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BioRxiv : the Preprint Server For... Jun 2024ECHS1 Deficiency (ECHS1D) is a rare and devastating pediatric disease that currently has no defined treatments. This disorder results from missense loss-of-function...
ECHS1 Deficiency (ECHS1D) is a rare and devastating pediatric disease that currently has no defined treatments. This disorder results from missense loss-of-function mutations in the gene that result in severe developmental delays, encephalopathy, hypotonia, and early death. ECHS1 enzymatic activity is necessary for the beta-oxidation of fatty acids and the oxidation of branched-chain amino acids within the inner mitochondrial matrix. The pathogenesis of disease remains unknown, however it is hypothesized that disease is driven by an accumulation of toxic metabolites from impaired valine oxidation. To expand our knowledge on disease mechanisms, a novel mouse model of ECHS1D was generated that possesses a disease-associated knock-in (KI) allele and a knock-out (KO) allele. To investigate the behavioral phenotype, a battery of testing was performed at multiple time points, which included assessments of learning, motor function, endurance, sensory responses, and anxiety. Neurological abnormalities were assessed using wireless telemetry EEG recordings, pentylenetetrazol (PTZ) seizure induction, and immunohistochemistry. Metabolic perturbations were measured within the liver, serum, and brain using mass spectrometry and magnetic resonance spectroscopy. To test disease mechanisms, mice were subjected to disease pathway stressors and then survival, body weight gain, and epilepsy were assessed. Mice containing KI/KI or KI/KO alleles were viable with normal development and survival, and the presence of KI and KO alleles resulted in a significant reduction in ECHS1 protein. ECHS1D mice displayed reduced exercise capacity and pain sensation. EEG analysis revealed increased slow wave power that was associated with perturbations in sleep. ECHS1D mice had significantly increased epileptiform EEG discharges, and were sensitive to seizure induction, which resulted in death of 60% of ECHS1D mice. Under basal conditions, brain structure was grossly normal, although histological analysis revealed increased microglial activation in aged ECHS1D mice. Increased dietary valine only affected ECHS1D mice, which significantly exacerbated seizure susceptibility and resulted in death. Lastly, acute inflammatory challenge drove regression and early lethality in ECHS1D mice. In conclusion, we developed a novel model of ECHS1D that may be used to further knowledge on disease mechanisms and to develop therapeutics. Our data suggests altered metabolic signaling and inflammation may contribute to epilepsy in ECHS1D, and these alterations may be attributed to impaired valine metabolism.
PubMed: 38915588
DOI: 10.1101/2024.06.13.598697 -
Environment International Jun 2024Childhood exposure to polycyclic aromatic hydrocarbons (PAHs) or lead (Pb) is associated with epigenetic modifications. However, the effects of their co-exposures on...
Associations of co-exposure to polycyclic aromatic hydrocarbons and lead (Pb) with IGF1 methylation in peripheral blood of preschool children from an e-waste recycling area.
BACKGROUND
Childhood exposure to polycyclic aromatic hydrocarbons (PAHs) or lead (Pb) is associated with epigenetic modifications. However, the effects of their co-exposures on IGF1 (Insulin-like growth factor 1) methylation and the potential role in child physical growth are unclear.
METHODS
From our previous children study (N = 238, ages of 3-6), 75 children with higher total concentrations of urinary ten hydroxyl PAH metabolites (∑OH-PAHs) from an e-waste recycling area, Guiyu, and 75 with lower ∑OH-PAHs from Haojiang (reference area) were included. Pb and IGF1 P2 promoter methylation in peripheral blood were also measured. Multivariable linear regression analyses were performed to estimate individual associations, overall effects and interactions of co-exposure to OH-PAHs and Pb on IGF1 methylation were further explored using Bayesian kernel machine regression.
