RESUMO
We report the most comprehensive clinical and molecular characterization of XLH patients performed in Chile. We show high prevalence of musculoskeletal burden and pain, associated with significantly impaired physical capacity and quality of life, with many relevant complications presenting more frequently than previously reported in cohorts from developed countries. INTRODUCTION: Our current understanding of the clinical presentation and natural history of X-linked hypophosphatemia (XLH) comes mainly from cohorts from developed countries, with limited data on the clinical and genetic abnormalities of XLH patients in South America. OBJECTIVE: To describe the clinical, biochemical, and molecular presentation of patients with XLH in Chile. METHODS: Patients with XLH referred by endocrinologist throughout Chile were included. Demographic data and clinical presentation were obtained from a clinical interview. Surveys were applied for quality of life (QoL), pain, and functionality. FGF23 was measured by ELISA, and genetic testing was performed. Imaging studies were conducted to assess skeletal and renal involvement. RESULTS: We included 26 patients, aged 2-64 years, from 17 unrelated Chilean families. All pediatric patients but only 40% of adults were receiving conventional therapy, while 65% of all patients had elevated alkaline phosphatase. All patients had mutations in PHEX, including 5 novel variants. Radiographic skeletal events (RSE) and enthesopathies in adults were frequent (34% and 85%, respectively). The duration of treatment was associated with fewer RSE (p < 0.05). Most adults reported pain and impaired QoL, and 50% had impaired physical capacity. The number of enthesopathies was associated with worse pain and stiffness scores (p < 0.05). CONCLUSION: Chilean patients with XLH have a high prevalence of musculoskeletal burden associated with pain and impaired physical capacity and QoL, especially in adults who were generally undertreated. These data identify a significant unmet need, inform our understanding of the current status of patients, and can guide care for XLH patients in similarly socioeconomically defined countries.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Qualidade de Vida , Adulto , Criança , Chile/epidemiologia , Raquitismo Hipofosfatêmico Familiar/epidemiologia , Raquitismo Hipofosfatêmico Familiar/genética , Fator de Crescimento de Fibroblastos 23 , Testes Genéticos , Humanos , MutaçãoRESUMO
Adenoid cystic carcinoma is a malignant tumor which occurs frequently in hard palate associated with minor salivary glands. The lesion generally presents as a painful slow growing mass and it is characterized by recurrences and distant metastasis resulting in a poor prognosis for the patient. This paper reports an atypical adenoid cystic carcinoma with palatal perforation which occurred in a young woman. Initial diagnostic hypothesis were necrotizing sialometaplasia and lues. Although adenoid cystic carcinoma is common in hard palate, cases with palatal perforation are uncommon and may lead to delay in diagnosis and therapy.
Assuntos
Carcinoma Adenoide Cístico/patologia , Palato Duro/patologia , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares Menores/patologia , Adulto , Carcinoma Adenoide Cístico/diagnóstico , Carcinoma Adenoide Cístico/diagnóstico por imagem , Diagnóstico Tardio , Feminino , Humanos , Cavidade Nasal/patologia , Invasividade Neoplásica , Prognóstico , Radiografia , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/diagnóstico por imagem , Sialometaplasia Necrosante/diagnóstico , Sífilis/diagnósticoRESUMO
A new chemical structure, the 4,2',4",2'''-tetrahydroxy-6',6'''-dimethoxy-4'-O-4'''- bichalcone, named achyrobichalcone was isolated and identified from an Achyrocline satureioides spray-dried powder (SDP80). The thermal and photo stability of this new compound as well as that of the main polyphenols present in the spray dried powder, quercetin, luteolin, 3-O-metylquercetin and the corresponding kinetics of degradation are reported. In the long-term testing (30 +/- 2 degrees C/75 +/- 5% RH, 12 months), the total polyphenols contained in SDP80 demonstrated to be stable, remaining higher than 90% after a 12 month exposure. The photo stability testing revealed that all polyphenols were stable for 48 h when SDP80 was conditioned in amber or transparent flasks and exposed to UV-C radiation (light express LE UV, 254 nm, 30W). In contrast, when unprotected, the polyphenols demonstrated to be sensitive to both, thermal stress testing (80 +/- 2 degrees C), for 14 days and to UV-C radiation. Luteolin showed to be the most stable against UVC light and 3-O-methylquercetin against temperature. The achyrobichalcone demonstrated to be the more unstable against both, temperature and light. The kinetics of polyphenol thermal degradation (80 +/- 2 degrees C, 49 days) and photodegradation (UV-C radiation, 96 h) followed, 2nd and 1st order reaction, respectively.
