ABSTRACT
Regions of the normal arterial intima predisposed to atherosclerosis are sites of ongoing monocyte trafficking and also contain resident myeloid cells with features of dendritic cells. However, the pathophysiological roles of these cells are poorly understood. Here we found that intimal myeloid cells underwent reverse transendothelial migration (RTM) into the arterial circulation after systemic stimulation of pattern-recognition receptors (PRRs). This process was dependent on expression of the chemokine receptor CCR7 and its ligand CCL19 by intimal myeloid cells. In mice infected with the intracellular pathogen Chlamydia muridarum, blood monocytes disseminated infection to the intima. Subsequent CCL19-CCR7-dependent RTM was critical for the clearance of intimal C. muridarum. This process was inhibited by hypercholesterolemia. Thus, RTM protects the normal arterial intima, and compromised RTM during atherogenesis might contribute to the intracellular retention of pathogens in atherosclerotic lesions.
Subject(s)
Chemokine CCL19/metabolism , Chlamydia muridarum/immunology , Myeloid Cells/immunology , Myeloid Cells/metabolism , Receptors, CCR7/metabolism , Transendothelial and Transepithelial Migration , Tunica Intima/immunology , Tunica Intima/metabolism , Animals , CD11c Antigen/metabolism , Chlamydia Infections/immunology , Chlamydia Infections/metabolism , Chlamydia Infections/virology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Female , Gene Expression , Gene Expression Profiling , Lipopolysaccharides/immunology , Male , Mice , Mice, Knockout , Monocytes/immunology , Monocytes/metabolism , Monocytes/microbiology , RNA, Messenger/genetics , Signal Transduction , Toll-Like Receptors/metabolism , Tunica Intima/microbiologyABSTRACT
BACKGROUND: Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into the arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. S1P (sphingosine-1-phosphate) is a lipid mediator that regulates immune cell trafficking by signaling via 5 G-protein-coupled receptors (S1PRs [S1P receptors]). We investigated the role of S1P in the RTM of aortic intimal MCs. METHODS: Intravenous injection of lipopolysaccharide was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. RESULTS: In wild-type C57BL/6 mice, lipopolysaccharide induced intimal cell expression of S1pr1, S1pr3, and Sphk1 (a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked lipopolysaccharide-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked lipopolysaccharide-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima, and blunted lipopolysaccharide-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and lipopolysaccharide-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1+/+ and Sphk1-/- bone marrow. Stimulation with lipopolysaccharide increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. CONCLUSIONS: Functional and expression studies support a novel role for S1P signaling in the regulation of lipopolysaccharide-induced RTM and the homeostatic maintenance of aortic intimal MCs. Our data provide insight into how circulating plasma mediators help orchestrate intimal MC dynamics.
Subject(s)
Receptors, Lysosphingolipid , Transendothelial and Transepithelial Migration , Mice , Animals , Receptors, Lysosphingolipid/genetics , Receptors, Lysosphingolipid/metabolism , Lipopolysaccharides/toxicity , Mice, Inbred C57BL , Sphingosine/metabolism , Myeloid Cells/metabolism , Lysophospholipids/metabolism , Tunica Intima/metabolism , Phosphotransferases (Alcohol Group Acceptor)/genetics , Phosphotransferases (Alcohol Group Acceptor)/metabolismABSTRACT
Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mφ metabolism is poorly understood. We modeled lipid accumulation in cultured wild-type mouse thioglycolate-elicited peritoneal Mφs and bone marrow-derived Mφs with conditional (Lyz2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2, and Nfe2l2. Transfection studies employed RAW264.7 cells. Mφs were cultured for 24 h with oxidized low-density lipoprotein (oxLDL) or cholesterol and then were stimulated with LPS. Transcriptomics revealed that oxLDL accumulation in Mφs downregulated inflammatory, hypoxia, and cholesterol metabolism pathways, whereas the antioxidant pathway, fatty acid oxidation, and ABC family proteins were upregulated. Metabolomics and extracellular metabolic flux assays showed that oxLDL accumulation suppressed LPS-induced glycolysis. Intracellular lipid accumulation in Mφs impaired LPS-induced inflammation by reducing both hypoxia-inducible factor 1-α (HIF-1α) stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mφs. Intracellular lipid accumulation in Mφs also enhanced LPS-induced NF erythroid 2-related factor 2 (Nrf2)-mediated antioxidative defense that destabilizes HIF-1α, and Nrf2-deficient Mφs resisted the inhibitory effects of lipid accumulation on glycolysis and inflammatory gene expression. Furthermore, oxLDL shifted NADPH consumption from HIF-1α- to Nrf2-regulated apoenzymes. Thus, we postulate that repurposing NADPH consumption from HIF-1α to Nrf2 transcriptional pathways is critical in modulating inflammatory responses in Mφs with accumulated intracellular lipid. The relevance of our in vitro models was established by comparative transcriptomic analyses, which revealed that Mφs cultured with oxLDL and stimulated with LPS shared similar inflammatory and metabolic profiles with foamy Mφs derived from the atherosclerotic mouse and human aorta.
