production. The cor- imental studies have shown that glucocorticoid-induced leukocyte relation of IL-1β GCR with local IL-1β release was in the expected redistribution is speciﬁcally attributable to glucocorticoid receptor direction, but was not signiﬁcant. All of these results are the same signaling (25), and that the indirect assessment used here corre- whether the analyses include all subjects, or are limited to those lates with blunting of lymphocyte redistribution in response to infected by the virus. Cortisol levels as assessed by multiple sam- dexamethasone injection (24). Even so, it is possible that the action ples of saliva collected across the day before viral challenge were of another hormone or mechanism both highly correlated with unrelated to any of the three GCR measures (all P > 0.20) or to cortisol and having the same impact on leukocyte trafﬁcking as proinﬂammatory cytokine levels (all P > 0.40). Overall, these data cortisol could account for these effects. Likely alternative explan- are consistent with the hypothesis that a decreased sensitivity of ations include that the associations are attributable to subject leukocytes to the inhibitory effects of cortisol (increased GCR) health (e.g., infections) or to receptor sensitivity to E and/or NE.
reﬂects a decreased ability of cortisol to regulate the production of Health is not an issue here, because subjects are carefully local proinﬂammatory cytokines in response to infection.
screened for excellent health. Further, we found that neither Enor NE were correlated with leukocyte counts under any of the relevant conditions (similar results in ref. 5). We also found We proposed that exposure to a major stressful life event can result consistent evidence across studies 1 and 2, even though study 2 in GCR, which, in turn, would interfere with HPA down-regulation used a standard direct assessment of GCR.
of local proinﬂammatory cytokine response to an infectious agent.
We found no effects of cortisol levels on disease risk (e.g., refs.
Without appropriate cortisol regulation of the local cytokine re- 19, 20), GCR, or inﬂammation. This apparent lack of a role for sponse, there would be an exaggerated expression of the signs of circulating cortisol levels is consistent with the possibility that URI, which are generated by the proinﬂammatory response. In impaired target tissue response to the regulatory effects of this study 1, stress—deﬁned as a recent stressful life experience asso- hormone may overshadow any modulatory inﬂuences that might ciated with long-term threat—predicted an increased risk of result from changes in circulating concentrations of cortisol itself.
Association between plasma cortisol and the ratio of neutrophils to lymphocytes for subjects who developed and did not develop a cold after exposure to a rhinovirus. Lack of correlation is a marker of GCR. Filled circles/solid line, meets cold criterion; open circles/dashed line, does not meet cold criterion.
Simple effect associations of cold status with Study 1. Subjects and design. The subjects were 125 men and 151 women, meanage 29.13 y (SD = 9.09 y) who responded to newspaper advertisements and were judged to be in good health after a medical examination. Subjects were paid $800 for their participation.
After we assessed life stress, complete blood counts, cortisol, demographics, anthropomorphics, and virus-speciﬁc antibody levels, subjects were quaran- tined in separate rooms, exposed to one of two RVs and followed for 5 d with nasal washes for viral isolation and assessment of symptoms and signs of a Analyses control for age, sex, race, body mass index, education, prechallenge Experimental plan. At the medical screening, age, education, race, sex, body ﬁc antibody titers, season, and virus type. *P < 0.05, **P < 0.01.
weight, and height were also assessed and used as baseline data for thosedeemed eligible. Eligible subjects returned to the hospital 4 and 5 wk later In the case of the common cold, a disease for which expression (1–2 wk before viral challenge) for two blood samples for determination of of the signs/symptoms of illness is driven by the inﬂammatory complete blood counts, antibody to the challenge virus, and plasma cortisoland for the stressful life event interview.
response, the failure of the HPA to regulate the production of After completing the baseline assessments, subjects entered quarantine.
