3D Printing of Metals with sub-10 µm Resolution.

The ability to manufacture 3D metallic architectures with microscale resolution is greatly pursued because of their diverse applications in microelectromechanical systems (MEMS) including microelectronics, mechanical metamaterials, and biomedical devices. However, the well-developed photolithography and emerging metal additive manufacturing technologies have limited abilities in manufacturing micro-scaled metallic structures with freeform 3D geometries. Here, for the first time, the high-fidelity fabrication of arbitrary metallic motifs with sub-10 µm resolution is achieved by employing an embedded-writing embedded-sintering (EWES) process. A paraffin wax-based supporting matrix with high thermal stability is developed, which permits the printed silver nanoparticle ink to be pre-sintered at 175 °C to form metallic green bodies. Via carefully regulating the matrix components, the printing resolution is tuned down to ≈7 µm. The green bodies are then embedded in a supporting salt bath and further sintered to realize freeform 3D silver motifs with great structure fidelity. 3D printing of various micro-scaled silver architectures is demonstrated such as micro-spring arrays, BCC lattices, horn antenna, and rotatable windmills. This method can be extended to the high-fidelity 3D printing of other metals and metal oxides which require high-temperature sintering, providing the pathways toward the design and fabrication of 3D MEMS with complex geometries and functions.

The Surgical Strategy Cerebrospinal Fluid Decompression Facilitates Outcomes of Adults with Chiari Malformation Type I: An Observational, Real-World, Single-Center Study of 528 Patients.

OBJECTIVE: We designed this study to introduce the surgical strategy cerebrospinal fluid (CSF) decompression in treatment of Chiari malformation type I and compared CSF decompression with other surgical strategies to provide a solid basis for patient counseling. METHODS: The study enrolled 528 consecutive patients with CMI who underwent surgical interventions from 2012 to 2022. The surgical strategy for these patients was bony and dural decompression, anatomical reduction of herniated tonsils, or CSF decompression. Short-term results were determined after 3 months; long-term outcomes were evaluated at last follow-up (at least 18 months). RESULTS: CSF decompression was independently associated with better long- or short-term primary outcomes than anatomical reduction of herniated tonsils or bony and dural decompression (P < 0.001). Compared with short-term, the long-term outcomes were better in patients who underwent CSF decompression (P = 0.035), but were worse in patients with bony and dural decompression (P = 0.03). Specific surgical techniques cannot affect the long- and short-term outcomes of patients with Chiari malformation type I. CSF decompression provided better long-term syringomyelia improvement than short-term (181/218, 83% vs. 169/218, 77.5%; P < 0.001). CONCLUSIONS: CSF decompression, but not a specific surgical technique or operative method, was associated with favorable neurological outcomes in ADULT patients with Chiari malformation type I. The surgical technique and operative method should be selected according to the characteristics of each patient and the intraoperative condition to normalize CSF circulation at the craniovertebral junction area. The intraoperative target, smooth CSF flow out from the fourth ventricle and in to the bilateral Luschka foramina, could be observed.

Ultrafast Ultrasound Vector Doppler for Small Vasculature Imaging.

Ultrafast Doppler has been accepted as a novel modality for small vasculature imaging with high sensitivity, high spatiotemporal resolution, and high penetration. However, the conventional Doppler estimator adopted in studies of ultrafast ultrasound imaging is only sensitive to the velocity component along the beam direction and has angle-dependent limitations. Vector Doppler has been developed with the goal of angle-independent velocity estimation but is typically employed for relatively large vessels. In this study, combining multiangle vector Doppler strategy and ultrafast sequencing, ultrafast ultrasound vector Doppler (ultrafast UVD) is developed for small vasculature hemodynamic imaging. The validity of the technique is demonstrated through experiments on a rotational phantom, rat brain, human brain, and human spinal cord. A rat brain experiment shows that compared with the ultrasound localization microscopy (ULM) velocimetry, which is widely accepted as an accurate flow velocimetry technique, the average relative error (ARE) of the velocity magnitude estimated by ultrafast UVD is approximately 16.2%, with a root-mean-square error (RMSE) of the velocity direction of 26.7°. It is demonstrated that ultrafast UVD is a promising tool for accurate blood flow velocity measurement, especially for the organs, including brain and spinal cord with vasculature typically exhibiting tendential alignment of vascular trees.

