RESUMO
More than 30 years have elapsed since it was recognised that folic acid supplementation could substantially reduce the risk of open neural tube defects (ONTDs). During that time, many countries have adopted policies of food fortification with demonstrable reduction in the incidence of both cranial and spinal ONTDs. Improved prenatal detection and termination has also resulted in a reduction in the number of affected live births. Nonetheless, in the USA about 1500 children, and in the UK around 500 children are born each year with myelomeningocele (MMC) and so the management of MMC and its complications continues to constitute a significant clinical workload for many paediatric neurosurgical units around the world.Until recently, the options available following antenatal diagnosis of MMC were termination of pregnancy or postnatal repair. As a result of the MOMS trial, prenatal repair has become an additional option in selected cases (Adzick et al., N Engl J Med 364(11):993-1004, 2011). Fetal surgery for myelomeningocele is now offered in more than 30 centres worldwide. The aim of this chapter is to review the experimental basis of prenatal repair of MMC, to critically evaluate the neurosurgical implications of this intervention and to describe the technique of 'open' repair, comparing this with emerging minimally invasive alternatives.
Assuntos
Terapias Fetais , Meningomielocele , Procedimentos Neurocirúrgicos , Criança , Feminino , Humanos , Gravidez , Unidades Hospitalares , Meningomielocele/cirurgia , VitaminasRESUMO
INTRODUCTION: Profound uterine relaxation is required for open fetal surgery. This is typically achieved by the administration of high-dose halogenated anesthetic agents. However, this anesthetic technique is associated with adverse cardiovascular effects in the fetus and may have long-term neurocognitive effects as well. CASE PRESENTATION: We pre-sent reports for 2 patients in whom uterine relaxation was maintained with nitroglycerin and magnesium infusions without any exposure to halogenated anesthetic agents. There were no adverse fetal or maternal effects from this technique. DISCUSSION/CONCLUSION: To the best of our knowledge, these are the first reports of open fetal surgery being performed without the use of halogenated anesthetic agents. This has potential short- and long-term benefits for the fetus, particularly as more complex and longer duration minimally invasive procedures are developed.
Assuntos
Anestésicos , Terapias Fetais , Feminino , Feto/cirurgia , Humanos , Gravidez , Cuidado Pré-NatalRESUMO
BACKGROUND: Toll-like receptor (TLR) agonists are key immunomodulatory factors that can markedly ameliorate or exacerbate hypoxic-ischemic brain injury. We recently demonstrated that central infusion of the TLR7 agonist Gardiquimod (GDQ) following asphyxia was highly neuroprotective after 3 days but not 7 days of recovery. We hypothesize that this apparent transient neuroprotection is associated with modulation of seizure-genic processes and hemodynamic control. METHODS: Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion (20.9 ± 0.5 min) and were monitored continuously for 7 days. GDQ 3.34 mg or vehicle were infused intracerebroventricularly from 1 to 4 h after asphyxia. RESULTS: GDQ infusion was associated with sustained moderate hypertension that resolved after 72 h recovery. Electrophysiologically, GDQ infusion was associated with reduced number and burden of postasphyxial seizures in the first 18 h of recovery (p < 0.05). Subsequently, GDQ was associated with induction of slow rhythmic epileptiform discharges (EDs) from 72 to 96 h of recovery (p < 0.05 vs asphyxia + vehicle). The total burden of EDs was associated with reduced numbers of neurons in the caudate nucleus (r2 = 0.61, p < 0.05) and CA1/2 hippocampal region (r2 = 0.66, p < 0.05). CONCLUSION: These data demonstrate that TLR7 activation by GDQ modulated blood pressure and suppressed seizures in the early phase of postasphyxial recovery, with subsequent prolonged induction of epileptiform activity. Speculatively, this may reflect delayed loss of early protection or contribute to differential neuronal survival in subcortical regions.
