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1.
Br Poult Sci ; 64(1): 47-55, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36129068

RESUMO

1. This study assessed 1) the effects of Paracoccus carotinifaciens supplementation containing high astaxanthin levels on egg production performance and quality, 2) dynamics of carotenoids levels in the egg yolk and 3) taste of astaxanthin-rich egg yolk.2. Laying hens were fed diets containing different levels of P. carotinifaciens-derived astaxanthin (ASX; 0, 2, 4, 8, or 16 ppm) for 28 d (experiment 1) or a diet containing 16 ppm astaxanthin for 28 d followed by a 0 ppm astaxanthin diet for 28 days (experiment 2).3. Production performance, egg quality and egg yolk carotenoid levels were examined in experiment 1 (Ex1) and the dynamics of egg yolk carotenoid levels and egg yolk taste in experiment 2 (Ex2).4. ASX supplementation did not affect production performance or egg quality. ASX levels in the egg yolk became saturated after seven days of 16 ppm supplementation and decreased to less than one-tenth of the saturated levels seven days after supplementation cessation. Supplementation with 16 ppm ASX for 28 d did not affect egg yolk taste.5. Supplementation resulted in the production of ASX-rich eggs for a brief period without affecting production performance, egg quality or taste. Understanding the time taken for the incorporation of ASX into egg yolks is beneficial for value-added egg production and may help in minimising supplementation costs.


Assuntos
Galinhas , Óvulo , Feminino , Animais , Gema de Ovo , Dieta/veterinária , Carotenoides , Suplementos Nutricionais/análise , Ração Animal/análise , Ovos/análise
2.
Phys Rev Lett ; 124(18): 183001, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32441980

RESUMO

Differences in postcollision interaction (PCI) effects on Kr L_{3}M_{4,5}M_{4,5} Auger electron spectra were observed, depending on whether the initial photoionization occurred slightly above the K threshold or slightly above the L_{3} threshold. For the former, KL fluorescence emission most likely happens and then Auger processes due to the L_{3} hole follow. The time delay due to fluorescence causes a reduced shift of the Auger peak and tailing toward lower energy, since the Auger overtaking of the photoelectron happens later in time and at a location farther away from the ionic core, compared to the case for the simple one-step L_{3}M_{4,5}M_{4,5} Auger decay after L-shell photoionization. Time-dependent theory for PCI in multistep processes agrees well with experiment, illustrating the effect as an internal clock for the time-sequence of the dynamical process.

3.
Scand J Rheumatol ; 48(6): 491-496, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31272272

RESUMO

Objectives: Kawasaki disease (KD) is a systemic vasculitis of early childhood. Intravenous immunoglobulin (IVIG) is the standard treatment for KD. However, IVIG is not effective in approximately 15% of children with KD, and the mechanisms for this are unclear. We investigated changes in monocyte and T-cell activation from pre- to post-IVIG in IVIG-effective and IVIG-resistant KD.Method: We analysed peripheral CD14+CD16+ cells and human leucocyte antigen-DR (HLA-DR) expression on CD4+ and CD8+ cells in 46 children with KD who were admitted to Yamaguchi University Hospital between January 2011 and May 2016. We compared the kinetics in the absolute numbers of CD14+CD16+ cells, CD4+HLA-DR+ cells, and CD8+HLA-DR+ cells before and after IVIG treatment between IVIG-effective and IVIG-resistant groups.Results: Among the 46 subjects, 30 had IVIG-effective KD and 16 had IVIG-resistant KD. The absolute number of CD14+CD16+ cells in the IVIG-effective group decreased significantly after IVIG, while that in the IVIG-resistant group showed no change after IVIG. The absolute number of CD4+HLA-DR+ cells increased significantly after IVIG in both groups. The absolute number of CD8+HLA-DR+ cells before IVIG was low and significantly increased after IVIG in the IVIG-resistant group, while that in the IVIG-effective group showed no change after IVIG.Conclusions: Our results suggest that insufficient control of monocyte suppression and T-cell activation, especially in terms of the CD8-related immune system, are associated with IVIG resistance. The restoration of T-cell suppression may be important for KD recovery. These findings provide insight into the mechanism of IVIG resistance.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Ativação Linfocitária , Monócitos/imunologia , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Antígenos HLA-DR/análise , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/imunologia
4.
Phys Rev Lett ; 121(17): 171802, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30411920

