RESUMO
Spermatid production is a complex regulatory process in which coordination between hormonal control and apoptosis plays a pivotal role in maintaining a balanced number of sperm cells. Apoptosis in spermatogenesis is controlled by pro-apoptotic and anti-apoptotic molecules. Hormones involved in the apoptotic process during spermatogenesis include gonadotrophins, sex hormones, and glucocorticoid (GC). GC acts broadly as an apoptosis inducer by binding to its receptor (glucocorticoid receptor: GR) during organ development processes, such as spermatogenesis. However, the downstream pathway induced in GC-GR signaling and the apoptotic process during spermatogenesis remains poorly understood. We reported previously that GC induces full-length glucocorticoid-induced transcript 1 (GLCCI1-long), which functions as an anti-apoptotic mediator in thymic T cell development. Here, we demonstrate that mature murine testis expresses a novel isoform of GLCCI1 protein (GLCCI1-short) in addition to GLCCI1-long. We demonstrate that GLCCI1-long is expressed in spermatocytes along with GR. In contrast, GLCCI1-short is primarily expressed in spermatids where GR is absent; instead, the estrogen receptor is expressed. GLCCI1-short also binds to LC8, which is a known mediator of the anti-apoptotic effect of GLCCI1-long. A luciferase reporter assay revealed that ß-estradiol treatment synergistically increased Glcci1-short promotor-driven luciferase activity in Erα-overexpressing cells. Together with the evidence that the conversion of testosterone to estrogen is preceded by aromatase expression in spermatids, we hypothesize that estrogen induces GLCCI1-short, which, in turn, may function as a novel anti-apoptotic mediator in mature murine testis.
Assuntos
Glucocorticoides , Sêmen , Masculino , Camundongos , Animais , Espermatogênese , Espermátides , EstrogêniosRESUMO
BACKGROUND: Although desmopressin therapy is effective in treating polyuric monosymptomatic nocturnal enuresis (MNE), the relatively high rates of recurrence are problematic. To date, the treatment protocol on the discontinuation of oral desmopressin melt (ODM) tablet, MinirinMelt, has not been established. We tested two protocols of tapering ODM when the patients achieved full response on ODM, and compared the treatment outcomes. METHODS: One hundred and fifty-seven polyuric MNE children were newly treated with ODM at the authors' outpatient clinics (Juntendo Nerima Hospital and Musashi-Murayama Hospital). When the patients did not respond to the 8 week ODM therapy, we added another options such as alarm, anti-cholinergics, and imipramine (92 patients; 58.6%). Sixty-five patients (41.4%) achieved full response on ODM alone, and 49 of them accepted gradual tapering of ODM: group B (n = 25), 240 µg ODM per day â 120 µg ODM per day â 120 µg ODM per alternate day â cessation; and group C (n = 24), 240 µg ODM per day â 120 µg ODM per day â 60 µg ODM per day â 60 µg ODM per alternate day â cessation. RESULTS: Fourteen patients in group B (56%) and four in group C (17%) had relapses of enuresis after the discontinuation of ODM (P = 0.026). CONCLUSIONS: Gradual tapering of ODM therapy in MNE patients leads to better outcome.
Assuntos
Enurese Noturna/tratamento farmacológico , Pacientes Ambulatoriais , Micção/efeitos dos fármacos , Adolescente , Antidiuréticos/administração & dosagem , Criança , Desamino Arginina Vasopressina/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Enurese Noturna/fisiopatologia , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Micção/fisiologiaRESUMO
As most recombinant lysosomal enzymes are incorporated into cells via mannose 6-phosphate (M6P) receptors, the M6P content is important for effective enzyme replacement therapy (ERT) for lysosomal diseases. However, there have been no comprehensive reports of the M6P contents of lysosomal enzymes. We developed an M6P assay method comprising three steps, i.e., acid hydrolysis of glycoproteins, derivatization of M6P, and high-performance liquid chromatography, and determined the M6P contents of six recombinant lysosomal enzymes now available for ERT and one in the process of development. The assay is easy, specific, and reproducible. The results of the comparative study revealed that the M6P contents of agalsidase alfa, agalsidase beta, modified α-N-acetylgalactosaminidase, alglucosidase alfa, laronidase, idursulfase, and imiglucerase are 2.1, 2.9, 5.9, 0.7, 2.5, 3.2, and <0.3 mol/mol enzyme, respectively. The results were correlated with those of the biochemical analyses previously performed and that of the binding assay of exposed M6P of the enzymes with the domain 9 of the cation-independent M6P receptor. This assay method is useful for comparison of the M6P contents of recombinant lysosomal enzymes for ERT.
