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1.
Circ J ; 85(3): 243-251, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33487604

RESUMO

BACKGROUND: The associations between body mass index (BMI) and incidence of atrial fibrillation (AF) in young men are scarce, especially in Asian countries, given the differences in BMI between Asians and Western populations.Methods and Results:This study analyzed 17,865 middle-aged Japanese men without AF from a cohort of employees undergoing annual health examinations. AF incidence was evaluated during a follow-up period (median 4.0 years, interquartile range 2.0-7.1 years). Among young men aged 30-49 years, AF incidence was 0.64/1,000 person-years, whereas it was 2.54/1,000 and 7.60/1,000 person-years among men aged 50-59 and ≥60 years, respectively. Multivariable Cox regression analysis among young men revealed age (hazard ratio [HR] 3.28 by 10-years' increase, 95% confidence interval [CI] 1.72-6.25, P<0.001), BMI (BMI-quadratic, HR 1.01, 95% CI 1.00-1.01, P<0.001, BMI-linear, HR 0.95, 95% CI 0.86-1.05, P=0.33), and electrocardiogram (ECG) abnormalities, such as PQ prolongation, supraventricular beat, and p wave abnormality (HR 8.79, 95% CI 3.05-25.32, P<0.001), were significantly associated with AF incidence. There was a reverse J-shaped association between BMI and AF incidence in young men, whereby the presence of ECG abnormality inversely influenced the BMI-incident AF relationship. A linear association between BMI and AF incidence in men aged 50-59 and ≥60 years was present. CONCLUSIONS: AF incidence displays a reverse J-shaped relationship with BMI in young men, but a linear association in men aged ≥50 years. The paradoxical relationship seen in young men only may reflect atrial electrical or structural abnormalities.

2.
Clin Nutr ; 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33298333

RESUMO

BACKGROUND & AIMS: Metabolic syndrome (MS) is associated with adverse outcomes, and visceral adipose tissue (VAT) is associated with MS. Recently, VAT has been classified into intraperitoneal VAT (IVAT) and retroperitoneal VAT (RVAT). This study aimed to evaluate the association of IVAT and RVAT with the prevalence of MS or its components. METHODS: In our cross-sectional study, the prevalence of MS or its components was analyzed in 803 middle-aged Japanese participants. The cross-sectional area of the abdominal adipose tissue was evaluated from an unenhanced computed tomography scan at the third lumbar vertebra, and IVAT or RVAT was analyzed using a specialized software. The areas were normalized for the square of the participants' height in meters and described as the IVAT or RVAT area index. RESULTS: In age, sex, and BMI adjusted model, the IVAT, or RVAT area index was independently associated with the prevalence of MS. After simultaneous inclusion of IVAT, RVAT, and deep and superficial subcutaneous adipose tissue area indices for multivariate logistic regression analysis, the IVAT area index was found to be independently associated with the prevalence of MS (adjusted odds ratio [OR], 1.03; 95% confidence intervals [CI], 1.02-1.08) and its components, including waist circumference (OR, 1.07; 95% CI, 1.03-1.10), glucose (1.03; 1.01-1.05), triglycerides (1.03; 1.00-1.05), and high-density lipoprotein cholesterol (1.03; 1.00-1.05), whereas the RVAT area index was not. The RVAT area index was independently associated with the prevalence of component-blood pressure (1.06; 1.02-1.11), whereas the IVAT area index was not. CONCLUSIONS: IVAT and RVAT are associated differently with the prevalence of MS and its components.

