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Endometriosis is a common gynecological disorder affecting around 10% of reproductive-age women. Although many hypotheses were proposed, genetic alteration has been considered as one of the key factors promoting pathogenesis. Due to racial/ethnic disparities in the process of hormone regulation and nutrition metabolism, a genome-wide association study (GWAS) with 2794 cases and 27,940 controls was conducted in a Taiwanese-Han population. Our study identified five significant susceptibility loci for endometriosis, and three of them, WNT4 (on the 1p36.12), RMND1 (6q25.1), and CCDC170 (6q25.1), have been previously associated with endometriosis across different populations, including European and Japanese descent cohorts. Other two including C5orf66/C5orf66-AS2 (5q31.1) and STN1 (10q24.33) are newly identified ones. Functional network analysis of potent risk genes revealed the involvement of cancer susceptibility and neurodevelopmental disorders in endometriosis development. In addition, long non-coding RNAs (lncRNAs) C5orf66 and C5orf66-AS2 can interact with many RNA-binding proteins (RBPs) which can influence RNA metabolic process, mRNA stabilization, and mRNA splicing, leading to dysregulation in tumor-promoting gene expression. Those findings support clinical observations of differences in the presentation of endometriosis in Taiwanese-Han population with higher risks of developing deeply infiltrating/invasive lesions and the associated malignancies.
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INTRODUCTION: Our objective was to assess abnormalities of the odontoid-hip axis (OD-HA) angle in a mild scoliotic population to determine whether screening for malalignment would help predict the distinction between progressive and stable adolescent idiopathic scoliosis (AIS) at early stage. MATERIALS AND METHODS: All patients (non-scoliotic and AIS) underwent a biplanar X-ray between 2013 and 2020. In AIS, inclusion criteria were Cobb angle between 10° and 25°; Risser sign lower than 3; age higher than 10 years; and no previous treatment. A 3D spine reconstruction was performed, and the OD-HA was computed automatically. A reference corridor for OD-HA values in non-scoliotic subjects was calculated as the range [5th-95th percentiles]. A severity index, helping to distinguish stable and progressive AIS, was calculated and weighted according to the OD-HA value. RESULTS: Eighty-three non-scoliotic and 205 AIS were included. The mean coronal and sagittal OD-HA angles in the non-scoliotic group were 0.2° and -2.5°, whereas in AIS values were 0.3° and -0.8°, respectively. For coronal and sagittal OD-HA, 27.5% and 26.8% of AIS were outside the reference corridor compared with 10.8% in non-scoliotic (OR = 3.1 and 3). Adding to the severity index a weighting factor based on coronal OD-HA, for thoracic scoliosis, improved the positive predictive value by 9% and the specificity by 13%. CONCLUSION: Analysis of OD-HA suggests that AIS patients are almost three times more likely to have malalignment compared with a non-scoliotic population. Furthermore, analysis of coronal OD-HA is promising to help the clinician distinguish between stable and progressive thoracic scoliosis.
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Cifosis , Escoliosis , Humanos , Adolescente , Niño , Escoliosis/diagnóstico por imagen , Escoliosis/cirugía , Estudios Longitudinales , Cifosis/diagnóstico por imagen , Estudios de Cohortes , Radiografía , Estudios RetrospectivosRESUMEN
LRRK2 mutations are the leading cause of familial Parkinson's disease (PD) and are a significant risk factor for idiopathic PD cases. However, the molecular mechanisms underlying the degeneration of dopaminergic (DA) neurons in LRRK2 PD patients remain unclear. To determine the translatomic impact of LRRK2 expression in DA neurons, we employed gene set enrichment analysis (GSEA) to analyze a translating ribosome affinity purification (TRAP) RNA-seq dataset from a DA-neuron-specific-expressing Drosophila model. We found that the tyrosine metabolism pathway, including tyrosine hydroxylase (TH), is downregulated in DA neurons with LRRK2 overexpression; in contrast, the Hippo signaling pathway is downregulated in the G2019S mutant compared to wild-type LRRK2 in the DA neurons. These results imply that the downregulation of tyrosine metabolism occurs before pronounced DA neuron loss and that LRRK2 may downregulate the tyrosine metabolism in a DA-neuron-loss-independent way.
