Mutational landscape of primary spinal cord astrocytoma.

Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic alterations of SCAs is not well understood. Herein, we describe genome-sequencing analyses of primary SCAs, aiming to characterize the mutational landscape of primary SCAs. We utilized whole exome sequencing (WES) to analyze somatic nucleotide variants (SNVs) and copy number variants (CNVs) among 51 primary SCAs. Driver genes were searched using four algorithms. GISTIC2 was used to detect significant CNVs. Additionally, recurrently mutated pathways were also summarized. A total of 12 driver genes were identified. Of those, H3F3A (47.1%), TP53 (29.4%), NF1 (19.6%), ATRX (17.6%), and PPM1D (17.6%) were the most frequently mutated genes. Furthermore, three novel driver genes seldom reported in glioma were identified: HNRNPC, SYNE1, and RBM10. Several germline mutations, including three variants (SLC16A8 rs2235573, LMF1 rs3751667, FAM20C rs774848096) that were associated with risk of brain glioma, were frequently observed in SCAs. Moreover, 12q14.1 (13.7%) encompassing the oncogene CDK4 was recurrently amplified and negatively affected patient prognosis. Besides frequently mutated RTK/RAS pathway and PI3K pathway, the cell cycle pathway controlling the phosphorylation of retinoblastoma protein (RB) was mutated in 39.2% of patients. Overall, a considerable degree of the somatic mutation landscape is shared between SCAs and brainstem glioma. Our work provides a key insight into the molecular profiling of primary SCAs, which might represent candidate drug targets and complement the molecular atlas of glioma. © 2023 The Pathological Society of Great Britain and Ireland.

Tethered cord syndrome from pediatric and adult perspectives: a comprehensive systematic review of 6135 cases.

OBJECTIVE: This study aimed to investigate the differences in clinical features, diagnostic examination, treatment, and pathological results between adult-onset and pediatric-onset tethered cord syndrome (TCS). METHODS: The authors searched the PubMed, Embase, and Cochrane Library databases through January 2023 for reports on TCS, extracting information on clinical features, imaging data, treatment modalities, prognosis, and pathological research results. A total of 6135 cases from 246 articles were included in the analysis. This review was conducted in accordance with the 2020 PRISMA guidelines and registered on PROSPERO. RESULTS: The most common adult clinical manifestations were pain, urinary symptoms, and numbness; in children, they were urinary symptoms, skin lesions, bowel symptoms, and unspecific motor deficits. Surgical treatment was the primary approach for both adults and children, with a higher clinical improvement rate observed in adults. However, adults also had a higher rate of surgical complications than children. TCS pathological studies have not yet identified the differences between adults and children, and the pathogenesis of adult-onset TCS requires further investigation. CONCLUSIONS: Adult-onset and pediatric-onset TCS exhibit certain differences in clinical characteristics, diagnostic examinations, and treatments. However, significant differences have not been found in current pathological studies between adults and children. Systematic review registration no.: CRD42023479450 (www.crd.york.ac.uk/prospero).

Dissection of mendelian predisposition and complex genetic architecture of craniovertebral junction malformation.

The craniovertebral junction (CVJ) is an anatomically complex region of the axial skeleton that provides protection of the brainstem and the upper cervical spinal cord. Structural malformation of the CVJ gives rise to life-threatening neurological deficits, such as quadriplegia and dyspnea. Unfortunately, genetic studies on human subjects with CVJ malformation are limited and the pathogenesis remains largely elusive. In this study, we recruited 93 individuals with CVJ malformation and performed exome sequencing. Manual interpretation of the data identified three pathogenic variants in genes associated with Mendelian diseases, including CSNK2A1, MSX2, and DDX3X. In addition, the contribution of copy number variations (CNVs) to CVJ malformation was investigated and three pathogenic CNVs were identified in three affected individuals. To further dissect the complex mutational architecture of CVJ malformation, we performed a gene-based rare variant association analysis utilizing 4371 in-house exomes as control. Rare variants in LGI4 (carrier rate = 3.26%, p = 3.3 × 10-5) and BEST1 (carrier rate = 5.43%, p = 5.77 × 10-6) were identified to be associated with CVJ malformation. Furthermore, gene set analyses revealed that extracellular matrix- and RHO GTPase-associated biological pathways were found to be involved in the etiology of CVJ malformation. Overall, we comprehensively dissected the genetic underpinnings of CVJ malformation and identified several novel disease-associated genes and biological pathways.

