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BACKGROUND: The current pediatric practice of monitoring for infantile iron deficiency (ID) via hemoglobin (Hgb) screening at one y of age does not identify preanemic ID nor protect against later neurocognitive deficits. OBJECTIVES: To identify biomarkers of iron-related metabolic alterations in the serum and brain and determine the sensitivity of conventional iron and heme indices for predicting risk of brain metabolic dysfunction using a nonhuman primate model of infantile ID. METHODS: Simultaneous serum iron and RBC indices, and serum and cerebrospinal fluid (CSF) metabolomic profiles were determined in 20 rhesus infants, comparing iron sufficient (IS; N = 10) and ID (N = 10) infants at 2 and 4 mo of age. RESULTS: Reticulocyte hemoglobin (RET-He) was lower at 2 wk in the ID group. Significant IS compared with ID differences in serum iron indices were present at 2 mo, but Hgb and RBC indices differed only at 4 mo (P < 0.05). Serum and CSF metabolomic profiles of the ID and IS groups differed at 2 and 4 mo (P < 0.05). Key metabolites, including homostachydrine and stachydrine (4-5-fold lower at 4 mo in ID group, P < 0.05), were altered in both serum and CSF. Iron indices and RET-He at 2 mo, but not Hgb or other RBC indices, were correlated with altered CSF metabolic profile at 4 mo and had comparable predictive accuracy (area under the receiver operating characteristic curve scores, 0.75-0.80). CONCLUSIONS: Preanemic ID at 2 mo was associated with metabolic alterations in serum and CSF in infant monkeys. Among the RBC indices, only RET-He predicted the future risk of abnormal CSF metabolic profile with a predictive accuracy comparable to serum iron indices. The concordance of homostachydrine and stachydrine changes in serum and CSF indicates their potential use as early biomarkers of brain metabolic dysfunction in infantile ID.
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Anemia Ferropénica , Encefalopatías , Deficiencias de Hierro , Animales , Lactante , Humanos , Niño , Anemia Ferropénica/complicaciones , Anemia Ferropénica/diagnóstico , Macaca mulatta/metabolismo , Pronóstico , Hierro/metabolismo , Hemoglobinas/metabolismo , Encefalopatías/metabolismo , Biomarcadores , Encéfalo/metabolismoRESUMEN
Chronic multisymptom illnesses (CMI) such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Long-COVID, and Gulf War Illness (GWI) are associated with an elevated risk of post-exertional malaise (PEM), an acute exacerbation of symptoms and other related outcomes following exercise. These individuals may benefit from personalized exercise prescriptions which prioritize risk minimization, necessitating a better understanding of dose-response effects of exercise intensity on PEM. METHODS: Veterans with GWI (n = 40) completed a randomized controlled crossover experiment comparing 20 min of seated rest to light-, moderate-, and vigorous-intensity cycling conditions over four separate study visits. Symptoms, pain sensitivity, cognitive performance, inflammatory markers (C-reactive protein and plasma cytokines) were measured before and within 1 h after exercise and seated rest. Physical activity behavior was measured ≥ 7 days following each study visit via actigraphy. Linear mixed effects regression models tested the central hypothesis that higher intensity exercise would elicit greater exacerbation of negative outcomes, as indicated by a significant condition-by-time interaction for symptom, pain sensitivity, cognitive performance, and inflammatory marker models and a significant main effect of condition for physical activity models. RESULTS: Significant condition-by-time interactions were not observed for primary or secondary measures of symptoms, pain sensitivity, cognitive performance, and a majority of inflammatory markers. Similarly, a significant effect of condition was not observed for primary or secondary measures of physical activity. CONCLUSIONS: Undesirable effects such as symptom exacerbation were observed for some participants, but the group-level risk of PEM following light-, moderate-, or vigorous-intensity exercise was no greater than seated rest. These findings challenge several prior views about PEM and lend support to a broader body of literature showing that the benefits of exercise outweigh the risks.
