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1.
Front Genet ; 14: 1198821, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37529781

RESUMO

The amount of Insulin Growth Factor 2 (IGF2) controls the rate of embryonal and postnatal growth. The IGF2 and adjacent H19 are the imprinted genes of the telomeric cluster in the 11p15 chromosomal region regulated by differentially methylated regions (DMRs) or imprinting centers (ICs): H19/IGF2:IG-DMR (IC1). Dysregulation due to IC1 Loss-of-Methylation (LoM) or Gain-of-Methyaltion (GoM) causes Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS) disorders associated with growth retardation or overgrowth, respectively. Specific features define each of the two syndromes, but isolated asymmetry is a common cardinal feature, which is considered sufficient for a diagnosis in the BWS spectrum. Here, we report the case of a girl with right body asymmetry, which suggested BWS spectrum. Later, BWS/SRS molecular analysis identified IC1_LoM revealing the discrepant diagnosis of SRS. A clinical re-evaluation identified a relative macrocephaly and previously unidentified growth rate at lower limits of normal at birth, feeding difficulties, and asymmetry. Interestingly, and never previously described in IC1_LoM SRS patients, since the age of 16, she has developed hand-writer's cramps, depression, and bipolar disorder. Trio-WES identified a VPS16 heterozygous variant [NM_022575.4:c.2185C>G:p.Leu729Val] inherited from her healthy mother. VPS16 is involved in the endolysosomal system, and its dysregulation is linked to autosomal dominant dystonia with incomplete penetrance and variable expressivity. IGF2 involvement in the lysosomal pathway led us to speculate that the neurological phenotype of the proband might be triggered by the concurrent IGF2 deficit and VPS16 alteration.

2.
Eur J Contracept Reprod Health Care ; 27(1): 34-38, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34342528

RESUMO

PURPOSE: The COVID-19 pandemic and national lockdown from 9 March to 4 May 2020 changed social, familial, and sexual relationships, as well as how citizens interact with the health services. How these profound changes have affected sexuality, contraception and voluntary terminations of pregnancy is still largely undescribed. The main objective of this study was therefore to find out whether the COVID-19 pandemic and ensuing lockdown affected the demand for legal abortion. MATERIAL AND METHODS: The study period was divided into three phases: the pre-pandemic (January and February 2020); lockdown (March and April); and post-lockdown (May and June). The number and characteristics of women requesting pregnancy termination each month during that time were compared with the stats for the same months in the preceding three years (2017-2019). RESULTS: Immediately after national lockdown, the number of voluntary abortions markedly declined (-40.45%). The effect was more evident in women below 20 years of age (-66.67%), employed versus unemployed women (-42.71% vs. -21.05), and non-Italian versus Italian citizens (-53.01 vs. -32.85). No difference was found in the mean time from request to execution of the procedure, or in the type of the procedure used. CONCLUSION(S): National lockdown reduced the number of unwanted pregnancies, especially in younger women. The Italian health service's response to the demand appears to have been unaffected by the pandemic. However, as the demand for abortion is still high, probably due to unplanned pregnancies among cohabitants within a stable relationship, contraception guidance should be improved among women traditionally deemed low-risk in terms of sexual behaviour.


Assuntos
COVID-19 , Pandemias , Controle de Doenças Transmissíveis , Feminino , Humanos , Itália/epidemiologia , Gravidez , SARS-CoV-2
3.
Genes (Basel) ; 12(4)2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920573

RESUMO

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine-Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani-Bhoj-Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.


