https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)61452-9.pdf

Selenium and human health

Following the publication of the landmark trial of Clark et al. in 1996 that appeared to show that Se could reduce the risk of cancer, awareness of the importance of Se to human health has markedly increased. As a result, there is now much more aggressive marketing of Se supplements and functional foods, even in situations where additional consumption of Se is inappropriate. The present review addresses how Se gets into the food chain, the wide variability in Se content of foods and the very different levels of intake between countries and regions. Though it is clear that there are adverse consequences for health of both deficient and excessive intake, health effects at intermediate levels of intake are less certain. Thus it is difficult to define optimal intake which depends on a large number of factors, such as which functions of Se are most relevant to a particular disease state, which species of Se is most prominent in the Se source, which health condition is being considered, the adequacy or otherwise of intake of other nutrients, the presence of additional stressors, and lastly whether the ability to make selenoproteins may be compromised. These complexities need to be understood, particularly by policy makers, in order to make informed judgments. Potential solutions for increasing Se intake, where required, include agronomic biofortification and genetic biofortification or, for individuals, increased intake of naturally Se-rich foods, functional foods or supplements. The difficulties of balancing the risks and benefits in relation to Se intake are highlighted.

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Food-chain selenium and human health: emphasis on intake.

Immune support by micronutrients is historically based on vitamin C deficiency and supplementation in scurvy in early times. It has since been established that the complex, integrated immune system needs multiple specific micronutrients, including vitamins A, D, C, E, B6, and B12, folate, zinc, iron, copper, and selenium, which play vital, often synergistic roles at every stage of the immune response. Adequate amounts are essential to ensure the proper function of physical barriers and immune cells; however, daily micronutrient intakes necessary to support immune function may be higher than current recommended dietary allowances. Certain populations have inadequate dietary micronutrient intakes, and situations with increased requirements (e.g., infection, stress, and pollution) further decrease stores within the body. Several micronutrients may be deficient, and even marginal deficiency may impair immunity. Although contradictory data exist, available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection. Micronutrients with the strongest evidence for immune support are vitamins C and D and zinc. Better design of human clinical studies addressing dosage and combinations of micronutrients in different populations are required to substantiate the benefits of micronutrient supplementation against infection.

A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection

Selenium (Se) is a potent nutritional antioxidant that carries out biological effects through its incorporation into selenoproteins. Given the crucial roles that selenoproteins play in regulating reactive oxygen species (ROS) and redox status in nearly all tissues, it is not surprising that dietary Se strongly influences inflammation and immune responses. The notion that Se "boosts" the immune system has been supported by studies involving aging immunity or protection against certain pathogens. However, studies examining the effects of Se status on other types of immunity such as antiparasitic responses or allergic asthma have suggested more Se may not always be beneficial. In this review, we summarize and compare the available data regarding how the levels of Se affect different types of immunity. Overall, determining how Se intake differentially affects various types of immune responses and dissecting the mechanisms by which this occurs will lead to a better utilization of Se-supplementation for human diseases involving the immune system.

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The influence of selenium on immune responses.

Prescription opioid misuse is an emerging public health concern with significant health and psychological risks. Though opioid analgesic therapy for chronic pain is often efficacious, and most patients take medicine as prescribed, some individuals exhibit addictive tendencies toward opioids (Fishbain, Cole, Lewis, Rosomoff, & Rosomoff, 2007). Opioid addiction among chronic pain patients involves cognitive, affective, and behavioral dysregulation that, when coupled with persistent or worsening pain, may result in significant functional impairment and suffering (Hojsted, Nielsen, Guldstrand, Frich, & Sjogren, 2010). Opioid addiction may be presaged by the occurrence of opioid misuse behaviors, such as dose escalation or use of prescribed opioids to self-medicate negative emotions and stress (Butler et al., 2007); these medication-misusing behaviors are common, with more than one-in-ten chronic pain patients exhibiting signs of opioid misuse (Fishbain et al., 2007). Although opioid agents with lower addiction liability like buprenorphine can effectively substitute for unauthorized opioid use (Ling et al., 2002), extant treatments for opioid addiction are typically ineffective in the absence of ongoing maintenance pharmacotherapy (Weiss et al., 2011). Further, persons seeking treatment for chronic pain respond especially poorly to motivational and behavioral addiction treatments (Larson et al., 2007). Current best practices for persons with chronic pain who are at risk for prescription opioid misuse and addiction (e.g., Jamison, Serraillier, & Michner, 2011; Oliver et al., 2012) include frequent opioid adherence monitoring, opioid treatment agreements and compliance training, and cognitive-behavioral substance misuse counseling (Jamison et al., 2010). Yet, new interventions are needed to effectively address the maladaptive cognitive-affective processes and appetitive responses elicited by pain, stress, and drug-related cues that undergird the risk chain from chronic pain to opioid misuse and addiction.