RESULTS
Methylation of IGF1 (CG-232) was lower (38.00 vs. 39.74 %, P < 0.001), but of CG-207 and CG-137 were higher (59.94 vs. 58.41 %; 57.60 vs. 56.28 %, both P < 0.05) in exposed children than the reference. The elevated urinary 2-OHPhe was associated with reduced methylation of CG-232 (B = -0.051, 95 % CI: -0.096, -0.005, P < 0.05), whereas blood Pb was positively associated with methylation of CG-108 (B = 0.106, 95 %CI: 0.013, 0.199, P < 0.05), even after full adjustment. Methylations of CG-224 and 218 significantly decreased when all OH-PAHs and Pb mixtures were set at 35th - 40th and 45th - 55th percentile compared to when all fixed at 50th percentile. There were bivariate interactions of co-exposure to the mixtures on methylations of CG-232, 224, 218, and 108. Methylations correlated with height, weight, were observed in the exposed children.
CONCLUSIONS
Childhood co-exposure to high PAHs and Pb from the e-waste may be associated with IGF1 promoter methylation alterations in peripheral blood. This, in turn, may interrupt the physical growth of preschool children.
PubMed: 38908275
DOI: 10.1016/j.envint.2024.108833 -
PloS One 2024It is well known that maternal diet affects the development of offspring. Herein, the relationship between maternal intake of fermented foods during pregnancy and...
BACKGROUND
It is well known that maternal diet affects the development of offspring. Herein, the relationship between maternal intake of fermented foods during pregnancy and offspring development was investigated.
METHODS
The diet of 103,060 pregnant women at >4 months of gestation who were enrolled in the Japan Environment and Children's Study was analyzed. Their intake levels of fermented soybeans (miso and natto), yogurt, and cheese were investigated. The developmental status of the offspring at 3 years of age was assessed using the Ages and Stages Questionnaires (ASQ-3). Multivariable logistic regression analysis was performed to determine the risk of maternal intake levels of the fermented foods associated with subsequent developmental delay in the offspring.
RESULTS
Intake of cheese was associated with a reduced risk of child developmental delay in all intake level groups from the second quartile onward. Intakes of miso and yogurt were associated with a reduced risk of developmental delay in communication skills in the fourth quartile. There was no association between intake of natto and developmental delay.
CONCLUSION
Maternal consumption of fermented foods during pregnancy may reduce the risk of later developmental delay in offspring. It is therefore important to review the mother's diet for fermented foods during pregnancy. However, further studies are warranted to evaluate the factors influencing the association between diet and offspring development.
Topics: Female; Humans; Japan; Pregnancy; Child, Preschool; Fermented Foods; Adult; Male; Child Development; Diet; Surveys and Questionnaires; Maternal Nutritional Physiological Phenomena
PubMed: 38905296
DOI: 10.1371/journal.pone.0305535 -
Gut Microbes 2024The gut microbiota, comprising trillions of diverse microorganisms inhabiting the intestines of animals, forms a complex and indispensable ecosystem with profound... (Review)
Review
The gut microbiota, comprising trillions of diverse microorganisms inhabiting the intestines of animals, forms a complex and indispensable ecosystem with profound implications for the host's well-being. Its functions include contributing to developing the host's immune response, aiding in nutrient digestion, synthesizing essential compounds, acting as a barrier against pathogen invasion, and influencing the development or regression of various pathologies. The dietary habits of the host directly impact this intricate community of gut microbes. Diet influences the composition and function of the gut microbiota through alterations in gene expression, enzymatic activity, and metabolome. While the impact of diet on gut ecology is well-established, the investigation into the relationship between dietary consumption and microbial genotypic diversity has been limited. This review provides an overview of the relationship between diet and gut microbiota, emphasizing the impact of host nutrition on both short- and long-term evolution in the mammalian gut. It is evident that the evolution of the gut microbiota occurs even on short timescales through the acquisition of novel mutations, within the gut bacteria of individual hosts. Consequently, we discuss the importance of considering alterations in bacterial genomic diversity when analyzing microbiota-dependent effects on host physiology. Future investigations into the various microbiota-related traits shall greatly benefit from a deeper understanding of commensal bacterial evolutionary adaptation.
Topics: Gastrointestinal Microbiome; Animals; Diet; Humans; Bacteria; Symbiosis; Biological Evolution; Host Microbial Interactions
PubMed: 38904092
DOI: 10.1080/19490976.2024.2369337 -
Frontiers in Pediatrics 2024West syndrome (WS) is a devastating epileptic encephalopathy with onset in infancy and early childhood. It is characterized by clustered epileptic spasms, developmental...
