Light Therapy for Cancer-Related Fatigue in (Non-)Hodgkin Lymphoma Survivors: Results of a Randomized Controlled Trial.

PURPOSE: To evaluate the short- and long-term effects of light therapy on fatigue (primary outcome) and sleep quality, depression, anxiety, quality of life, and circadian rhythms (secondary outcomes) in survivors of (non-)Hodgkin lymphoma presenting with chronic cancer-related fatigue. METHODS: We randomly assigned 166 survivors (mean survival 13 years) to a bright white light intervention (BWL) or dim white light comparison (DWL) group. Measurements were completed at baseline (T0), post-intervention (T1), at three (T2), and nine (T3) months follow-up. A mixed-effect modeling approach was used to compare linear and non-linear effects of time between groups. RESULTS: There were no significant differences between BWL and DWL in the reduction in fatigue over time. Both BWL and DWL significantly (p < 0.001) improved fatigue levels during the intervention followed by a slight reduction in this effect during follow-up (EST0-T1 = -0.71; EST1-T3 = 0.15). Similar results were found for depression, sleep quality, and some aspects of quality of life. Light therapy had no effect on circadian rhythms. CONCLUSIONS: BWL was not superior in reducing fatigue compared to DWL in HL and DLBCL survivors. Remarkably, the total sample showed clinically relevant and persistent improvements on fatigue not commonly seen in longitudinal observational studies in these survivors.

Age, BMI, and inflammation: Associations with emotion recognition.

Experimental studies show that inflammation impairs the ability to interpret the mental state of another person, denoted theory of mind (ToM). The current study attempted a conceptual replication in states associated with elevated low-grade inflammation, i.e., high body weight and advanced age. Ninety young (M = 26.3 years, SD = 4.1) or older (M = 70.7 years, SD = 4.0) participants with either a normal body mass index (BMI) (M = 22.4, SD = 2.2) or high BMI (M = 33.1, SD = 3.8) completed the Reading the Mind in the Eyes Test (RMET) to assess emotion recognition. Plasma interleukin-6 (IL-6) level was measured to index low-grade inflammation. As anticipated, elevated IL-6 levels were found with higher BMI, although not with increased age. IL-6 was associated with poorer task performance, independent of potential demographic and health confounders (e.g., sex, education, smoking status, alcohol intake, presence of medical conditions, and medication intake). Analyses also revealed an interaction whereby young individuals with a high BMI showed worse RMET performance compared to their normal BMI counterparts, whereas the opposite pattern was found in older individuals. The present observational study replicated experimental results showing that elevated low-grade inflammation is correlated with a lower ability to infer the mental states of others. These findings suggest that also naturalistic conditions of (protracted) low-grade inflammation may alter emotion recognition.

Salivary Biomarkers in Psychoneuroimmunology.

As molecular biology advances, an increasing number of proteins are becoming detectable at very low levels in different biological tissues. In this regard, saliva holds vast promise. Unlike blood, saliva can be sampled 1) non-invasively; 2) across all ages (newborn to elderly); 3) in the field; 4) by study participants; and 5) many times per day. With respect to psychoneuroimmunology (PNI), physiological measures of stress such as cortisol have been well characterized. Alpha amylase provides another physiological index of stress; it is a measure of autonomic nervous system activation and is quantifiable in saliva. Other salivary measures, such as inflammatory biomarkers and immunoglobulin A (IgA), provide valuable information pertaining to the effects of stress on inflammation, mucosal immunity, and oral health. Importantly, due to various methodological issues and a lack of strong correlation between saliva and blood measures, investigators should proceed with caution in drawing conclusions from measures of salivary inflammation that pertain to systemic immunity or generalized health.

Low-grade inflammation decreases emotion recognition - Evidence from the vaccination model of inflammation.

