Cerebrospinal Fluid Lysophosphatidylcholine Species for Distinguishing Narrowing of the Lumbar Spine.

BACKGROUND: Reoperation, sometimes multiple, is common with progressively worse outcomes in patients with degenerative lumbar spine diseases. Lysophosphatidylcholine (LPC), a precursor of lysophosphatidic acid, in the cerebrospinal fluid (CSF) is a possible biomarker for neuropathic pain and discriminating neuropathic pain caused by lumbar spinal canal stenosis (LSCS) from other etiologies. This study aimed to explore this possible use of LPC species in the CSF. METHODS: Patients with LSCS (n = 137) and persistent spinal pain syndrome (n = 22) were subjected in this multi-site observational study. The CSF was collected by lumbar puncture. Using liquid chromatography-tandem mass spectrometry, we measured 6 LPC species, (16:0), (18:0), (18:1), (18:2), (20:4), and (22:6), in the CSF. We compared the LPC values between the groups and determined the cutoff levels that could efficiently discriminate the groups with high accuracy. RESULTS: The levels of all measured LPC species were significantly higher in the LSCS group than the persistent spinal pain syndrome group. Four LPC species demonstrated more than 0.80 area under the curve obtained from the receiver operating characteristic curve analysis. Although the specificity of cutoff levels for the 6 LPC species was low to moderate, their sensitivity was consistently high. CONCLUSIONS: The existing diagnostic protocols combining physical examinations and morphological imaging studies for lumbar spinal pain have limited sensitivity. Measuring LPC species in the CSF is a promising objective laboratory test and could be suitable for detecting the presence of lumbar spinal stenosis and can help indications for surgery.

Clinical and safety outcomes of simultaneous bilateral total knee arthroplasty for Japanese octogenarian patients: a retrospective analysis.

PURPOSE: The demand for simultaneous bilateral total knee arthroplasty (SiBTKA) in older adults is expected to increase with an aging population, thus necessitating evaluating its efficacy and safety. However, there is limited information regarding the clinical outcomes of SiBTKA in older adults, particularly in octogenarians. We aimed to assess the clinical outcomes and safety of SiBTKA in Japanese patients aged ≥ 80 years. METHODS: Of the 176 consecutive knees that underwent SiBTKA between July 2016 and January 2022 at our hospital, 172 were selected. They were divided into two groups according to the patient age as follows: the octogenarian group (≥ 80 years, 74 knees) and the younger control group (< 80 years, 98 knees). In addition, we assessed their preoperative clinical information, clinical outcomes using the Knee Society Score for knee (KSS-K) and function (KSS-F), and the incidence of early (≤ 90 days) and late (> 90 days) postoperative complications. RESULTS: The mean follow-up period was 3.5 years. The KSS-K scores of both groups improved postoperatively than that preoperatively. Both preoperative and postoperative KSS-F scores were lower in the octogenarians; however, their improvement rates were similar to those of the younger controls. We observed no significant intergroup differences in early or late postoperative complications, including infection, systemic complications, periprosthetic fractures, aseptic loosening, and mortality. CONCLUSION: SiBTKA for octogenarians had clinical outcomes and postoperative complication incidence similar to that for younger controls. Therefore, SiBTKA may be a safe and effective treatment option for octogenarians with painful bilateral knee deformities.

A case of subacute combined degeneration of the spinal cord diagnosed with difficulty due to a history of treatment for pyogenic spondylitis.

Early diagnosis of spinal cord subacute combined degeneration (SCD) is difficult, especially in pre-existing lower extremity impairment cases. We report a case of progressive SCD diagnosed after severe anemia. The peripheral symptoms of SCD other than gait disturbance should also be well understood and given close attention.

Preoperative incidence and risk factors of deep vein thrombosis in Japanese patients undergoing total hip arthroplasty.