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Neuronas Dopaminérgicas , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Animales , Humanos , Neuronas Dopaminérgicas/metabolismo , Drosophila/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Mutación , Degeneración Nerviosa/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Tirosina/metabolismoRESUMEN
Microglia are neuroglia in the brain with an innate immune function and participate in the progress of neurodegenerative diseases. Osthole (OST) is a coumarin derivative extracted from Cnidium monnieri and bears a microglia-antagonizing ability. However, the underlying mechanism of the antagonism is not clear. The lipopolysaccharides-induced microglial BV2 cell line and amyloid-overexpressing fruit fly were used as models to study OST treatment. We found that OST treatment is sufficient to evoke NRF2 cascade under an LPS-induced inflammatory environment, and silencing NRF2 is sufficient to abolish the process. Moreover, we found that OST is sufficient to antagonize microglial activation in both LPS-induced BV2 cells and Aß-overexpressing fruit flies, and silencing NRF2 abolishes OST's antagonism. Furthermore, OST treatment rescued survival, climbing, and the learning ability of Aß-overexpressing fruit flies and relieved oxidative stress. In conclusion, we proved that OST antagonizes microglial activation induced by either LPS or Aß and that NRF2 is necessary for OST's antagonism.
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Cumarinas , Microglía , Cumarinas/farmacología , Lipopolisacáridos , Microglía/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Ratones , Línea Celular , DrosophilaRESUMEN
BACKGROUND: Our previous studies found disproportionate anteroposterior vertebral size is associated with severity of the scoliotic curves in adolescent idiopathic scoliosis (AIS) patients. Subsequent studies showed wedging of vertebral bodies (VB) had less contribution than intervertebral discs (IVD) to the anterior-posterior vertebral column length discrepancy in severe-AIS. However, the exact morphological changes of IVD were not clearly defined. This study aimed to evaluate the morphological and pathological changes of IVD and VB in AIS girls and healthy female controls. METHODS: This study included 33 age-matched female controls and 76 AIS girls with a right-sided thoracic curvature. Wedge angle, height ratio and distance ratio of VB and IVD were measured on the best midline coronal and sagittal planes from reformatted MRI spine. Volumes of VB, IVD and nucleus pulposus (NP) were also evaluated on volumetric images. One-way ANOVA with Bonferroni correction and Pearson correlation tests were used. RESULTS: There was significant difference in wedge angle and height ratio of VB and IVD between AIS and controls. In severe-AIS, the position of NP was significantly shifted to the convexity when compared with non-severe AIS and controls. Whereas, the volume of IVD and NP in severe-AIS was found to be significantly smaller. In addition, Cobb angle was significantly correlated with wedge angle and height ratio, and inversely correlated with the volume of NP. CONCLUSIONS: In addition to wedging of VB and IVD, there was significantly reduced volume of IVD and NP in AIS patients with severe curve, insinuating the mechanical effect of scoliosis leads to a compression on both IVD and NP before significant disc desiccation occurs. We postulate that the compression of IVD and NP can contribute to curve progression in severe-AIS, these patients are more prone to disc degeneration in adulthood if no operative treatment is offered. Further longitudinal study on these parameters is still warranted.
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Disco Intervertebral , Cifosis , Escoliosis , Adolescente , Adulto , Femenino , Humanos , Disco Intervertebral/diagnóstico por imagen , Disco Intervertebral/patología , Cifosis/patología , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Escoliosis/cirugíaRESUMEN
BACKGROUND: Imidacloprid (IMD) is a widely used neonicotinoid-targeting insect nicotine acetylcholine receptors (nAChRs). However, off-target effects raise environmental concerns, including the IMD's impairment of the memory of honeybees and rodents. Although the down-regulation of inotropic glutamate receptor (iGluR) was proposed as the cause, whether IMD directly manipulates the activation or inhibition of iGluR is unknown. Using electrophysiological recording on fruit fly neuromuscular junction (NMJ), we found that IMD of 0.125 and 12.5 mg/L did not activate glutamate receptors nor inhibit the glutamate-triggered depolarization of the glutamatergic synapse. However, chronic IMD treatment attenuated short-term facilitation (STF) of NMJ by more than 20%. Moreover, by behavioral assays, we found that IMD desensitized the fruit flies' response to mechanosensitive, nociceptive, and photogenic stimuli. Finally, the treatment of the antioxidant osthole rescued the chronic IMD-induced phenotypes. We clarified that IMD is neither agonist nor antagonist of glutamate receptors, but chronic treatment with environmental-relevant concentrations impairs glutamatergic plasticity of the NMJ of fruit flies and interferes with the sensory response by mediating oxidative stress.
