Postoperative Complications of Surgery for Cervical Spondylotic Myelopathy with and Without Athetoid Cerebral Palsy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: With the aging of the Japanese population, patients with athetoid cerebral palsy (ACP) are getting older, and the rate of surgery for CSM is increasing in ACP patients. However, postoperative complications of such surgery among adult patients with ACP have not been reported yet. We investigated postoperative complications of surgery for CSM with ACP and compared them with those of surgery for CSM without ACP using a national inpatient database of Japan. METHODS: Using the Diagnosis Procedure Combination database, we identified 61382 patients who underwent surgery for CSM from July 2010 to March 2018. We examined patient backgrounds, surgical procedures, and type of hospital, and a 4:1 propensity score matching was performed to compare the outcomes between the non-ACP and ACP groups. RESULTS: There were 60 847 patients without ACP and 535 patients with ACP. The mean age was 68.5 years in the non-ACP group and 55 years in the ACP group. The percentages of patients who underwent fusion surgery were 21.6% and 68.8% in the non-ACP and ACP groups, respectively. The 4:1 propensity score matching selected 1858 in the non-ACP group and 465 in the ACP group. The ACP group was more likely to have postoperative urinary tract infection (.4% vs 2.8%, P < .001), postoperative pneumonia (.4% vs 2.4%, P < .001), and 90-day readmission for reoperation (1.9% vs 4.3%, P = .003). CONCLUSIONS: We found that ACP patients were more vulnerable to postoperative complications and reoperation after CSM than non-ACP patients.

Does Surgical Treatment Affect the Degree of Anxiety or Depression in Patients With Degenerative Cervical Myelopathy?

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Preoperative mental state has been reported as one of the factors affecting the surgical outcomes of spine surgery, but few studies have examined in detail how patients' mental state is affected by spine surgery. The purpose of this study was to investigate using the Hospital Anxiety and Depression Scale (HADS) whether surgery improves preoperative depression and anxiety in patients with degenerative cervical myelopathy. METHODS: We investigated patient-reported outcomes (Mental Component Summary, Physical Component Summary of SF-12 Health Survey, and EQ-5D, Neck Disability Index, JOACMEQ, satisfaction with treatment) and HADS one year after surgery, comparing them before and after surgery between April 2017 and February 2020. Among the cases diagnosed as preoperative anxiety and depression, we additionally compared the patient-reported outcomes based on the presence or absence of postoperative improvement in mental state, having also investigated the correlation between patient-reported outcomes and HADS for sub-analysis. RESULTS: Among the 99 patients eligible for inclusion in the present study, we found that patient-reported outcomes and the HADS scores improved significantly after surgery. There was a moderate correlation between the amount of change in HADS-D score before and after surgery and the amount of change in NDI (moderate, r = .41), NRS of neck (moderate, r = .46), and JOACMEQ (cervical spine function; moderate, r = .43, upper extremity function; moderate, r = .41, QOL; moderate, r = .41). CONCLUSIONS: We found that surgical treatment for patients with degenerative cervical myelopathy may improve postoperative anxiety and depression as well as other patient-reported outcomes.

Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development.

The Runt-related transcription factor (Runx) family plays various roles in the homeostasis of cartilage. Here, we examined the role of Runx2 and Runx3 for osteoarthritis development in vivo and in vitro. Runx3-knockout mice exhibited accelerated osteoarthritis following surgical induction, accompanied by decreased expression of lubricin and aggrecan. Meanwhile, Runx2 conditional knockout mice showed biphasic phenotypes: heterozygous knockout inhibited osteoarthritis and decreased matrix metallopeptidase 13 (Mmp13) expression, while homozygous knockout of Runx2 accelerated osteoarthritis and reduced type II collagen (Col2a1) expression. Comprehensive transcriptional analyses revealed lubricin and aggrecan as transcriptional target genes of Runx3, and indicated that Runx2 sustained Col2a1 expression through an intron 6 enhancer when Sox9 was decreased. Intra-articular administration of Runx3 adenovirus ameliorated development of surgically induced osteoarthritis. Runx3 protects adult articular cartilage through extracellular matrix protein production under normal conditions, while Runx2 exerts both catabolic and anabolic effects under the inflammatory condition.

RSPO2 defines a distinct undifferentiated progenitor in the tendon/ligament and suppresses ectopic ossification.