The ability to adequately interpret the mental state of another person is key to complex human social interaction. Recent evidence suggests that this ability, considered a hallmark of 'theory of mind' (ToM), becomes impaired by inflammation. However, extant supportive empirical evidence is based on experiments that induce not only inflammation but also induce discomfort and sickness, factors that could also account for temporary social impairment. Hence, an experimental inflammation manipulation was applied that avoided this confound, isolating effects of inflammation and social interaction. Forty healthy male participants (mean age = 25, SD = 5 years) participated in this double-blind placebo-controlled crossover trial. Inflammation was induced using Salmonella Typhi vaccination (0.025 mg; Typhim Vi, Sanofi Pasteur, UK); saline-injection was used as a control. About 6 h 30 m after injection in each condition, participants completed the Reading the Mind in the Eyes Test (RMET), a validated test for assessing how well the mental states of others can be inferred through observation of the eyes region of the face. Vaccination induced systemic inflammation, elevating IL-6 by +419% (p < .001), without fever, sickness symptoms (e.g., nausea, light-headedness), or mood changes (all p's > .21). Importantly, compared to placebo, vaccination significantly reduced RMET accuracy (p < .05). RMET stimuli selected on valence (positive, negative, neutral) provided no evidence of a selective impact of treatment. By utilizing an inflammation-induction procedure that avoided concurrent sicknesses or symptoms in a double-blinded design, the present study provides further support for the hypothesis that immune activation impairs ToM. Such impairment may provide a mechanistic link explaining social-cognitive deficits in psychopathologies that exhibit low-grade inflammation, such as major depression.

The Associations of Endotoxemia With Systemic Inflammation, Endothelial Activation, and Cardiovascular Outcome in Kidney Transplantation.

OBJECTIVE: Cardiovascular disease is the leading cause of death in kidney transplant recipients (KTRs), yet incompletely accountable by traditional risk factors. Inflammation is an unconventional cardiovascular risk factor, with gut-derived endotoxemia potentially driving inflammation and endothelial disease. Comparable data are lacking in kidney transplantation. This study investigated the associations of endotoxemia with inflammation, endothelial activation, and 5-year cardiovascular events in KTRs. Determinants of endotoxemia were also explored. DESIGN AND METHODS: This is a single-center cross-sectional study with prospective follow-up from a prevalent cohort of 128 KTRs. MAIN OUTCOME MEASURES: Demographic, nutritional and clinical predictors of inflammation (high-sensitivity C-reactive protein [hsCRP]), endothelial activation (sE-selectin), and endotoxemia (endotoxin) were assessed. Follow-up data on 5-year cardiovascular event rates were collected. RESULTS: Endotoxemia (P = .03), reduced 25-hydroxyvitamin D (P = .04), high fructose intake (P < .001), decreased fiber intake (P < .001), and abdominal obesity (P = .002) were independently associated with elevated hsCRP. In turn, endotoxemia (P = .007) and increasing hsCRP (P = .02) were both independently associated with raised sE-selectin. Furthermore, endotoxemia predicted increased cardiovascular event rate (P = .02), independent of hsCRP and a global measure of cardiovascular risk estimated by a validated algorithm of 7-year risk for major adverse cardiac events in kidney transplantation. Determinants of endotoxemia included reduced 25-hydroxyvitamin D (P < .001), hypertriglyceridemia (P < .001), increased fructose intake (P = .01), and abdominal obesity (P = .01). CONCLUSIONS: Endotoxemia in KTRs contributes to inflammation, endothelial activation, and increased cardiovascular events. This study highlights the clinical relevance of endotoxemia in KTRs, suggesting future interventional targets.

A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood.

BACKGROUND: Recent insights into the role of the human microbiota in cognitive and affective functioning have led to the hypothesis that probiotic supplementation may act as an adjuvant strategy to ameliorate or prevent depression. OBJECTIVE: Heightened cognitive reactivity to normal, transient changes in sad mood is an established marker of vulnerability to depression and is considered an important target for interventions. The present study aimed to test if a multispecies probiotic containing Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, and Lactococcus lactis (W19 and W58) may reduce cognitive reactivity in non-depressed individuals. DESIGN: In a triple-blind, placebo-controlled, randomized, pre- and post-intervention assessment design, 20 healthy participants without current mood disorder received a 4-week probiotic food-supplement intervention with the multispecies probiotics, while 20 control participants received an inert placebo for the same period. In the pre- and post-intervention assessment, cognitive reactivity to sad mood was assessed using the revised Leiden index of depression sensitivity scale. RESULTS: Compared to participants who received the placebo intervention, participants who received the 4-week multispecies probiotics intervention showed a significantly reduced overall cognitive reactivity to sad mood, which was largely accounted for by reduced rumination and aggressive thoughts. CONCLUSION: These results provide the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood. Probiotics supplementation warrants further research as a potential preventive strategy for depression.

Vaccine-induced inflammation attenuates the vascular responses to mental stress.