local proinﬂammatory cytokines contributes to the risk for clinical During the ﬁrst 24 h of quarantine (before viral challenge), they had a nasal illness. Because inﬂammation plays a role in progression of mul- examination (including a nasal wash culture for RV) and were excluded if there tiple diseases, this model not only provides an explanation for the was any indication of recent or current URI or illness. An update stressful life increased risk for URI under stress, but might provide a more event interview was administered at this time to identify events occurring general explanation for why prolonged stress would play a role in between the initial interview and quarantine. Baseline respiratory signs (nasalmucociliary clearance and nasal mucus production) and symptoms were other inﬂammatory diseases as well. Moreover, although the focus assessed. At the end of the ﬁrst 24 h of quarantine, subjects were given nasal here has been on GCR in circulating leukocytes and neutrophils, drops containing a low infectious dose of either RV21 (N = 129) or RV39 (N = stress could also be associated with illness expression through its 147). Quarantine continued for 5 d after challenge. Nasal secretion samples effect on the glucocorticoid sensitivity of other cells involved in for virus culture were collected on each of the 5 d. Subjects were also tested immune defenses (26). For example, glucocorticoid receptors (GR) on each day for respiratory symptoms, nasal mucociliary clearance, and nasal are expressed by cells involved with antigen presentation, such as mucus production. Approximately 28 d postchallenge, a blood sample wascollected for assaying convalescent antibodies to the challenge virus. All dendrocytes and macrophages, not only in circulation but also at investigators were blinded to subjects’ status on all baseline assessments.
speciﬁc sites of infection and in draining lymph nodes.
Stressful life events. Life events were assessed by a standardized semistructured Parodoxically, proinﬂammatory cytokines are thought to both interview, the Bedford College Life Events and Difﬁculties Schedule (LEDS) up-regulate immunity to the virus and produce cold symptoms (29), and conducted by trained interviewers. We considered only those events (13). However, here stress and GCR, conditions associated with that occurred during the last 12 mo. Ratings of events were performed in an increased levels of local proinﬂammatory cytokine, predicted a independent laboratory by consensus groups consisting of at least fourtrained interviewers. The interview staff was blind to other study measures.
greater risk of clinical illness. These data are consistent with Raters were also blind to individuals’ subjective responses to the stressful those of other viral-challenge studies that found a positive as- events and used “dictionaries” of precedent examples to rate each stressful sociation between proinﬂammatory cytokine levels and symptom experience reported during the interview on long-term threat (i.e., threat that is sustained beyond the immediate experience of the event). Dictionary An unexplained inconsistency in the data from study 2 is that ratings are based on the likely response of an average person to a stressor local IL-6 and TNF-α, but not IL-1β, were correlated with GCR occurring in the context of the subject’s particular set of biographical cir- measured by the whole blood ex vivo assay. It is possible that this cumstances. It is the long-term threat of an experience that is thought todetermine its implications for health. Here, we deﬁne stress as a life experi- discrepancy is due to the relative insensitivity of the IL-1β assay.
ence, irrespective of duration (including both acute events and chronic dif- Alternatively, it may reﬂect a differential sensitivity of these ﬁculties in LEDS parlance), that was rated as having high moderate or marked cytokines to glucocorticoid suppression (27).
long-term threat. We excluded stress resulting from physical illness to avoid Finally, future research on GCR would beneﬁt from quanti- confounding a chronic health condition with susceptibility and stressful ﬁcation of GR subtypes, whose relative abundance might un- events in which the subject was not a major focus.
derlie the ﬁndings observed here. Chronic stress does not appear GCR. We conducted a complete blood count and assayed for cortisol in each oftwo blood samples collected 1 and 2 wk prechallenge. Correlations between cell to affect expression of GRα, the active isoform of the receptor counts from the two blood draws ranged from 0.61 to 0.76, P < 0.001. Plasma (11). However, there is evidence linking stress and cytokines to cortisol was measured using a double-antibody competitive RIA. The correla- higher levels of GRβ and a lower GRα/GRβ ratio (28). This tion between cortisol in the two samples was 0.70, P < 0.001. Because we were could prove important because GRβ is a dominant negative re- concerned with stable differences in cortisol and in cell distributions that occur ceptor for cortisol, which can suppress GRα activity and thereby in response to prolonged stress, we averaged the two values in both cases.
