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Research Square Jul 2023This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, analyzed the entire expressed transcriptome in...
This study on severe malarial anemia (SMA: Hb < 6.0 g/dL), a leading global cause of childhood morbidity and mortality, analyzed the entire expressed transcriptome in whole blood from children with non-SMA (Hb ≥ 6.0 g/dL, n = 41) and SMA (n = 25). Analyses revealed 3,420 up-regulated and 3,442 down-regulated transcripts, signifying impairments in host inflammasome activation, cell death, innate immune responses, and cellular stress responses in SMA. Immune cell profiling showed a decreased antigenic and immune priming response in children with SMA, favoring polarization toward cellular proliferation and repair. Enrichment analysis further identified altered neutrophil and autophagy-related processes, consistent with neutrophil degranulation and altered ubiquitination and proteasome degradation. Pathway analyses highlighted SMA-related alterations in cellular homeostasis, signaling, response to environmental cues, and cellular and immune stress responses. Validation with a qRT-PCR array showed strong concordance with the sequencing data. These findings identify key molecular themes in SMA pathogenesis, providing potential targets for new malaria therapies.
PubMed: 37503086
DOI: 10.21203/rs.3.rs-3150748/v1 -
Current Pollution Reports Sep 2023There is a growing interest in understanding the health effects of exposure to per- and polyfluoroalkyl substances (PFAS) through the study of the human metabolome. In...
PURPOSE OF REVIEW
There is a growing interest in understanding the health effects of exposure to per- and polyfluoroalkyl substances (PFAS) through the study of the human metabolome. In this systematic review, we aimed to identify consistent findings between PFAS and metabolomic signatures. We conducted a search matching specific keywords that was independently reviewed by two authors on two databases (EMBASE and PubMed) from their inception through July 19, 2022 following PRISMA guidelines.
RECENT FINDINGS
We identified a total of 28 eligible observational studies that evaluated the associations between 31 different PFAS exposures and metabolomics in humans. The most common exposure evaluated was legacy long-chain PFAS. Population sample sizes ranged from 40 to 1,105 participants at different stages across the lifespan. A total of 19 studies used a non-targeted metabolomics approach, 7 used targeted approaches, and 2 included both. The majority of studies were cross-sectional ( = 25), including four with prospective analyses of PFAS measured prior to metabolomics.
SUMMARY
Most frequently reported associations across studies were observed between PFAS and amino acids, fatty acids, glycerophospholipids, glycerolipids, phosphosphingolipids, bile acids, ceramides, purines, and acylcarnitines. Corresponding metabolic pathways were also altered, including lipid, amino acid, carbohydrate, nucleotide, energy metabolism, glycan biosynthesis and metabolism, and metabolism of cofactors and vitamins. We found consistent evidence across studies indicating PFAS-induced alterations in lipid and amino acid metabolites, which may be involved in energy and cell membrane disruption.
PubMed: 37753190
DOI: 10.1007/s40726-023-00269-4 -
Eye and Vision (London, England) Aug 2023This study aims to detect alterations in the spatio-chromatic pseudophakic vision produced by multifocal diffractive intraocular lenses (IOLs) and provides a physical...
BACKGROUND
This study aims to detect alterations in the spatio-chromatic pseudophakic vision produced by multifocal diffractive intraocular lenses (IOLs) and provides a physical interpretation.
METHODS
In vitro characterization of the imaging performance of two diffractive IOLs: AT LISA Tri (Zeiss) and FineVision (PhysIOL) in on-bench model eye illuminated with red (R, 625 nm), green (G, 530 nm) and blue (B, 455 nm) lights. We used the metrics: energy efficiency (EE), area under the modulation transfer function, longitudinal chromatic aberration (LCA), and halo intensity. Through-focus (TF) analysis and calculation of the expected defocus curve under white (W) daylight were included. In vivo visual acuity (VA) of 50 pseudophakics (60 eyes) was assessed under W, R, G, B lights at far and near. Two clinical experiments evaluated LCA and R, G, B TF-EE effects on pseudophakic vision and their relative importance.
RESULTS
Clinical mean VA values under W light agreed with the predicted values at far and near for both IOLs. LCA measurements and R, G, B TF-EE curves were consistent with their lens design based on the 0th and 1st diffraction orders operative for far and near vision, respectively. LCA effects were compensated at near but noticed at far (- 0.75 D under B light). We detected strong asymmetry in visual resolution depending on the object distance and the illuminating wavelength-red predominance at far, blue predominance at near-in consistency with the TF-EE measurements.