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Proteínas de Drosophila , Drosophila melanogaster , Animales , Cumarinas , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Neonicotinoides/farmacología , Plasticidad Neuronal/fisiología , Nitrocompuestos , Nocicepción , Estrés Oxidativo , Receptores de Glutamato/metabolismoRESUMEN
Fragility fractures are related to the loss of bone integrity and deteriorated morphology of osteocytes. Our previous studies have reported that low-magnitude high-frequency vibration (LMHFV) promoted osteoporotic fracture healing. As osteocytes are known for mechanosensing and initiating bone repair, we hypothesized that LMHFV could enhance osteoporotic fracture healing through enhancing morphological changes in the osteocyte lacuna-canalicular network (LCN) and mineralization. A metaphyseal fracture model was established in female Sprague-Dawley rats to investigate changes in osteocytes and healing outcomes from early to late phase post-fracture. Our results showed that the LCN exhibited an exuberant outgrowth of canaliculi in the osteoporotic fractured bone at day 14 after LMHFV. LMHFV upregulated the E11, dentin matrix protein 1 (DMP1), and fibroblast growth factor 23 (FGF23), but downregulated sclerostin (Sost) in osteocytes. Moreover, LMHFV promoted mineralization with significant enhancements of Ca/P ratio, mineral apposition rate (MAR), mineralizing surface (MS/BS), and bone mineral density (BMD) in the osteoporotic group. Consistently, better healing was confirmed by microarchitecture and mechanical properties, whereas the enhancement in osteoporotic group was comparable or even greater than the normal group. This is the first report to reveal the enhancement effect of LMHFV on the osteocytes' morphology and functions in osteoporotic fracture healing.
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Curación de Fractura/fisiología , Osteocitos/citología , Fracturas Osteoporóticas/terapia , Vibración/uso terapéutico , Animales , Densidad Ósea/fisiología , Femenino , Inmunohistoquímica , Pruebas Mecánicas , Microscopía Confocal , Microscopía Electrónica de Rastreo , Fracturas Osteoporóticas/metabolismo , Ovariectomía , Ratas , Ratas Sprague-Dawley , Microtomografía por Rayos XRESUMEN
OBJECTIVES: Adolescent idiopathic scoliosis (AIS) is the most common spinal disorder in children. A severity index was recently proposed to identify the stable from the progressive scoliosis at the first standardized biplanar radiographic exam. The aim of this work was to extend the validation of the severity index and to determine if curve location influences its predictive capabilities. METHODS: AIS patients with Cobb angle between 10° and 25°, Risser 0-2, and no previous treatment were included. They underwent standing biplanar radiography and 3D reconstruction of the spine and pelvis, which allowed to calculate their severity index. Patients were grouped by curve location (thoracic, thoracolumbar, lumbar). Patients were followed up until skeletal maturity (Risser ≥ 3) or brace prescription. Their outcome was compared to the prediction made by the severity index. RESULTS: In total, 205 AIS patients were included; 82% of them (155/189, 95% confidence interval [74-90%]) were correctly classified by the index, while 16 patients were unclassified. Positive predictive ratio was 78% and negative predictive ratio was 86%. Specificity (78%) was not significantly affected by curve location, while patients with thoracic and lumbar curves showed higher sensitivity (≥ 89%) than those with thoracolumbar curves (74%). CONCLUSIONS: In this multicentric cohort of 205 patients, the severity index was used to predict the risk of progression from mild to moderate scoliosis, with similar results of typical major curve types. This index represents a novel tool to aid the clinician and the patient in the modulation of the follow-up and, for progressive patients, their decision for brace treatment. KEY POINTS: ⢠The severity index of adolescent idiopathic scoliosis has the potential to detect patients with progressive scoliosis as early as the first exam. ⢠Out of 205 patients, 82% were correctly classified as either stable or progressive by the severity index. ⢠The location of the main curve had small effect on the predictive capability of the index.
