RESUMEN
PURPOSE: MKNR3 is a paternally expressed gene whose mutations are the main cause of central precocious puberty (CPP). Protein circulating levels can be easily measured, as demonstrated in idiopathic CPP and healthy controls. No data are available for patients harboring an MKRN3 mutation. Our aim was to perform MKRN3 mutation screening and to investigate if circulating protein levels could be a screening tool to identify MKRN3 mutation in CPP patients. METHODS: We enrolled 140 CPP girls and performed MKRN3 mutation analysis. Patients were stratified into two groups: idiopathic CPP (iCPP) and MKRN3 mutation-related CPP (MKRN3-CPP). Clinical characteristics were collected. Serum MKRN3 values were measured by a commercially available ELISA assay kit in MKRN3-CPP and a subgroup of 15 iCPP patients. RESULTS: We identified 5 patients with MKRN3 mutations: one was a novel mutation (p.Gln352Arg) while the others were previously reported (p.Arg328Cys, p.Arg345Cys, p.Pro160Cysfs*14, p.Cys410Ter). There was a significant difference in circulating MKRN3 values in MKRN3-CPP compared to iCPP (p < 0.001). In MKRN3-CPP, the subject harboring Pro160Cysfs*14 presented undetectable levels. Subjects carrying the missense mutations p.Arg328Cys and p.Gln352Arg showed divergent circulating protein levels, respectively 40.56 pg/mL and undetectable. The patient with the non-sense mutation reported low but measurable MKRN3 levels (12.72 pg/mL). CONCLUSIONS: MKRN3 defect in patients with CPP cannot be predicted by MKRN3 circulating levels, although those patients presented lower protein levels than iCPP. Due to the great inter-individual variability of the assay and the lack of reference values, no precise cut-off can be identified to suspect MKRN3 defect.
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Mutación , Pubertad Precoz , Ubiquitina-Proteína Ligasas , Humanos , Pubertad Precoz/genética , Pubertad Precoz/sangre , Pubertad Precoz/diagnóstico , Femenino , Ubiquitina-Proteína Ligasas/genética , Niño , Ribonucleoproteínas/genética , Ribonucleoproteínas/sangre , Preescolar , Análisis Mutacional de ADN , Estudios de Casos y Controles , Biomarcadores/sangreRESUMEN
PURPOSE: We aimed (i) evaluating the relationship between non-alcoholic fatty liver disease (NAFLD) and thyroid function tests, (ii) testing if the relationship between NAFLD and thyroid dysfunction could be driven by the obesity and the IR degree, and (iii) exploring the influence of the patatin-like phospholipase domain-containing protein-3 (PNPLA3) I148M and the transmembrane 6 superfamily member 2 (TM6SF2) E167K polymorphisms on the association between NAFLD and thyroid function in children. METHODS: We examined 2275 children and adolescents with obesity. Subclinical hypothyroidism (SH) was defined by thyroid-stimulating hormone (TSH) > 4.2 µUI/ml with normal fT3 and fT4. RESULTS: Children with NAFLD showed higher SH prevalence than those without NAFLD (15.7% Vs 7.4%;p = 0.001) and showed an adjusted odds ratio (aOR) to have SH of 1.68 (95% CI:1.01-2.80;p = 0.04) while patients with SH had an aOR to show NAFLD of 2.13(95% CI:1.22-3.73;p = 0.008). Patients having severe obesity and IR degree presented an aOR to show both NAFLD and SH of 3.61 (95% CI:1.78-7.33;p < 0.0001). Subjects with NAFLD carrying the TM6SF2 167 K allele had lower TSH levels than non-carriers (p = 0.03) and showed an aOR to have SH of 0.10 (95% CI: 0.01-0.79;p = 0.02). No differences were found in carriers of the PNPLA3 148 M allele. A general linear model for TSH variance showed a significant association of TSH with TM6SF2 genotypes only in the NAFLD group (p = 0.001). CONCLUSION: Children with obesity and NAFLD presented increase risk of SH and vice versa likely due to the adverse effect of duration of obesity, obesity degree, and IR. The TM6SF2 E167K exerts a protective role against SH in children with obesity and NAFLD.