CONCLUSIONS
Diffractive multifocal IOL designs produce asymmetries in the spatio-chromatic vision of pseudophakics beyond the alterations strictly due to LCA. VA asymmetry for far/near object distance under R and B illumination is clinically detectable in subjects implanted with IOLs with 0th and 1st diffraction orders for far and near vision, respectively. Such VA asymmetry cannot be explained solely from the influence of defocus, as would be derived from a chromatic difference of power, but mainly from the wavelength dependence of the EE.
PubMed: 37525263
DOI: 10.1186/s40662-023-00350-5 -
Psychoneuroendocrinology Jul 2023Stress before conception and during pregnancy is associated with less favorable maternal and child health. Alterations in prenatal cortisol levels may serve as a central... (Review)
Review
BACKGROUND
Stress before conception and during pregnancy is associated with less favorable maternal and child health. Alterations in prenatal cortisol levels may serve as a central biological pathway linking stress to adverse maternal and child health. Research examining associations between maternal stress from childhood through pregnancy and prenatal cortisol has not been comprehensively reviewed.
METHOD
The current scoping review of 48 papers synthesizes studies reporting on associations between stress before conception and during pregnancy with maternal cortisol in pregnancy. Eligible studies measured childhood, the proximal preconception period, pregnancy, or lifetime stress based on stress exposures or appraisals and measured cortisol in saliva or hair during pregnancy.
RESULTS
Higher maternal childhood stress was associated with higher cortisol awakening responses and alterations in typical pregnancy-specific changes in diurnal cortisol patterns across studies. In contrast, most studies of preconception and prenatal stress reported null associations with cortisol and those reporting significant effects were inconsistent in direction. A few studies found that the associations between stress and cortisol during pregnancy varied as a function of several moderators including social support and environmental pollution.
CONCLUSIONS
Although many studies have evaluated effects of maternal stress on prenatal cortisol, this scoping review is the first to synthesize existing literature on this topic. The association between stress before conception and during pregnancy and prenatal cortisol may depend on the developmental timing of stress and several moderators. Maternal childhood stress was more consistently associated with prenatal cortisol than proximal preconception or pregnancy stress. We discuss methodological and analytic factors that may contribute to mixed findings.
Topics: Pregnancy; Female; Child; Humans; Hydrocortisone; Prenatal Exposure Delayed Effects; Fertilization; Mothers; Pregnancy Complications; Saliva; Stress, Psychological; Pituitary-Adrenal System; Hypothalamo-Hypophyseal System
PubMed: 37119659
DOI: 10.1016/j.psyneuen.2023.106115 -
Biomedicine & Pharmacotherapy =... Sep 2023Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K...
Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K antagonists (i.e., acenocoumarol, warfarin) the interindividual variability of DOACs is significant, and may be related to adverse drug reaction occurrence or drug inefficacy, namely hemorrhagic or thromboembolic events. Since there is not a consistent analytic practice to monitor the anticoagulant activity of DOACs, previously reported polymorphisms in genes coding for proteins responsible for the activation, transport, or metabolism of DOACs were studied. The study population comprised 60 healthy volunteers, who completed two randomized, crossover bioequivalence clinical trials between two different rivaroxaban formulations. The effect of food, sex, biogeographical origin and 55 variants (8 phenotypes and 47 single nucleotide polymorphisms) in drug metabolizing enzyme genes (such as CYP2D6, CYP2C9, NAT2) and transporters (namely, ABCB1, ABCG2) on rivaroxaban pharmacokinetics was tested. Individuals dosed under fasting conditions presented lower t (2.21 h vs 2.88 h, β = 1.19, R =0.342, p = 0.012) compared to fed volunteers. NAT2 slow acetylators presented higher AUC corrected by dose/weight (AUC/DW; 8243.90 vs 7698.20 and 7161.25 h*ng*mg /ml*kg, β = 0.154, R =0.250, p = 0.044), higher C/DW (1070.99 vs 834.81 and 803.36 ng*mg /ml*kg, β = 0.245, R =0.320, p = 0.002), and lower t (2.63 vs 3.19 and 4.15 h, β = -0.346, R =0.282, p = 0.047) than NAT2 rapid and intermediate acetylators. No other association was statistically significant. Thus, slow NAT2 appear to have altered rivaroxaban pharmacokinetics, increasing AUC and C. Nonetheless, further research should be conducted to verify NAT2 involvement on rivaroxaban pharmacokinetics and to determine its clinical significance.
