Chronic stress and mortality among older adults.
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Aged↗
Biomedical subjects
R Glaser
Publications and source records attributed to R Glaser.
Single- and double-proton-transfer in the aggregate between cytosine and guaninediazonium ion.
[formula: see text] The structure of "guaninediazonium ion" in its aggregate with cytosine has been explored with ab initio and density functional methods. The hydrogen-bonded aggregate between cytosine and guaninediazonium ion, 1, is a stable minimum, 3. While the isolated enol tautomer of guaninediazonium ion, 2, is significantly more stable than 1, the tautomeric aggregate 4 that results from double-proton-transfer in 3 is almost isoenergetic with 3. Most interesting and entirely unexpected is the finding that neither 3 nor 4 is predicted to be the thermodynamically predominant structure. Instead, single-proton-transfer to cytosine results in the most stable cytosinium-guaninediazo complex, 5.
Cytosine↗
Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption.
BACKGROUND: Xenotransplantation would provide a solution to the current shortage of organs for transplantation. Our group has been successful in inducing tolerance in mice and monkey models of allogeneic transplantation. The present study attempts to extend the same tolerance-inducing regimen to a pig-to-baboon organ transplantation model. METHODS: Nine baboons underwent a conditioning regimen (consisting of nonmyeloablative or myeloablative whole body and thymic irradiation, splenectomy, antithymocyte globulin, pharmacologic immunosuppression and porcine bone marrow transplantation [BMTx]), which has previously been demonstrated to induce donor-specific allograft tolerance in monkeys. In addition, immunoadsorption of anti-alphaGal antibody (Ab) was performed. Four of the nine baboons received pig kidney transplants (KTx), and one also underwent repeat transplantation with an SLA-matched kidney. Two received heterotopic pig heart transplants (HTx). Three baboons underwent conditioning without organ transplantation for long-term studies of natural Ab kinetics. RESULTS: In the three baboons that received the conditioning regimen without an organ transplant, immunoadsorption reduced Ab by approximately 90%, but recovery of Ab to pretreatment level or higher occurred within 7 days. In contrast, the level of Ab remained low after organ transplant. No Ab to pig antigens other than alphaGal was detected in any baboon before or after BMTx, KTx, or HTx. No graft succumbed to hyperacute rejection. KTx function began to deteriorate within 3-6 days, with oliguria and hematuria progressing to anuria, and the kidneys were excised after 3, 6, 9, 11, and 14 days, respectively. One HTx ceased functioning at 8 days; the second baboon died with a contracting HTx at 15 days. Features of coagulopathy and thrombocytopenia developed in all six transplanted baboons (high D-dimer, prolonged prothrombin time and partial thromboplastin time, and falling fibrinogen) resulting in serious bleeding complications in two baboons, one of which died on day 9. Donor organs showed progressive acute humoral rejection with deposits of IgM, IgG, and complement; a focal mononuclear cellular infiltrate was also observed. The ureter was the earliest structure of the KTx affected by rejection, with progression to necrosis. CONCLUSIONS: This conditioning regimen prevented hyperacute rejection but was ineffective in preventing the return of Ab, which was associated with the development of acute humoral rejection with features of coagulopathy. No baboon developed anti-pig Ab other than alphaGal Ab. Further modifications of the protocol directed toward suppression of production of Ab are required to successfully induce tolerance to pig organs in baboons.
Animals↗
Stress-related changes in proinflammatory cytokine production in wounds.
BACKGROUND: Several recent studies have shown that stress markedly delays wound healing. This study assessed the relationship between psychological stress and the secretion of proinflammatory cytokines at an actual wound site, providing in vivo data on the development of local immune responses that are central in the early stages of wound repair. METHODS: To study the dynamics of inflammation, skin blisters were induced on the forearm of 36 women (mean age, 57 years) by suction. After the blister roofs were removed, a plastic template was taped to the arm, and wells were filled with 70% autologous serum in buffer. Specimens were aspirated from blister chamber wells 5 and 24 hours after wounding. RESULTS: Women with higher perceived stress scores demonstrated significantly lower levels of 2 key cytokines--interleukin 1alpha and interleukin 8--at wound sites. In addition, subjects who had low levels of both cytokines after 24 hours reported more stress and negative affect, and they had higher levels of salivary cortisol than those who had high cytokine levels. CONCLUSION: Consistent with the evidence that stress delays wound healing, these data suggest a possible mechanism: psychological stress has measurable effects on proinflammatory cytokine production in the local wound environment.
