ABSTRACT
OBJECTIVE: Erosive hand osteoarthritis (eHOA) is a subtype of hand osteoarthritis (OA) that develops in finger joints with pre-existing OA and is differentiated by clinical characteristics (hand pain/disability, inflammation, and erosions) that suggest inflammatory or metabolic processes. METHOD: This was a longitudinal nested case-cohort design among Osteoarthritis Initiative participants who had hand radiographs at baseline and 48-months, and biospecimens collected at baseline. We classified incident radiographic eHOA in individuals with ≥1 joint with Kellgren-Lawrence ≥2 and a central erosion present at 48-months but not at baseline. We used a random representative sample (n = 1282) for comparison. We measured serum biomarkers of inflammation, insulin resistance and dysglycemia, and adipokines using immunoassays and enzymatic colorimetric procedures, blinded to case status. RESULTS: Eighty-six participants developed incident radiographic eHOA. In the multivariate analyses adjusted for age, gender, race, smoking, and body mass index, and after adjustment for multiple analyses, incident radiographic eHOA was associated with elevated levels of interleukin-7 (risk ratio (RR) per SD = 1.30 [95% confidence interval (CI) 1.09, 1.55] p trend 0.01). CONCLUSION: This exploratory study suggests an association of elevated interleukin-7, an inflammatory cytokine, with incident eHOA, while other cytokines or biomarkers of metabolic inflammation were not associated. Interleukin-7 may mediate inflammation and tissue damage in susceptible osteoarthritic finger joints and participate in erosive progression.
Subject(s)
Hand Joints , Osteoarthritis , Humans , Hand Joints/diagnostic imaging , Interleukin-7 , Osteoarthritis/diagnostic imaging , Inflammation , BiomarkersABSTRACT
BACKGROUND: Dietary guidance is set on the basis of age and life stage and defines older adults as ≥60 y. Yet, little is known about if and/or how diet quality differs beyond the age of 60. OBJECTIVE: The objective of this study was to compare the dietary intakes of 60-69 (n = 2079), 70-79 (n = 1181), and 80+ y old (n = 644) noninstitutionalized men and women in the United States using the Healthy Eating Index 2015 (HEI) and the What We Eat in America food categories. METHODS: Data were obtained from National Health and Nutrition Examination Survey 2015-2016 and 2017-March 2020. HEI and component scores were calculated using the population ratio method. Population estimates for dietary intake were calculated as the average reported over 2 separate nonconsecutive 24-h dietary recalls. RESULTS: In men and women, the reported energy intake was lower among the 80+ y olds (kcal/d men-80+: 1884 ± 30, 70-79: 2022 ± 33, 60-69: 2142 ± 39; women-80+: 1523 ± 36; 70-79: 1525 ± 33, 60-69: 1650 ± 25; P-trend < 0.001). Total HEI scores did not differ significantly across the 3 age categories, but the 80+ y olds had significantly lower scores for the green vegetables and beans component than the 60-69 y olds [men-mean (95% confidence interval): 2.0 (1.5, 2.5) compared with 3.4 (2.6, 4.1); women-2.3 (1.8, 2.8) compared with 4.4 (3.7, 5.0)]. In women, the percentage of daily calories from protein was significantly lower in the 80+ y olds than in the 60-69 and 70-79 y olds (12.9% ± 0.6%, compared with 17.0% ± 0.9% and 15.6% ± 0.6%, respectively). Protein intake did not differ significantly among the 3 age groups in men. The 80+ y old men and women reported consuming a significantly higher percentage of calories from snacks and sweets compared with the 60-69 y olds (men-80+: 18.1% ± 0.8%, 60-69: 15.4% ± 0.7%; women-80+: 19.6% ± 0.8%, 60-69: 15.5% ± 0.7%). CONCLUSION: The diet of 80+ y olds differed from that of 60-69 y olds in some key components, including energy, snacks and sweets, protein, and green vegetables. Future research is needed to determine if there are health-related consequences to these differences.