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Hipotiroidismo , Enfermedad del Hígado Graso no Alcohólico , Adolescente , Humanos , Niño , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Obesidad/complicaciones , Obesidad/genética , Hipotiroidismo/complicaciones , Hipotiroidismo/epidemiología , Hipotiroidismo/genética , Tirotropina/genética , HígadoRESUMEN
PURPOSE: We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement. METHODS: We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects. RESULTS: A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8 years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients. CONCLUSION: A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.
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Enanismo , Maduración Sexual , Masculino , Femenino , Humanos , Ubiquitina-Proteína Ligasas/genética , Mutación , Proteínas de la Membrana/genética , Fenotipo , Proteínas de Unión al Calcio/genéticaRESUMEN
CONTEXT: Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS. OBJECTIVE: This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI). METHODS: We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6 years. RESULTS: MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 ± 22 pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007). CONCLUSIONS: The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.
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Síndrome de Prader-Willi , Niño , Estudios Transversales , Estradiol , Hormona Folículo Estimulante , Hemoglobina Glucada , Humanos , Proyectos Piloto , Síndrome de Prader-Willi/genética , Testosterona , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
INTRODUCTION: Dexmedetomidine is the sedative agent administered in combination with remifentanil and low dose of sevoflurane in the interventional arm of the ongoing TREX trial (Trial Remifentanil DExmedetomidine). The TREX pilot study (published in Paediatr Anaesth 2019;29:59-67) established infusion rates higher than those initially proposed. This could be attributed to an inappropriate target concentration for sedation or incorrect initial pharmacokinetic parameter estimates. METHODS: The TREX study is a Phase III, randomized, active controlled, parallel group, blinded evaluator, multicentre, superiority trial comparing neurological outcome after standard sevoflurane anaesthesia with dexmedetomidine/remifentanil and low dose sevoflurane anaesthesia in children aged less than 2 years undergoing anaesthesia of 2 hours or longer. In this report, dexmedetomidine pharmacokinetics were analysed in the interventional arm of the Italian population. RESULTS: There were 162 blood samples from 32 infants (22 male and 10 female). The median (IQR) age was 12 (5.2-15.5) months, weight 9.9 (7.3-10.8) kg. Duration of anaesthesia ranged from 2-6 hours. None of the children were born premature (median postnatal age 39 weeks, IQR 38-40 weeks). A 3-compartment PK model that incorporated allometric scaling and a maturation function demonstrated plasma concentration observations from the current Italian arm of the TREX study were consistent with those predicted by a "universal" model using pooled data obtained from neonates to adults. CONCLUSIONS: This current PK analysis from the Italian arm of the TREX study confirms that plasma concentration of dexmedetomidine is predictable using known covariates such as age and size. The initial target concentration (0.6 µg.L-1 ) used to sedate children cared for in the intensive care after cardiac surgery was inadequate for infants in the current TREX study. A target concentration 1 mcg.L-1 , corresponding to a loading dose of 1 mcg.kg-1 followed by an infusion of 1 mcg.kg-1 .hour-1 , provided adequate sedation.
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Neurofibromatosis type 1 (NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines (NSML) or RASopathy phenotype. We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of NS. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. Next-generation sequencing analysis of all RASopathy genes identified p.Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal magnetic resonance imaging scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first report of a SOS1 mutation associated with hypertrophic neuropathy resembling plexiform neurofibromas, a rare complication in Noonan phenotypes with mutations in RASopathy genes. Our results highlight the overlap between RASopathies, suggesting that NF1 diagnostic criteria need rethinking. Genetic analysis of RASopathy genes should be considered when diagnosis is uncertain.
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Mutación Missense , Neurofibromatosis 1/genética , Síndrome de Noonan/genética , Proteína SOS1/genética , Nervios Espinales/metabolismo , Adolescente , Adulto , Salud de la Familia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Madres , Neurofibromatosis 1/patología , Síndrome de Noonan/patología , Fenotipo , Nervios Espinales/patologíaRESUMEN
Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of-frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction.