Establishment of SIAISi018-A, an induced pluripotent stem cell (iPSC) line from a healthy 45-year-old Chinese Han.

A 45-year-old Han Male from China contributed peripheral blood mononuclear cells induced by reprogramming human OKSM transcription factors (OCT3/4, KLF4 SOX2 and C-MYC) with a non-integrated additional vector system. Immunological markers confirmed the pluripotent nature of IPSC. Spontaneous tridermal differentiation confirmed the differentiation ability of IPSC with normal karyotype.

Establishment of SIAISi017-A, an induced pluripotent stem cell(iPSC)line from a healthy 25-year-old Chinese Hui.

With the development of cytology, the establishment of cell models in vitro has become a powerful means to study the mechanism and treatment of diseases. Here we successfully generated the IPSC-derived modeling system of a 25-year-old healthy male. His peripheral blood mononuclear cells (PBMC) were reprogrammed using human OKSM (SOX2, OCT3/4, KLF4, and C-MYC) transcription factors using a non-integrated additional vector system. Immunocytochemistry demonstrated that IPSCS expressed all the markers of pluripotency and demonstrated their ability to differentiate spontaneously from three hypoderms in vitro. Karyotype is normal.

Surgical Outcomes of Spinal Cord Intramedullary Cavernous Malformation: A Retrospective Study of 83 Patients in a Single Center over a 12-Year Period.

OBJECTIVE: Spinal cord intramedullary cavernous malformation (SICM) is kind of rare vascular disease, and the therapeutic strategy is still under debate. The purpose of this article is to analyze outcome of SICM surgical resection and to find the possible factors indicating a better outcome. METHODS: A retrospective analysis of 83 patients with SICM in a single center from 2005 to 2017 was performed. Neurologic status was assessed using the McCormick Scale. Clinical information was collected and analyzed using multivariate logistic regression analysis. RESULTS: Eighty patients with SICM were included, 48% of whom were male (n = 40). The mean age was 39.0 years; 7% of patients (n = 6) had a family history and 4% of patients (n = 3) had multiple lesions; and 41% (n = 34) were found with definite hemorrhage. Before surgery, neurologic status of the patients was 43.4%, 31.3%, 13.3%, and 12.0% in grades I (n = 36), II (n = 26), III (n = 11), and IV (n = 10), respectively. Sixty-three patients received long-term follow-up, of whom 19 improved, 39 remained in stable condition, and 5 deteriorated. Patients with duration of symptoms less than 3 months showed a higher improved outcome rate than those with duration longer than 3 months. CONCLUSIONS: The finding suggests that if total resection of SICM is achievable, surgical therapy could be considered to avoid risks of severe complications followed by lesion bleeding. Early microsurgical resection (usually within 3 months) for patients with SICM can lead to better clinical outcomes.

MicroRNA-494 improves functional recovery and inhibits apoptosis by modulating PTEN/AKT/mTOR pathway in rats after spinal cord injury.

Multiple cellular, molecular, and biochemical changes contribute to the etiology and treatment outcome of contusion spinal cord injury (SCI). MicroRNAs (miRNAs) aberrant expression have been found after SCI in recent studies. However, little is known about the functional significance of the unique role of miRNAs in SCI. Here, we established a rat SCI model and performed the miRNA microarray to analyze miRNAs expression at different times post-SCI. Microarray data revealed that 14 miRNAs were upregulated and 46 miRNAs were downregulated by 2 times compared with sham rat spinal cords, and miR-494 was one of the miRNAs being most significantly downregulated. Subsequently, we investigated miR-494 function and found that upregulation of miR-494 by agomir-494 improves functional recovery, reduces lesion size and inhibits apoptotic cell in rats following SCI. Moreover, our data showed that miR-494 suppresses phosphatase and tensin homolog (PTEN), a negative regulator of AKT/mTOR pathway, through directly targeting its 3'-UTR in BV-2 cells. Most importantly, we demonstrated that overexpression of miR-494 activates AKT/mTOR signaling pathway via inhibiting PTEN expression in rat SCI model. These findings suggested that miR-494 harbored the protective effect after SCI by modulating PTEN/AKT/mTOR pathway in rats and it is a potential candidate for SCI therapeutics.