Assuntos
Aminoquinolinas/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Imidazóis/uso terapêutico , Convulsões/prevenção & controle , Receptor 7 Toll-Like/agonistas , Aminoquinolinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Eletroencefalografia , Feminino , Terapias Fetais/métodos , Hipóxia-Isquemia Encefálica/complicações , Imidazóis/farmacologia , Gravidez , Nascimento Prematuro , Convulsões/etiologia , OvinosRESUMO
Intrauterine growth restriction affects up to 10% of all pregnancies, leading to fetal programming with detrimental consequences for lifelong health. However, no therapeutic strategies have so far been effective to ameliorate these consequences. Our previous study has demonstrated that a single dose of nutrients administered into the amniotic cavity, bypassing the often dysfunctional placenta via intra-amniotic administration, improved survival at birth but not birthweight in an intrauterine growth restriction rabbit model. The aim of this study was to further develop an effective strategy for intra-amniotic fetal therapy in an animal model. Intrauterine growth restriction was induced by selective ligation of uteroplacental vessels on one uterine horn of pregnant rabbits at gestational day 25, and fetuses were delivered by cesarean section on GD30. During the five days of intrauterine growth restriction development, three different methods of intra-amniotic administration were used: continuous intra-amniotic infusion by osmotic pump, multiple intra-amniotic injections, and single fetal intraperitoneal injection. Technical feasibility, capability to systematically reach the fetus, and survival and birthweight of the derived offspring were evaluated for each technique. Continuous intra-amniotic infusion by osmotic pump was not feasible owing to the high occurrence of catheter displacement and amnion rupture, while methods using two intra-amniotic injections and one fetal intraperitoneal injection were technically feasible but compromised fetal survival. Taking into account all the numerous factors affecting intra-amniotic fetal therapy in the intrauterine growth restriction rabbit model, we conclude that an optimal therapeutic strategy with low technical failure and positive fetal impact on both survival and birthweight still needs to be found.
Assuntos
Retardo do Crescimento Fetal/dietoterapia , Terapias Fetais/instrumentação , Nutrientes/administração & dosagem , Terapia Nutricional/instrumentação , Líquido Amniótico/metabolismo , Animais , Peso ao Nascer , Catéteres/efeitos adversos , Feminino , Retardo do Crescimento Fetal/tratamento farmacológico , Terapias Fetais/métodos , Bombas de Infusão/efeitos adversos , Injeções Intraperitoneais/efeitos adversos , Terapia Nutricional/métodos , CoelhosRESUMO
Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed in order to improve the outcome of these treatments for HA patients. Taking advantage of preclinical mouse models of hemophilia, several strategies have been proposed in recent years to prevent inhibitor formation and eradicate the pre-existing immunity to FVIII inhibitor positive patients. Herein, we will review some of the most promising strategies developed to avoid and eradicate inhibitors, including the use of immunomodulatory drugs or molecules, oral or transplacental delivery as well as cell and gene therapy approaches. The goal is to improve and potentiate the current ITI protocols and eventually make them obsolete.
Assuntos
Fator VIII/imunologia , Hemofilia A/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Isoanticorpos/imunologia , Transferência Adotiva , Animais , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Portadores de Fármacos , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Fator IXa/imunologia , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Fator X/imunologia , Feminino , Terapias Fetais , Terapia Genética , Hemofilia A/imunologia , Hemofilia A/terapia , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Imunoterapia Adotiva , Isoanticorpos/biossíntese , Tecido Linfoide/imunologia , Camundongos , Modelos Animais , Células Vegetais , Gravidez , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Linfócitos T Reguladores/transplanteRESUMO
PURPOSE: The aim of this study was to survey the frequency of various anesthetic techniques used in the anesthetic management of both the mother and fetus during fetal therapies in Japan. METHODS: We sent a postal survey to the institutions with physicians who held membership of the Japan Society of Fetal Therapy to describe maternal and fetal anesthetic management during fetal therapies performed from January 2016 to March 2017. The therapies included were thoracoamniotic shunting (TAS), intrauterine transfusion (IUT), radiofrequency ablation (RFA), fetoscopic laser photocoagulation (FLP), fetoscopic endotracheal occlusion (FETO), and ex utero intrapartum treatment (EXIT). Survey respondents were asked to specify the standard anesthetic technique used in each of these procedures done during the study period. RESULTS: The most common anesthetic techniques used in each therapy were sedation/analgesia with local anesthesia in TAS (31%), local anesthesia alone in IUT (47%), neuraxial anesthesia in RFA (50%), FLP (66%) and FETO (100%), and general endotracheal anesthesia in EXIT. Fetal analgesia was utilized in 61% of TAS, 33% of IUT, 10% of RFA, 22% of FLP, 100% of FETO, and 50% of EXIT. In all fetal therapies, the most common route of administration for fetal anesthesia was maternal administration. CONCLUSION: In this first published description of the frequency of various anesthetic techniques used during fetal therapies in Japan, we found that anesthetic techniques varied depending on the degree of invasiveness to the mother and fetus. Fetal anesthesia was not always performed, and the most common route for fetal anesthesia was maternal administration.