PURPOSE: Preoperative deep vein thrombosis (DVT) is a risk factor for postoperative venous thromboembolism (VTE), causing severe mortality. Early detection of preoperative DVT is essential to prevent postoperative VTE. However, little is known regarding preoperative DVT in patients undergoing major surgery. The present study aimed to determine the incidence and risk factors of preoperative DVT in patients admitted for total hip arthroplasty (THA). METHODS: From August 2017 to September 2022, 243 patients admitted for THA at our institution were enrolled in this study. Patients medical records and preoperative laboratory data were retrospectively collected. According to the results of lower-limb ultrasonography, patients were divided into either the non-DVT (n = 136) or DVT (n = 43) group. The incidence of DVT and independent risk factors for preoperative DVT were investigated using univariate and multivariate logistic regression analyses. RESULTS: The mean age was 74.0 ± 8.4 years. Preoperative DVT was diagnosed in 43 of the 243 (17.7%) patients. The risk of DVT was significantly high (p < 0.05) in patients with advanced age, increased D-dimer levels, and malnutrition status, as assessed by the Geriatric Nutritional Risk Index (GNRI). Multivariate analysis showed that advanced age, increased D-dimer level, and malnutrition status assessed by the GNRI were independent risk factors for preoperative DVT. CONCLUSION: A high incidence of preoperative DVT was observed in patients undergoing THA. Advanced age, increased D-dimer levels, and malnutrition assessed by the GNRI increased the risk of preoperative DVT. Screening high-risk subgroups for preoperative DVT is necessary to prevent postoperative VTE.

Usefulness of lysophosphatidylcholine measurement in the cerebrospinal fluid for differential diagnosis of neuropathic pain: Possible introduction into clinical laboratory testing.

BACKGROUND: The differential diagnosis of neuropathic pain, especially discrimination between neuropathic pain caused by spinal canal stenosis (SCS) and neuropathic pain associated with causes other than SCS, is sometimes difficult; however, it is important for surgical application. METHODS: We established a reliable method for measuring lysophosphatidylcholine (LPC), a precursor of lysophosphatidic acids which are known as being pain initiators, using a liquid chromatography-tandem mass spectrometry method, and measured the LPC concentrations in the cerebrospinal fluid (CSF) in patients with SCS (SCS group; n = 76), patients with neuropathic pain caused by non-SCS diseases (Others group; n = 49), and control subjects without pain (control group; n = 92). RESULTS: Both within-run and between-run CV(%) were almost < 10 %, suggesting an enough performance for clinical introduction. The CSF concentrations of LPC (16:0) and LPC (18:0) were higher in the SCS group than those in the Control or Others group; the concentrations of LPC (18:1), LPC (18:2), LPC (20:4), LPC (22:6) levels were higher in the SCS group than those in the control or others group, but they were also higher in the Others group than those in the control group. The areas under the curve in the ROC curve analyses of LPC (18:1) for discriminating between the SCS and control groups, others and control groups, and SCS and others groups were 0.994, 0.860, and 0.869, respectively. CONCLUSIONS: LPC measurement in the CSF is useful for the differential diagnosis of neuropathic pain, especially for surgical decision-making, which is expected for clinical introduction.

Clinical and radiological outcomes of total hip arthroplasty in octogenarian patients using a three-dimensional porous titanium cup: a retrospective analysis in Japanese patients.

PURPOSE: Osteointegration of a three-dimensional (3D) porous titanium material has been experimentally proven, but only a few studies have shown the clinical outcomes of a 3D porous titanium cup in the Japanese elderly population. The purpose of this study was to compare the short-and-medium term clinical and radiographic results of total hip arthroplasty (THA) using a 3D porous titanium cup in patients aged ≥ 80 (octogenarians) versus those aged < 80 (younger controls). METHODS: A total of 104 hips that underwent THA using a 3D porous titanium cup (SQRUM TT, Kyocera Medical) were enrolled in the study and were divided into two groups according to age: the octogenarian group (≥ 80, n = 42) and the younger control group (< 80, n = 62). Furthermore, we evaluated patient characteristics, clinical outcomes determined by the Japanese Orthopedic Association score, cup alignment, and incidence of radiolucent lines around the cup. RESULTS: The mean follow-up period was 4.2 and 4.0 years (p = 0.29) for octogenarians and younger controls, respectively. The clinical outcomes were excellent, and no revision surgery occurred until the last follow-up in both groups. The number of patients with radiolucent lines at the final evaluation was 21 of 62 (33.9%) in younger controls and 16 of 42 (38.1%) in octogenarians. CONCLUSION: THA with 3D porous titanium cup for octogenarians had similar clinical outcomes and incidence of radiolucent lines as those of younger controls, suggesting that the 3D porous titanium cup may be useful in THA for octogenarians. Further investigations will confirm its long-term outcomes.

Different Profiles of the Triad of Lysophosphatidylcholine, Lysophosphatidic Acid, and Autotaxin in Patients with Neuropathic Pain Diseases: a Preliminary Observational Study.