Subject(s)
Atherosclerosis , Hypercholesterolemia , Humans , Mice , Animals , NF-E2-Related Factor 2/metabolism , Lipopolysaccharides/metabolism , NADP/metabolism , Macrophages/metabolism , Lipoproteins, LDL/metabolism , Glycolysis , Atherosclerosis/metabolism , Cholesterol/metabolism , Antioxidants/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolismABSTRACT
PURPOSE: To assess the effect of nanoglass (NG) particles and multiwalled carbon nanotubes' (MWCNTs) addition on Vickers hardness (VH), degree of conversion (DC), and abrasion resistance of 3D-printed denture base resin. MATERIALS AND METHODS: 3D-printed denture base resin was reinforced using silanized NG and MWCNTs to obtain four groups: Control, 0.25 wt% NG reinforced resin, 0.25 wt% MWCNTs reinforced resin, and a combination group of 0.25 wt% of both fillers. All specimens (N = 176) were tested before and after thermal aging (600 cycles) for VH (n = 22), DC, and abrasion resistance (n = 22). Abrasion resistance specimens were subjected to 60,000 brushing strokes, and then assessed for surface roughness (Ra) and weight loss. Specimens were then scanned with a benchtop scanner before and after abrasion to produce a color map of topographical changes from superimposed images. Data were analyzed using ANOVA tests followed by Tukey post hoc test. Kruskal-Wallis test was used to compare percent change among groups, followed by Dunn post hoc test (α = 0.05). RESULTS: The interaction between nanofiller content and thermal cycling displayed a significant effect on VH and DC. The 0.25% NG expressed the highest VH before aging but revealed the highest percent decrease after aging. Nanofiller content, thermal aging, and brushing displayed a significant interaction impact on the Ra values. CONCLUSIONS: The addition of nanofillers resulted in an overall improvement in resin microhardness and abrasion resistance. The 0.25% MWCNTs group revealed the lowest Ra with the least percent change in VH and DC, while the combination one displayed the least change in weight.
ABSTRACT
RATIONALE: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. OBJECTIVE: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. METHODS AND RESULTS: Ldlr-/- mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr-/- relative to Ldlr+/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT. CONCLUSIONS: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.
Subject(s)
Atherosclerosis/metabolism , Gamma Rays , Lipoproteins, LDL/metabolism , Tunica Intima/radiation effects , Animals , Aorta/metabolism , Aorta/radiation effects , Mice , Mice, Inbred C57BL , Receptors, LDL/deficiency , Receptors, LDL/genetics , Transcriptome , Tunica Intima/metabolismABSTRACT
BACKGROUND: Data regarding the risk of infection related to reusable bronchoscopes, the global drive toward disposable technology and the COVID-19 pandemic have led to an increase in the use and production of single use or disposable bronchoscopes. An in-depth comparison of all available devices has not been published. METHODS: A benchtop comparison of the Ambu®aScopeTM, Boston Scientific® EXALTTM Model B, the Surgical Company Broncoflex© Vortex, Pentax® Medical ONE Pulmo™, and Vathin® H-SteriscopeTM (all 2.8â mm inner dimension other than the Pentax single-use flexible bronchoscope (3â mm)) was undertaken including measurement of maximal flexion and extension angles, thumb force required and suction with and without biopsy forceps. Thereafter, preclinical assessment was performed with data collected including experience, gender, hand size, and scope preference. RESULTS: The Vathin single-use flexible bronchoscope had the biggest range of tip movement from flexion to extension with and without forceps. The Boston single-use flexible bronchoscope required the maximal thumb force but had the least reduction of tip movement with forceps. The Boston single-use flexible bronchoscope significantly outperformed all other scopes including the standard Pentax scope and was the only scope capable of suctioning pseudo-mucus around the forceps. Although there was no significant difference in preference in the overall group, females and those with smaller hand size preferred the Pentax and males the Broncoflex single-use flexible bronchoscope. CONCLUSIONS: Currently available single-use flexible bronchoscopes differ in several factors other than scope sizes and monitor including suction, turning envelope, and handle size. Performance in the clinical setting will be key to their success.
