RESUMEN
A comprehensive set of fully integrated anthropometric measures is needed to evaluate human growth from conception to infancy so that consistent judgments can be made about the appropriateness of fetal and infant growth. At present, there are 2 barriers to this strategy. First, descriptive reference charts, which are derived from local, unselected samples with inadequate methods and poor characterization of their putatively healthy populations, commonly are used rather than prescriptive standards. The use of prescriptive standards is justified by the extensive biologic, genetic, and epidemiologic evidence that skeletal growth is similar from conception to childhood across geographic populations, when health, nutrition, environmental, and health care needs are met. Second, clinicians currently screen fetuses, newborn infants, and infants at all levels of care with a wide range of charts and cutoff points, often with limited appreciation of the underlying population or quality of the study that generated the charts. Adding to the confusion, infants are evaluated after birth with a single prescriptive tool: the World Health Organization Child Growth Standards, which were derived from healthy, breastfed newborn infants, infants, and young children from populations that have been exposed to few growth-restricting factors. The International Fetal and Newborn Growth Consortium for the 21st Century Project addressed these issues by providing international standards for gestational age estimation, first-trimester fetal size, fetal growth, newborn size for gestational age, and postnatal growth of preterm infants, all of which complement the World Health Organization Child Growth Standards conceptually, methodologically, and analytically. Hence, growth and development can now, for the first time, be monitored globally across the vital first 1000 days and all the way to 5 years of age. It is clear that an integrative approach to monitoring growth and development from pregnancy to school age is desirable, scientifically supported, and likely to improve care, referral patterns, and reporting systems. Such integration can be achieved only through the use of international growth standards, especially in increasingly diverse, mixed ancestry populations. Resistance to new scientific developments has been hugely problematic in medicine; however, we are confident that the obstetric and neonatal communities will join their pediatric colleagues worldwide in the adoption of this integrative strategy.
Asunto(s)
Antropometría/métodos , Desarrollo Infantil , Desarrollo Fetal , Edad Gestacional , Desarrollo Óseo , Niño , Preescolar , Continuidad de la Atención al Paciente , Femenino , Gráficos de Crecimiento , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Valores de ReferenciaRESUMEN
BACKGROUND: Posterior fossa malformation (PFM) is a relatively uncommon prenatal brain malformation. Genetic diagnostic approaches, including chromosome karyotyping, copy number variant (CNV) testing, and whole-exome sequencing (WES), have been applied in several cases of fetal structural malformations. However, the clinical value of appropriate genetic diagnostic approaches for different types of PFMs has not been confirmed. Therefore, in this study, we aimed to analyze the value of different combined genetic diagnostic approaches for various types of fetal PFMs. METHODS: This retrospective study was conducted at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital. Fifty-one pregnant women diagnosed with fetal PFMs who underwent genetic testing in our hospital from January 1, 2017 to December 31, 2022 were enrolled; women with an isolated enlarged cisterna magna were excluded. All participants were categorized into two groups according to the presence of other abnormalities: isolated and non-isolated PFMs groups. Different combined approaches, including karyotype analysis, CNV testing, and trio-based WES, were used for genetic analysis. The detection rates of karyotype analysis, CNV testing, and WES were measured in the isolated and non-isolated groups. RESULTS: In isolated PFMs, pathogenic/likely pathogenic (P/LP) CNVs were detected in four cases (36.36%, 4/11), whereas G-banding karyotyping and WES showed negative results. In non-isolated PFMs, a sequential genetic approach showed a detection rate of 47.5% (19/40); karyotyping revealed aneuploidies in five cases (16.67%, 5/30), CNV testing showed P/LP CNVs in five cases (16.13%, 5/31), and WES identified P/LP variants (in genes CEP20, TMEM67, OFD1, PTPN11, ARID1A, and SMARCA4) in nine cases (40.91%, 9/22). WES showed a detection rate of 83.33% (5/6) in fetuses with Joubert syndrome. Only six patients (five with Blake's pouch cyst and one with unilateral cerebellar hemisphere dysplasia) survived. CONCLUSIONS: We recommend CNV testing for fetuses with isolated PFMs. A sequential genetic approach (karyotyping, CNV testing, and WES) may be beneficial in fetuses with non-isolated PFMs. Particularly, we recommend WES as the first-line genetic diagnostic tool for Joubert syndrome.