The mechanisms underlying neuropathic pain remain unclear. Lysophosphatidic acid (LPA) is a bioactive phospholipid derived mainly from lysophosphatidylcholine (LPC) by extracellular autotaxin (ATX), and has attracted attention as a candidate biomarker of neuropathic pain. We aimed to investigate the levels of LPA, LPC, and ATX in patients with lumbar spinal canal stenosis (LSCS) or other neuropathic pain diseases, and to distinguish the underlying mechanism of LSCS from other neuropathic pain conditions. Furthermore, the levels of phosphorylated neurofilament heavy chain (pNF-H), an objective surrogate marker of axonal damage, were also measured. Cerebrospinal fluid (CSF) samples were obtained from 56 patients with LSCS (n = 31) and various etiologies other than LSCS (n = 25). Patients with LSCS complained of pain intensity comparable to that of patients without LSCS. The LPA levels were significantly higher in patients with LSCS than in non-LSCS patients, while the ATX levels were significantly lower. However, the differences in LPC and pNF-H levels between the two patient groups were not significant. The LPA/LPC ratio was significantly higher in the LSCS group. Notably, the difference in LPA between the two groups diminished in the analysis of covariance (ANCOVA) with ATX as a covariate. Thus, it helped to reveal that LPA synthesis in patients with LSCS depends more efficiently on ATX than in non-LSCS neuropathic pain patients with other etiologies. Our findings further suggest that the triad of LPA, LPC, and ATX in LSCS may contribute to the development and maintenance of neuropathic pain in a manner different from non-LSCS neuropathic conditions.

Intraosseous epidermal cyst of the great toe that was difficult to distinguish from chronic osteomyelitis: A case report and literature review.

Obtaining a correct intraosseous epidermal cyst diagnosis is difficult due to the extreme rarity of this cyst. Further, the clinical manifestations and radiographic findings are very similar to those of a malignancy or infection. Early histopathological analysis is required for accurate diagnosis and for avoiding unnecessary antibiotic administration and amputation.

Lysophosphatidic acids and their substrate lysophospholipids in cerebrospinal fluid as objective biomarkers for evaluating the severity of lumbar spinal stenosis.

Lysophospholipids (LPLs) are known to have potentially important roles in the initiation and maintenance of neuropathic pain in animal models. This study investigated the association between the clinical severity of lumbar spinal stenosis (LSS) and the cerebrospinal fluid (CSF) levels of LPLs, using human samples. We prospectively identified twenty-eight patients with LSS and fifteen controls with idiopathic scoliosis or bladder cancer without neurological symptoms. We quantified LPLs from CSF using liquid chromatography-tandem mass spectrometry. We assessed clinical outcome measures of LSS (Neuropathic Pain Symptom Inventory (NPSI) and Zurich Claudication Questionnaire (ZCQ)) and categorized patients into two groups according to their severity. Five species of lysophosphatidic acid (LPA), nine species of lysophosphatidylcholine (LPC), and one species of lysophosphatidylinositol (LPI) were detected. The CSF levels of all species of LPLs were significantly higher in LSS patients than controls. Patients in the severe NPSI group had significantly higher LPL levels (three species of LPA and nine species of LPC) than the mild group. Patients in the severe ZCQ group also had significantly higher LPL levels (four species of LPA and nine species of LPC). This investigation demonstrates a positive correlation between the CSF levels of LPLs and the clinical severity of LSS. LPLs are potential biomarkers for evaluating the severity of LSS.

Mental State Can Influence the Degree of Postoperative Axial Neck Pain Following Cervical Laminoplasty.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: To investigate factors influencing the incidence of moderate to severe postoperative axial neck pain following cervical laminoplasty. METHODS: We reviewed 125 patients with cervical myelopathy who underwent double-door laminoplasty. The primary outcomes were the Numerical Rating Scale score (NRS score, 0-10) for neck pain, the Short Form 36 (SF-36) Health Survey score (Physical and Mental Component Summary scores [PCS and MCS, respectively]), and satisfaction. Imaging parameters on plain radiographs and magnetic resonance imaging were also evaluated. Patients with moderate to severe postoperative neck pain (NRS ≥ 5) were compared with those with no or mild neck pain (NRS ≤ 4). RESULTS: One hundred and three patients (82%) with complete data were eligible for inclusion. There were 67 men and 36 women, with a mean age of 65 years (32-89 years). Twenty-five patients (23%) had moderate to severe postoperative axial pain (NRS ≥ 5) and were compared with the other 78 patients (NRS ≤ 4), which revealed several predictive factors, including female sex, the presence of preoperative neck pain, low postoperative PCS, low preoperative and postoperative MCS, and satisfaction with the treatment. Multivariable logistic regression analysis revealed that the postoperative MCS (P = .002) was a risk factor for postoperative neck pain, although the preoperative MCS did not reach statistical significance (P = .06). CONCLUSIONS: Patients with a low mental state, possibly before surgery, are at a high risk for postoperative axial neck pain. None of the imaging parameters were statistically different.