Blood Pressure↗
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.
Adult↗
NMR studies of electrostatic potential distribution around biologically important molecules.
A new experimental approach has been developed to study the distribution of local electrostatic potential around specific protons in biologically important molecules. The approach is the development of a method denoted as "spin label/spin probe," which was proposed by one of us (. Mol. Biol. 6:498-507). The proposed method is based upon the quantitative measurement of the contribution of differently charged nitroxide probes to the spin lattice relaxation rate (1/T1) of protons in the molecule of interest, followed by calculation of local electrostatic potential using the classical Debye equation. In parallel, the theoretical calculation of potential distribution with the use of the MacSpartan Plus 1.0 program has been performed. Application of the method to solutions of simple organic molecules (aliphatic and aromatic alcohols, aliphatic carboxylates (propionate anion), and protonated ethyl amine and imidazole) allowed us to estimate the effective potential around the molecules under investigation. These were found to be in good agreement with theoretically expected values. This technique was then applied to zwitterionic amino acids bearing neutral and charged side chains (glycine, lysine, histidine, and aspartic acid). The reliability of the general approach is proved by the data presented in this paper. Application of this new methodology can afford insight into the biochemical significance of electrostatic effects in biological systems.
Alcohols↗
Psychoneuroimmunology and cancer: fact or fiction?
There is substantial evidence from both healthy populations as well as individuals with cancer linking psychological stress with immune downregulation. This discussion highlights natural killer (NK) cells, because of the role that they may play in malignant disease. In addition, distress or depression is also associated with two important processes for carcinogenesis: poorer repair of damaged DNA, and alterations in apoptosis. Conversely, the possibility that psychological interventions may enhance immune function and survival among cancer patients clearly merits further exploration, as does the evidence suggesting that social support may be a key psychological mediator. These studies and others suggest that psychological or behavioural factors may influence the incidence or progression of cancer through psychosocial influences on immune function and other physiological pathways.
Apoptosis↗
Effect of pig-specific cytokines on mobilization of hematopoietic progenitor cells in pigs and on pig bone marrow engraftment in baboons.
Mixed hematopoietic chimerism has been found to be a requirement for achieving specific immunologic hyporesponsiveness. Some of the requirements for in vitro and in vivo coexistence of discordant hematopoietic systems in the pig-to-baboon (or human) model have been investigated. We have tested the efficacy of pig-specific cytokines (PSC) (IL3, SCF, GM-CSF) in the mobilization of porcine bone marrow (BM) progenitors in vivo (i) in the pig and (ii) in baboons that underwent a conditioning regimen and porcine BM transplantation. In a preliminary in vitro study, porcine BM cells were incubated in various media to assess the effect of human plasma on pig progenitors in a colony-forming unit (CFU) assay. In in vivo studies, four pigs received PSC and one control pig did not. Six baboons underwent natural antibody removal, with subsequent pig BM transplantation. Four of these six underwent nonmyeloablative (n=2) or myeloablative (n=2) conditioning and all received PSC treatment. Two baboons did not receive PSC, one of which underwent a nonmyeloablative regimen. Sequential blood samples and BM biopsies in pigs and baboons were analyzed by CFU assay for the detection of porcine cells. Baboon samples were analyzed by polymerase chain reaction (PCR) to detect porcine DNA. In the case of the in vitro tests, colony forming by porcine progenitors was not inhibited by media containing human plasma and for the in vivo tests, PSC increased the number of progenitors in pig BM; mobilization of progenitors into the peripheral blood was observed. PSC-treated baboons which experienced transient depletion of leukocytes < 1,000/ml (as an effect of the conditioning regimen) had porcine BM cells detectable by PCR for as long as day 316 after BM transplantation. In conclusion we found that: (i) under the conditions of these studies, in vitro porcine progenitor cell growth was not inhibited by human plasma containing natural antibody and complement; (ii) PSC treatment led to an increased number of progenitors in pig BM and peripheral blood; (iii) the combination of an effective conditioning regimen and treatment with PSC was capable of inducing long-term survival of pig progenitors in baboons, although only a low level of engraftment was achieved.
Animals↗
Chronic stress associated with spousal caregiving of patients with Alzheimer's dementia is associated with downregulation of B-lymphocyte GH mRNA.