Topics: Humans; Rivaroxaban; Healthy Volunteers; Anticoagulants; Polymorphism, Single Nucleotide; Phenotype; Arylamine N-Acetyltransferase
PubMed: 37385211
DOI: 10.1016/j.biopha.2023.115058 -
Neuropharmacology Oct 2023The inbred mouse strain, BTBR TItpr3/J (BTBR), possesses neuronal and circuit abnormalities that underlie atypical behavioral profiles resembling the major symptoms of...
The inbred mouse strain, BTBR TItpr3/J (BTBR), possesses neuronal and circuit abnormalities that underlie atypical behavioral profiles resembling the major symptoms of human autism spectrum disorder (ASD). Forebrain serotonin (5-HT) transmission has been implicated in ASD-related behavioral alterations. In this study, we assessed 5-HT signals and the functional responsiveness in BTBR mice compared to standard C57BL/6J (B6) control mice to elucidate how 5-HT alterations contribute to behavioral abnormalities in BTBR mice. A lower number of 5-HT neurons in the median raphe, but not in the dorsal raphe, was observed in male and female BTBR mice. Acute systemic injection of buspirone, a 5-HT1A receptor agonist, induced c-Fos in several brain regions in both B6 and BTBR mice; however, blunted c-Fos induction in BTBR mice was documented in the cingulate cortex, basolateral amygdala (BLA), and ventral hippocampus (Hipp). Decreased c-Fos responses in these regions are associated with a lack of buspirone effects on anxiety-like behavior in BTBR mice. Analysis of mRNA expression following acute buspirone injection indicated that 5HTR1a gene downregulation (or upregulation) occurred in the BLA and Hipp of B6 mice, respectively, but not BTBR mice. The mRNA expression of factors associated with neurogenesis or the pro-inflammatory state was not consistently altered by acute buspirone injection. Therefore, 5-HT responsivity via 5-HT1A receptors in the BLA and Hipp are linked to anxiety-like behavior, in which circuits are disrupted in BTBR mice. Other distinct 5-HT circuits from the BLA and Hipp that regulate social behavior are restricted but preserved in BTBR mice.
Topics: Humans; Mice; Male; Female; Animals; Autistic Disorder; Autism Spectrum Disorder; Buspirone; Serotonin; Mice, Inbred C57BL; Mice, Inbred Strains; Social Behavior; Disease Models, Animal; Phenotype; RNA, Messenger
PubMed: 37301467
DOI: 10.1016/j.neuropharm.2023.109634 -
Biological Psychiatry. Cognitive... May 2024There has been renewed interest in the use of 3,4-methylenedioxy-methamphetamine (MDMA) and serotonergic psychedelics in the treatment of multiple psychiatric disorders.... (Review)
Review
There has been renewed interest in the use of 3,4-methylenedioxy-methamphetamine (MDMA) and serotonergic psychedelics in the treatment of multiple psychiatric disorders. Many of these compounds are known to produce prosocial effects, but how these effects relate to therapeutic efficacy and the extent to which prosocial effects are unique to a particular drug class is unknown. In this article, we present a narrative overview and compare evidence for the prosocial effects of MDMA and serotonergic psychedelics to elucidate shared mechanisms that may underlie the therapeutic process. We discuss 4 categories of prosocial effects: altered self-image, responses to social reward, responses to negative social input, and social neuroplasticity. While both categories of drugs alter self-perception, MDMA may do so in a way that is less related to the experience of mystical-type states than serotonergic psychedelics. In the case of social reward, evidence supports the ability of MDMA to enhance responses and suggests that serotonergic psychedelics may also do so, but more research is needed in this area. Both drug classes consistently dampen reactivity to negative social stimuli. Finally, preclinical evidence supports the ability of both drug classes to induce social neuroplasticity, promoting adaptive rewiring of neural circuits, which may be helpful in trauma processing. While both MDMA and serotonergic psychedelics produce prosocial effects, they differ in the mechanisms through which they do this. These differences affect the types of psychosocial interventions that may work best with each compound.