Subject(s)
Bronchoscopes , COVID-19 , Male , Female , Humans , Pandemics , Disposable Equipment , Bronchoscopy/methodsABSTRACT
Plasmodium vivax ookinete surface protein, Pvs25, is a candidate for a transmission-blocking vaccine (TBV) for malaria. Pvs25 has four EGF-like domains containing 22 cysteine residues forming 11 intramolecular disulfide bonds, a structural feature that makes its recombinant protein expression difficult. In this study, we report the high expression of recombinant Pvs25 as a soluble form in silkworm, Bombyx mori. The Pvs25 protein was purified from hemolymphs of larvae and pupae by affinity chromatography. In the Pvs25 expressed by silkworm, no isoforms with inappropriate disulfide bonds were found, requiring no further purification step, which is necessary in the case of Pichia pastoris-based expression systems. The Pvs25 from silkworm was confirmed to be molecularly uniform by sodium dodecyl sulfate gel electrophoresis and size-exclusion chromatography. To examine the immunogenicity, the Pvs25 from B. mori was administered to BALB/c mice subcutaneously with oil adjuvant. The Pvs25 produced by silkworm induced potent and robust immune responses, and the induced antisera correctly recognized P. vivax ookinetes in vitro, demonstrating the potency of Pvs25 from silkworm as a candidate for a malaria TBV. To the best of our knowledge, this is the first study to construct a system for mass-producing malaria TBV antigens using silkworm.
Subject(s)
Bombyx , Malaria Vaccines , Malaria, Vivax , Animals , Antigens, Protozoan/genetics , Antigens, Surface , Bombyx/genetics , Disulfides , Malaria Vaccines/genetics , Malaria, Vivax/prevention & control , Mice , Plasmodium vivax/geneticsABSTRACT
The outcomes of lymphocyte-depleting antibody induction therapy (LDAIT), [thymoglobulin (ATG) or alemtuzumab (ALM)] versus interleukin-2 receptor antagonist (IL-2RA) in the nonbroadly-sensitized [pretransplant calculated panel reactive antibody (cPRA), <80%] adult deceased donor kidney transplant recipients (adult-DDKTRs) are understudied. In this registry, study of 55 593 adult-DD-KTRs, outcomes of LDAIT [(ATG, N = 32 985) and (ALM, N = 9429)], and IL-2RA (N = 13 179) in <10% and 10-79% cPRA groups was analyzed. Adjusted odds ratio (aOR) of one-year biopsy-proven acute rejection (BPAR) was lower; while, aOR of 1-year composite of re-hospitalization, graft loss, or death was higher with LDAIT than IL2-RA in both cPRA groups. Adjusted odds ratio (aOR) of delayed graft function was higher with LDAIT than IL-2RA in the <10% cPRA group. Adjusted hazard ratio (aHR) of 5-year death-censored graft loss (DCGL) in both <80% cPRA groups seemed higher with ALM than other inductions [(<10% cPRA: ALM versus IL2RA, aHR = 1.11, 95% CI = 1.00-1.23 and ATG versus ALM: aHR = 0.84, 95% CI = 0.77-0.91; 10-79% cPRA: ALM versus IL2RA, aHR = 1.29, 95% CI = 1.02-1.64; and ATG versus ALM, aHR = 0.83, 95% CI = 0.70-0.98)]. Five-year aHR of death did not differ among induction therapies in both cPRA groups. In nonbroadly sensitized adult-DDKTRs, LDAIT is more protective against 1-year BPAR (not 5-year mortality) than IL-2RA; the trend of a higher 5-year DCGL risk with ALM than ATG or IL-2RA needs further investigation.