Subject(s)
Diet , Independent Living , Male , Humans , Female , United States , Aged , Nutrition Surveys , Snacks , EatingABSTRACT
PURPOSE: There is controversy regarding the optimal treatment for lateral elbow tendinopathy (LET), and not all available treatment options have been compared directly with placebo/control. A network meta-analysis was conducted to compare the effectiveness of different LET treatments directly and indirectly against control/placebo based on a validated outcome, the Patient-Rated Tennis Elbow Evaluation (PRTEE) pain score. METHODS: Randomized, controlled trials comparing different treatment methods for LET were included, provided they reported outcome data using the PRTEE pain score. A network meta-analysis with random effect was used to combine direct and indirect evidence between treatments compared with placebo in the short term (up to six weeks) and midterm (more than six weeks and up to six months) after intervention. RESULTS: Thirteen studies with 12 comparators including control/placebo were eligible. The results indicated no significant improvement in PRTEE pain score in the short term across all treatments compared with control/placebo. In the midterm, physiotherapy/exercise showed benefit against placebo (mean difference: -4.32, 95% confidence interval: -7.58 and -1.07). Although steroid injections, dry needling, and autologous blood also exhibited potential treatment effects, it is crucial for the clinician to consider certain pitfalls when considering these treatments. The limited number of small studies and paucity of data call for caution in interpreting the results and need for further evidence. CONCLUSIONS: Patients should be informed that there is currently no strong evidence that any treatment produces more rapid improvement in pain symptoms when compared with control/placebo in the short and medium terms. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.
Subject(s)
Network Meta-Analysis , Pain Measurement , Tennis Elbow , Humans , Tennis Elbow/therapy , Elbow Tendinopathy/therapy , Patient Reported Outcome Measures , Physical Therapy Modalities , Exercise Therapy/methods , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Peer support is a promising intervention to mitigate post-ICU disability, however there is a paucity of rigorously designed studies. OBJECTIVES: The objective of this study was to establish feasibility of an in-person, co-designed, peer-support model. METHODS: Prospective, randomised, adaptive, single-centre pilot trial with blinded outcome assessment, conducted at a university-affiliated hospital in Melbourne, Australia. Intensive care unit survivors (and their nominated caregiver, where survivor and caregiver are referred to as a dyad), >18 years of age, able to speak and understand English and participate in phone surveys, were eligible. Participants were randomised to the peer-support model (six sessions, fortnightly) or usual care (no follow-up or targeted information). Two sequential models were piloted: 1. Early (2-3 weeks post hospital discharge) 2. Later (4-6 weeks post hospital discharge). Primary outcome was feasibility of implementation measured by recruitment, intervention attendance, and outcome completion. Secondary outcomes included post-traumatic stress and social support. RESULTS: Of the 231 eligible patients, 80 participants were recruited. In the early model we recruited 38 participants (28 patients, 10 carers; 18 singles, 10 dyads), with an average (standard deviation) age of 60 (18) years; 55 % were female. Twenty-two participants (58 %) were randomised to intervention. Participants in the early intervention model attended a median (interquartile range) of 0 (0-1) sessions (total 24 sessions), with 53% (n = 20) completing the main secondary outcome of interest (Impact of Event Scale) at the baseline and 37 % (n = 14) at the follow-up. For the later model we recruited 42 participants (32 patients, 10 carers; 22 singles, 10 dyads), with an average (standard deviation) age of 60.4 (15.4) years; 50 % were female. Twenty-one participants (50 %) were randomised to intervention. The later intervention model attended a median (interquartile range) of 1 (0-5) sessions (total: 44 sessions), with the main secondary outcome impact of events scale (IES-R) completed by 41 (98 %) participants at baseline and 29 (69 %) at follow-up. CONCLUSIONS: In this pilot trial, a peer-support model that required in-person attendance delivered in a later posthospital phase of recovery appeared more feasible than an early model. Further research should investigate alternative modes of intervention delivery to improve feasibility (ACTRN12621000737831).