Assuntos
Cromograninas/genética , Cromossomos Humanos Par 20/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Síndrome de Silver-Russell/diagnóstico , Dissomia Uniparental/genética , Adulto , Criança , Diagnóstico Diferencial , Feminino , Impressão Genômica , Humanos , Lactente , Masculino , Idade Materna , Herança Materna , Patologia Molecular , Linhagem , Fenótipo , Síndrome de Silver-Russell/genética
4.
Front Genet ; 10: 955, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749829

RESUMO

Introduction: Silver-Russell syndrome (SRS) is an imprinting disorder primarily caused by genetic and epigenetic aberrations on chromosomes 11 and 7. SRS is a rare growth retardation disorder often misdiagnosed due to its heterogeneous and non-specific clinical features. The Netchine-Harbison clinical scoring system (NH-CSS) is the recommended tool for differentiating patients into clinical SRS or unlikely SRS. However, the clinical diagnosis is molecularly confirmed only in about 60% of patients, leaving the remaining substantial proportion of SRS patients with unknown genetic etiology. Materials and Methods: A cohort of 34 Italian patients with SRS or SRS-like features scored according to the NH-CSS and without any SRS-associated (epi)genetic alterations was analyzed by high-resolution array-based comparative genomic hybridization (CGH) in order to identify potentially pathogenic copy number variants (CNVs). Results and Discussion: In seven patients, making up 21% of the initial cohort, five pathogenic and two potentially pathogenic CNVs were found involving distinct genomic regions either previously associated with growth delay conditions (1q24.3-q25.3, 17p13.3, 17q22, and 22q11.2-q11.22) and with SRS spectrum (7p12.1 and 7p15.3-p14.3) or outlined for the first time (19q13.42), providing a better definition of reported and as yet unreported SRS overlapping syndromes. All the variants involve genes with a defined role in growth pathways, and for two genes mapping at 7p, IGF2BP3 and GRB10, the association with SRS turns out to be reinforced. The deleterious effect of the two potentially pathogenic variants, comprising GRB10 and ZNF331 genes, was explored by targeted approaches, though further studies are needed to validate their pathogenic role in the SRS etiology. In conclusion, we reconfirm the utility of performing a genome-wide scan to achieve a differential diagnosis in patients with SRS or similar features and to highlight novel chromosome alterations associated with SRS and growth retardation disorders.

5.
Genet Res (Camb) ; 101: e3, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30829192

RESUMO

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients. The authors from different reference centres for BWS and SRS have identified single patients with unexpected and even contradictory molecular findings in respect to the clinical diagnosis. These patients clinically do not fit the characteristic phenotypes of SRS or BWS, but illustrate their clinical heterogeneity. Thus, comprehensive molecular testing is essential for accurate diagnosis and appropriate management, to avoid premature clinical diagnosis and anxiety for the families.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Síndrome de Silver-Russell/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Cromossomos Humanos Par 11/genética , Metilação de DNA , Predisposição Genética para Doença/genética , Testes Genéticos , Humanos , Fenótipo , Síndrome de Silver-Russell/diagnóstico
6.
Int J Mol Sci ; 19(4)2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29621152

RESUMO

Angelman syndrome (AS, MIM 105830) is a rare neurodevelopmental disorder affecting 1:10-20,000 children. Patients show moderate to severe intellectual disability, ataxia and absence of speech. Studies on both post-mortem AS human brains and mouse models revealed dysfunctions in the extra synaptic gamma-aminobutyric acid (GABA) receptors implicated in the pathogenesis. Taurine is a free intracellular sulfur-containing amino acid, abundant in brain, considered an inhibiting neurotransmitter with neuroprotective properties. As taurine acts as an agonist of GABA-A receptors, we aimed at investigating whether it might ameliorate AS symptoms. Since mice weaning, we orally administered 1 g/kg/day taurine in water to Ube3a-deficient mice. To test the improvement of motor and cognitive skills, Rotarod, Novel Object Recognition and Open Field tests were assayed at 7, 14, 21 and 30 weeks, while biochemical tests and amino acid dosages were carried out, respectively, by Western-blot and high-performance liquid chromatography (HPLC) on frozen whole brains. Treatment of Ube3am-/p+ mice with taurine significantly improved motor and learning skills and restored the levels of the post-synaptic PSD-95 and pERK1/2-ERK1/2 ratio to wild type values. No side effects of taurine were observed. Our study indicates taurine administration as a potential therapy to ameliorate motor deficits and learning difficulties in AS.


