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Oxidative Stress and Inflammation Are Associated With Age-Related Endothelial Dysfunction in Men With Low Testosterone.
Babcock, MC, DuBose, LE, Witten, TL, Stauffer, BL, Hildreth, KL, Schwartz, RS, Kohrt, WM, Moreau, KL
The Journal of clinical endocrinology and metabolism. 2022;107(2):e500-e514
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Serum testosterone declines gradually with age at a rate of ~1% per year after the third decade. Vascular aging, featuring endothelial dysfunction mediated by oxidative stress and inflammation, is a major risk factor for the development of age-associated cardiovascular disease (CVD). The aim of this study was to examine the effects of low testosterone on cardiovascular aging in men. This study is a cross-sectional study which recruited 58 healthy men of all races/ethnic backgrounds aged 50-75 years (middle-aged/older) and 18-40 years (young). Results show that middle-aged/older men with lower testosterone have evidence of “accelerated” vascular aging, as indicated by a greater age-associated endothelial dysfunction of large arteries compared with their age-matched peers. The greater macrovascular endothelial dysfunction in middle-aged/older men with chronically low testosterone was independent of CVD risk factors or symptoms of androgen deficiency. Furthermore, increased systemic oxidative stress and inflammation are mechanistically linked to the greater age-associated endothelial dysfunction in middle-aged/older men with lower testosterone. Authors conclude that normal physiological levels of testosterone may be beneficial to cardiovascular health by attenuating the age-related decline in endothelial function.
Abstract
CONTEXT Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-aged/older men is associated with increased CVD risk. OBJECTIVE We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. METHODS This cross-sectional study included 58 healthy, nonsmoking men categorized as young (N = 20; age 29 ± 4 years; testosterone 500 ± 58 ng/dL), middle-aged/older with higher testosterone (N = 20; age 60 ± 6 years; testosterone 512 ± 115 ng/dL), and middle-aged/older lower testosterone (N = 18; age 59 ± 8 years; testosterone 269 ± 48 ng/dL). Brachial artery flow-mediated dilation (FMDBA) was measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status and oxidized low-density lipoprotein cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. RESULTS During saline, FMDBA was reduced in middle-aged/older compared with young, regardless of testosterone status (P < 0.001). FMDBA was reduced in middle-aged/older lower testosterone (3.7% ± 2.0%) compared with middle-aged/older higher testosterone (5.7% ± 2.2%; P = 0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3% ± 1.6%; P = 0.022) in middle-aged/older lower testosterone but had no effect in young (P = 0.992) or middle-aged/older higher testosterone (P = 0.250). FMDBA correlated with serum testosterone (r = 0.45; P < 0.001), IL-6 (r = -0.41; P = 0.002), and CRP (r = -0.28; P = 0.041). CONCLUSION Healthy middle-aged/older men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.
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COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status.
Thomas, T, Stefanoni, D, Reisz, JA, Nemkov, T, Bertolone, L, Francis, RO, Hudson, KE, Zimring, JC, Hansen, KC, Hod, EA, et al
JCI insight. 2020;5(14)
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There is increasing urgency for the development of Covid-19 therapies. Treatments preventing infection and decreasing the amount of virus in the body have largely been unsuccessful and so the focus has turned to host biological pathways, which may be altered by Covid-19 infection. This observational study of forty-nine Covid-19 positive and negative individuals aimed to determine alterations in the hosts metabolism. The results showed that Covid-19 infection was associated with disrupted host inflammatory and immune pathways. Markers for kidney dysfunction were also increased alongside raised blood sugar levels and fatty acids in the blood. It was concluded that inflammatory markers may be an indicator for disease severity and a target for Covid-19 therapy. Dietary therapy could be used to target blood fatty acid changes brought about by Covid-19 infection. This study could be used by healthcare professionals to understand that inflammation is increased in Covid-19 patients and in lieu of approved therapies, dietary intervention may be of benefit.
Abstract
BACKGROUNDReprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocks.METHODSTo investigate metabolic effects of SARS-CoV-2 infection, we evaluated serum metabolites of patients with COVID-19 (n = 33; diagnosed by nucleic acid testing), as compared with COVID-19-negative controls (n = 16).RESULTSTargeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity. Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels. Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen).CONCLUSIONIn conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.FUNDINGBoettcher Foundation Webb-Waring Biomedical Research Award; National Institute of General and Medical Sciences, NIH; and National Heart, Lung, and Blood Institute, NIH.
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Reductions in anti-inflammatory gut bacteria are associated with depression in a sample of young adults.