3.
Diabetol Metab Syndr ; 12(1): 103, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33292449

RESUMO

AIM: Diabetes mellitus (DM) is associated with adverse outcomes, and visceral adipose tissue (VAT), classified into intraperitoneal VAT (IVAT) and retroperitoneal VAT (RVAT), is associated with insulin resistance. This study aimed to evaluate the association of IVAT and RVAT with the prevalence or incidence of DM. METHODS: In this cross-sectional, retrospective, cohort study, the prevalence and incidence of DM was analyzed in 803 and 624 middle-aged Japanese participants, respectively. The cross-sectional area of the abdominal adipose tissue was evaluated from an unenhanced computed tomography scan at the third lumbar vertebrae, and the IVAT or RVAT was analyzed using specialized software. The areas were normalized for the square value of the participants' height in meters and described as the IVAT or RVAT area index. RESULTS: The IVAT area index (adjusted odds ratio [OR], 1.04; 95% confidence intervals [CI], 1.02-1.07, per 1.0 cm2/m2) or IVAT/RVAT area ratio (1.89; 1.23-2.85, per 1.0) was independently associated with the prevalence of DM, whereas the RVAT area index was not. During a follow-up (mean) of 3.7 years, 30 participants were diagnosed with DM. The IVAT area index (adjusted hazards ratio [HR], 1.02; 95% CI 1.003-1.04, per 1.0 cm2/m2) or IVAT/RVAT area ratio (2.25; 1.40-3.43, per 1.0) was independently associated with the incidence of DM, whereas the RVAT area index was not. CONCLUSIONS: IVAT, but not RVAT, is associated with the prevalence or incidence of DM.

4.
PLoS Genet ; 16(12): e1009232, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33347437

RESUMO

Motile cilia can beat with distinct patterns, but how motility variations are regulated remain obscure. Here, we have studied the role of the coiled-coil protein CFAP53 in the motility of different cilia-types in the mouse. While node (9+0) cilia of Cfap53 mutants were immotile, tracheal and ependymal (9+2) cilia retained motility, albeit with an altered beat pattern. In node cilia, CFAP53 mainly localized at the base (centriolar satellites), whereas it was also present along the entire axoneme in tracheal cilia. CFAP53 associated tightly with microtubules and interacted with axonemal dyneins and TTC25, a dynein docking complex component. TTC25 and outer dynein arms (ODAs) were lost from node cilia, but were largely maintained in tracheal cilia of Cfap53-/- mice. Thus, CFAP53 at the base of node cilia facilitates axonemal transport of TTC25 and dyneins, while axonemal CFAP53 in 9+2 cilia stabilizes dynein binding to microtubules. Our study establishes how differential localization and function of CFAP53 contributes to the unique motion patterns of two important mammalian cilia-types.

5.
Clin Nutr ESPEN ; 40: 314-319, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33183556

RESUMO

BACKGROUND & AIMS: Higher hemoglobin levels are associated with incident metabolic syndrome (MetS), and higher mean corpuscular volume (MCV) is associated with adverse outcomes. The objective of this study is to evaluate the combined effect of MCV and hemoglobin levels on incident MetS. METHODS: In our cross-sectional study, we analyzed the prevalence of MetS in 20,162 middle-aged Japanese subjects without anemia and with normal MCV levels, as they underwent physical checkups. We subsequently analyzed incident MetS in 11,110 subjects. In order to evaluate the combined effect on incident MetS, the subjects were divided into four study groups according to cutoff values of hemoglobin and MCV for identifying the prevalence of MetS. RESULTS: In the cross-sectional study, hemoglobin (adjusted odds ratio [aOR], 1.02; P < 0.0001 in men and OR, 1.04; P < 0.0001 in women, per 1.0 g/L) and MCV (aOR, 0.93; P < 0.0001 in men and OR, 0.94; P = 0.0005 in women, per 1.0 fL) were independently associated with the prevalence of MetS. In the longitudinal cohort study, hemoglobin (adjusted hazards ratio [aHR, 1.12; P = 0.0006, per 1.0 g/L) and MCV (aHR, 0.96; P < 0.0001, per 1.0 fL) were independently associated with incident MetS in men but not in women. Then, the lower hemoglobin/higher MCV group showed decreased HRs for incidence of MetS compared with other groups of men but not of women. CONCLUSIONS: Among the subjects without anemia and with normal MCV levels, higher hemoglobin or lower MCV levels were associated with higher prevalence of MetS in men and women. In addition, lower hemoglobin with higher MCV showed a decreased risk of MetS in men. We suggested that the assessment of hemoglobin and MCV levels could be used as practical screening tool for MetS.