Assuntos
Síndrome de Angelman/tratamento farmacológico , Taurina/uso terapêutico , Síndrome de Angelman/metabolismo , Síndrome de Angelman/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos , Ácido gama-Aminobutírico/metabolismo
7.
J Clin Endocrinol Metab ; 103(6): 2225-2233, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29546330

RESUMO

Context: There is little information on the long-term natural history of Silver-Russell syndrome (SRS). Objective: To describe the phenotypes and metabolic status in adults with SRS. Design: Clinical and metabolic evaluations in adults with a molecular diagnosis of SRS. Participants: Seven patients (aged 18 to 46 years; mean age, 26.9 years) were studied. Two had chromosome 7 maternal uniparental disomy, three had 11p15 loss of methylation, and two had 11p15 duplication. Setting: Single tertiary university center. Main Outcome Measures: Netchine-Harbison (NH) clinical score, oral glucose tolerance test, lipid profiles, bone mineral density (BMD; lumbar spine at L1 to L4 and total body), lean body mass (LBM), absolute fat mass (kg), fat mass percentage, fat mass index (FMI), and trunk/limb fat ratio were evaluated. Results: The NH score declined in all but two patients during adulthood, and all patients but one displayed relative macrocephaly. Two patients were underweight, four patients had a normal body mass index, and one was obese. Two patients had glucose intolerance and hyperinsulinemia; two showed a high total cholesterol level with low high-density lipoprotein (HDL) cholesterol levels. BMD was within the normal range, whereas a high fat mass percentage, FMI, and trunk/limb fat ratio and a low LBM were found. The trunk/limb fat ratio showed an inverse relation with HDL cholesterol levels. Conclusions: The diagnosis of SRS seems to be reliable in adults, although some clinical signs become less pronounced with age. Glucose, lipids, and body composition should be monitored over time.


Assuntos
Composição Corporal/genética , Densidade Óssea/genética , Síndrome de Silver-Russell/diagnóstico , Dissomia Uniparental/genética , Adolescente , Adulto , Metilação de DNA , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Síndrome de Silver-Russell/genética , Adulto Jovem
9.
Clin Epigenetics ; 8: 23, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26933465

RESUMO

BACKGROUND: Multiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver-Russell (SRS) and Beckwith-Wiedemann (BWS) syndromes. The molecular diagnosis of these opposite growth disorders requires a multi-approach flowchart to disclose known primary and secondary (epi)genetic alterations; however, up to 20 and 30 % of clinically diagnosed BWS and SRS cases remain without molecular diagnosis. The complex structure of the 11p15 region with variable CpG methylation and low-rate mosaicism may account for missed diagnoses. Here, we demonstrate the relevance of complementary techniques for the assessment of different CpGs and the importance of testing multiple tissues to increase the SRS and BWS detection rate. RESULTS: Molecular testing of 147 and 450 clinically diagnosed SRS and BWS cases provided diagnosis in 34 SRS and 185 BWS patients, with 9 SRS and 21 BWS cases remaining undiagnosed and herein referred to as "borderline." A flowchart including complementary techniques and, when applicable, the analysis of buccal swabs, allowed confirmation of the molecular diagnosis in all borderline cases. Comparison of methylation levels by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in borderline and control cases defined an interval of H19/IGF2:IG-DMR loss of methylation that was distinct between "easy to diagnose" and "borderline" cases, which were characterized by values ≤mean -3 standard deviations (SDs) compared to controls. Values ≥mean +1 SD at H19/IGF2: IG-DMR were assigned to borderline hypermethylated BWS cases and those ≤mean -2 SD at KCNQ1OT1: TSS-DMR to hypomethylated BWS cases; these were supported by quantitative pyrosequencing or Southern blot analysis. Six BWS cases suspected to carry mosaic paternal uniparental disomy of chromosome 11 were confirmed by SNP array, which detected mosaicism till 10 %. Regarding the clinical presentation, borderline SRS were representative of the syndromic phenotype, with exception of one patient, whereas BWS cases showed low frequency of the most common features except hemihyperplasia. CONCLUSIONS: A conclusive molecular diagnosis was reached in borderline methylation cases, increasing the detection rate by 6 % for SRS and 5 % for BWS cases. The introduction of complementary techniques and additional tissue analyses into routine diagnostic work-up should facilitate the identification of cases undiagnosed because of mosaicism, a distinctive feature of epigenetic disorders.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Cromossomos Humanos Par 11/genética , Síndrome de Silver-Russell/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Southern Blotting/métodos , Criança , Pré-Escolar , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Humanos , Lactente , Masculino , Mosaicismo , Reação em Cadeia da Polimerase Multiplex/métodos , Análise de Sequência com Séries de Oligonucleotídeos , Síndrome de Silver-Russell/genética
10.
J Neurosurg ; 118(4): 821-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23350777

