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1.
Placenta ; 100: 81-88, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32871493

RESUMO

INTRODUCTION: Pregnant women with sickle cell disease (SCD) are at high risk for sickle cell-related complications, obstetrical complications, and perinatal morbidity. Chronic inflammation and the proangiogenic environment associated with SCD have been associated with endothelial damage. It is unknown whether SCD complications could be associated with placental dysfunction or abnormal placental morphology. Moreover, circulating angiogenic factors in pregnant women with SCD are unexplored. METHODS: Clinical records, placental and blood samples were collected at term delivery for 21 pregnant patients with SCD and 19 HbAA pregnant controls with adapted to gestational age birth weight newborns. Histological and stereological analyses and scanning electron microscopy (SEM) of the placenta, and PlGF and sFlt1 measurements in blood were performed. RESULTS: In the SCD group, the parenchyma-forming villi of placentas were thinner than in controls, and increased fibrinoid necrosis and an overabundance of syncytial knots were seen. SEM revealed elongated intermediate villous endings with a reduction in the number of terminal villi compared to controls, indicating a significant branching defect in SCD placentas. Finally, SCD patients had an imbalance in the angiogenic ratio of sFlt1/PlGF (p = 0.008) with a drop of PlGF concentrations. DISCUSSION: We evidence for the first time both abnormal placenta morphology and altered sFlt1/PlGF ratio in SCD patients, uncorrelated with maintained placental efficiency and fetal growth.

2.
J Med Genet ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928894

RESUMO

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. SCN1A encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of SCN1A are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in SCN1A in three unrelated individuals with AMC. METHODS: Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo. RESULTS: AMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that SCN1A is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement. CONCLUSION: We show for the first time that SCN1A variants are responsible for early-onset motor defect leading to AMC indicating a critical role of SCN1A in prenatal motor development and broadening the phenotypic spectrum of variants in SCN1A.

3.
Am J Obstet Gynecol ; 223(1): 91.e1-91.e4, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-165418

RESUMO

COVID-19 can severely affect pregnant women Furthermore, issues regarding vertical transmission of severe acute respiratory syndrome coronavirus 2 are emerging. In patients and neonates who are showing symptoms of coronavirus disease 2019, real-time polymerase chain reaction of nasal and throat swabs, sputum, and feces is performed to detect the presence of severe acute respiratory syndrome coronavirus 2. In addition, real-time polymerase chain reaction of vaginal swabs, amniotic fluid, placenta, cord blood, neonatal blood, or breast milk for the detection of severe acute respiratory syndrome coronavirus 2 did not show substantial results. Viremia was present in 1% of adult patients who were showing symptoms of coronavirus disease 2019. Here, we reviewed 12 articles published between Feb. 10, 2020, and April 4, 2020, that reported on 68 deliveries and 71 neonates with maternal infection in the third trimester of pregnancy. To determine whether infection occurred congenitally or perinatally, perinatal exposure, mode of delivery, and time interval from delivery to the diagnosis of neonatal infection were considered. Neonates with severe acute respiratory syndrome coronavirus 2 infection are usually asymptomatic. In 4 cases, a diagnostic test for severe acute respiratory syndrome coronavirus 2 infection was performed within 48 hours of life. Furthermore, detection rates of real-time polymerase chain reaction and the interpretation of immunoglobulin M and immunoglobulin G antibodies levels in cord and neonatal blood were discussed in relation with the immaturity of the fetal and neonatal immune system.