We found no associations between monocyte percentage and cortisol in the entire sample or in sample subsets split by stress or colds. Thus, we could not usewhether cortisol was associated with monocytes as a marker of GCR. Our dataare therefore based on the associations of cortisol with percentages of lym- Partial correlations of glucocorticoid resistance curves phocytes and neutrophils. We also use the ratio of neutrophils to lymphocytes (AUC) with nasal cytokine AUCs: Entire sample and infected subset (log10) as an overall marker of the trafﬁcking of these cells (5, 24).
Epinephrine and Norepinephrine. Urine was obtained from 24-h collections that began on day 0 of quarantine. E and NE were measured using high per- formance liquid chromatography with electrochemical detection. Values areexpressed in micrograms per milligram of creatinine (log10).
Infection. Nasal washes were performed daily during quarantine to provide samples of nasal secretions for virus culture (30). Neutralizing antibodies to the challenge virus were tested in prechallenge and 28-d postchallenge se-rum samples (30).
Signs of illness. On each day of quarantine, we collected two objective signs of disease—mucus weights and mucociliary clearance function. Mucus weights Analyses control for age, sex, race, years of education, body mass index, were determined by collecting used tissues in sealed plastic bags (31). The prechallenge antibody, and season. *P < 0.10, **P < 0.05, ***P < 0.01.
bags were weighed and the weight of the tissues and bags subtracted. To adjust for baseline, mucus weight on the day before challenge (mode = 0) maximized the rate of infection by including only subjects with prechallenge was subtracted from each daily mucus weight after challenge. Adjusted viral-speciﬁc antibody titers ≤4.
weights with negative values were scored as 0. The adjusted postchallenge During the ﬁrst 24 h of quarantine (before viral challenge) nasal muco- weights were summed to create an adjusted total mucus weight.
ciliary clearance and nasal mucus production were assessed. Volunteers were Nasal mucociliary clearance function refers to the effectiveness of nasal cilia excluded if they had signs or symptoms of a cold and excluded from analysis if in clearing mucus from the nasal passage toward the nasopharnyx. Clearance a viral pathogen was isolated from the nasal lavage obtained at that time.
function was assessed as the time required for a dye administered into the nose Subjects were then given nasal drops containing an infectious dose of to reach the nasopharnyx (31). Each daily time was adjusted (by subtracting) RV39. On each day of quarantine nasal lavage samples were collected for for baseline (negative values were scored as 0) and the adjusted average time virus culture and assessment of local proinﬂammatory cytokines. Approxi- in minutes was calculated across the postchallenge days of the trial.
mately 28 d postchallenge, blood was collected for serological testing. The Clinical illness. Subjects were considered to have a cold if they were both investigators were blinded to all baseline measures.
infected and met objective illness criteria. They were classiﬁed as infected if the Infection. Infection was assessed with the same procedures used in study 1.
challenge virus was isolated on any of the 5 postchallenge study days or if there GCR. We used a standard in vitro assay to measure GCR that assessed the was a fourfold or greater rise in virus-speciﬁc serum neutralizing antibody titer ability of dexamethasone (0, 10, 50, and 250 nM) to suppress lipopolysac- between prechallenge and 28-d postchallenge. Illness criterion was based on charide (30 ng/mL) stimulated lymphocyte production of IL-1β, IL-6, and TNF- objective indicators of illness—a total adjusted mucus weight of ≥10 g or an α. The remaining procedures were the same as those used in Miller et al. (6).
adjusted average mucociliary nasal clearance time of ≥7 min (21).