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Estudios Cruzados , Ejercicio Físico , Síndrome del Golfo Pérsico , Veteranos , Humanos , Masculino , Persona de Mediana Edad , Ejercicio Físico/fisiología , Femenino , Adulto , Proteína C-Reactiva/metabolismo , Cognición/fisiología , Citocinas/sangreRESUMEN
Cardiovascular disease is the leading cause of death in the USA and is known to be exacerbated by elevated mechanical stress from hypertension. Caveolae are plasma membrane structures that buffer mechanical stress but have been found to be reduced in pathological conditions associated with chronically stretched myocardium. To explore the physiological implications of the loss of caveolae, we used human engineered cardiac tissue (ECT) constructs, composed of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and hiPSC-derived cardiac fibroblasts, to develop a long-term cyclic stretch protocol that recapitulates the effects of hypertension on caveolae expression, membrane tension, and the ß-adrenergic response. Leveraging this new stretch protocol, we identified neutral sphingomyelinases (nSMase) as mechanoregulated mediators of caveolae loss, ceramide production and the blunted ß-adrenergic response in this human cardiac model. Specifically, in our ECT model, nSMase inhibition via GW4869 prevented stretch-induced loss of caveolae-like structures, mitigated nSMase-dependent ceramide production, and maintained the ECT contractile kinetic response to isoprenaline. These findings are correlated with a blood lipidomic analysis in middle-aged and older adults, which revealed an increase of the circulating levels of ceramides in adults with hypertension. Furthermore, we found that conduction slowing from increased pressure loading in mouse left ventricle was abolished in the context of nSMase inhibition. Collectively, these findings identify nSMase as a potent drug target for mitigating stretch-induced effects on cardiac function. KEY POINTS: We have developed a new stretch protocol for human engineered cardiac tissue that recapitulates changes in plasma membrane morphology observed in animal models of pressure/volume overload. Stretch of engineered cardiac tissue induces activation of neutral sphingomyelinase (nSMase), generation of ceramide, and disassembly of caveolae. Activation of nSMase blunts cardiac ß-adrenergic contractile kinetics and mediates stretch-induced slowing of conduction and upstroke velocity. Circulating ceramides are increased in adults with hypertension, highlighting the clinical relevance of stretch-induced nSMase activity.
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OBJECTIVES: This analysis examined if financial hardship was associated with age-related decrements in kidney function using a material-psychosocial-behavioral framework. We also tested if this association was mediated by comorbidity of cardiometabolic risk factors (obesity, elevated blood pressure, and insulin resistance). METHODS: Data from 1,361 Non-Hispanic (NH) Black and white adults (ages 26-94; NH Black = 258) were obtained from the Wave 3 and Refresher phases of the Midlife in the United States (MIDUS) project. Kidney function was based on serum creatinine-based estimated glomerular filtration rate (CKD-EPI formula without race adjustment). Financial hardship was evaluated in three domains: material (income to poverty line ratio, health insurance coverage, and public/government financial assistance), psychological (perceived financial status, control over financial status, and perceived financial strains), and behavioral responses (financial adjustment/coping such as sold possessions and cutting back on spending). RESULTS: More severe financial hardship (overall score and in each domain) was associated with age-related decrements in eGFR, even after adjusting for sociodemographic, education, and health-related covariates. The association between financial hardship and age-related decrements in eGFR was conditional on sex but not race. Finally, cardiometabolic risk factors mediated the association between financial hardship and age-related decrements in eGFR. CONCLUSIONS: These findings affirm the negative effects of financial hardship on age-related decrements in renal clearance. In addition to incorporating traditionally used indicators of SES, such as education and income, future research on social hallmarks of aging should also consider the role of financial hardship on the aging process and age-related diseases.