BACKGROUND
West syndrome (WS) is a devastating epileptic encephalopathy with onset in infancy and early childhood. It is characterized by clustered epileptic spasms, developmental arrest, and interictal hypsarrhythmia on electroencephalogram (EEG). Hypsarrhythmia is considered the hallmark of WS, but its visual assessment is challenging due to its wide variability and lack of a quantifiable definition. This study aims to analyze the EEG patterns in WS and identify computational diagnostic biomarkers of the disease.
METHOD
Linear and non-linear features derived from EEG recordings of 31 WS patients and 20 age-matched controls were compared. Subsequently, the correlation of the identified features with structural and genetic abnormalities was investigated.
RESULTS
WS patients showed significantly elevated alpha-band activity (0.2516 vs. 0.1914, < 0.001) and decreased delta-band activity (0.5117 vs. 0.5479, < 0.001), particularly in the occipital region, as well as globally strengthened theta-band activity (0.2145 vs. 0.1655, < 0.001) in power spectrum analysis. Moreover, wavelet-bicoherence analysis revealed significantly attenuated cross-frequency coupling in WS patients. Additionally, bi-channel coherence analysis indicated minor connectivity alterations in WS patients. Among the four non-linear characteristics of the EEG data (i.e., approximate entropy, sample entropy, permutation entropy, and wavelet entropy), permutation entropy showed the most prominent global reduction in the EEG of WS patients compared to controls (1.4411 vs. 1.5544, < 0.001). Multivariate regression results suggested that genetic etiologies could influence the EEG profiles of WS, whereas structural factors could not.
SIGNIFICANCE
A combined global strengthening of theta activity and global reduction of permutation entropy can serve as computational EEG biomarkers for WS. Implementing these biomarkers in clinical practice may expedite diagnosis and treatment in WS, thereby improving long-term outcomes.
PubMed: 38903771
DOI: 10.3389/fped.2024.1406772 -
Frontiers in Neuroscience 2024Recently a broad range of phenotypic abnormalities related to the neurodevelopmental and neurodegenerative disorder NEDAMSS (Neurodevelopmental Disorder with Regression,... (Review)
Review
Recently a broad range of phenotypic abnormalities related to the neurodevelopmental and neurodegenerative disorder NEDAMSS (Neurodevelopmental Disorder with Regression, Abnormal Movements, Loss of Speech, and Seizures) have been associated with rare single-nucleotide polymorphisms (SNPs) or insertion and deletion variants (Indel) in the intron-less gene IRF2BPL. Up to now, 34 patients have been identified through whole exome sequencing carrying different heterozygous pathogenic variants spanning the intron-less gene from the first polyglutamine tract at the N-terminus to the C3HC4 RING domain of the C-terminus of the protein. As a result, the phenotypic spectrum of the patients is highly heterogeneous and ranges from abnormal neurocognitive development to severe neurodegenerative courses with developmental and seizure-related encephalopathies. While the treatment of IRF2BPL-related disorders has focused on alleviating the patient's symptoms by symptomatic multidisciplinary management, there has been no prospect of entirely relieving the symptoms of the individual patients. Yet, the recent advancement of CRISPR-Cas9-derived gene editing tools, leading to the generation of base editors (BEs) and prime editors (PEs), provide an encouraging new therapeutic avenue for treating NEDAMSS and other neurodevelopmental and neurodegenerative diseases, which contain SNPs or smaller Indels in post-mitotic cell populations of the central nervous system, due to its ability to generate site-specific DNA sequence modifications without creating double-stranded breaks, and recruiting the non-homologous DNA end joining repair mechanism.
PubMed: 38903604
DOI: 10.3389/fnins.2024.1426177 -
Parasites & Vectors Jun 2024Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonosis caused by the SFTS virus (SFTSV). Understanding the prevalence of SFTSV RNA in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonosis caused by the SFTS virus (SFTSV). Understanding the prevalence of SFTSV RNA in humans, vertebrate hosts and ticks is crucial for SFTS control.