This risk chain initiates from prolonged use of opioids, which produces physical dependence via neuroadaptations resulting in tolerance, withdrawal, and, in some cases, opioid-induced hyperalgesia (Chu, Angst, & Clark, 2008). Heightened pain sensitivity, when coupled with tolerance to the analgesic effects of opioids, can result in increased opioid craving (Ren, Shi, Epstein, Wang, & Lu, 2009) and consumption (Martell et al., 2007), and can elicit negative emotions that feed back to magnify pain perception. This process may result in appraisal of pain sensations as threatening and perseveration on the affective components of pain (Garland, 2012). Consequently, opioids are often misused to self-medicate (Khantzian, 1997; Kirsh, Jass, Bennett, Hagen, & Passik, 2007) the negative affective states and autonomic arousal that cause, co-occur with, or result from pain (Janig, 1995; Martenson, Cetas, & Heinricher, 2009). As with pain, stress and negative affect can become internal cues associated with past opioid use episodes that elicit the habit of opioid use, particularly among opioid misusers who take opioids to cope with emotional distress. Concomitantly, the habitual drive to engage in prescription opioid misuse (including unauthorized dose escalation) involves implicit neurocognitive operations that promote craving and aberrant drug taking (Goldstein et al., 2009; Stacy & Wiers, 2010) by biasing attention towards opioid-related cues (e.g., the sight of a pill bottle) (Garland, Froeliger, Passik, & Howard, 2012). Theory suggests that addiction occurs when the appetitive motivation to obtain natural rewards is re-organized around seeking drug-induced reward and the desire to alleviate dysphoria stemming from withdrawal and aversive experiences (e.g., pain and stress) (Alcaro & Panksepp, 2011; Koob & Le Moal, 2008). In that regard, decreased responsiveness to natural reinforcers has been observed among opiate dependent individuals and is robustly predictive of future opiate consumption (Lubman et al., 2009; Lubman, Allen, Peters, & Deakin, 2007, 2008).

Hence, the problem of co-occurring chronic pain and prescription opioid misuse may involve a cycle of behavioral escalation where nociception and stress amplify pain and provoke recurrent self-medication with opioids, which in turn biases attention towards opioid-related cues that come to elicit the habit of opioid use despite ever diminishing analgesia and increasing dysphoria (Garland, Froeliger, Zeidan, Partin, & Howard, 2013). Despite such risks, opioids remain medically necessary for many individuals experiencing prolonged and intractable pain. Thus, therapeutic interventions are needed to target comorbid pain and opioid misuse. Though cognitive-behavioral therapy (CBT) has been shown to produce therapeutic reductions in pain (Williams, Eccleston, & Morley, 2012) and opioid misuse (Jamison et al., 2010) in isolation, there is scant research on psychological treatments that simultaneously address symptoms of co-occurring chronic pain and opioid misuse. To that end, we conducted an early-stage randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE) (Garland, 2013), a novel multimodal intervention that integrates mindfulness training, cognitive reappraisal skills, and positive emotion regulation into a therapeutic approach designed to modify attentional biases, habit behavior, affective dysregulation, and autonomic stress responses underlying the feedback loop between chronic pain, craving, and opioid misuse behaviors.

Each of these three intervention components has been shown to be beneficial in isolation. Mindfulness training leads to reductions in pain (Gaylord et al., 2011; Kabat-Zinn et al., 1992; Rosenzweig et al., 2010; Zeidan et al., 2011) that are mediated by increased nonreactivity to aversive mental experiences and reinterpretation of affectively-laden pain sensations as innocuous sensory signals (Garland, Gaylord, Palsson, Faurot, Mann, & Whitehead, 2012). Moreover, mindfulness training produces salutary effects on emotional distress (Grossman, Niemann, Schmidt, & Walach, 2004; Hofmann, Sawyer, Witt, & Oh, 2010) and addiction-related factors (Bowen et al., 2009; Garland, Froeliger, & Howard, 2013), including attentional bias and autonomic cue-reactivity (Garland, Gaylord, Boettiger, & Howard, 2010). Similarly, cognitive reappraisal has been shown to significantly decrease negative emotions and downregulate stress physiology (Ochsner & Gross, 2005), as well as reduce substance craving (Kober et al., 2011). In complementary fashion, positive emotion regulatory strategies (e.g., savoring pleasant events) may upregulate positive affect, reduce anhedonia, and promote psychological resilience (Garland, Fredrickson, Kring, Johnson, Meyer, & Penn, 2010). MORE, which was originally tested as a treatment for alcohol dependence (Garland, Gaylord et al., 2010), capitalizes on the synergy of these three treatment components by integrating them into a multimodal intervention.