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Escoliosis , Adolescente , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Humanos , Estudios Longitudinales , Estudios Retrospectivos , Escoliosis/diagnóstico por imagen , Columna Vertebral/diagnóstico por imagen , Resultado del TratamientoRESUMEN
BACKGROUND: Vertebral compression fractures (VCFs) are the most common among all osteoporotic fractures. The body may compensate to the kyphosis from vertebral compression fractures with lordosis of the adjacent spinal segments, rotation of the pelvis, knee flexion and ankle dorsiflexion. However, the detailed degree of body compensation, especially the lower limb, remains uncertain. Herein, the aim of this study is to investigate the values of global sagittal alignments (GSA) parameters, including the spine, pelvis and lower limbs, in patients with and without VCFs, as well as to evaluate the effect of VCFs on various quality of life (QoL) parameters. METHODS: A cross-sectional study was conducted from May 2015 to June 2018. A total of 142 patients with VCFs aged over 60 years old and 108 age-matched asymptomatic controls were recruited. Whole body sagittal alignment including thoracic kyphosis (TK), lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI), sagittal vertical axis (SVA), T1-pelvic angle (TPA), knee-flex angle (KA) and ankle-flex angle (AA) were measured. In addition, lower back pain and quality of life were assessed using self-reported questionnaires. RESULTS: Compared to asymptomatic controls, patients with VCF showed significantly greater TK (33.4o ± 16.4o vs 28.4o ± 11.4o; p < 0.01), PT (25.4o ± 10.5o vs 16.6o ± 8.9o; p < 0.001), PI (54.6o ± 11.8o vs 45.8o ± 12.0o; p < 0.001), SVA (49.1 mm ± 39.6 mm vs 31.5 mm ± 29.3 mm; p < 0.01), and TPA (28.6o ± 10.8o vs 14.8o ± 8.6o; p < 0.001). Whereas for lower limb alignment, patients with VCF showed significantly higher KA (10.1o ± 7.8o vs 6.0o ± 6.4o; p < 0.001) and AA (7.0o ± 3.9o vs 4.8o ± 3.6o; p < 0.001) than controls. The number of VCF significantly correlated with lower limb alignments (KA and AA) and global sagittal balance (TPA). VCF patients showed poorer quality of life assessment scores in terms of SF-12 (30.0 ± 8.3 vs 72.4 ± 16.9; p < 0.001), ODI (37.8 ± 24.0 vs 18.7 ± 16.6; p < 0.001) and VAS (3.8 ± 2.8 vs 1.9 ± 2.2; p < 0.001). CONCLUSION: This is the first study to illustrate the abnormal lower limb alignment exhibited in patients with VCF. Patients with VCF showed an overall worse global sagittal alignment and decreased quality of life. Poorer global sagittal alignment of VCF patients also imply worse quality of life and more severe VCF.
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Fracturas por Compresión , Lordosis , Fracturas de la Columna Vertebral , Anciano , Estudios Transversales , Fracturas por Compresión/diagnóstico por imagen , Fracturas por Compresión/etiología , Humanos , Lordosis/diagnóstico por imagen , Extremidad Inferior/diagnóstico por imagen , Vértebras Lumbares , Persona de Mediana Edad , Pelvis/diagnóstico por imagen , Calidad de Vida , Fracturas de la Columna Vertebral/diagnóstico por imagen , Columna VertebralRESUMEN
Ergosta-7,9(11),22-trien-3ß-ol (EK100) was isolated from the Taiwan-specific medicinal fungus Antrodia camphorata, which is known for its health-promotion and anti-aging effects in folk medicine. Alzheimer's disease (AD) is a major aging-associated disease. We investigated the efficacy and potential mechanism of ergosta-7,9(11),22-trien-3ß-ol for AD symptoms. Drosophila with the pan-neuronal overexpression of human amyloid-ß (Aß) was used as the AD model. We compared the life span, motor function, learning, memory, oxidative stress, and biomarkers of microglia activation and inflammation of the ergosta-7,9(11),22-trien-3ß-ol-treated group to those of the untreated control. Ergosta-7,9(11),22-trien-3ß-ol treatment effectively improved the life span, motor function, learning, and memory of the AD model compared to the untreated control. Biomarkers of microglia activation and inflammation were reduced, while the ubiquitous lipid peroxidation, catalase activity, and superoxide dismutase activity remained unchanged. In conclusion, ergosta-7,9(11),22-trien-3ß-ol rescues AD deficits by modulating microglia activation but not oxidative stress.
