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1.
Global Spine J ; : 21925682211007116, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33823627

RESUMO

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To evaluate whether pre-existing adjacent spinal canal stenosis (SCS) is associated with short-term outcomes after lumbar fusion surgery. METHODS: We included patients with lumbar spinal stenosis treated surgically between July 2015 and December 2017 at 4 centers. All patients had the same pathology, with L4-S1 as the culprit sections. Patients were divided into 2 groups based on the cerebrospinal fluid occlusion sign on MRI at the adjacent L3/4 level. Patients without SCS (grade 0) and with mild SCS (grade 1) were classified into the non-stenosis (NS) and mild stenosis (MS) groups, respectively. All patients underwent PLIF and completed at least 1-year follow-up. The incidence of adjacent segment degeneration (ASDeg) and clinical outcomes were compared between the 2 groups. RESULTS: A total of 308 patients (NS, 156; MS, 152) met the inclusion criteria. The incidence of ASDeg in the NS group (n = 40, 25.6%) was significantly lower than that in the MS group (n = 74, 48.7%; P < .001). The most frequent type of ASDeg in the 2 groups was the SCS-aggravated type. No significant difference was observed in adjacent segment disease incidence between the 2 groups (P = .243). The NS group had better outcomes according to the clinical function scores (P < .05). CONCLUSIONS: The cerebrospinal fluid occlusion sign on MRI is valuable for evaluating the adjacent segment with pre-existing degeneration. Patients with mild SCS in adjacent segments were more likely to have ASDeg, and the most frequent type of ASDeg was the SCS-aggravated type at early follow-up.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33677662

RESUMO

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Miller Fisher syndrome (MFS) have been reported. We want to summarize the main features of patients with MFS and COVID-19. A PubMed search was performed on 8 October to identify references reporting cases with MFS associated with COVID-19 from the first report of COVID-19 to 8 October 2020 using the following keywords: "Miller Fisher syndrome" AND "COVID-19" OR "SARS-CoV-2". A systematic review from the first report of coronavirus disease 2019 (COVID-19) to 8 October 2020 revealed 7 cases with Miller Fisher syndrome (MFS) associated with COVID-19. The 7 cases came from 5 countries but most of these patients were from Europe (85.7%), especially Spain. There are 5 cases of MFS diagnosed after the laboratory confirmation of SARS-CoV-2 infection. The mean onset time of MFS-associated neurological symptoms was 14.75 days after the diagnosis of COVID-19. However, the two remaining cases presented initially with MFS-associated neurological symptoms followed by the diagnosis of COVID-19. The most common symptoms of COVID-19-associated MFS were perioral paresthesias (57.1%), ataxia (57.1%), blurred vision (42.9), ophthalmoplegia (42.9), and generalized areflexia (42.9). However, more cohort and case-control studies are required to establish the epidemiological linkage.

3.
Brief Bioinform ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33783485

RESUMO

Tumor suppressor genes (TSGs) exhibit distinct evolutionary features. We speculated that TSG promoters could have evolved specific features that facilitate their tumor-suppressing functions. We found that the promoter CpG dinucleotide frequencies of TSGs are significantly higher than that of non-cancer genes across vertebrate genomes, and positively correlated with gene expression across tissue types. The promoter CpG dinucleotide frequencies of all genes gradually increase with gene age, for which young TSGs have been subject to a stronger evolutionary pressure. Transcription-related features, namely chromatin accessibility, methylation and ZNF263-, SP1-, E2F4- and SP2-binding elements, are associated with gene expression. Moreover, higher promoter CpG dinucleotide frequencies and chromatin accessibility are positively associated with the ability of TSGs to resist downregulation during tumorigenesis. These results were successfully validated with independent datasets. In conclusion, TSGs evolved specific promoter features that optimized cancer resistance through achieving high expression in normal tissues and resistance to downregulation during tumorigenesis.

4.
Cell Prolif ; : e13024, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33751722

RESUMO

OBJECTIVES: Guillain-Barré syndrome (GBS) results from autoimmune attack on the peripheral nerves, causing sensory, motor and autonomic abnormalities. Emerging evidence suggests that there might be an association between COVID-19 and GBS. Nevertheless, the underlying pathophysiological mechanism remains unclear. MATERIALS AND METHODS: We performed bioinformatic analyses to delineate the potential genetic crosstalk between COVID-19 and GBS. RESULTS: COVID-19 and GBS were associated with a similar subset of immune/inflammation regulatory genes, including TNF, CSF2, IL2RA, IL1B, IL4, IL6 and IL10. Protein-protein interaction network analysis revealed that the combined gene set showed an increased connectivity as compared to COVID-19 or GBS alone, particularly the potentiated interactions with CD86, IL23A, IL27, ISG20, PTGS2, HLA-DRB1, HLA-DQB1 and ITGAM, and these genes are related to Th17 cell differentiation. Transcriptome analysis of peripheral blood mononuclear cells from patients with COVID-19 and GBS further demonstrated the activation of interleukin-17 signalling in both conditions. CONCLUSIONS: Augmented Th17 cell differentiation and cytokine response was identified in both COVID-19 and GBS. PBMC transcriptome analysis also suggested the pivotal involvement of Th17 signalling pathway. In conclusion, our data suggested aberrant Th17 cell differentiation as a possible mechanism by which COVID-19 can increase the risk of GBS.

5.
BMC Surg ; 21(1): 106, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648467

RESUMO

BACKGROUND: Early onset scoliosis (EOS) may cause malnutrition in affected patients. Growing-rod treatment has been an effective protocol for treating EOS. The objective of this study is to demonstrate whether growing-rod treatment improves nutritional status of EOS patients. METHODS: Fifty-two EOS patients who had dual growing-rod surgery was enrolled. The minimum follow-up was 3-years. Their body weights were normalized based on the data of two National Population Census of China. Z-scores were used to indicate the standard deviation from the median body weight-for-age. RESULTS: The median follow-up time was 6 years. Preoperatively, the prevalence of malnutrition (Z < - 2) was 21.2%, and reduced to 9.6% at the end of the follow-up. Preoperatively, the average Z-score was - 0.94, and it increased to - 0.65 at the latest follow-up (p < 0.05). Patients with preoperative Z-score below - 1 had more significant increase of Z-scores (- 2.15 vs - 1.26, p < 0.001). A significant negative correlation between the change of Z-score and the preoperative Z-score (correlation coefficient - 0.65, p < 0.001). CONCLUSIONS: The growing rod surgery and lengthening procedures significantly improves the nutrition status of EOS patients. The body weight gains are more significant in patients with lower body weights.


Assuntos
Estado Nutricional , Escoliose , China , Seguimentos , Humanos , Escoliose/cirurgia , Resultado do Tratamento
6.
J Cell Mol Med ; 25(6): 2909-2917, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33497543

RESUMO

Melatonin is well-documented to have the ability of reducing nerve inflammation and scavenging free radicals. However, the therapeutic effect of melatonin on spinal cord injury has not been fully described. In this study, we assessed the effect of melatonin on T9 spinal cord injury established by Allen method in rats. Melatonin deficiency significantly delayed the recovery of sensory and motor functions in SCI rats. Treatment with melatonin significantly alleviated neuronal apoptosis and accelerated the recovery of spinal cord function. These results suggest that melatonin is effective to ameliorate spinal cord injury through inhibition of neuronal apoptosis and promotion of neuronal repair.

7.
Spectrochim Acta A Mol Biomol Spectrosc ; 247: 119141, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33188973

RESUMO

Melatonin (MLT), as a neurotransmitter and an endogenous neurohormone, plays an important role in physiological functions through interactions with specific receptors. The conformations of MLT are closely related to its biological activities and functions. However, the internal relationship between the structure and interaction of MLT and its allosteric transition remains unclear. In this work, we obtain the broadband fingerprint terahertz (THz) spectrum of MLT in the range of 0.5-18 THz using the air-plasma terahertz time-domain spectroscopy (THz-TDS) system. DFT calculations are employed to analyze the vibration characteristics of MLT. The result shows that the low-frequency vibrations mainly come from the strong coupling between inter- and intramolecular vibrations, and the contribution of intramolecular vibrations gradually dominates with increasing frequency. Meanwhile, the local vibrations of the different functional groups distribute widely in the THz low-frequency band, relating to the diversity of conformational changes in the molecule. The intermolecular hydrogen bonds (HBs) have distinct resonant responses and play critical roles in the THz low-frequency vibrations. The study reveals the complex characteristics of the resonant coupling of MLT with THz electromagnetic waves. The results will help to understand the conformational preferences of MLT in neural signal transmission processes.

8.
Brief Bioinform ; 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33190150

RESUMO

Patients with spinal muscular atrophy (SMA) are susceptible to the respiratory infections and might be at a heightened risk of poor clinical outcomes upon contracting coronavirus disease 2019 (COVID-19). In the face of the COVID-19 pandemic, the potential associations of SMA with the susceptibility to and prognostication of COVID-19 need to be clarified. We documented an SMA case who contracted COVID-19 but only developed mild-to-moderate clinical and radiological manifestations of pneumonia, which were relieved by a combined antiviral and supportive treatment. We then reviewed a cohort of patients with SMA who had been living in the Hubei province since November 2019, among which the only 1 out of 56 was diagnosed with COVID-19 (1.79%, 1/56). Bioinformatic analysis was carried out to delineate the potential genetic crosstalk between SMN1 (mutation of which leads to SMA) and COVID-19/lung injury-associated pathways. Protein-protein interaction analysis by STRING suggested that loss-of-function of SMN1 might modulate COVID-19 pathogenesis through CFTR, CXCL8, TNF and ACE. Expression quantitative trait loci analysis also revealed a link between SMN1 and ACE2, despite low-confidence protein-protein interactions as suggested by STRING. This bioinformatic analysis could give hint on why SMA might not necessarily lead to poor outcomes in patients with COVID-19.

9.
Global Spine J ; : 2192568220972080, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33203246

RESUMO

STUDY DESIGN: Retrospective case series. OBJECTIVES: To present outcomes concerning patients with early-onset mixed-type congenital scoliosis (EOMTCS) treated with the traditional single growing rod (TSGR), focusing on the growth of unsegmented levels (USLs). METHODS: Patients with EOMTCS who underwent TSGR and had a minimum of 4 USLs, 4 distractions, and 3-year follow-up were enrolled. Spine radiographs before and after index surgery and at the latest follow-up were evaluated. The length of the concave and convex side of USLs and thoracic parameters were measured. The absolute value and percentage of growth were calculated. RESULTS: Fourteen patients (mean age, 7.3 ± 2.8 years) were enrolled. The average follow-up duration was 4.9 ± 1.2 years, during which time 84 distractions and 8 final fusions were performed. The average number of USLs was 6.3 ± 2.2. The total and annual percent growth of concave side of USLs was significantly higher than convex side (32.2 ± 13.3% vs. 23.9 ± 9.5%, p = 0.007; 6.8 ± 2.7%/year vs. 5.1% ± 2.2%/year, p = 0.007, respectively). The concave-to-convex ratio of USLs increased from 58.6 ± 6.4 ± 7.6% at baseline to 68.8 ± 9.3% at the latest follow-up (p < 0.001). The Campbell's space available for lung ratio increased from 74.9 ± 11.1% at baseline to 89.6 ± 7.0% at the latest follow-up (p < 0.001). CONCLUSIONS: In patients with EOMTCS, unilateral repetitive lengthening with TSGR can accelerate the growth of the concave side of USLs and improve the symmetry of the thorax.

10.
Orthop Surg ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33184974

RESUMO

OBJECTIVE: The aim of the present study was to explore the surgical treatment and prognosis of 27 cases of neurofibromatosis type 1 with severe dystrophic kyphosis. METHODS: We performed surgical treatment for scoliosis and kyphosis caused by dystrophic curves at Peking Union Medical College Hospital, Beijing, China from December 2015 to December 2017. The study included 21 patients with moderate to severe kyphosis, 12 males and 9 females, with an average age of 14.95 ± 6.05 years. All patients had kyphosis angles greater than 70° and had more than four skeletal developmental defects. A total of 6 patients with severe kyphosis, 2 males and 4 females, with an average age of 12.5 years, had more than five skeletal developmental defects with a kyphosis angle greater than 90° or a lumbar kyphosis angle greater than 40°. According to the patient's own situation, we adopted a low-grade surgery scheme (grades 1 or 2) or a high-grade surgery scheme (grades 3-6). The low-grade surgery was mainly lower articular surface resection or pontodestomy, and the high-grade surgery was mainly apical vertebral body or upper discectomy. All patients were followed up to determine their prognosis. RESULTS: Statistical analysis showed that there was a significant difference in preoperative and postoperative scores between the two groups (P < 0.05), and scoliosis correction showed that surgical treatment had a significant effect on scoliosis kyphosis. The mean follow-up time was 66.7 months. Follow-up results showed that 50% of complications after internal fixation were related to high-level surgery. Complications included displacement of the titanium cage, removal of the lamina hook, formation of pseudoarthrosis, and internal fixation failure (with a rate of 7.7%-14.3%). In contrast, there were no associated symptoms for low-grade surgery. In addition, the results showed that gender, age, extent of resection, height, and body mass index had no significant effect on preoperative, postoperative, and prognostic indicators of patients (P > 0.05). CONCLUSION: Early identification of dysplastic scoliosis-related deformities plays an important role in surgical planning and prognosis, and low-level surgical procedures are more favorable for patients' prognosis.

11.
Eur Spine J ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33091143

RESUMO

BACKGROUND: To compare clinical effect and safety between posterior fossa decompression with duraplasty (PFDD) and posterior fossa decompression without duraplasty (PFD) in treatment of Chiari type I malformation and basilar impression. METHODS: A comprehensive computer search was conducted from 2000 to 2019. The quality assessment was performed by the QUADAS-2 tool. The clinical value of comparison between PFDD and PFD was evaluated by using the pooled estimate of sensitivity and specificity. In addition, sensitivity analysis and bias analysis were applied to ensure the accuracy of the results. RESULTS: Finally, 468 patients were enrolled in 6 studies and ultimately met the eligibility criteria. The PFDD and PFD groups were 282 and 186, respectively. The meta-analysis showed no significant difference in the Chicago Chiari Outcome Scale (COSS score) (MD = 0.14, 95% CI [-0.23, 0.50], P = 0.47; P = heterogeneity = 0.86, I2 = 0%). Meanwhile, Significant difference existed in length of stay (MD = -1.08, 95% CI [-1.32, -0.84], P = 0.001; heterogeneity P < 0.000001, I2 = 85%) and complications (OR = 0.35, 95%CI [0.20, 0.62], P = 0.0003; P for Heterogeneity = 0.04, I2 = 56%). CONCLUSION: PFD is a more efficient and safer therapy than PFDD in the treatment of Chiari type I malformation with basilar impression.

12.
Analyst ; 145(18): 6006-6013, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32756617

RESUMO

Dopamine (DA) is an essential neurotransmitter and hormone of the nervous system, its structural and conformational properties play critical roles in biological functions and signal transmission processes. Although this neuroactive molecule has been studied extensively, the low-frequency vibration features that are closely related to the conformation and molecular interactions in the terahertz (THz) band still remain unclear. In this study, a broadband THz time-domain spectroscopy (THz-TDS) system in the frequency band of 0.5-18 THz was used to characterize the unique THz fingerprint of DA. In addition, density functional theory (DFT) calculations were performed to analyze the vibrational properties of DA. The results suggest that each THz resonant absorption peak of DA corresponds to specific vibrational modes, and the collective vibration also exists in the broadband THz range. Moreover, the interactions between the DA ligand and the D2 and D3 receptors were investigated by docking, and the simulated THz spectra were obtained. The results indicate the dominant role of hydrogen bonding interactions and the specificity of molecular conformation. This work may help to understand the resonance coupling between THz electromagnetic waves and neurotransmitters.

13.
BMC Musculoskelet Disord ; 21(1): 455, 2020 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-32652978

RESUMO

BACKGROUND: Spinal deformities constitute one of the most common types of manifestations of neurofibromatosis type-1 (NF-1), which can lead to either dystrophic or non-dystrophic early-onset scoliosis (EOS). Surgical treatment for EOS with NF-1 is challenging, and the outcomes have rarely been reported. The anterior-posterior procedure is widely used, but posterior-only fusion is theoretically easier and safer to perform. Is it possible that a new surgery that accommodates growth is a better choice? A direct comparison between posterior fusion and growth-friendly surgery in terms of surgical outcomes has not yet been conducted in dystrophic EOS with NF-1 patients. METHODS: Baseline information was extracted from the NF-1 database at our institute with approval from the local ethics committee. All enrolled patients were diagnosed with NF-1. Clinical and radiographic data were recorded preoperatively, after the initial surgery, and at the final follow-up. Implant-related, alignment, neurological complication and unplanned revision surgery data were recorded. We compared the outcomes of these two groups in terms of curve correction, growth parameters, complications and unplanned revision surgeries. RESULTS: There were eight patients in the PF group and eight patients in the GR group, with a mean follow-up of 51.0 ± 17.5 months. The main curve size was similar (PF 67.38° ± 17.43° versus GR 75.1° ± 26.43°, P = 0.501), and there were no significant differences in the initial surgery correction rate or the rate of correction. However, the patients in the GR group exhibited more T1-S1 growth during the follow-up overall and per year than did those in the PF group. The operative time was significantly longer for the PF group than for the GR group (PF, 4.39 ± 1.38 vs. GR, 3.00 ± 0.42 h; p = 0.008). Significantly fewer segments were involved in the PF group (8.25 ± 3.20) than in the GR group (13.00 ± 1.60). CONCLUSION: For the initial treatment of dystrophic EOS in patients with NF-1, the GR technique is possibly a more appropriate treatment than is the PF technique in terms of trunk growth. However, the repeated procedures required for GR may be a considerable disadvantage. More studies with direct measurement of pulmonary function must be conducted to determine the effect of GR on pulmonary development. More studies with larger sample sizes and longer follow-up periods are needed to fully assess the treatment strategies.

14.
Phys Chem Chem Phys ; 22(32): 17791-17797, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32578603

RESUMO

The cooling-induced formation of a hydrate in aqueous NaCl solutions was probed using terahertz time-domain spectroscopy (THz-TDS). It was found that the NaCl hydrate formation is accompanied by the emergence of four new absorption peaks at 1.60, 2.43, 3.34 and 3.78 THz. Combining X-ray diffraction measurements with solid-state based density functional theory (DFT) calculations, we assign the observed terahertz absorption peaks to the vibrational modes of the formed NaCl·2H2O hydrate during cooling. This work shows that THz-TDS based analysis has great potential in studying ionic hydrates and the newly revealed collective vibrational modes could be sensitive indicators to achieve quantitative analysis in phase transitions and lattice dynamics.

15.
J Bone Joint Surg Am ; 102(16): 1405-1415, 2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32530873

RESUMO

BACKGROUND: Both patients with Chiari-I malformation (CIM) with syringomyelia and those with idiopathic syringomyelia (ISm) have a syrinx and can have scoliosis as well. However, there is no literature regarding differences between CIM and ISm in terms of radiographic outcomes and surgical complications after posterior fusion, to our knowledge. The aim of the present study was to compare radiographic features, clinical outcomes, and surgical complications after posterior spinal fusion between patients with CIM-associated scoliosis and those with ISm-associated scoliosis. METHODS: One hundred and twenty patients with syringomyelia-associated scoliosis were retrospectively analyzed. Twenty-one patients with scoliosis secondary to CIM were enrolled and matched by sex, age, and the Cobb angle of the scoliotic curve with 21 patients with scoliosis secondary to ISm. All patients underwent 1-stage posterior fusion surgery. Coronal and sagittal radiographic parameters were evaluated before surgery, immediately after surgery, and at the final follow-up (at least 2 years). We also collected data regarding syringeal features, neurological deficits, intraoperative neuromonitoring, and complications. RESULTS: Sex, age, preoperative coronal/sagittal scoliosis parameters, and neurological deficits were similar between the matched CIM and ISm groups. On average, the CIM group had a longer syrinx (12.3 ± 3.6 versus 8.9 ± 4.5 vertebral levels, p = 0.010) than the ISm group. The CIM and ISm groups showed similar correction rates for primary curves (70.9% ± 10.6% versus 69.5% ± 16.3%, p = 0.739). There were no significant differences in coronal/sagittal correction, intraoperative neuromonitoring abnormalities, surgical complications, or Scoliosis Research Society-22 questionnaire scores between the 2 groups. CONCLUSIONS: Despite matched demographic and scoliotic coronal parameters, patients with CIM had longer syrinxes compared with patients with ISm. One-stage posterior fusion achieved comparable clinical and radiographic outcomes for both CIM- and ISm-associated scoliosis without significant differences in neurological complications. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

16.
Environ Sci Pollut Res Int ; 27(25): 31699-31705, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32500497

RESUMO

Exposure to air pollution is known to increase the risks for cardiovascular, pulmonary and metabolic diseases. Growing evidences also indicated that air pollution exposure during pregnancy could negatively impact on early embryonic development and children's health. We performed RNA sequencing to identify deregulated mRNAs in air pollution-exposed rat embryos. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to analyse the potential cellular functions of deregulated mRNAs. Our analysis indicated that a total of 1678 mRNAs were differentially expressed on gestation day 9 upon in utero exposure to fine particulate matter of > 200 µg/m3, among which 1098 mRNAs were downregulated and 580 mRNAs were upregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed gap junction, cell adhesion, axon guidance and the neurotrophin signalling pathway as key biological processes perturbed by air pollution exposure. Furthermore, reconstruction of the mRNA regulatory network highlighted the central roles of Tbx4, Bmp4, Sox10, Wnt9b, Bmp7 and Foxc2. These data suggested that embryonic mRNA deregulation may underlie the formation of air pollution-associated congenital defects.


Assuntos
Poluição do Ar , RNA Longo não Codificante , Animais , Criança , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Exposição Materna , Gravidez , RNA Mensageiro , Ratos
17.
J Med Genet ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381727

RESUMO

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

18.
Kidney Int ; 98(4): 1020-1030, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32450157

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUTs) are the most common cause of chronic kidney disease in children. Human 16p11.2 deletions have been associated with CAKUT, but the responsible molecular mechanism remains to be illuminated. To explore this, we investigated 102 carriers of 16p11.2 deletion from multi-center cohorts, among which we retrospectively ascertained kidney morphologic and functional data from 37 individuals (12 Chinese and 25 Caucasian/Hispanic). Significantly higher CAKUT rates were observed in 16p11.2 deletion carriers (about 25% in Chinese and 16% in Caucasian/Hispanic) than those found in the non-clinically ascertained general populations (about 1/1000 found at autopsy). Furthermore, we identified seven additional individuals with heterozygous loss-of-function variants in TBX6, a gene that maps to the 16p11.2 region. Four of these seven cases showed obvious CAKUT. To further investigate the role of TBX6 in kidney development, we engineered mice with mutated Tbx6 alleles. The Tbx6 heterozygous null (i.e., loss-of-function) mutant (Tbx6+/‒) resulted in 13% solitary kidneys. Remarkably, this incidence increased to 29% in a compound heterozygous model (Tbx6mh/‒) that reduced Tbx6 gene dosage to below haploinsufficiency, by combining the null allele with a novel mild hypomorphic allele (mh). Renal hypoplasia was also frequently observed in these Tbx6-mutated mouse models. Thus, our findings in patients and mice establish TBX6 as a novel gene involved in CAKUT and its gene dosage insufficiency as a potential driver for kidney defects observed in the 16p11.2 microdeletion syndrome.

19.
J Cell Mol Med ; 24(12): 7015-7022, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32394619

RESUMO

Congenital scoliosis (CS) is a form of spinal curvature resulting from anomalous development of vertebrae. Recent studies demonstrated that circRNAs could serve as potential biomarkers of disease diagnosis. Genome-wide circRNAs expression in seven CS patients and three healthy controls was initially detected. Bioinformatics analysis was conducted to explore the potential pathological pathway of CS. Quantitative PCR (qPCR) was performed to validate the selected circRNAs in the replication cohort with 32 CS patients and 30 healthy controls. Logistic regression controlling for gender was conducted to compare the expression difference. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value. Twenty-two differentially expressed circRNAs were filtered from genome-wide circRNA sequencing. Seven circRNAs were validated by qPCR. Only hsa_circ_0006719 was confirmed to have a higher expression level in the CS group than the healthy control group (P = 0.036). Receiver operating characteristic curve also suggested that hsa_circ_0006719 had significant diagnostic value for CS (AUC = 0.739, P = 0.001). We described the first study of circRNAs in CS and validated hsa_circ_0006719 as a potential novel diagnostic biomarker of CS.

20.
Am J Med Genet A ; 182(7): 1664-1672, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32369272

RESUMO

Vertebral malformations (VMs) are caused by alterations in somitogenesis and may occur in association with other congenital anomalies. The genetic etiology of most VMs remains unknown and their identification may facilitate the development of novel therapeutic and prevention strategies. Exome sequencing was performed on both the discovery cohort of nine unrelated probands from the USA with VMs and the replication cohort from China (Deciphering Disorders Involving Scoliosis & COmorbidities study). The discovery cohort was analyzed using the PhenoDB analysis tool. Heterozygous and homozygous, rare and functional variants were selected and evaluated for their ClinVar, HGMD, OMIM, GWAS, mouse model phenotypes, and other annotations to identify the best candidates. Genes with candidate variants in three or more probands were selected. The replication cohort was analyzed by another in-house developed pipeline. We identified rare heterozygous variants in KIAA1217 in four out of nine probands in the discovery cohort and in five out of 35 probands in the replication cohort. Collectively, we identified 11 KIAA1217 rare variants in 10 probands, three of which have not been described in gnomAD and one of which is a nonsense variant. We propose that genetic variations of KIAA1217 may contribute to the etiology of VMs.

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