Assuntos
Anestésicos/administração & dosagem , Terapias Fetais/estatística & dados numéricos , Fetoscopia/estatística & dados numéricos , Anestesia Geral/estatística & dados numéricos , Anestesia Local/estatística & dados numéricos , Feminino , Humanos , Japão , Gravidez , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: This study presented outcomes of classical hysterotomy with modified antiprostaglandin therapy for intrauterine repair of foetal myelomeningocele (fMMC) performed in a single perinatal centre. STUDY DESIGN: Forty-nine pregnant women diagnosed with fMMC underwent classic hysterotomy with anti-prostaglandin management, complete amniotic fluid replacement and high dose indomethacin application. RESULTS: The average gestational age (GA) at delivery was 34.4 ± 3.4 weeks, with no births before 30 weeks GA. There were 2 foetal deaths. Complete reversal of hindbrain herniation (HH), assessed in magnetic resonance imaging at 30-31 weeks GA was found in 72% of foetuses (mostly with HH grade I prior to fMMC repair). Our protocol resulted in rare use of magnesium sulphate (6%), low incidence of chorioamniotic membrane separation - chorioamniotic membrane separation (6%), preterm premature rupture of membranes - preterm premature rupture of membranes (pPROM; 15%) and preterm labour - preterm labour (PTL; 17%). The postoperative wound continuity of the uterus was usually stable (in 72% of patients), with low frequency of scar thinning (23%). CONCLUSION: Our protocol results in rare use of tocolytics, and the low occurrences of CMS, pPROM and PTL in relation to other study cohorts: Management of Myelomeningocele Study, Children's Hospital of Philadelphia, and Vanderbilt University Medical Centre.
Assuntos
Líquido Amniótico , Anti-Inflamatórios não Esteroides/uso terapêutico , Terapias Fetais/métodos , Histerotomia , Indometacina/uso terapêutico , Meningomielocele/cirurgia , Procedimentos Cirúrgicos Obstétricos , Complicações Pós-Operatórias/prevenção & controle , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Feminino , Terapias Fetais/efeitos adversos , Terapias Fetais/mortalidade , Idade Gestacional , Humanos , Histerotomia/efeitos adversos , Histerotomia/mortalidade , Indometacina/efeitos adversos , Meningomielocele/diagnóstico por imagem , Meningomielocele/mortalidade , Procedimentos Cirúrgicos Obstétricos/efeitos adversos , Procedimentos Cirúrgicos Obstétricos/mortalidade , Mortalidade Perinatal , Polônia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Gravidez , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
OBJECTIVE: To determine if intrauterine intraumbilical supplementation with amino acids (AA) and glucose can improve neonatal outcome of severe growth restricted human fetuses (IUGR). METHODS: Prospective pilot study of intrauterine treatment of severe IUGR fetuses [n=14, 27 weeks of gestation (range 23-31)] with cerebroplacental ratio <1, with long-term intraumbilical AA and glucose supplementation (10% of feto-placental blood volume/day) using a perinatal port system alone (n=5) or combined with hyperbaric oxygenation (n=1, HBO) vs. control group (n=8). RESULTS: The duration of continuous intraumbilical AA/glucose supplementation was 11 (6-13) days. Daily intravascular fetal nutrition significantly prolonged the brain sparing to delivery interval by 24 (14-33) days vs. 5.6 (2-12) days in controls. Fetal nutrition reduced blood flow resistance in the placental circulation but did not affect the Doppler profile of cerebral arteries. Higher weight gain of 113.5 (36-539) g was observed following supplementation compared to 33.3 (8-98) g in the control group (P<0.05). In spite of this, fetuses below 28 weeks of gestation did not sufficiently benefit from infused commercial AA. We found a reduced fetal plasma concentration of the essential AA histidine, threonine, lysine and arginine, and non-essential AA taurine, in severe IUGR fetuses in both groups. Long-term supplementation with a commercial AA formula led to a slight, but not significant, reduction of histidine, threonine, lysine, arginine, asparagine and glutamine. However, the concentration of tryptophan and glutamic acid slightly increased. HBO can be combined with AA supplementation via a port system. In one case, the port system was also successfully used for fetal blood transfusion. CONCLUSIONS: Intravascular treatment of IUGR with fetal nutrition can prolong pregnancy with severe placental insufficiency and brain sparing for many weeks. However, rather than normalizing AA concentrations, an enhanced AA imbalance was observed in IUGR fetuses following supplementation. These deviations in AA concentrations prevent the recommendation for use of commercial AA solutions for prenatal treatment of extreme preterm IUGR fetuses.