Treatment of spinal cord injury by an advanced cell transplantation technology using brain-derived neurotrophic factor-transfected mesenchymal stem cell spheroids.

Curing spinal cord injury (SCI) is challenging because of the onset of multiple and irreversible pathological responses to such injury. To suppress the responses, we employed an advanced cell transplantation technology integrating three-dimensional spheroid cell transplantation with non-viral gene transfection using biodegradable polycations. Brain-derived neurotrophic factor (BDNF)-transfected mesenchymal stem cell (MSC) spheroids were transplanted at thoraces level (Th9) to SCI region in mice. BDNF-transfected MSC spheroid transplantation led to a significantly enhanced recovery of hindlimb motor function in acute phase of SCI with myelinated axons preserved at the SCI region, while use of either technology in isolation, BDNF transfection or spheroid culture, exerted only a limited therapeutic effect, demonstrating the importance of integrated approaches. Secretion of endogenous therapeutic proteins, such as anti-inflammatory factors, was greater in MSC spheroids than in monolayer culture MSCs, and these factors appeared to act synergistically alongside BDNF secretion in SCI treatment. This study forms a basis for cell therapy regulating complex pathophysiologic processes.

The crucial role of Erk2 in demyelinating inflammation in the central nervous system.

BACKGROUND: Brain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation. METHODS: We used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes. RESULTS: First, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3-4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2. CONCLUSIONS: Our results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of distinct demyelinating diseases.

Phosphorylated neurofilament subunit levels in the serum of cervical compressive myelopathy patients.

We investigated the serum levels of the phosphorylated form of the high molecular weight neurofilament subunit (pNF-H) in patients with cervical compressive myelopathy. pNF-H is becoming increasingly recognized as a biomarker for axonal injury, however, it remains unclear whether serum pNF-H is elevated in chronic spinal cord compression. We examined 26 patients who underwent surgery for cervical compressive myelopathy. Peripheral blood samples were obtained both preoperatively and 1 week after surgery to evaluate the serum pNF-H levels using an enzyme-linked immunosorbent assay. A history of recent aggravation of myelopathy was also investigated. Of the 26 myelopathy patients, the preoperative serum pNF-H level was negative in 20 patients and moderately elevated in six. Patients who were positive for pNF-H were more likely to have had a recent aggravation of myelopathy compared with the pNF-H negative patients (83 versus 25%; p=0.02). All patients who were positive for pNF-H before surgery remained positive after surgery. Two patients who became positive after surgery demonstrated a neurologic deterioration associated with the surgery. In conclusion, the serum pNF-H level was negative in the majority of patients with cervical compressive myelopathy. Our results suggest that an elevated serum level of pNF-H is associated with an acute worsening of myelopathy and that a positive conversion of pNF-H after surgery is a marker of perioperative neural damage.

Elevated levels of phosphorylated neurofilament heavy subunit in the cerebrospinal fluid of patients with lumbar spinal stenosis: preliminary findings.

BACKGROUND CONTEXT: The phosphorylated neurofilament heavy subunit (pNfH) is an axon fiber structural protein that is released into the cerebrospinal fluid (CSF) after nerve damage. Although the previous studies have reported elevated CSF levels of pNfH in various neurological diseases, including amyotrophic lateral sclerosis, these levels have not been examined in patients with spinal stenosis. PURPOSE: The purpose of this study was to investigate the CSF levels of pNfH in patients with lumbar spinal stenosis (LSS) and to examine the relationship between CSF levels of pNfH and the severity of LSS. STUDY DESIGN: This is a prospective observational study. PATIENT SAMPLE: We included consecutive patients with LSS who were undergoing myelography for preoperative evaluation. The CSF samples from patients with idiopathic scoliosis were used as the controls. OUTCOME MEASURES: Physiological measures: CSF levels of pNfH were measured using an enzyme-linked immunosorbent assay. The Zurich Claudication Questionnaire (ZCQ) and the Numerical Rating Scale (NRS) for sciatic pain were used to assess the clinical severity of LSS, and patients were grouped into tertiles according to their symptom severity and pain grading. Axial magnetic resonance imaging was used to evaluate the morphological severity of LSS, and patients were classified into three groups based on their morphological grading (using the CSF/rootlet ratio). METHODS: Analysis of variance was used to examine the relationship between the CSF levels of pNfH and the severity of LSS. RESULTS: Thirty-three patients with LSS were included (13 men and 20 women and mean age 73.2 [range 58-88] years). Most patients (n=32) were positive for pNfH in their CSF (mean 1,344 [149-9,250] pg/mL), whereas all control subjects were negative for pNfH in their CSF. Regarding the association with clinical severity, patients in the third tertiles of ZCQ and NRS tended to have higher levels of pNfH compared with the other groups. There was no association between the CSF level of pNfH and the morphological severity of LSS. CONCLUSIONS: This study detected elevated pNfH levels in the CSF of patients with LSS. Patients with severe clinical symptoms were more likely to exhibit high levels of pNfH. Our results indicate the potential usefulness of pNfH as a biomarker for compressive spinal disorders.