Subject(s)
Kidney Transplantation , Adult , Antilymphocyte Serum/therapeutic use , Graft Rejection , Graft Survival , Humans , Immunosuppressive Agents/therapeutic use , Registries , Retrospective StudiesABSTRACT
The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V), criterion symptom listings are frequently used in clinical practice as checklists to make diagnoses. However, most DSM-V conditions are, in fact, syndromes, that is, collections of signs and symptoms that commonly occur together in the clinic. This report discusses the value of syndromes in medicine and psychiatry. It is argued that a more precise future enumeration of brain circuits and the pathogenesis of psychiatric conditions will help us better understand and treat psychiatric syndromes, but they are unlikely to eliminate the need to categorize psychiatric conditions. We expect that biomarkers will play an increasingly critical role in psychiatric diagnosis. Beyond a better mechanistic understanding of the DSM-V syndromes, future diagnostic efforts will need to increase the focus on function and address risk factors for nonresponse and relapse. We suggest that new artificial intelligence advances will increase the efficiency and acceptability of psychiatric diagnosis and assist with treatment delivery.
Subject(s)
Diagnostic and Statistical Manual of Mental Disorders , Mental Disorders/diagnosis , Psychiatry/trends , Biomarkers , Forecasting , Humans , Mental Disorders/psychologyABSTRACT
Gabapentin is almost exclusively cleared by the kidney and thus presents challenges in patients with kidney failure. Gabapentin is known to be effectively cleared by hemodialysis, but the efficiency of clearance by peritoneal dialysis (PD) has not been previously described. We report a case of gabapentin toxicity in a patient on long-term PD who was treated with continuous automated cycling PD. We find that continuous PD provides significant clearance of gabapentin. With 2-L exchanges every 2 hours, we document an apparent elimination half-life of 41.33 hours, which is substantially shorter than the reported elimination half-life of 132 hours in the absence of kidney function. Further, our patient's symptoms of gabapentin toxicity gradually improved and had fully resolved after about 36 hours of dialysis. Gabapentin clearance by PD was estimated at 94% of urea clearance. We conclude that intensive PD provides gabapentin clearance that approximates that of urea and is an effective but slow method to treat gabapentin overdose and toxicity.
Subject(s)
Amines/poisoning , Analgesics/poisoning , Cyclohexanecarboxylic Acids/poisoning , Diabetic Nephropathies/therapy , Diabetic Neuropathies/drug therapy , Fever/chemically induced , Kidney Failure, Chronic/therapy , Myoclonus/chemically induced , Peritoneal Dialysis/methods , Poisoning/therapy , gamma-Aminobutyric Acid/poisoning , Diabetic Nephropathies/complications , Diabetic Neuropathies/complications , Female , Gabapentin , Humans , Kidney Failure, Chronic/complications , Middle Aged , Poisoning/complicationsABSTRACT
We develop the proposal in this review that schizophrenia is a syndrome made up of component symptom complexes, each with distinctive clinical correlates, pathophysiology, and selective treatments. Psychosis is the necessary component of the syndrome; it has a young-adult onset and is sensitive to current antipsychotic drugs. Cognitive dysfunction often precedes psychosis onset, does not present an episodic course, and is poorly responsive to antipsychotic drugs. Treatments for cognition are being developed largely on the basis of animal pharmacology. Drugs for component symptom complexes will theoretically be coadministered to independent symptomatic end points. Animal models, some with genetic characteristics, can be more easily and directly developed to match an individual component than to match an illness definition as broad as schizophrenia.
Subject(s)
Antipsychotic Agents/pharmacology , Drug Delivery Systems , Schizophrenia/drug therapy , Animals , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Disease Models, Animal , Drug Design , Humans , Schizophrenia/physiopathology , Schizophrenic Psychology , Young AdultABSTRACT
PURPOSE: We aimed to investigate the role of the recipient's age strata in modifying the associations between risk factors and mortality in non-elderly adult kidney transplant (KT) recipients (KTR). METHODS: We stratified 108,695 adult KTRs between 2000 and 2016 with conditional 1-year survival after KT into cohorts based on age at transplant: 18-49 years and 50-64 years. We excluded KTRs aged < 18 years or > / = 65 years. KTRs were observed for 5 years during the 2nd through 6th years post-KT for the outcome, all-cause mortality. RESULTS: Increasing recipient age strata (18-49-year-old and 50-64-year-old) correlated with decreasing 6-year post-KT survival rates conditional on 1-year survival (79% and 57%, respectively, p < 0.0001). Middle adult age stratum was associated with a higher risk of all-cause mortality than young adult age stratum in KTRs of Hispanic/Latino and other races [HR = 1.23, 95% CI = 1.04-1.45 and HR = 1.51, 95% CI = 1.16-1.97, respectively] and with a primary native renal diagnosis of hypertension or glomerulonephritis [HR = 1.32, 95% CI = 1.12-1.55 and HR = 1.29, 95% CI = 1.10-151, respectively]. When compared with the young adult age stratum, the middle adult age stratum had a mitigating effect on the higher risk of mortality associated with sirolimus-mycophenolate or sirolimus-tacrolimus than the standard calcineurin inhibitor-mycophenolate regimen [HR = 0.75, 95% CI = 0.57-0.99 and HR = 0.71, 95% CI = 0.57-0.89, respectively]. CONCLUSION: Among adult non-elderly KTRs, the age strata, 18-49 years, and 50-64 years, have varying modifying effects on the strength and direction of associations between some specific risk factors and all-cause mortality.