Assuntos
Cateterismo Venoso Central/métodos , Retardo do Crescimento Fetal/terapia , Terapias Fetais/métodos , Nutrição Parenteral/métodos , Dispositivos de Acesso Vascular , Adulto , Aminoácidos/administração & dosagem , Feminino , Glucose/administração & dosagem , Humanos , Projetos Piloto , Insuficiência Placentária , Gravidez , Estudos Prospectivos , Veias Umbilicais , Adulto JovemRESUMO
Spina bifida remains a challenging neurosurgical entity to manage despite both an increased awareness of the disease as well as a decreased incidence due to folic acid supplementation. We review the spectrum of neural tube defects, which are the second most common serious congenital defect and the most common of the central nervous system, and discuss the latest management paradigms. The challenges of timely diagnosis and treatment of spina bifida occulta and the latest advances in fetal repair of spina bifida aperta (myelomeningocele) will be discussed. The authors review the literature and share their experience with managing neural tube defects.
Assuntos
Espinha Bífida Oculta/diagnóstico , Espinha Bífida Oculta/cirurgia , Feminino , Doenças Fetais/cirurgia , Terapias Fetais/métodos , Feto/cirurgia , Humanos , GravidezRESUMO
BACKGROUND: Eczema affects 3.5% of the global population, with peak prevalence during infancy. Eczema has no cure, but probiotics have been suggested as a preventative measure. OBJECTIVE: To comprehensively analyze the impact of prenatal and postnatal probiotic supplementation on the prevention of infantile and childhood eczema. METHODS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and PubMed were searched for randomized controlled trials regarding probiotic usage and eczema development from 1945 to 2013. Participants included were 7 years old or younger with probiotic exposure in utero or below 6 months of age and who was not diagnosed previously. RESULTS: 27 publications describing 16 studies assessing 10 probiotics in 2,797 participants met our criterion. The pooled relative risk of all the studies, 0.74 (95% confidence interval 0.67, 0.82), indicated that probiotic supplementation in the first several years of life did have a significant impact on development of eczema. During evaluation of the studies, heterogeneity of terms and definitions for similar primary and secondary outcomes were identified. CONCLUSION: The use of probiotic supplements during pregnancy and/or during infancy creates a statistically significant decline in the incidence of eczema. The heterogeneity of terms and definitions regarding eczema is the major limitation of these studies.
Assuntos
Bifidobacterium , Suplementos Nutricionais/microbiologia , Eczema/prevenção & controle , Lactobacillus , Probióticos/uso terapêutico , Criança , Pré-Escolar , Dermatite Atópica/diagnóstico , Eczema/diagnóstico , Terapias Fetais , Humanos , Lactente , Recém-Nascido , Terminologia como AssuntoRESUMO
PURPOSE: Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. METHODS: CDH was created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. RESULTS: Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82%±12% in Normal-Placebo, 61%±5% in CDH-Placebo, 116%±6% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Normalized expression of ß-sGC was 105%±15% in Normal-Placebo, 82%±3% in CDH-Placebo, 158%±16% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Endothelial NOS and ß-sGC were significantly decreased in CDH (p=0.0007 and 0.01 for eNOS and ß-sGC, respectively), and tadalafil significantly increased eNOS expression (p=0.0002). CONCLUSIONS: PDE5 inhibitors can cross the placental barrier. ß-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH.