6.
J Diabetes Investig ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206465

RESUMO

AIMS: Sarcopenia and visceral obesity are major global public health issues, and higher mean corpuscular volume (MCV) levels are related to adverse outcomes. Nonetheless, no study has determined the association between MCV and body composition. Therefore, we evaluated the association between MCV levels and trunk muscle quality, muscle quantity, and visceral fat area (VFA). MATERIALS AND METHODS: In our cross-sectional study, we investigated 702 middle-aged Japanese subjects without anemia and with normal MCV levels who underwent physical checkups. The cross-sectional area of skeletal muscle or visceral fat was analyzed by computed tomography (CT). RESULTS: In the adjusted model, the MCV was independently associated with the VFA index (ß = -0.107, p = 0.0007), total skeletal muscle index (ß = 0.053, p = 0.0341), and total skeletal muscle density (ß = 0.099, p = 0.0012). MCV as a continuous variable was relared to the prevalence of sarcopenia (odds ratios [OR], 0.93; 95% confidence intervals (CI), 0.88-0.98, per 1.0 fL increment; p = 0.0097) and visceral obesity (OR, 0.91; 95% CI, 0.86-0.97, per 1.0 fL increment; p = 0.0046). The highest MCV quartile was independently associated with the prevalence of sarcopenia (OR, 0.48; 95% CI, 0.27-0.83; p = 0.0089) and visceral obesity (OR, 0.49; 95% CI, 0.27-0.88; p = 0.0170), compared to the lowest quartile. CONCLUSIONS: In subjects without anemia and with normal MCV levels, a lower MCV was associated with unfavorable body composition, including lower muscle quality, lower muscle quantity, sarcopenia and visceral obesity.

7.
Sci Adv ; 6(30): eaba1195, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32743070

RESUMO

Immotile cilia sense extracellular signals such as fluid flow, but whether Ca2+ plays a role in flow sensing has been unclear. Here, we examined the role of ciliary Ca2+ in the flow sensing that initiates the breaking of left-right (L-R) symmetry in the mouse embryo. Intraciliary and cytoplasmic Ca2+ transients were detected in the crown cells at the node. These Ca2+ transients showed L-R asymmetry, which was lost in the absence of fluid flow or the PKD2 channel. Further characterization allowed classification of the Ca2+ transients into two types: cilium-derived, L-R-asymmetric transients (type 1) and cilium-independent transients without an L-R bias (type 2). Type 1 intraciliary transients occurred preferentially at the left posterior region of the node, where L-R symmetry breaking takes place. Suppression of intraciliary Ca2+ transients delayed L-R symmetry breaking. Our results implicate cilium-derived Ca2+ transients in crown cells in initiation of L-R symmetry breaking in the mouse embryo.

8.
Nutr Metab Cardiovasc Dis ; 30(7): 1161-1168, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32448718

RESUMO

BACKGROUND AND AIMS: The metabolic syndrome has been reported by cross-sectional studies to have an association with skeletal muscle quality and quantity. Using a longitudinal study design, this study aimed to explicate the association between muscle characteristics assessed with computed tomography (CT) and the incidence and progression of metabolic syndrome. METHODS AND RESULTS: In this retrospective study on a cohort of employees undergoing annual physical examinations, we evaluated data from 554 participants without metabolic syndrome. The cross-sectional skeletal muscle area was determined based on CT data at the level of the third lumbar vertebra, and the skeletal muscle density (SMD) and skeletal muscle index (SMI) were measured. The participants were divided into four study groups according to the sex-specific median values for SMI and SMD. We followed the participants for a mean period of 3.1 years. In the sex- and age-adjusted model, SMI and SMD had an interaction effect on the longitudinal change in number of metabolic syndrome components (ß = -0.074, p = 0.0727). Multiple regression analyses revealed that both low SMI and SMD was significantly associated with the change (ß = 0.131, p = 0.0281), whereas the low SMI and high SMD, and high SMI and low SMD were not. Both low SMI and SMD (hazard ratio (HR), 2.42; 95% confidence interval, 1.28-4.78) showed an increased adjusted HR for incident metabolic syndrome. CONCLUSION: The participants with both low quality and quantity of skeletal muscles were associated with the incidence and progression of metabolic syndrome, whereas those with only low quantity or quality of skeletal muscles were not.