4.
Am J Obstet Gynecol ; 223(1): 91.e1-91.e4, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376317

RESUMO

COVID-19 can severely affect pregnant women Furthermore, issues regarding vertical transmission of severe acute respiratory syndrome coronavirus 2 are emerging. In patients and neonates who are showing symptoms of coronavirus disease 2019, real-time polymerase chain reaction of nasal and throat swabs, sputum, and feces is performed to detect the presence of severe acute respiratory syndrome coronavirus 2. In addition, real-time polymerase chain reaction of vaginal swabs, amniotic fluid, placenta, cord blood, neonatal blood, or breast milk for the detection of severe acute respiratory syndrome coronavirus 2 did not show substantial results. Viremia was present in 1% of adult patients who were showing symptoms of coronavirus disease 2019. Here, we reviewed 12 articles published between Feb. 10, 2020, and April 4, 2020, that reported on 68 deliveries and 71 neonates with maternal infection in the third trimester of pregnancy. To determine whether infection occurred congenitally or perinatally, perinatal exposure, mode of delivery, and time interval from delivery to the diagnosis of neonatal infection were considered. Neonates with severe acute respiratory syndrome coronavirus 2 infection are usually asymptomatic. In 4 cases, a diagnostic test for severe acute respiratory syndrome coronavirus 2 infection was performed within 48 hours of life. Furthermore, detection rates of real-time polymerase chain reaction and the interpretation of immunoglobulin M and immunoglobulin G antibodies levels in cord and neonatal blood were discussed in relation with the immaturity of the fetal and neonatal immune system.


Assuntos
Infecções por Coronavirus/transmissão , Transmissão Vertical de Doença Infecciosa , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/virologia , Líquido Amniótico/virologia , Betacoronavirus , Cesárea , Infecções por Coronavirus/diagnóstico , Feminino , Humanos , Recém-Nascido , Pandemias , Placenta/virologia , Pneumonia Viral/diagnóstico , Gravidez
5.
Am J Obstet Gynecol ; 223(2): 256.e1-256.e9, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32283072

RESUMO

BACKGROUND: Despite undisputable benefits, midtrimester prenatal surgery is not a cure for myelomeningocele (MMC): residual intracranial and motor deficits leading to lifelong handicap question the timing of prenatal surgery. Indeed, the timing and intensity of intrauterine spinal cord injury remains ill defined. OBJECTIVE: We aimed to describe the natural history of neuronal loss in MMC in utero based on postmortem pathology. STUDY DESIGN: Pathology findings were analyzed in 186 cases of myelomeningocele with lesion level between S1 and T1. Using a case-control, cross-sectional design, we investigated the timewise progression and topographic extension of neuronal loss between 13 and 39 weeks. Motor neurons were counted on histology at several spinal levels in 54 isolated MMC meeting quality criteria for cell counting. These were expressed as observed-to-expected ratios, after matching for gestational age and spinal level with 41 controls. RESULTS: Chiari II malformation increased from 30.7% to 91.6% after 16 weeks. The exposed spinal cord displayed early, severe, and progressive neuronal loss: the observed-to-expected count dropped from 17% to ≤2% after 16 weeks. Neuronal loss extended beyond the lesion to the upper levels: in cases <16 weeks, the observed-to-expected motor neuron count was 60% in the adjacent spinal cord, decreasing at a rate of 16% per week. Progressive loss was also found in the upper thoracic cord, but in much smaller proportions. The observed-over-expected ratio of motor neurons was not correlated with the level of myelomeningocele. CONCLUSIONS: Significant neuronal loss is present ≤16 weeks in the exposed cord and progressively extends cranially. Earlier prenatal repair (<16 weeks) could prevent Chiari II malformation in 69.3% of cases, rescue the 17% remaining motor neurons in the exposed cord, and prevent the extension to the upper spinal cord.


Assuntos
Malformação de Arnold-Chiari/patologia , Idade Gestacional , Meningomielocele/patologia , Neurônios Motores/patologia , Medula Espinal/patologia , Aborto Induzido , Malformação de Arnold-Chiari/embriologia , Autopsia , Progressão da Doença , Feminino , Terapias Fetais , Humanos , Vértebras Lombares , Meningomielocele/embriologia , Meningomielocele/cirurgia , Procedimentos Neurocirúrgicos , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Estudos Retrospectivos , Sacro , Vértebras Torácicas
6.
J Gynecol Obstet Hum Reprod ; 49(5): 101694, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31981627

RESUMO

Monochorionic pregnancies are associated with a higher risk of perinatal morbidity and mortality than dichorionic pregnancies. Early determination of chorionicity by an ultrasound exam between 11+0 and 14+0 weeks' gestation (WG) is essential for the subsequent management of twin pregnancies. The presence of the T-sign is the most specific sign for determination of monochorionicity. During the second trimester, the presence of two distinct placental masses has a lower specificity in determining the chorionicity. We report here two cases of a monochorionic pregnancy with a bipartite placenta, suggesting that a placenta with two separate masses, each with a distinct cord insertion is not always indicative of a dichorionic pregnancy.'