RESUMO

The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of 14.7(7.6)×10^{20} protons on target in the neutrino (antineutrino) mode, 89 ν_{e} candidates and seven anti-ν_{e} candidates are observed, while 67.5 and 9.0 are expected for δ_{CP}=0 and normal mass ordering. The obtained 2σ confidence interval for the CP-violating phase, δ_{CP}, does not include the CP-conserving cases (δ_{CP}=0, π). The best-fit values of other parameters are sin^{2}θ_{23}=0.526_{-0.036}^{+0.032} and Δm_{32}^{2}=2.463_{-0.070}^{+0.071}×10^{-3} eV^{2}/c^{4}.

5.
Br J Dermatol ; 174(6): 1327-36, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26822223

RESUMO

BACKGROUND: Squamous cell carcinoma antigen (SCCA) belongs to the ovalbumin-serpin family and is a known tumour marker. Expression of SCCA is upregulated in the serum and skin of patients with psoriasis. OBJECTIVES: The aim of this study was to determine SCCA2 levels in association with disease severity and treatment efficacy in patients with psoriasis. MATERIALS AND METHODS: Patients with psoriasis (n = 123) and healthy controls (n = 25) were enrolled in this prospective cross-sectional study. Enzyme-linked immunosorbent assay (ELISA) analysis was performed to determine serum SCCA2 levels. SCCA2 expression in skin was evaluated using immunohistochemical analysis. Serum SCCA2 levels were compared with Psoriasis Area Severity Index (PASI) scores. The effect of treatment on serum SCCA2 levels was assessed using serial examinations. Induction of SCCA2 by several psoriatic cytokines in human keratinocytes was evaluated. RESULTS: The serum levels of SCCA2 were significantly higher in patients with psoriasis than healthy controls and correlated well with disease severity. Increased SCCA2 staining was observed in lesional skin but not in nonlesional skin of patients with psoriasis. In addition, SCCA2 expression levels in skin correlated with serum concentrations of SCCA2. SCCA2 significantly decreased according to improvement of PASI scores. Interleukin (IL)-17 and IL-22 synergistically increased the production of SCCA2 at both mRNA and protein levels in human keratinocytes. CONCLUSIONS: Significant elevation of SCCA2 is associated with disease severity and reflects treatment efficacy. SCCA2 may be a useful biomarker in psoriasis, reflecting T-helper 17-type inflammation - the main determinant of the severity of psoriasis.


Assuntos
Antígenos de Neoplasias/metabolismo , Psoríase/sangue , Serpinas/metabolismo , Pele/metabolismo , Biomarcadores/metabolismo , Estudos Transversais , Fármacos Dermatológicos/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-17/metabolismo , Interleucina-17/fisiologia , Interleucinas/metabolismo , Interleucinas/fisiologia , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Psoríase/tratamento farmacológico , Resultado do Tratamento , Interleucina 22
7.
J Periodontal Res ; 48(6): 773-80, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23586648

RESUMO

BACKGROUND AND OBJECTIVE: Periodontitis is a chronic inflammatory disease that leads to bone resorption by osteoclasts (OCs). Several factors contribute to the differentiation of OCs from hematopoietic precursors. Cellular chemotactic factors are expressed in periodontitis tissue, but the effects of these chemoattractants on OCs are not well understood. Here we examined the effects of chemoattractants produced in inflamed periodontal tissue on OC chemotaxis. MATERIAL AND METHODS: Rat bone-marrow OCs were cultured in OC culture medium for 3 or 6 d. Using EZ-TAXIScan™, the chemotactic response of these OCs to several chemoattractants [monocyte chemotactic protein-1; macrophage inflammatory protein 1α; regulated on activation, normal T-cell expressed and secreted; stromal cell-derived factor-1α; and complement activation product 5a (C5a)] was measured. In addition, we measured the effect of C5a-specific inhibitors on chemotactic responses toward C5a. The recorded chemotactic responses were quantitatively analysed using ImageJ software. RESULTS: Chemoattractants associated with periodontal disease significantly increased the chemotactic activity of differentiated rat OCs in a concentration-dependent manner, with C5a inducing the highest chemotactic activity of OCs cultured for 3 or 6 d. The C5a-specific inhibitor significantly inhibited chemotaxis toward C5a in a concentration-dependent manner. CONCLUSION: We suggest that C5a plays an important role in pathologic bone resorption in periodontal disease by stimulating the chemotaxis of OCs. Therefore, C5a is a potential target for the treatment of periodontal disease.


