RESUMO
GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.
Assuntos
Fator 15 de Diferenciação de Crescimento , Hiperêmese Gravídica , Náusea , Vômito , Animais , Feminino , Humanos , Camundongos , Gravidez , Talassemia beta/sangue , Talassemia beta/metabolismo , Feto/metabolismo , Fator 15 de Diferenciação de Crescimento/sangue , Fator 15 de Diferenciação de Crescimento/metabolismo , Hormônios/sangue , Hormônios/metabolismo , Hiperêmese Gravídica/complicações , Hiperêmese Gravídica/metabolismo , Hiperêmese Gravídica/prevenção & controle , Hiperêmese Gravídica/terapia , Náusea/sangue , Náusea/complicações , Náusea/metabolismo , Placenta/metabolismo , Vômito/sangue , Vômito/complicações , Vômito/metabolismoRESUMO
OBJECTIVES: To validate prospectively transvaginal ultrasound assessment of the lower uterine segment (LUS) scar at the time of first-trimester screening in women with previous Cesarean section (CS) and to determine its feasibility and accuracy in stratifying women according to the risk for placenta accreta spectrum (PAS) disorder. METHODS: Women with a history of CS were recruited between 11 + 0 and 13 + 6 weeks' gestation and underwent LUS scar assessment using transvaginal ultrasound. A standardized midsagittal plane, which included the cervicoisthmic canal (CIC), the uterine scar and the placental site, was obtained. The scar was described in terms of its size (narrow or dehiscent) and its location in relation to the CIC (within or above), with each LUS scar classified into one of four groups based on these features. Placental location was assessed and classified as high- or low-lying. Women were stratified according to the risk of PAS, based on the relationship between the scar location and placental site. Women were considered high risk when the scar was above the CIC and the placenta was low-lying (i.e. when the placenta was overlying an exposed scar) and low risk when the scar was within the CIC and/or the placenta was high. High-risk patients were followed up at 20 weeks and 28-30 weeks for the development of PAS. Maternal demographics, detailed obstetric history and obstetric outcome were collected. RESULTS: First-trimester transvaginal ultrasound was offered to 535 women with prior CS during the study period. A LUS scar was visualized in 79.9% (401/502) of those who agreed to undergo the examination. At this scan, the LUS scar was above the CIC in 9.0% (36/401) of women, but only 5.7% (23/401) additionally had a low-lying placenta overlying the scar. Of these 23 high-risk women, two were found to have PAS on the mid-trimester screening scan and one was noted to have placental adherence during evacuation following mid-trimester termination of pregnancy. On the first-trimester scan, 94.3% (378/401) of women were at low risk of PAS. This screening protocol yielded a positive likelihood ratio of 21.33 (95% CI, 13.02-34.96), sensitivity of 100% (95% CI, 29.24-100%), specificity of 95.31% (95% CI, 92.39-97.35%), positive predictive value of 16.7% (95% CI, 5.8-39.2%) and negative predictive value of 100% (95% CI, 98.4-100%). On multivariable regression analysis performed to identify confounding variables associated with a LUS scar above the CIC, only maternal body mass index ≥ 30 kg/m2 was significant (odds ratio (OR), 2.42 (95% CI, 1.04-5.39); P = 0.03). Although there was a trend towards an increased risk of a LUS scar above the CIC in women with prior elective prelabor CS (OR, 1.72 (95% CI, 0.80-3.68)), this association did not reach statistical significance. CONCLUSIONS: Routine transvaginal ultrasound assessment of the location of the LUS scar and placenta at the time of first-trimester screening between 11 + 0 and 13 + 6 weeks' gestation in women with prior CS is a feasible and effective tool to identify those at risk of subsequent development of PAS disorder. A finding of placental implantation over an exposed LUS scar seems to be cardinal in predicting the risk of PAS disorder in women with prior CS, with an excellent negative predictive value. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
Assuntos
Cesárea/efeitos adversos , Cicatriz/diagnóstico por imagem , Placenta Acreta/diagnóstico por imagem , Medição de Risco/métodos , Ultrassonografia Pré-Natal/métodos , Adulto , Cicatriz/complicações , Estudos de Viabilidade , Feminino , Idade Gestacional , Humanos , Placenta/diagnóstico por imagem , Placenta Acreta/etiologia , Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Útero/diagnóstico por imagem , Útero/patologia , Útero/cirurgiaRESUMO
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.