7.
Neurobiol Dis ; 136: 104709, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31843706

RESUMO

Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two "severe" G424R and K389N variants (responsible for severe ID and CCA) and the "mild" A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.

8.
Cell Mol Neurobiol ; 40(5): 829-843, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31865501

RESUMO

Sustained activation of pro-apoptotic signaling due to a sudden and prolonged disturbance of cerebral blood circulation governs the neurodegenerative processes in prefrontal cortex (PFC) of rats whose common carotid arteries are permanently occluded. The adequate neuroprotective therapy should minimize the activation of toxicity pathways and increase the activity of endogenous protective mechanisms. Several neuroprotectants have been proposed, including progesterone (P4). However, the underlying mechanism of its action in PFC following permanent bilateral occlusion of common carotid arteries is not completely investigated. We, thus herein, tested the impact of post-ischemic P4 treatment (1.7 mg/kg for seven consecutive days) on previously reported aberrant neuronal morphology and amount of DNA fragmentation, as well as the expression of progesterone receptors along with the key elements of Akt/Erk/eNOS signal transduction pathway (Bax, Bcl-2, cytochrome C, caspase 3, PARP, and the level of nitric oxide). The obtained results indicate that potential amelioration of histological changes in PFC might be associated with the absence of activation of Bax/caspase 3 signaling cascade and the decline of DNA fragmentation. The study also provides the evidence that P4 treatment in repeated regiment of administration might be effective in neuronal protection against ischemic insult due to re-establishment of the compromised action of Akt/Erk/eNOS-mediated signaling pathway and the upregulation of progesterone receptors.

10.
Neuroscience ; 410: 128-139, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095985

RESUMO

Transient ischemic attack (TIA) represents brief neurological dysfunction of vascular origin without detectable infarction. Despite major clinical relevance characterization of post-TIA molecular changes using appropriate experimental model is lacking and no therapeutic agent has been established yet. Neurosteroid dehydroepiandrosterone (DHEA) arose as one of the candidates for cerebral ischemia treatment but its effects on TIA-like condition remain unknown. Seeking an animal model applicable for investigation of molecular alterations in mild ischemic conditions such as TIA, 15-min bilateral common carotid artery occlusion with 24-h reperfusion was performed to induce ischemia/ reperfusion (I/R) injury in adult male Wistar rats. Additionally, effects of 4-h post-operative DHEA treatment (20 mg/kg) were investigated in physiological and I/R conditions in hippocampus (HIP) and prefrontal cortex (PFC). The study revealed absence of sensorimotor deficits, cerebral infarcts and neurodegeneration along with preserved HIP and PFC overall neuronal morphology and unaltered malondialdehyde and reduced glutathione level following I/R and/or DHEA treatment. I/R induced nitric oxide burst in HIP and PFC was accompanied with increased neuronal nitric oxide synthase protein level exclusively in HIP. DHEA had no effects in physiological conditions, while increase of Bax/Bcl2 ratio and dissipation of mitochondrial membrane potential in treated I/R group suggested DHEA-mediated exacerbation of post-ischemic changes that might lead to pro-apoptotic events in HIP. Interestingly, DHEA restored I/R-induced NO to the control level in PFC. Obtained results indicated that I/R may serve as an appropriate model for investigation of molecular changes and treatment outcome following mild ischemic conditions such as TIA.