Assuntos
Achyrocline/química , Chalconas/análise , Chalconas/efeitos da radiação , Cromatografia Líquida de Alta Pressão , Dessecação , Estabilidade de Medicamentos , Etanol , Temperatura Alta , Cinética , Luz , Espectroscopia de Ressonância Magnética , Fenóis/análise , Fenóis/efeitos da radiação , Extratos Vegetais/análise , Pós , Padrões de Referência , SolventesRESUMO
Neurotensin (NT) is a tridecapeptide distributed in central and peripheral nervous systems, which can behave as a neurotransmitter or neuromodulator at central and peripheral levels. Herein we tested the potential effect of this peptide on quinuclidinyl benzilate ([3H]-QNB) binding to muscarinic receptor in rat CNS membranes. It was observed that NT decreased up to 50-70% ligand binding at 1x10(-7) M-1x10(-5) M concentration in cerebral cortex, cerebellum and striatum. In the hippocampus, NT exerted a biphasic effect, behaving as a stimulator in the presence of 1x10(-12) M-1x10(-10) M concentration but as an inhibitor at 1x10(-8) M-1x10(-5) M concentration. In order to test the involvement of high-affinity NT receptor (NTS1) in NT inhibitory effect, assays were carried out in the presence of 1x10(-6) M NT and/or SR 48692 (Sanofi-Aventis, U.S., Inc.), a specific antagonist for this receptor, dissolved in dimethylsulfoxide (DMSO) 10% v/v. As controls, membranes incubated with DMSO and/or NT 1x10(-6) M plus DMSO were processed. It was found that NT+DMSO decreased [3H]-QNB binding to cerebral cortex, cerebellum and hippocampal membranes by 49%, 32% and 53%, respectively. This inhibition was not observed with the DMSO control group. Membrane preincubation with 1x10(-6) M SR 48692 failed to alter NT effect on binding. SR 48692 at 1x10(-6) M concentration decreased the binding by 50% only in cerebral cortex membranes, suggesting a possible direct effect of the antagonist on muscarinic receptors in this area. It was therefore concluded that the high-affinity NT receptor may not be involved in ligand binding inhibition to muscarinic receptor by NT.
Assuntos
Neurotensina/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Neurotensina/metabolismo , Animais , Masculino , Ratos , Ratos WistarRESUMO
Methylmalonic acidemias are metabolic disorders caused by a severe deficiency of methylmalonyl-CoA mutase activity, which are characterized by neurological dysfunction, including convulsions. It has been reported that the accumulating metabolite, L-methylmalonic acid (MMA), inhibits succinate dehydrogenase leading to ATP depletion in vitro, and that the intrastriatal injection of MMA induces convulsions through secondary NMDA receptor stimulation. In this study we investigated the effect of creatine (1.2, 3.6 and 12.0 mg/kg, (i.p.), [DOSAGE ERROR CORRECTED] succinate (1.5 micromol/striatum) and MK-801 (3 nmol/striatum) on the convulsions and on the striatal lactate increase induced by MMA (4.5 micromol/striatum) in rats. The effect of creatine on the striatal phosphocreatine content and on MMA-induced phosphocreatine depletion was also evaluated. Creatine, succinate and MK-801 pretreatment decreased the number and duration of convulsive episodes and the lactate increase elicited by MMA. Creatine, but not succinate, prevented the convulsions and the lactate increase induced by the direct stimulation of NMDA receptors. Acute creatine administration increased the total striatal phosphocreatine content and prevented MMA-induced phosphocreatine depletion. Our results suggest that MMA increases lactate production through secondary NMDA receptor activation, and it is proposed that the anticonvulsant effect of creatine against MMA-induced convulsions may be due to an increase in the phosphocreatine content available for metabolic purposes.