Assuntos
Desenvolvimento Infantil/fisiologia , Estado Nutricional/fisiologia , Puberdade/fisiologia , Receptor Tipo 3 de Melanocortina/metabolismo , Maturidade Sexual/fisiologia , Adolescente , Idoso de 80 Anos ou mais , Animais , Criança , Ciclo Estral/genética , Ciclo Estral/fisiologia , Feminino , Homozigoto , Humanos , Hipotálamo/citologia , Hipotálamo/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Melanocortinas/metabolismo , Menarca/genética , Menarca/fisiologia , Camundongos , Fenótipo , Puberdade/genética , Receptor Tipo 3 de Melanocortina/deficiência , Receptor Tipo 3 de Melanocortina/genética , Maturidade Sexual/genética , Fatores de Tempo , Aumento de PesoRESUMO
OBJECTIVE: More than 300 genetic variants have been robustly associated with measures of human adiposity. Highly penetrant mutations causing human obesity do so largely by disrupting satiety pathways in the brain and increasing food intake. Most of the common obesity-predisposing variants are in, or near, genes expressed highly in the brain, but little is known of their function. Exploring the biology of these genes at scale in mammalian systems is challenging. We sought to establish and validate the use of a multicomponent screen for feeding behaviour phenotypes, taking advantage of the tractable model organism Drosophila melanogaster. METHODS: We validated a screen for feeding behaviour in Drosophila by comparing results after disrupting the expression of centrally expressed genes that influence energy balance in flies to those of 10 control genes. We then used this screen to explore the effects of disrupted expression of genes either a) implicated in energy homeostasis through human genome-wide association studies (GWAS) or b) expressed and nutritionally responsive in specific populations of hypothalamic neurons with a known role in feeding/fasting. RESULTS: Using data from the validation study to classify responses, we studied 53 Drosophila orthologues of genes implicated by human GWAS in body mass index and found that 15 significantly influenced feeding behaviour or energy homeostasis in the Drosophila screen. We then studied 50 Drosophila homologues of 47 murine genes reciprocally nutritionally regulated in POMC and agouti-related peptide neurons. Seven of these 50 genes were found by our screen to influence feeding behaviour in flies. CONCLUSION: We demonstrated the utility of Drosophila as a tractable model organism in a high-throughput genetic screen for food intake phenotypes. This simple, cost-efficient strategy is ideal for high-throughput interrogation of genes implicated in feeding behaviour and obesity in mammals and will facilitate the process of reaching a functional understanding of obesity pathogenesis.
Assuntos
Apetite/genética , Apetite/fisiologia , Comportamento Alimentar/fisiologia , Animais , Índice de Massa Corporal , Encéfalo , Drosophila melanogaster/genética , Metabolismo Energético , Estudo de Associação Genômica Ampla , Genótipo , Homeostase , Hipotálamo/metabolismo , Neurônios/metabolismo , Estado Nutricional , Obesidade/metabolismo , FenótipoRESUMO
Genome-wide association studies have revealed that single nucleotide polymorphisms in fat mass and obesity-associated transcript (FTO) are robustly associated with body mass index and obesity. Expression of Fto in the hypothalamic arcuate nucleus is bidirectionally regulated as a function of nutritional status; decreasing following a 48-h fast and increasing after 10-week exposure to a high-fat diet. Here, we utilize an in vitro approach to determine which nutrients could regulate FTO levels at a cellular level. Using mouse and human cell lines, we find that FTO levels are not influenced by serum starvation. We demonstrate, however, that both glucose and total amino-acid deprivation regulates FTO expression. In particular, we have found that FTO mRNA and protein levels are dramatically downregulated by total amino-acid deprivation in mouse hypothalamic N46 cells, mouse embryonic fibroblasts and in human HEK293 cells. The drop rate of Fto mRNA is faster than its rate of natural degradation, pointing to regulation at the transcriptional level, which is reversible upon amino-acid replacement. Strikingly, this downregulation was seen only with essential amino-acid deficiency and not nonessential amino acids. These data suggest that FTO might have a role in the sensing of essential amino-acid availability.