BACKGROUND: It has been demonstrated that growth hormone (GH) is synthesized and secreted by human peripheral mononuclear cells (PBMC), and the expression of GH mRNA can be found throughout the human immune system. METHODS: We studied a population of female caregivers of patients with Alzheimer's dementia (AD) who suffered from the stress of caring for these patients. We utilized quantitative RT-PCR to determine GH mRNA levels in T- and B-cell populations from PBMC. Subjects were nine caregivers of AD patients and nine age- and sex-matched controls. RESULTS: In the control group we found a threefold greater GH mRNA expression in B cells than in T cells. This finding was consistent with our previous in situ hybridization observation, suggesting GH mRNA in predominately B-cell areas of immune organs in humans. We also found that the expression of GH mRNA from total peripheral blood mononuclear cells and B cells in caregivers was 50% and 60% respectively less than that in the control group. CONCLUSIONS: Because the B-cell population is the source of antibody production, our findings suggest that the decrease in B-cell GH mRNA may contribute to the poor immune response to influenza virus vaccination that has been reported previously in chronically stressed caregivers.
Aged↗
Metabolic flux ratio analysis of genetic and environmental modulations of Escherichia coli central carbon metabolism.
The response of Escherichia coli central carbon metabolism to genetic and environmental manipulation has been studied by use of a recently developed methodology for metabolic flux ratio (METAFoR) analysis; this methodology can also directly reveal active metabolic pathways. Generation of fluxome data arrays by use of the METAFoR approach is based on two-dimensional (13)C-(1)H correlation nuclear magnetic resonance spectroscopy with fractionally labeled biomass and, in contrast to metabolic flux analysis, does not require measurements of extracellular substrate and metabolite concentrations. METAFoR analyses of E. coli strains that moderately overexpress phosphofructokinase, pyruvate kinase, pyruvate decarboxylase, or alcohol dehydrogenase revealed that only a few flux ratios change in concert with the overexpression of these enzymes. Disruption of both pyruvate kinase isoenzymes resulted in altered flux ratios for reactions connecting the phosphoenolpyruvate (PEP) and pyruvate pools but did not significantly alter central metabolism. These data indicate remarkable robustness and rigidity in central carbon metabolism in the presence of genetic variation. More significant physiological changes and flux ratio differences were seen in response to altered environmental conditions. For example, in ammonia-limited chemostat cultures, compared to glucose-limited chemostat cultures, a reduced fraction of PEP molecules was derived through at least one transketolase reaction, and there was a higher relative contribution of anaplerotic PEP carboxylation than of the tricarboxylic acid (TCA) cycle for oxaloacetate synthesis. These two parameters also showed significant variation between aerobic and anaerobic batch cultures. Finally, two reactions catalyzed by PEP carboxykinase and malic enzyme were identified by METAFoR analysis; these had previously been considered absent in E. coli cells grown in glucose-containing media. Backward flux from the TCA cycle to glycolysis, as indicated by significant activity of PEP carboxykinase, was found only in glucose-limited chemostat culture, demonstrating that control of this futile cycle activity is relaxed under severe glucose limitation.
Aerobiosis↗
Stress and immunity: implications for viral disease and wound healing.
It is now well established that psychological stress can downregulate the cellular immune response. Communication between the central nervous system and the immune system occurs via a complex network of bidirectional signals linking the nervous, endocrine, and immune systems. Stress disrupts the homeostasis of this network, which in turn, alters immune function. In this review, we discuss the role of stress in modulating cellular immune function and the potential health implications of this downregulation.
Down-Regulation↗
The UVA light used during the fluorescence microscopy assay affects the level of intracellular calcium being measured in experiments with electric-field exposure.
In the present paper, the induction of calcium signals in neuroblastoma cells, cells of T-cell leukemia, and osteogenic sarcoma cells were investigated in relation to the UVA irradiation used in fluorescence microscopy. Methods were developed to measure both the mean UVA irradiance and the intensity profile in the UVA-illuminated area of the microscope. This allowed us to calculate the applied UVA radiant exposure of the cells during each experiment. This investigation was undertaken because of the conflicting results in the literature on the effects of electromagnetic fields on the signals of the calcium-sensitive fluorescence probe FURA-2 in lymphocytes. Taking into account that each group used a different system with different optics and lamps, these conflicting results are now at least partially understandable. Our measurements indicate that in a typical experiment with FURA-2 the cells were irradiated with up to 776 kJ m(-2) during 25 min of exposure to UVA light. This causes changes in intracellular free Ca(2+) concentrations ([Ca(2+)](i)). Designating cells in which the [Ca(2+)](i) was distinctly increased during the experiment as "responding", we found Hill-type dependences on the irradiance. Jurkat cells showed a 50% response even at 10 kJ m(-2) and osteosarcoma cells at about 60 kJ m(-2), whereas neuroblastoma cells even at the maximum possible dose responded only minimally. In the case of neuroblastoma cells, we found a dependence of this effect on the CO(2) partial pressure during the preincubation. An electrical treatment with an a.c. field (5 kHz sinusoidal, amplitude modulation 16 Hz 100%, 800 V m(-1), 5 min) had a significant effect on intracellular calcium in neuroblastoma cells only in the case of cells that were not pretreated with CO(2) with high fluences of UVA irradiation. In conclusion, these results indicate that the possibility of UVA artifacts must be considered in all experiments using fluorescence microscopy. Furthermore, our results lead to the hypothesis that oxidative stress could be the link between UVA and electric-field effects.