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BACKGROUND: Infantile iron deficiency (ID) causes anemia and compromises neurodevelopment. Current screening relies on hemoglobin (Hgb) determination at 1 year of age, which lacks sensitivity and specificity for timely detection of infantile ID. Low reticulocyte Hgb equivalent (RET-He) indicates ID, but its predictive accuracy relative to conventional serum iron indices is unknown. OBJECTIVES: The objective was to compare diagnostic accuracies of iron indices, red blood cell (RBC) indices, and RET-He for predicting the risk of ID and IDA in a nonhuman primate model of infantile ID. METHODS: Serum iron, total iron binding capacity, unsaturated iron binding capacity, transferrin saturation (TSAT), Hgb, RET-He, and other RBC indices were determined at 2 wk and 2, 4, and 6 mo in breastfed male and female rhesus infants (N = 54). The diagnostic accuracies of RET-He, iron, and RBC indices for predicting the development of ID (TSAT < 20%) and IDA (Hgb < 10 g/dL + TSAT < 20%) were determined using t tests, area under the receiver operating characteristic curve (AUC) analysis, and multiple regression models. RESULTS: Twenty-three (42.6%) infants developed ID and 16 (29.6%) progressed to IDA. All 4 iron indices and RET-He, but not Hgb or RBC indices, predicted future risk of ID and IDA (P < 0.001). The predictive accuracy of RET-He (AUC = 0.78, SE = 0.07; P = 0.003) for IDA was comparable to that of the iron indices (AUC = 0.77-0.83, SE = 0.07; P ≤ 0.002). A RET-He threshold of 25.5 pg strongly correlated with TSAT < 20% and correctly predicted IDA in 10 of 16 infants (sensitivity: 62.5%) and falsely predicted possibility of IDA in only 4 of 38 unaffected infants (specificity: 89.5%). CONCLUSIONS: RET-He is a biomarker of impending ID/IDA in rhesus infants and can be used as a hematological parameter to screen for infantile ID.
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Anemia Ferropénica , Anemia , Deficiencias de Hierro , Masculino , Femenino , Animales , Reticulocitos/química , Reticulocitos/metabolismo , Anemia/metabolismo , Hemoglobinas/metabolismo , Hierro/metabolismo , Primates/metabolismoRESUMEN
Increased synthesis and release of inflammatory signalling proteins is common among individuals with hematologic malignancies undergoing hematopoietic cell transplantation (HCT) due to intensive conditioning regimens and complications such as graft-versus-host-disease and infections. Prior research indicates that inflammatory responses can activate central nervous system pathways that evoke changes in mood. This study examined relationships between markers of inflammatory activity and depression symptoms following HCT. Individuals undergoing allogeneic (n = 84) and autologous (n = 155) HCT completed measures of depression symptoms pre-HCT and 1, 3, and 6 months post-HCT. Proinflammatory (IL-6, TNF-α) and regulatory (IL-10) cytokines were assessed by ELISA in peripheral blood plasma. Mixed-effects linear regression models indicated that patients with elevated IL-6 and IL-10 reported more severe depression symptoms at the post-HCT assessments. These findings were replicated when examining both allogeneic and autologous samples. Follow-up analyses clarified that relationships were strongest for neurovegetative, rather than cognitive or affective, symptoms of depression. These findings suggest that anti-inflammatory therapeutics targeting an inflammatory mediator of depression could improve quality of life of HCT recipients.
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Trasplante de Células Madre Hematopoyéticas , Interleucina-10 , Humanos , Depresión/psicología , Citocinas , Calidad de Vida/psicología , Interleucina-6 , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
Substance use and depression frequently co-occur. Adolescence appears to be a vulnerable developmental period for increases in both substance use and depressive symptoms, often attributed to rapid maturation of reward and motivation systems. Another contributing factor could be inflammatory signaling, which has been associated with both substance use disorder and depression. Prior research indicates that an increase in inflammatory activity can cause physical and emotional malaise, which resembles depression, and the anhedonia and somatic symptoms could lead to substance use. This perspective that substance use is a type of self-medication in response to anhedonia and subjective experiencing of increased inflammatory physiology has not been investigated previously. To test these associations, we used path analysis to examine concurrent and prospective associations between three pro-inflammatory markers, specific depressive symptoms, and substance use frequency in a diverse sample of older adolescents. Participants completed repeated self-report measures of specific depressive symptoms (i.e., dysphoria, anhedonia, somatic concerns, negative cognitions, and functional difficulties) and substance use frequency. Blood was collected to quantify circulating levels of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). This analysis showed an indirect effect of IL-6 and TNF-α levels on future substance use, but only via functional difficulties. Substance use also predicted future functional difficulties. Only anhedonia directly predicted future substance use frequency. These findings help to more precisely identify pathways through which inflammatory physiology and specific depressive symptoms synergistically confer risk for substance use.