Assuntos
Creatina/uso terapêutico , Ácido Láctico/metabolismo , Ácido Metilmalônico/toxicidade , Convulsões/prevenção & controle , Animais , Comportamento Animal , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/lesões , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/toxicidade , Antagonistas de Aminoácidos Excitatórios , Masculino , N-Metilaspartato/toxicidade , Fosfocreatina/metabolismo , Protetores contra Radiação , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Ácido Succínico/farmacologiaRESUMO
OBJECTIVE: The diagnosis of hemophilia was reported as delayed in historic studies. We therefore investigated this issue to provide current epidemiologic data in a large series of patients. STUDY DESIGN: The French cohort provided the opportunity to investigate the age at diagnosis and the circumstances of diagnosis in 599 individuals with hemophilia born between 1980 and 1994. The type and the severity of hemophilia, the family history, and the period of birth were analyzed as potential modifying factors. RESULTS: The median age at diagnosis was 7.7 months, with significant differences among subgroups: 5.8 months in severe hemophilia, 9.0 months in moderate forms, 28.6 months in mild forms, 0.4 months in the case of hemophilic brothers, and 10.1 months in de novo hemophilia, which accounted for 55.3% of cases. In severe forms we observed a trend for earlier diagnosis throughout 3 consecutive periods from 1980 to 1994. Of bleeding episode, testing due to family history, or routine testing, bleeding was the main circumstance of diagnosis (59.9%). CONCLUSIONS: Diagnosis was made earlier than in historic series, but it remained somewhat delayed. Early diagnosis will require efforts in the fields of genetic counseling and specific diagnosis of early bleeding, even without family history, because of the high incidence of de novo hemophilia.
Assuntos
Hemofilia A/diagnóstico , Fatores Etários , Pré-Escolar , Estudos de Coortes , Saúde da Família , Feminino , França/epidemiologia , Hemofilia A/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Thy-1 is an abundant neuronal glycoprotein in mammals. Despite such prevalence, Thy-1 function remains largely obscure in the absence of a defined ligand. Astrocytes, ubiquitous cells of the brain, express a putative Thy-1 ligand that prevents neurite outgrowth. In this paper, a ligand molecule for Thy-1 was identified, and the consequences of Thy-1 binding for astrocyte function were investigated. RESULTS: Thy-1 has been implicated in cell adhesion and, indeed, all known Thy-1 sequences were found to contain an integrin binding, RGD-like sequence. Thy-1 interaction with beta3 integrin on astrocytes was demonstrated in an adhesion assay using a thymoma line (EL-4) expressing high levels of Thy-1. EL-4 cells bound to astrocytes five times more readily than EL-4(-f), control cells lacking Thy-1. Binding was blocked by either anti-Thy-1 or anti-beta3 antibodies, by RGD-related peptides, or by soluble Thy-1-Fc chimeras. However, neither RGE/RLE peptides nor Thy-1(RLE)-Fc fusion protein inhibited the interaction. Immobilized Thy-1-Fc, but not Thy-1(RLE)-Fc fusion protein supported the attachment and spreading of astrocytes in a Mn(2+)-dependent manner. Binding to Thy-1-Fc was inhibited by RGD peptides. Moreover, vitronectin, fibrinogen, denatured collagen (dcollagen), and a kistrin-derived peptide, but not fibronectin, also mediated Mn(2+)-dependent adhesion, suggesting the involvement of beta3 integrin. The addition of Thy-1 to matrix-bound astrocytes induced recruitment of paxillin, vinculin, and focal adhesion kinase (FAK) to focal contacts and increased tyrosine phosphorylation of proteins such as p130(Cas) and FAK. Furthermore, astrocyte binding to immobilized Thy-1-Fc alone was sufficient to promote focal adhesion formation and phosphorylation on tyrosine. CONCLUSIONS: Thy-1 binds to beta3 integrin and triggers tyrosine phosphorylation of focal adhesion proteins in astrocytes, thereby promoting focal adhesion formation, cell attachment, and spreading.