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Proteínas Portadoras/genética , Dermatitis/genética , Trastornos del Crecimiento/genética , Microcefalia/genética , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Proteínas de Ciclo Celular , Hibridación Genómica Comparativa , Consanguinidad , Dermatitis/fisiopatología , Exones/genética , Femenino , Trastornos del Crecimiento/diagnóstico por imagen , Trastornos del Crecimiento/fisiopatología , Homocigoto , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Microcefalia/fisiopatología , Mutación , Linaje , FenotipoRESUMEN
The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis.
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Grasa Abdominal/metabolismo , Apolipoproteína C-III/genética , Hígado Graso/genética , Hepatitis C Crónica/genética , Lipasa/genética , Proteínas de la Membrana/genética , Adulto , Anciano , Anciano de 80 o más Años , Hígado Graso/patología , Femenino , Genotipo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/patología , Humanos , Italia , Masculino , Persona de Mediana Edad , Proteínas Mutantes/genética , Mutación Missense , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
BACKGROUND: Cholangiocarcinoma (CCA) is a rare biliary tract tumor with poor prognosis that often is challenging to diagnose and the majority of patients present with advanced stage. Squamous cell carcinoma antigen 1 (SCCA1) overexpression has been found in different tumors associated with poor prognosis and chemoresistance. AIMS: To assess the presence and possible prognostic role of SCCA1/2 isoforms in bile and serum of patients with CCA. METHODS: Forty seven surgical patients (36 with CCA and 11 with benign diseases) were prospectively included in the study. Serum and bile specimens were collected at the time of surgery and free and IgM-complexed SCCA was quantified by ELISA (Xeptagen, srl). RESULTS: Free or IgM linked SCCA was rarely found in serum, while SCCA was detectable in bile samples of patients with CCA, especially in those with extrahepatic form (43% vs 17%, p = 0.008), but not in controls. Despite similar tumor stage, these positive patients presented a trend toward a higher percentage of portal invasion (27% vs 15%) and of tumor recurrence than negative cases (62% vs 40%), although the difference was not statistically significant. CONCLUSION: These preliminary results indicate that bile testing for SCCA is a specific marker of extrahepatic CCA, with potential prognostic value.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Bilis , Biomarcadores de Tumor , Recurrencia Local de Neoplasia , Neoplasias Hepáticas/diagnóstico , Colangiocarcinoma/diagnóstico , Inmunoglobulina M , Neoplasias de los Conductos Biliares/diagnósticoRESUMEN
The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an α2 adrenergic receptor (α2AR) antagonist and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn particular attention in Alzheimer Disease (AD) pathophysiology. In this context, the objective of this study was to investigate the effects of the dual-acting PEA-OXA in an AD-like model in mice. A combined computational and experimental approach was used to evaluate the ability of PEA-OXA to bind α2A-AR subtype, and to investigate the effects of PEA-OXA treatment on neuropathological (behavioural and functional) effects induced by soluble Amyloid ß 1-42 (sAß1-42) intracerebroventricular injection. Computational analysis revealed the PEA-OXA ability to bind the α2A-AR, a pharmacological target for AD, in two alternative poses, one overlapping the Na+ binding site. In vivo studies indicated that chronic treatment with PEA-OXA (10 mg/kg, os) restored the cognitive (discriminative and spatial memory) deficits and social impairments induced by sAß injection. Consistently, electrophysiological analysis showed a recovery of the long-term potentiation in the hippocampus (Lateral Entorhinal Cortex-Dentate Gyrus pathway), while neuroinflammation, i.e., increased pro-inflammatory cytokines levels and microglia cells density were reduced. These data provide the basis for further investigation of the pro-cognitive aptitude of PEA-OXA by proposing it as an adjuvant in the treatment in AD, for which the available pharmacological approaches remain unsatisfactory. Moreover, this study offers new future direction in research investigating the role of α2AR in neuropsychiatric illness and therapies.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones , Animales , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Receptores Adrenérgicos alfa 2 , Modelos Animales de Enfermedad , Conducta Social , CogniciónRESUMEN
Retinol binding protein 4 (RBP4) is an adipokine involved in the pathogenesis of insulin resistance in obese adults and children. Since insulin resistance occurs during puberty, independently of adiposity, a role for RBP4 in the onset of this phenomenon may be hypothesized. In order to verify our hypothesis, we studied 90 subjects (45 obese and 45 lean controls). A complete physical examination was assessed, the z-score body mass index (BMI) was calculated, fat mass was assessed by bioelectric impedance analysis, and pubertal stage was assessed according to Tanner. Serum insulin and serum RBP4 levels were assayed. Obese and lean children differed for z-score BMI, fat mass, homeostasis model assessment of insulin resistance (HOMA-IR) and RBP4 levels. z-score BMI and HOMA-IR showed a direct correlation with RBP4 in the total population. When the subjects were divided in lean and obese, this correlation was evident only in obese (r2: 0.2; p=0.009 and r2: 0.2; p=0.01), but not in lean subjects (r2: 0.09; p=0.1 and r2: 0.03; p=0.4). Both in obese and lean HOMA-IR values were higher in pubertal subjects than in pre-pubertal (p<0.001), while serum RBP4 levels were similar in pubertal and in pre-pubertal subjects (>0.1). We conclude that RBP4 is correlated with adiposity and insulin resistance in obese children, but it is not involved in the insulin resistance occurring during puberty.
