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AIM: We aimed to investigate the long-term impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D). MATERIALS AND METHODS: In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP-1 RA treatment and those who did not receive glucose-lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event. RESULTS: After propensity score matching, the study included 12,123 individuals in each group. GLP-1 RA treatment was associated with a significantly lower risk of all-cause mortality (hazard ratio 0.23; 95% confidence interval 0.15-0.34) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation (all p < 0.05). GLP-1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions. CONCLUSIONS: In this large observational study, GLP-1 RAs showed long-term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP-1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population.
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Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.
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Transtornos da Impressão Genômica , Síndrome de Silver-Russell , Recém-Nascido , Feminino , Gravidez , Humanos , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patologia , Metilação de DNA/genética , Fenótipo , Dissomia Uniparental/genéticaRESUMO
AIMS: To analyse the genome-wide association study (GWAS) data of patients with type 1 diabetes mellitus (T1D) in order to develop a risk score for the genetic effects on T1D risk and age at diagnosis in the Taiwanese population. MATERIALS AND METHODS: We selected 610 patients with T1D and 2511 healthy individuals from an electronic medical record database of more than 300 000 individuals with genetic information, analysed their GWAS data, and developed a polygenic risk score (PRS). RESULTS: The PRS, based on 149 selected single-nucleotide polymorphisms, could effectively predict T1D risk. A PRS increase was associated with increased T1D risk (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.72-2.55). Moreover, a 1-unit increase in standardized T1D PRS decreased the age at diagnosis by 0.74 years. Combined PRS and human leukocyte antigen (HLA) DQA1*03:02-DQA1*05:01 genotypes could accurately predict T1D risk. In multivariable models, HLA variants and PRS were independent risk factors for T1D risk (OR 3.76 [95% CI 1.54-9.16] and 1.71 [95% CI 1.37-2.13] for HLA DQA1*03:02-DQA1*05:01 and PRS, respectively). In a limited study population of those aged ≤18 years, PRS remained significantly associated with T1D risk. The association between T1D PRS and age at diagnosis was more obvious among males and patients aged ≤18 years. CONCLUSIONS: Polygenic risk score and HLA variations enable personalized risk estimates, enhance newborn screening efficiency for ketoacidosis prevention, and addresses the gap in data on T1D prediction in isolated Asian populations.
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Diabetes Mellitus Tipo 1 , Masculino , Recém-Nascido , Humanos , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Fatores de Risco , Medição de RiscoRESUMO
Long non-coding RNA steroid receptor RNA activators (LncRNA SRAs) are implicated in the ß-cell destruction of Type 1 diabetes mellitus (T1D), but functional association remains poorly understood. Here, we aimed to verify the role of LncRNA SRA regulation in ß-cells. LncRNA SRAs were highly expressed in plasma samples and peripheral blood mononuclear cells (PBMCs) from T1D patients. LncRNA SRA was strongly upregulated by high-glucose treatment. LncRNA SRA acts as a microRNA (miR)-146b sponge through direct sequence-structure interactions. Silencing of lncRNA SRA increased the functional genes of Tregs, resulting in metabolic reprogramming, such as decreased lactate levels, repressed lactate dehydrogenase A (LDHA)/phosphorylated LDHA (pLDHA at Tyr10) expression, decreased reactive oxygen species (ROS) production, increased ATP production, and finally, decreased ß-cell apoptosis in vitro. There was a positive association between lactate level and hemoglobin A1c (HbA1c) level in the plasma from patients with T1D. Recombinant human interleukin (IL)-2 treatment repressed lncRNA SRA expression and activity in ß-cells. Higher levels of lncRNA-SRA/lactate in the plasma are associated with poor regulation in T1D patients. LncRNA SRA contributed to T1D pathogenesis through the inhibition of miR-146b in ß-cells, with activating signaling transduction of interleukin-1 receptor-associated kinase 1 (IRAK1)/LDHA/pLDHA. Taken together, LncRNA SRA plays a critical role in the function of ß-cells.
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Proteínas de Transporte/genética , Diabetes Mellitus Tipo 1/patologia , Células Secretoras de Insulina/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Adolescente , Antagomirs/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Retroalimentação Fisiológica/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Hemoglobinas Glicadas/análise , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , L-Lactato Desidrogenase/metabolismo , Ácido Láctico/metabolismo , Masculino , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , RNA Longo não Codificante/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Adulto JovemRESUMO
RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible.