Long Coding RNA XIST Contributes to Neuronal Apoptosis through the Downregulation of AKT Phosphorylation and Is Negatively Regulated by miR-494 in Rat Spinal Cord Injury.

Recent evidence has suggested that long non-coding RNAs (lncRNAs) may play a significant role in the pathogenesis of several neurological diseases, including spinal cord injury (SCI). However, little is known about the role of lncRNAs in SCI. The aim of the present study was to evaluate the potential functions of lncRNAs in SCI and to identify the underlying mechanisms of action. We firstly analyzed Gene Expression Omnibus (GEO) datasets to investigate aberrantly-expressed lncRNAs which might be involved in the pathogenesis of SCI. The long non-coding RNA X-inactive specific transcript (XIST) was found to be one of the most significantly upregulated lncRNAs in the GEO dataset analysis, and is associated with apoptosis. We, therefore, selected this as a candidate lncRNA and investigated its function. We found that knockdown of lncRNA-XIST by Lv-shRNA had a prominent protective effect on SCI recovery by suppressing apoptosis through reactivation of the PI3K/AKT signaling pathway in rat spinal cord tissue. In particular, our results suggested that lncRNA-XIST may act as a competitive endogenous RNA, effectively becoming a sink for miR-494, leading to derepression of its target gene, phosphatase and tensin homolog deleted on chromosome ten (PTEN). In addition, an inverse relationship between lncRNA-XIST and miR-494 was observed in spinal cord tissues of SCI rats. Further study demonstrated that antagomiR-494 could reverse the protective effects of lncRNA-XIST knockdown on SCI rats through blocking the PTEN/PI3K/AKT signaling pathway. These results suggested that lncRNA-XIST knockdown may play an important role in limiting neuronal apoptosis in rats following SCI, and that the observed protective effects of lncRNA-XIST knockdown might have been mediated by its regulation on the phosphorylation of AKT by competitively binding miR-494. These findings have revealed, for the first time, the importance of the XIST/miR-494/PTEN/AKT signaling axis in the pathogenesis of SCI and suggest that lncRNA-XIST may be a promising molecular target for SCI therapy.

The Molecular Feature of HOX Gene Family in the Intramedullary Spinal Tumors.

STUDY DESIGN: The expression of HOXB13 and HOXA9 proteins was detected. OBJECTIVE: The purpose of this study was to investigate the molecular signature of spinal ependymoma (EPN) and astrocytoma, 2 most common types of intramedullary spinal tumor. SUMMARY OF BACKGROUND DATA: Intramedullary spinal tumor is unusual. It leads to high neurological morbidity and mortality without treatment. Till now, its molecular feature has been elucidated up to a little extent. METHODS: A total of 37 cases of spinal EPN, including 12 myxopapillary EPNs (MEPNs), 18 classic EPNs, and 7 anaplastic EPNs, and another 12 cases of astrocytoma were selected for this study. Immunohistochemical analysis of a large cohort of patients providing clinical tumor samples was performed to compare the expression of HOXB13 and HOXA9 not only between spinal EPN and astrocytoma but also among all 3 World Health Organization grades of spinal EPN. RESULTS: The results showed that HOXB13 and HOXA9 were selectively expressed in spinal EPN instead of astrocytoma. Furthermore, we found the strongest positive response of HOXB13 in MEPN whereas that of HOXA9 was ubiquitously detected in all subgroups of EPN. CONCLUSION: Both specificity and sensitivity of HOXB13 in MEPN indicated that HOXB13 might be a diagnostic marker to distinguish MEPN from other 2 types of EPN and a promising therapeutic target for MEPN. The strong immunoreactivity of HOXA9 in spinal EPN suggested an indispensable role in the progression of spinal EPN, and further research on its molecular function will provide new clues for the development of treatment options. LEVEL OF EVIDENCE: N /A.