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INTRODUCTION: Venous thrombo-embolism (VTE) is a recognised complication of foot and ankle surgery. There are multiple possible anticoagulation treatments available in the UK to mitigate the risk of developing VTE. Our primary objective was to assess the variability of chemical anticoagulation prescribed in patients undergoing foot and ankle procedures. METHODS: This was a UK-based national, multicenter, prospective audit spanning a collection duration of 9 months on all foot and ankle procedures, carried out in 68 UK centers between 1st June 2022 and 30th November 2022, with a further 3-month follow up period. All patients who underwent a foot and ankle surgical procedure (including Achilles tendon rupture treatment) were included in this study. RESULTS: Data on a total of 13,569 patients was submitted. Following data cleansing, 11,363 patients were available for further analysis, with anticoagulation data available for 11,099 patients. There were eleven different chemical anticoagulation treatments recorded across the cohort. A total of 3630 (31.95 %) patients received no chemical anticoagulation. The patients receiving chemical anticoagulation medication could be split into 4 main groups. The most common chemical anticoagulation received was low molecular weight heparin (LMWH) (6303, 84.4 % of patients receiving chemical anticoagulation). Aspirin was given in 4.1 % (308 patients), a Factor Xa inhibitor in 10 % (744 patients) and other anticoagulants (e.g. Warfarin) in 1.5 % (114 patients). The overall VTE rate in this sub analysis of patients receiving chemical anticoagulation, was 1.1 % (83 cases out of 7469). There was no significant difference seen in incidence of VTE between types of anticoagulants, when confounding factors were considered. The duration of post-operative chemical prophylaxis used by participants for most chemical anticoagulants was 6 weeks (64.50 %). CONCLUSION: There was significant variability of chemical anticoagulants reported in the study, with five different categories of anticoagulants used (including no chemical anticoagulation), and none clearly superior/inferior. The duration of anticoagulation was consistent across types of thromboprophylaxis.
ABSTRACT
Acute myeloid leukaemia (AML) creates an immunosuppressive environment to conventional T cells through Arginase 2 (ARG2)-induced arginine depletion. We identify that AML blasts release the acute phase protein serum amyloid A (SAA), which acts in an autocrine manner to upregulate ARG2 expression and activity, and promote AML blast viability. Following in vitro cross-talk invariant natural killer T (iNKT) cells become activated, upregulate mitochondrial capacity, and release IFN-γ. iNKT retain their ability to proliferate and be activated despite the low arginine AML environment, due to the upregulation of Large Neutral Amino Acid Transporter-1 (LAT-1) and Argininosuccinate Synthetase 1 (ASS)-dependent amino acid pathways, resulting in AML cell death. T cell proliferation is restored in vitro and in vivo. The capacity of iNKT cells to restore antigen-specific T cell immunity was similarly demonstrated against myeloid-derived suppressor cells (MDSCs) in wild-type and Jα18-/- syngeneic lymphoma-bearing models in vivo. Thus, stimulation of iNKT cell activity has the potential as an immunotherapy against AML or as an adjunct to boost antigen-specific T cell immunotherapies in haematological or solid cancers.