Assuntos
Aminoácidos Essenciais/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Glucose/metabolismo , Oxigenases de Função Mista/metabolismo , Obesidade/metabolismo , Oxo-Ácido-Liases/metabolismo , Proteínas/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Animais , Western Blotting , Linhagem Celular , Dieta Hiperlipídica , Regulação para Baixo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Camundongos , Obesidade/genética , Obesidade/fisiopatologia , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Fatores de TempoRESUMO
ß-Cell dysfunction is a critical component in the development of type 2 diabetes. Whilst both genetic and environmental factors contribute to the development of the disease, relatively little is known about the molecular network that is responsible for diet-induced functional changes in pancreatic ß-cells. Recent genome-wide association studies for diabetes-related traits have generated a large number of candidate genes that constitute possible links between dietary factors and the genetic susceptibility for ß-cell failure. Here, we summarize recent approaches for identifying nutritionally regulated transcripts in islets on a genome-wide scale. Polygenic mouse models for type 2 diabetes have been instrumental for investigating the mechanism of diet-induced ß-cell dysfunction. Enhanced oxidative metabolism, triggered by a combination of dietary carbohydrates and fat, appears to play a critical role in the pathophysiology of diet-induced impairment of islets. More systematic studies of gene-diet interactions in ß-cells of rodent models in combination with genetic profiling might reveal the regulatory circuits fundamental for the understanding of diet-induced impairments of ß-cell function in humans.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Dieta , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , Animais , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Teste de Tolerância a Glucose , Humanos , Insulina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Herança MultifatorialRESUMO
We present a foetus affected by trisomy 9, a rare chromosomal disorder, which was diagnosed in a low-risk patient during the first trimester of pregnancy. The finding of multiple structural foetal anomalies at the first trimester screening prompted chorionic villus sampling. Evaluation of the quantitative fluorescent polymerase chain reaction was normal, but the final karyotype result revealed a diagnosis of trisomy 9. First trimester screening for detection of foetal anomalies is highly effective. Although rapid molecular methods are available for prenatal diagnosis of common autosomal and sex chromosome aneuploidies, it is essential to obtain a full karyotype in order to exclude the less commonly encountered chromosomal abnormalities.
Assuntos
Amostra da Vilosidade Coriônica , Primeiro Trimestre da Gravidez , Trissomia/diagnóstico , Ultrassonografia Pré-Natal , Aborto Eugênico , Adulto , Cromossomos Humanos Par 9/diagnóstico por imagem , Feminino , Humanos , GravidezRESUMO
Sacrococcygeal teratoma (SCT) is a congenital tumour that can be diagnosed by ultrasonography (USG). We present our experience with the management of two cases of SCT in our institution between 2008 and 2009. In the first case, SCT was diagnosed at 17 weeks' gestation. The patient was followed up with fortnightly USG to monitor the tumour size, foetal growth and signs of foetal hydrops. The patient delivered a baby girl by Caesarean section at 37 weeks, with good Apgar scores. The neonate underwent an uneventful resection of SCT on Day 1 of life. In the second case, SCT was diagnosed at 20 weeks during screening. In view of foetal hydrops and anaemia, the patient underwent three in utero foetal blood transfusions. A baby boy was delivered by Caesarean section at 28 weeks. There was a large friable SCT with massive haemorrhage. Despite maximal resuscitative efforts, the neonate died 30 minutes after birth.
Assuntos
Doenças Fetais/patologia , Região Sacrococcígea/patologia , Teratoma/diagnóstico por imagem , Teratoma/patologia , Adulto , Evolução Fatal , Feminino , Doenças Fetais/diagnóstico , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Gravidez , Resultado da Gravidez , Teratoma/diagnóstico , Resultado do Tratamento , Ultrassonografia Pré-NatalRESUMO
OBJECTIVE: To evaluate the degree of agreement in first-trimester nasal bone assessment in a group of sonographers before and after training, using a semi-quantitative scoring system. METHODS: Four sonographers who routinely perform first-trimester screening were first shown 46 images from both normal and trisomy 21 pregnancies. For each image, they were asked to score from 0 (disagree) to 3 (agree) on five different criteria that were deemed important in nasal-bone assessment, including image size, plane and visibility of nasal bone. A training program was then conducted, and a repeat exercise was carried out using the same 46 images. Finally, in a third exercise, images from 42 patients were presented, some having more than one image. The sonographers were required to give one overall nasal-bone score for each patient. In each exercise interobserver agreement was evaluated by intraclass correlation coefficient (ICC). RESULTS: Before training, the sonographers agreed reasonably well on the five proposed criteria (ICC, 0.752), with some disagreement on their perceived image quality. The training program further improved the agreement (ICC, 0.790), particularly on whether the nasal bone was the biggest and brightest echogenic component. Agreement was excellent when they were asked to give one overall score on the nasal bone based on multiple images from one patient (ICC, 0.929). CONCLUSION: The proposed scoring system can be used to improve consistency and reliability in first-trimester nasal-bone assessment.