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Deficiências do Desenvolvimento/genética , Cardiopatias Congênitas/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Síndrome de Costello/genética , Síndrome de Costello/fisiopatologia , Estudos Transversais , Deficiências do Desenvolvimento/classificação , Deficiências do Desenvolvimento/patologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatologia , Fácies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/fisiopatologia , Feminino , Cardiopatias Congênitas/fisiopatologia , Comunicação Interatrial/genética , Comunicação Interatrial/fisiopatologia , Humanos , Síndrome LEOPARD/genética , Síndrome LEOPARD/fisiopatologia , Masculino , Síndrome de Noonan/fisiopatologia , Estudos Retrospectivos , Proteínas ras/genéticaRESUMO
BACKGROUND/PURPOSE: Birth defects (BDs) are main causes of mortality and disability in infants and children. The aims of this study were to analyze the prevalence, types and risk factors of BDs in Taiwan. METHODS: Data of all births (including live and stillbirths), types, characteristics, and associated risk factors of BDs were obtained from the National Birth Registry and National Health Insurance Research Data base in Taiwan between 2005 and 2014. Birth defects were coded according to International Classification of Diseases 9th Revision-Clinical Modification codes 740-759. RESULTS: A total of 55,299 infants were diagnosed as having BDs among 2,033,004 births. The prevalence of BDs was 271.66 per 10,000 births. The prevalence of BDs did not change significantly between 2005 and 2014, there was a higher birth rate and lower BDs in 2012 (year of dragon) in Taiwan. The most common type of BDs was cardiovascular abnormalities, and ventricular septal defect was the most common disease. Extreme maternal age (<18 years or â§30 years), preterm, and low birth weight were associated with BDs. Maternal diseases associated with BDs included hypertension, cardiovascular diseases, renal diseases, genitourinary infections, anemia, mental disorders, and diabetes mellitus. CONCLUSION: The prevalence of BDs was 271.66 per 10,000 births. The most common types of BDs were cardiovascular abnormalities. If we can reduce maternal chronic diseases, we will decrease the prevalence of BDs.
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Anormalidades Congênitas/epidemiologia , Saúde Materna , Vigilância da População , Anormalidades Cardiovasculares/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Anormalidades Congênitas/etiologia , Bases de Dados Factuais , Feminino , Comunicação Interventricular/epidemiologia , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Idade Materna , Gravidez , Prevalência , Fatores de Risco , Taiwan/epidemiologiaRESUMO
OBJECTIVE: Longitudinal studies on neurobehavioral development in relation to prenatal and postnatal exposure to phthalates in school-age children and adolescents are limited. We investigated the association of prenatal and childhood phthalate exposure with the development of behavioral syndromes in 8-14-year-old children. METHOD: We recruited 430 pregnant women from 2000 to 2001 and followed their children at the ages of 2, 5, 8, 11, and 14 years, yielding 153 mother-child pairs in total. Urine samples from pregnant women in the third trimester and from children at 2-8 years of age were analyzed for the concentrations of seven urinary phthalate metabolites: monomethyl phthalate, monoethyl phthalate, monobutyl phthalate, monobenzyl phthalate (MBzP), and three di(2-ethylhexyl) phthalate (DEHP) metabolites, namely mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. Behavioral syndromes in children aged 8-14 years were assessed using the Child Behavior Checklist. We constructed mixed models to examine these associations after adjustments for potential covariates. RESULTS: Maternal urinary MEHP levels were associated with higher scores for internalizing problems (ßâ¯=â¯0.028, 95% confidence interval [CI]: 0.0004, 0.055) and externalizing problems (ßâ¯=â¯0.040, 95% CI: 0.013, 0.066). Associations of the maternal urinary sum of DEHP metabolite levels with delinquent behavior scores and externalizing problems scores were positive (ßâ¯=â¯0.035, 95% CI: 0.013, 0.057 for delinquent behavior; ßâ¯=â¯0.026, 95% CI: 0.001, 0.050 for externalizing problems). Furthermore, children's urinary MBzP levels were associated with higher scores for social problems (ßâ¯=â¯0.018, 95% CI: 0.001, 0.035). Similar patterns were observed for borderline and clinical ranges. CONCLUSION: Early-life exposure to phthalates may influence behavioral syndrome development in children. Future studies are needed to replicate these findings, and efforts to reduce exposures to phthalates during critical early life stages may be warranted.