Area under the dexamethasone curve (adjusted for an unstimulated control) Statistical analyses. We conducted two sets of regression analyses, each pre- dicting the percentage of neutrophils, lymphocytes, and the N/L ratio. The Proinﬂammatory cytokines. We measured IL-1β, IL-6, and TNF-α in nasal secre- ﬁrst set included the standard covariates, a dichotomous variable repre- tions. Nasal wash ﬂuid was assayed for cytokine protein using the BioSource senting life stress (1 = stress, 0 = no stress), continuous plasma cortisol, and the Ten-plex bead immunoassay and methods provided by the manufacturer interaction of life stress and cortisol. We predicted an interaction with leu- (BioSource International). Assays were performed in duplicate using a Luminex kocyte counts increasing (neutrophils and N/L ratio) or decreasing (lym- 100 bead-based immunoassay system. To control for basal nasal cytokine phocytes) with increasing cortisol levels for those without a major stressful life levels, prechallenge cytokine values were subtracted from the values obtained event but not for those with an event. The second set included standard on each of the 5 postchallenge days. Nasal cytokine area under the curve (AUC) covariates, dichotomous variables for life stress, and cold status (1 = cold, 0 = was derived from these baseline-adjusted values and computed using the no cold) and the interaction of life stress and cold status. We again predicted an interaction with cortisol associated with leukocyte counts among those Cortisol. Subjects provided seven saliva samples (collected at wake-up and at 1, without colds but not among those with colds. We also calculated the simple 2, 4, 7, 9, and 14 h after wake-up) on the day preceding viral challenge by slopes for each group in all analyses and tested whether they were signiﬁ- chewing on cotton rolls until saturated and then storing the rolls in plastic salivettes. Code numbers provided by hand-held computers were used to guarantee timely collection of samples. Saliva cortisol level was determined Study 2. Subjects and design. The subjects were 39 men and 43 women (mean age = 36.9 y, SD = 9.2 y) who responded to advertisements and were judged to 10 AUC adjusted for wake-up time was used to represent be in good health. They were paid $800 for their participation. Three subjectswere excluded due to incomplete nasal cytokine data.
After we assessed GCR and the standard control variables, subjects were ACKNOWLEDGMENTS. Preparation of this paper was supported by GrantAT006694 from the National Center for Complementary and Alternative quarantined in separate rooms, exposed to a rhinovirus and followed for 5 d with Medicine; conducting the studies, by Grants MH47234 and MH50430 from nasal washes to assess viral shedding and local proinﬂammatory cytokines.
the National Institute of Mental Health and Grants HL65111 and HL65112 Experimental plan. At the medical screening we also collected speciﬁc serum from the National Heart, Lung, and Blood Institute; and the assay of antibody titer to the challenge virus, demographics, weight, and height.
glucocorticoid resistance in study 2, by the MacArthur Foundation Research Because we were interested in inﬂammatory response to infection, we Network on Socioeconomic Status and Health.
1. Cohen S, Janicki-Deverts D, Miller GE (2007) Psychological stress and disease. JAMA 18. Pedersen A, Zachariae R, Bovbjerg DH (2010) Inﬂuence of psychological stress on upper respiratory infection—a meta-analysis of prospective studies. Psychosom Med 2. McEwen BS (1998) Protective and damaging effects of stress mediators. N Engl J Med 19. Cohen S, et al. (2008) Objective and subjective socioeconomic status and susceptibility 3. McEwen BS, Seeman T (1999) Protective and damaging effects of mediators of stress.
to the common cold. Health Psychol 27:268–274.
Elaborating and testing the concepts of allostasis and allostatic load. Ann N Y Acad Sci 20. Edwards S, Hucklebridge F, Clow A, Evans P (2003) Components of the diurnal cortisol cycle in relation to upper respiratory symptoms and perceived stress. Psychosom Med 4. Miller GE, Chen E, Zhou ES (2007) If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. Psychol Bull 133:25–45.
21. Cohen S, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM, Jr. (1997) Social ties and 5. Cole SW (2008) Social regulation of leukocyte homeostasis: The role of glucocorticoid susceptibility to the common cold. JAMA 277:1940–1944.
sensitivity. Brain Behav Immun 22:1049–1055.
22. Fauci AS, Dale DC, Balow JE (1976) Glucocorticosteroid therapy: Mechanisms of action 6. Meagher MW, Johnson RR, Good E, Welsh TH (2006) Psychoneuroimmunology, eds and clinical considerations. Ann Intern Med 84:304–315.