Subject(s)
Leukemia, Myeloid, Acute , Myeloid-Derived Suppressor Cells , Natural Killer T-Cells , Humans , Cell Proliferation , ArginineABSTRACT
BACKGROUND: Vitamin K activates matrix Gla protein (MGP), a key inhibitor of vascular calcification. There is a high prevalence of sub-clinical vitamin K deficiency in patients with end-stage kidney disease. METHODS: A parallel randomized placebo-controlled pilot trial was designed to determine whether 10 mg of phylloquinone thrice weekly versus placebo modifies coronary artery calcification progression over 12 months in patients requiring hemodialysis with a coronary artery calcium score (CAC) ≥30 Agatston Units (ClinicalTrials.gov identifier NCT01528800). The primary outcome was feasibility (recruitment rate, compliance with study medication, study completion and adherence overall to study protocol). CAC score was used to assess calcification at baseline and 12 months. Secondary objectives were to explore the impact of phylloquinone on vitamin K-related biomarkers (phylloquinone, dephospho-uncarboxylated MGP and the Gla-osteocalcin to Glu-osteocalcin ratio) and events of clinical interest. RESULTS: A total of 86 patients with a CAC score ≥30 Agatston Units were randomized to either 10 mg of phylloquinone or a matching placebo three times per week. In all, 69 participants (80%) completed the trial. Recruitment rate (4.4 participants/month) and medication compliance (96%) met pre-defined feasibility criteria of ≥4.17 and ≥90%, respectively. Patients randomized to phylloquinone for 12 months had significantly reduced levels of dephospho-uncarboxylated MGP (86% reduction) and increased levels of phylloquinone and Gla-osteocalcin to Glu-osteocalcin ratio compared with placebo. There was no difference in the absolute or relative progression of coronary artery calcification between groups. CONCLUSION: We demonstrated that phylloquinone treatment improves vitamin K status and that a fully powered randomized trial may be feasible.
Subject(s)
Coronary Artery Disease , Vascular Calcification , Humans , Vitamin K/therapeutic use , Vitamin K 1/therapeutic use , Osteocalcin/therapeutic use , Pilot Projects , Coronary Artery Disease/drug therapy , Vascular Calcification/drug therapy , Calcium-Binding Proteins , Extracellular Matrix Proteins , Renal Dialysis , Vitamin K 2/pharmacologyABSTRACT
We have previously proposed temporal recalibration to account for trends in survival over time to improve the calibration of predictions from prognostic models for new patients. This involves first estimating the predictor effects using data from all individuals (full dataset) and then re-estimating the baseline using a subset of the most recent data whilst constraining the predictor effects to remain the same. In this article, we demonstrate how temporal recalibration can be applied in competing risk settings by recalibrating each cause-specific (or subdistribution) hazard model separately. We illustrate this using an example of colon cancer survival with data from the Surveillance Epidemiology and End Results (SEER) program. Data from patients diagnosed in 1995-2004 were used to fit two models for deaths due to colon cancer and other causes respectively. We discuss considerations that need to be made in order to apply temporal recalibration such as the choice of data used in the recalibration step. We also demonstrate how to assess the calibration of these models in new data for patients diagnosed subsequently in 2005. Comparison was made to a standard analysis (when improvements over time are not taken into account) and a period analysis which is similar to temporal recalibration but differs in the data used to estimate the predictor effects. The 10-year calibration plots demonstrated that using the standard approach over-estimated the risk of death due to colon cancer and the total risk of death and that calibration was improved using temporal recalibration or period analysis.
Subject(s)
Colonic Neoplasms , Humans , Calibration , Prognosis , Proportional Hazards Models , Colonic Neoplasms/diagnosisABSTRACT
INTRODUCTION: Vitamin D purportedly protects against cognitive decline and dementia based on observational data using circulating 25-hydroxyvitamin D (25(OH)D). Little is known about vitamin D in the human brain and the association with dementia or neuropathology. METHODS: Decedents of the Rush Memory and Aging Project (n = 290) had vitamin D concentrations measured in four brain regions. Associations with cognitive and neuropathological outcomes were estimated using linear and logistic regression. RESULTS: The main form of vitamin D in all brain regions measured was 25(OH)D3 . Higher brain 25(OH)D3 concentrations were associated with a 25% to 33% lower odds of dementia or mild cognitive impairment (MCI) at the last visit before death (all P ≤ .031). However, brain 25(OH)D concentrations were not associated with any post-mortem neuropathology outcome studied. DISCUSSION: Higher brain 25(OH)D3 concentrations were associated with better cognitive function prior to death. Additional research is needed to clarify the specific mechanisms underlying this potentially protective relationship.