Liu, RT, Rowan-Nash, AD, Sheehan, AE, Walsh, RFL, Sanzari, CM, Korry, BJ, Belenky, P
Brain, behavior, and immunity. 2020;88:308-324
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Alterations to the gut microbiota may be associated with depression and anxiety disorders through a pathway known as the gut-brain axis. Inflammation may be the mediator between the two, as individuals with major depressive disorder (MDD) have reported high levels of inflammation, which the gut microbiota may have the capacity to protect against. This observational study of the gut microbiota of 90 young adults with MDD and 47 healthy controls aimed to determine the relationship between inflammatory gut microbiota and symptoms of depression. The results showed changes to several species of gut microbiota in those with MDD and that the level of change was related to MDD symptom severity. These changes were observed even in those taking psychotropic medications. Changes at the taxonomic level indicated that those with higher symptoms of depression had more pronounced differences compared with healthy controls. Although the observed differences were indicative of an inflammatory microbiome, no changes were observed in blood markers of inflammation between those individuals with MDD and healthy controls. It was concluded that the gut microbiome of individuals with MDD was different from healthy individuals in favour of an inflammatory environment. This study could be used by healthcare professionals to understand that the status of the gut microbiota may be an important measure in individuals with MDD and that a treatment plan to ensure gut health is considered may help with symptoms of depression.
Abstract
We assessed the gut microbiota of 90 American young adults, comparing 43 participants with major depressive disorder (MDD) and 47 healthy controls, and found that the MDD subjects had significantly different gut microbiota compared to the healthy controls at multiple taxonomic levels. At the phylum level, participants with MDD had lower levels of Firmicutes and higher levels of Bacteroidetes, with similar trends in the at the class (Clostridia and Bacteroidia) and order (Clostridiales and Bacteroidales) levels. At the genus level, the MDD group had lower levels of Faecalibacterium and other related members of the family Ruminococcaceae, which was also reduced relative to healthy controls. Additionally, the class Gammaproteobacteria and genus Flavonifractor were enriched in participants with MDD. Accordingly, predicted functional differences between the two groups include a reduced abundance of short-chain fatty acid production pathways in the MDD group. We also demonstrated that the magnitude of taxonomic changes was associated with the severity of depressive symptoms in many cases, and that most changes were present regardless of whether depressed participants were taking psychotropic medications. Overall, our results support a link between MDD and lower levels of anti-inflammatory, butyrate-producing bacteria, and may support a connection between the gut microbiota and the chronic, low-grade inflammation often observed in MDD patients.
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Proteomic profiles before and during weight loss: Results from randomized trial of dietary intervention.
Figarska, SM, Rigdon, J, Ganna, A, Elmståhl, S, Lind, L, Gardner, CD, Ingelsson, E
Scientific reports. 2020;10(1):7913
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Understanding biological substances, or "biomarkers" that are present in the body of individuals with obesity, could lead to personalised dietary recommendations for weight loss. Current research on biomarkers in individuals with obesity who have undergone a weight loss intervention is lacking. This secondary analysis of a randomised control trial study of 609 healthy and obese adults over 6 months, aimed to identify biomarkers associated with obesity, determine any changes with weight loss and if these could be used to make personalised recommendations. 263 biomarkers were tested and the results showed that 102 were associated with body mass index (BMI). 88 were elevated in individuals with a higher BMI. Upon weight loss, a large number of these decreased and a small number increased. The type of diet had no influence on how these biomarkers changed and only one could be used to predict weight loss. It was concluded that many of the biomarkers were connected to BMI and many changed with weight loss, however none of the biomarkers studied could be used to individualise dietary recommendations. This study could be used by healthcare professionals to understand that the role of biomarkers in personalising recommendations is complex and more research may be needed.
Abstract
Inflammatory and cardiovascular biomarkers have been associated with obesity, but little is known about how they change upon dietary intervention and concomitant weight loss. Further, protein biomarkers might be useful for predicting weight loss in overweight and obese individuals. We performed secondary analyses in the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) randomized intervention trial that included healthy 609 adults (18-50 years old) with BMI 28-40 kg/m2, to evaluate associations between circulating protein biomarkers and BMI at baseline, during a weight loss diet intervention, and to assess predictive potential of baseline blood proteins on weight loss. We analyzed 263 plasma proteins at baseline and 6 months into the intervention using the Olink Proteomics CVD II, CVD III and Inflammation arrays. BMI was assessed at baseline, after 3 and 6 months of dietary intervention. At baseline, 102 of the examined inflammatory and cardiovascular biomarkers were associated with BMI (>90% with successful replication in 1,584 overweight/obese individuals from a community-based cohort study) and 130 tracked with weight loss shedding light into the pathophysiology of obesity. However, out of 263 proteins analyzed at baseline, only fibroblast growth factor 21 (FGF-21) predicted weight loss, and none helped individualize dietary assignment.
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Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-based Commentary.