The effect of local intraoperative corticosteroid application on postoperative dysphagia following anterior cervical spine surgery.

Dysphagia is a common complication following anterior cervical spine surgery (ACSS). Although several literatures have reported the potential benefit of local corticosteroid application on dysphagia, its safety and efficacy are still unclear. A systematic review was performed aiming to evaluate the evidence of local corticosteroid application in prevention or treatment of postoperative dysphagia following ACSS. A systematic search was performed in September 2018 in PubMed and Embase database. The following information was extracted: study investigator, year of publication, number of patients, study design, inclusion/exclusion criteria, administration protocol of steroid, type of surgical procedure, number of levels performed, assessment methodology of dysphagia, radiologic assessment of prevertebral soft tissue swelling (PSTS), follow-up time points, outcome of dysphagia, and corticosteroid-related complications. Qualitative synthesis was performed. Finally, 5 studies met the inclusion/exclusion criteria. Four studies found that local corticosteroid application could decrease the incidence and magnitude of postoperative dysphagia while 1 study showed no effect on dysphagia significantly at 6 weeks and 3 months follow-up time. A total of 2325 patients received local corticosteroid intraoperatively; no early corticosteroid-related complication was reported. Totally, 4 adverse events occurred in long-term follow-up time, including 2 bone nonunion at 1.5 and 2.5 years postoperatively, 2 esophageal perforation at 2 months and 11 months of follow-up, respectively. Local corticosteroid application can reduce the incidence and severity of dysphagia following ACSS without increasing early corticosteroid-related complications. But further high-quality study is necessary to analyze potential delayed complications.

Dural ossification associated with ossification of posterior longitudinal ligament in the cervical spine: a retrospective analysis.

OBJECTIVE: Dural ossification (DO) is common in patients with ossification of the posterior longitudinal ligament (OPLL). The existence of DO makes surgery challenging and increases the risk of complications. The aim of this study was to investigate the incidence, distribution and radiological characteristics of DO associated with OPLL. METHODS: From January 2017 to January 2019, 55 patients with cervical OPLL were treated in our single center using an anterior cervical approach microsurgery. Preoperative CT images of decompressed segments were evaluated to identify imaging signs of DO. The 'double-layer sign' (DLS), 'parenthese sign' (PS) and 'hook sign' (HS) were considered to be characteristic imaging findings of DO in OPLL. Two kinds of confusing signs (false double-layer) were identified. RESULTS: Nineteen segments from 15 patients with OPLL had DO related to OPLL. The incidence of DO in OPLL segments was 30.16% (19/63), and the incidence of DO in patients with OPLL was 27.27% (15/55). DO occurred at the intervertebral space level in 14 cases and at the posterior level of the vertebral body in 5 cases. The sensitivity and specificity of imaging diagnosis were 89.47% (17/19) and 81.82% (36/44), respectively. The positive predictive value was relatively low, 68.00% (17/25), due to the false-positive double-layer sign. The negative predictive value was 94.74% (36/38). CONCLUSION: DO was relatively common in cervical OPLL. DLS might be misdiagnosed. PS and HS can vividly and intuitively describe the imaging features of DO and have high diagnostic accuracy.

A novel classification and its clinical significance in Chiari I malformation with syringomyelia based on high-resolution MRI.