Identification of dysregulated miRNAs and their regulatory signature in glioma patients using the partial least squares method.

Using microarray data, the present study identified differentially expressed microRNAs (miRNAs) and evaluated their regulatory characteristics in high-grade glioma patients, with the aim to further the understanding into the underlying etiology of the condition. Previously, studies have generally implemented regression or variance analysis, which ignores various background biological factors. However, in the present study, analysis was performed with microarray data collected from the Gene Expression Omnibus database using a partial least squares-based method, which is more sensitive in handling microarray data. Among the six identified differentially expressed miRNAs, hsa-miR-21 and hsa-miR-612 have been previously reported to be associated with glioma. In addition, the remaining miRNAs, hsa-miR-4680, hsa-miR-1908, hsa-miR-4656 and hsa-miR-4467, may also contribute to glioma progression since they are all associated with the tumorigenesis of other types of cancer. Moreover, the expression levels of hsa-miR-1908, hsa-miR-4656 and hsa-miR-4680 have been identified to significantly correlate with the survival rate. Enrichment analysis of the dysregulated target genes revealed that the selected miRNAs primarily affect biological processes in the nervous system and the protein phosphorylation process. Therefore, the results may offer a new understanding into the pathogenesis of high-grade glioma.

[Prognostic analyses of intramedullary high grade astrocytomas].

OBJECTIVE: To explore the prognostic factors of intramedullary high grade astrocytomas. METHODS: Retrospective analyses were conducted for 21 surgical patients with high grade astrocytoma in spinal cord during 2008 to 2012 at our hospital. Their preoperative and postoperative profiles were recorded and evaluated by modified McCormick classification scheme. RESULTS: Their median age was 32.5 years. There were anaplastic astrocytoma (n = 14) and glioblastoma (n = 7). The prognoses of high grade astrocytomas were correlated with pathology grade and MIB-1 index. No statistic significance existed in age, gender, McCormick score, extent of resection, radiotherapy or chemotherapy. CONCLUSION: Intramedullary high grade astrocytoma has a low incidence, but its outcome is poor. Once definitely diagnosed, operation is recommended as early as possible. Frozen pathology should be performed to determine the extent of resection. After operation, chemotherapy and radiotherapy are also suggested.

Pathway and network analysis in glioma with the partial least squares method.

Gene expression profiling facilitates the understanding of biological characteristics of gliomas. Previous studies mainly used regression/variance analysis without considering various background biological and environmental factors. The aim of this study was to investigate gene expression differences between grade III and IV gliomas through partial least squares (PLS) based analysis. The expression data set was from the Gene Expression Omnibus database. PLS based analysis was performed with the R statistical software. A total of 1,378 differentially expressed genes were identified. Survival analysis identified four pathways, including Prion diseases, colorectal cancer, CAMs, and PI3K-Akt signaling, which may be related with the prognosis of the patients. Network analysis identified two hub genes, ELAVL1 and FN1, which have been reported to be related with glioma previously. Our results provide new understanding of glioma pathogenesis and prognosis with the hope to offer theoretical support for future therapeutic studies.

Identifying hedgehog signaling specific microRNAs in glioblastomas.