Assuntos
Composição Corporal , Síndrome Metabólica/epidemiologia , Músculo Esquelético/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Progressão da Doença , Feminino , Nível de Saúde , Humanos , Incidência , Japão/epidemiologia , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Tronco
9.
Nutrition ; 74: 110752, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32203879

RESUMO

OBJECTIVES: Diabetes mellitus is a major global public health issue. Cross-sectional studies have demonstrated that skeletal muscle quality and quantity by computed tomography (CT) is related to glucose metabolism. However, to our knowledge, no longitudinal study has yet to elucidate the association between muscle quality determined by CT and glucose metabolism. Thus, the aim of this study was to evaluate the association between muscle quality and glucose metabolism. METHODS: In this retrospective study, we evaluated data from 621 middle-aged Japanese individuals without diabetes mellitus from a cohort of employees undergoing annual physical examinations. The cross-sectional skeletal muscle area was determined based on CT data at the level of the third lumbar vertebrae, and the skeletal muscle index (SMI) and density (SMD) were calculated. Low-attenuation muscle (LAM) and normal-attenuation muscle (NAM) were identified and quantified using thresholds of -29 to +29 HU and +30 to +150 HU, respectively. RESULTS: We followed the individuals for a mean period of 3 y, and 27 of them developed diabetes mellitus during this period. Multiple Cox regression analyses revealed that, even after adjustment for visceral fat area index, the LAM index (hazard ratio [HR], 3.07; 95% confidence interval [CI], 1.00-7.52) showed an increased adjusted HR for incident diabetes mellitus. When total SMI and SMD were used in the same models, only total SMD (HR, 0.90; 95% CI, 0.81-0.99) showed a decreased adjusted HR for incident diabetes mellitus. CONCLUSIONS: Both LAM index and total SMD were associated with a higher risk for incident diabetes mellitus, whereas NAM index and total SMI were not.

10.
Nat Ecol Evol ; 4(2): 261-269, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31907383

RESUMO

Unidirectional fluid flow generated by motile cilia at the left-right organizer (LRO) breaks left-right (L-R) symmetry during early embryogenesis in mouse, frog and zebrafish. The chick embryo, however, does not require motile cilia for L-R symmetry breaking. The diversity of mechanisms for L-R symmetry breaking among vertebrates and the trigger for such symmetry breaking in non-mammalian amniotes have remained unknown. Here we examined how L-R asymmetry is established in two reptiles, Madagascar ground gecko and Chinese softshell turtle. Both of these reptiles appear to lack motile cilia at the LRO. The expression of the Nodal gene at the LRO in the reptilian embryos was found to be asymmetric, in contrast to that in vertebrates such as mouse that are dependent on cilia for L-R patterning. Two paralogues of the Nodal gene derived from an ancient gene duplication are retained and expressed differentially in cilia-dependent and cilia-independent vertebrates. The expression of these two Nodal paralogues is similarly controlled in the lateral plate mesoderm but regulated differently at the LRO. Our in-depth analysis of reptilian embryos thus suggests that mammals and non-mammalian amniotes deploy distinct strategies dependent on different Nodal paralogues for rendering Nodal activity asymmetric at the LRO.