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Resistencia a la Insulina , Pubertad/metabolismo , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Adolescente , Biomarcadores/sangre , Biomarcadores/metabolismo , Índice de Masa Corporal , Niño , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina/fisiología , Masculino , Obesidad/sangre , Obesidad/metabolismo , Obesidad/fisiopatología , Pubertad/sangre , Pubertad/fisiología , Delgadez/sangre , Delgadez/metabolismo , Delgadez/fisiopatologíaAsunto(s)
Hormona Adrenocorticotrópica/deficiencia , Codón sin Sentido/genética , Color del Cabello/genética , Degradación de ARNm Mediada por Codón sin Sentido/genética , Obesidad/genética , Proopiomelanocortina/genética , Adulto , Preescolar , Cabello/química , Homocigoto , Humanos , Hipoglucemia/tratamiento farmacológico , Masculino , Melaninas/análisis , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
We have investigated the in vivo and in vitro regulation of the human urokinase-type plasminogen activator (uPA) gene by interleukin-1 (IL-1) and analyzed the transcription factors and signalling pathways involved in the response of the -2.0-kb uPA enhancer to IL-1 induction and to tetradecanoyl phorbol acetate (TPA) induction. Mutational analysis showed the cooperative activity of the Ets-binding site (EBS) and the two AP-1 elements of the enhancer. The results reveal that the EBS is required for the response to both inducers mediated by Ets-2, which is regulated at a level subsequent to DNA binding, by an IL-1- and phorbol ester-inducible transactivation domain. Both the IL-1 and the TPA-mediated induction result in a drastic increase of AP-1 binding to the downstream site of the enhancer (uPA 3' TPA-responsive element), while a mostly qualitative change, resulting from the interplay between ATF-2 homodimers and c-Jun-ATF-2 heterodimers, takes place at the upstream AP-1 element. The analysis of two distinct mitogen-activated protein kinase pathways shows that stress-activated protein kinase-Jun N-terminal kinase activation, resulting in the phosphorylation of ATF-2, c-Jun, and JunD, is required not only for the IL-1- but also for the TPA-dependent induction, while the extracellular signal-related kinase 1 (ERK-1) and ERK-2 activation is involved in the TPA- but not in the IL-1-dependent stimulation of the uPA enhancer.
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Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas de Unión al ADN , Proteínas Represoras , Activador de Plasminógeno de Tipo Uroquinasa/genética , Factor de Transcripción Activador 2 , Secuencia de Bases , Sitios de Unión/genética , Línea Celular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , ADN/genética , Cartilla de ADN/genética , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1/farmacología , Datos de Secuencia Molecular , Proteína Proto-Oncogénica c-ets-2 , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Acetato de Tetradecanoilforbol/farmacología , Transactivadores/metabolismo , Factor de Transcripción AP-1/metabolismo , Factores de Transcripción/metabolismo , Activación TranscripcionalRESUMEN
BACKGROUND: Coeliac disease is a complex disorder influenced by environmental and genetic factors. A genome wide linkage study identified the myosin IXB (MYO9B) as a gene possibly associated with coeliac disease. Recently, a Dutch study reported a strong association of a single SNP, rs 2305764, of MYO9B with coeliac disease. However, two successive studies carried out on British and Swedish/Norwegian cohorts reported lack of association of the MYO9B variant with coeliac disease. AIMS: The aim of the present study is to verify the effects of the MYO9B rs 2305764 polymorphism on disease risk in a Mediterranean population of coeliac children. PATIENTS AND METHODS: To address this issue, an association study was performed in 223 (127 females) Italian coeliac children and adolescents and in 600 controls. RESULTS: The allelic frequencies of the MYO9B rs 2305764 polymorphism found in our patients and in the population control were not statistically different (P=0.46). CONCLUSION: The MYO9B gene rs 2305764 polymorphism is not associated to coeliac disease in coeliac children from Southern Italy. This is in accordance with the most recent reports. Ethnic differences or a false positive result might explain the discrepancy with the Dutch study.