Assuntos
Fatores Quimiotáticos/farmacologia , Quimiotaxia/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Periodontite/fisiopatologia , Animais , Células da Medula Óssea/fisiologia , Reabsorção Óssea/fisiopatologia , Técnicas de Cultura de Células , Diferenciação Celular , Quimiocina CCL2/farmacologia , Quimiocina CCL3/farmacologia , Quimiocina CCL5/farmacologia , Quimiocina CXCL12/farmacologia , Complemento C5a/farmacologia , Meios de Cultura , Relação Dose-Resposta a Droga , Ratos , Ratos Sprague-Dawley , Serina Endopeptidases/farmacologia , Fatores de Tempo
8.
J Clin Pharm Ther ; 38(3): 230-5, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23530940

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Demonstration of the utility of electronic medical records (EMRs) for pharmacovigilance (PV) has been highly anticipated. Analysis using appropriately selected EMRs should enable accurate estimation of adverse drug event (ADE) frequencies and thus promote appropriate regulatory actions. Statin-induced myopathy (SIM) is a clinically important ADE, but pharmacoepidemiological methodology for detecting this ADE with high predictability has not yet been established. This study aimed to develop a detection algorithm, highly selective for SIM using EMRs. METHODS: We collected EMRs on prescriptions, laboratory tests, diagnoses and medical practices from the hospital information system of Kobe University Hospital, Japan, for a total of 5109 patients who received a statin prescription from April 2006 to March 2009. The current algorithm for extracting SIM-suspected patients consisted of three steps: (i) event detection: increase in creatine kinase (CK) and subsequent statin discontinuation, (ii) filtration by exclusion factors (disease diagnosis/medical practices) and (iii) refinement by the time course of CK values (baseline, event and recovery). A causal relationship between the event and statin prescription (probable/possible/unlikely) was judged by review of patient medical charts by experienced pharmacists. The utility of the current algorithm was assessed by calculating the positive predictive value (PPV). In a comparative analysis, subjects screened in step 1 were extracted by the diagnostic term/code for 'myopathy/rhabdomyolysis', and the PPV of this diagnostic data approach was also estimated. RESULTS AND DISCUSSION: Five subjects with suspected SIM were identified using our proposed algorithm, giving a frequency of 0·1% for the adverse event. Review of the medical charts revealed that the causal association of SIM with statin use was judged as 'Likely (probable/possible)' for all five suspected patients; thus, the PPV was estimated as 100% (95% confidence interval: 56·6-100%). The higher utility of the current algorithm compared with the diagnostic data approach was also shown by assessing the PPV (100 vs. 33·3%). WHAT IS NEW AND CONCLUSION: We report on a detection algorithm with high predictability for SIM using EMRs. Combined use of exclusion criteria for disease, medical practice data and time course of CK values contributes to better prediction of SIM. The utility of the proposed algorithm should be further confirmed in a larger study.


Assuntos
Algoritmos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Farmacovigilância
9.
Phys Rev Lett ; 106(3): 030801, 2011 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-21405263

RESUMO

The Avogadro constant links the atomic and the macroscopic properties of matter. Since the molar Planck constant is well known via the measurement of the Rydberg constant, it is also closely related to the Planck constant. In addition, its accurate determination is of paramount importance for a definition of the kilogram in terms of a fundamental constant. We describe a new approach for its determination by counting the atoms in 1 kg single-crystal spheres, which are highly enriched with the 28Si isotope. It enabled isotope dilution mass spectroscopy to determine the molar mass of the silicon crystal with unprecedented accuracy. The value obtained, NA = 6.022,140,78(18) × 10(23) mol(-1), is the most accurate input datum for a new definition of the kilogram.