Assuntos
Doenças das Artérias Carótidas/metabolismo , Artéria Carótida Primitiva/metabolismo , Desidroepiandrosterona/administração & dosagem , Mediadores da Inflamação/metabolismo , Ataque Isquêmico Transitório/metabolismo , Adjuvantes Imunológicos/administração & dosagem , Animais , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/patologia , Artéria Carótida Primitiva/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/patologia , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos , Ratos Wistar , Resultado do Tratamento
11.
Am J Med Genet A ; 179(7): 1351-1356, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31050392

RESUMO

Split-hand/foot malformation (SHFM) is a genetically heterogeneous congenital limb malformation typically limited to a defect of the central rays of the autopod, presenting as a median cleft of hands and feet. It can be associated with long bone deficiency or included in more complex syndromes. Among the numerous genetic causes, WNT10B homozygous variants have been recently identified in consanguineous families, but remain still rarely described (SHFM6; MIM225300). We report on three novel SHFM families harboring WNT10B variants and review the literature, allowing us to highlight some clinical findings. The feet are more severely affected than the hands and there is a frequent asymmetry without obvious side-bias. Syndactyly of third-fourth fingers was a frequent finding (62%). Polydactyly, which was classically described in SHFM6, was only present in 27% of patients. No genotype-phenotype correlation is delineated but heterozygous individuals might have mild features of SHFM, suggesting a dose-effect of the WNT10B loss-of-function.

12.
Am J Hum Genet ; 104(2): 213-228, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.


Assuntos
Fator 10 de Crescimento de Fibroblastos/genética , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/mortalidade , Pneumopatias/genética , Pneumopatias/mortalidade , Transdução de Sinais/genética , Proteínas com Domínio T/genética , Variações do Número de Cópias de DNA/genética , Feminino , Fator 10 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Idade Gestacional , Humanos , Recém-Nascido , Doenças do Recém-Nascido/metabolismo , Doenças do Recém-Nascido/patologia , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Pneumopatias/metabolismo , Pneumopatias/patologia , Masculino , Herança Materna , Organogênese , Herança Paterna , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas com Domínio T/metabolismo
13.
Clin Genet ; 95(3): 384-397, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30614526

RESUMO

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

14.
Clin Genet ; 95(3): 420-426, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30633342

RESUMO

Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.

15.
Hum Mol Genet ; 28(5): 778-795, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388224

RESUMO

Mutations in KIF14 have previously been associated with either severe, isolated or syndromic microcephaly with renal hypodysplasia (RHD). Syndromic microcephaly-RHD was strongly reminiscent of clinical ciliopathies, relating to defects of the primary cilium, a signalling organelle present on the surface of many quiescent cells. KIF14 encodes a mitotic kinesin, which plays a key role at the midbody during cytokinesis and has not previously been shown to be involved in cilia-related functions. Here, we analysed four families with fetuses presenting with the syndromic form and harbouring biallelic variants in KIF14. Our functional analyses showed that the identified variants severely impact the activity of KIF14 and likely correspond to loss-of-function mutations. Analysis in human fetal tissues further revealed the accumulation of KIF14-positive midbody remnants in the lumen of ureteric bud tips indicating a shared function of KIF14 during brain and kidney development. Subsequently, analysis of a kif14 mutant zebrafish line showed a conserved role for this mitotic kinesin. Interestingly, ciliopathy-associated phenotypes were also present in mutant embryos, supporting a potential direct or indirect role for KIF14 at cilia. However, our in vitro and in vivo analyses did not provide evidence of a direct role for KIF14 in ciliogenesis and suggested that loss of kif14 causes ciliopathy-like phenotypes through an accumulation of mitotic cells in ciliated tissues. Altogether, our results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through its conserved function in cytokinesis during kidney and brain development.


Assuntos
Anormalidades Congênitas/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Nefropatias/congênito , Rim/anormalidades , Cinesina/genética , Mutação com Perda de Função , Microcefalia/genética , Proteínas Oncogênicas/genética , Animais , Anormalidades Congênitas/metabolismo , Citocinese/genética , Modelos Animais de Doenças , Feminino , Imunofluorescência , Genes Letais , Estudos de Associação Genética/métodos , Loci Gênicos , Humanos , Rim/metabolismo , Nefropatias/genética , Nefropatias/metabolismo , Cinesina/química , Cinesina/metabolismo , Masculino , Microcefalia/metabolismo , Microcefalia/patologia , Proteínas Oncogênicas/química , Proteínas Oncogênicas/metabolismo , Linhagem , Fenótipo , Relação Estrutura-Atividade , Peixe-Zebra
16.
J Sports Med Phys Fitness ; 59(6): 955-961, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29845839