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Comportamento , Poluentes Ambientais , Ésteres , Sistema Nervoso , Ácidos Ftálicos , Adolescente , Adulto , Comportamento/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Exposição Ambiental , Poluentes Ambientais/toxicidade , Poluentes Ambientais/urina , Ésteres/toxicidade , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Sistema Nervoso/efeitos dos fármacos , Ácidos Ftálicos/análise , Ácidos Ftálicos/toxicidade , Ácidos Ftálicos/urina , Gravidez , Problemas SociaisRESUMO
BACKGROUND: Insulin and insulin-like growth factor (IGF)-1 coupled with growth hormone helps control timing of sexual maturation. Mutations and variants in multiple genes are associated with development or reduced risk of central precocious puberty (CPP). METHODS: We assessed single nucleotide polymorphisms (SNPs) in the IGF-1, IGF-2, IGF-3, IGF-1 receptor (IGF1R), IGF-2 receptor (IGF2R), and IGF -binding protein 3 (IGFBP-3) genes, and their association with demographics and metabolic proteins in girls with CPP. Z-scores of height, weight, and body mass index (BMI) were calculated with the WHO reference growth standards for children. RESULTS: IGF-1 serum levels of CPP group exhibited a higher correlation with bone age, z-scores of height and weight, and luteinizing hormone (LH) than those of control group, regardless of BMI adjustment. In the CPP group, height was associated with IGF-2(3580), an adenine to guanine (A/G) SNP at position + 3580. BMI in the CPP group was associated with IGF-2(3580), IGF1R, and the combinations of [IGF-2(3580) + IGF2R], and [IGF-2(3580) + IGFBP-3]. Body weight in the CPP group was associated with the combination of [IGF-2(3580) + IGFBP-3] (p = 0.024). Weight and BMI were significantly associated with the combination of [IGF-2(3580) + IGF2R + IGFBP-3] in the CPP group. These associations were not significantly associated with z-scores of weight, height, or BMI. The distribution of these genotypes, haplotypes, and allele frequencies were similar between control and CPP groups. CONCLUSIONS: These known SNPs of these IGF-1 axis genes appear to play minor roles in the risk for development of CPP.
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Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like I/genética , Insulina/genética , Puberdade Precoce/genética , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 2/genética , Biomarcadores/sangue , Criança , Estudos de Coortes , Feminino , Estudos de Associação Genética/métodos , Humanos , Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Puberdade Precoce/sangue , Puberdade Precoce/diagnóstico , Receptor IGF Tipo 1/sangue , Receptor IGF Tipo 2/sangueRESUMO
BACKGROUND: Phthalates are widely used in industry, personal care products, and medications. Recent studies have suggested that phthalate exposure alters thyroid hormones. However, longitudinal studies concerning the association between phthalate exposure and thyroid function in children are scant. Therefore, we examined the association between pre- and postnatal phthalate exposure and thyroid function in children born in 2000-2001. METHODS: We studied 181 mother-child pairs in central Taiwan and followed-up the children from 2000 to 2009 at 2, 5, and 8 years old. We measured serum levels of thyroxine (T4), free T4, triiodothyronine (T3), and thyroid-stimulating hormone in children by using radioimmunoassay. We quantified seven phthalate metabolites, representing the five most commonly used phthalates, in maternal and child urine samples by using liquid chromatography-tandem mass spectrometry. The metabolites were monoethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) derived from di(2-ethylhexyl) phthalate (DEHP), monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobutyl phthalate (MBP), and monobenzyl phthalate (MBzP). We constructed a linear mixed model to examine these associations after adjustments for covariates. RESULTS: The T4 levels were inversely associated with maternal urinary MEHHP (ß = -0.028 [95% confidence interval (CI) = -0.051, -0.006]) and MEOHP (ß = -0.027 [-0.050, -0.003]), with similar T3 levels being observed in boys, even when the children exposure levels were considered spontaneously. In the girls, the free T4 levels were inversely associated with levels of maternal urinary MEP (ß = -0.042), maternal urinary MBzP (ß = -0.050), and children's urinary MEHP (ß = -0.027). CONCLUSIONS: Early life phthalate exposure was associated with decreased thyroid hormone levels in young children.