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Depresión , Trastornos Relacionados con Sustancias , Humanos , Adolescente , Depresión/psicología , Anhedonia/fisiología , Factor de Necrosis Tumoral alfa , Proteína C-Reactiva/análisis , Interleucina-6RESUMEN
There is increasing concern about the potential effects of anesthesia exposure on the developing brain. The effects of relatively brief anesthesia exposures used repeatedly to acquire serial magnetic resonance imaging scans could be examined prospectively in rhesus macaques. We analyzed magnetic resonance diffusion tensor imaging (DTI) of 32 rhesus macaques (14 females, 18 males) aged 2 weeks to 36 months to assess postnatal white matter (WM) maturation. We investigated the longitudinal relationships between each DTI property and anesthesia exposure, taking age, sex, and weight of the monkeys into consideration. Quantification of anesthesia exposure was normalized to account for variation in exposures. Segmented linear regression with two knots provided the best model for quantifying WM DTI properties across brain development as well as the summative effect of anesthesia exposure. The resulting model revealed statistically significant age and anesthesia effects in most WM tracts. Our analysis indicated there were major effects on WM associated with low levels of anesthesia even when repeated as few as three times. Fractional anisotropy values were reduced across several WM tracts in the brain, indicating that anesthesia exposure may delay WM maturation, and highlight the potential clinical concerns with even a few exposures in young children.
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Anestesia , Sustancia Blanca , Masculino , Animales , Femenino , Sustancia Blanca/diagnóstico por imagen , Macaca mulatta , Imagen de Difusión Tensora/métodos , EncéfaloRESUMEN
The effects of iron deficiency (ID) during infancy extend beyond the hematologic compartment and include short- and long-term adverse effects on many tissues including the brain. However, sensitive biomarkers of iron-dependent brain health are lacking in humans. To determine whether serum and cerebrospinal fluid (CSF) biomarkers of ID-induced metabolic dysfunction are concordant in the pre/early anemic stage of ID before anemia in a nonhuman primate model of infantile iron deficiency anemia (IDA). ID (n = 7), rhesus infants at 4 mo (pre-anemic period) and 6 mo of age (anemic) were examined. Hematological, metabolomic, and proteomic profiles were generated via HPLC/MS at both time points to discriminate serum biomarkers of ID-induced brain metabolic dysfunction. We identified 227 metabolites and 205 proteins in serum. Abnormalities indicating altered liver function, lipid dysregulation, and increased acute phase reactants were present in ID. In CSF, we measured 210 metabolites and 1,560 proteins with changes in ID infants indicative of metabolomic and proteomic differences indexing disrupted synaptogenesis. Systemic and CSF proteomic and metabolomic changes were present and concurrent in the pre-anemic and anemic periods. Multiomic serum and CSF profiling uncovered pathways disrupted by ID in both the pre-anemic and anemic stages of infantile IDA, including evidence for hepatic dysfunction and activation of acute phase response. Parallel changes observed in serum and CSF potentially provide measurable serum biomarkers of ID that reflect at-risk brain processes prior to progression to clinical anemia.
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Anemia Ferropénica , Anemia , Deficiencias de Hierro , Anemia Ferropénica/líquido cefalorraquídeo , Animales , Biomarcadores , Humanos , Hierro , Macaca mulatta , ProteómicaRESUMEN
Over the last decade, multiple studies have highlighted the essential role of gut microbiota in normal infant development. However, the sensitive periods during which gut bacteria are established and become associated with physical growth and maturation of the brain are still poorly defined. This study tracked the assembly of the intestinal microbiota during the initial nursing period, and changes in community structure after transitioning to solid food in infant rhesus monkeys (Macaca mulatta). Anthropometric measures and rectal swabs were obtained at 2-month intervals across the first year of life and bacterial taxa identified by 16S rRNA gene sequencing. At 12 months of age, total brain and cortical regions volumes were quantified through structural magnetic resonance imaging. The bacterial community structure was dynamic and characterized by discrete maturational phases, reflecting an early influence of breast milk and the later transition to solid foods. Commensal microbial taxa varied with diet similar to findings in other animals and human infants; however, monkeys differ in the relative abundances of Lactobacilli and Bifidobacteria, two taxa predominant in breastfed human infants. Higher abundances of taxa in the phylum Proteobacteria during nursing were predictive of slower growth trajectories and smaller brain volumes at one year of age. Our findings define discrete phases of microbial succession in infant monkeys and suggest there may be a critical period during nursing when endogenous differences in certain taxa can shift the community structure and influence the pace of physical growth and the maturational trajectory of the brain.