METHODS
A systematic review and meta-analysis were conducted to determine the prevalence of SFTSV RNA in humans, vertebrate hosts and questing ticks. Nine electronic databases were searched for relevant publications, and data on SFTSV RNA prevalence were extracted. Pooled prevalence was estimated using a random effects model. Subgroup analysis and multivariable meta-regression were performed to investigate sources of heterogeneity.
RESULTS
The pooled prevalence of SFTSV RNA in humans was 5.59% (95% confidence interval [CI] 2.78-9.15%) in those in close contact (close contacts) with infected individuals (infected cases) and 0.05% (95% CI 0.00-0.65%) in healthy individuals in endemic areas. The SFTSV infection rates in artiodactyls (5.60%; 95% CI 2.95-8.96%) and carnivores (6.34%; 95% CI 3.27-10.23%) were higher than those in rodents (0.45%; 95% CI 0.00-1.50%). Other animals, such as rabbits, hedgehogs and birds, also played significant roles in SFTSV transmission. The genus Haemaphysalis was the primary transmission vector, with members of Ixodes, Dermacentor, and Amblyomma also identified as potential vectors. The highest pooled prevalence was observed in adult ticks (1.03%; 95% CI 0.35-1.96%), followed by nymphs (0.66%; 95% CI 0.11-1.50%) and larvae (0.01%; 95% CI 0.00-0.46%). The pooled prevalence in ticks collected from endemic areas (1.86%; 95% CI 0.86-3.14%) was higher than that in ticks collected in other regions (0.41%; 95% CI 0.12-0.81%).
CONCLUSIONS
Latent SFTSV infections are present in healthy individuals residing in endemic areas, and close contacts with SFTS cases are at a significantly higher risk of infection. The type of animal is linked to infection rates in vertebrate hosts, while infection rates in ticks are associated with the developmental stage. Further research is needed to investigate the impact of various environmental factors on SFTSV prevalence in vertebrate hosts and ticks.
Topics: Animals; Humans; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Ticks; Vertebrates; Prevalence; RNA, Viral
PubMed: 38902842
DOI: 10.1186/s13071-024-06341-2 -
BMC Public Health Jun 2024Responsive feeding, when caregivers attend to children's signals of hunger and satiation and respond in an emotionally supportive and developmentally appropriate way, is...
BACKGROUND
Responsive feeding, when caregivers attend to children's signals of hunger and satiation and respond in an emotionally supportive and developmentally appropriate way, is associated with the development of healthy eating behaviors, improved diet quality, and healthy weight status for children. However, gaps in the literature remain on how factors, such as maternal depressive symptoms and child temperament, influence feeding interactions.
METHODS
This longitudinal secondary data analysis explored the association between maternal depressive symptom trajectory and child temperament with maternal feeding practices in women with obesity who participated in a prenatal lifestyle intervention trial. Mothers self-reported depressive symptoms at baseline, 35 weeks gestation, and 6, 12, and 18 months postpartum. At 18- and 24-months postpartum, mothers completed self-reported assessments of feeding practices and child temperament and completed in-home video-recorded meals with their child, coded using the Responsiveness to Child Feeding Cues Scale. We used group-based trajectory modeling to identify distinct trajectories of depressive symptoms and generalized regressions to assess the association between symptom trajectory group and feeding. We also explored interactions between depressive symptoms and child temperament.
RESULTS
Three distinct trajectories of depressive symptoms were identified: No-Minimal and Decreasing, Mild-Moderate and Stable, and Moderate-Severe and Stable. At 18-months, when compared to the No-Minimal and Decreasing group, membership in the Moderate-Severe and Stable group was associated with higher observed responsiveness to child satiation cues ([Formula: see text] =2.3, 95%CI = 0.2, 4.4) and lower self-reported pressure to eat ([Formula: see text]=-0.4, 95%CI= -0.7, 0.0). When compared to the No-Minimal and Decreasing group, membership in the Mild-Moderate and Stable group was associated with higher self-reported restriction ([Formula: see text] =0.4, 95%CI = 0.0,0.7). The associations between trajectory group membership and feeding practices did not reach statistical significance at 24 months. Associations between depressive symptoms and restriction were moderated by child effortful control at 18 months [Formula: see text]) and surgency at 24 months [Formula: see text]).