Assuntos
Antígenos CD/metabolismo , Astrócitos/metabolismo , Adesões Focais/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Antígenos Thy-1/metabolismo , Antígenos Thy-1/fisiologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Antígenos CD/imunologia , Encéfalo/metabolismo , Adesão Celular , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Integrina beta3 , Camundongos , Dados de Sequência Molecular , Neurônios/metabolismo , Oligopeptídeos/farmacologia , Fosfotirosina/metabolismo , Glicoproteínas da Membrana de Plaquetas/imunologia , Ratos , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Antígenos Thy-1/química , Células Tumorais CultivadasRESUMO
The administration of convulsant drugs has proven a powerful tool to study experimental epilepsy. We have already reported that the administration of convulsant 3-mercaptopropionic acid (mp) at 150 mg/kg enhances binding affinity of muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB) to certain rat CNS membranes during seizure and postseizure without affecting site number. Results obtained with a 100-mg/kg dose of mp have shown reversible increases in [3H]QNB binding to cerebellum and hippocampus, whereas a delayed response has been found in striatum. Neither a subconvulsant dose nor in vitro addition modifies binding. In order to evaluate preseizure, seizure as well as early (30 min) and late (24 h) postseizure stages, we employed a 50 mg/kg dose and tested [3H]QNB binding to CNS membranes. Changes in binding were as follows (in %): in cerebellum, +37, +86, and +40 at preseizure, seizure and early postseizure stages, respectively, but there was a decrease at late postseizure; in hippocampus, +27 at pre- and seizure stages, but a decrease at early and late postseizure. No changes were found in striatum or cerebral cortex membranes at any stage studied. Saturation curves analysed by Scatchard plots indicated that changes in [3H]QNB binding to cerebellar membranes are attributable to an increase in ligand affinity at seizure, followed by a decrease in binding site number at postseizure. A similar profile was observed for hippocampus except that the decrease in binding site number, though lower than at postseizure, was already evident at seizure stage. Results confirm a region-specific response to the convulsant and transient changes provide an example of neuronal plasticity.
Assuntos
Ácido 3-Mercaptopropiônico/farmacologia , Encéfalo/metabolismo , Quinuclidinil Benzilato/farmacocinética , Receptores Muscarínicos/metabolismo , Animais , Membrana Celular/metabolismo , Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Convulsivantes/farmacologia , Corpo Estriado/metabolismo , Hipocampo/metabolismo , Cinética , Ligantes , Masculino , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Muscarínicos/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/metabolismo , TrítioRESUMO
Calcitonin (CT) is a peptide produced by the thyroid gland, whose best described role is to prevent bone reabsorption, though it also participates in other biological functions through both central and peripheral mechanisms. CT is able to inhibit brain Na(+), K(+)-ATPase activity (Rodríguez de Lores Arnaiz, López Ordieres, Peptides 1997;18:613-5) and a relationship between such enzyme activity and cholinergic function has been suggested. Accordingly, we tested CT effect on [(3)H]-quinuclidinyl benzilate ([(3)H]-QNB) binding to rat CNS membranes to determine whether the peptide is able to modify the cholinergic muscarinic receptor as well. It was found that 1x10(-7)-1x10(-5) M CT decreased 20-70% ligand binding to hippocampal, cerebellar, cortical and striatal membranes. Scatchard analysis of saturation curves showed that 5x10(-6) M CT significantly modified binding kinetic constants, thus it increased roughly 220% K(d) values and decreased 20-36% B(max) values in cerebral cortical and cerebellar membranes. Since the peptide decreases affinity ligand binding and reduces the number of binding sites, CT may well be acting as a cholinergic modulator through a decrease in muscarinic receptor functionality.
Assuntos
Encéfalo/metabolismo , Calcitonina/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Ligantes , Masculino , Ratos , Ratos WistarRESUMO
Two brain soluble fractions, named peaks I and II, which respectively stimulate and inhibit neuronal Na+, K+-ATPase activity, have been isolated by gel filtration in Sephadex G-50. Since cholinergic transmission seems related to such enzyme activity, in this study we evaluated the effect of brain peak I, peak II, a more purified fraction II-E and commercial ouabain, on specific binding of the muscarinic antagonist [3H]quinuclidinyl benzilate to membranes from rat cerebellum, hippocampus and cerebral cortex. We found that binding was increased by peak I and decreased by peak II, II-E and ouabain, all effects proving concentration-dependent. Since the changes exerted on the muscarinic receptor followed a pattern similar to the one already described for synaptosomal membrane Na+, K+-ATPase activity, both systems seem to interact at a functional level.