Subject(s)
Cognitive Dysfunction , Dementia , Humans , Aged , Independent Living , Vitamin D , Vitamins , BrainABSTRACT
Neutrophils are the main effector cells during inflammation, but they can also control excessive inflammatory responses by secreting anti-inflammatory cytokines. However, the mechanisms that modulate their plasticity remain unclear. We now show that systemic serum amyloid A 1 (SAA-1) controls the plasticity of neutrophil differentiation. SAA-1 not only induced anti-inflammatory interleukin 10 (IL-10)-secreting neutrophils but also promoted the interaction of invariant natural killer T cells (iNKT cells) with those neutrophils, a process that limited their suppressive activity by diminishing the production of IL-10 and enhancing the production of IL-12. Because SAA-1-producing melanomas promoted differentiation of IL-10-secreting neutrophils, harnessing iNKT cells could be useful therapeutically by decreasing the frequency of immunosuppressive neutrophils and restoring tumor-specific immune responses.
Subject(s)
Cell Differentiation/immunology , Interleukin-10/immunology , Melanoma/immunology , Natural Killer T-Cells/immunology , Neutrophils/immunology , Serum Amyloid A Protein/immunology , Animals , Cell Line, Tumor , Female , Humans , Mice , Mice, Inbred C57BL , Neutrophils/cytologyABSTRACT
Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.
Subject(s)
Arginine/metabolism , Argininosuccinate Synthase/metabolism , Immunotherapy, Adoptive/methods , Leukemia, Myeloid, Acute/therapy , Neuroblastoma/therapy , Ornithine Carbamoyltransferase/metabolism , T-Lymphocytes/transplantation , Animals , Apoptosis , Argininosuccinate Synthase/genetics , Cell Proliferation , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Metabolic Engineering/methods , Mice , Mice, Nude , Neuroblastoma/immunology , Neuroblastoma/metabolism , Neuroblastoma/pathology , Ornithine Carbamoyltransferase/genetics , Receptors, Chimeric Antigen/chemistry , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Vitamin K is a term that comprises a family of structurally related quinones, phylloquinone (PK) and the menaquinones (MKn), that share a common naphthoquinone ring but vary in sidechain length (n) and saturation. Dietary PK is a biosynthetic precursor to tissue menaquinone-4 (MK4), but little is known about the absorption and metabolism of dietary MKn. OBJECTIVE: To characterize the absorption and metabolism of dietary MKn relative to PK. METHODS: In the 4-week diet study, 10-week-old male and female C57BL/6 mice were pair-fed a vitamin K deficient diet (control) or a diet supplemented with 5.0 µmol/kg total PK, MK4, and/or MK9 (separately and in combination). In the 1-week stable isotope study, 12-week-old mice were pair-fed diets containing 2.2 µmol/kg PK (unlabeled control), 2H7PK, 13C11MK4, 2H7MK7, or 2H7MK9. Vitamin K tissue content was quantified by HPLC and/or LC-MS, and concentrations were compared by sex and diet group using 2-factor ANOVA. RESULTS: Regardless of the form(s) of vitamin K provided in the diet, tissue MK4 concentrations did not differ across equimolar supplemented groups in the kidney, adipose, reproductive organ, bone, or pancreas in either males or females in the diet study (all P values > 0.05). Isotopic labeling confirmed the naphthoquinone ring of MK4 in tissues originated from the administered dietary PK or MKn. Despite equimolar supplementation, accumulation of the administered dietary form differed across diet groups in small intestinal segments (all P values < 0.002) and the liver (P < 0.001). Female mice had greater total vitamin K than males in every tissue examined (P < 0.05). CONCLUSIONS: Dietary PK, MK4, MK7, and MK9 all served as precursors to tissue MK4 in mice. This study expands our understanding of vitamin K metabolism and supports a common conversion mechanism of all dietary vitamin K forms to MK4. Further investigation of the metabolism and physiological roles of MK4 that may be independent of classical vitamin K function is warranted.