CONCLUSION
A Moderate-Severe and Stable depressive symptom trajectory was associated with more responsive feeding practices and a Mild-Moderate and Stable trajectory was associated with higher restrictive feeding. Preliminary evidence suggests that depressive symptoms impact mothers' ability to match their use of restriction to the temperamental needs of their child.
Topics: Humans; Female; Depression; Feeding Behavior; Adult; Longitudinal Studies; Mothers; Infant; Temperament; Pregnancy; Mother-Child Relations; Obesity; Male
PubMed: 38898428
DOI: 10.1186/s12889-024-19110-8 -
Seizure May 2024People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM)...
INTRODUCTION
People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM) to PwID is driven by trials excluding them. Levetiracetam (LEV) is a first-line ASM in the UK. Concerns exist regarding LEV's behavioural and psychological adverse effects, particularly in PwID. There is no high-quality evidence comparing effectiveness and adverse effects in PwID to those without, prescribed LEV.
METHODS
Pooled casenote data for patients prescribed LEV (2000-2020) at 18 UK NHS Trusts were analysed. Demographics, starting and maximum dose, adverse effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed.
RESULTS
173 PwID (mild 53 M/P 120) were compared to 200 without ID. Mean start and maximum dose were similar across all groups. PwID (Mild & M/P) were less likely to withdraw from treatment (P = 0.036). No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in LEV's efficacy i.e. >50 % seizure reduction. Significant association emerged between ID severity and psychiatric adverse effects (P = 0.035). More irritability (14.2 %) and aggression (10.8 %) were reported in M/P PwID.
CONCLUSION
PwID and epilepsy have high rates of premature mortality, comorbidities, treatment resistance and polypharmacy but remain poorly researched for ASM use. This is the largest studied cohort of PwID trialled on LEV compared to general population controls. Findings support prescribing of LEV for PwID as a first-line ASM.
PubMed: 38897161
DOI: 10.1016/j.seizure.2024.05.010 -
Frontiers in Public Health 2024Internet addiction and depressive symptoms are common mental health problems in adolescents. Due to the comorbidity of Internet addiction and depressive symptoms, their...
OBJECTIVE
Internet addiction and depressive symptoms are common mental health problems in adolescents. Due to the comorbidity of Internet addiction and depressive symptoms, their mutual relationship influences their developmental trajectories over time. Thus, this study aimed to identify the joint trajectories of Internet addiction and depressive symptoms, and examined the individual, family, and school antecedents of these trajectories among Chinese adolescents.
METHODS
Using a battery of self-report scales, three waves of data collection were conducted in a Chinese adolescent sample ( = 1,301). The co-developmental trajectories of Internet addiction and depressive symptoms were extracted by adopting parallel-process latent class growth modeling (PPLCGM). Multinomial logistic regression was performed to assess predictive factors.
RESULTS
Four unique joint trajectory classes were detected: the Health Group ( = 912, 70.1%), Comorbidity-Worsening Group ( = 85, 6.5%), Asymptomatic-Comorbid Risk Group ( = 148, 11.4%), and Prominent Depressive Symptoms-Remission Group ( = 156, 12.0%). Individual, family, and school factors (e.g., gender, positive youth development, family function, academic performance) significantly predicted the membership in these distinct co-developmental trajectories.
CONCLUSION
Our findings illustrate that the joint development of Internet addiction and depressive symptoms among adolescents presents a heterogeneous distribution, which could better inform prevention and intervention strategies since each co-developmental trajectory may represent unique experience for adolescents who need targeted treatment. Various individual, family, and school factors are important predictors that play different roles in distinguishing the joint trajectories of Internet addiction and depressive symptoms during this critical developmental transition period.
Topics: Humans; Adolescent; Female; Male; Depression; Internet Addiction Disorder; China; Comorbidity; Risk Factors; Self Report; Internet
PubMed: 38894983
DOI: 10.3389/fpubh.2024.1374762