Assuntos
Padronização Corporal , Cílios , Animais , Embrião de Galinha , Madagáscar , Camundongos , Répteis , Peixe-Zebra
11.
Clin Nutr ; 39(6): 1818-1825, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31439352

RESUMO

BACKGROUND & AIMS: Metabolic syndrome is a cluster of metabolic abnormalities. Skeletal muscle attenuation and area evaluated by computer tomography (CT) may provide valuable information about patients with metabolic disorder. Therefore, we examined the association between skeletal muscle characteristics and metabolic syndrome, and investigated the combined effect of quantitative and qualitative muscle parameters. METHODS: In this cross-sectional study, we analyzed 808 middle-aged Japanese subjects. The cross-sectional area of skeletal muscle was evaluated based on CT at the third lumbar vertebrae. The subjects were divided into four groups according to the median levels of skeletal muscle index (SMI) and density (SMD). RESULTS: Eighty-five men and twenty-two women had metabolic syndrome. In the adjusted model, SMI and SMD had an interaction effect on the number of metabolic syndrome components (p = 0.0398 in men and p = 0.0306 in women). When SMI and SMD were considered as independent variables for multiple regression analysis, SMI (ß = -0.155, p = 0.0019 in men and ß = -0.295, p < 0.0001 in women) and SMD (ß = -0.355, p < 0.0001 in men and ß = -0.324, p < 0.0001 in women) were both independently associated with the number of metabolic syndrome components. The subgroup with presence of low SMI and low SMD levels had a significantly higher prevalence of metabolic syndrome than that observed in other groups. CONCLUSIONS: Therefore, we suggest that not only muscle quantity but also quality is independently associated with metabolic syndrome.

12.
Liver Int ; 40(1): 120-130, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518481

RESUMO

BACKGROUND & AIMS: Sarcopenia is reported to be associated with nonalcoholic fatty liver disease (NAFLD). Evaluation of skeletal muscle attenuation and area by computed tomography (CT) may represent a promising approach for evaluation of the risk of NAFLD. We examined the association between skeletal muscle characteristics and NAFLD and investigated the combined effect of these parameters on the prevalence of NAFLD. METHODS: In this cross-sectional study, we analysed data from 632 middle-aged Japanese subjects without daily alcohol intake (353 men and 279 women) from a cohort of employees undergoing annual health examinations. The cross-sectional skeletal muscle area was evaluated on the basis of CT data at the level of the third lumbar vertebrae, and the skeletal muscle index (SMI) and density (SMD) were calculated. The subjects were divided into four study groups according to their SMI and SMD relative to median values. RESULTS: One hundred forty men and forty-three women had NAFLD. Total SMI (odds ratio [OR] per 1.0 cm2 /kg/m2 increase 0.43, 95% confidence interval [CI] 0.29-0.64 in men and OR 0.21, 95% CI 0.10-0.42 in women) and total SMD (OR, per 1.0 Hounsfield Unit increase 0.88, 95% CI 0.83-0.93 in men and 0.88, 0.82-0.95 in women) were significantly associated with the prevalence of NAFLD after adjusting for covariates. The subgroup with simultaneous presence of low SMI and low SMD was associated with a significantly higher prevalence of NAFLD compared with other groups. CONCLUSIONS: Both SMI and SMD are independently associated with the prevalence of NAFLD.

13.
Genes Cells ; 24(11): 731-745, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31554018

RESUMO

Cluap1/IFT38 is a ciliary protein that belongs to the IFT-B complex and is required for ciliogenesis. In this study, we have examined the behaviors of Cluap1 protein in nonciliated and ciliated cells. In proliferating cells, Cluap1 is located at the distal appendage of the mother centriole. When cells are induced to form cilia, Cluap1 is found in a novel noncentriolar compartment, the cytoplasmic IFT spot, which mainly exists once in a cell. Other IFT-B proteins such as IFT46 and IFT88 are colocalized in this spot. The cytoplasmic IFT spot is present in mouse embryonic fibroblasts (MEFs) but is absent in ciliogenesis-defective MEFs lacking Cluap1, Kif3a or Odf2. The cytoplasmic IFT spot is also found in mouse embryos but is absent in the Cluap1 mutant embryo. When MEFs are induced to form cilia, the cytoplasmic IFT spot appears at an early step of ciliogenesis but starts to disappear when ciliogenesis is mostly completed. These results suggest that IFT-B proteins such as Cluap1 accumulate in a previously undescribed cytoplasmic compartment during ciliogenesis.