Richman, S, Morris, MC, Broderick, G, Craddock, TJA, Klimas, NG, Fletcher, MA
Clinical therapeutics. 2019;41(5):798-805
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Myalgic encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/ CFS), is a disease characterized by an inability to exert oneself physically, often coupled with a combination of other symptoms, including sleep disorders, severe unpredictable pain, and compromised cognitive abilities. The aim of this review was to delineate a number of the more prominent treatments for ME/CFS into different categories and evaluate the methods and results of corresponding drug trials. Results indicate that: • antiviral drugs appear to show limited efficacy in treating ME/CFS over a broad demographic. • there is a lack of clinical research focusing on the use of specific cyclooxygenase-2 inhibitors [analgesic] to treat ME/CFS. • antidepressants may be of use in delivering improvements in the quality of life of patients with ME/CFS. • recalibration of endocrine-immune regulation may be involved in supporting the persistence of ME/CFS and may be responsible at least in part for its resistance to single agent interventions. Authors conclude that there is a great need for larger, longitudinal studies focused on a more clearly defined subset of ME/CFS as well as a greater consideration of potential synergies between interventions and the suitability of combination therapies.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by prolonged periods of fatigue, chronic pain, depression, and a complex constellation of other symptoms. Currently, ME/CFS has no known cause, nor are the mechanisms of illness well understood. Therefore, with few exceptions, attempts to treat ME/CFS have been directed mainly toward symptom management. These treatments include antivirals, pain relievers, antidepressants, and oncologic agents as well as other single-intervention treatments. Results of these trials have been largely inconclusive and, in some cases, contradictory. Contributing factors include a lack of well-designed and -executed studies and the highly heterogeneous nature of ME/CFS, which has made a single etiology difficult to define. Because the majority of single-intervention treatments have shown little efficacy, it may instead be beneficial to explore broader-acting combination therapies in which a more focused precision-medicine approach is supported by a systems-level analysis of endocrine and immune co-regulation.
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Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial.
Fowler, AA, Truwit, JD, Hite, RD, Morris, PE, DeWilde, C, Priday, A, Fisher, B, Thacker, LR, Natarajan, R, Brophy, DF, et al
JAMA. 2019;322(13):1261-1270
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Previous research has found that Vitamin C reduces widespread inflammation, as well as blood clotting and other vascular problems associated with sepsis. This randomised controlled trial of 167 patients in ICU with sepsis and acute respiratory distress syndrome (ARDS) were administered with high dose intravenous Vitamin C or placebo every 6 hours for 96 hours, to assess impacts on organ failure, inflammation and vascular injury. The authors found no statistically significant differences between the Vitamin C group and placebo in relation to organ failure, inflammation and vascular injury at 28 day follow up and call for further research. Healthcare practitioners may like to read critiques of this research available on Nutrition Evidence available here https://www.nutrition-evidence.com/article/31785700?term=31785700 and here https://www.nutrition-evidence.com/article/33117837?term=33117837
Abstract
Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.
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Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence.
Zhang, L, Rana, I, Shaffer, RM, Taioli, E, Sheppard, L
Mutation research. Reviews in mutation research. 2019;781:186-206
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Glyphosate is a highly effective broad-spectrum herbicide that is typically applied in mixtures known as glyphosate-based herbicides (GBHs). Glyphosate and its metabolites persist in food, water, and dust, potentially indicating that everyone may be exposed ubiquitously. The objective of this study was to focus on an a priori hypothesis - the highest biologically relevant exposure to GBHs, i.e., higher levels, longer durations and/or with sufficient lag and latency, will lead to increased risk of non-Hodgkin lymphoma (NHL) in humans. This study is a meta-analysis of six studies (one cohort and five case-control control studies) with almost 65,000 participants. Results demonstrated a significantly increased NHL risk in highly GBH-exposed individuals. Authors conclude that the overall evidence from human, animal, and mechanistic studies presented in this study, supports a compelling link between exposures to GBHs and increased risk for NHL.
Abstract
Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.
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Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.
Elhassan, YS, Kluckova, K, Fletcher, RS, Schmidt, MS, Garten, A, Doig, CL, Cartwright, DM, Oakey, L, Burley, CV, Jenkinson, N, et al
Cell reports. 2019;28(7):1717-1728.e6
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As the body ages, there is a decline in muscle mass and function, which can be combatted with diet, exercise, and supplementation. Nicotinamide riboside (NR) or vitamin B3 has been shown in animal studies to promote healthy muscle, however its effects in human muscle are unknown. This randomised control trial of overweight older men aimed to determine if NR can be used by muscle and whether it has any effect on muscle function. The results showed that NR supplementation (1 g/day) for 3 weeks can be used by the muscle but had no effect on muscle function as shown by the hand grip test. Supplementation also decreased energy production in muscle and had anti-inflammatory effects. It was concluded that NR is available to muscle and that it may have anti-inflammatory properties, which may be of benefit to older individuals.