BACKGROUND: The existing classification in Chiari I malformation (CM-I) has limited significance for the selection of surgical methods. OBJECTIVE: The purpose of this study was to investigate the surgery of CM-I with syringomyelia based on the high-resolution MR imaging (HRMRI) findings. METHODS: Data from 115 patients were collected and retrospectively analyzed. For those with syringomyelia up to the level of C1, HRMRI was performed and according to the communication status between the fourth ventricle and the syringomyelia, patients can be divided into four types, namely Type A: classic communicating; Type B: partial communicating; Type C: non-communicating; Type D: atrophic. All operations were performed with Foramen magnum and Magendie dredging (FMMD), and all intradural factors that may have induced the obstruction of CSF circulation were recorded. The efficiency of operation on syringomyelia was evaluated by mJOA, imaging findings, and complications in the follow-up periods. RESULTS: The postoperative follow-up period was from 12 to 24 months, with an average of 14.3 months. At 1 year, the mJOA of 115 patients was significantly higher than that before the operations (before surgery 12.1 ± 2.3 vs. after surgery 14. 2 ± 1.4, P < 0.05). In addition, postoperative re-examination showed that the size of the syringomyelia was reduced or completely resolved in patients of Type A, 100% (2/2); Type B, 81% (9/11); Type C, 84% (81/97); and Type D, 20% (1/5). CONCLUSIONS: According to our new classification based on HRMRI, FMMD is the key to surgical treatment, especially for Type A and Type B patients.

Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome.

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.

Hydrogen Peroxide Emission and Fate Indoors during Non-bleach Cleaning: A Chamber and Modeling Study.

Activities such as household cleaning can greatly alter the composition of air in indoor environments. We continuously monitored hydrogen peroxide (H2O2) from household non-bleach surface cleaning in a chamber designed to simulate a residential room. Mixing ratios of up to 610 ppbv gaseous H2O2 were observed following cleaning, orders of magnitude higher than background levels (sub-ppbv). Gaseous H2O2 levels decreased rapidly and irreversibly, with removal rate constants (kH2O2) 17-73 times larger than air change rate (ACR). Increasing the surface-area-to-volume ratio within the room caused peak H2O2 mixing ratios to decrease and kH2O2 to increase, suggesting that surface uptake dominated H2O2 loss. Volatile organic compound (VOC) levels increased rapidly after cleaning and then decreased with removal rate constants 1.2-7.2 times larger than ACR, indicating loss due to surface partitioning and/or chemical reactions. We predicted photochemical radical production rates and steady-state concentrations in the simulated room using a detailed chemical model for indoor air (the INDCM). Model results suggest that, following cleaning, H2O2 photolysis increased OH concentrations by 10-40% to 9.7 × 105 molec cm-3 and hydroperoxy radical (HO2) concentrations by 50-70% to 2.3 × 107 molec cm-3 depending on the cleaning method and lighting conditions.

Predictors of mortality in patients with primary spinal cord glioblastoma.

PURPOSE: Primary spinal cord glioblastoma (GBM) is a rare and devastating disease. Little attention was ever paid to this rare disease. As a result, the standard treatment protocol and prognostic factors of primary spinal cord GBM were not well established. The aim of this study was to determine the predictors associated with survival in patients with primary spinal cord GBM. METHODS: A total of 122 patients with primary spinal cord GBM from Surveillance, Epidemiology, and End Results database and our institution were included in this retrospective analysis. Information about age, sex, race, tumor invasion, extent of resection, radiation, chemotherapy and year of diagnosis was collected. Univariate and multivariate accelerated failure time (AFT) regression model was performed to identify prognostic factors. RESULTS: Of the 122 patients, 102 (83.6%) expired at the time of data collection. Overall survival at 1 year, 2 years, 3 years and 5 years was 48.4%, 22.8%, 17.1% and 8.4%, respectively, and median survival time was 12 months. Only radiation was found to be associated with survival in the AFT regression model (time ratio 1.94, 95% CI 1.01-3.72, p < 0.05). Radiotherapy could improve survival slightly; patients who received RT survived approximately two times as long as patients who did not receive RT, but the advantage was short term. CONCLUSION: The survival of primary spinal cord GBM is poor in the current treatment strategy. Radiotherapy was associated with better survival, but the advantage was short term.

TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model.

PURPOSE: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model. METHODS: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS). RESULTS: In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 × 10‒8), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 × 10‒3); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 × 10‒7), while intraspinal anomalies were uncommon (P = 7.0 × 10‒7). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 × 10‒15). A Tbx6-/mh (mild-hypomorphic) mouse model supported that a gene dosage effect underlies the TACS phenotype. CONCLUSION: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10% of CS.

Vertebral artery dissection caused by atlantoaxial dislocation: a case report and review of literature.

BACKGROUND: Atlantoaxial dislocation (AAD) is the most common craniovertebral junction malformation (CVJm) which are anomalies of the bones and soft tissues surrounding the foramen magnum. It usually leads to neurologic abnormalities because of instability of this mobile area. But vertebral artery dissection (VAD) caused by AAD is uncommon. CASE REPORT: We report a 15-year-old boy who presented with acute onset of bilateral VAD leading to posterior circulation ischemic stroke (PCIS). Computed tomography angiography (CTA) indicated dissection and occlusion of bilateral intracranial vertebral arteries and AAD with os odontoideum. After antithrombotic treatment for 3 months, the patient got complete revascularization and received posterior C1-C2 fusion. DISCUSSION: There have only been tens of cases of PCIS caused by CVJm. We reviewed these relevant literatures and suggested that more attention should be paid to vascular impairment for patients with CVJm.

Comparative analysis of serum proteome in congenital scoliosis patients with TBX6 haploinsufficiency - a first report pointing to lipid metabolism.

Congenital scoliosis (CS) is a three-dimensional deformity of the spine affecting quality of life. We have demonstrated TBX6 haploinsufficiency is the most important contributor to CS. However, the pathophysiology at the protein level remains unclear. Therefore, this study was to explore the differential proteome in serum of CS patients with TBX6 haploinsufficiency. Sera from nine CS patients with TBX6 haploinsufficiency and nine age- and gender-matched healthy controls were collected and analysed by isobaric tagged relative and absolute quantification (iTRAQ) labelling coupled with mass spectrometry (MS). In total, 277 proteins were detected and 20 proteins were designated as differentially expressed proteins, which were submitted to subsequent bioinformatics analysis. Gene Ontology classification analysis showed the biological process was primarily related to 'cellular process', molecular function 'structural molecule activity' and cellular component 'extracellular region'. IPA analysis revealed 'LXR/RXR activation' was the top pathway, which is a crucial pathway in lipid metabolism. Hierarchical clustering analysis generated two clusters. In summary, this study is the first proteomic research to delineate the total and differential serum proteins in TBX6 haploinsufficiency-caused CS. The proteins discovered in this experiment may serve as potential biomarkers for CS, and lipid metabolism might play important roles in the pathogenesis of CS.

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease.

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 × 10-6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.

The genetic landscape and clinical implications of vertebral anomalies in VACTERL association.

VACTERL association is a condition comprising multisystem congenital malformations, causing severe physical disability in affected individuals. It is typically defined by the concurrence of at least three of the following component features: vertebral anomalies (V), anal atresia (A), cardiac malformations (C), tracheo-oesophageal fistula (TE), renal dysplasia (R) and limb abnormalities (L). Vertebral anomaly is one of the most important and common defects that has been reported in approximately 60-95% of all VACTERL patients. Recent breakthroughs have suggested that genetic factors play an important role in VACTERL association, especially in those with vertebral phenotypes. In this review, we summarised the genetic studies of the VACTERL association, especially focusing on the genetic aetiology of patients with vertebral anomalies. Furthermore, genetic reports of other syndromes with vertebral phenotypes overlapping with VACTERL association are also included. We aim to provide a further understanding of the genetic aetiology and a better evidence for genetic diagnosis of the association and vertebral anomalies.

Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome: a single centre study of a cohort of 164 patients.

OBJECTIVE: The aim was to assess the clinical, laboratory and radiological features of SAPHO syndrome. METHODS: We recruited all patients presenting to Peking Union Medical College Hospital from 2004 to 2015 diagnosed with SAPHO syndrome. The medical data, laboratory test results and imaging were collected for all patients. RESULTS: One hundred and sixty-four patients (111 women and 53 men) were recruited to our cohort. The mean age of the patients was 40.71 years. Nine patients had osteoarticular symptoms without skin involvement. One hundred and forty-three and 25 patients had palmoplantar pustulosis and severe acne, respectively. Psoriasis vulgaris was accompanied by palmoplantar pustulosis or severe acne in 24 patients. One hundred and sixty-four patients suffered from pain in the anterior chest wall, followed by spine (12 in the cervical region, 36 in the thoracic region and 111 in the lumbosacral region) and peripheral joint (136 patients) involvement. None of the patients had IBD. The hs-CRP level was increased in 70.8% patients. Only 2.4% were HLA-B27 positive. CT scan indicated osteolysis, sclerosis and hyperostosis in the anterior chest wall and spine in SAPHO syndrome patients. The bull-horn sign was the typical characteristic of SAPHO syndrome seen in bone scintigraphy images. One hundred and thirty-one (79.9%), 85 (51.8%), 100 (61%) and 54 (32.9%) patients took NSAIDs, CSs, DMARDs and oral bisphosphonates, respectively. CONCLUSION: SAPHO syndrome is predominant in middle-age women, characterized by dermatological and osteoarticular manifestations with unknown aetiology. CT scan and bone scintigraphy are useful for diagnosis. There is still no standard treatment to control the disease.

[Advances in congenital vertebral malformation caused by genomic copy number variation].

Congenital vertebral malformation (CVM) is a congenital vertebral structural deformity caused by abnormal somitogenesis during embryonic development, of which the reason lies in gene mutation or abnormal regulation of the genes that coordinate somitogenesis during embryonic period. ICVAS had proposed a new classification algorithm for CVM, which facilitated exploration for its genetic etiology. Genomic Copy Number Variation (CNV) is a kind of DNA mutation, which is important for human evolution, phenotype polymorphism and diseases. Series of advances have been made on genetic causes of CVM, especially on CVM caused by CNV. CNVs of chromosome 16p11.2, 10q24.31, 17p11.2, 20p11, 22q11.2 and a few other regions are associated with CVM, indicating that gene dosage may play important roles in the development of the spinal cord.

Automatic segmentation of spine x-ray images based on multiscale feature enhancement network.

BACKGROUND: Automatic segmentation of vertebrae in spinal x-ray images is crucial for clinical diagnosis, case analysis, and surgical planning of spinal lesions. PURPOSE: However, due to the inherent characteristics of x-ray images, including low contrast, high noise, and uneven grey scale, it remains a critical and challenging problem in computer-aided spine image analysis and disease diagnosis applications. METHODS: In this paper, a Multiscale Feature Enhancement Network (MFENet), is proposed for segmenting whole spinal x-ray images, to aid doctors in diagnosing spinal-related diseases. To enhance feature extraction, the network incorporates a Dual-branch Feature Extraction Module (DFEM) and a Semantic Aggregation Module (SAM). The DFEM has a parallel dual-branch structure. The upper branch utilizes multiscale convolutional kernels to extract features from images. Employing convolutional kernels of different sizes helps capture details and structural information at different scales. The lower branch incorporates attention mechanisms to further optimize feature representation. By modeling the feature maps spatially and across channels, the network becomes more focused on key feature regions and suppresses task-irrelevant information. The SAM leverages contextual semantic information to compensate for details lost during pooling and convolution operations. It integrates high-level feature information from different scales to reduce segmentation result discontinuity. In addition, a hybrid loss function is employed to enhance the network's feature extraction capability. RESULTS: In this study, we conducted a multitude of experiments utilizing dataset provided by the Spine Surgery Department of Henan Provincial People's Hospital. The experimental results indicate that our proposed MFENet demonstrates superior segmentation performance in spinal segmentation on x-ray images compared to other advanced methods, achieving 92.61 ± 0.431 for MIoU, 92.42 ± 0.329 for DSC, and 99.51 ± 0.037 for Global_accuracy. CONCLUSIONS: Our model is able to more effectively learn and extract global contextual semantic information, significantly improving spinal segmentation performance, further aiding doctors in analyzing patient conditions.