Assuntos
Carbolinas/uso terapêutico , Doenças Fetais/tratamento farmacológico , Terapias Fetais , Hérnias Diafragmáticas Congênitas , Óxido Nítrico Sintase Tipo III/biossíntese , Inibidores da Fosfodiesterase 5/uso terapêutico , Animais , Carbolinas/administração & dosagem , Carbolinas/farmacologia , GMP Cíclico/análise , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática/efeitos dos fármacos , Feminino , Hérnia Diafragmática/complicações , Hérnia Diafragmática/embriologia , Hérnia Diafragmática/enzimologia , Hérnia Diafragmática/prevenção & controle , Hipertensão Pulmonar/embriologia , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/embriologia , Hipertrofia Ventricular Direita/enzimologia , Hipertrofia Ventricular Direita/etiologia , Pulmão/química , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Pulmão/patologia , Troca Materno-Fetal , Óxido Nítrico Sintase Tipo III/genética , Tamanho do Órgão/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/farmacologia , Gravidez , Distribuição Aleatória , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Ovinos , TadalafilaRESUMO
Open spina bifida is a non-lethal fetal anomaly. Significant advances in the prevention, diagnosis and treatment of open spina bifida have been made over the past 75 years. The most significant strategy for the prevention of open spina bifida has been with folic acid supplementation; however, further investigation into the complicated role that genetics and the environment play in metabolism are coming to light. Ultrasound is the gold standard diagnostic tool for spina bifida. Three-dimensional ultrasound and magnetic resonance imaging are also beginning to play a role in the characterisation of the open spina bifida spinal lesion. Lesion level has been closely correlated to short and long-term outcomes, and prenatal characterisation of lesion level on ultrasound is important for patient counselling. Long-term outcomes of people living with spina bifida are available and should be used for non-directive patient counselling about pregnancy choices for women with open spina bifida.
Assuntos
Disrafismo Espinal/diagnóstico por imagem , Ultrassonografia Pré-Natal , Aborto Eugênico , Feminino , Terapias Fetais/efeitos adversos , Humanos , Imageamento por Ressonância Magnética , Testes para Triagem do Soro Materno , Gravidez , Fatores de Risco , Disrafismo Espinal/sangue , Disrafismo Espinal/complicações , Disrafismo Espinal/epidemiologia , Disrafismo Espinal/cirurgia , alfa-Fetoproteínas/metabolismoRESUMO
OBJECTIVE: Neural stem cells (NSCs) may promote spinal cord repair in fetuses with experimental spina bifida. We sought to determine the fate of amniotic-derived NSCs (aNSCs) after simple intra-amniotic injection in a syngeneic model of spina bifida. METHODS: Fetal neural tube defects were induced on 20 pregnant Lewis dams by prenatal administration of retinoic acid. Ten dams served as amniotic fluid donors for epigenetic isolation of aNSCs, which were expanded and labeled with 5-bromo-2'-deoxyuridine. The remaining 10 dams received intra-amniotic injections of the processed aNSCs, blindly in all their fetuses (n = 37) on gestational day 17 (term = E21-22). Fetuses with spina bifida underwent screening for the presence of donor aNSCs in the spinal cord at term. RESULTS: Donor cells were identified in 93.3% of the animals with spina bifida, selectively populating the neural placode, typically in clusters, retaining an undifferentiated morphology, and predominantly on exposed neural surfaces, though some were detected deeper in neighboring neural tissue. CONCLUSIONS: The amniotic cavity can serve as a route of administration of NSCs in experimental spina bifida. Simple intra-amniotic delivery of NSCs may be a practical adjuvant to regenerative strategies for the treatment of spina bifida.
Assuntos
Líquido Amniótico/citologia , Modelos Animais de Doenças , Doenças Fetais/terapia , Terapias Fetais , Células-Tronco Neurais/transplante , Disrafismo Espinal/patologia , Disrafismo Espinal/terapia , Transplante de Células-Tronco/métodos , Animais , Feminino , Doenças Fetais/patologia , Terapias Fetais/métodos , Gravidez , Ratos , Ratos Endogâmicos Lew , Disrafismo Espinal/embriologiaRESUMO
PURPOSE: Connexin 43 (Cx43), a major gap junction protein, is necessary for alveologenesis and plays an important role in the differentiation of type II to type I alveolar epithelial cells. Knockout mice of Cx43 display severe pulmonary hypoplasia (PH). Prenatal administration of retinoic acid (RA) is known to stimulate alveologenesis in nitrofen-induced PH. Recent studies revealed that retinoids upregulate Cx43 expression. We hypothesized that gene expression of Cx43 is downregulated during alveologenesis and that administration of RA upregulates Cx43 expression in the nitrofen-induced PH. METHODS: Pregnant rats were exposed to olive oil or nitrofen on day 9 (D9) of gestation. Retinoic acid was given intraperitoneally on D18, D19, and D20. Fetal lungs were harvested on D18 and D21 and divided into control, nitrofen, control+RA (D21), and nitrofen+RA (D21). The Cx43 expression levels were determined using reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: On D18 and D21, Cx43 relative messenger RNA expression levels were significantly downregulated in nitrofen compared with those in the control group. On D21, expression levels of Cx43 were significantly upregulated in nitrofen+RA and control+RA compared with those in nitrofen group. Immunohistochemical studies confirmed these results. CONCLUSION: Downregulation of Cx43 expression may interfere with normal alveologenesis. Upregulation of Cx43 pulmonary gene expression after RA treatment may promote lung growth by stimulating alveologenesis in nitrofen-induced PH.