10.
Curr Opin Cell Biol ; 12(3): 302-7, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10801459

RESUMO

There have been three major advances in the understanding of the Ran pathway during the past two years: first, a general model for Ran's function in nuclear transport has been proposed and extensively tested. Second, crystal structures for many proteins that regulate or interact with Ran have been reported, which provide molecular details of how Ran works. Third, it has been documented that Ran regulates mitotic spindle assembly in a transport-independent fashion.


Assuntos
Núcleo Celular/fisiologia , Proteína ran de Ligação ao GTP/fisiologia , Animais , Transporte Biológico Ativo , Núcleo Celular/enzimologia , Citoplasma/fisiologia , Mitose/fisiologia , Modelos Biológicos , Fuso Acromático/fisiologia
11.
Cell Cycle ; 20(4): 345-352, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33459116

RESUMO

DNA Topoisomerase II (TopoII) uses ATP hydrolysis to decatenate chromosomes so that sister chromatids can faithfully segregate in mitosis. When the TopoII enzyme cycle stalls due to failed ATP hydrolysis, the onset of anaphase is delayed, presumably to allow extra time for decatenation to be completed. Recent evidence revealed that, unlike the spindle assembly checkpoint, this TopoII checkpoint response requires Aurora B and Haspin kinases and is triggered by SUMOylation of the C-terminal domain of TopoII.


Assuntos
Aurora Quinase B/fisiologia , DNA Topoisomerases Tipo II/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Pontos de Checagem da Fase M do Ciclo Celular/fisiologia , Metáfase/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Proteínas de Ciclo Celular/fisiologia , Genes cdc/fisiologia , Humanos , Mitose/fisiologia
12.
Poult Sci ; 98(6): 2570-2576, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753716

RESUMO

Intestinal glucose absorption varies with growth; however, the dynamics of these variations has not been yet fully elucidated in broiler chickens. The present study aimed to compare jejunal glucose uptake and maltose digestion in broilers of 2 different ages, i.e., 1- vs. 5 wk old. Oral D-maltose gavage, everted sac, and Ussing chamber experiments were carried out to investigate intestinal glucose absorption and mRNA expression of glucose-transport-related genes as well as jejunal maltase activity. Upon gavage, glucose concentrations peaked at 10 min post-administration in 1-wk-old chicks, while they peaked at 40 min in 5-wk-old chickens. Glucose concentrations at 10 min were significantly higher in the 1-wk-old chicks (P = 0.010). Using the everted sacs experimental setup, 5 intestinal regions i.e., duodenum, proximal jejunum, distal jejunum, proximal ileum, and distal ileum, were targeted to examine D-maltose digestion and glucose transport across the intestinal mucosa. In the distal and proximal ileum, glucose concentrations were found to be significantly higher in the serosal compartment of the 1-wk-old chicks upon incubation with D-maltose (25 mM) (P < 0.05), while in the mucosal compartment the levels were significantly higher in the 5-wk-old chickens (P < 0.05). An Ussing chamber setup was employed to measure glucose-induced short-circuit current (ΔIsc) in the mucosal epithelium of the jejunum. In response to the addition of D-maltose (10 mM) into the mucosal compartment, ΔIsc was significantly higher in the 1-wk-old chicks (P = 0.018). Furthermore, no variations in jejunal maltase activity were observed between the 2 age groups. While jejunal glucose absorption was lower in the 5-wk-old chickens, the mRNA expression levels of jejunal SGLT1, GLUT2, and Na+/K+-ATPase did not show any significant differences between the 2 age groups. Our results suggest that the active transport of glucose across the jejunal epithelium decreases upon growth in broiler chickens but is not accompanied by any variations in maltase activity or in the expression of glucose-absorption-related genes.