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Enfermedad de Alzheimer/tratamiento farmacológico , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Drosophila , Humanos , Microglía/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Polyporales/químicaRESUMEN
Adolescent idiopathic scoliosis (AIS) is a prevalent spinal deformity occurring during peripubertal growth period that affects 1-4% of adolescents globally without clear etiopathogenetic mechanism. Low bone mineral density is an independent and significant prognostic factor for curve progression. Currently, the cause underlying low bone mass in AIS remains elusive. Osteocytes play an important role in bone metabolism and mineral homeostasis, but its role in AIS has not been studied. In the present study, iliac bone tissues were harvested from 21 patients with AIS (mean age of 14.3 ± 2.20 yr old) with a mean Cobb angle of 55.6 ± 10.61° and 13 non-AIS controls (mean age of 16.5 ± 4.79 yr old) intraoperatively. Acid-etched scanning electron microscopy (SEM) images of AIS demonstrated abnormal osteocytes that were more rounded and cobblestone-like in shape and were aligned in irregular clusters with shorter and disorganized canaliculi. Further quantitative analysis with FITC-Imaris technique showed a significant reduction in the canalicular number and length as well as an increase in lacunar volume and area in AIS. SEM with energy-dispersive X-ray spectroscopy analysis demonstrated a lower calcium-to-phosphorus ratio at the perilacunar/canalicular region. Moreover, microindentaion results revealed lower values of Vickers hardness and elastic modulus in AIS when compared with controls. In addition, in the parallel study of 99 AIS (27 with severe Cobb angle of 65.8 ± 14.1° and 72 with mild Cobb angle of 26.6 ± 9.1°) with different curve severity, the serum osteocalcin level was found to be significantly and negatively associated with the Cobb angle. In summary, the findings in this series of studies demonstrated the potential link of abnormal osteocyte lacuno-canalicular network structure and function to the observed abnormal bone mineralization in AIS, which may shed light on etiopathogenesis of AIS.-Chen, H., Zhang, J., Wang, Y., Cheuk, K.-Y., Hung, A. L. H., Lam, T.-P., Qiu, Y., Feng, J. Q., Lee, W. Y. W., Cheng, J. C. Y. Abnormal lacuno-canalicular network and negative correlation between serum osteocalcin and Cobb angle indicate abnormal osteocyte function in adolescent idiopathic scoliosis.
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Huesos/ultraestructura , Osteocalcina/sangre , Osteocitos/citología , Escoliosis/sangre , Absorciometría de Fotón , Adolescente , Enfermedades Óseas Metabólicas/sangre , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Microscopía Electrónica de Rastreo , Escoliosis/diagnóstico por imagen , Escoliosis/cirugía , Adulto JovenRESUMEN
The transition zone (TZ) is a domain at the base of the cilium that is involved in maintaining ciliary compartment-specific sensory and signaling activity by regulating cilia protein composition. Mutations in TZ proteins result in cilia dysfunction, often causing pleiotropic effects observed in a group of human diseases classified as ciliopathies. The purpose of this study is to describe the importance of the TZ component Meckel-Grüber syndrome 6 ( Mks6) in several organ systems and tissues regarding ciliogenesis and cilia maintenance using congenital and conditional mutant mouse models. Similar to MKS, congenital loss of Mks6 is embryonic lethal, displaying cilia loss and altered cytoskeletal microtubule modifications but only in specific cell types. Conditional Mks6 mutants have a variable cystic kidney phenotype along with severe retinal degeneration with mislocalization of phototransduction cascade proteins. However, other phenotypes, such as anosmia and obesity, which are typically associated with cilia and TZ dysfunction, were not evident. These data indicate that despite Mks6 being a core TZ component, it has tissue- or cell type-specific functions important for cilia formation and cilia sensory and signaling activities. Lewis, W. R., Bales, K. L., Revell, D. Z., Croyle, M. J., Engle, S. E., Song, C. J., Malarkey, E. B., Uytingco, C. R., Shan, D., Antonellis, P. J., Nagy, T. R., Kesterson, R. A., Mrug, M. M., Martens, J. R., Berbari, N. F., Gross, A. K., Yoder, B. K. Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone.
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Cilios/metabolismo , Proteínas del Citoesqueleto/genética , Mutación , Acetilación , Animales , Trastornos de la Motilidad Ciliar/genética , Citoplasma/metabolismo , Encefalocele/genética , Femenino , Genes Letales , Enfermedades Renales Quísticas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Trastornos del Olfato/genética , Fenotipo , Enfermedades Renales Poliquísticas/genética , Degeneración Retiniana/genética , Retinitis Pigmentosa/genética , Tubulina (Proteína)/metabolismo , Aumento de Peso/genéticaRESUMEN