Assuntos
Conexina 43/biossíntese , Terapias Fetais , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hérnias Diafragmáticas Congênitas , Pulmão/embriologia , Tretinoína/uso terapêutico , Animais , Diferenciação Celular/efeitos dos fármacos , Conexina 43/genética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/efeitos dos fármacos , Feminino , Hérnia Diafragmática/induzido quimicamente , Hérnia Diafragmática/embriologia , Hérnia Diafragmática/metabolismo , Injeções Intraperitoneais , Pulmão/metabolismo , Pulmão/patologia , Éteres Fenílicos/toxicidade , Gravidez , RNA Mensageiro/biossíntese , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/citologia , Mucosa Respiratória/embriologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tretinoína/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Mutations in the coactivator CREB-binding protein (CBP) are a major cause of the human skeletal dysplasia Rubinstein-Taybi syndrome (RTS); however, the mechanism by which these mutations affect skeletal mineralization and patterning is unknown. Here, we report the identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as a key regulator of CBP activity and demonstrate that its functions map to both osteoprogenitor cells and mature osteoblasts. In osteoblasts, PDK1 activated the CREB/CBP complex, which in turn controlled runt-related transcription factor 2 (RUNX2) activation and expression of bone morphogenetic protein 2 (BMP2). These pathways also operated in vivo, as evidenced by recapitulation of RTS spectrum phenotypes with osteoblast-specific Pdk1 deletion in mice (Pdk1osx mice) and by the genetic interactions observed in mice heterozygous for both osteoblast-specific Pdk1 deletion and either Runx2 or Creb deletion. Finally, treatment of Pdk1osx and Cbp+/- embryos with BMPs in utero partially reversed their skeletal anomalies at birth. These findings illustrate the in vivo function of the PDK1-AKT-CREB/CBP pathway in bone formation and provide proof of principle for in utero growth factor supplementation as a potential therapy for skeletal dysplasias.
Assuntos
Proteína Morfogenética Óssea 2/administração & dosagem , Proteína Morfogenética Óssea 7/administração & dosagem , Proteína de Ligação a CREB/genética , Terapias Fetais/métodos , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/terapia , Animais , Desenvolvimento Ósseo/genética , Desenvolvimento Ósseo/fisiologia , Proteína Morfogenética Óssea 2/genética , Proteína de Ligação a CREB/deficiência , Subunidade alfa 1 de Fator de Ligação ao Core/deficiência , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/deficiência , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Mutação , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Gravidez , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Proteínas Recombinantes/administração & dosagem , Síndrome de Rubinstein-Taybi/embriologia , Síndrome de Rubinstein-Taybi/metabolismo , Transdução de Sinais , ÚteroRESUMO
We report a case of severe fetal anemia associated with maternal anti-M antibody that was treated by direct injection of pooled human immunoglobulin into the fetal abdominal cavity. Four treatments at a dosage of 2 g per-kg estimated fetal body weight were performed, and no side effects were observed. A healthy baby girl was delivered transvaginally at 38 weeks, with neither exchange transfusion nor phototherapy required. Follow-up over 12 months found no indications of anemia or developmental delay in the child. This is believed to be the first report of fetal anemia in a blood-type-incompatible pregnancy being treated successfully with only direct immunoglobulin injection into the fetus. The immunoglobulin may have functioned as a neutralizing antibody causing the anemia to improve.