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Animales Recién Nacidos/crecimiento & desarrollo , Encéfalo/fisiología , Microbioma Gastrointestinal , Leche/microbiología , Proteobacteria/fisiología , Animales , Encéfalo/microbiología , Dieta , Heces/microbiología , Femenino , Macaca mulatta , MasculinoRESUMEN
BACKGROUND: High-density lipoprotein (HDL) plays a critical role in protection against atherosclerosic and cardiovascular disease (ASCVD). In addition to contributing to clearing excess vascular cholesterol, HDL particles exhibit antioxidative functions, helping to attenuate adverse effects of oxidized low-density lipoproteins. However, these beneficial properties can be undermined by oxidative stress, inflammation, and unhealthy lifestyles and diet, as well as influenced by race and sex. Thus, when assessing cardiovascular risk, it is important to consider multifactorial aspects of HDL, including antioxidant activity rather than just total amount and type of HDL-cholesterol (HDL-C) particles. Because prior research showed HDL peroxide content (HDLperox) can be inversely associated with normal anti-oxidant HDL activity, elevated HDLperox may serve as a bioindicator of HDL dysfunction. METHODS: In this study, data from a large national cohort of Americans was utilized to determine the impact of sex, race, and diabetes status on HDLperox in middle-aged and older adults. A previously developed cell-free fluorometric method was utilized to quantify HDLperox in serum depleted of apo-B containing lipoproteins. RESULTS: In keeping with predictions, white men and diabetics exhibited HDLperox in the atypical upper range, suggestive of less functional HDL. White men had higher HDLperox levels than African American males (13.46 ± 6.10 vs. 10.88 ± 5.81, p < .001). There was also a significant main effect of type 2 diabetes (F(1,1901) = 14.9, p < .0001). Overall, African Americans evinced lower HDLperox levels, despite more obesity (10.3 ± 4.7 vs.11.81 ± 5.66 for Whites) suggesting that other aspects of lipid metabolism and psychosocial factors account for the higher prevalence of ASCVD in African Americans. CONCLUSION: This research helps to provide a more comprehensive understanding of HDL function in a racially and metabolically diverse adult population. HDLperox content was significantly different in adults with type 2 diabetes, and distinctive in nondiabetic White males, and suggests other processes account for the higher prevalence of ASCVD among African Americans.
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HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Peróxidos Lipídicos/sangre , Grupos Raciales/estadística & datos numéricos , Negro o Afroamericano/estadística & datos numéricos , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Estados Unidos , Población Blanca/estadística & datos numéricosRESUMEN
BACKGROUND: Microbiome research has expanded to consider contributions of microbial kingdoms beyond bacteria, including fungi (i.e., the mycobiome). However, optimal specimen handling protocols are varied, including uncertainty of how enzymes utilized to facilitate fungal DNA recovery may interfere with bacterial microbiome sequencing from the same samples. METHODS: With Institutional Animal Care and Use Committee approval, fecal samples were obtained from 20 rhesus macaques (10 males, 10 females; Macaca mulatta). DNA was extracted using commercially available kits, with or without lyticase enzyme treatment. 16S ribosomal RNA (bacterial) and Internal Transcribed Spacer (ITS; fungal) sequencing was performed on the Illumina MiSeq platform. Bioinformatics analysis was performed using Qiime and Calypso. RESULTS: Inclusion of lyticase in the sample preparation pipeline significantly increased usable fungal ITS reads, community alpha diversity, and enhanced detection of numerous fungal genera that were otherwise poorly or not detected in primate fecal samples. Bacterial 16S ribosomal RNA amplicons obtained from library preparation were statistically unchanged by the presence of lyticase. CONCLUSIONS: We demonstrate inclusion of the enzyme lyticase for fungal cell wall digestion markedly enhances mycobiota detection while maintaining fidelity of microbiome identification and community features in non-human primates. In restricted sample volumes, as are common in limited human samples, use of single sample DNA isolation will facilitate increased rigor and controlled approaches in future work.