RESUMO

OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide. A combination of carmustine wafers with the Stupp treatment regimen has only been investigated in retrospective studies. METHODS: In a single-institution prospective study, the authors assessed 12-month progression-free survival (PFS), toxicity, and overall survival in patients with glioblastoma treated with surgery, carmustine wafers, radiotherapy, and 6-month metronomic temozolomide chemotherapy. Thirty-five patients with de novo glioblastoma, between the ages of 18 and 70 years, and with Karnofsky Performance Scale scores of at least 70, were included in the study. Patients were followed monthly and assessed using MRI every 2 months. RESULTS: After a median follow-up of 15 months, the median time to tumor progression was 12.5 months and median survival was 17.8 months. Due to toxicity (mostly hematological), 7 patients had to prematurely stop temozolomide treatment. Twenty-two patients developed Grade 3 CD4(+) lymphocytopenia. Three patients developed oral-esophageal candidiasis, 2 developed pneumonia, and 1 developed a dorsolumbar zoster. Early intracranial hypertension was observed in 1 patient, and 1 was treated empirically for suspected brain abscess. One patient died of Legionella pneumonia soon after repeat surgery. CONCLUSIONS: Overall, this treatment schedule produced promising results in terms of PFS without a marked increase in toxicities as compared with the Stupp regimen. However, the gain in median survival using this schedule was less clear. Only prospective comparative trials will determine whether these preliminary results will translate into a long-term survival advantage with an acceptable toxicity profile.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Carmustina/uso terapêutico , Dacarbazina/análogos & derivados , Glioblastoma/terapia , Procedimentos Neurocirúrgicos , Radioterapia , Administração Metronômica , Administração Oral , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/mortalidade , Carmustina/administração & dosagem , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , Glioblastoma/mortalidade , Humanos , Avaliação de Estado de Karnofsky , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Temozolomida , Resultado do Tratamento , Adulto Jovem
11.
Int J Neuropsychopharmacol ; 13(2): 143-53, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19573264