Assuntos
Galinhas/metabolismo , Glucose/metabolismo , Jejuno/metabolismo , Maltose/metabolismo , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Transporte Biológico Ativo , Galinhas/genética , Galinhas/crescimento & desenvolvimento , Digestão/fisiologia , Epitélio/metabolismo , Expressão Gênica , Mucosa Intestinal/metabolismo , Masculino , RNA Mensageiro
13.
Neuroscience ; 156(2): 381-9, 2008 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-18755247

RESUMO

We investigated the subtype of prejunctional muscarinic receptors associated with inhibition of acetylcholine (ACh) released from the mouse bladder. We measured endogenous ACh release in the bladder obtained from the wild-type mice and muscarinic 1-5 (M1-M5) receptor knockout (KO) mice. Electrical field stimulation increased ACh release in all bladder preparations obtained from wild-type and M1-M5 receptor KO mice. The amount of ACh released from M1-M3 and M5 receptor KO mice was equal to that in the wild-type mice. In contrast, the amount of electrical field stimulation-induced ACh release in M4 receptor KO mice was significantly larger than that in the wild-type mice, but the extent of increase was small. Atropine increased electrical field stimulation-induced ACh release to levels found in wild-type mice in all M1-M5 receptor KO mice. In M2/M4 receptor double KO mice, the amount of electrical field stimulation-induced ACh release was equivalent to that in the M4 receptor KO mice. The cholinergic component of electrical field stimulation-induced contraction (in the presence of alpha,beta-methylene ATP) in the detrusor of M4 receptor KO mice was no different from that in the detrusor of wild-type mice. M4 receptor immunoreactivity was located between smooth muscle cells, colocalized with choline acetyltransferase immunoreactivity. These results indicate that the prejunctional inhibitory muscarinic receptors are of the M4 and non-M2 receptor subtypes. The nature of the non-M2 receptors remains unknown.


Assuntos
Acetilcolina/metabolismo , Receptores Muscarínicos/classificação , Receptores Muscarínicos/fisiologia , Bexiga Urinária/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Anestésicos Locais/farmacologia , Animais , Atropina/farmacologia , Colina O-Acetiltransferase/metabolismo , Relação Dose-Resposta à Radiação , Estimulação Elétrica/métodos , Feminino , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antagonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Contração Muscular/efeitos da radiação , Músculos/efeitos dos fármacos , Músculos/metabolismo , Músculos/efeitos da radiação , RNA Mensageiro/metabolismo , Receptores Muscarínicos/deficiência , Tetrodotoxina/farmacologia , Bexiga Urinária/citologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/efeitos da radiação
14.
Hum Exp Toxicol ; 37(7): 725-741, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28920463

RESUMO

Rose hip is the fruit of the rose plant, which is widely used in food, cosmetics and as a traditional medicine. Therefore, rose hip is considered safe and has a sufficient history of consumption as food. However, few studies have reported on the safety of rose hip extracts in toxicological analyses. Thus, to evaluate the safety of rosehip polyphenol MJ (RHPMJ), an aqueous ethanol extract standardized with the trans-tiliroside content, we performed genotoxicity and 90-day repeated oral dose toxicity studies in compliance with the Organisation for Economic Co-operation and Development-Good Laboratory Practice. RHPMJ did not induce gene mutations in reverse mutation tests of Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2 uvrA strains and did not induce chromosomal aberrations in cultured Chinese hamster lung (CHL/IU) cells. Moreover, micronucleus tests using rat bone marrow showed RHPMJ had no micronucleus-inducing potential. Finally, 90-day repeated oral dose toxicity studies (100-1000 mg/kg) in male and female rats showed no treatment-related toxicity in rats. These data indicate that the RHPMJ had no genotoxicity and a no-observed-adverse-effect level greater than 1000 mg/kg in rats.