Inflammation is associated with poorer vascular function, with evidence to suggest that inflammation can also impair the vascular responses to mental stress. This study examined the effects of vaccine-induced inflammation on vascular responses to mental stress in healthy participants. Eighteen male participants completed two stress sessions: an inflammation condition having received a typhoid vaccination and a control (non-inflamed) condition. Tumor necrosis factor-alpha and interleukin-6 (p's<.001) increased following vaccination, confirming modest increases in inflammation. Mental stress increased blood flow, blood pressure, heart rate, and cardiac output in both conditions (all p's<.001), but the blood flow response to stress was attenuated having received the vaccination compared to the control condition (p's<.05). These results further implicate the interaction between inflammation and the vasculature as a mechanism through which stress may trigger myocardial infarction.

Consistent associations between measures of psychological stress and CMV antibody levels in a large occupational sample.

Cytomegalovirus (CMV) is a herpes virus that has been implicated in biological aging and impaired health. Evidence, largely accrued from small-scale studies involving select populations, suggests that stress may promote non-clinical reactivation of this virus. However, absent is evidence from larger studies, which allow better statistical adjustment for confounding and mediating factors, in more representative samples. The present study involved a large occupational cohort (N=887, mean age=44, 88% male). Questionnaires assessed psychological (i.e., depression, anxiety, vital exhaustion, SF-12 mental health), demographic, socioeconomic (SES), and lifestyle variables. Plasma samples were analyzed for both the presence and level of CMV-specific IgG antibodies (CMV-IgG), used as markers for infection status and viral reactivation, respectively. Also assessed were potential biological mediators of stress-induced reactivation, such as inflammation (C-reactive protein) and HPA function (awakening and diurnal cortisol). Predictors of CMV infection and CMV-IgG among the infected individuals were analyzed using logistic and linear regression analyses, respectively. Confirming prior reports, lower SES (education and job status) was positively associated with infection status. Among those infected (N=329), higher CMV-IgG were associated with increased anxiety (ß=.14, p<.05), depression (ß=.11, p=.06), vital exhaustion (ß=.14, p<.05), and decreased SF-12 mental health (ß=-.14, p<.05), adjusting for a range of potential confounders. Exploratory analyses showed that these associations were generally stronger in low SES individuals. We found no evidence that elevated inflammation or HPA-function mediated any of the associations. In the largest study to date, we established associations between CMV-IgG levels and multiple indicators of psychological stress. These results demonstrate the robustness of prior findings, and extend these to a general working population. We propose that stress-induced CMV replication warrants further research as a psychobiological mechanism linking stress, aging and health.

Psychoneuroendocrine interventions aimed at attenuating immunosenescence: a review.

There is evidence suggesting that immunosenescence can be accelerated by external factors such as chronic stress. Here we review potential psychoneuroendocrine determinants of premature aging of the immune system and discuss available interventions aimed at attenuating immunosenescence. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis. The immunological impact of such neuroendocrine dysregulation may be further amplified by a dramatic decline in dehydroepiandrosterone (DHEA) levels, acting in part as an endogenous glucocorticoid antagonist. Stress-buffering strategies show beneficial effects on various biomarkers in elderly populations. Likewise, supplementation of DHEA, melatonin or growth hormone has yielded significant beneficial effects in a number of studies, including: increased well-being, memory performance, bone mineral density and improved immunocompetence as evidenced by results of in vitro (T cell proliferation, cytotoxicity, cytokine production), and in vivo immune challenges. However, the side-effects of hormonal supplementation are also discussed. Finally, moderate exercise via the promotion of cortisol/DHEA balance or epigenetic modifications, is associated with lower serum pro-inflammatory cytokines, greater lymphoproliferative responses and lower counts of senescent T cells. Taken together, these data suggest that immune system is plastic and immunosenescence can be attenuated psychoneuroendocrine interventions.

Association of 25-hydroxyvitamin D with type 2 diabetes among patients undergoing coronary angiography: cross-sectional findings from the LUdwigshafen Risk and Cardiovascular Health (LURIC) Study.