ABSTRACT
Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis. Yet, how lipid loading modulates Mφ inflammatory responses remains unclear. We endeavored to gain mechanistic insights into how pre-loading with free cholesterol modulates Mφ metabolism upon LPS-induced TLR4 signaling. We found that activities of prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH) are higher in cholesterol loaded Mφs post-LPS stimulation, resulting in impaired HIF-1α stability, transactivation capacity and glycolysis. In RAW264.7 cells expressing mutated HIF-1α proteins resistant to PHDs and FIH activities, cholesterol loading failed to suppress HIF-1α function. Cholesterol accumulation induced oxidative stress that enhanced NRF2 protein stability and triggered a NRF2-mediated antioxidative response prior to and in conjunction with LPS stimulation. LPS stimulation increased NRF2 mRNA and protein expression, but it did not enhance NRF2 protein stability further. NRF2 deficiency in Mφs alleviated the inhibitory effects of cholesterol loading on HIF-1α function. Mutated KEAP1 proteins defective in redox sensing expressed in RAW264.7 cells partially reversed the effects of cholesterol loading on NRF2 activation. Collectively, we showed that cholesterol accumulation in Mφs induces oxidative stress and NRF2 stabilization, which when combined with LPS-induced NRF2 expression leads to enhanced NRF2-mediated transcription that ultimately impairs HIF-1α-dependent glycolytic and inflammatory responses.
Subject(s)
Cholesterol , Hypoxia-Inducible Factor 1, alpha Subunit , Lipopolysaccharides , Macrophages , NF-E2-Related Factor 2 , Signal Transduction , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Animals , Mice , Macrophages/metabolism , Macrophages/drug effects , Macrophages/immunology , Cholesterol/metabolism , RAW 264.7 Cells , Signal Transduction/drug effects , Oxidative Stress/drug effects , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Up-Regulation/drug effects , Toll-Like Receptor 4/metabolismABSTRACT
The accumulation of lipid and the formation of macrophage foam cells is a hallmark of atherosclerosis, a chronic inflammatory disease. To better understand the role of macrophage lipid accumulation in inflammation during atherogenesis, we studied early molecular events that follow the accumulation of oxidized low-density lipoprotein (oxLDL) in cultured mouse macrophages. We previously showed that oxLDL accumulation downregulates the inflammatory response in conjunction with downregulation of late-phase glycolysis. In this study, we show that within hours after LPS stimulation, macrophages with accumulated oxLDL maintain early-phase glycolysis but selectively downregulate activation of AKT2, one of three AKT isoforms. The inhibition of AKT2 activation reduced LPS-induced ATP citrate lyase activation, acetyl-CoA production, and acetylation of histone 3 lysine 27 (H3K27ac) in certain inflammatory gene promoters. In contrast to oxLDL, multiple early LPS-induced signaling pathways were inhibited in macrophages with accumulated cholesterol, including TBK1, AKT1, AKT2, MAPK, and NF-κB, and early-phase glycolysis. The selective inhibition of LPS-induced AKT2 activation was dependent on the generation of mitochondrial oxygen radicals during the accumulation of oxLDL in macrophages prior to LPS stimulation. This is consistent with increased oxidative phosphorylation, fatty acid synthesis, and oxidation pathways found by comparative transcriptomic analyses of oxLDL-loaded versus control macrophages. Our study shows a functional connection between oxLDL accumulation, inactivation of AKT2, and the inhibition of certain inflammatory genes through epigenetic changes that occur soon after LPS stimulation, independent of early-phase glycolysis.