Ader R, Felton D, Cohen N (Academic, New York), 4th Ed, Vol II, pp 1107–1124.
23. Dhabhar FS, Miller AH, McEwen BS, Spencer RL (1996) Stress-induced changes in blood 7. Marques AH, Silverman MN, Sternberg EM (2009) Glucocorticoid dysregulations and leukocyte distribution. Role of adrenal steroid hormones. J Immunol 157:1638–1644.
their clinical correlates. From receptors to therapeutics. Ann N Y Acad Sci 1179:1–18.
24. Cole SW, Mendoza SP, Capitanio JP (2009) Social stress desensitizes lymphocytes to 8. Bailey M, Engler H, Hunzeker J, Sheridan JF (2003) The hypothalamic-pituitary-adre- regulation by endogenous glucocorticoids: Insights from in vivo cell trafﬁcking dy- nal axis and viral infection. Viral Immunol 16:141–157.
namics in rhesus macaques. Psychosom Med 71:591–597.
9. Stark JL, et al. (2001) Social stress induces glucocorticoid resistance in macrophages.
25. Miller AH, et al. (1994) Effects of selective type I and II adrenal steroid agonists on immune cell distribution. Endocrinology 135:1934–1944.
10. Miller GE, Cohen S, Ritchey AK (2002) Chronic psychological stress and the regulation 26. Webster JI, Tonelli L, Sternberg EM (2002) Neuroendocrine regulation of immunity.
of pro-inﬂammatory cytokines: A glucocorticoid-resistance model. Health Psychol 21: 27. DeRijk R, et al. (1997) Exercise and circadian rhythm-induced variations in plasma 11. Miller GE, et al. (2008) A functional genomic ﬁngerprint of chronic stress in humans: cortisol differentially regulate interleukin-1 β (IL-1 β), IL-6, and tumor necrosis factor-α Blunted glucocorticoid and increased NF-kappaB signaling. Biol Psychiatry 64:266–272.
(TNF α) production in humans: High sensitivity of TNF α and resistance of IL-6. J Clin 12. Nathan C (2002) Points of control in inﬂammation. Nature 420:846–852.
13. Hendley JO (1998) The host response, not the virus, causes the symptoms of the 28. Derijk RH, et al. (2001) A human glucocorticoid receptor gene variant that increases common cold. Clin Infect Dis 26:847–848.
the stability of the glucocorticoid receptor beta-isoform mRNA is associated with 14. Cohen S, Tyrrell DAJ, Smith AP (1991) Psychological stress and susceptibility to the rheumatoid arthritis. J Rheumatol 28:2383–2388.
common cold. N Engl J Med 325:606–612.
29. Brown GW, Harris TO (1989) Life Events and Illness (Guilford, New York).
15. Cohen S, et al. (1998) Types of stressors that increase susceptibility to the common 30. Gwaltney JM, Jr., Colonno RJ, Hamparian VV, Turner RB (1989) Diagnostic Procedures cold in healthy adults. Health Psychol 17:214–223.
for Viral, Rickettsial and Chlamydial Infections, eds Schmidt NJ, Emmons RW (Amer- 16. Cohen S, Doyle WJ, Skoner DP (1999) Psychological stress, cytokine production, and ican Public Health Association, Washington, DC), 6th Ed, pp 579–614.
severity of upper respiratory illness. Psychosom Med 61:175–180.
31. Doyle WJ, McBride TP, Swarts JD, Hayden FG, Gwaltney JM, Jr. (1988) The response of 17. Stone AA, et al. (1992) Development of common cold symptoms following experimental the nasal airway, middle ear, and Eustachian tube to provocative rhinovirus chal- rhinovirus infection is related to prior stressful life events. Behav Med 18:115–120.
Cyclobenzaprine tablets (Fexmid, Flexeril ) What is this medicine? CYCLOBENZAPRINE (sye kloe BEN za preen) is a muscle relaxer. It is used to treat muscle pain, spasms, and stiffness. This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions. What should I tell my health care provider before I take this medicine? They need to know if you