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Microbiota , Micobioma , Animales , Femenino , Glucano Endo-1,3-beta-D-Glucosidasa , Macaca mulatta/genética , Masculino , Complejos Multienzimáticos , Micobioma/genética , Péptido Hidrolasas , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Non-human primates are commonly used in neuroimaging research for which general anaesthesia or sedation is typically required for data acquisition. In this analysis, the cumulative effects of exposure to ketamine, Telazol® (tiletamine and zolazepam), and the inhaled anaesthetic isoflurane on early brain development were evaluated in two independent cohorts of typically developing rhesus macaques. METHODS: Diffusion MRI scans were analysed from 43 rhesus macaques (20 females and 23 males) at either 12 or 18 months of age from two separate primate colonies. RESULTS: Significant, widespread reductions in fractional anisotropy with corresponding increased axial, mean, and radial diffusivity were observed across the brain as a result of repeated anaesthesia exposures. These effects were dose dependent and remained after accounting for age and sex at time of exposure in a generalised linear model. Decreases of up to 40% in fractional anisotropy were detected in some brain regions. CONCLUSIONS: Multiple exposures to commonly used anaesthetics were associated with marked changes in white matter microstructure. This study is amongst the first to examine clinically relevant anaesthesia exposures on the developing primate brain. It will be important to examine if, or to what degree, the maturing brain can recover from these white matter changes.
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Anestesia General/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/diagnóstico por imagen , Animales , Animales Recién Nacidos , Encéfalo/metabolismo , Imagen de Difusión Tensora/tendencias , Femenino , Macaca mulatta , MasculinoRESUMEN
Early adverse care has long-term impacts on physical and mental health. The influence of rearing conditions on the infant's gut microbiota and its relationship with developmental health has become more evident. The microbiome is essential for normal growth and metabolism, and the signaling from the gut to the brain may underlie individual differences in resilience later in life. Microbial diversity and composition were determined using 16S rRNA gene amplicon sequencing in fecal samples from 17 adolescents adopted internationally from orphanages into the United States and 18 adolescents reared in birth families who had similar educational and income levels. Analyses focused on diversity of the microbial community structure and differences in the abundance of specific bacterial taxa. Blood samples were used to immunophenotype the numbers of several T-cell subsets and cytomegalovirus (CMV) seropositivity. Negative binomial regression analysis revealed several operational taxonomic units that were significantly different based on early rearing conditions and CMV seropositivity. There were significant associations between the relative abundance of certain taxa, the percentages of T-cell subsets in circulation, and CMV seropositivity. These findings demonstrate a possible link between the gut microbiota and associations with immune alterations initiated by early life adversity.
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Experiencias Adversas de la Infancia , Microbioma Gastrointestinal , Microbiota , Adolescente , Humanos , Prueba de Estudio Conceptual , ARN Ribosómico 16S/genéticaRESUMEN
Chronic, systemic inflammation is implicated in physical and mental health; little is known about whether sex and racial differences detected in adulthood are observed during adolescence or about normative changes occurring during adolescence. This longitudinal, United States-based study examined four biomarkers of systemic inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and IL-8) in 315 adolescents (51% female; 58% black; baseline age = 16.49 years (SD = 1.56; range: 12.14-21.28)] at three timepoints. Notable results included: general decline in inflammatory biomarkers in older adolescents, lower levels of TNF-α/IL-8 in black adolescents, elevated CRP/IL-6 in females, and especially higher levels of IL-6 in black, female adolescents. Implications are discussed, particularly the potential health implications of elevated IL-6 in black females.