BACKGROUND: Although computed tomography (CT) is commonly used to diagnose the scoliotic spine in patients with adolescent idiopathic scoliosis (AIS) preoperatively, it is limited by the high radiation and prone scanning position. Recently, a new biplanar stereoradiography (EOS) was used to image the scoliotic spine in an upright posture with significantly less radiation in non-severe AIS subjects. However, its reliability to assess preoperative AIS patients remains unreported. Hence, the purpose of this study is to compare the scoliotic curvature between prone (CT) and upright positions (EOS) in preoperative AIS patients. METHODS: Thirty-three pre-operative AIS patients (mean age:18.4 ± 4.2) were recruited. EOS was used to scan the whole thoracic spine at upright position. Whereas on the same day, a conventional CT scan was used to evaluate the spine in prone position. The three-dimensional reconstruction of EOS and CT of the spine were then generated. Using previous validated techniques, multiple scoliotic parameters in both modalities were determined. The agreement between the two modalities was compared using the Bland-Altman test, whereas the correlation was assessed by the intraclass correlation coefficient (ICC). RESULTS: The mean ICC (prone and upright) of intra-rater/inter-rater reliabilities for the measured parameters were 0.985,0.961/0.969,0.903, respectively. Thoracic Cobb angles, intervertebral wedging and lumbar lordosis correlated significantly between upright EOS imaging radiographs (62.9 ± 9.3°,6.4 ± 2.9° and 48.8 ± 12.4°) and prone CT (47.3 ± 10.0°,5.8 ± 2.7° and 27.9 ± 11.4°; P < 0.001). The apical vertebral wedging and apical intervertebral disc wedging showed a good correlation among the two modalities (upright, 6.5 ± 3.5° and 6.4 ± 2.9°; prone, 6.5 ± 3.6° and 5.8 ± 2.7°; R2 ≥ 0.94; P < 0.01). Similarly, there was significant correlation in apical intervertebral rotation (R2 = 0.834; P < 0.01) between the prone CT (3.4 ± 3.0°) and upright EOS (3.8 ± 3.2°). In addition, the Cobb angle was significantly larger in upright EOS (62.9 ± 9.3°) than in prone CT (47.3 ± 10.0°, P < 0.01) position. There was significant underestimation on scoliotic severity in the prone position when compared with upright position. CONCLUSIONS: Importantly, the image acquisition and reconstruction from EOS can better provide accurate three-dimensional spinal representations of the scoliotic curvature in preoperative AIS patients. Moreover, our findings suggested that scoliotic curvatures in preoperative AIS patients can be largely represented by both imaging modalities despite the difference in body positioning.
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Cifosis , Escoliosis , Adolescente , Adulto , Humanos , Imagenología Tridimensional , Cifosis/diagnóstico por imagen , Radiografía , Reproducibilidad de los Resultados , Escoliosis/diagnóstico por imagen , Escoliosis/cirugía , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: Resident macrophages regulate homeostatic and disease processes in multiple tissues, including the kidney. Despite having well defined markers to identify these cells in mice, technical limitations have prevented identification of a similar cell type across species. The inability to identify resident macrophage populations across species hinders the translation of data obtained from animal model to human patients. METHODS: As an entry point to determine novel markers that could identify resident macrophages across species, we performed single-cell RNA sequencing (scRNAseq) analysis of all T and B cell-negative CD45+ innate immune cells in mouse, rat, pig, and human kidney tissue. RESULTS: We identified genes with enriched expression in mouse renal resident macrophages that were also present in candidate resident macrophage populations across species. Using the scRNAseq data, we defined a novel set of possible cell surface markers (Cd74 and Cd81) for these candidate kidney resident macrophages. We confirmed, using parabiosis and flow cytometry, that these proteins are indeed enriched in mouse resident macrophages. Flow cytometry data also indicated the existence of a defined population of innate immune cells in rat and human kidney tissue that coexpress CD74 and CD81, suggesting the presence of renal resident macrophages in multiple species. CONCLUSIONS: Based on transcriptional signatures, our data indicate that there is a conserved population of innate immune cells across multiple species that have been defined as resident macrophages in the mouse. Further, we identified potential cell surface markers to allow for future identification and characterization of this candidate resident macrophage population in mouse, rat, and pig translational studies.
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Antígenos de Diferenciación de Linfocitos B/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunidad Innata/genética , Molécula 1 de Adhesión Intercelular/inmunología , Macrófagos/metabolismo , Análisis de Varianza , Animales , Biomarcadores/metabolismo , Células Cultivadas , Citometría de Flujo , Regulación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Parabiosis , Ratas , Ratas Sprague-Dawley , Análisis de Secuencia de ARN , Especificidad de la EspecieRESUMEN
The genetic architecture of adolescent idiopathic scoliosis (AIS) remains poorly understood. Here we present the result of a 4-stage genome-wide association study composed of 5,953 AIS patients and 8,137 controls. Overall, we identified three novel susceptible loci including rs7593846 at 2p14 near MEIS1 (Pcombined = 1.19 × 10-13, OR = 1.21, 95% CI = 1.10-1.32), rs7633294 at 3p14.1 near MAGI1 (Pcombined = 1.85 × 10-12, OR = 1.20, 95% CI = 1.09-1.32), and rs9810566 at 3q26.2 near TNIK (Pcombined = 1.14 × 10-11, OR = 1.19, 95% CI = 1.08-1.32). We also confirmed a recently reported region associated with AIS at 20p11.22 (Pcombined = 1.61 × 10-15, OR = 1.22, 95% CI = 1.12-1.34). Furthermore, we observed significantly asymmetric expression of Wnt/beta-catenin pathway in the bilateral paraspinal muscle of AIS patients, including beta-catenin, TNIK, and LBX1. This is the first study that unveils the potential role of Wnt/beta-catenin pathway in the development of AIS, and our findings may shed new light on the etiopathogenesis of AIS.