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Enfermedad Celíaca/genética , Predisposición Genética a la Enfermedad/genética , Miosinas/genética , Polimorfismo de Nucleótido Simple , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Lactante , Italia/epidemiología , Masculino , Polimorfismo Genético , Población Blanca/genéticaRESUMEN
BACKGROUND: In recent years, many studies have evaluated the effects of noninvasive brain stimulation (NIBS) techniques for the treatment of several neurological and psychiatric disorders. Positive results led to approval of NIBS for some of these conditions by the Food and Drug Administration in the USA. The therapeutic effects of NIBS have been related to bi-directional changes in cortical excitability with the direction of change depending on the choice of stimulation protocol. Although after-effects are mostly short lived, complex neurobiological mechanisms related to changes in synaptic excitability bear the potential to further induce therapy-relevant lasting changes. OBJECTIVE: To review recent neurobiological findings obtained from in vitro and in vivo studies that highlight molecular and cellular mechanisms of short- and long-term changes of synaptic plasticity after NIBS. FINDINGS: Long-term potentiation (LTP) and depression (LTD) phenomena by itself are insufficient in explaining the early and long term changes taking place after short episodes of NIBS. Preliminary experimental studies indicate a complex scenario potentially relevant to the therapeutic effects of NIBS, including gene activation/regulation, de novo protein expression, morphological changes, changes in intrinsic firing properties and modified network properties resulting from changed inhibition, homeostatic processes and glial function. CONCLUSIONS: This review brings into focus the neurobiological mechanisms underlying long-term after-effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) recently obtained from in vitro and in vivo studies, both in animals and humans.
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Encéfalo/fisiología , Trastornos Mentales/terapia , Estimulación Transcraneal de Corriente Directa/tendencias , Estimulación Magnética Transcraneal/tendencias , Animales , Depresión/diagnóstico , Depresión/fisiopatología , Depresión/terapia , Humanos , Potenciación a Largo Plazo/fisiología , Trastornos Mentales/diagnóstico , Trastornos Mentales/fisiopatología , Plasticidad Neuronal/fisiología , Técnicas Estereotáxicas/tendencias , Estimulación Transcraneal de Corriente Directa/métodos , Estimulación Magnética Transcraneal/métodosRESUMEN
BACKGROUND: The Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant has been associated with liver steatosis, high alanine transaminase (ALT) levels and reduced plasma levels of liver-derived triglyceride-rich lipoproteins. OBJECTIVES: The objectives of this study were to investigate in a group of obese children the association among the 167K allele of TM6SF2 gene and ALT, cholesterol and triglycerides levels, and hepatic steatosis, and to evaluate the potential interaction between this variant and the I148M patatin like phospholipase 3 gene (PNPLA3) polymorphism on liver enzymes. METHODS: We genotyped 1010 obese children for TM6SF2 E167K and PNPLA3â I148M polymorphisms. Anthropometrical and biochemical data were collected. Ultrasound imaging of the liver was performed. RESULTS: The 167K allele showed an association with steatosis (P < 0.0001), higher ALT levels (P < 0.001) and lower total cholesterol (P < 0.00001), low-density lipoprotein cholesterol (P < 0.0001), triglycerides (P = 0.02) and non-high-density lipoprotein cholesterol levels (P < 0.000001). The subjects homozygous for the PNPLA3 148M allele carrying the rare variant of TM6SF2 showed an odds ratio of 12.2 (confidence interval 3.8-39.6, P = 0.000001) to present hypertransaminasaemia compared with the remaining patients. CONCLUSION: Although the TMS6SF2 E167K variant predisposes the obese children to non-alcoholic fatty liver disease, there is an association between this variant and lower levels of cardiovascular risk factors. Overall, the data suggest differential effects of TMS6SF2 E167K variant on liver and heart health.