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Proteína C-Reactiva , Inflamación , Adolescente , Adulto , Biomarcadores , Proteína C-Reactiva/análisis , Femenino , Humanos , Interleucina-6 , Masculino , Factor de Necrosis Tumoral alfa , Estados UnidosRESUMEN
BACKGROUND: Iron deficiency is the most common nutrient deficiency in human infants aged 6 to 24 mo, and negatively affects many cellular metabolic processes, including energy production, electron transport, and oxidative degradation of toxins. There can be persistent influences on long-term metabolic health beyond its acute effects. OBJECTIVES: The objective was to determine how iron deficiency in infancy alters the serum metabolomic profile and to test whether these effects persist after the resolution of iron deficiency in a nonhuman primate model of spontaneous iron deficiency. METHODS: Blood was collected from naturally iron-sufficient (IS; n = 10) and iron-deficient (ID; n = 10) male and female infant rhesus monkeys (Macaca mulatta) at 6 mo of age. Iron deficiency resolved without intervention upon feeding of solid foods, and iron status was re-evaluated at 12 mo of age from the IS and formerly ID monkeys using hematological and other indices; sera were metabolically profiled using HPLC/MS and GC/MS with isobaric standards for identification and quantification at both time points. RESULTS: A total of 413 metabolites were measured, with differences in 40 metabolites identified between IS and ID monkeys at 6 mo (P$\le $ 0.05). At 12 mo, iron-related hematological parameters had returned to normal, but the formerly ID infants remained metabolically distinct from the age-matched IS infants, with 48 metabolites differentially expressed between the groups. Metabolomic profiling indicated altered liver metabolites, differential fatty acid production, increased serum uridine release, and atypical bile acid production in the ID monkeys. CONCLUSIONS: Pathway analyses of serum metabolites provided evidence of a hypometabolic state, altered liver function, differential essential fatty acid production, irregular uracil metabolism, and atypical bile acid production in ID infants. Many metabolites remained altered after the resolution of ID, suggesting long-term effects on metabolic health.
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Metaboloma/fisiología , Enfermedades de los Monos/sangre , Animales , Ácidos y Sales Biliares/biosíntesis , Dieta/veterinaria , Ácidos Grasos/biosíntesis , Femenino , Deficiencias de Hierro , Hígado/fisiopatología , Macaca mulatta , Masculino , Metabolómica/métodos , Estudios Prospectivos , Uracilo/metabolismoRESUMEN
BACKGROUND: There is substantial evidence that many depressed individuals experience impaired executive functioning. Understanding the causes of executive dysfunction in depression is clinically important because cognitive impairment is a substantial contributor to functional impairment. This study investigated whether elevated levels of an inflammatory cytokine [interleukin-6 (IL-6)] and/or higher body mass index (BMI) concurrently and/or prospectively accounted for the relationship between depressive symptoms and impaired executive functioning in adolescents. METHODS: A diverse, community sample of adolescents (N = 288; mean age = 16.33; 51.4% female; 59.0% African-American) completed assessments of height and weight, IL-6, depressive symptoms, and self-report/behavioral measures of executive functioning (selective attention, switching attention) and future orientation annually over 3 years. Adolescents experiencing acute illness or medical conditions that affect inflammation were excluded from analyses. Path analysis within a structural equation modeling framework simultaneously examined the concurrent and prospective relationships between BMI, IL-6, depressive symptoms, and the measures of cognitive functioning across three timepoints. RESULTS: Across all timepoints, higher BMI was prospectively associated with higher levels of IL-6 and depressive symptoms, while higher levels of IL-6 were associated with worse performance on three behavioral and self-report measures of cognitive functioning. Higher depressive symptoms also were prospectively associated with elevated IL-6 and both higher depressive symptoms and a higher BMI predicted worse future executive functioning via increased IL-6. CONCLUSIONS: More severe depressive symptoms and increased BMI may disrupt executive functioning via elevated IL-6.
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Índice de Masa Corporal , Disfunción Cognitiva/fisiopatología , Depresión/fisiopatología , Función Ejecutiva/fisiología , Inflamación/sangre , Adolescente , Niño , Disfunción Cognitiva/etiología , Depresión/complicaciones , Femenino , Humanos , Inflamación/complicaciones , Interleucina-6/sangre , Estudios Longitudinales , Masculino , Obesidad Infantil/sangre , Obesidad Infantil/complicaciones , Obesidad Infantil/fisiopatologíaRESUMEN
This study investigated whether longitudinal changes in inflammatory physiology moderated the relationship between recent stressful life events and subsequent depressive symptoms in adolescence. A diverse sample of adolescents representative of an urban community (Nâ¯=â¯129; Age at baselineâ¯=â¯12.5â¯years; 48.8% female; 55.0% African American) completed measures of stressful life events, depressive symptoms, and two annual blood draws (BD1 and BD2). Controlling for inflammatory activity at BD1, depression at BD1, demographics and the time between assessments, increases in interleukin-6 (IL-6; bâ¯=â¯0.878, pâ¯=â¯.007) and C-reactive protein (CRP; bâ¯=â¯0.252, pâ¯=â¯.024) from BD1 to BD2 interacted with recent stressful life events before BD1 to predict severity of depressive symptoms at BD2. Similar associations were evident for IL-6 (bâ¯=â¯2.074, pâ¯=â¯.040) and CRP (bâ¯=â¯0.919, pâ¯=â¯.050) when considering acute stressful life events that had occurred within the two weeks before the first blood collection. More frequent stressful life events before BD1 predicted significantly more severe depressive symptoms at BD2, but only for adolescents with moderate (50th percentile) and high (84th percentile) levels of IL-6 and CRP at BD2. In conclusion, adolescents who experienced both recent stressful life events and larger increases in inflammatory activity following these stressors were at increased risk for more severe depressive symptoms after approximately one year. The findings indicate that the interaction of stress and larger changes in inflammatory activity following these stressors are prognostic risk factors for depression severity in adolescents.