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Moléculas de Adhesión Celular Neuronal/genética , Proteínas de Homeodominio/genética , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinasas/genética , Escoliosis/genética , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Moléculas de Adhesión Celular , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Quinasas del Centro Germinal , Guanilato-Quinasas , Proteínas de Homeodominio/biosíntesis , Humanos , Masculino , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Polimorfismo de Nucleótido Simple , Escoliosis/patología , Factores de Transcripción/biosíntesis , Vía de Señalización Wnt , beta Catenina/biosíntesis , beta Catenina/genéticaRESUMEN
Recently, noncoding RNAs have been thought to play important roles in the sporadic occurrence of spinal deformity of adolescent idiopathic scoliosis (AIS). As a prognostic factor for curve progression, low bone mass has been hypothesized to crosstalk with AIS pathogenesis. Abnormal osteoblasts activities are reported in AIS without a clear mechanism. In this study, bone biopsies from patients with AIS and control subjects and the primary osteoblasts derived from those samples were used to identify the potential microRNA (miRNA) candidates that interfere with osteoblasts and osteocytes function. Microarray analysis identified miRNA-145-5p (miR-145) as a potential upstream regulator. miR-145 and ß-catenin mRNA ( CTNNB1) were overexpressed in AIS bone tissues and primary osteoblasts, and their expression correlated positively in AIS. Knockdown of miR-145 restored impaired osteocyte activity through the down-regulation of active ß-catenin expression and its transcriptional activity. Significant negative correlations between circulating miR-145 and serum sclerostin, osteopontin, and osteoprotegerin were noted in patients with AIS, which was in line with our cellular findings. This is the first study to demonstrate the effect of aberrant miRNA expression and its effect on osteocyte function in AIS, which may contribute to the low bone mass. Our findings also provide insight into the development of circulating microRNAs as a bone quality biomarker or even a prognostic biomarker for AIS.-Zhang, J., Chen, H., Leung, R. K. K., Choy, K. W., Lam, T. P., Ng, B. K. W., Qiu,Y., Feng, J. Q., Cheng, J. C. Y., Lee, W. Y. W. Aberrant miR-145-5p/ß-catenin signal impairs osteocyte function in adolescent idiopathic scoliosis.
RESUMEN
BACKGROUND: Previous GWASs have revealed several susceptible variants associated with adolescent idiopathic scoliosis (AIS). Risk prediction based on these variants can potentially improve disease prognosis. We aimed to evaluate the combined effects of genetic factors on the development of AIS and to further develop a genetic predictive model. METHODS: A total of 914 AIS patients and 1441 normal controls were included in the discovery stage, which was followed by the replication stage composed of 871 patients and 1239 controls. Genotyping assay was performed to analyze 10 previously reported susceptible variants, including rs678741 of LBX1, rs241215 of AJAP1, rs13398147 of PAX3, rs16934784 of BNC2, rs2050157 of GPR126, rs2180439 of PAX1, rs4940576 of BCL2, rs7593846 of MEIS1, rs7633294 of MAGI1 and rs9810566 of TNIK. Logistic regression analysis was performed to generate a risk predictive model. The predicted risk score was calculated for each participant in the replication stage. RESULTS: The association of the 10 variants with AIS was successfully validated. The established model could explain approximately 7.9% of the overall variance. In the replication stage, patients were found to have a remarkably higher risk score as compared to the controls (44.2 ± 14.4 vs. 33.9 ± 12.5, p <0.001). There was a remarkably higher proportion of the risk score i.e. >40 in the patients than in the controls (59% vs. 28.9%, p <0.001). CONCLUSION: Risk predictive model based on the previously reported genetic variants has a remarkable discriminative power. More clinical and genetic factors need to be studied, to further improve the proba-bility to predict the onset of AIS.