Abstract
Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.
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The Sleep-Immune Crosstalk in Health and Disease.
Besedovsky, L, Lange, T, Haack, M
Physiological reviews. 2019;99(3):1325-1380
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The interaction between sleep and immunity is an established phenomena. This thorough review article summarises sleep changes in response to both infectious and non-infectious immune system challenges and describes the role of sleep in supporting the immune system. Details are provided of how sleep affects the innate immune system (first line, rapid defence against infection) as well as the adaptive immune system (second line, delayed defence against infection), using a feedback system which promotes host defence. Sleep is associated with reduced infection risk and can improve infection outcome and vaccination responses. Sleep deprivation is also associated with chronic, low-grade inflammation. Nutrition Practitioners wishing to support immunity can focus on sleep as a simple lifestyle measure to enhance resilience.
Abstract
Sleep and immunity are bidirectionally linked. Immune system activation alters sleep, and sleep in turn affects the innate and adaptive arm of our body's defense system. Stimulation of the immune system by microbial challenges triggers an inflammatory response, which, depending on its magnitude and time course, can induce an increase in sleep duration and intensity, but also a disruption of sleep. Enhancement of sleep during an infection is assumed to feedback to the immune system to promote host defense. Indeed, sleep affects various immune parameters, is associated with a reduced infection risk, and can improve infection outcome and vaccination responses. The induction of a hormonal constellation that supports immune functions is one likely mechanism underlying the immune-supporting effects of sleep. In the absence of an infectious challenge, sleep appears to promote inflammatory homeostasis through effects on several inflammatory mediators, such as cytokines. This notion is supported by findings that prolonged sleep deficiency (e.g., short sleep duration, sleep disturbance) can lead to chronic, systemic low-grade inflammation and is associated with various diseases that have an inflammatory component, like diabetes, atherosclerosis, and neurodegeneration. Here, we review available data on this regulatory sleep-immune crosstalk, point out methodological challenges, and suggest questions open for future research.
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High-Dose Vitamin D3 Administration Is Associated With Increases in Hemoglobin Concentrations in Mechanically Ventilated Critically Ill Adults: A Pilot Double-Blind, Randomized, Placebo-Controlled Trial.
Smith, EM, Jones, JL, Han, JE, Alvarez, JA, Sloan, JH, Konrad, RJ, Zughaier, SM, Martin, GS, Ziegler, TR, Tangpricha, V
JPEN. Journal of parenteral and enteral nutrition. 2018;42(1):87-94
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Anaemia is common in critically ill patients and is associated with increased mortality and potentially an extended need for a ventilator. Treatment for anaemia can be invasive and carries a level of risk; therefore further studies on complementary therapies are warranted. Vitamin D has the potential to decrease anaemia through decreasing the production of the iron-regulatory hormone hepcidin. The study aimed to test whether high dose vitamin D would affect haemoglobin concentrations in critically ill patients. In this pilot double-blind randomised control trial, 30 critically ill patients were assigned 250,000 IU vitamin D, 500,000 IU vitamin D or placebo split over 5 doses in 5 days. Blood was taken weekly for up to four weeks and analysed for vitamin D and hepcidin concentrations. Vitamin D concentrations increased significantly in both groups that received vitamin D, compared to no change in the placebo group. Compared to placebo, haemaglobin concentrations significantly increased by 8% in the group receiving 500,000 IU vitamin D but not in the lower dose group. After one week, hepcidin concentrations were significantly decreased in the 500,000 IU vitamin D group, however this was not sustained and no differences between either group and placebo were observed at the end of the study. This did not translate into a reduction in anaemia in either group at any point throughout the study. Extremely high dose vitamin D supplementation was shown to significantly increase circulating vitamin D concentrations and acutely reduce hepcidin. Although anaemia was not affected, clinicians could use this study as an example of safe usage of high dose vitamin D in critically ill patients to improve haemaglobin concentrations, which could reduce the need for invasive treatments, reduce hospital stay duration and treatment costs.
Abstract
BACKGROUND Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults. MATERIALS AND METHODS Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D3 (D3 ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D3 , or 100,000 IU D3 daily for 5 days (totaling 250,000 IU D3 and 500,000 IU D3 , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time. RESULTS At enrollment, >75% of participants in all groups had plasma 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D3 group, hemoglobin concentrations increased significantly over time (Pgroup × time = .01) compared with placebo but did not change in the 250,000-IU D3 group (Pgroup × time = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D3 group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D3 group. CONCLUSION In these critically ill adults, treatment with 500,000 IU D3 was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies.