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1.
J Cell Sci ; 135(5)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33414166

RESUMO

Ferroptosis is a regulated, non-apoptotic form of cell death, characterized by hydroxy-peroxidation of discrete phospholipid hydroperoxides, particularly hydroperoxyl (Hp) forms of arachidonoyl- and adrenoyl-phosphatidylethanolamine, with a downstream cascade of oxidative damage to membrane lipids, proteins and DNA, culminating in cell death. We recently showed that human trophoblasts are particularly sensitive to ferroptosis caused by depletion or inhibition of glutathione peroxidase 4 (GPX4) or the lipase PLA2G6. Here, we show that trophoblastic ferroptosis is accompanied by a dramatic change in the trophoblast plasma membrane, with macro-blebbing and vesiculation. Immunofluorescence revealed that ferroptotic cell-derived blebs stained positive for F-actin, but negative for cytoplasmic organelle markers. Transfer of conditioned medium that contained detached macrovesicles or co-culture of wild-type target cells with blebbing cells did not stimulate ferroptosis in target cells. Molecular modeling showed that the presence of Hp-phosphatidylethanolamine in the cell membrane promoted its cell ability to be stretched. Together, our data establish that membrane macro-blebbing is characteristic of trophoblast ferroptosis and can serve as a useful marker of this process. Whether or not these blebs are physiologically functional remains to be established.

2.
Placenta ; 108: 32-38, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33812183

RESUMO

Programmed cell death is a central process in the control of tissue development, organismal physiology, and disease. Ferroptosis is a recently identified form of programmed cell death that is uniquely defined by redox-active iron-dependent hydroxy-peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids and a loss of lipid peroxidation repair capacity. This distinctive form of lipotoxic cell death has been recently implicated in multiple human diseases, spanning ischemia-reperfusion heart injury, brain damage, acute kidney injury, cancer, and asthma. Intriguingly, settings that have been associated with ferroptosis are linked to placental physiology and trophoblast injury. Such circumstances include hypoxia-reperfusion during placental development, physiological uterine contractions or pathological changes in placental bed perfusion, the abundance of trophoblastic iron, evidence for lipotoxicity during the pathophysiology of major placental disorders such as preeclampsia, fetal growth restriction, and preterm birth, and reduced glutathione peroxidation capacity and lipid peroxidation repair during placental injury. We recently interrogated placental ferroptosis in placental dysfunction in human and mouse pregnancy, dissected its relevance to placental injury, and validated the role of glutathione peroxidase-4 in guarding placental trophoblasts against ferroptotic injury. We also uncovered a role for the phospholipase PLA2G6 (PNPLA9) in attenuating trophoblast ferroptosis. Here, we summarize current data on trophoblast ferroptosis, and the role of several proteins and microRNAs as regulators of this process. Our text offers insights into new opportunities for regulating ferroptosis as a means for protecting placental trophoblasts against lipotoxic injury.

3.
Nat Chem Biol ; 17(4): 465-476, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542532

RESUMO

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2ß (iPLA2ß, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2ß averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2ß expression and a PD-relevant phenotype. Thus, iPLA2ß is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.


Assuntos
Ferroptose/fisiologia , Fosfolipases A2 do Grupo VI/metabolismo , Animais , Araquidonato 15-Lipoxigenase/metabolismo , Modelos Animais de Doenças , Feminino , Fosfolipases A2 do Grupo VI/fisiologia , Humanos , Ferro/metabolismo , Leucotrienos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Peróxidos Lipídicos/metabolismo , Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Doença de Parkinson/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Fosfolipases/metabolismo , Fosfolipídeos/metabolismo , Ratos , Ratos Endogâmicos Lew
4.
Proc Natl Acad Sci U S A ; 117(44): 27319-27328, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33087576

RESUMO

The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidylethanolamine (Hp-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to nontoxic lipid alcohols in a tissue-specific manner. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental dysfunction is largely unknown. We found that spontaneous preterm birth is associated with ferroptosis and that inhibition of GPX4 causes ferroptotic injury in primary human trophoblasts and during mouse pregnancy. Importantly, we uncovered a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolize Hp-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia/reoxygenation injury in vivo. Together, we identified ferroptosis signaling in the human and mouse placenta, established a role for PLA2G6 in attenuating trophoblastic ferroptosis, and provided mechanistic insights into the ill-defined placental lipotoxicity that may inspire PLA2G6-targeted therapeutic strategies.

5.
Am J Perinatol ; 37(3): 291-295, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31858499

RESUMO

OBJECTIVE: Animal studies indicate a possible intrauterine immunological imprinting in pregnancies complicated by hypothyroidism. We aimed to evaluate whether exposure to maternal hypothyroidism during pregnancy increases the risk of long-term infectious morbidity of the offspring. STUDY DESIGN: A retrospective cohort study compared the long-term risk of hospitalization associated with infectious morbidity in children exposed and unexposed in utero to maternal hypothyroidism. Outcome measures included infectious diagnoses obtained during any hospitalization of the offspring (up to the age of 18 years). RESULTS: The study included 224,950 deliveries. Of them, 1.1% (n = 2,481) were diagnosed with maternal hypothyroidism. Children exposed to maternal hypothyroidism had a significantly higher rate of hospitalizations related to infectious morbidity (13.2 vs. 11.2% for control; odds ratio: 1.2; 95% confidence interval: 1.08-1.36; p = 0.002). Specifically, incidences of ear, nose, and throat; respiratory; and ophthalmic infections were significantly higher among the exposed group. The Kaplan-Meier curve indicated that children exposed to maternal hypothyroidism had higher cumulative rates of long-term infectious morbidity. In the Cox proportional hazards model, maternal hypothyroidism remained independently associated with an increased risk of infectious morbidity in the offspring while adjusting for confounders. CONCLUSION: Maternal hypothyroidism during pregnancy is associated with significant pediatric infectious morbidity of the offspring.


Assuntos
Doenças Transmissíveis/epidemiologia , Hipotireoidismo , Doenças do Recém-Nascido/epidemiologia , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Feminino , Hospitalização , Humanos , Incidência , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Gravidez , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco
6.
Am J Perinatol ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31756758

RESUMO

OBJECTIVE: To determine whether isolated single umbilical artery (iSUA), even absent identifiable genitourinary (GU) abnormalities, increases the risk of GU infection during childhood. STUDY DESIGN: Retrospective population-based comparison of fetuses with iSUA versus normal three-vessel cords. Fetuses with growth restriction, prematurity, multiple gestations, and anatomical or chromosomal anomalies were excluded. The primary outcome was hospital-associated GU infection during the first 18 years of life. Kaplan-Meier's survival curves were used to assess cumulative risk; Cox's multivariable models were used to adjust for confounders. RESULTS: Among 227,599 term singleton deliveries, children with iSUA (n = 729) had a higher incidence (1.8 vs. 0.6%, p < 0.001) and cumulative incidence (log-rank test, p < 0.001) of hospital-associated GU infection. The Cox's models confirmed these findings (hazard ratio: >2.82, confidence interval: 1.63-4.87 in composite models). CONCLUSION: iSUA represents an independent risk factor for GU infection. Urinary tract imaging may be warranted.

7.
Am J Perinatol ; 36(9): 975-980, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30477033

RESUMO

OBJECTIVE: Previous studies suggested maternal hypothyroidism during pregnancy to be associated with cognitive impairment of the offspring. Scarce data exist regarding long-term endocrine health of the offspring. This study was aimed to assess whether children born to mothers with hypothyroidism during pregnancy are at an increased risk for long-term endocrine morbidity. STUDY DESIGN: A retrospective population-based cohort study compared long-term endocrine morbidity of children born between the years 1991 and 2014 to mothers with and without hypothyroidism. Multiple gestations, fetuses with congenital malformations, and women lacking prenatal care were excluded. Hospitalizations of the offspring up to the age of 18 years involving endocrine morbidity were evaluated according to a predefined set of ICD-9 codes. Kaplan-Meier's survival curves were used to compare the cumulative risk and a Cox multivariable model was used to adjust for confounders. RESULTS: During the study period, 217,910 deliveries met the inclusion criteria; 1.1% of which were with maternal hypothyroidism (n = 2,403). During the follow-up period, the cumulative incidence of endocrine morbidity among children born to mothers with hypothyroidism was 27 per 1,000 person-years and 0.47 per 1,000 person-years in the comparison group (relative risk: 2.14; 95% confidence interval [CI]: 1.21-3.79). The Kaplan-Meier's survival curve demonstrated a significantly higher cumulative endocrine morbidity in children born to mothers with hypothyroidism (log-rank test, p = 0.007). In the Cox regression model controlled for maternal age, birth weight, preterm birth, maternal diabetes, hypertensive disorders of pregnancy, induction of labor, and mode of delivery, maternal hypothyroidism was found to be independently associated with pediatric endocrine morbidity in the offspring (adjusted hazard ratio = 1.92, 95% CI: 1.08-3.4, p = 0.025). CONCLUSION: Maternal hypothyroidism appears to be independently associated with long-term pediatric endocrine morbidity of the offspring.


Assuntos
Doenças do Sistema Endócrino/etiologia , Hipotireoidismo , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Adolescente , Criança , Pré-Escolar , Diabetes Mellitus/etiologia , Feminino , Hospitalização , Humanos , Hipoglicemia/etiologia , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Obesidade Pediátrica/etiologia , Gravidez , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Doenças da Glândula Tireoide/etiologia
8.
Arch Gynecol Obstet ; 298(4): 781-787, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30116931

RESUMO

PURPOSE: To investigate whether patients with a history of recurrent pregnancy loss (RPL) have an increased risk for future female malignancies. METHODS: A retrospective population-based study compared the incidence of long-term female malignancies in a cohort of women with and without a history of RPL (2 or more consecutive pregnancy losses). Deliveries occurred between the years 1988 and 2013, with a mean follow-up duration of 12 years. Women with known malignancies before the index pregnancy were excluded from the analysis. Female malignancies were divided according to specific type including ovary, breast, uterine and uterine cervix. Kaplan-Meier survival curve was used to estimate the cumulative incidence of malignancies. Cox proportional hazards model was used to determine the adjusted hazard ratios (HR) for female malignancy after controlling for confounders. RESULTS: During the study period, 106,265 patients met the inclusion criteria; 6.6% (n = 7052) of patients had a diagnosis of RPL. During the follow-up period, patients with RPL had a significantly increased risk of being diagnosed with female malignancies as a group, while individually there was an increased risk of breast and uterine cervix cancer. Using a Kaplan-Meier survival curve, patients with a history of RPL had a significantly higher cumulative incidence of female malignancies. Using a Cox proportional hazards model, adjusted for confounders such as smoking, parity, and diabetes mellitus, a history of RPL remained independently associated with female malignancies (adjusted HR 1.4; P = 0.003). CONCLUSIONS: RPL is independently associated with long-term female malignancies. Patients with a history of RPL may benefit from counseling and screening for breast and uterine cervix cancer in particular.


Assuntos
Aborto Habitual , Neoplasias da Mama/etiologia , Neoplasias dos Genitais Femininos/etiologia , Adulto , Feminino , Humanos , Gravidez , Modelos de Riscos Proporcionais , Estudos Retrospectivos
9.
Arch Gynecol Obstet ; 296(6): 1103-1107, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28975407

RESUMO

PURPOSE: To investigate whether children born with isolated single umbilical artery (iSUA) at term are at an increased risk for long-term pediatric hospitalizations due to respiratory morbidity. METHODS: Design: a population-based cohort study compared the incidence of long-term, pediatric hospitalizations due to respiratory morbidity in children born with and without iSUA at term. SETTING: Soroka University Medical Center. PARTICIPANTS: all singleton pregnancies of women who delivered between 1991 and 2013. MAIN OUTCOME MEASURE(S): hospitalization due to respiratory morbidity. ANALYSES: Kaplan-Meier survival curves were used to estimate cumulative incidence of respiratory morbidity. A Cox hazards model analysis was used to establish an independent association between iSUA and pediatric respiratory morbidity of the offspring while controlling for clinically relevant confounders. RESULTS: The study included 232,281 deliveries. 0.3% were of newborns with iSUA (n = 766). Newborns with iSUA had a significantly higher rate of long-term respiratory morbidity compared to newborns without iSUA (7.6 vs 5.5%, p = 0.01). Using a Kaplan-Meier survival curve, newborns with iSUA had a significantly higher cumulative incidence of respiratory hospitalizations (log rank = 0.006). In the Cox model, while controlling for the maternal age, gestational age, and birthweight, iSUA at term was found to be an independent risk factor for long-term respiratory morbidity (adjusted HR = 1.39, 95% CI 1.08-1.81; p = 0.012). CONCLUSION: Newborns with iSUA are at an increased risk for long-term respiratory morbidity.


Assuntos
Resultado da Gravidez , Artéria Umbilical Única/mortalidade , Nascimento a Termo , Adulto , Peso ao Nascer , Estudos de Casos e Controles , Criança , Feminino , Idade Gestacional , Hospitalização , Humanos , Incidência , Recém-Nascido , Israel/epidemiologia , Estimativa de Kaplan-Meier , Pneumopatias/epidemiologia , Masculino , Morte Perinatal , Mortalidade Perinatal , Gravidez , Fatores de Risco , Artéria Umbilical Única/patologia
10.
Arch Gynecol Obstet ; 295(6): 1477-1482, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28389884

RESUMO

PURPOSE: To investigate whether patients with a history of gestational diabetes mellitus (GDM) have an increased risk for long-term ophthalmic morbidity. METHODS: Design a population-based study compared the incidence of long-term maternal ophthalmic morbidity in a cohort of women with and without a history of GDM. Setting Soroka University Medical Center. PARTICIPANTS: All singleton pregnancies of women who delivered between 1988 and 2013. Main outcome measure(s) Diagnosis of ophthalmic morbidity. Analyses A Kaplan-Meier survival curve was used to estimate cumulative incidence of ophthalmic morbidity. Cox proportional hazards models were used to estimate the adjusted hazard ratios (HR) for ophthalmic morbidity. RESULTS: During the study period, 104,751 deliveries met the inclusion criteria; 9.4% (n = 9888) of which occurred in patients with a diagnosis of GDM during at least one of their pregnancies. Patients with GDM had a significantly higher incidence of ophthalmic morbidity such as glaucoma, diabetic retinopathy, and retinal detachment compared with controls (0.1 vs. 0.02%, p < 0.001; 0.2 vs. 0.04%, p < 0.001; 0.2 vs. 0.1%, p < 0.001, respectively). Patients with concurrent GDM and preeclampsia had a significantly higher incidence of total ophthalmic complications compared to patients with GDM only (1 vs. 0.6%, respectively, p < 0.001). Using Kaplan-Meier survival curve, patients with a previous diagnosis of GDM had significantly higher cumulative incidence of ophthalmic morbidity (p < 0.001, log-rank test). In the Cox proportional hazards model, a history of GDM remained independently associated with ophthalmic morbidity (adjusted HR 2.0; 95% CI 1.5-2.8; p < 0.001). CONCLUSIONS: GDM is an independent risk factor for long-term maternal ophthalmic morbidity.


Assuntos
Diabetes Gestacional/patologia , Oftalmopatias/epidemiologia , Adulto , Oftalmopatias/complicações , Feminino , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Idade Materna , Morbidade , Pré-Eclâmpsia/patologia , Gravidez , Modelos de Riscos Proporcionais , Fatores de Risco
11.
Paediatr Perinat Epidemiol ; 31(2): 149-156, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28181680

RESUMO

BACKGROUND: Preterm delivery may affect the development of the upper airways resulting in a higher risk of obstructive sleep apnoea (OSA). We investigated whether children born at early term (37-38 6/7 weeks' gestation) are at an increased risk for childhood OSA as compared with those born later. METHODS: In this population-based cohort analysis all singleton deliveries occurring between 1991-2013 at a single regional tertiary medical centre were included. Gestational age upon delivery was sub-divided into: early preterm (<33 6/7 weeks' gestation), late preterm (34-36 6/7), early term, full term (39-40 6/7), late term (41-41 6/7), and post term (>42 0/7). Incidence of OSA related hospitalizations of the offspring, up to the age of 18 years, was evaluated. A survival curve and a Cox model were used to assess the association. RESULTS: During the study period 240 953 deliveries met the inclusion criteria. OSA hospitalization (n = 1320) rates decreased as gestational age increased from 1.1% in the early preterm group, 0.8% in late preterm, 0.7% at early term, 0.5% in full term, 0.4% in late term, to 0.3% in post term born children. In the Cox regression, early term delivery exhibited an increased risk for paediatric OSA (adjusted hazard ratio (HR) 1.3 95% Confidence interval (CI) 1.2, 1.5) while late and post term deliveries were associated with significantly lower OSA risk when compared with full term (HR 0.8 95% CI 0.6, 0.9 and HR 0.6 95% CI 0.4, 0.8, respectively). CONCLUSIONS: Early term deliveries are associated with higher rates of paediatric OSA, which decrease gradually as gestational age advances.


Assuntos
Nascimento Prematuro , Apneia Obstrutiva do Sono/etiologia , Adolescente , Análise de Variância , Criança , Pré-Escolar , Feminino , Idade Gestacional , Hospitalização/estatística & dados numéricos , Humanos , Israel/epidemiologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Fatores de Risco , Apneia Obstrutiva do Sono/epidemiologia
12.
PLoS One ; 12(2): e0172174, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28199380

RESUMO

INTRODUCTION: Research in animal models and preliminary clinical studies in humans support the use of pravastatin for the prevention of preeclampsia. However, its use during pregnancy is still controversial due to limited data about its effect on the human placenta and fetus. METHODS: In the present study, human placental cotyledons were perfused in the absence or presence of pravastatin in the maternal reservoir (PraM). In addition, placental explants were treated with pravastatin for 5, 24 and 72 h under normoxia and hypoxia. We monitored the secretion of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), endothelial nitric oxide synthase (eNOS) expression and activation and the fetal vasoconstriction response to angiotensin-II. RESULTS: The concentrations of PlGF, sFlt-1 and sEng were not significantly altered by pravastatin in PraM cotyledons and in placental explants compared to control. Under hypoxic conditions, pravastatin decreased sFlt-1 concentrations. eNOS expression was significantly increased in PraM cotyledons but not in pravastatin-treated placental explants cultured under normoxia or hypoxia. eNOS phosphorylation was not significantly affected by pravastatin. The feto-placental vascular tone and the fetal vasoconstriction response to angiotensin-II, did not change following exposure of the maternal circulation to pravastatin. CONCLUSION: We found that pravastatin does not alter the essential physiological functions of the placenta investigated in the study. The relevance of the study lays in the fact that it expands the current knowledge obtained thus far regarding the effect of the drug on the normal human placenta. This data is reassuring and important for clinicians that consider the treatment of high-risk patients with pravastatin, a treatment that exposes some normal pregnancies to the drug.


Assuntos
Anticolesterolemiantes/farmacologia , Modelos Biológicos , Placenta/efeitos dos fármacos , Pravastatina/farmacologia , Endoglina/genética , Endoglina/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Placenta/metabolismo , Fator de Crescimento Placentário/genética , Fator de Crescimento Placentário/metabolismo , Gravidez , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
13.
Metallomics ; 9(3): 228-238, 2017 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-28091657

RESUMO

Traditionally, proteins are considered to perform a single role, be it as an enzyme, a channel, a transporter or as a structural scaffold. However, recent studies have described moonlighting proteins that perform distinct and independent functions; for example, TRPM7 is both an ion channel and a kinase. ZnT-1 is a member of the Carrier Diffusion Facilitator family that is expressed throughout the phylogenetic tree from bacteria to humans. Since its cloning in 1995, ZnT-1 is considered a major extruder of Zn2+ based on its capability to protect cells against zinc toxicity. Recently, we reported that ZnT-1 inhibits the L-type calcium channel (LTCC), a major Zn2+ and Ca2+ entry pathway. Here we show that ZnT-1 is a dual-function protein by demonstrating that its abilities to exchange Zn2+/H+ and to inhibit the LTCC are independent of each other and are mediated by different parts of the protein. Specifically, mutations in the membrane-spanning helices that render ZnT-1 unable to transport zinc do not prevent it from inhibiting the LTCC. Moreover, a fragment consisting of the intracellular ZnT-1 C-terminal, which lacks all ion-transfer segments, inhibits the LTCC as efficiently as wild-type ZnT-1. Our data therefore indicates that ZnT-1 performs two structurally independent functions related to zinc homeostasis.


Assuntos
Canais de Cálcio Tipo L/química , Proteínas de Transporte de Cátions/metabolismo , Xenopus/fisiologia , Zinco/farmacologia , Sequência de Aminoácidos , Animais , Células CHO , Canais de Cálcio Tipo L/metabolismo , Proteínas de Transporte de Cátions/genética , Cricetinae , Cricetulus , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Células HEK293 , Homeostase , Humanos , Transporte de Íons , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação , Oócitos/citologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Alinhamento de Sequência
14.
Pediatr Pulmonol ; 52(2): 198-204, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27458900

RESUMO

OBJECTIVE: Newborns exhibit the lowest immediate respiratory morbidity rates when born following 39 completed weeks of gestation. We sought to determine whether early-term delivery (37-38 + 6 weeks' gestation) impacts on long-term pediatric respiratory morbidity. STUDY DESIGN: In this population-based prospective cohort analysis, all term singleton deliveries occurring between 1991 and 2013 at a single tertiary medical center were included. Gestational age upon delivery was sub-divided into: early (37-38 + 6 weeks' gestation), full (39-40 + 6 weeks' gestation), late (41-41 + 6 weeks' gestation), and post-term (>42 weeks) deliveries. The incidence of long-term hospitalizations (up to the age of 18 years) of the offspring due to a set of predefined respiratory morbidities was evaluated. Survival curves were used to compare cumulative morbidity incidence. A Cox hazards regression model was used to control for confounders. RESULTS: During the study period, 229,142 term deliveries met the inclusion criteria. Of those, 24% (n = 55,202) occurred at early term. Hospitalizations up to the age of 18 years, as a result of complications in the respiratory system were significantly more common in the early-term group as compared with full and late-term delivery groups. In the Cox regression model, while controlling for multiple confounders, early-term delivery exhibited an independent association with long-term respiratory morbidity (adjusted HR = 1.24, CI 1.19-1.29, P < 0.001). CONCLUSION: Deliveries occurring at early term are associated with higher rates of pediatric respiratory hospitalizations compared with full and late-term deliveries. Pediatr Pulmonol. 2017;52:198-204. © 2016 Wiley Periodicals, Inc.


Assuntos
Idade Gestacional , Hospitalização/estatística & dados numéricos , Doenças Respiratórias/epidemiologia , Nascimento a Termo , Adolescente , Adulto , Asma/epidemiologia , Bronquiolite/epidemiologia , Criança , Pré-Escolar , Parto Obstétrico , Feminino , Humanos , Incidência , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Influenza Humana/epidemiologia , Estudos Longitudinais , Morbidade , Pneumonia/epidemiologia , Gravidez , Gravidez Prolongada/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Infecções Respiratórias/epidemiologia , Fatores de Risco , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-27219201

RESUMO

OBJECTIVE: The long-term impact of placenta previa on term infants is unknown. We aimed to investigate whether abnormal placentation increases the risk for long-term morbidity of the term offspring. STUDY DESIGN: A population-based cohort study compared the incidence of long-term hospitalizations up to the age of 18 due to cardiovascular, endocrine, neurological, hematological, respiratory and urinary morbidity of children born at term in pregnancies diagnosed with placenta previa and those without. Deliveries occurred between the years 1991-2013 in a tertiary medical center. Multiple pregnancies, and fetal congenital malformations were excluded. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence over time. A multivariable generalized estimating equation (GEE) logistic regression model analysis was used to control for confounders and for maternal clusters. RESULTS: During the study period 233,123 term deliveries met the inclusion criteria; 0.2% (n=502) of the children were born to mothers with placenta previa. During the follow-up period, children born to mothers with placenta previa did not have an increased risk for long-term cardiovascular, endocrine, hematological, neurological, respiratory, and urinary morbidity. CONCLUSION: Term offsprings of mothers diagnosed with placenta previa do not appear to be at an increased risk for long-term morbidity up to the age of 18.


Assuntos
Hospitalização/estatística & dados numéricos , Placenta Prévia/epidemiologia , Adolescente , Doenças Cardiovasculares/epidemiologia , Criança , Pré-Escolar , Doenças do Sistema Endócrino/epidemiologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Pneumopatias/epidemiologia , Masculino , Doenças do Sistema Nervoso/epidemiologia , Gravidez , Resultado da Gravidez/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Nascimento a Termo
16.
Arch Gynecol Obstet ; 294(5): 931-935, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27048509

RESUMO

OBJECTIVE: To determine whether an isolated single umbilical artery (iSUA) is an independent risk factor for perinatal mortality in term neonates with normal estimated fetal weight (EFW) prior to delivery. METHOD: A population-based study was conducted, including all deliveries occurring between 1993 and 2013, in a tertiary medical center. Pregnancies with and without iSUA were compared. Multiple gestations, chromosomal, and structural abnormalities were excluded from the cohort. Only pregnancies delivered at term with normal EFW evaluated prior to delivery were included. Stratified analysis was performed using multiple logistic regression models to evaluate the risk of adverse outcomes and perinatal mortality for iSUA fetuses. RESULTS: During the study period, 233,123 deliveries occurred at "Soroka" University Medical Center, out of which 786 (0.3 %) were diagnosed with iSUA. Different pregnancy complications were more common with iSUA fetuses including: placental abruption (OR = 3.4), true knot of cord (OR = 3.5) and cord prolapse (OR = 2.8). Induction of labor and cesarean delivery were also more common in these pregnancies (OR = 1.5 and OR = 1.9, respectively). iSUA neonates had lower Apgar scores at 1 and 5 min (OR = 1.8, OR = 1.9, respectively) compared to the control group and perinatal mortality rates were higher both antenatally (IUFD, OR = 8.1) and postnatally (PPD, OR = 6.1). CONCLUSION: iSUA appears to be an independent predictor of adverse perinatal outcomes in term neonates.


Assuntos
Artéria Umbilical Única/mortalidade , Adulto , Feminino , Humanos , Recém-Nascido , Israel/epidemiologia , Morte Perinatal , Mortalidade Perinatal , Gravidez , Estudos Retrospectivos , Fatores de Risco , Artéria Umbilical Única/patologia , Resultado do Tratamento
17.
J Crohns Colitis ; 10(11): 1267-1272, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27085078

RESUMO

BACKGROUND AND AIMS: To investigate whether offspring of women suffering from inflammatory bowel disease [IBD] during their pregnancy are at an increased risk for long-term paediatric morbidity. METHODS: In this population-based cohort study, we investigated the incidence of long-term [up to the age of 18 years] hospitalizations due to cardiovascular, endocrine, neurological, haematological, respiratory, gastrointestinal, and urinary paediatric morbidities of offspring of mothers affected by IBD during their pregnancy. Deliveries occurred between the years 1991 and 2014 in a regional tertiary medical centre. Newborns with congenital malformations as well as multiple pregnancies were excluded from the study. RESULTS: During the study period, 255 352 deliveries met the inclusion criteria; 278 offspring were born to mothers with IBD. During the follow-up period, children born to mothers with IBD did not have an increased risk for long-term [up to the age of 18 years] morbidity compared with the control group. CONCLUSION: Maternal IBD during pregnancy is not a risk factor for long-term paediatric morbidity of the offspring.


Assuntos
Doenças Inflamatórias Intestinais/complicações , Complicações na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Morbidade , Gravidez , Estudos Retrospectivos , Fatores de Risco
18.
Am J Perinatol ; 33(7): 708-14, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26874352

RESUMO

Objective Spontaneous preterm deliveries (PTDs) have been consistently associated with maternal vascular complications. We aimed to investigate an association between PTD and subsequent maternal ophthalmic morbidity. Study Design In this population-based cohort study, we included all singleton deliveries occurring between 1988 and 2013. We excluded women with known ophthalmic disease. The exposure was at least one pregnancy with PTD. Outcomes included different maternal ophthalmic morbidity. The cumulative incidence and adjusted hazard ratios were assessed using a Kaplan-Meier survival curve and Cox hazards models. Results Of the 105,018 patients included, 17,600 (16.7%) delivered preterm. Patients with a history of PTD (both induced and spontaneous) had higher rates of ophthalmic complications (odds ratio [OR]: 2.12; confidence interval [CI]: 1.6-2.7; p < 0.001), specifically diabetic retinopathy and glaucoma (OR: 4.79 and 2.48, respectively). A linear association was found between the number of previous PTDs and ophthalmic complications (0.2% for no PTD; 0.4% for one PTD; 0.6% for two or more PTDs; p < 0.001) and for early and late PTD (p < 0.001). A Cox model revealed an independent association between PTD and ophthalmic complications (adjusted hazard ratio: 2.2; 95% CI: 1.6-2.9). Conclusion A history of PTD is an independent risk factor for ophthalmic morbidity.