Assuntos
Terapia de Reposição de Enzimas , Lisossomos/enzimologia , Manosefosfatos/química , Receptor IGF Tipo 2/química , Humanos , Hidrolases/química , Isoenzimas/química , Lisossomos/química , Manosefosfatos/isolamento & purificação , Receptor IGF Tipo 2/metabolismo , Proteínas Recombinantes/química , alfa-Galactosidase/químicaRESUMO
BACKGROUND: The major pathogenic factors involved in nocturnal enuresis are nocturnal polyuria, small bladder capacity and/or detrusor overactivity, and a high arousal threshold. Desmopressin is the first-line therapy for the patients with diuresis-dependent nocturnal enuresis. Yokukansan, a traditional Japanese medicine, has been used in Japan to treat patients with nervousness, insomnia, and children with night terrors and temper tantrums. We experienced the positive effect of Yokukansan in some of the patients who did not respond well to desmopressin therapy. METHODS: In total, 32 children with monosymptomatic nocturnal enuresis with nocturnal polyuria were treated with oral desmopressin melt tablets, which were approved for clinical use in Japan on 29 May 2012. This treatment was effective for 14 of them. For the rest (n = 18), Yokukansan was introduced in combination with desmopressin. RESULTS: Yokukansan was effective for 12 out of the 18 cases. CONCLUSIONS: Yokukansan should be a candidate for the medication of nocturnal enuresis.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional , Enurese Noturna/tratamento farmacológico , Fitoterapia , Adolescente , Criança , Humanos , Japão , Enurese Noturna/diagnóstico , Indução de Remissão , Inquéritos e QuestionáriosRESUMO
It is postulated that chickens (Gallus gallus domesticus) became domesticated from wild junglefowls in Southeast Asia nearly 10,000 years ago. Based on 19 individual samples covering various chicken breeds, red junglefowl (G. g. gallus), and green junglefowl (G. varius), we address the origin of domestic chickens, the relative roles of ancestral polymorphisms and introgression, and the effects of artificial selection on the domestic chicken genome. DNA sequences from 30 introns at 25 nuclear loci are determined for both diploid chromosomes from a majority of samples. The phylogenetic analysis shows that the DNA sequences of chickens, red and green junglefowls formed reciprocally monophyletic clusters. The Markov chain Monte Carlo simulation further reveals that domestic chickens diverged from red junglefowl 58,000+/-16,000 years ago, well before the archeological dating of domestication, and that their common ancestor in turn diverged from green junglefowl 3.6 million years ago. Several shared haplotypes nonetheless found between green junglefowl and chickens are attributed to recent unidirectional introgression of chickens into green junglefowl. Shared haplotypes are more frequently found between red junglefowl and chickens, which are attributed to both introgression and ancestral polymorphisms. Within each chicken breed, there is an excess of homozygosity, but there is no significant reduction in the nucleotide diversity. Phenotypic modifications of chicken breeds as a result of artificial selection appear to stem from ancestral polymorphisms at a limited number of genetic loci.