Subject(s)
Vitamin K 1 , Vitamin K , Animals , Diet , Female , Male , Mice , Mice, Inbred C57BL , Vitamin K/metabolism , Vitamin K 1/metabolism , Vitamin K 2/analogs & derivatives , Vitamin K 2/metabolismABSTRACT
Previous articles in Statistics in Medicine describe how to calculate the sample size required for external validation of prediction models with continuous and binary outcomes. The minimum sample size criteria aim to ensure precise estimation of key measures of a model's predictive performance, including measures of calibration, discrimination, and net benefit. Here, we extend the sample size guidance to prediction models with a time-to-event (survival) outcome, to cover external validation in datasets containing censoring. A simulation-based framework is proposed, which calculates the sample size required to target a particular confidence interval width for the calibration slope measuring the agreement between predicted risks (from the model) and observed risks (derived using pseudo-observations to account for censoring) on the log cumulative hazard scale. Precise estimation of calibration curves, discrimination, and net-benefit can also be checked in this framework. The process requires assumptions about the validation population in terms of the (i) distribution of the model's linear predictor and (ii) event and censoring distributions. Existing information can inform this; in particular, the linear predictor distribution can be approximated using the C-index or Royston's D statistic from the model development article, together with the overall event risk. We demonstrate how the approach can be used to calculate the sample size required to validate a prediction model for recurrent venous thromboembolism. Ideally the sample size should ensure precise calibration across the entire range of predicted risks, but must at least ensure adequate precision in regions important for clinical decision-making. Stata and R code are provided.
Subject(s)
Models, Statistical , Calibration , Computer Simulation , Humans , Prognosis , Sample SizeABSTRACT
BACKGROUND: Hospital clinicians report poor psychosocial well-being during the COVID-19 pandemic. Few studies have reported data at more than one time point. AIMS: To compare psychosocial well-being among hospital clinicians at two different time points during the COVID-19 pandemic in 2020. METHODS: Participants included doctors, nurses, midwives and allied health clinicians at a multi-site, public health service in Melbourne, Australia. Data were collected via two cross-sectional, online surveys: May to June (wave 1; n = 638) and October to December 2020 (wave 2; n = 358). The Depression, Anxiety and Stress Scale (DASS-21) assessed psychological well-being in the past week. Investigator-devised questions assessed COVID-19 concerns and perceived work impacts. General linear models were used to assess impact of wave on psychological distress. RESULTS: There were no significant demographic differences between the two groups. Both positive (e.g. learning experience) and negative (e.g. risk of getting COVID-19) impacts were reported. In both waves, staff were most concerned about health risks to family members. Wave 2 respondents were significantly more likely than wave 1 respondents to indicate concerns about colleagues having COVID-19, increased workloads, leave cancellation and increased conflict at work (all P < 0.001). Adjusting for sex, age, self-rated health and discipline group, depression, anxiety and stress scores were significantly higher for respondents in the second than the first wave (all P < 0.001). CONCLUSIONS: Psychological well-being of hospital clinicians was significantly worse during the second wave of the COVID-19 pandemic than the first. Sustained occupational and psychosocial support is recommended even when immediate COVID-19 concerns and impacts resolve.
Subject(s)
COVID-19 , Anxiety/epidemiology , Anxiety/etiology , COVID-19/epidemiology , Cross-Sectional Studies , Depression/epidemiology , Depression/etiology , Hospitals , Humans , Longitudinal Studies , Pandemics , SARS-CoV-2 , Surveys and QuestionnairesABSTRACT
HIV-1 traffics through dendritic cells (DCs) en route to establishing a productive infection in T lymphocytes but fails to induce an innate immune response. Within DC endosomes, HIV-1 somehow evades detection by the pattern-recognition receptor (PRR) Toll-like receptor 8 (TLR8). Using a phosphoproteomic approach, we identified a robust and diverse signaling cascade triggered by HIV-1 upon entry into human DCs. A secondary siRNA screen of the identified signaling factors revealed several new mediators of HIV-1 trans-infection of CD4+ T cells in DCs, including the dynein motor protein Snapin. Inhibition of Snapin enhanced localization of HIV-1 with TLR8+ early endosomes, triggered a pro-inflammatory response, and inhibited trans-infection of CD4+ T cells. Snapin inhibited TLR8 signaling in the absence of HIV-1 and is a general regulator of endosomal maturation. Thus, we identify a new mechanism of innate immune sensing by TLR8 in DCs, which is exploited by HIV-1 to promote transmission.