Assuntos
Extratos Vegetais/toxicidade , Polifenóis/toxicidade , Rosa , Animais , Linhagem Celular , Cricetulus , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Feminino , Frutas , Masculino , Testes de Mutagenicidade , Nível de Efeito Adverso não Observado , Ratos Sprague-Dawley , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Testes de Toxicidade Subcrônica
15.
J Clin Invest ; 105(7): 935-43, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10749573

RESUMO

Insulin receptor substrates (IRS-1 and -2) are essential for intracellular signaling by insulin and IGF-I, anabolic regulators of bone metabolism. Mice lacking the IRS-1 gene IRS-1(-/-) showed severe osteopenia with low bone turnover. IRS-1 was expressed in osteoblasts, but not in osteoclasts, of wild-type (WT) mice. IRS-1(-/-) osteoblasts treated with insulin or IGF-I failed to induce tyrosine phosphorylation of cellular proteins, and they showed reduced proliferation and differentiation. Osteoclastogenesis in the coculture of hemopoietic cells and osteoblasts depended on IRS-1 expression in osteoblasts and could not be rescued by IRS-1 expression in hemopoietic cells in the presence of not only IGF-I but also 1,25(OH)(2)D(3). In addition, osteoclast differentiation factor (RANKL/ODF) was not induced by these factors in IRS-1(-/-) osteoblasts. We conclude that IRS-1 deficiency in osteoblasts impairs osteoblast proliferation, differentiation, and support of osteoclastogenesis, resulting in low-turnover osteopenia. Osteoblastic IRS-1 is essential for maintaining bone turnover, because it mediates signaling by IGF-I and insulin and, we propose, also by other factors, such as 1,25(OH)(2)D(3).


Assuntos
Remodelação Óssea , Osteoblastos/fisiologia , Fosfoproteínas/fisiologia , Animais , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Células Cultivadas , Feminino , Fêmur/crescimento & desenvolvimento , Proteínas Substratos do Receptor de Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoporose/metabolismo , Fosfoproteínas/genética , Transdução de Sinais , Tíbia/crescimento & desenvolvimento
16.
Neuromuscul Disord ; 27(12): 1087-1098, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29054425

RESUMO

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management.


Assuntos
Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/fisiopatologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Miastênicas Congênitas/classificação , Síndromes Miastênicas Congênitas/epidemiologia , Espanha/epidemiologia , Adulto Jovem
17.
Neurogastroenterol Motil ; 18(3): 226-33, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16487414

RESUMO

Our previous study showed that atropine significantly inhibited the sustained relaxation induced by electrical field stimulation (EFS) in the circular muscle strips prepared from the mouse antrum, and that pituitary adenylate cyclase activating peptide (PACAP) partially mediated the sustained relaxation. The muscarinic receptor subtype associated with the sustained relaxation was examined in the present study by using each muscarinic receptor subtype of knockout (KO) mice. EFS-induced sustained relaxation in the antrum prepared from M(2) receptor KO mice was significantly less than that of wild-type mice. Atropine failed to inhibit this relaxation. On the other hand, similar sustained relaxation and inhibitory effects of atropine to those of wild-type mice were observed in M(1), M(3) and M(4) receptor KO mice. Exogenously added PACAP-27 relaxed the antral strips of wild-type and M(2) receptor KO mice to a similar extent. Immunohistochemical study revealed that M(2) receptor immunoreactivity was localized with PACAP-immunoreactivity in enteric neurons within the antrum of wild-type mice. In contrast, atropine did not affect the EFS-induced sustained relaxation in the gastric fundus. These results suggest that M(2) receptors modulate the sustained relaxation, probably through the regulation of PACAP release, in the mouse antrum.