The aim of this study was to evaluate the feasibility of developing a clinical trial comparing acute (pre-post) and longer-term (3-month follow-up) efficacy of MORE with that of a conventional support group (SG) in reducing chronic pain and prescription opioid misuse. The study employed an active control condition which attempted to control for non-specific therapeutic factors such as social interaction and support. We hypothesized that participation in MORE would be associated with significantly greater reductions in pain severity, pain interference, stress symptoms, and desire for opioids than would participation in a SG. We also hypothesized that compared to SG participants, a significantly greater proportion of individuals completing MORE who met clinical criteria for prescription opioid use disorder before treatment would no longer meet opioid use disorder criteria following treatment. Insofar as clinicians in the field must often make dichotomous diagnostic judgments in practice and may need to ascertain the extent to which a disorder can be rendered subclinical following treatment (cf., Eftekhari et al., 2013), we were interested in whether MORE could reduce symptoms below the clinical threshold for opioid use disorder. Lastly, although MORE was designed to target a wide array of cognitive, affective, and autonomic mechanisms as detailed above, in the present study we tested the effects of the intervention on a focused set of mediators selected for their direct relevance to primary study outcomes. Because emotional reactivity and maladaptive appraisals of pain and stress undergird the risk chain linking chronic pain and opioid misuse, we hypothesized that the therapeutic effects of MORE on pain severity and opioid use disorder status would be associated with increased nonreactivity, cognitive reappraisal, and reinterpretation of pain sensations as innocuous sensory information.

/pdf/mindfulness-oriented-recovery-enhancement-for-chronic-pain-1runx3wwo2.pdf

Mindfulness-Oriented Recovery Enhancement for Chronic Pain and Prescription Opioid Misuse: Results from an Early Stage Randomized Controlled Trial

Background Despite findings that selenium supplementation may improve immune functioning, definitive evidence of its impact on human immunodeficiency virus (HIV) disease severity is lacking. Methods High selenium yeast supplementation (200 μg/d) was evaluated in a double-blind, randomized, placebo-controlled trial. Intention-to-treat analyses assessed the effect on HIV-1 viral load and CD4 count after 9 months of treatment. Unless otherwise indicated, values are presented as mean ± SD. Results Of the 450 HIV-1–seropositive men and women who underwent screening, 262 initiated treatment and 174 completed the 9-month follow-up assessment. Mean adherence to study treatment was good (73.0% ± 24.7%) with no related adverse events. The intention-to-treat analyses indicated that the mean change (Δ) in serum selenium concentration increased significantly in the selenium-treated group and not the placebo-treated group (Δ = 32.2 ± 24.5 vs 0.5 ± 8.8 μg/L; P P P 10 units), and decreased CD4 count (Δ = −25.8 ± 147.4 cells/μL). In contrast, selenium-treated subjects whose serum selenium increase was greater than 26.1 μg/L evidenced excellent treatment adherence (86.2% ± 13.0%), no change in HIV-1 viral load (Δ = −0.04 ± 0.7 log 10 units), and an increase in CD4 count (Δ = +27.9 ± 150.2 cells/μL). Conclusions Daily selenium supplementation can suppress the progression of HIV-1 viral burden and provide indirect improvement of CD4 count. The results support the use of selenium as a simple, inexpensive, and safe adjunct therapy in HIV spectrum disease. Trial Registration isrctn.org Identifier:ISRCTN22553118

https://jamanetwork.com/journals/jamainternalmedicine/articlepdf/411535/ioi60173_148_154.pdf

Suppression of human immunodeficiency virus type 1 viral load with selenium supplementation: a randomized controlled trial.

Differences on measures of metabolic syndrome X and coronary heart disease (CHD) risk, as well as potential pathophysiological mediators, inflammation, and oxidative stress, were examined as a function of HIV serostatus and highly active antiretroviral therapy (HAART) regimen with and without protease inhibitors (PIs) Data from 164 men and women, aged 18 to 55 yr, were used to compare 82 HIV+ subjects who were free of hepatitis C virus and were on a stable HAART regimen for >/=6 mo, with 82 seronegative subjects matched on age, sex, body mass index, and ethnicity For the HIV+ subjects, after controlling for diabetes status and HIV disease progression, PI exposure was associated with greater oxidative stress, triglyceridemia, and lipidemia than it was for non-PI-exposed HIV+ subjects, and the risk of a future myocardial infarction was up to 56% greater in PI-exposed than in non-PI-exposed subjects and 129% greater than in controls Although it is likely that the greatest proportion of CHD risk in the HIV+ subjects may be accounted for by pathological conditions linked to HIV infection in interaction with mediating processes such as inflammation, central obesity, and dyslipidemia, which was greater than in controls, it appears that PI medications may exacerbate oxidative stress and hypertriglyceridemia to enhance this risk

HIV, metabolic syndrome X, inflammation, oxidative stress, and coronary heart disease risk : role of protease inhibitor exposure.

Background: Despite findings that selenium supplementation may improve immune functioning, definitive evidence of its impact on human immunodeficiency virus (HIV) disease severity is lacking. Methods: High selenium yeast supplementation (200 µg/d) was evaluated in a double-blind, randomized, placebo-controlled trial. Intention-to-treat analyses assessed the effect on HIV-1 viral load and CD4 count after 9 months of treatment. Unless otherwise indicated, values are presented as mean±SD. Results: Of the 450 HIV-1–seropositive men and women who underwent screening, 262 initiated treatment and 174 completed the 9-month follow-up assessment. Mean adherence to study treatment was good (73.0%±24.7%) with no related adverse events. The intention-to-treat analyses indicated that the mean change () in serum selenium concentration increased significantly in the selenium-treated group and not the placebo-treated group (=32.2±24.5 vs 0.5±8.8 µg/L;P.001), and greater levels predicted decreased HIV-1 viral load (P.02), which predicted increased CD4 count (P.04). Findings remained significant after covarying age, sex, ethnicity, income, education, current and past cocaine and other drug use, HIV symptom classification, antiretroviral medication regimen and adherence, time since HIV diagnosis, and hepatitis C virus coinfection. Follow-up analyses evaluating treatment effectiveness indicated that the nonresponding selenium-treated subjects whose serum selenium change was less than or equal to 26.1 µg/L displayed poor treatment adherence (56.8%±29.8%), HIV-1 viral load elevation (=0.29±1.1 log10 units), and decreased CD4 count (=�25.8±147.4 cells/µL). In contrast, selenium-treated subjects whose serum selenium increase was greater than 26.1 µg/L evidenced excellent treatment adherence (86.2%±13.0%), no change in HIV-1 viral load (=�0.04±0.7 log10 units), and an increase in CD4 count (=27.9±150.2 cells/µL). Conclusions: Daily selenium supplementation can suppress the progression of HIV-1 viral burden and provide indirect improvement of CD4 count. The results support the use of selenium as a simple, inexpensive, and safe adjunct therapy in HIV spectrum disease.

Suppression of Human Immunodeficiency Virus Type 1 Viral Load With Selenium Supplementation

The cardiometabolic syndrome (CMS) has been an organizing conceptual framework for subclinical cardiovascular pathophysiology. Using cross-sectional data from 338 healthy men and women aged 18 to 55 years, the study examined the role of central adiposity and insulin sensitivity and assessed potential relationships with other metabolic indices (insulin sensitivity, glucose tolerance, fibrinolysis, lipidemia, endothelial function, and inflammation) and measures of cardiac structure and function (cardiac mass, compliance and contractility, myocardial oxygen demand, and blood pressure). Structural equation modeling analyses, which controlled for sex, age, and race, demonstrated good fit to the data. The derived relationships provided a physiologically consistent model of CMS, with an initiating role for central adiposity and insulin resistance. The model accounted for 30% and 82% of the variance in diastolic blood pressure and myocardial oxygen demand, respectively. The findings suggest predominant pathways through which subclinical metabolic processes may exert pathogenic impact on the heart and vasculature.

Johanna R. Klaus

Papers

Suppression of human immunodeficiency virus type 1 viral load with selenium supplementation: a randomized controlled trial.

HIV, metabolic syndrome X, inflammation, oxidative stress, and coronary heart disease risk : role of protease inhibitor exposure.

Suppression of Human Immunodeficiency Virus Type 1 Viral Load With Selenium Supplementation

Central Obesity and Insulin Resistance in the Cardiometabolic Syndrome: Pathways to Preclinical Cardiovascular Structure and Function