Aberrant activation of hedgehog (Hh) signaling pathway plays an important role in the development and proliferation of glioblastoma (GBM) cells. However, its mechanism remains unknown. MicroRNAs (miRNAs) are short non-coding RNA molecules which are involved in the post-transcriptional regulation of genes, and enrolled in signaling transduction network in tumors. This study was designed to investigate the role of miRNAs targeting the Hh signaling pathway in GBMs. According to the expression level of Gli1 mRNA measured by real time PCR, GBM samples were assigned to Gli1 high or low expression group. MiRNA microarray was applied to screen the dysregulated miRNA. As a result, 17 miRNAs were differentially expressed between Gli1 high expression and low expression groups (p < 0.005). Thirteen miRNAs including miR-125b-1 were downregulated, while only 4 miRNAs including miR-144 were upregulated in Gli1 high expression group. In summary, our study presents a subset of miRNAs which target the Hh signaling pathway in GBMs, and throws some light on the aberrant activation mechanism.

Outcomes in treatment for primary spinal anaplastic ependymomas: a retrospective series of 20 patients.

OBJECT: Little is known regarding the anaplastic variant of primary ependymomas that involve the spinal cord. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of primary spinal anaplastic ependymomas (PSAEs). METHODS: Medical records were reviewed in 20 patients with pathologically proven PSAEs who underwent surgical treatment at the Department of Neurosurgery in Huashan Hospital between 1999 and 2008. RESULTS: This series included 7 women and 13 men between the ages of 2 and 67 years (mean 31.9 years). The mean preoperative course was 9.3 months (range 20 days to 48 months). The most common PSAE locations were the cervical and thoracic spinal cords. The most common presenting symptom was weakness, followed by numbness, bowel or bladder dysfunction, and pain. Gross-total resection (GTR) was achieved in 17 patients, and a subtotal removal was performed in 3 patients. Nine patients received radiation therapy and/or chemotherapy. The mean follow-up duration was 83.5 months. Functional assessment of the 10 patients available at the latest follow-up evaluation showed that 2 had worsened and 8 remained unchanged from their preoperative status. There were 2 local recurrences and 1 lung metastasis. CONCLUSIONS: Patients with PSAEs presented with a much shorter preoperative course than patients with Grade II ependymomas in previous studies. Patients with tumors that involved the cervical spinal cord experienced a worse outcome. Surgical removal of PSAEs, with the goal of GTR, is beneficial to patients. The role of radiation therapy and chemotherapy in PSAEs remains to be determined in further studies.

Towards retinal ganglion cell regeneration.

Traumatic optic nerve injury and glaucoma are among the leading causes of incurable vision loss across the world. What is worse, neither pharmacological nor surgical interventions are significantly effective in reversing or halting the progression of vision loss. Advances in cell biology offer some hope for the victims of optic nerve damage and subsequent partial or complete visual loss. Retinal ganglion cells (RGCs) travel through the optic nerve and carry all visual signals to the brain. After injury, RGC axons usually fail to regrow and die, leading to irreversible loss of vision. Various kinds of cells and factors possess the ability to support the process of axon regeneration for RGCs. This article summarizes the latest advances in RGC regeneration.

[The diagnosis and surgical management for intramedullary spinal cord cavernous angioma].

OBJECTIVE: The clinical diagnosis and surgical management of intramedullary spinal cord cavernous angioma were discussed. METHOD: Total 19 patients with intramedullary cavernous angioma were analyzed retrospectively on the clinical manifestation, radiographic feature, diagnosis and differentiation, surgical technique and caution. Of all the 19 patients, averaging 38.7 years old, 14 were male and 5 were female. Nine patients were followed. RESULT: All the 19 patients pathologically diagnosed with spinal cord cavernous angioma got good surgical results, besides one patient showed loss of proprioception. Nine patients were followed up and all demonstrated improvement on neurological function. CONCLUSION: The clinical symptom of most of the patients with spinal cord cavernous angioma presented mildly at onset, but deteriorated gradually because of repeated prehemorrhage. Since the lesion showed some characteristic in MRI, MRI examination was regarded as an important diagnostic tool. Dissection should be done between the tumor and the gliosis during the surgical procedure, special attention should be paid to avoiding tumor residual. It was not necessary to aggressively evacuate the hematoma derived from tumor hemorrhage, which extended along the central canal up and down, except obvious occupied syndrome exited.