Assuntos
Síndrome de Down/diagnóstico por imagem , Osso Nasal/diagnóstico por imagem , Primeiro Trimestre da Gravidez , Ultrassonografia Pré-Natal/métodos , Síndrome de Down/embriologia , Feminino , Humanos , Osso Nasal/embriologia , Variações Dependentes do Observador , Gravidez , Garantia da Qualidade dos Cuidados de Saúde , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
We have addressed the question of how different rodent species cope with the life-threatening homeostatic challenge of dehydration at the level of transcriptome modulation in the supraoptic nucleus (SON), a specialised hypothalamic neurosecretory apparatus responsible for the production of the antidiuretic peptide hormone arginine vasopressin (AVP). AVP maintains water balance by promoting water conservation at the level of the kidney. Dehydration evokes a massive increase in the regulated release of AVP from SON axon terminals located in the posterior pituitary, and this is accompanied by a plethora of changes in the morphology, electrophysiological properties, biosynthetic and secretory activity of this structure. Microarray analysis was used to generate a definitive catalogue of the genes expressed in the mouse SON, and to describe how the gene expression profile changes in response to dehydration. Comparison of the genes differentially expressed in the mouse SON as a consequence of dehydration with those of the rat has revealed many similarities, pointing to common processes underlying the function-related plasticity in this nucleus. In addition, we have identified many genes that are differentially expressed in a species-specific manner. However, in many cases, we have found that the hyperosmotic cue can induce species-specific alterations in the expression of different genes in the same pathway. The same functional end can be served by different means, via differential modulation, in different species, of different molecules in the same pathway. We suggest that pathways, rather than specific genes, should be the focus of integrative physiological studies based on transcriptome data.
Assuntos
Desidratação/fisiopatologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/fisiologia , Camundongos , Ratos , Transdução de Sinais/fisiologia , Núcleo Supraóptico/metabolismo , Animais , Desidratação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/genética , Especificidade da EspécieRESUMO
Leptin plays a major role in coordinating the integrated response of the brain to changes in nutritional state. Leptin receptor expressing neurones within the arcuate nucleus (ARC) of the hypothalamus sense circulating leptin and densely innervate other regions of the hypothalamus, including the paraventricular nucleus (PVN). In the ARC, leptin is known to alter the expression of genes with important roles in the control of energy balance, and the aim of the present study was to obtain a more comprehensive picture of the action of leptin in these nuclei. Mice were ad libitum fed, or fasted for 48 h when receiving either sham or i.p. leptin treatment. We used laser capture microdissection and microarrays to identify leptin-regulated transcripts within the ARC. Expression of 639 genes are increased and 452 decreased within the fasted ARC. Leptin regulates 15% and 20% of these genes, respectively. In addition to expected changes in Pomc, Agrp, Npy and Cart, pathway analysis indicated that leptin regulated other genes concerned with energy homeostasis and endocrine function. As previously reported for the PVN, leptin also altered the expression of genes involved in nervous system development and synaptic function. However, aside from a small number of such genes (e.g. Gap43), leptin influenced the expression of different sets of neuronal developmental genes in the ARC and PVN. In conclusion, the present study identifies a set of genes that are regulated, at least in part, by leptin in the ARC, highlighting these as candidates for possible roles in leptin action and resistance.