Assuntos
Evolução Biológica , Galinhas/genética , Galliformes/genética , Variação Genética , Animais , Sequência de Bases , Núcleo Celular/genética , Cromossomos/genética , DNA Concatenado/genética , DNA Mitocondrial/genética , Haplótipos/genética , Íntrons/genética , Funções Verossimilhança , Cadeias de Markov , Método de Monte Carlo , Filogenia , Dinâmica Populacional , Especificidade da EspécieRESUMO
Thin basement membrane nephropathy (TBMN) is characterized clinically by persistent hematuria, minimal proteinuria, normal renal function, another family member with hematuria, and a benign course. Especially in childhood TBMN, proteinuria of any degree is reported to be uncommon. We report on a boy with benign familial hematuria found by urinary screening at 3 years of age who presented with nephrotic syndrome (NS) at 15 years of age. His renal histology showed TBMN associated with minimal change disease (MCD). Treatment with corticosteroid resulted in complete remission of NS in a short period of time, while isolated hematuria persisted during the follow-up period despite this therapy. We speculate, therefore, that the nephrotic range proteinuria is not due to TBMN but rather is the manifestation of associated MCD. Several cases of TBMN with NS have been reported in adults, but it has not yet been reported in children in the literature. To our knowledge, this is the first case of childhood TBMN associated with NS resulting from coincidental MCD.
Assuntos
Membrana Basal/patologia , Hematúria/complicações , Nefrose Lipoide/complicações , Síndrome Nefrótica/complicações , Adolescente , Membrana Basal/ultraestrutura , Pré-Escolar , Seguimentos , Humanos , Masculino , Nefrose Lipoide/patologiaRESUMO
Although immunosuppressive regimens of corticosteroids combined with high-dose intravenous cyclophosphamide (IVCY) have been reported to suppress the activity of lupus nephritis, there is controversy regarding its application for children and adolescents, because of its potential toxicity including gonadal dysfunction. On the basis of the recent finding that a low-dose IVCY regimen for induction therapy in adult lupus nephritis effectively achieves renal remission comparable with that achieved with a conventional high-dose IVCY regimen, we treated two children with severe lupus nephritis by low-dose (fixed dose of 500 mg m(-2), cumulative dose 3 g m(-2), approximately one-fourth of the conventional high-dose IVCY regimen) IVCY and oral mizoribine (5 mg kg(-1) day(-1)) and steroids (3 methylprednisolone pulse followed by oral prednisolone). They responded well to this regimen, showing remarkable improvement in both histological and clinical manifestations in a short period of time. From these findings we suggest that the new low-dose IVCY regimen may be as effective as the conventional high-dose IVCY regimen, without significant adverse effect, for induction therapy in children with severe lupus nephritis (class III or IV).
Assuntos
Ciclofosfamida/administração & dosagem , Glucocorticoides/uso terapêutico , Imunossupressores/administração & dosagem , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/fisiopatologia , Ribonucleosídeos/administração & dosagem , Administração Oral , Criança , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Injeções Intravenosas , Rim/patologia , Nefrite Lúpica/patologia , Masculino , Metilprednisolona/uso terapêutico , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Indução de Remissão , Ribonucleosídeos/uso terapêutico , Índice de Gravidade de DoençaRESUMO
Cyclosporin A (CsA) is an effective treatment for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS), but its use can be complicated by renal toxicity and a high incidence of relapses after withdrawal. We report 9 adolescent patients with childhood-onset FR-SDNS who had been treated with long-term CsA that resulted in moderate-to-severe CsA nephropathy (CsAN). They were treated with high-dose (mean: 10.1 mg/kg per day) mizoribine (MZR) in an attempt to allow weaning of CsA and/or steroid therapy, and reduce the frequency of relapses. Seven out of 9 patients were weaned off CsA by 1-year follow-up, although in the remaining 2 patients, MZR did not show any beneficial effects. Overall, this high-dose MZR therapy results in significant steroid sparing and reduction in relapse rates in our patients. Our experience shows that high-dose MZR therapy in patients with FR-SDNS who are also CsA-dependent appears to be effective in reducing CsA exposure as well as in decreasing the frequency of relapses.