Knockdown of best1 Gene in Zebrafish Caused Abnormal Neuronal and Skeletal Development - A Subtype of Craniovertebral Junction Malformation?

OBJECTIVE: To investigate the developmental defects caused by knockdown of best1 gene in zebrafish as a model for a subtype of craniovertebral junction (CVJ) malformation. METHODS: Two antisense morpholinos (MOs) were designed targeting zebrafish best1 to block translation (ATG-MO) or to disrupt splicing (I3E4-MO). MOs were microinjected into fertilized one-cell embryos. Efficacy of splicing MO was confirmed by reverse transcription-polymerase chain reaction. Phenotypes were analyzed and quantified by microscopy at multiple developmental stages. Neuronal outgrowth was assessed in transgenic zebrafish expressing green fluorescent protein in neurons. Skeletal ossification was visualized by Calcein staining. RESULTS: Knockdown of best1 resulted in zebrafish embryos with shorter body length, curved axis, low survival rate, microcephaly, reduced eye size, smaller head and brain, impaired neuronal outgrowth, and reduced ossification of craniofacial and vertebral bone. CONCLUSION: Best1 gene plays critical roles in ophthalmologic, neurological and skeletal development in zebrafish. A patient with a premature stop codon in BEST1 gene exhibited similar phenotypes, implying a subtype of CVJ malformation.

Long-Term Impairment of the Blood-Spinal Cord Barrier in Patients With Post-Traumatic Syringomyelia and its Effect on Prognosis.

STUDY DESIGN: Cohort study. OBJECTIVE: The aim of this study was to explore the association between blood-spinal cord barrier (BSCB) markers and other factors associated with an unfavorable outcome among patients with post-traumatic syringomyelia (PTS) who achieved successful intradural adhesion lysis (IAL). SUMMARY OF BACKGROUND DATA: Only approximately half of PTS patients receiving IAL have a favorable outcome. PATIENTS AND METHODS: Forty-six consecutive patients with PTS and 19 controls (CTRL) were enrolled. All PTS patients underwent physical and neurological examinations and spinal magnetic resonance imaging before and 3 to 12 months after IAL. All patients underwent myelography before surgery. BSCB disruption was detected by increased intrathecal and serum concentrations of albumin, immunoglobulin (Ig)G, IgA, and IgM. A multivariable analysis was performed with a logistic regression model to identify factors associated with unfavorable outcomes. Receiver operating characteristic curves were calculated to investigate the diagnostic value of biomarkers. RESULTS: The ages and general health of the PTS and CTRL groups did not differ significantly. QAlb, IGAQ, IGGQ, and IGMQ was significantly higher in PTS patients than in controls ( P =<0.001). The degree of intradural adhesion was significantly higher in the unfavorable outcome group than in the favorable outcome group ( P <0.0001). QAlb, immunoglobulin (Ig)AQ, IGGQ, and IGMQ was significantly correlated with clinical status ( R =-0.38, P <0.01; R =-0.47, P =0.03; R =-0.56, P =0.01; R =-0.43, P =0.05, respectively). Higher QAlb before surgery (odds ratio=2.66; 95% CI: 1.134-6.248) was significantly associated with an unfavorable outcome. The receiver operating characteristic curve analysis demonstrated a cutoff for QAlb higher than 10.62 with a specificity of 100% and sensitivity of 96.3%. CONCLUSION: This study is the first to detect increased permeability and BSCB disruption in PTS patients. QAlb>10.62 was significantly associated with unfavorable clinical outcomes following intradural decompression. LEVEL OF EVIDENCE: Level III-prognostic.