Assuntos
Núcleo Arqueado do Hipotálamo/fisiologia , Jejum/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Leptina/metabolismo , Animais , Masculino , Camundongos , Análise em Microsséries , Dados de Sequência MolecularRESUMO
Growing evidence suggests the tachykinin neurokinin B (NKB) may modulate gonadotrophin secretion and play a role in sex-steroid feedback within the reproductive axis. NKB signalling has recently been identified as being necessary for normal human reproductive function, although the precise mechanisms underpinning this role remain to be established. We have used rodents to explore further the role of NKB within the reproductive axis. In particular, we have studied its interactions with kisspeptin, a neuropeptide essential for reproductive function in rodent and human with close anatomical links to NKB within the hypothalamus. Intraperitoneal administration of NKB (50 nmol) to male mice had no effect on circulating luteinsing hormone (LH) levels and, although i.p. kisspeptin (15 nmol) increased LH five-fold, co-administration of NKB and kisspeptin was indistinguishable from kisspeptin alone. Intracerebroventricular administration of NKB (10 nmol) to male mice also had no effect on LH levels, with 1 nmol kisspeptin i.c.v. significantly increasing LH compared to control (0.37 +/- 0.18 versus 5.11 +/- 0.28 ng/ml, respectively). Interestingly, i.c.v. co-administration of NKB and kisspeptin caused a significant increase in LH concentrations compared to kisspeptin alone (8.96 +/- 1.82 versus 5.11 +/- 0.28 ng/ml respectively). We used hypothalamic explants from rats to assess the effect of NKB on gonadotrpohin-releasing hormone (GnRH) secretion ex vivo. Doses of NKB up to 1000 nm failed to stimulate GnRH secretion, whereas 100 nm kisspeptin robustly increased GnRH secretion. Of note, co-administration of NKB with kisspeptin abrogated the effect of kisspeptin, producing no GnRH release above basal state. Finally, we analysed the expression of Tac2/Tacr3 (genes encoding NKB and NK3R, respectively) within the arcuate nucleus in different nutritional states. After a 48-h fast, the expression of both Tac2 and Tacr3 showed a significant increase, in contrast to levels of Kiss1 and Kiss1r mRNA, which remained unchanged. In male rodent models, NKB and kisspeptin have different effects upon gonadotrophin release and appear to interact in a complex manner.
Assuntos
Hormônio Luteinizante/metabolismo , Neurocinina B/farmacologia , Proteínas/farmacologia , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Jejum/metabolismo , Hormônio Liberador de Gonadotropina/sangue , Hormônio Liberador de Gonadotropina/metabolismo , Kisspeptinas , Hormônio Luteinizante/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurocinina B/administração & dosagem , Precursores de Proteínas/biossíntese , Proteínas/administração & dosagem , Ratos , Ratos Wistar , Receptores de Taquicininas/biossíntese , Taquicininas/biossínteseRESUMO
AIMS/HYPOTHESIS: Numerous new genes have recently been identified in genome-wide association studies for type 2 diabetes. Most are highly expressed in beta cells and presumably play important roles in their function. However, these genes account for only a small proportion of total risk and there are likely to be additional candidate genes not detected by current methodology. We therefore investigated islets from the polygenic New Zealand mouse (NZL) model of diet-induced beta cell dysfunction to identify novel genes and pathways that may play a role in the pathogenesis of diabetes. METHODS: NZL mice were fed a diabetogenic high-fat diet (HF) or a diabetes-protective carbohydrate-free HF diet (CHF). Pancreatic islets were isolated by laser capture microdissection (LCM) and subjected to genome-wide transcriptome analyses. RESULTS: In the prediabetic state, 2,109 islet transcripts were differentially regulated (>1.5-fold) between HF and CHF diets. Of the genes identified, 39 (e.g. Cacna1d, Chd2, Clip2, Igf2bp2, Dach1, Tspan8) correlated with data from the Diabetes Genetics Initiative and Wellcome Trust Case Control Consortium genome-wide scans for type 2 diabetes, thus validating our approach. HF diet induced early changes in gene expression associated with increased cell-cycle progression, proliferation and differentiation of islet cells, and oxidative stress (e.g. Cdkn1b, Tmem27, Pax6, Cat, Prdx4 and Txnip). In addition, pathway analysis identified oxidative phosphorylation as the predominant gene-set that was significantly upregulated in response to the diabetogenic HF diet. CONCLUSIONS/INTERPRETATION: We demonstrated that LCM of pancreatic islet cells in combination with transcriptional profiling can be successfully used to identify novel candidate genes for diabetes. Our data strongly implicate glucose-induced oxidative stress in disease progression.