RESUMO

Gamma-hydroxybutyric acid (GHB) is an endogenous brain substance that has diverse neuropharmacological actions, including rewarding properties in different animal species and in humans. As other drugs of abuse, GHB affects the firing of ventral tegmental neurons (VTA) in anaesthetized animals and hyperpolarizes dopaminergic neurons in VTA slices. However, no direct behavioural data on the effects of GHB applied in the VTA or in the target regions of its dopaminergic neurons, e.g. the nucleus accumbens (NAc), are available. Here, we investigated the effects of various doses of intravenous GHB in maintaining self-administration (from 0.001 to 10 mg/kg per infusion), and its ability to induce conditioned place preference (CPP) in rats when given orally (175-350 mg/kg) or injected directly either in the VTA or NAc (from 10 to 300 microg/0.5 microl per side). Our results indicate that while only 0.01 mg/kg per infusion GHB maintained self-administration, although not on every test day, 350 mg/kg GHB given orally induced CPP. CPP was also observed when GHB was injected in the VTA (30-100 microg/0.5 microl per side) but not in the NAc. Together with recent in-vitro findings, these results suggest that the rewarding properties of GHB mainly occur via disinhibition of VTA dopaminergic neurons.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Oxibato de Sódio/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Injeções Intravenosas , Masculino , Microinjeções , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Autoadministração , Oxibato de Sódio/administração & dosagem
12.
Int J Neuropsychopharmacol ; 12(6): 793-803, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19123962

RESUMO

We recently found that the response of DBA/2 mice to SSRIs in the forced swim test (FST) was impaired and they also had a smaller basal and citalopram-stimulated increase in brain extracellular serotonin (5-HT) than 'responder' strains. We employed intracerebral microdialysis, FST and selective antagonists of 5-HT1A and 5-HT2C receptors to investigate whether enhancing the increase in extracellular 5-HT reinstated the anti-immobility effect of citalopram in the FST. WAY 100635 (0.3 mg/kg s.c.) or SB 242084 (1 mg/kg s.c.), respectively a selective 5-HT1A and 5-HT2C receptor antagonist, raised the effect of citalopram (5 mg/kg) on extracellular 5-HT in the medial prefrontal cortex of DBA/2N mice (citalopram alone 5.2+/-0.3 fmol/20 microl, WAY 100635+citalopram 9.9+/-2.1 fmol/20 microl, SB 242084+ citalopram 7.6+/-1.0 fmol/20 microl) to the level reached in 'responder' mice given citalopram alone. The 5-HT receptor antagonists had no effect on the citalopram-induced increase in extracellular 5-HT in the dorsal hippocampus. The combination of citalopram with WAY 100635 or SB 242084 significantly reduced immobility time in DBA/2N mice that otherwise did not respond to either drug singly. Brain levels of citalopram in mice given citalopram alone or with 5-HT antagonists did not significantly differ. The results confirm that impaired 5-HT transmission accounts for the lack of effect of citalopram in the FST and suggest that enhancing the effect of SSRIs on extracellular 5-HT, through selective blockade of 5-HT1A and 5-HT2C receptors, could be a useful strategy to restore the response in treatment-resistant depression.


Assuntos
Córtex Cerebral/citologia , Líquido Extracelular/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Serotonina/metabolismo , Aminopiridinas/farmacologia , Análise de Variância , Animais , Antidepressivos/farmacocinética , Córtex Cerebral/efeitos dos fármacos , Citalopram/farmacocinética , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Líquido Extracelular/efeitos dos fármacos , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Microdiálise/métodos , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia
13.
J Med Chem ; 51(18): 5813-22, 2008 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-18800769

RESUMO

Starting from the previously reported 5-HT 7 receptor agents 4-7 with N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamide structure, the 1-(2-methylthiophenyl)-, 1-(2-diphenyl)-, 1-(2-isopropylphenyl)-, and 1-(2-methoxyphenyl)piperazine derivatives 8-31 were designed with the primary aim to obtain new compounds endowed with suitable physicochemical properties for rapid and extensive penetration into the brain. The affinities for 5-HT 7, 5-HT 1A, and D 2 receptors of compounds 8-31 were assessed, and several compounds displayed 5-HT 7 receptor affinities in the nanomolar range. Among these, N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (25) showed high 5-HT 7 receptor affinity (Ki = 0.58 nM), high selectivity over 5-HT 1A and D 2 receptors (324- and 245-fold, respectively), and agonist properties (maximal effect = 82%, EC 50 = 0.60 microM). After intraperitoneal injection in mice, 25 rapidly reached the systemic circulation and entered the brain. Its brain concentration-time profile paralleled that in plasma, indicating that 25 rapidly and freely distributes across the blood-brain barrier. Compound 25 underwent N-dealkylation to the corresponding 1-arylpiperazine metabolite.