Assuntos
Cílios/metabolismo , Citoplasma/metabolismo , Proteínas do Citoesqueleto/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Animais , Cílios/ultraestrutura , Citoplasma/ultraestrutura , Fibroblastos , Proteínas de Choque Térmico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cinesina , Camundongos , Camundongos Knockout , Proteínas Supressoras de Tumor
14.
Diabetol Metab Syndr ; 11: 12, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740147

RESUMO

Background: Metabolic syndrome is characterized by the clustering of different metabolic abnormalities. Total bilirubin and gamma-glutamyltransferase (GGT) levels have been reported to be associated with this condition. However, the extent to which the interaction between these parameters affects metabolic syndrome is unknown. Therefore, we examined the association of total bilirubin and GGT levels with metabolic syndrome, and investigated the combined effect of the two parameters. Methods: In this retrospective cohort study, we analyzed 8992 middle-aged Japanese subjects (4586 men, 4406 women; mean age, 44.8 ± 9.3 years) without metabolic syndrome from a cohort of employees undergoing annual health examinations. They were divided into four groups according to median total bilirubin and GGT levels: both-low, GGT-high, total bilirubin-high, and both-high. The incident of metabolic syndrome was evaluated during a follow-up of 2.8 ± 1.2 years. Results: The incident rate of metabolic syndrome during the follow-up was 4.6% in the both-low group, 12.1% in the GGT-high group, 2.7% in the total bilirubin-high group, and 10.6% in the both-high group. Total bilirubin and GGT have an interaction effect on the risk of incident metabolic syndrome (p = 0.0222). The both-low [hazard ratio (HR), 1.37; 95% confidence interval (CI) 1.002-1.89], GGT-high (HR, 1.88; 95% CI 1.42-2.52), and both-high (HR, 2.07; 95% CI 1.56-2.80) groups showed an increased adjusted HR for incident metabolic syndrome after adjusting for covariates compared with the total bilirubin-high group. Conclusions: The simultaneous presence of high total bilirubin and low GGT levels may be associated with a lower incidence of metabolic syndrome.

15.
Nat Commun ; 8(1): 1492, 2017 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-29138408

RESUMO

Anterior-posterior (A-P) polarity of mouse embryos is established by distal visceral endoderm (DVE) at embryonic day (E) 5.5. Lefty1 is expressed first at E3.5 in a subset of epiblast progenitor cells (L1epi cells) and then in a subset of primitive endoderm cells (L1dve cells) fated to become DVE. Here we studied how prospective DVE cells are selected. Lefty1 expression in L1epi and L1dve cells depends on Nodal signaling. A cell that experiences the highest level of Nodal signaling begins to express Lefty1 and becomes an L1epi cell. Deletion of Lefty1 alone or together with Lefty2 increased the number of prospective DVE cells. Ablation of L1epi or L1dve cells triggered Lefty1 expression in a subset of remaining cells. Our results suggest that selection of prospective DVE cells is both random and regulated, and that a fixed prepattern for the A-P axis does not exist before the blastocyst stage.


Assuntos
Embrião de Mamíferos/metabolismo , Endoderma/metabolismo , Fatores de Determinação Direita-Esquerda/genética , Proteína Nodal/metabolismo , Transdução de Sinais , Vísceras/metabolismo , Animais , Padronização Corporal , Cromossomos Artificiais Bacterianos , Embrião de Mamíferos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Camundongos , Camundongos Transgênicos , Processos Estocásticos
16.
Dev Cell ; 40(5): 439-452.e4, 2017 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-28292423