Topics: Humans; N-Methyl-3,4-methylenedioxyamphetamine; Hallucinogens; Social Behavior; Serotonin Agents; Reward; Neuronal Plasticity; Self Concept; Animals
PubMed: 38341085
DOI: 10.1016/j.bpsc.2024.02.001 -
BMC Medicine Nov 2023The early life stage is critical for the gut microbiota establishment and development. We aimed to investigate the lifelong impact of famine exposure during early life... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The early life stage is critical for the gut microbiota establishment and development. We aimed to investigate the lifelong impact of famine exposure during early life on the adult gut microbial ecosystem and examine the association of famine-induced disturbance in gut microbiota with type 2 diabetes.
METHODS
We profiled the gut microbial composition among 11,513 adults (18-97 years) from three independent cohorts and examined the association of famine exposure during early life with alterations of adult gut microbial diversity and composition. We performed co-abundance network analyses to identify keystone taxa in the three cohorts and constructed an index with the shared keystone taxa across the three cohorts. Among each cohort, we used linear regression to examine the association of famine exposure during early life with the keystone taxa index and assessed the correlation between the keystone taxa index and type 2 diabetes using logistic regression adjusted for potential confounders. We combined the effect estimates from the three cohorts using random-effects meta-analysis.
RESULTS
Compared with the no-exposed control group (born during 1962-1964), participants who were exposed to the famine during the first 1000 days of life (born in 1959) had consistently lower gut microbial alpha diversity and alterations in the gut microbial community during adulthood across the three cohorts. Compared with the no-exposed control group, participants who were exposed to famine during the first 1000 days of life were associated with consistently lower levels of keystone taxa index in the three cohorts (pooled beta - 0.29, 95% CI - 0.43, - 0.15). Per 1-standard deviation increment in the keystone taxa index was associated with a 13% lower risk of type 2 diabetes (pooled odds ratio 0.87, 95% CI 0.80, 0.93), with consistent results across three individual cohorts.
CONCLUSIONS
These findings reveal a potential role of the gut microbiota in the developmental origins of health and disease (DOHaD) hypothesis, deepening our understanding about the etiology of type 2 diabetes.
Topics: Adult; Humans; Middle Aged; China; Cohort Studies; Diabetes Mellitus, Type 2; East Asian People; Famine; Gastrointestinal Microbiome; Microbiota; Prenatal Exposure Delayed Effects; Starvation; Adolescent; Young Adult; Aged; Aged, 80 and over
PubMed: 37907866
DOI: 10.1186/s12916-023-03123-y -
Revista Espanola de Enfermedades... Oct 2023A 27-year-old Nepalese male presented with recurrent abdominal pain accompanied by a lower stool consistency over the past 2 years. These episodes occurred several times...
A 27-year-old Nepalese male presented with recurrent abdominal pain accompanied by a lower stool consistency over the past 2 years. These episodes occurred several times a year, lasting 1 to 2 weeks, and resolved spontaneously, after adjustment of diet and/or medication for symptomatic control (e.g., antispasmodics, probiotics). Over the last year, the patient had undergone an extensive diagnostic investigation, which revealed no alterations in the laboratory workup, abdominal scan, esophagogastroduodenoscopy, and colonoscopy, including biopsies of the duodenum, and colon, so the symptoms have been attributed to irritable bowel syndrome. However, the symptoms had become more frequent, so the patient was referred to our gastroenterology department. We repeated and extended the work-up. Laboratory investigations showed an elevated erythrocyte sedimentation rate and faecal calprotectin. The remaining laboratory as well an extensive stool workup for infection were unremarkable. Esophagogastroduodenoscopy and ileocolonoscopy were normal. Small bowel capsule endoscopy revealed jejunal mucosa with lymphangiectasias, pseudopolypoids formations and superficial longitudinal ulcers, these findings were corroborated by the double-balloon enteroscopy, and biopsies showed marked architectural distortion, chronic inflammatory infiltrate, and an epithelioid granuloma. The clinical, endoscopic, biochemical, and histological findings were consistent with isolated jejunal Crohn's disease. The patient started adalimumab with complete remission after one year. We present this case given its exuberant endoscopic findings and due to the difficulty in making the diagnosis due to its rarity, location, and unspecific presentation.
PubMed: 36562531
DOI: 10.17235/reed.2022.9423/2022