Assuntos
Anemia Hemolítica , Doenças Fetais , Imunoglobulinas , Injeções Intraperitoneais , Anemia Hemolítica/diagnóstico , Anemia Hemolítica/imunologia , Anemia Hemolítica/fisiopatologia , Anemia Hemolítica/terapia , Anticorpos/sangue , Incompatibilidade de Grupos Sanguíneos/diagnóstico , Incompatibilidade de Grupos Sanguíneos/imunologia , Incompatibilidade de Grupos Sanguíneos/fisiopatologia , Incompatibilidade de Grupos Sanguíneos/terapia , Cordocentese , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/imunologia , Doenças Fetais/fisiopatologia , Doenças Fetais/terapia , Monitorização Fetal , Terapias Fetais , Feto/imunologia , Feto/fisiopatologia , Histocompatibilidade Materno-Fetal/imunologia , Humanos , Imunização Passiva , Imunoglobulinas/administração & dosagem , Imunoglobulinas/efeitos adversos , Lactente , Recém-Nascido , Gravidez , Resultado da Gravidez , Resultado do Tratamento , Adulto JovemRESUMO
The normal fetal cardiac rhythm is characterized by a regular heart rate ranging between 100 and 160 -180 beats/min with a normal 1: 1 atrioventricular electromechanical relationship during each cardiac cycle. Fetal tachycardia occurring in approximately 0.5% of all pregnancies and it is an important cause of fetal morbidity and mortality. A fetal tachycardic heart is at risk for developing low cardiac output, hydrops and ultimately fetal death or significant neurological morbidity. Different conditions can play a role to determine the natural history of tachycardic fetus as gestational age, underlying pathophysiology of the arrhythmia, fetal heart rate, duration of the tachyarrhythmia, and presence or absence of cardiac dysfunction. Reliable diagnosis in utero of fetal arrhythmia is possible by ultrasound examination of the fetal heart. In fact pulsed wave Doppler guided by two-dimensional echocardiography provided important information on cardiac rhythm as it study the blood flow from different chambers. With the introduction of the latest myocardial deformation methodology, the fetal tachyarrhythmias can be diagnosed more accu notrately. Precise diagnosis of cardiac arrhythmias in the fetus is crucial for a managed therapeutic approach. The choice of management is correlated to many factors: gestational age, underlying pathophysiology of the arrhythmia, fetal heart rate, duration of the tachyarrhythmia, and presence or absence of cardiac dysfunction. A large review of fetal arrhythmias was been reported in our work.
Assuntos
Antiarrítmicos/uso terapêutico , Monitorização Fetal , Terapias Fetais , Complicações Cardiovasculares na Gravidez , Taquicardia Supraventricular , Antiarrítmicos/administração & dosagem , Ecocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Idade Gestacional , Humanos , Magnetocardiografia , Gravidez , Diagnóstico Pré-Natal/métodos , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/diagnóstico por imagem , Taquicardia Supraventricular/tratamento farmacológico , Ultrassonografia Pré-NatalRESUMO
Tachyarrhythmias can occur at any age from the developing fetus through adulthood. However, in deference to adult-onset ischemic cardiac issues, abnormal heart rhythms occurring in the young are often due to developmental alterations of the cardiac conduction tissue, genetically-inherited changes of myocardial cellular ion membrane properties and both pre- and post-surgical repair of associated structural congenital heart anatomical defects. And different from adults, abnormal rhythms occurring in the young can spontaneously disappear with progressive patient growth. Both supra- and ventricular tachyarrhythmias occur in the young although atrial rhythm abnormalities far exceed those of the ventricle. In both, pharmacologic therapies to alter tissue conduction and refractoriness remain the mainstay for initial intervention in the infant and young child, reserving more invasive and potentially harmful ablation therapies for drug-refractory cases. The purpose of the review is to present common and uncommon tachyarrhythmias which can occur in the fetus and throughout infancy. Emphasis will be placed on their electrocardiographic identification, recognition of any associated structural congenital heart defects and recommended pharmacologic management. Drug therapies will be divided according to mechanism of action and discussions of which particular agent is potentially best-suited to treat which specific tachyarrhythmia. A listing of current pharmacologic agents used in the young with appropriate dosages is included.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antiarrítmicos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Taquicardia , Antiarrítmicos/administração & dosagem , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/tratamento farmacológico , Ablação por Cateter , Criança , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Terapias Fetais , Cardiopatias Congênitas/tratamento farmacológico , Humanos , Lactente , Taquicardia/classificação , Taquicardia/diagnóstico , Taquicardia/tratamento farmacológico , Taquicardia/cirurgiaRESUMO