Subject(s)
Dendritic Cells/immunology , Dendritic Cells/virology , HIV-1/pathogenicity , Host-Pathogen Interactions , Signal Transduction , Toll-Like Receptor 8/metabolism , Vesicular Transport Proteins/metabolism , CD4-Positive T-Lymphocytes/virology , Cell Line , HIV-1/immunology , HumansABSTRACT
BACKGROUND: Vitamins D and K, which are present in human brain, may have a role in neurodegenerative disease. OBJECTIVES: Given the interest in measuring nutrient concentrations in archived brain samples, it is important to evaluate whether freezer storage time affects these concentrations. Therefore, we evaluated differences in vitamin D and vitamin K concentrations in human brain samples stored for various lengths of time. METHODS: Postmortem brain samples were obtained from 499 participants in the Rush Memory and Aging Project (mean age 92 y, 72% female). Concentrations of vitamins D and K and their metabolites were measured in 4 regions (midtemporal cortex, midfrontal cortex, cerebellum, anterior watershed white matter) using LC-MS/MS and HPLC, respectively. The predominant forms were 25-hydroxycholecalciferol [25(OH)D3] and menaquinone-4 (MK4). ANOVA was used to determine if concentrations differed according to storage time. RESULTS: The geometric mean of the mean 25(OH)D3 concentration (across 4 regions) in brains stored for 1.1 to 6.0 y did not differ from that in brains stored ≤1.0 y (all P ≥ 0.37), whereas 25(OH)D3 in brains stored >6.0 y was 31-40% lower (P ≤ 0.003). MK4 had similar results, with the geometric mean MK4 concentration in the brains stored ≥9.0 y being 48-52% lower than those in brains stored ≤1.0 y (P ≤ 0.012). The 25(OH)D3 and MK4 concentrations were positively correlated across all 4 regions (all Spearman ρ ≥ 0.79, P < 0.001). CONCLUSIONS: 25(OH)D3 and MK4 appear to be stable in brain tissue from older adults stored at -80°C for up to 6 and 9 y, respectively, but not longer. Freezer storage time should be considered in the design and interpretation of studies using archived brain tissue.
Subject(s)
Brain Chemistry , Specimen Handling , Time Factors , Vitamin D/chemistry , Vitamin K/chemistry , Adolescent , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
OBJECTIVE: Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well understood. Low vitamin K intake and incomplete carboxylation of the vitamin K-dependent protein osteocalcin may promote insulin resistance. We assessed relationships of osteocalcin concentration, carboxylation, and fragmentation with CKD and glucose homeostasis in a cross-sectional study. METHODS: We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2 not treated with dialysis) and 37 (17 female) healthy controls. Total osteocalcin was measured by immunoassay, and osteocalcin carboxylation and fragmentation status by liquid chromatography-electrospray ionization-based mass spectrometric immunoassay. Endpoints included glucose tolerance (based on 2-hour oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), and pancreatic beta-cell function (intravenous glucose tolerance test). RESULTS: The total plasma osteocalcin concentration was higher in the CKD group (mean [standard deviation] 102.9 [147.5]) than that in the control group (53.6 [51.1] ng/mL, P = .03), and more osteocalcin was circulating as fragments. The extent of osteocalcin carbocylation did not differ between individuals with and without CKD. Osteocalcin concentration, carboxylation, and fragmentation were not associated with any measure of glucose homeostasis in multivariable-adjusted analyses. CONCLUSIONS: In CKD, circulating osteocalcin concentrations are elevated, in part due to larger proportions of fragmented forms. However, osteocalcin carboxylation status is not significantly different between individuals with and without CKD. Our data also do not provide support for the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.