Animals↗
Stress-associated immune modulation: relevance to viral infections and chronic fatigue syndrome.
The frequent association of an active viral infection with the symptoms of CFS led researchers to hypothesize that chronic fatigue syndrome (CFS) is induced by a virus. Results of these studies indicated that despite clinical support for this hypothesis, there were no clear data linking viruses to CFS. In this overview, we will explore the interrelation of the immune, endocrine, and central nervous systems, and the possibility that stress and/or the reactivation/replication of a latent virus (such as Epstein Barr virus) could modulate the immune system to induce CFS. Relevant research conducted in the developing field of psychoneuroimmunology will be reviewed, with a particular focus on cytokine synthesis, natural killer (NK) cell activity, and T-lymphocyte function, as they relate to CFS.
Fatigue Syndrome, Chronic↗
Anti-Gal(alpha)1-3Gal antibody response to porcine bone marrow in unmodified baboons and baboons conditioned for tolerance induction.
BACKGROUND: Mixed lymphohematopoietic chimerism can provide an effective means of inducing longterm immunological tolerance and has been documented in a monkey allograft model. A conditioning regimen including nonmyeloablative or myeloablative irradiation and splenectomy has been used to induce chimerism in a pig-to-primate transplantation model. Since the presence of anti-Gal(alpha)1-3Gal (alphaGal) natural antibodies leads to the hyperacute rejection of pig organs transplanted into primates, extracorporeal immunoaffinity adsorption (EIA) of anti-alphaGal antibodies is also included in the regimen. The effect of the tolerance induction protocol on the anti-alphaGal antibody response has been assessed. METHODS: Anti-alphaGal antibody was measured after the EIA of plasma through an alphaGal immunoaffinity column in baseline studies involving two unmodified baboons, one splenectomized baboon, and one baboon that received a challenge with porcine bone marrow (BM), and in three groups of baboons (n=2 in each group) that received different conditioning regimens for tolerance induction. Group 1 received a nonmyeloablative conditioning regimen without porcine BM transplantation. Group 2 received nonmyeloablative conditioning with pig BM transplantation and pig cytokine therapy. Group 3 received myeloablative conditioning, an autologous BM transplant (with BM depleted of CD2+ or CD2+/CD20+ cells), and pig BM transplantation. RESULTS: In the baseline studies, a single EIA of anti-alphaGal antibodies in an unmodified animal initially depleted anti-alphaGal antibody, followed by a mild rebound. Nonmyeloablative conditioning (group 1) in the absence of pig cell exposure reduced the rate of anti-alphaGal antibody return. Pig BM cells markedly stimulated anti-alphaGal antibody production in an unmodified baboon (alphaGal IgM and IgG levels increased 40- and 220-fold, respectively). This response was significantly reduced (to an only 2- to 5.5-fold increase of IgM and IgG) in baboons undergoing nonmyeloablative conditioning (group 2). A myeloablative conditioning regimen (group 3) prevented the antibody response to pig BM, with the reduction in response being greater in the baboon that received autologous BM depleted of both CD2+ and CD20+ cells. No new antibody directed against pig non-aGal antigens was detected in any baboon during the 1 month follow-up period. CONCLUSIONS: (i) EIA of anti-alphaGal antibody in unmodified baboons results in a transient depletion followed by a mild rebound of antibody; (ii) exposure to pig BM cells results in a substantial increase in anti-alphaGal antibody production; (iii) a nonmyeloablative conditioning regimen reduces the rate of antibody return and (iv) markedly reduces the response to pig BM cells; (v) the anti-alphaGal response is completely suppressed by a myeloablative regimen if CD2+ and CD20+ cells are eliminated from the autologous BM inoculum. Furthermore, (vi) challenge with pig BM cells appears to stimulate only an anti-alphaGal antibody response without the development of other (non-alphaGal) anti-pig antibodies. We conclude that regimens used for T-cell tolerance induction can be beneficial in reducing the anti-alphaGal antibody response to porcine BM.