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Exposição Ambiental , Ácidos Ftálicos/urina , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Dietilexilftalato/análogos & derivados , Dietilexilftalato/urina , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos , Taiwan , Testes de Função Tireóidea , Adulto JovemRESUMO
BACKGROUND: Phthalate diesters are commonly used and have been well established as environmental endocrine disruptors. However, few studies have examined their effects on sex steroid hormones in children. We followed children over time to examine the association between pre- and post-natal phthalate exposure and sex steroid hormone levels at 2, 5, 8, and 11 years of age. METHODS: We recruited 430 pregnant women from central Taiwan from 2000 to 2001 and assessed their children at birth, 2, 5, 8, and 11 years of age. We studies children with at least one measurement for both phthalate and hormone levels during each any of the follow-up time point (n = 193). Estradiol, free testosterone, testosterone, and progesterone were measured from venous blood. Three monoesters of di-2-ethylhexyl phthalate (DEHP), mono-benzyl phthalate, mono-n-butyl phthalate, mono-ethyl phthalate, and mono-methyl phthalate were measured in maternal urine collected during the 3rd trimester and child urine collected at each follow-up point. The sum of mono-2-ethylhexyl phthalate (∑MEHP) was calculated by summing the concentrations of the three DEHP monoesters. Generalized estimating equation regression analysis with repeated measures was used to estimate associations between phthalate metabolites and hormone levels. RESULTS: After adjustment for potential confounders, maternal ∑MEHP level was associated with decreased levels of progesterone in girls (ß = -0.309 p = 0.001). The child ∑MEHP concentration was associated with decreased levels of progesterone for girls (ß = -0.194, p = 0.003) and with decreased levels of free testosterone for boys (ß = -0.124, p = 0.004). CONCLUSIONS: Early-life DEHP exposure may alter sex steroid hormones of children over time, which may pose potential reproductive health risks.
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Exposição Ambiental/efeitos adversos , Hormônios Esteroides Gonadais/sangue , Ácidos Ftálicos/toxicidade , Ácidos Ftálicos/urina , Efeitos Tardios da Exposição Pré-Natal , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Projetos Piloto , Gravidez , TaiwanRESUMO
OBJECTIVES: Symptoms of post-traumatic distress in mothers of preterm infants have been a subject of mental health research. The aim of this study was to assess the prevalence of and risk factors associated with such symptoms in mothers of preterm infants in Taiwan. METHODS: This was a cross-sectional study performed between January 1, 2010 and June 30, 2011. One hundred and two mothers of preterm infants born at less than 37 weeks gestation and with a subsequent neonatal intensive care unit (NICU) stay between 2005 and 2009 were recruited. Participants completed a demographic questionnaire, the Impact of Event Scale-Revised (IES-R), the Center for Epidemiologic Studies Depression Scale (CES-D) and the neuroticism subscale of the Maudsley Personality Inventory (MPI). The preterm infants' data were taken from medical records. RESULTS: The prevalence of symptoms of distress was 25.5% (26/102) in the participants. These symptoms were associated with previous miscarriages, preterm premature rupture of membranes, neurotic personality and depression. CONCLUSIONS: The experience of preterm birth and NICU hospitalization can be traumatic to mothers. Early support for mothers during the preterm infants' NICU stay and transition to home care are recommended.
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Recém-Nascido Prematuro/psicologia , Mães/psicologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Escalas de Graduação Psiquiátrica Breve/estatística & dados numéricos , Estudos Transversais , Humanos , Mães/estatística & dados numéricos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
Phthalate esters are widely used plasticizers that are present in many daily used products. Although some of their reproductive effects have been reported, pubertal development effects from prenatal exposure to phthalates awaits further investigations. A population based birth cohort was established (N=437 at baseline) with maternal exposure to phthalates assessed in urine collected at the third trimester of pregnancy in 2001 and 2002. Their 133 children with prenatal phthalates exposure were followed up for the outcomes of pubertal development by sequential physical examinations at eight and 11 years old in 2009 and 2012. Urinary concentrations of major phthalate metabolites (i.e., mono-2-ethylhexyl phthalate [MEHP], mono-(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP], mono-(2-ethyl-5-oxohexyl) phthalate [MEOHP], mono-butyl phthalate [MBP], mono-benzyl phthalate [MBzP], monomethyl phthalate [MMP], and mono-ethyl phthalate [MEP]) were determined using liquid chromatography linked to tandem mass spectrometry. The reproductive development measurements included bone age (for both genders), testicle size (for boys), uterus size, and ovarian volume (for girls). We reported results of 133 children with complete data by applying generalized estimating equations for the repeated continuous outcomes. After controlling for Tanner stage, we detected a significant association between reduced uterus size and increasing phthalate exposure in the 2(nd) tertile relative to the 1st tertile of creatinine-corrected MEHP (B=-0.40; 95% C.I.: -0.73, -0.07, relative to the 1st tertile) and total DEHP (B=-0.39, 95% C.I.:-0.66, -0.01 for the 2nd tertile and B=0.34, 95% C.I.: -0.67, -0.01 for the 3rd tertile, relative to the 1st tertile) with a linear trend among girls. MBzP was also found negatively associated with bone age/chronological age ratio (B=-0.07, 95% CI: -0.13, -0.01 for the 3rd tertile, relative to the 1st tertile) with a linear trend for girls. We found no evidence of an association between phthalate exposure and ovarian volume or testicle size. This analysis suggests phthalate exposure may affect specific pubertal development characteristics in human beings. Further studies with larger sample sizes and longer follow-up period are warranted.