RESUMO

BACKGROUND: Different variables determine the performance of cyclists, which brings up the question how these parameters may help in their classification by specialty. The aim of the study was to determine differences in cardiorespiratory parameters of male cyclists according to their specialty: flat riders (N.=21), hill riders (N.=35), or sprinters (N.=20) and obtain the multivariate model for further cyclists classification by specialties, based on selected variables. METHODS: Seventeen variables were measured at submaximal and maximum load on the cycle ergometer Cosmed E 400HK (Cosmed, Rome, Italy) (initial 100 W with 25-W increase, 90-100 rpm). Multivariate discriminant analysis was used to determine which variables group cyclists within their specialty, and to predict which variables can direct cyclists to a particular specialty. RESULTS: Among nine variables that statistically contribute to the discriminant power of the model, achieved power on the anaerobic threshold and the produced CO2 had the biggest impact. The obtained discriminatory model correctly classified 91.43% of flat riders, 85.71% of hill riders, while sprinters were classified completely correct (100%), i.e. 92.10% of examinees were correctly classified, which point out the strength of the discriminatory model. CONCLUSIONS: Respiratory indicators mostly contribute to the discriminant power of the model, which may significantly contribute to training practice and laboratory tests in future.


Assuntos
Limiar Anaeróbio/fisiologia , Ciclismo/fisiologia , Aptidão Cardiorrespiratória/psicologia , Adulto , Ciclismo/classificação , Análise Discriminante , Ergometria , Humanos , Itália , Masculino
17.
Curr Neuropharmacol ; 17(1): 84-98, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28521702

RESUMO

BACKGROUND: Extracellular adenine nucleotides and nucleosides, such as ATP and adenosine, are among the most recently identified and least investigated diffusible signaling factors that contribute to the structural and functional remodeling of the brain, both during embryonic and postnatal development. Their levels in the extracellular milieu are tightly controlled by various ectonucleotidases: ecto-nucleotide pyrophosphatase/phosphodiesterases (E-NPP), alkaline phosphatases (AP), ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5'- nucleotidase (eN). METHODS: Studies related to the expression patterns of ectonucleotidases and their known features during brain development are reviewed, highlighting involvement of these enzymes in synapse formation and maturation in physiological as well as in pathological states. RESULTS: During brain development and in adulthood all ectonucleotidases have diverse expression pattern, cell specific localization and function. NPPs are expressed at early embryonic days, but the expression of NPP3 is reduced and restricted to ependymal area in adult brain. NTPDase2 is dominant ectonucleotidase existing in the progenitor cells as well as main astrocytic NTPDase in the adult brain, while NTPDase3 is fully expressed after third postnatal week, almost exclusively on varicose fibers. Specific brain AP is functionally associated with synapse formation and this enzyme is sufficient for adenosine production during neurite growth and peak of synaptogenesis. eN is transiently associated with synapses during synaptogenesis, however in adult brain it is more glial than neuronal enzyme. CONCLUSION: Control of extracellular adenine nucleotide levels by ectonucleotidases are important for understanding the role of purinergic signaling in developing tissues and potential targets in developmental disorders such as autism.


Assuntos
5'-Nucleotidase/metabolismo , Encéfalo/enzimologia , Encéfalo/crescimento & desenvolvimento , Sinapses/enzimologia , Animais , Encefalopatias/enzimologia , Encefalopatias/patologia , Humanos , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/patologia , Neurogênese , Transdução de Sinais
18.
Prenat Diagn ; 38(10): 772-778, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29949202

RESUMO

We report a multiplex family with a GATA1 gene mutation responsible for a massive fetal cerebral hemorrhage occurring at 36 weeks. Two other stillbirth cousins presented with fetal hydrops and congenital hemochromatosis' phenotype at 37 and 12 weeks of gestation. Molecular screening revealed the presence of a c.613G>A pathogenic allelic variation in exon 4 of GATA1 gene in the 3 male siblings and their carrier mothers. The diagnosis of a GATA1 gene mutation may be suspected in cases of male fetuses with intracerebral bleeding, particularly if a history of prior fetal loss(es) and mild maternal thrombocytopenia are also present.