Animals↗
Social stress and the reactivation of latent herpes simplex virus type 1.
Psychological stress is thought to contribute to reactivation of latent herpes simplex virus (HSV). Although several animal models have been developed in an effort to reproduce different pathogenic aspects of HSV keratitis or labialis, until now, no good animal model existed in which application of a psychological laboratory stressor results in reliable reactivation of the virus. Reported herein, disruption of the social hierarchy within colonies of mice increased aggression among cohorts, activated the hypothalamic-pituitary-adrenal axis, and caused reactivation of latent HSV type 1 in greater than 40% of latently infected animals. However, activation of the hypothalamic-pituitary-adrenal axis using restraint stress did not activate the latent virus. Thus, the use of social stress in mice provides a good model in which to investigate the neuroendocrine mechanisms that underlie behaviorally mediated reactivation of latent herpesviruses.
Animals↗
The influence of psychological stress on the immune response to vaccines.
We compared virus-specific antibody and T-cell responses to influenza virus vaccination in 32 caregivers of Alzheimer's disease (AD) patients and matched control subjects. Caregivers showed a poorer antibody response and virus-specific T-cell response following vaccination compared to the control subjects as measured by fourfold increases in antibody titers to the vaccine and lower levels of virus-induced IL-2 levels in vitro. We performed a second study in which forty-eight medical students were inoculated with a series of three injections of the hepatitis-B (HEP-B) vaccine to coincide with the third day of three, three-day examination blocks. Twelve of the 48 medical students seroconverted after the first injection; these students were characterized by falling into the lower stressed/lower anxiety group of students. Students who reported greater social support and lower anxiety and stress demonstrated a higher antibody response to the vaccine and a more vigorous T-cell response to HEP-B surface antigen at the end of the third examination experience. The differences in antibody and T-cell responses to HEP-B and influenza virus vaccinations provide a demonstration of how stress may be able to alter both the cellular and humoral immune responses to vaccines and novel pathogens in both younger and older adults.
Aged↗
Marital stress: immunologic, neuroendocrine, and autonomic correlates.
Ninety newlywed couples (mean age = 25), selected on the basis of extremely stringent mental and physical health criteria, were admitted to a hospital research unit for 24 hours to provide a detailed assessment of conflict-resolution behaviors and changes in autonomic, endocrine, and immune function. Among these newlyweds, negative or hostile behaviors during marital conflict (coded from videotaped interactions) were associated with increased levels of epinephrine, norepinephrine, growth hormone, and ACTH as well as greater immunological change over the subsequent 24 hours. Wives demonstrated greater and more persistent physiological changes related to marital conflict than husbands. To assess the generalizability of these physiological changes, a similar laboratory paradigm was used with 31 older couples (mean age = 67) who had been married an average of 42 years. Consistent with the data from newlyweds, both endocrinological and immunological data showed significant relationships to negative behavior during marital conflict in these older couples. These findings suggest that abrasive marital interactions have important endocrinological and immunological correlates.
Autonomic Nervous System↗
Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis.
We examined the effects of brief psychological stressors on cardiovascular, neuroendocrine, and cellular immune response in 22 older women to investigate the common effects of stress across systems. Results revealed that psychological stressors heightened cardiac sympathetic activation, elevated plasma catecholamine concentrations, and affected the cellular immune response (ps < 0.05). In a replication and extension, 27 women caring for a spouse with a progressive dementia (high chronic stress) and 37 controls category matched for age and family income (low chronic stress) performed the 12-min laboratory stressor. Measures were taken before (low acute stress) and immediately following (high acute stress) exposure to the laboratory stressors as well as 30 min after termination of the stressor (recovery period). Acute stress again heightened cardiac sympathetic activation, elevated plasma catecholamine concentrations, and affected cellular immune responses (ps < 0.05), whereas chronic stress was associated with higher reports of negative affect, enhanced cardiac sympathetic activation, elevated blood pressure and plasma levels of ACTH, and diminished production of interleukin-1 beta (ps < 0.05). Correlational analyses in both studies further suggested that individuals who showed the greatest stress-related changes in HPA activation also exhibited the greatest diminution in cellular immune response.
Autonomic Nervous System↗