Subject(s)
ATP Citrate (pro-S)-Lyase , Atherosclerosis , Lipoproteins, LDL , Animals , Mice , Acetyl Coenzyme A , Acetylation , Acyltransferases , ATP Citrate (pro-S)-Lyase/genetics , Lipopolysaccharides , Macrophages , Epigenesis, GeneticABSTRACT
OBJECTIVE: Our objective was to identify consistent predictors of multiple adverse outcomes of adult deceased donor (DD) kidney transplant recipients (KTRs) of varying sensitization status. METHODS: We used the national transplant database in studying 62037 adult DD-KTRs between Dec. 2007 and Jun. 2015 stratified into sensitization cohorts based on calculated panel reactive antibody (CPRA) of <10%, 10%-79%, and ≥80%. We used multivariable logistic regressions for the analysis of risks for delayed graft function (DGF), and of acute rejection (AR) and hospitalization in the first year of transplant, and Cox hazard regression for 5-year overall graft loss (OAGL) and death. RESULTS: The kidney donor risk index (KDRI) highest two quartiles ≥1.45 and 1.15-1.44 were the most consistent predictors for 100% of adverse outcomes (OAGL, death, DGF, AR, and hospitalization) with high significance (P<0.0001) across all sensitization cohorts. The two risk factors that were consistently associated with 80% of adverse outcomes across sensitization cohorts were: (1) pre-transplant dialysis duration >2 years was significantly associated with increased risks of overall graft loss, death, DGF, and hospitalization; and (2) Black KTR race was significantly associated with increased risks of DGF, AR, and hospitalization, and decreased risk of death. Diabetes and KTR age >65 (years) were significant risk factors for overall loss and death across sensitization cohorts. CONCLUSIONS: The two highest KDRI quartiles, pre-transplant dialysis duration >2 years, and African American recipient race are consistent predictors of multiple adverse outcomes in adult DDKTRs across sensitization strata and should be among the factors considered in clinical decision-making and research models in kidney transplantation.
ABSTRACT
BACKGROUND: Human leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). METHODS: In a secondary analysis from a previous study, 166,256 adult KTRs in 2000-2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1-3, and 4-6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. RESULTS: Compared with 0 HLA-mm, 1-3 HLA-mm was not associated, and 4-6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94-1.17 and HR = 1.11, 95% CI = 1.00-1.34, respectively]. Both 1-3 HLA-mm and 4-6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08-1.18) and (HR = 1.16, 95% CI = 1.09-1.22), respectively]. KTR's history of pre-transplant cancer, age 50-64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1-3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1-3 and 4-6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. CONCLUSION: Direct association between SOM and the degree of HLA mismatching is equivocal and limited to the 4-6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.
Subject(s)
Kidney Transplantation , Neoplasms , Adult , Male , Humans , Middle Aged , Kidney Transplantation/adverse effects , Histocompatibility Testing , Kidney , HLA Antigens , Risk Factors , Neoplasms/epidemiology , Graft SurvivalABSTRACT
The ongoing development and integration of telehealth within CF care has been accelerated in response to the Covid-19 pandemic, with many centres publishing their experiences. Now, as the restrictions of the pandemic ease, the use of telehealth appears to be waning, with many centres returning to routine traditional face-to-face services. For most, telehealth is not integrated into clinical care models, and there is a lack of guidance on how to integrate such a service into clinical care. The aims of this systematic review were to first identify manuscripts which may inform best CF telehealth practices, and second, to analyse these finding to determine how the CF community may use telehealth to improve care for patients, families, and Multidisciplinary Teams into the future. To achieve this, the PRISMA review methodology was utilised, in combination with a modified novel scoring system that consolidates expert weighting from key CF stakeholders, allowing for the manuscripts to be placed in a hierarchy in accordance with their scientific robustness. From the 39 found manuscripts, the top ten are presented and further analysed. The top ten manuscripts are exemplars of where telehealth is used effectively within CF care at this time, and demonstrate specific use cases of its potential best practices. However, there is a lack of guidance for implementation and clinical decision making, which remains an area for improvement. Thus, it is suggested that further work explores and provides guidance for standardised implementation into CF clinical practice.
Subject(s)
COVID-19 , Cystic Fibrosis , Telemedicine , Humans , Cystic Fibrosis/diagnosis , Cystic Fibrosis/epidemiology , Cystic Fibrosis/therapy , Pandemics , COVID-19/epidemiologyABSTRACT
The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1 s (ppFEV1), and a mean difference in sweat chloride of -39.3 mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4-6 weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients' preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12 weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV1 was 80.7% on standard dose, and 83.4% at 12 weeks on reduced dose; sweat chloride was 33.4 and 34 mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24 weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.