Assuntos
Dieta para Diabéticos , Dieta , Regulação da Expressão Gênica , Ilhotas Pancreáticas/fisiologia , Síndrome Metabólica/genética , Animais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Divisão Celular/fisiologia , Amplificação de Genes , Perfilação da Expressão Gênica , Hiperglicemia/genética , Hiperglicemia/prevenção & controle , Ilhotas Pancreáticas/citologia , Cinética , Masculino , Síndrome Metabólica/veterinária , Camundongos , Herança Multifatorial , Reação em Cadeia da Polimerase , RNA/genética , RNA/isolamento & purificação , Transcrição GênicaRESUMO
CONTEXT: The PNPLA3 I148M variant (rs738409) is robustly associated with hepatic steatosis. Intriguingly, initial findings in cohorts with a mean body mass index (BMI) of 30 kg m(-2) also suggested that it is associated with elevated liver enzymes but not with insulin resistance and dyslipidaemia. OBJECTIVE: To determine whether the PNPLA3 variant alters the susceptibility of morbidly obese subjects to develop liver injury and metabolic sequelae. PARTICIPANTS AND METHODS: The study was carried out in 678 obese Italians (mean BMI = 41 kg m(-2)) who were genotyped for the I148M variant. All participants provided fasting blood samples and then underwent oral glucose tolerance tests. MAIN OUTCOME MEASURES: Indices of liver injury (alanine transaminase (ALT), aspartate transaminase (AST)), glucose tolerance and insulin resistance were measured. RESULTS: Markers of hepatic injury such as ALT and AST were significantly higher in carriers of the 148M allele (P = 2.2 x 10(-5) and 0.001, respectively). In all, 50% of 148M risk allele homozygotes had pathological levels of ALT (>40 U l(-1)) compared with 25% of 148I allele homozygotes (P = 0.005). Glucose tolerance and insulin sensitivity were similar in all three genotypes. CONCLUSION: Obese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance.
Assuntos
Fígado Gorduroso/enzimologia , Variação Genética/genética , Resistência à Insulina/genética , Lipase/genética , Proteínas de Membrana/genética , Obesidade Mórbida/genética , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Índice de Massa Corporal , Fígado Gorduroso/sangue , Feminino , Predisposição Genética para Doença/genética , Genótipo , Teste de Tolerância a Glucose , Humanos , Itália , Lipase/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Obesidade Mórbida/sangue , Obesidade Mórbida/etnologiaRESUMO
INTRODUCTION: Turner syndrome is the most common sex chromosomal abnormality in female foetuses, and is associated with a high proportion of cardiac anomalies. The aim of this study was to look at the incidence, demographical data and epidemiological pattern of Turner syndrome in Singapore from 1999 to 2004 and to examine the birth defects associated with this condition, specifically with reference to cardiac defects. METHODS: Data on Turner syndrome cases born in 1999-2004 were retrieved from the National Birth Defects Registry (NBDR) and analysed. Data on congenital cardiac defect cases notified to the NBDR in the same time period were also retrieved and compared with the Turner syndrome cases. RESULTS: There were a total of 101 cases of Turner syndrome in the six-year period from 1999-2004, yielding an overall incidence of 0.85 per 1,000 female live births, or one in 1,180 female live births. The incidence was lowest among Indians (0.38 per 1,000) compared to Malays (0.72 per 1,000) and Chinese (0.90 per 1,000). 75 cases (74.3 percent) had the 45,X karyotype, while the other 26 cases (25.7 percent) were mosaics. The mean maternal age for 45,X was lower (32.2 years, range 22-42) compared to mosaics (34.5 years, range 27-40). 19.8 percent (20/101) were live births, 38.6 percent (39/101) were terminated pregnancies and 41.6 percent (42/101) were spontaneous miscarriages. 13.9 percent of Turner syndrome babies had cardiac defects compared to 1.2 percent in the general population (p-value is less than 0.0001). Major cardiac defects found among Turner syndrome babies compared to the general population included the coarctation of the aorta (5.9 percent compared to 0.03 percent, p-value is less than 0.0001), atrial septal defects (3.0 percent compared to 0.6 percent, p-value is 0.006), a hypoplastic left heart (2.0 percent compared to 0.05 percent, p-value is less than 0.0001), aortic hypoplasia (3.0 percent compared to 0.01 percent, p-value is less than 0.0001) and dextrocardia (1.0 percent compared to 0.02 percent, p-value is 0.0002). CONCLUSION: Cardiac defects, particularly left-sided ones, are significantly more common among Turner syndrome foetuses. The true incidence of this syndrome is likely to be higher than that quoted in this study, and can only be solved when a complete screening of an entire population has been performed.