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Ácidos Ftálicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Maturidade Sexual/efeitos dos fármacos , Criança , Cromatografia Líquida , Estudos de Coortes , Ésteres/química , Feminino , Seguimentos , Humanos , Masculino , Ácidos Ftálicos/química , Gravidez , Taiwan , Espectrometria de Massas em TandemRESUMO
The authors present a case of citrullinemia with a genotype of argininosuccinate synthetase (ASS1), c.380 G>A (p.R127Q)/c.380 G>A (p.R127Q), in two alleles. A 3-day-old female infant presented with status epilepticus and coma. Laboratory data showed hyperammonemia and marked lactic acidosis in the blood and cerebrospinal fluid; electroencephalography showed severely suppressed cerebral activity and focal paroxysmal volleys of slow and sharp waves (< 1Hz) over the left hemisphere. Real-time transcranial Doppler ultrasonography showed a brain edema and high peaked systolic and low diastolic flows in basal, anterior, and middle cerebral arteries; however, immediately after a blood exchange transfusion, systolic flows were lower and diastolic flows were higher. The resistance indices were significantly different (means: 0.58 vs. 0.37; p=0.01). The patient was placed on diet therapy. After six blood exchange transfusions and peritoneal dialysis, her neurologic examination results and serum ammonia and lactate values were normal. The authors found that electroencephalography and transcranial Doppler ultrasonography were useful for the diagnosis and follow-up treatment of neonatal citrullinemia.
Assuntos
Argininossuccinato Sintase/genética , Citrulinemia/diagnóstico , Eletroencefalografia , Hiperamonemia/diagnóstico , Ultrassonografia Doppler Transcraniana , Transfusão de Sangue , Citrulinemia/terapia , Feminino , Humanos , Hiperamonemia/terapia , Recém-Nascido , MutaçãoRESUMO
OBJECTIVE: To investigate the relationships of sleep patterns and respiratory disturbance index (RDI) with key physiological parameters (height, body mass index (BMI), bone age (BA), and IGF-1 levels) in children aged 6 to 16 years with self-perceived short stature. METHODS: For this cross-sectional study, conducted from October 2019 to November 2021, 238 children aged 6 to 16 years with self-perceived short stature were enrolled. The primary outcomes of sleep patterns and the RDI were non-invasively collected at home using the LARGAN Health AI-Tech Sleep Apnea and Sleep Quality Examination System, which operates based on polygraphy. Additionally, various physiological parameters, including height, BMI, bone age, and IGF-1 levels, were measured to assess their associations with sleep patterns and RDI. RESULTS: Significant age-related reductions were observed in both the total and deep sleep durations. Children aged 6-9 years averaged 8.5 ± 1.0 h of total sleep, which decreased to 8.1 ± 1.1 h in ages 10-11 and further to 7.5 ± 0.9 h in ages 12-16 (p < 0.0001). Deep sleep followed a similar pattern, decreasing from 4.4 ± 1.1 h in the youngest group to 3.3 ± 1.0 h in the oldest (p < 0.0001). Notably, girls experienced significantly longer deep sleep than boys, averaging 4.0 ± 1.2 h compared to 3.6 ± 1.2 h (p = 0.0153). In a multivariable regression analysis, age (beta = 4.89, p < 0.0001) and RDI (beta = -0.54, p = 0.0022) were significantly associated with body height. Age and deep sleep duration (beta = -0.02, p = 0.0371) were significantly associated with BMI. CONCLUSIONS: The results demonstrate significant age-related decreases in the total and deep sleep duration among children with self-perceived short stature, along with a notable association between RDI and body height and an association between deep sleep duration and BMI. These findings suggest that sleep disturbances in pediatric endocrine patients are intricately linked with physiological growth parameters. The identified correlations underline the importance of monitoring sleep patterns in this demographic to better understand the impact of endocrine disorders on developmental health. Further research is needed to explore interventions that could alleviate these sleep disturbances, thereby potentially improving outcomes for the affected children.