Assuntos
Relaxamento Muscular/fisiologia , Músculo Liso/metabolismo , Antro Pilórico/metabolismo , Receptor Muscarínico M2/metabolismo , Animais , Atropina/farmacologia , Estimulação Elétrica , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Antagonistas Muscarínicos/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Técnicas de Cultura de Órgãos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Antro Pilórico/efeitos dos fármacos , Receptor Muscarínico M2/efeitos dos fármacos , Vasodilatadores/farmacologia
18.
Neurogastroenterol Motil ; 28(6): 827-36, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26787195

RESUMO

BACKGROUND: For the contraction and relaxation of gastric smooth muscles to occur, the intracellular Ca(2+) concentration must be increased and decreased, respectively. The Na(+) /Ca(2+) exchanger (NCX) is a plasma membrane transporter that is involved in regulating intracellular Ca(2+) concentrations. METHODS: To determine the role of NCX in gastrointestinal tissues, we examined electric field stimulation (EFS)-induced relaxations in the circular muscles of the gastric fundus in NCX1 and NCX2 heterozygote knockout mice (HET). KEY RESULTS: The myenteric plexus layers and the longitudinal and circular muscle layers in the gastric fundus of wild-type mice (WT) were strongly immunoreactive to NCX1 and NCX2. EFS induced a transient relaxation that was apparent during the stimulus and a sustained relaxation that persisted after the end of the stimulus. The amplitudes of EFS-induced transient relaxation and sustained relaxation were greater in NCX1 HET and NCX2 HET than in WT. When an inhibitor of nitric oxide synthase was added following the EFS, neither NCX1 HET nor NCX2 HET exhibited transient relaxation, similar to WT. Furthermore, when a PACAP antagonist was added following the EFS, sustained relaxation in NCX1 HET and NCX2 HET was not observed, similar to WT. Next, we examined the effect of NCX heterozygous deficiency on relaxation in response to NO and PACAP in smooth muscles. The magnitude of NOR-1- and PACAP-induced relaxations in NCX1 HET and NCX2 HET was similar to that of WT. CONCLUSIONS & INFERENCES: In this study, we demonstrate that NCX1 and NCX2 expressed in neurons regulate the motility in the gastric fundus.


Assuntos
Fundo Gástrico/fisiologia , Trânsito Gastrointestinal/fisiologia , Heterozigoto , Relaxamento Muscular/fisiologia , Trocador de Sódio e Cálcio/biossíntese , Animais , Motilidade Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Trocador de Sódio e Cálcio/genética
19.
AJNR Am J Neuroradiol ; 37(4): 698-705, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26585267

RESUMO

BACKGROUND AND PURPOSE: West syndrome is an epileptic encephalopathy characterized by epileptic spasms, a specific pattern on electroencephalography of hypsarrhythmia, and developmental regression. Our aim was to assess white matter abnormalities in West syndrome of unknown etiology. We hypothesized that diffusion tensor imaging reveals white matter abnormalities, especially in patients with poor seizure and developmental outcomes. MATERIALS AND METHODS: We enrolled 23 patients with new-onset West syndrome of unknown etiology. DTI was performed at 12 and 24 months of age. Fractional anisotropy images were compared with those of controls by using tract-based spatial statistics. We compared axial, radial, and mean diffusivity between patients and controls in the fractional anisotropy skeleton. We determined correlations of these parameters with developmental quotient, electroencephalography, and seizure outcomes. We also compared DTI with hypometabolism on fluorodeoxyglucose positron-emission tomography. RESULTS: At 12 months of age, patients showed widespread fractional anisotropy reductions and higher radial diffusivity in the fractional anisotropy skeleton with a significant difference on tract-based spatial statistics. The developmental quotient at 12 months of age correlated positively with fractional anisotropy and negatively with radial and mean diffusivity. Patients with seizure and abnormal findings on electroencephalography after initial treatments had lower fractional anisotropy and higher radial diffusivity. At 24 months, although tract-based spatial statistics did not show significant differences between patients and controls, tract-based spatial statistics in the 10 patients with a developmental quotient of <70 had significant fractional anisotropy reduction. In patients with unilateral temporal lobe hypometabolism on PET, tract-based spatial statistics showed greater fractional anisotropy reduction in the temporal lobe ipsilateral to the side of PET hypometabolism. CONCLUSIONS: Diffuse abnormal findings on DTI at 12 months of age suggest delayed myelination as a key factor underlying abnormal findings on DTI. Conversely, asymmetric abnormal findings on DTI at 24 months may reflect underlying focal pathologies.