Asunto(s)
Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Cariotipificación , Diagnóstico Prenatal , Humanos , Femenino , Variaciones en el Número de Copia de ADN/genética , Embarazo , Cariotipificación/métodos , Secuenciación del Exoma/métodos , Diagnóstico Prenatal/métodos , Adulto , Estudios Retrospectivos , Pruebas Genéticas/métodos , Fosa Craneal Posterior/anomalíasRESUMEN
BACKGROUND: As a pattern recognition receptor, Toll-like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during sepsis and explore the mechanism of TLR7 in septic cardiomyopathy. METHODS: We generated a mouse model of septic cardiomyopathy by challenging with lipopolysaccharide (LPS). TLR7-knockout (TLR7-/- ), wild-type (WT) mice, cardiac-specific TLR7-transgenic (cTG-TLR7) overexpression, and littermates WT (LWT) mice were subjected to septic model. Additionally, to verify the role and mechanism of TLR7 in vitro, we transfected neonatal rat ventricular myocytes (NRVMs) with Ad-TLR7 and TLR7 siRNA before LPS administration. The effects of TLR7 were assessed by Ca2+ imaging, western blotting, immunostaining, and quantitative real-time polymerase chain reaction (qPCR). RESULTS: We found that TLR7 knockout markedly exacerbated sepsis-induced systolic dysfunction. Moreover, cardiomyocytes isolated from TLR7-/- mice displayed weaker Ca2+ handling than that in WT mice in response to LPS. Conversely, TLR7 overexpression alleviated LPS-induced systolic dysfunction, and loxoribine (TLR7-specific agonist) improved LPS-induced cardiac dysfunction. Mechanistically, these optimized effects were associated with enhanced the adenosine (cAMP)-protein kinase A (PKA) pathway, which upregulated phosphorylate-phospholamban (p-PLN) (Ser16) and promoted sarco/endoplasmic reticulum Ca2+ ATPase (Serca) and Ryanodine Receptor 2 (RyR2) expression in the sarcoplasmic reticulum (SR), and ultimately restored Ca2+ handling in response to sepsis. While improved Ca2+ handling was abrogated after H89 (a specific PKA inhibitor) pretreatment in cardiomyocytes isolated from cTG-TLR7 mice. Consistently, TLR7 overexpression improved LPS-induced Ca2+ -handling decrement in NRVMs. Nevertheless, TLR7 knockdown showed a deteriorative phenotype. CONCLUSIONS: Our data demonstrated that activation of TLR7 protected against sepsis-induced cardiac dysfunction through promoting cAMP-PKA-PLN pathway, and we revealed that TLR7 might be a novel therapeutic target to block the septic cardiomyopathy and support systolic function during sepsis.
Asunto(s)
Cardiomiopatías/complicaciones , Cardiomiopatías/prevención & control , Glicoproteínas de Membrana/farmacología , Sepsis/complicaciones , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Sístole , Receptor Toll-Like 7RESUMEN
Both uteroglobin knockout and antisense transgenic mice develop pathological and clinical features similar to immunoglobulin A (IgA) nephropathy. However, several association studies of uteroglobin G38A polymorphism and IgA nephropathy showed controversial findings. We used meta-analysis to assess the impact of the uteroglobin G38A polymorphism on susceptibility to and progression of IgA nephropathy. Six studies involving uteroglobin G38A genotyping of 930 patients with IgA nephropathy and 768 healthy controls were included. No significant publication bias was found (Egger's linear regression, P = 0.763; 95% confidence interval [CI], -0.610 to 0.476). All control samples were in Hardy-Weinberg proportion. No association between the AA genotype and risk for IgA nephropathy relative to both other genotypes (odds ratio [OR], 1.05; 95% CI, 0.71 to 1.54) or A allele and risk for IgA nephropathy (OR, 0.96; 95% CI, 0.84 to 1.11) were shown in the total meta-analysis. In both Asian and European subgroups, the overall effect of the AA genotype and A allele also showed no significant difference. There also was no significant association between uteroglobin AA genotype or A allele and IgA nephropathy progression (OR, 3.62; 95% CI, 0.59 to 22.34; OR, 2.19, 95% CI, 0.37 to 13.14, respectively). We suggest that uteroglobin G38A polymorphism is not related to the development and progression of IgA nephropathy.