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BACKGROUND: Obesity is a major health concern worldwide. Previous studies have suggested that phthalate plasticizers are obesogens. However, the relationship between early-life phthalate exposure and long-term obesity development remains unknown. OBJECTIVE: We investigated the association between prenatal phthalate exposure and children's body mass index (BMI) patterns in an 18-year birth cohort follow-up study in Taiwan. METHODS: Our analytical lab quantified seven phthalate metabolites in maternal urine during pregnancy using quantitative liquid chromatography-tandem mass spectrometry. In addition, we calculated BMI z scores for participated children at each follow-up, utilized trajectory analysis to describe children's BMI z-score patterns at 2-18 years of age, and adopted generalized estimating equations (GEE) and multivariate logistic regression models to assess the association between prenatal phthalate exposure and BMI z scores in children. RESULTS: A total of 208 mother-child pairs were included in the analysis. Maternal urinary diethyl phthalate (DEP) metabolites were associated with the increase of BMI z scores in children aged 2-18 years in the GEE model. Doubled maternal urinary ∑mDEHP (3 mono hexyl-metabolites of di-ethyl-hexyl phthalate (DEHP) increased the risk of children being in the stable-high BMI trajectory group until the age of eighteen. IMPACT STATEMENT: We observed that BMI trajectories of children remained stable after the age of 5 years. During each follow-up, a higher frequency of overweight or obese was observed in children, ranging from 15.9% to 35.6% for girls and 15.2-32.0% for boys, respectively. Prenatal phthalate exposure was associated with increasing BMI z scores in children. Prenatal DEHP exposure was associated with a stable-high BMI trajectory in children up to the age of 18 years.
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Índice de Massa Corporal , Exposição Materna , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Humanos , Ácidos Ftálicos/urina , Feminino , Gravidez , Criança , Adolescente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Exposição Materna/efeitos adversos , Seguimentos , Taiwan , Pré-Escolar , Masculino , Poluentes Ambientais/urina , Coorte de Nascimento , Estudos de Coortes , AdultoRESUMO
BACKGROUND/AIM: Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder characterized by sphingomyelin accumulation causing progressive lung disease, respiratory failure, and death. PATIENTS AND METHODS: This retrospective observational study used the TriNetX database of electronic health records for 15,108 patients with ASMD from 2000-2020. After exclusions, 8,980 individuals were followed for 10 or 20 years. Outcomes included incidence and prevalence of respiratory disorders. Associations of age, sex and race were assessed. RESULTS: Nearly all respiratory outcomes increased significantly over 20 versus 10 years. Other respiratory disorders, specified respiratory disorders and secondary pulmonary hypertension exhibited the greatest increases, reflecting progressive lung damage in ASMD. While outcomes were poor overall, older age, male sex, and racial minority status associated with greater risks, indicating differences in disease progression or care. CONCLUSION: This study confirms the progressive nature of ASMD and need for close monitoring and treatment of pulmonary complications to reduce long-term morbidity and mortality. Genetic testing enabling diagnosis even for milder, adult-onset forms is critical to optimize outcomes.
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Doença de Niemann-Pick Tipo A , Doenças de Niemann-Pick , Adulto , Humanos , Masculino , Seguimentos , Esfingomielina Fosfodiesterase/genética , Doença de Niemann-Pick Tipo A/diagnóstico , Doença de Niemann-Pick Tipo A/genética , PulmãoRESUMO
BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient's cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.