Assuntos
Deficiências do Desenvolvimento/patologia , Convulsões/patologia , Espasmos Infantis/patologia , Substância Branca/patologia , Hormônio Adrenocorticotrópico/metabolismo , Anisotropia , Deficiências do Desenvolvimento/etiologia , Imagem de Tensor de Difusão , Eletroencefalografia , Feminino , Fluordesoxiglucose F18 , Humanos , Lactente , Masculino , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Convulsões/etiologia , Espasmos Infantis/diagnóstico por imagem , Resultado do Tratamento , Substância Branca/diagnóstico por imagem , Substância Branca/crescimento & desenvolvimento
20.
Biochim Biophys Acta ; 1092(3): 311-8, 1991 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-1646640

RESUMO

In this study, we investigated the possibility that cultured keratinocytes from normal human adult skin produce 1,25-dihydroxyvitamin D-3 (1,25(OH)2D3, a biologically active form of vitamin D-3) from 25-hydroxyvitamin D-3 [25(OH)D3], and that 1,25(OH)2D3 endogenously produced by keratinocytes is involved in the self regulation of their growth and differentiation. To determine whether 1,25(OH)2D3 is produced from 25(OH)D3 by skin keratinocytes, 25(OH)[3H]D3 was added to keratinocyte cultures and incubated for 1 h and 5 h. The intracellular and extracellular metabolites were analyzed by three chromatographic systems. The three chromatograms revealed that the major metabolite produced from 25(OH)D3 was 1,25(OH)2D3. Most of the 1,25(OH)2D3 endogenously produced from 25(OH)D3 remained within the cells. To examine the time course of 1,25(OH)2D3 production, the amount of 1,25(OH)[3H]D3 was measured at 15 min, 1 h, 5 h and 10 h, being at a maximum 1 h after the addition of 25(OH)D3. These data indicate that keratinocytes rapidly convert 25(OH)D3 to 1,25(OH)2D3 and that 1,25(OH)2D3 is not released into the medium. To determine whether endogenously produced 1,25(OH)2D3 is involved in the regulation of growth and differentiation of normal human keratinocytes, we examined the effects of 1,25(OH)2D3 and 25(OH)D3 on their growth and differentiation. Keratinocyte growth was inhibited to 52.6% and 23.4% by 10(-8) M and 10(-7) M 1,25(OH)2D3 and to 80.5% and 23.9% by 10(-8) M and 10(-7) M 25(OH)D3, respectively. Differentiation of these cells was evaluated by quantifying the number which express involucrin, a precursor protein of cornified envelope. The population of involucrin expressing cells (differentiated cells) increased from 6.2% to 14.5% by 2.5.10(-7) M 1,25(OH)2D3, and to 11.8% by 2.5.10(-7) M 25(OH)D3. These results clearly indicate that 25(OH)D3 is as effective on human keratinocytes as 1,25(OH)2D3 in inhibiting growth and inducing differentiation, although to a slightly lesser extent than 1,25(OH)2D3. The possibility that the effect of 25(OH)D3 is mediated through binding to the 1,25(OH)2D3 receptor can be excluded, since a competitive binding assay revealed that the affinity of 25(OH)D3 for the 1,25(OH)2D3 receptor in a cytosolic extract of keratinocytes was 100-times lower than that of 1,25(OH)2D3. Thus, these results suggest that 1,25(OH)2D3 endogenously produced in keratinocytes from 25(OH)D3 is involved in the regulation of their growth and differentiation in vitro.


Assuntos
Calcifediol/metabolismo , Calcitriol/metabolismo , Queratinócitos/metabolismo , Ligação Competitiva , Calcifediol/farmacologia , Calcitriol/biossíntese , Calcitriol/farmacologia , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Fracionamento Celular , Células Cultivadas , Replicação do DNA/efeitos dos fármacos , Imunofluorescência , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Precursores de Proteínas/biossíntese , Precursores de Proteínas/imunologia , Ensaio Radioligante , Receptores de Calcitriol , Receptores de Esteroides/metabolismo , Timidina/metabolismo , Fatores de Tempo
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