OBJECTIVE: Evidence suggests that vitamin D may protect against the onset of diabetes. However, the mechanisms underlying the role of vitamin D on glycaemic status are unclear and warrant further investigation. We sought to determine the relationship between serum 25-hydroxyvitamin D (25[OH]D) and glycaemic status among intermediate-to-high-risk patients scheduled for coronary angiography. METHODS: Participants were 3316 male and female patients (mean ± SD age, 62·7 ± 10·6 years). Four categories were formed according to serum 25[OH]D levels. The association between serum 25[OH]D and diabetes was assessed using multivariable logistic regression. RESULTS: Fasting and 2 h post-load glucose, HbA1c and the HOMA-IR indices diminished with increasing serum 25[OH]D levels (P < 0·001). However, no associations were observed between insulin, pro-insulin or C-peptide and serum 25[OH]D concentrations. The pro-inflammatory markers IL-6 and hs-CRP also decreased considerably with higher vitamin D levels (P < 0·001). After full adjustment, those with optimal serum 25[OH]D levels had a reduced odds for fasting diabetes (OR = 0·63; 95% CI, 0·46-0·86; Ptrend = 0·01), 2 h post-load diabetes (OR = 0·46; 95% CI, 0·29-0·74; Ptrend = 0·004), both fasting/2 h post-load diabetes (OR = 0·61; 95% CI, 0·42-0·87; Ptrend = 0·001) and all of the combined hyperglycaemic states (OR = 0·68; 95% CI, 0·52-0·80; Ptrend = 0·01). CONCLUSIONS: Higher serum 25[OH]D levels were associated with better glycaemic status and lower inflammation. Should these observations be confirmed in future studies, vitamin D supplementation may prove a useful adjunct in attenuating the onset of diabetes.

Vitamin D levels predict all-cause and cardiovascular disease mortality in subjects with the metabolic syndrome: the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.

OBJECTIVE: Optimal vitamin D levels are associated with reduced cardiovascular and all-cause mortality. We investigated whether optimal 25-hydroxyvitamin D (25[OH]D) is protective in individuals with the metabolic syndrome. RESEARCH DESIGN AND METHODS: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study is a cohort study of subjects referred for coronary angiography between 1997 and 2000, from which 1,801 with the metabolic syndrome were investigated. Mortality was tracked for a median of 7.7 years. Multivariable survival analysis was used to estimate the association between 25(OH)D levels and mortality. RESULTS: Most subjects (92%) had suboptimal levels of 25(OH)D (<75 nmol/L), with 22.2% being severely deficient (<25 nmol/L). During follow-up, 462 deaths were recorded, 267 (57.8%) of which were cardiovascular in origin. After full adjustment, including the metabolic syndrome components, those with optimal 25(OH)D levels showed a substantial reduction in all-cause (hazard ratio [HR] 0.25 [95% CI 0.13-0.46]) and cardiovascular disease mortality (0.33 [0.16-0.66]) compared with those with severe vitamin D deficiency. For specific cardiovascular disease mortality, there was a strong reduction for sudden death (0.15 [0.04-0.63]) and congestive heart failure (0.24 [0.06-1.04]), but not for myocardial infarction. The reduction in mortality was dose-dependent for each of these causes. CONCLUSIONS: Optimal 25(OH)D levels substantially lowered all-cause and cardiovascular disease mortality in subjects with the metabolic syndrome. These observations call for interventional studies that test whether vitamin D supplementation provides a useful adjunct in reducing mortality in these subjects.

Stress as a determinant of saliva-mediated adherence and coadherence of oral and nonoral microorganisms.

OBJECTIVE: The mucosal secretory proteins, such as the salivary proteins, play a key role in the acquisition and regulation of the mucosal microflora. Most notably, some microorganisms utilize the host's secretory proteins to adhere to the mucosa; a first step in colonization and infection. The secretory proteins also influence colonization by affecting the binding among microorganisms, a process denoted as coadherence. Previously we reported that acute stressors cause specific changes in saliva composition. The present study investigated to what extent these changes influence saliva-mediated microbial adherence and coadherence (ex vivo). METHODS: Thirty-two male undergraduates provided unstimulated saliva before and during a control condition and two stressors: A memory test and a surgery video presentation. We used saliva-coated microplates to test the adherence of bacteria for which the oral cavity is either a natural reservoir (eg, viridans streptococci) or a portal of entry (eg, Helicobacter pylori). We also tested the saliva-mediated co-adherence between Streptococcus gordonii and the yeast Candida albicans. Correlation analyses were performed to determine the relationships between changes in microbial adherence and the concentrations of potential salivary ligands, viz. cystatin S, the mucins MUC5B and MUC7, S-IgA, lactoferrin, alpha-amylase, and total salivary protein. RESULTS: During the memory test, saliva-mediated adhesion of Streptococcus sanguis, Streptococcus gordonii, and H. pylori increased, whereas the coadherence of C. albicans with S. gordonii decreased. During the surgical video presentation the saliva-mediated adherence of H. pylori, S. sanguis, and Streptococcus mitis increased. These changes were independent of salivary flow rate, but correlated with specific changes in salivary protein composition. CONCLUSION: The results show that even moderate stressors, by altering the activity of the mucosal secretory glands, may affect microbial colonization processes such as adherence and coadherence. This study hereby presents a mechanism by which stress may affect the mucosal microflora and susceptibility to infectious disease.