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LDL-Colesterol/sangre , Hígado/enzimología , Proteínas de la Membrana/sangre , Enfermedad del Hígado Graso no Alcohólico/enzimología , Obesidad Infantil/sangre , Polimorfismo de Nucleótido Simple , Adolescente , Alanina Transaminasa , Alelos , Niño , HDL-Colesterol/sangre , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Italia/epidemiología , Lipasa/metabolismo , Lipoproteínas/sangre , Masculino , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad Infantil/complicaciones , Obesidad Infantil/genética , Factores de Riesgo , Triglicéridos/sangreRESUMEN
This study analysed the impact of PNPLA3 variants on liver histology of 168 HIV/hepatitis C virus (HCV)-coinfected patients who were naïve for HCV treatment. A athologist unaware of the patients' condition graded liver fibrosis and necroinflammation (Ishak) and steatosis (Kleiner). Patients were tested for PNPLA3 variants and genotyped for the PNPLA3 rs738409 C to G variant underlying the I148M substitution. All were hepatitis B surface antigen negative and stated no alcohol abuse. The mean age was 40.6 (37.6-44.1) years, 72.6% were males, 42% had HCV genotype 3, 38.9% HCV genotype 1 and 79.2% were receiving highly active antiretroviral therapy. The 79 patients with the PNPLA3 p.148I/M or M/M variants more frequently showed severe steatosis (score 3-4) than the 89 with PNPLA3 p.148I/I (43% vs. 24.7%, p 0.001), whereas no difference was observed in the degree of necroinflammation or fibrosis. Compared with 112 patients with lower scores, 56 with severe steatosis showed higher body mass index (p 0.03), higher rate of HCV genotype 3 (55.6% vs. 35.2%, p 0.01), PNPLA3 p.148I/M or M/M (60.7% vs. 39.3%, p 0.01) and lower CD4(+) cells/mm(3) (514.00 (390.5-673.0) vs. 500.00 (399.0-627.0); p 0.002). At multivariate analysis, body mass index (p 0.01), HCV genotype 3 (p 0.006), CD4(+) cell count (p 0.005) and PNPLA3 p.148I/M or M/M variants (p 0.01) were found to be independent predictors of severe liver steatosis. The PNPLA3 p.148 I/M or M/M variants and CD4(+) cell count were the only independent predictors of severe steatosis in patients with HCV non-3 genotypes. This is the first study to show that among HIV/HCV-coinfected patients the PNPLA3 p.148I/M or M/M variant have substantially less impact on steatosis for those with HCV genotype 3 than non-genotype 3.
Asunto(s)
Predisposición Genética a la Enfermedad , Infecciones por VIH/complicaciones , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/patología , Lipasa/genética , Hígado/patología , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple , Adulto , Sustitución de Aminoácidos , Hígado Graso/patología , Femenino , Genotipo , Hepatitis C Crónica/genética , Histocitoquímica , Humanos , Cirrosis Hepática/patología , Masculino , Necrosis/patologíaRESUMEN
Cocaine- and amphetamine-regulated transcript (CART) inhibits feeding and induces the expression of c-Fos in hypothalamic areas implicated in appetite regulation. Furthermore, the CART peptide is found in neurons regulating sympathetic outflow, which in turn play an integral role in regulating body temperature and energy expenditure. The CART gene was screened by single-strand conformation polymorphism and automatic sequencing in 130 (72 girls) unrelated obese Italian children and adolescents. Their Z-scores (mean +/- SD) of relative to BMI percentiles was 3.9 +/- 1.8, and the average age at obesity onset was 4.7 +/- 2.6 years. Two previously described silent polymorphisms were found in the 3' untranslated region: an adenine deletion at position 1457 in 9 patients (allele frequency 0.035) and an A/G substitution at position 1475 in 11 patients (allele frequency 0.042). We found no difference between the obese patients heterozygous for one of these polymorphisms and those patients homozygous for the wild allele with respect to their age of obesity onset, BMI Z-scores, and leptin levels. A missense mutation of G729C resulting in the substitution of Leu with Phe at codon 34, within the NH2-terminal CART region, has been detected in the heterozygous state in a 10-year-old obese boy who has been obese since the age of 2 years. The patient belongs to a large family of obese subjects. The mutation cosegregated with the severe obesity phenotype over three generations and was not found in the control population. Resting metabolic rates were lower than expected in the propositus (-14%) and his mother (-16%), who carried the mutation. Leucine at codon 34, conserved in this position in the human and in the rat sequences, immediately precedes a couple of lysine residues that may well represent a dibasic processing site. The Leu34Phe mutation might alter the susceptibility to proteolysis of this potential processing site, likely altering the CART effect on thermogenesis and energy expenditure.