Assuntos
Síndrome de Turner/epidemiologia , Síndrome de Turner/genética , Adulto , Aberrações Cromossômicas , Anormalidades Congênitas/genética , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Humanos , Incidência , Recém-Nascido , Cariotipagem , Idade Materna , Mosaicismo , Singapura , Síndrome de Turner/complicaçõesRESUMO
We describe a male neonate with foetal hydrops due to foetal anaemia caused by Kell isoimmunisation. The severity of anaemia was monitored by Doppler ultrasonography of the middle cerebral artery peak systolic velocity, and this was used to time the foetal blood transfusions. The 33-year-old Indian mother received a total of five foetal blood transfusions from 21 weeks to 31 weeks of gestation, resulting in resolution of the anaemia and hydrops.
Assuntos
Anemia Hemolítica Autoimune/terapia , Incompatibilidade de Grupos Sanguíneos/terapia , Ecoencefalografia , Transfusão de Eritrócitos/métodos , Hidropisia Fetal/sangue , Hidropisia Fetal/terapia , Sistema do Grupo Sanguíneo de Kell , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Adulto , Anemia Hemolítica Autoimune/sangue , Incompatibilidade de Grupos Sanguíneos/sangue , Cesárea , Feminino , Hematócrito , Humanos , Recém-Nascido , Masculino , Gravidez , Segundo Trimestre da Gravidez , Veias UmbilicaisRESUMO
INTRODUCTION: Cleft deformities, though non-lethal, receive much attention from parents and doctors alike because of their obvious physical disfigurement, social stigma and associated feeding and vocal articulation problems. There is also an association with chromosomal defects for certain cleft deformities. The aim of this study is to examine the incidence, demographic data and epidemiological trend of this condition over a ten-year period, and to compare our data with other local studies, as well as to examine the chromosomal defects associated with this condition. METHODS: Data of cleft deformity cases born during the period 1993-2002 was retrieved from the National Birth Defects Registry and analysed. RESULTS: There were a total of 859 cases of cleft deformities in the ten-year period 1993-2002, giving an overall incidence of 1.87 per 1,000 live births, with an increasing trend noted. Incidence was highest among the Chinese and lowest among the Indians. There were more males with cleft deformities compared with females. The risk of aneuploidy rose by about ten-fold in syndromic cleft cases, compared to non-syndromic cleft cases. There were two cases of Trisomy 21 in the non-syndromic cleft lip and palate group, giving an incidence of 1:133. CONCLUSION: The race-specific and gender-specific differences in cleft incidence suggest genetic and environmental factors which warrant further studies. The increased risk of aneuploidy among syndromic clefts, as well as the finding of Trisomy 21 in non-syndromic cleft lip and palate cases suggest a need for karyotyping in these two groups of antenatally-diagnosed cleft deformities.
Assuntos
Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Aneuploidia , Fenda Labial/etiologia , Fissura Palatina/etiologia , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Síndrome de Down , Feminino , Predisposição Genética para Doença , Humanos , Cariotipagem , Masculino , Prevalência , Sistema de Registros , Risco , Singapura , SíndromeRESUMO
INTRODUCTION: The 22q11 deletion syndrome (22q11DS) is associated with many congenital structural anomalies, notably cardiac defects (conotruncal anomalies) and velopharyngeal insufficiency, as well as neurodevelopmental and psychiatric findings in later life. Recent studies have tried to ascertain the true population incidence of this condition. However, this is difficult due to possible under-ascertainment from incomplete genetic testing in possible cases. The aim of this study is to investigate the local incidence and association of this deletion syndrome with other congenital structural anomalies, with emphasis on cardiac defects. METHODS: Data of 22q11 deletion cases born in 2000-2003 were retrieved from the Singapore National Birth Defects Registry (NBDR) and analysed. Data of congenital cardiac defect cases notified to NBDR in the same period were also retrieved and compared with the deletion cases. RESULTS: There were a total of 17 cases of 22q11DS in the four-year period 2000-2003, giving an overall incidence of 1.02 per 10,000 live-births or one in 9,804 births. 94 percent (16/17 cases) were associated with other structural anomalies, and of these, 68.8 percent (11/16 cases) had single system anomalies. Cardiac anomalies were the most common (100 percent). The deletion contributed to 0.86 percent (one in 116 cases) of all cardiac defects born during the same period. A higher contribution of this deletion was noted for interrupted aortic arch (10 percent), pulmonary atresia (12.7 percent) and truncus arteriosus (11.1 percent). CONCLUSION: In view of the high proportion of this deletion among certain cardiac defects, genetic testing should be made available to investigate the true burden and contribution of this deletion. As more genetic testing is done for this deletion, we are likely to see an increase in incidence, reflecting the true prevalence of this condition.