RESUMO

Polarization of node cells along the anterior-posterior axis of mouse embryos is responsible for left-right symmetry breaking. How node cells become polarized has remained unknown, however. Wnt5a and Wnt5b are expressed posteriorly relative to the node, whereas genes for Sfrp inhibitors of Wnt signaling are expressed anteriorly. Here we show that polarization of node cells is impaired in Wnt5a-/-Wnt5b-/- and Sfrp mutant embryos, and also in the presence of a uniform distribution of Wnt5a or Sfrp1, suggesting that Wnt5 and Sfrp proteins act as instructive signals in this process. The absence of planar cell polarity (PCP) core proteins Prickle1 and Prickle2 in individual cells or local forced expression of Wnt5a perturbed polarization of neighboring wild-type cells. Our results suggest that opposing gradients of Wnt5a and Wnt5b and of their Sfrp inhibitors, together with intercellular signaling via PCP proteins, polarize node cells along the anterior-posterior axis for breaking of left-right symmetry.


Assuntos
Padronização Corporal , Polaridade Celular , Transdução de Sinais , Proteínas Wnt/metabolismo , Proteína Wnt-5a/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Comunicação Celular , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas com Domínio LIM/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Modelos Biológicos , Proteínas/metabolismo
17.
Dev Biol ; 381(1): 203-12, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23742838

RESUMO

Qilin is one of several genes in zebrafish whose mutation results in cystic kidney. We have now studied the role of its mouse ortholog, Cluap1, in embryonic development by generating Cluap1 knockout (Cluap1-/-) mice. Cluap1-/- embryos died mid-gestation manifesting impairment of ciliogenesis in various regions including the node and neural tube. The basal body was found to be properly docked to the apical membrane of cells in the mutant, but the axoneme failed to grow. Cluap1 is a ciliary protein and is preferentially localized at the base and tip of cilia. Hedgehog signaling, as revealed with a Pacthed1-lacZ reporter gene, was lost in Cluap1-/- embryos at embryonic day (E) 8.5 but was ectopically expanded at E9.0. The Cluap1 knockout embryos also failed to manifest left-right asymmetric expression of Nodal in the lateral plate, most likely as a result of the loss of Hedgehog signaling in node crown cells that in turn leads to pronounced down-regulation of Gdf1 expression in these cells. Crown cell-specific restoration of Cluap1 expression rescued Gdf1 expression in crown cells and left-sided Nodal expression in the lateral plate of mutant embryos. Our results suggest that Cluap1 contributes to ciliogenesis by regulating the intraflagellar transport (IFT) cycle at the base and tip of the cilium.


Assuntos
Cílios/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Morfogênese/genética , Animais , Padronização Corporal , Regulação para Baixo , Fibroblastos/metabolismo , Genes Reporter , Genótipo , Proteínas Hedgehog/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Óperon Lac , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutação , Transdução de Sinais
18.
No Shinkei Geka ; 40(12): 1071-7, 2012 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-23180744

RESUMO

BACKGROUND: Visual loss following craniotomy is a serious postoperative complication in which elevation of ocular pressure during retraction of the skin flap may cause retinal ischemia. We reported that continuous monitoring of extraocular pressure with the FlexiForce sensor may avoid excessive skin flap retraction during craniotomy and thus prevent ocular complications. METHODS: Between January 2008 and December 2011, we analyzed data from 46 consecutive patients for whom continuous monitoring of extraocular pressure with FlexiForce sensor was performed. This sensor continuously displays the compressive force, allowing surgeons to check values on the monitor at any time. An alarm sounds if 50 gf is exceeded. We analyzed the temporal course of extraocular pressure and the relationship with patient characteristics. RESULT: No visual complications were encountered in this patient series. Maximum compressive force during craniotomy was 35.8±27.2 gf, with increases typically seen when surgeons used hooks or drills. However, due to the alarm, no prolonged periods of high force were noted in any patient. Effective methods for reducing force were: (1) taking off hooks on the compressive side; (2) changing the direction of hook tension; and (3) placing cushions such as gauze under the side of the skin flap. Maximum compressive force during microsurgery was 21.8±18.4 gf, and correlated with the beginning force of microsurgery. CONCLUSION: Compressive force was greatly reduced compared to the force reported previously. The etiologies of visual disability are not fully understood, but this sensor may be helpful in reducing extraocular compression.