Ectopic endochondral ossification in the tendon/ligament is caused by repetitive mechanical overload or inflammation. Tendon stem/progenitor cells (TSPCs) contribute to tissue repair, and some express lubricin [proteoglycan 4 (PRG4)]. However, the mechanisms of ectopic ossification and association of TSPCs are not yet known. Here, we investigated the characteristics of Prg4-positive (+) cells and identified that R-spondin 2 (RSPO2), a WNT activator, is specifically expressed in a distinct Prg4+ TSPC cluster. The Rspo2+ cluster was characterized as mostly undifferentiated, and RSPO2 overexpression suppressed ectopic ossification in a mouse Achilles tendon puncture model via chondrogenic differentiation suppression. RSPO2 expression levels in patients with ossification of the posterior longitudinal ligament were lower than those in spondylosis patients, and RSPO2 protein suppressed chondrogenic differentiation of human ligament cells. RSPO2 was induced by inflammatory stimulation and mechanical loading via nuclear factor κB. Rspo2+ cells may contribute to tendon/ligament homeostasis under pathogenic conditions.

Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma.

Single-cell RNA sequencing (scRNAseq) has been used to assess the intra-tumor heterogeneity and microenvironment of pancreatic ductal adenocarcinoma (PDAC). However, previous knowledge is not fully universalized. Here, we built a single cell atlas of PDAC from six datasets containing over 70 samples and >130,000 cells, and demonstrated its application to the reanalysis of the previous bulk transcriptomic cohorts and inferring cell-cell communications. The cell decomposition of bulk transcriptomics using scRNAseq data showed the cellular heterogeneity of PDAC; moreover, high levels of tumor cells and fibroblasts were indicative of poor-prognosis. Refined tumor subtypes signature indicated the tumor cell dynamics in intra-tumor and their specific regulatory network. We further identified functionally distinct tumor clusters that had close interaction with fibroblast subtypes via different signaling pathways dependent on subtypes. Our analysis provided a reference dataset for PDAC and showed its utility in research on the microenvironment of intra-tumor heterogeneity.

Effect of Spinal Alignment Changes on Lower Back Pain in Patients Treated with Total Hip Arthroplasty for Hip Osteoarthritis.

Background and objectives: The influence of changes in spinal alignment after total hip arthroplasty (THA) on improvement in lower back pain (LBP) remains controversial. To evaluate how changes in spinal malalignment correlate with improvement in preoperative LBP in patients who underwent THA for hip osteoarthritis. Materials and Methods: From November 2015 to January 2017, 104 consecutive patients who underwent unilateral THA were prospectively registered. Whole spine X-rays and patient-reported outcomes (PROs) were obtained preoperatively and 12 months postoperatively. The PROs used were the Numerical Rating Scale (NRS) for back pain, EuroQol 5 Dimension, and Short Form-12. Results: Seventy-four (71%) patients with complete data were eligible for the analysis. The sagittal parameters changed slightly but significantly. Coronal alignment significantly improved. Twenty-six (37%) patients had LBP preoperatively. These patients had smaller lumbar lordosis (LL), larger PT, and larger PI minus LL than the patients without LBP. Fourteen (54%) of the 26 patients with preoperative LBP showed pain improvement, but there were no significant differences in the radiographic parameters. Conclusions: Although preoperative LBP was likely to be resolved after THA, there were no significant correlations between alignment changes and LBP improvement. The cause of LBP in patients with hip osteoarthritis (OA) patients might be multifactorial.

Divergence in chondrogenic potential between in vitro and in vivo of adipose- and synovial-stem cells from mouse and human.

BACKGROUND: Somatic stem cell transplantation has been performed for cartilage injury, but the reparative mechanisms are still conflicting. The chondrogenic potential of stem cells are thought as promising features for cartilage therapy; however, the correlation between their potential for chondrogenesis in vitro and in vivo remains undefined. The purpose of this study was to investigate the intrinsic chondrogenic condition depends on cell types and explore an indicator to select useful stem cells for cartilage regeneration. METHODS: The chondrogenic potential of two different stem cell types derived from adipose tissue (ASCs) and synovium (SSCs) of mice and humans was assessed using bone morphogenic protein-2 (BMP2) and transforming growth factor-ß1 (TGFß1). Their in vivo chondrogenic potential was validated through transplantation into a mouse osteochondral defect model. RESULTS: All cell types showed apparent chondrogenesis under the combination of BMP2 and TGFß1 in vitro, as assessed by the formation of proteoglycan- and type 2 collagen (COL2)-rich tissues. However, our results vastly differed with those observed following single stimulation among species and cell types; apparent chondrogenesis of mouse SSCs was observed with supplementation of BMP2 or TGFß1, whereas chondrogenesis of mouse ASCs and human SSCs was observed with supplementation of BMP2 not TGFß1. Human ASCs showed no obvious chondrogenesis following single stimulation. Mouse SSCs showed the formation of hyaline-like cartilage which had less fibrous components (COL1/3) with supplementation of TGFß1. However, human cells developed COL1/3+ tissues with all treatments. Transcriptomic analysis for TGFß receptors and ligands of cells prior to chondrogenic induction did not indicate their distinct reactivity to the TGFß1 or BMP2. In the transplanted site in vivo, mouse SSCs formed hyaline-like cartilage (proteoglycan+/COL2+/COL1-/COL3-) but other cell types mainly formed COL1/3-positive fibrous tissues in line with in vitro reactivity to TGFß1. CONCLUSION: Optimal chondrogenic factors driving chondrogenesis from somatic stem cells are intrinsically distinct among cell types and species. Among them, the response to TGFß1 may possibly represent the fate of stem cells when locally transplanted into cartilage defects.

Lubricin Contributes to Homeostasis of Articular Cartilage by Modulating Differentiation of Superficial Zone Cells.

Lubricin encoded by the proteoglycan 4 (Prg4) gene is produced from superficial zone (SFZ) cells of articular cartilage and synoviocytes, which is indispensable for lubrication of joint surfaces. Loss-of-function of human and mouse Prg4 results in early-onset arthropathy accompanied by lost SFZ cells and hyperplastic synovium. Here, we focused on increases in the thickness of articular cartilage in Prg4-knockout joints and analyzed the underlying mechanisms. In the late stage of articular cartilage development, the articular cartilage was thickened at 2 to 4 weeks and the SFZ disappeared at 8 weeks in Prg4-knockout mice. Similar changes were observed in cultured Prg4-knockout femoral heads. Cell tracking showed that Prg4-knockout SFZ cells at 1 week of age expanded to deep layers after 1 week. In in vitro experiments, overexpression of Prg4 lacking a mucin-like domain suppressed differentiation of ATDC5 cells markedly, whereas pellets of Prg4-knockout SFZ cells showed enhanced differentiation. RNA sequencing identified matrix metalloproteinase 9 (Mmp9) as the top upregulated gene by Prg4 knockout. Mmp9 expressed in the SFZ was further induced in Prg4-knockout mice. The increased expression of Mmp9 by Prg4 knockout was canceled by IκB kinase (IKK) inhibitor treatment. Phosphorylation of Smad2 was also enhanced in Prg4-knockout cell pellets, which was canceled by the IKK inhibitor. Expression of Mmp9 and phosphorylated Smad2 during articular cartilage development was enhanced in Prg4-knockout joints. Lubricin contributes to homeostasis of articular cartilage by suppressing differentiation of SFZ cells, and the nuclear factor-kappa B-Mmp9-TGF-ß pathway is probably responsible for the downstream action of lubricin. © 2020 American Society for Bone and Mineral Research (ASBMR).

The Utility of the Energy Subtraction Method for Thoracic Spine Radiography in Clinical Practice: An Analysis of 25 Patients With Multiple Myeloma.