We prospectively evaluated whether combined antenatal corticosteroid and vitamin K administration have any benefit, over and above that of corticosteroid or vitamin K used alone, in reducing the frequency and the degree of PIVH in premature newborns less than 35 weeks' gestation. All of these 280 pregnant women were randomly allocated into five groups according to the in-patient sequence. Group A (vitamin K1 group) including 38 pregnant women (40 newborns) received antenatal intramuscular or intravenously injection of vitamin K1 10 mg per day for 2-7 days. Group B (single dose corticosteroid group) including 57 pregnant women (63 newborns) received antenatal intramuscular or intravenously injection of dexamethasone 10 mg per day for 1 day. Group C (two dose corticosteroid group) including 62 pregnant women (70 newborns) received antenatal intramuscular or intravenously injection of dexamethasone 10 mg per day for 2 days. Group D (combined using dexamethasone and vitamin K1) including 41 pregnant women (44 newborns) received dexamethasone 10 mg per day for 1 day and vitamin K110 mg per day for 2-7 days. Control group, including 82 pregnant women (87 newborns) were received neither dexamethasone nor vitamin K1 injection. The results showed PIVH was diagnosed in 17 of 40 (42.5%) in Group A, 34 of 63 (54.0%) in Group B, 36 of 70 (51.4%) in Group C, 14 of 44 (31.8%) in Group D, and 57 of 87 (65.2%) in control infants (p = 0.004). More infants in the control group had grade III or IV intracranial hemorrhage after birth (p = 0.049). After antenatal supplement of dexamethasone and vitamin K1, both the total incidence of PIVH and the frequency of severe PIVH decreased significantly. The total and severe incidence of PIVH in Group B (single doses dexamethasone) and Group C (two courses dexamethasone) there were no significant difference. It showed that after antenatal supplement of dexamethasone and vitamin K1, both the total incidence of PIVH and the frequency of severe PIVH decreased significantly, and combined antenatal corticosteroid and vitamin K administration have much benefit, over and above that of corticosteroid or vitamin K used alone.
Assuntos
Fatores de Coagulação Sanguínea/metabolismo , Hemorragia Cerebral/prevenção & controle , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Doenças do Prematuro/prevenção & controle , Vitamina K 1/uso terapêutico , Feminino , Sangue Fetal , Terapias Fetais , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Gravidez , Cuidado Pré-Natal , Estudos Prospectivos , Vitamina K 1/administração & dosagemRESUMO
AIMS: Infants less than 35 weeks' gestation age are susceptible to periventricular-intraventricular hemorrhage (PIVH). This may be partially attributable to low concentrations of vitamin K-dependent coagulation factors. The purposes of this study were: (1) to determine the umbilical blood activity levels of vitamin K-dependent coagulation factors II, VII, IX and X; (2) to investigate the change in activities of these factors in premature infants' umbilical blood after prenatal administration of vitamin K1 to the mothers; and (3) to study the prophylactic effects on PIVH after maternal antenatal supplemental vitamin K1. METHODS: Pregnant women in preterm labor at less than 35 weeks of gestation were randomly selected to receive antenatal vitamin K1 10 mg per day injection intramuscularly or intravenously for 2-7 days (vitamin K1 group, n = 40), or no such treatment (control group, n = 50). At the same period, cord blood samples were collected from thirty full-term neonates to compare the factor levels with those of premature infants. Intracranial ultrasound was performed by the same sonographer to determine the presence and severity of PIVH. RESULTS: The activities of vitamin K-dependent coagulation factors in umbilical blood in the control group were: factor II 25.64+/-9.49%, factor VII 59.00+/-17.66%, factor IX 24.67+/-8.88%, and factor X 30.16+/-5.02%. In full-term infants, the respective values were: factor II 36.70+/-4.88%, factor VII 64.54+/-10.62%, factor IX 30.18+/-5.69%, and factor X 34.32+/-12.63%. In vitamin K1 group these factors were: factor II 36.35+/-6.88%, factor VII 69.59+/-16.55%, factor IX 25.71+/-10.88%, and factor X 39.26+/-8.02%. The data suggest the absence of vitamin K-dependent coagulation factors in preterm infants, and antenatal supplement of vitamin K1 may increase the cord blood activity of factor II, VII and factor X (P < 0.001). In addition, the overall rates of PIVH in the vitamin K1 group and in controls were 32.4 and 52.0%, respectively (P = 0.036), and the frequency of severe PIVH was 5.0 and 20.0%, respectively (P = 0.038). CONCLUSIONS: Administration of vitamin K1 to pregnant women at less than 35 weeks' gestation age may result in improved coagulation and may reduce the incidence as well as the severity degree of PIVH.