Assuntos
Retinopatia Diabética/epidemiologia , Oftalmopatias/epidemiologia , Nascimento Prematuro/epidemiologia , Adulto , Retinopatia Diabética/etiologia , Oftalmopatias/etiologia , Feminino , Seguimentos , Idade Gestacional , Humanos , Incidência , Israel , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Razão de Chances , Gravidez , Modelos de Riscos Proporcionais , Fatores de Risco , Adulto Jovem
19.
Am J Perinatol ; 33(7): 703-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26871904

RESUMO

Objective To investigate whether patients with a history of preeclampsia have an increased risk of long-term ophthalmic complications. Study Design A population-based study comparing the incidence of long-term maternal ophthalmic complications in a cohort of women with and without a history of preeclampsia. Results During the study period, a total of 103,183 deliveries met the inclusion criteria; 8.1% (n = 8,324) occurred in patients with a diagnosis of preeclampsia during at least one of their pregnancies. Patients with preeclampsia had a significantly higher incidence of long-term ophthalmic morbidity such as diabetic retinopathy and retinal detachment. In addition, a positive linear correlation was found between the severity of preeclampsia and the prevalence of future ophthalmic morbidities (0.3 vs. 0.5 vs. 2.2%, respectively). Kaplan-Meier survival curve indicated that women with preeclampsia had higher rates of total ophthalmic morbidity (0.2 vs. 0.4%, for no preeclampsia and with preeclampsia, respectively; odds ratio = 2.06, 95% confidence interval: 1.42-2.99; p < 0.001). In a Cox proportional hazards model, adjusted for confounders, a history of preeclampsia remained independently associated with ophthalmic complications. Conclusion Preeclampsia is an independent risk factor for long-term maternal ophthalmic morbidity, specifically diabetic retinopathy and retinal detachment. This risk is more substantial depending on the severity of the disease.


Assuntos
Oftalmopatias/epidemiologia , Pré-Eclâmpsia/epidemiologia , Adulto , Oftalmopatias/etiologia , Feminino , Seguimentos , Humanos , Incidência , Israel , Estimativa de Kaplan-Meier , Parto , Gravidez , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
20.
J Matern Fetal Neonatal Med ; 29(18): 2924-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26513488

RESUMO

OBJECTIVE: To investigate whether patients with a history of obesity during pregnancy have an increased risk for subsequent long-term ophthalmic complications, after controlling for diabetes and preeclampsia. METHODS: A population-based study compared the incidence of long-term maternal ophthalmic complications in a cohort of women with and without a history of obesity during pregnancy. Deliveries occurred between the years 1988 and 2013, with a mean follow-up duration of 12 years. RESULTS: During the study period 106 220 deliveries met the inclusion criteria; 2.2% (n = 2353) occurred in patients with a diagnosis of obesity during at least one of their pregnancies. These patients had a significantly higher incidence of ophthalmic complications in total and specifically of diabetic retinopathy. Using a Kaplan-Meier survival curve, we found that patients with a history of obesity during pregnancy had a significantly higher cumulative incidence of ophthalmic complications. Using a Cox proportional hazards model, adjusted for confounders such as maternal age, preeclampsia and diabetes mellitus, we found obesity during pregnancy remained independently associated with ophthalmic complications (adjusted HR, 2.4; 95% CI, 1.4-4.2; p = 0.003). CONCLUSION: Obesity during pregnancy is an independent risk factor for long-term ophthalmic complications, and specifically diabetic retinopathy.


Assuntos
Índice de Massa Corporal , Oftalmopatias/etiologia , Obesidade/complicações , Complicações na Gravidez , Adulto , Retinopatia Diabética/etiologia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Gravidez , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Adulto Jovem
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