Asunto(s)
Pruebas Genéticas , Mutación , Proteínas del Tejido Nervioso/genética , Obesidad/genética , Adolescente , Secuencia de Aminoácidos/genética , Secuencia de Bases/genética , Niño , Preescolar , Metabolismo Energético/genética , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Mutación/fisiología , Mutación Missense/genética , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , DescansoRESUMEN
BACKGROUND: Drug-resistant mutants may emerge in patients with chronic hepatitis B receiving lamivudine therapy. AIM: To evaluate whether different viral mutational patterns may be associated with clinical reactivation during lamivudine treatment in patients with chronic B hepatitis. METHODS: Eight anti-hepatitis B e-positive patients with (group A) and 14 patients without clinical exacerbation (five anti-hepatitis B e-positive, group B1; nine hepatitis B e antigen-positive, group B2) during lamivudine treatment were investigated. RESULTS: 'Polymerase region': M204V/I variants were found in all group A patients, but in none of group B1 (P=0.0007) and in four of nine of group B2 (44%; P=0.02) patients. The L180M substitution was detected in four of eight (50%) of group A and in none of groups B1 and B2. 'Core promoter': the double basic core promoter (A1762T/G1764A) variant was detected in seven of eight (87%) of group A and in one of five (20%; P=0.03) of group B1 and one of nine (11%; P=0.002) of group B2 patients. 'Precore': the G1896A stop codon mutation was present in seven of eight (87%) of group A and in zero of five (P=0.004) of group B1 and one of nine (11%; P=0.002) of group B2. CONCLUSIONS: Different mutational patterns were observed in the lamivudine-treated patients with and without exacerbation. There was an association of the basic core promoter and stop codon mutations with lamivudine resistance in patients with disease exacerbation.
Asunto(s)
Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/tratamiento farmacológico , Lamivudine/uso terapéutico , Mutación , Adulto , Secuencia de Aminoácidos , Codón de Terminación/genética , ADN Viral/sangre , Farmacorresistencia Viral/genética , Femenino , Estudios de Seguimiento , Antígenos e de la Hepatitis B/inmunología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Regiones Promotoras Genéticas/genética , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Activación Viral/genéticaRESUMEN
BACKGROUND: This study aimed to assess the early caries experience and the efficacy of a community based dental referral pathway in preschool refugees in Western Australia. METHODS: Preschool refugee children referred to the Western Australian paediatric hospital Refugee Health Clinic were prospectively screened for caries by a paediatric dentist before being referred to community dental clinics. Dental forms and medical records were audited to assess decayed, missing and filled teeth (dmft), medical data and dental services engagement. Poisson regression analysis determined the contribution of count variables to the final model. RESULTS: Among the 105 screened children (54% male, median age 3.2 years, 41% Burmese), community dental clinic engagement was low (46%, n=48). Of the 62% with caries (n=65/105, mean dmft 5.2, SD 4.1), 45% were recommended for specialist dental services and 48% were treated. After adjustment for age, gender and total number of teeth, caries incidence was significantly associated with BMI-for-age Z score (p=0.02). CONCLUSIONS: Preschool refugee caries burden was high. The community dental referral pathway was ineffective compared to co-located intersectorial dental screening. Specialist dental service needs are high in this cohort and require a targeted approach.