Assuntos
Hemorragia Cerebral/genética , Doenças Fetais/genética , Fator de Transcrição GATA1/genética , Adulto , Feminino , Genes Ligados ao Cromossomo X , Humanos , Mutação , Gravidez
19.
Prenat Diagn ; 38(9): 638-644, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29956346

RESUMO

OBJECTIVE: To evaluate neonatal mortality and morbidity up to 6 months in neonates with congenital diaphragmatic hernia (CDH) with or without a hernia sac. METHODS: Seventy-two cases of isolated CDH were included in a retrospective single-center study between January 2010 and December 2016. Hernia sac was defined at the time of surgery or at postmortem examination if the neonate died before surgery. RESULTS: Seventeen newborns (23.6%) had a hernia sac. Survival at 6 months was significantly greater for isolated CDH with a hernia sac: 100% versus 63.6% (P = .003). High-frequency oscillatory ventilation was used significantly more in the no hernia sac group (P = .04). At surgery, the need for patch repair was significantly lower in the hernia sac group: 12% versus 50% (P = .005). The prenatal observed/expected lung-to-head ratio was significantly higher in the hernia sac group than in the no hernia sac group: 49.7% versus 38.6% (P < .05). CONCLUSION: The presence of a hernia sac in CDH is associated with better outcome, especially survival at 6 months. If the presence of a hernia sac is recognized as a particular entity, which carries a good prognosis, it is necessary to be able to diagnose it prenatally, especially in the era of prenatal fetal surgery.


Assuntos
Hérnias Diafragmáticas Congênitas/mortalidade , Hérnias Diafragmáticas Congênitas/patologia , Feminino , França , Idade Gestacional , Cabeça/diagnóstico por imagem , Cabeça/embriologia , Hérnias Diafragmáticas Congênitas/cirurgia , Humanos , Recém-Nascido , Pulmão/diagnóstico por imagem , Pulmão/embriologia , Gravidez , Prognóstico , Estudos Retrospectivos , Ultrassonografia Pré-Natal
20.
Brain Res ; 1688: 73-80, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29577884

RESUMO

Excessive glutamate efflux and N-methyl-D-aspartate receptor (NMDAR) over-activation represent well-known hallmarks of cerebral ischemia/reperfusion (I/R) injury, still, expression of proteins involved in this aspect of I/R pathophysiology show inconsistent data. Neurosteroid dehydroepiandrosterone (DHEA) has been proposed as potent NMDAR modulator, but its influence on I/R-induced changes up to date remains questionable. Therefore, I/R-governed alteration of vesicular glutamate transporter 1 (vGluT1), synaptic NMDAR subunit composition, postsynaptic density protein 95 (PSD-95) and neuronal morphology alone or following DHEA treatment were examined. For that purpose, adult male Wistar rats were treated with a single dose of vehicle or DHEA (20 mg/kg i.p.) 4 h following sham operation or 15 min bilateral common carotid artery occlusion. Western blot was used for analyses of synaptic protein expressions in hippocampus and prefrontal cortex, while neuronal morphology was assessed using Nissl staining. Regional-specific postischemic changes were detected on protein level i.e. signs of neuronal damage in CA1 area was accompanied with hippocampal vGluT1, NR1, NR2B enhancement and PSD-95 decrement, while histological changes observed in layer III were associated with decreased NR1 subunit in prefrontal cortex. Under physiological conditions DHEA had no effect on protein and histological appearance, while in ischemic milieu it restored hippocampal PSD-95 and NR1 in prefrontal cortex to the control level. Along with intact neurons, ones characterized by morphology observed in I/R group were also present. Future studies involving NMDAR-related intracellular signaling and immunohistochemical analysis will reveal precise effects of I/R and DHEA treatment in selected brain regions.


Assuntos
Isquemia Encefálica/metabolismo , Desidroepiandrosterona/administração & dosagem , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Animais , Isquemia Encefálica/prevenção & controle , Desidroepiandrosterona/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Subunidades Proteicas/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Sinapses/efeitos dos fármacos , Sinaptossomos/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
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