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Doença de Gaucher , Osteoporose , Humanos , Densidade Óssea/genética , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Inflamassomos , Osteoporose/genética , Osteoporose/tratamento farmacológicoRESUMO
BACKGROUND/AIM: X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, results from loss-of-function mutations in the phosphate-regulating PHEX gene. Elevated fibroblast growth factor 23 (FGF23) contributes to hypophosphatemia in XLH. This study aimed to characterize PHEX variants and serum FGF23 profiles in Taiwanese patients with XLH. PATIENTS AND METHODS: We retrospectively reviewed the records of 102 patients clinically suspected of having hypophosphatemic rickets from 2006 to 2022. Serum intact Fibroblast growth factor-23 (iFGF23) levels were measured on clinic visit days. PHEX mutations were identified using Sanger sequencing, and negative cases were analyzed using whole-exome sequencing. RESULTS: The majority (92.1%) of patients exhibited elevated FGF23 compared with normal individuals. Among 102 patients, 44 distinct PHEX mutations were identified. Several mutations recurred in multiple unrelated Taiwanese families. We discovered a high frequency of novel PHEX mutations and identified variants associated with extreme FGF23 elevation and tumorigenesis. CONCLUSION: Our findings revealed the PHEX genotypic variants and FGF23 levels in Taiwanese patients with XLH. These results are crucial given the recent approval of burosumab, a monoclonal FGF23 antibody, for XLH therapy. This study provides key insights into the clinical management of XLH in Taiwan.
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Raquitismo Hipofosfatêmico Familiar , Humanos , Anticorpos Monoclonais , Raquitismo Hipofosfatêmico Familiar/genética , Raquitismo Hipofosfatêmico Familiar/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Mutação , Recidiva Local de Neoplasia , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Estudos RetrospectivosRESUMO
Taiwan is an emerging industrial country in subtropical Asia with a population of 23 million. There were around 200,000 newborns in 2011. Delayed first marriage, low birth rate, and rapid aging are major demographic issues. Genetic counseling services were established following the rapid introduction of genetic technology and enactment of relevant laws and regulations. Ultrasound was first used in 1968 to examine pregnant women. The first amniotic fluid laboratory was founded in 1981 to identify chromosomal abnormalities. In 1984, the Genetic Health Act was legislated for prevention and control of genetic disorders, and the metabolic disorder screen project was launched. National Health Insurance with overall coverage of prenatal examinations was established in 1995. A master-level genetic counseling program was launched in 2003 and by 2011 has graduated eighty students. Two professional societies have been formed to certify genetic counselors, and 66 professionals have been certified. In summary, genetic counseling services in Taiwan are continuously improving.
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Aconselhamento Genético/organização & administração , Feminino , Humanos , Gravidez , Desenvolvimento de Programas , TaiwanRESUMO
BACKGROUND: Individuals with Down syndrome are at a higher risk of cardiac, renal, and other health issues due to a complex disease physiology. However, few data exist on long-term disease risks to guide prevention and care. We aimed to determine the 10-year incidence of cardiac, renal, and urinary tract complications in Down syndrome versus matched controls. METHODS: This retrospective cohort study utilized a large collaborative database. We identified 32,444 patients with Down syndrome and matched controls, excluding those with pre-follow-up target events. Covariates included demographics, lifestyle factors, and comorbidities. Outcomes were ischemic heart disease, hypertension, hypothyroidism, epilepsy, urinary tract infections and chronic kidney disease. We calculated unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox regression and plotted Kaplan-Meier survival curves. FINDINGS: Over 10 years, Down syndrome patients showed a 3.7-fold higher ischemic heart disease risk (95% CI: 3.0-4.6) and a 1.6-fold higher hypertension risk (95% CI: 1.4-1.8) versus controls. Hypothyroidism (HR = 2.0; 95% CI: 1.7-2.4), epilepsy (HR = 4.5; 95% CI: 3.5-5.8), and urinary tract infection (HR = 3.9; 95% CI: 3.4-4.6) risks were also higher. Chronic kidney disease risk was 2.7-fold greater (95% CI: 2.1-3.5). Survival analysis confirmed a significantly higher incidence of all outcomes in Down syndrome (p < 0.0001). INTERPRETATION: This large study found major health challenges in Down syndrome, with risks 3- to 5-fold higher for chronic conditions versus matched controls over 10 years. Though survival remains high with proper care, focusing resources on the prevention and management of complications in this high-risk group can optimize well-being across the lifespan. Future research accounting for limitations here would provide definitive estimates of disease risk in Down syndrome to guide targeted health strategies.