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Depresión/sangre , Depresión/etiología , Inflamación/sangre , Inflamación/complicaciones , Acontecimientos que Cambian la Vida , Estrés Psicológico , Población Urbana , Adolescente , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Niño , Femenino , Humanos , Interleucina-6/sangre , Masculino , Estudios Prospectivos , Factores de Riesgo , Estrés Psicológico/sangre , Estrés Psicológico/complicacionesRESUMEN
Japan is an exceptionally healthy East Asian country with extended longevity. In addition, the typical levels of several proinflammatory proteins, including both C-reactive protein (CRP) and interleukin-6 (IL-6), are often reported to be low when compared to American and European populations. This analysis determined if blood levels of CRP and IL-6 were associated with 4 cultural practices reflective of Japanese behavior and customs -- drinking tea, eating seafood, consuming vegetables, and partaking in relaxing baths regularly - among 382 adults living in Tokyo. Regression models controlled for demographic factors, adiposity (BMI), physical exercise, smoking, alcohol use, and chronic illness (e.g., diabetes). Consuming a Japanese diet was associated with significantly lower CRP and IL-6 levels. More frequent bathing was associated with lower IL-6, but not specifically predictive of low CRP. This study has confirmed prior evidence for low inflammatory activity in Japanese adults and its association with several behavioral practices common in Japan.
Asunto(s)
Proteína C-Reactiva , Interleucina-6 , Adulto , Proteína C-Reactiva/análisis , Asia Oriental , Humanos , Japón , Estilo de Vida , ObesidadRESUMEN
BACKGROUND: There is a lack of empirical effort that systematically investigates the clustering of comorbidity among known risk factors (obesity, hypertension, diabetes, hypercholesterolemia, and elevated inflammation) of chronic kidney disease (CKD) and how different types of comorbidity may link differently to kidney function among healthy adult samples. This study modeled the clustering of comorbidity among risk factors, examined the association between the clustering of risk factors and kidney function, and tested whether the clustering of risk factors was associated with childhood SES. METHODS: The data were from 2118 participants (ages 25-84) in the Midlife in the United States (MIDUS) Study. Risk factors included obesity, elevated blood pressure (BP), high total cholesterol levels, poor glucose control, and increased inflammatory activity. Glomerular filtration rate (eGFR) was estimated from serum creatinine, calculated with the CKD-EPI formula. The clustering of comorbidity among risk factors and its association with kidney function and childhood SES were examined using latent class analysis (LCA). RESULTS: A five-class model was optimal: (1) Low Risk (class size = 36.40%; low probability of all risk factors), (2) Obese (16.42%; high probability of large BMI and abdominally obese), (3) Obese and Elevated BP (13.37%; high probability of being obese and having elevated BP), (4) Non-Obese but Elevated BP (14.95%; high probability of having elevated BP, hypercholesterolemia, and elevated inflammation), and (5) High Risk (18.86%; high probability for all risk factors). Obesity was associated with kidney hyperfiltration, while comorbidity between obesity and hypertension was linked to compromised kidney filtration. As expected, the High Risk class showed the highest probability of having eGFR < 60 ml/min/1.73 m2 (P = .12; 95%CI = .09-.17). Finally, higher childhood SES was associated with reduced probability of being in the High Risk rather than Low Risk class (ß = - 0.20, SE = 0.07, OR [95%CI] = 0.82 [0.71-0.95]). CONCLUSION: These results highlight the importance of considering the impact of childhood SES on risk factors known to be associated with CKD.