Assuntos
Craniotomia/métodos , Microcirurgia/métodos , Pressão , Adulto , Idoso , Olho/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Complicações Pós-Operatórias/prevenção & controle , Pressão/efeitos adversos
19.
J Exp Med ; 207(10): 2207-23, 2010 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-20855498

RESUMO

The therapeutic potential of hematopoietic stem cells/endothelial progenitor cells (HSCs/EPCs) for fracture healing has been demonstrated with evidence for enhanced vasculogenesis/angiogenesis and osteogenesis at the site of fracture. The adaptor protein Lnk has recently been identified as an essential inhibitor of stem cell factor (SCF)-cKit signaling during stem cell self-renewal, and Lnk-deficient mice demonstrate enhanced hematopoietic reconstitution. In this study, we investigated whether the loss of Lnk signaling enhances the regenerative response during fracture healing. Radiological and histological examination showed accelerated fracture healing and remodeling in Lnk-deficient mice compared with wild-type mice. Molecular, physiological, and morphological approaches showed that vasculogenesis/angiogenesis and osteogenesis were promoted in Lnk-deficient mice by the mobilization and recruitment of HSCs/EPCs via activation of the SCF-cKit signaling pathway in the perifracture zone, which established a favorable environment for bone healing and remodeling. In addition, osteoblasts (OBs) from Lnk-deficient mice had a greater potential for terminal differentiation in response to SCF-cKit signaling in vitro. These findings suggest that inhibition of Lnk may have therapeutic potential by promoting an environment conducive to vasculogenesis/angiogenesis and osteogenesis and by facilitating OB terminal differentiation, leading to enhanced fracture healing.


Assuntos
Consolidação da Fratura , Osteogênese , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fator de Células-Tronco/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Diferenciação Celular , Fraturas Ósseas/metabolismo , Fraturas Ósseas/fisiopatologia , Fraturas Ósseas/terapia , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Camundongos , Neovascularização Patológica , Neovascularização Fisiológica , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese/genética , Proteínas/genética , Transdução de Sinais , Células-Tronco/metabolismo , Células-Tronco/patologia
20.
J Neurosurg Anesthesiol ; 22(1): 67-72, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19816203

RESUMO

The aims of this study were to introduce our newly developed device equipped with a contact surface force sensor (FlexiForce) for monitoring extraocular compression continuously, and to illustrate its potential clinical application using this device in patients undergoing uncomplicated frontotemporal or bifrontal craniotomy for surgical clipping of unruptured anterior circulation aneurysms. In a pilot study with volunteers, we determined the critical force of 100 gf to cause painful ocular sensation. Then we performed the bilateral extraocular force measurements in 15 patients undergoing uncomplicated frontotemporal or bifrontal craniotomy for surgical clipping of unruptured anterior circulation aneurysms. Extraocular force increased immediately after retraction of the flap, increased to 144+/-26 gf (mean+/-SD) during lower craniotomy close to the orbit, was maintained at 91+/-18 gf during microsurgery, and returned close to baseline at 24+/-14 gf after restoration of skin flap retraction. Such changes were observed only on the surgical side in frontotemporal craniotomy. Abnormal increase in extraocular force was effectively reduced by placing a real-time digital panel meter to warn surgeons to avoid excessive skin flap retraction during the surgical procedure. In conclusion, this new tool may allow us to monitor the external forces that can be applied intraoperatively to the ocular globe in the supine position.


Assuntos
Craniotomia/métodos , Traumatismos Oculares/prevenção & controle , Aneurisma Intracraniano/cirurgia , Monitorização Intraoperatória/instrumentação , Complicações Pós-Operatórias/prevenção & controle , Pressão/efeitos adversos , Adulto , Idoso , Desenho de Equipamento , Traumatismos Oculares/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos
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