Assuntos
Cromossomos Humanos Par 22/genética , Deleção de Genes , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Sistema de Registros , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Singapura/epidemiologiaRESUMO
INTRODUCTION: Two of the most common malformations of the anterior abdominal wall include gastroschisis and omphalocele, both of which are associated with high morbidity and mortality. Studies have shown an increase in both conditions worldwide. These two conditions are considered separate entities because of their differences in epidemiology, physical characteristics and associations with other structural anomalies and chromosomal aberrations. This is the first local study to examine these two conditions. METHODS: Data of anterior abdominal wall defect cases of patients born during the period 1993-2002 were retrieved from the National Birth Defects Registry and analysed. RESULTS: There were a total of 121 cases of anterior abdominal wall defects in the ten-year period from 1993 to 2002, giving an overall incidence of 2.63 per 10,000 livebirths. The individual incidences of gastroschisis (n = 21) and omphalocele (n = 100) were 0.46 and 2.17 per 10,000 livebirths, respectively. 33 percent of women with foetal gastroschisis were younger than 25 years of age, and 31 percent of women with foetal omphalocele were older than 35 years of age. This was statistically significant when compared to the general obstetric population. Incidence of omphalocele was lowest among the Indian population. Total aneuploidy rate was 14.9 percent (18/121 cases), with omphalocele having a higher aneuploidy rate than gastroschisis (17 percent versus 4.8 percent). Omphaloceles are also more likely to be associated with cardiac defects (p-value equals 0.02). CONCLUSION: Our studies are consistent with the worldwide trend of an increasing prevalence of anterior abdominal wall defects. The race-specific differences suggest genetic and environmental factors that warrant further studies.
Assuntos
Gastrosquise/diagnóstico , Gastrosquise/epidemiologia , Hérnia Umbilical/diagnóstico , Hérnia Umbilical/epidemiologia , Adulto , Aberrações Cromossômicas , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Feminino , Humanos , Incidência , Masculino , Idade Materna , Pessoa de Meia-Idade , Sistema de Registros , Singapura , Fatores de TempoRESUMO
INTRODUCTION: This study aims to assess the epidemiology of severe preeclampsia in Singapore, the disease characteristics, maternal and perinatal outcome, and to identify risk factors for complications. METHODS: Data of 93 consecutive women with severe preeclampsia in KK Women's and Children's Hospital in Singapore was collected prospectively and analysed using the unpaired t-test for normally-distributed continuous variables and Fisher's exact chi-square test for discrete variables. Multivariate logistic regression analysis was performed for prediction of complicated cases. RESULTS: The incidence of severe pre-eclampsia was 29.3 per 10,000 deliveries, with an increased risk in women who were aged more than 35 years and who were nulliparous. The risk was also increased in women of the Malay race and they also had the tendency to book later, compared with the other races. 43 percent of women had maternal complications, including eclampsia, haemolysis/elevated liver enzymes/low platelets syndrome, oliguria, pulmonary oedema and placental abruption. Significantly raised levels of uric acid (439.5 +/- 114.1 micromol/L versus 395.4 +/- 96.7 micromol/L, p-value equals 0.047) and aspartate transaminase (80.1 +/- 107.4 IU/L versus 38.8 +/- 16.1 IU/L, p-value equals 0.021) were found in those with complications, compared to those without complications. The average gestation at time of diagnosis was 33 weeks and the average gestation at delivery was 34 weeks. 89.3 percent of women required caesarean section and 59.1 percent of women were admitted to intensive care. CONCLUSION: Age, parity and race are risk factors for severe preeclampsia with increased levels of uric acid and aspartate transaminase found in the complicated cases. The morbidity and cost of treatment of severe preeclampsia are high with a large percentage requiring caesarean section and intensive care admission.