Interpretation of thoracic spine radiographs is difficult because they cannot clearly depict the vertebrae due to overlap with soft tissues. This study aimed to evaluate whether thoracic spine radiographs obtained using the energy subtraction method could improve the accuracy of a diagnosis of thoracic osteolytic lesions. The authors analyzed 300 thoracic vertebrae from 25 patients with multiple myeloma who underwent thoracic spine radiography. All patients underwent thoracic spine radiography with 2 views. Two sets of images were prepared: computed radiography images (CR images) acquired using conventional processing parameters; and processed images for specifically visualizing bone, using the energy subtraction method (ES images). The CR images (CR group) and paired CR and ES images (CR+ES group) were interpreted in parallel by 5 orthopedic surgeons. The presence of osteolytic lesions was evaluated for each of the 12 thoracic vertebrae, and the sensitivity and specificity of the method were compared with computed tomography (CT), which is considered the gold standard. Subgroup analysis was also performed based on location. Osteolytic lesions were found on CT in 28 (9.3%) vertebrae of 12 patients. The overall sensitivities and specificities of the CR and CR+ES groups were 17.2% and 54.3%, respectively, and 95.6% and 98.0%, respectively, with statistically significant differences. Subgroup analysis showed particular improvement in the sensitivity for the CR+ES group in the middle thoracic spine compared with that at other locations. Thoracic spine radiographs generated using this method may improve the accuracy of diagnosis of thoracic osteolytic lesions. [Orthopedics. 2021;44(1):e31-e35.].

Associated factors for and progression rate of sacroiliac joint degeneration in subjects undergoing comprehensive medical checkups.

PURPOSE: Associated factors for and the natural course of sacroiliac (SI) joint degeneration in the normal population are unknown. The purpose of this study was to determine associated factors for and the progression rate of SI joint degeneration. METHODS: We enrolled 553 healthy middle-aged subjects who underwent the first and second comprehensive health screening at an interval of 5.9 years (range 3.0-10.7 years). The medical checkup included blood tests and whole-body computed tomography. We investigated associated factors of SI joint degeneration, the relationship of the laterality of degeneration between the SI and L4/5 facet joint, L5/S facet joint, and the natural course of SI joint degeneration over time. RESULTS: At the first checkup, 70 subjects (12.7%) showed substantial degeneration (type 2 or 3) of the SI joints. Multivariate analysis revealed that female sex; pubic symphysis degeneration, L4/5, and L5/S facet joint degeneration; high body mass index; and several blood parameters were associated factors for SI joint degeneration. Laterality of SI joint degeneration was significantly more frequent than that of L4/5 or L5/S facet joint degeneration. Kaplan-Meier survival analysis revealed that the progression rates of SI joint degeneration from type 0 (no degeneration) or type 1 (slight degeneration) to substantial degeneration amounted to 3.4% and 35.5% after 10 years, respectively. CONCLUSION: We found substantial SI joint degeneration in 12.7% of healthy middle-aged subjects and considered it to be part of the normal aging process. There may be individual factors associated with its occurrence. These slides can be retrieved under Electronic Supplementary Material.

Spinal cord swelling in patients with cervical compression myelopathy.

BACKGROUND: Intramedullary hyperintense lesions associated with spinal cord edema on T2-weighted MR images (T2WI) are rare findings in patients with cervical spondylosis and are poorly characterized. We investigated the clinical characteristics of spinal cord edema due to cervical spondylosis (SCECS). METHODS: In total, 214 patients with cervical spondylotic myelopathy who underwent surgery between April 2007 and March 2017 were divided into SCECS and non-SCECS groups with SCECS defined as follows: (1) intramedullary signal intensity (ISI) of the cervical spinal cord in sagittal T2WI extending to more than one vertebral body height; (2) "fuzzy" ISI, recognized as a faint intramedullary change with a largely indistinct and hazy border; and (3) a larger sagittal diameter of the spinal cord segment with ISI just above or below the cord compression area compared with areas of the cervical spine without ISI. Radiographic parameters, demographic characteristics, and the Japanese Orthopedic Association (JOA) surgical outcomes score were compared between the groups. RESULTS: Seventeen patients (7.9%) were diagnosed with SCECS. These patients were younger than those in the non-SCECS group [median (interquartile range), 64 (20) vs. 69 (15) years, respectively, p = 0.016], and the disease duration from onset to surgery was significantly shorter in the SCECS group than in the non-SCECS group [6 (7) vs. 20 (48) months, respectively]. No significant difference was observed between groups with respect to sex, radiologic findings, or surgical outcomes. CONCLUSION: The disease showed an earlier onset and more rapid progression in the patients with SCECS than in those without SCECS.

CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages.

CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-immunoglobulin; Abatacept) is a biologic drug for rheumatoid arthritis. CTLA4 binds to the CD80/86 complex of antigen-presenting cells and blocks the activation of T cells. Although previous reports showed that CTLA4-Ig directly inhibited osteoclast differentiation, the whole inhibitory mechanism of CTLA4-Ig for osteoclast differentiation is unclear. Bone marrow macrophages (BMMs) from WT mice were cultured with M-CSF and RANKL with or without the recombinant mouse chimera CTLA4-Ig. Intracellular calcium oscillations of BMMs with RANKL were detected by staining with calcium indicator fura-2 immediately after administration of CTLA4-Ig or after one day of treatment. Calcium oscillations were analyzed using Fc receptor gamma- (FcRγ-) deficient BMMs. CTLA4-Ig inhibited osteoclast differentiation and reduced the expression of the nuclear factor of activated T cells NFATc1 in BMMs in vitro. Calcium oscillations in BMMs were suppressed by CTLA4-Ig both immediately after administration and after one day of treatment. CTLA4-Ig did not affect osteoclastogenesis and did not cause remarkable changes in calcium oscillations in FcRγ-deficient BMMs. Finally, to analyze the effect of CTLA4-Ig in vivo, we used an LPS-induced osteolysis model. CTLA4-Ig suppressed LPS-induced bone resorption in WT mice, not in FcRγ-deficient mice. In conclusion, CTLA4-Ig inhibits intracellular calcium oscillations depending on FcRγ and downregulates NFATc1 expression in BMMs. © 2019 American Society for Bone and Mineral Research.

Hypoglossal Nerve Palsy as a Cause of Severe Dysphagia along with the Oropharyngeal Stenosis due to Occipitocervical Kyphosis.

Hypoglossal nerve palsy (HNP) is a potential cause of dysphagia. A 66-year-old man presented to our hospital with dysphagia and neck pain. One year prior to his first visit, he had been diagnosed with upper cervical tuberculosis and had undergone posterior C1-2 fixation. The physical examination led to the diagnosis of dysphagia with HNP, and he had severe weight loss. Radiographic examination revealed that the O-C kyphosis had been exacerbated and that the deformity was likely the primary cause of HNP. To restore the swallowing function, O-C fusion surgery was performed. Postoperatively, the patient showed immediate improvement of dysphagia with gradual recovery of hypoglossal nerve function. In the last follow-up evaluation, swallowing function was confirmed with no signs of HNP. Our results indicate that HNP could be more prevalent in cases with severe cervical kyphosis, being underdiagnosed due to the more apparent signs of the oropharyngeal narrowing.

Preventive Effect of Dynamic Stabilization Against Adjacent Segment Degeneration After Posterior Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To investigate the effects of dynamic stabilization with sublaminar taping (ST) on the upper segment adjacent to posterior lumbar interbody fusion (PLIF). SUMMARY OF BACKGROUND DATA: Hybrid procedures such as dynamic stabilization for adjacent segment in addition to spinal fusion have been developed for reduction of the mechanical stress and prevention of adjacent segment pathology (ASP). However, a few reports are available on hybrid procedures and their efficacy is still controversial. METHODS: Of the 116 patients who underwent L4/5 PLIF between August 2006 and September 2012, 76 patients with minimum 2-year follow up were included in this study. Fifty three patients underwent L4/5 PLIF with hybrid procedure using ST on L3 lamina (group U), and 23 patients underwent conventional L4/5 PLIF (group C). The adjacent segment degeneration (ASDeg) was determined by measurements of radiograph, computed tomography, and magnetic resonance imaging; the adjacent segment disease (ASDis) was evaluated on medical records. RESULTS: The incidence of ASDeg at L3/4 segment of group U (3.7%) was significantly less than that of group C (30.4%) (P = 0.003), although there were no significant differences at L2/3 (group U, 7.5%; group C, 13%) or L5/S1 segment (group U, 5.7%; group C, 8.7%). On the other hand, no significant difference was found between two groups in the incidence of ASDis in L2/3 to L5/S1 levels, and no patient underwent reoperation. Bivariable and multivariable logistic regression analyses for L3/4 segment ASDeg revealed that the difference of surgical procedure was the only significant factor. CONCLUSION: The current study showed that L4/5 PLIF with hybrid procedure using ST on L3 lamina significantly reduced the incidence of L3/4 ASDeg as compared with the conventional L4/5 PLIF without compromising L2/3 or L5/S1 segment. Although further studies and longer follow up are necessary, the hybrid procedure is expected to be effective for preventing ASP. LEVEL OF EVIDENCE: 4.