Subject(s)
Insulin Resistance , Renal Insufficiency, Chronic , Cross-Sectional Studies , Female , Glucose , Homeostasis , Humans , Osteocalcin , Renal DialysisABSTRACT
Therapeutic approaches which aim to target Acute Myeloid Leukaemia through enhancement of patients' immune responses have demonstrated limited efficacy to date, despite encouraging preclinical data. Examination of AML patients treated with azacitidine (AZA) and vorinostat (VOR) in a Phase II trial, demonstrated an increase in the expression of Cancer-Testis Antigens (MAGE, RAGE, LAGE, SSX2 and TRAG3) on blasts and that these can be recognised by circulating antigen-specific T cells. Although the T cells have the potential to be activated by these unmasked antigens, the low arginine microenvironment created by AML blast Arginase II activity acts a metabolic brake leading to T cell exhaustion. T cells exhibit impaired proliferation, reduced IFN-γ release and PD-1 up-regulation in response to antigen stimulation under low arginine conditions. Inhibition of arginine metabolism enhanced the proliferation and cytotoxicity of anti-NY-ESO T cells against AZA/VOR treated AML blasts, and can boost anti-CD33 Chimeric Antigen Receptor-T cell cytotoxicity. Therefore, measurement of plasma arginine concentrations in combination with therapeutic targeting of arginase activity in AML blasts could be a key adjunct to immunotherapy.
Subject(s)
Antigens, Neoplasm/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arginase/antagonists & inhibitors , Arginine/blood , Leukemia, Myeloid/therapy , Acute Disease , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Arginase/blood , Arginase/metabolism , Arginine/metabolism , Azacitidine/administration & dosage , Humans , Immunotherapy/methods , K562 Cells , Leukemia, Myeloid/immunology , Leukemia, Myeloid/metabolism , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Sialic Acid Binding Ig-like Lectin 3/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Vorinostat/administration & dosageABSTRACT
Background: Phylloquinone is the primary form of vitamin K in the diet and circulation. Large intra- and interindividual variances in circulating phylloquinone have been partially attributed to age. However, little is known about the nondietary factors that influence phylloquinone absorption and metabolism. Similarly, it is not known if phylloquinone absorption is altered by the individual's existing vitamin K status. Objective: The purpose of this secondary substudy was to compare plasma response with deuterium-labeled phylloquinone intake in older and younger adults after dietary phylloquinone depletion and repletion. Methods: Forty-two older [mean ± SD age: 67.2 ± 8.0 y; body mass index (BMI; in kg/m2): 25.4 ± 4.6; n = 12 men, 9 women] and younger (mean ± SEM age: 31.8 ± 6.6 y; BMI: 25.5 ± 3.3; n = 9 men, 12 women) adults were maintained on sequential 28-d phylloquinone depletion (â¼10 µg phylloquinone/d) and 28-d phylloquinone repletion (â¼500 µg phylloquinone/d) diets. On the 23rd d of each diet phase, participants consumed deuterated phylloquinone-rich collard greens (2H-phylloquinone). Plasma and urinary outcome measures over 72 h were compared by age group, sex, and dietary phase via 2-factor repeated-measures ANOVA. Results: The plasma 2H-phylloquinone area under the curve (AUC) did not differ in response to phylloquinone depletion or repletion, but was 34% higher in older than in younger adults (P = 0.02). However, plasma 2H-phylloquinone AUC was highly correlated with the serum triglyceride (TG) AUC (r2 = 0.45). After adjustment for serum TG response, the age effect on the plasma 2H-phylloquinone AUC was no longer significant. Conclusions: Plasma 2H-phylloquinone response did not differ between phylloquinone depletion and repletion in older and younger adults. The age effect observed was explained by the serum TG response and was completely attenuated after adjustment. Plasma response to phylloquinone intake, therefore, seems to be a predominantly lipid-driven effect and not dependent on existing vitamin K status. More research is required to differentiate the effect of endogenous compared with exogenous lipids on phylloquinone absorption. This trial was registered at clinicaltrials.gov as NCT00336232.