Assuntos
Piperazinas/química , Piperazinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Animais , Barreira Hematoencefálica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Camundongos , Estrutura Molecular , Piperazinas/farmacocinética
14.
Eur J Pharmacol ; 594(1-3): 117-24, 2008 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-18691569

RESUMO

We studied the antidepressant-like effect of paroxetine in strains of mice carrying different isoforms of tryptophan hydroxylase-2 (TPH-2), the enzyme responsible for the synthesis of brain serotonin (5-HT). The effect of paroxetine alone and in combination with pharmacological treatments enhancing or lowering 5-HT synthesis or melatonin was assessed in the forced swimming test in mice carrying allelic variants of TPH-2 (1473C in C57BL/6 and 1473G in DBA/2 and BALB/c). Changes in brain 5-hydroxytryptophan (5-HTP) accumulation and melatonin levels were measured by high-performance liquid chromatography. Paroxetine (2.5 and 5 mg/kg) reduced immobility time in C57BL/6J and C57BL/6N mice but had no such effect in DBA/2J, DBA/2N and BALB/c mice, even at 10 mg/kg. Enhancing 5-HT synthesis with tryptophan reinstated the antidepressant-like effect of paroxetine in DBA/2J, DBA/2N and BALB/c mice whereas inhibition of 5-HT synthesis prevented the effect of paroxetine in C57BL/6N mice. The response to paroxetine was not associated with changes in locomotor activity, brain melatonin or brain levels of the drug measured at the end of the behavioral test. These results support the importance of 5-HT synthesis in the response to SSRIs and suggest that melatonin does not contribute to the ability of tryptophan to rescue the antidepressant-like effect of paroxetine.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Depressão/psicologia , Atividade Motora/efeitos dos fármacos , Paroxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/fisiologia , Natação/psicologia , Animais , Química Encefálica/efeitos dos fármacos , Masculino , Melatonina/metabolismo , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Paroxetina/metabolismo , Serotonina/biossíntese , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Especificidade da Espécie , Triptofano/farmacologia
15.
Neuropathology ; 28(6): 633-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18384514

RESUMO

We report a case of glioblastoma (GBM) occurring 8 years after radiation therapy for a medulloblastoma. A 15-year-old boy underwent surgery and radiotherapy for a medulloblastoma and 8 years later he developed a second tumor at the same site. The second lesion showed different histological and molecular features, was diagnosed as a glioblastoma and fulfilled the criteria of radiation-induced neoplasm. Mutational analysis of the p53 gene showed a C to G transition at codon 176 in tumor DNA. LOH was detected at 17p and 19q. The tumor also showed O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and no amplification of EGF receptor. In conclusion, the radiation-induced MGMT hyper-methylation and p53 mutations may have a role in the development of a subgroup of radio-induced glioma (RIG), suggesting that these molecular alterations directly cooperate in the genesis of the post-irradiation GBM. Moreover RIGs seem to be a heterogeneous group of tumors that may resemble either primary or secondary GBM.


Assuntos
Glioblastoma/etiologia , Glioblastoma/genética , Meduloblastoma/genética , Meduloblastoma/radioterapia , Neoplasias Induzidas por Radiação/genética , Segunda Neoplasia Primária/etiologia , Adolescente , Criança , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 19/genética , Metilação de DNA , Receptores ErbB/genética , Amplificação de Genes , Genes p53 , Glioblastoma/patologia , Humanos , Perda de Heterozigosidade , Masculino , Meduloblastoma/patologia , Meduloblastoma/cirurgia , Mutação , Neoplasias Induzidas por Radiação/patologia , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Regiões Promotoras Genéticas
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