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Dementia is one of the diabetic complications under intensive study. Alteration of synaptic adhesion protein (SAP) associates with neurological diseases, including Alzheimer's disease. However, the regulation of SAPs in the brain of diabetes mellitus remains elusive. To pinpoint the candidate SAPs underlining the mechanism of diabetic dementia, we investigated expression profiling of SAPs in both streptozotocin (STZ)-induced diabetic mice, AppNL-G-F/NL-G-F mice, and amyloid precursor protein intracellular domain (AICD)-induced human neural cell line from public databases. DST (Dystonin/BPAG1) was identified upregulated in both models. Our finding suggests that DST alteration may involve in the mechanism of diabetic dementia.
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Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Distonina/metabolismo , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Humanos , RatonesRESUMEN
PURPOSE: To define the longitudinal rotation axis around which individual vertebrae rotate, and to establish the various extra- and intravertebral rotation patterns in thoracic adolescent idiopathic scoliosis (AIS) patients, for better understanding of the 3D development of the rotational deformity. METHODS: Seventy high-resolution CT scans from an existing database of thoracic AIS patients (Cobb angle: 46°-109°) were included to determine the vertebral axial rotation, rotation radius, intravertebral axial rotation, and local mechanical torsion for each spinal level, using previously validated image processing techniques. RESULTS: For all levels, the longitudinal rotation axis, from which the vertebrae rotate away from the midline, was localized posterior to the spine. The axis became closer to the spine at the apex: apex, r = 11.5 ± 5.1 cm versus two levels above (radius = 15.8 ± 8.5 cm; p < 0.001) and beneath (radius = 14.2 ± 8.2 cm; p < 0.001). The vertebral axial rotation, intravertebral axial rotation, and local mechanical torsion of the vertebral bodies were largest at the apex (21.9° ± 7.4°, 8.7° ± 13.5° and 3.0° ± 2.5°) and decreased toward the neutral, junctional zones (p < 0.001). CONCLUSION: In AIS, the vertebrae rotate away around an axis that is localized posterior to the spine. The distance between this axis and the spine is minimal at the apex and increases gradually to the neutral zones. The vertebral axial rotation is accompanied by smaller amounts of intravertebral rotation and local mechanical torsion, which increases toward the apical region. The altered morphology and alignment are important for a better understanding of the 3D pathoanatomical development of AIS and better therapeutic planning for bracing and surgical intervention. These slides can be retrieved under Electronic Supplementary Material.
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Escoliosis/diagnóstico por imagen , Vértebras Torácicas/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Humanos , Procesamiento de Imagen Asistido por Computador , RotaciónRESUMEN
Hepatorenal fibrocystic disease (HRFCD) is characterized by cysts in the kidney and liver with associated fibrosis and is the result of defects in proteins required for cilia function or assembly. Previous reports indicate that macrophages, mainly M2-like macrophages, contribute to HRFCD, although the origin of these cells (yolk sac-derived resident macrophages vs. bone marrow-derived infiltrating macrophages) and their contribution to the observed phenotypes are unknown. We utilize a congenital model of cilia dysfunction (IFT88Orpk) to study the importance of macrophages in HRFCD. Our data show a rapid expansion of the bile duct region and development of fibrosis between 2 and 4 wk of age. Immunofluorescence microscopy analysis reveals an accumulation of F4/80+ macrophages in regions exhibiting biliary hyperplasia in IFT88Orpk mice. Flow cytometry data show that cilia dysfunction leads to an accumulation of infiltrating macrophages (CD11bhi, F4/80lo) and a reduction of resident macrophage (CD11blo, F4/80hi) number. A majority of the infiltrating macrophages are Ly6chi profibrogenic macrophages. Along with the accumulation of immune cells, expression of proinflammatory and profibrotic transcripts, including TGF-ß, TNF-α, IL-1ß, and chemokine (C-C) motif ligand 2, is increased. Quantitative RT-PCR analysis of flow-sorted cells shows enhanced expression of CCL2 in cholangiocytes and enhanced expression of VEGF-A and IL-6 in Ly6chi macrophages. Genetic inhibition of Ly6chi macrophage accumulation in IFT88Orpk FVB CCR2-/- mice reduced biliary fibrosis but did not affect epithelial expansion. Collectively, these studies suggest that biliary epithelium with defects in primary cilia preferentially recruits Ly6chi infiltrating macrophages, which promote fibrotic progression in HRFCD pathogenesis. NEW & NOTEWORTHY These studies are the first to address the contribution of the infiltrating and resident macrophage niche during progression of hepatorenal fibrocystic disease (HRFCD). We show that the number of infiltrating macrophages is significantly upregulated in HRFCD mouse models. Finally, we show that prevention of Ly6chi infiltrating macrophage accumulation significantly reduces biliary fibrosis, but not biliary hyperplasia, suggesting that this population may be responsible for the fibrotic progression of the disease in HRFCD patients.