Intrathecal injection of a therapeutic gene-containing polyplex to treat spinal cord injury.

Spinal cord injury (SCI) is a serious clinical problem that suddenly deprives patients of neurologic function and drastically diminishes their quality of life. Gene introduction has the potential to be effective for various pathological states of SCI because various proteins can be produced just by modifying nucleic acid sequences. In addition, the sustainable protein expression allows to maintain its concentration at an effective level at the target site in the spinal cord. Here we propose an approach using a polyplex system composed of plasmid DNA (pDNA) and a cationic polymer, poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)], that has high capacity to promote endosome escape and the long-term safety by self-catalytically degrading within a few days. We applied brain-derived neurotrophic factor (BDNF)-expressing pDNA for SCI treatment by intrathecal injection of PAsp(DET)/pDNA polyplex. A single administration of polyplex for experimental SCI provided sufficient therapeutic effects including prevention of neural cell death and enhancement of motor function recovery. This lasted for a few weeks after SCI, demonstrating the capability of this system to express BDNF in a safe and responsible manner for treatment of various pathological states in SCI.

Lipopolysaccharide preconditioning facilitates M2 activation of resident microglia after spinal cord injury.

The inflammatory response following spinal cord injury (SCI) has both harmful and beneficial effects; however, it can be modulated for therapeutic benefit. Endotoxin/lipopolysaccharide (LPS) preconditioning, a well-established method for modifying the immune reaction, has been shown to attenuate damage induced by stroke and brain trauma in rodent models. Although such effects likely are conveyed by tissue-repairing functions of the inflammatory response, the mechanisms that control the effects have not yet been elucidated. The present study preconditioned C57BL6/J mice with 0.05 mg/kg of LPS 48 hr before inducing contusion SCI to investigate the effect of LPS preconditioning on the activation of macrophages/microglia. We found that LPS preconditioning promotes the polarization of M1/M2 macrophages/microglia toward an M2 phenotype in the injured spinal cord on quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Flow cytometric analyses reveal that LPS preconditioning facilitates M2 activation in resident microglia but not in infiltrating macrophages. Augmented M2 activation was accompanied by vascularization around the injured lesion, resulting in improvement in both tissue reorganization and functional recovery. Furthermore, we found that M2 activation induced by LPS preconditioning is regulated by interleukin-10 gene expression, which was preceded by the transcriptional activation of interferon regulatory factor (IRF)-3, as demonstrated by Western blotting and an IRF-3 binding assay. Altogether, our findings demonstrate that LPS preconditioning has a therapeutic effect on SCI through the modulation of M1/M2 polarization of resident microglia. The present study suggests that controlling M1/M2 polarization through endotoxin signal transduction could become a promising therapeutic strategy for various central nervous system diseases. © 2014 Wiley Periodicals, Inc.

In vivo messenger RNA introduction into the central nervous system using polyplex nanomicelle.

Messenger RNA (mRNA) introduction is a promising approach to produce therapeutic proteins and peptides without any risk of insertion mutagenesis into the host genome. However, it is difficult to introduce mRNA in vivo mainly because of the instability of mRNA under physiological conditions and its strong immunogenicity through the recognition by Toll-like receptors (TLRs). We used a novel carrier based on self-assembly of a polyethylene glycol (PEG)-polyamino acid block copolymer, polyplex nanomicelle, to administer mRNA into the central nervous system (CNS). The nanomicelle with 50 nm in diameter has a core-shell structure with mRNA-containing inner core surrounded by PEG layer, providing the high stability and stealth property to the nanomicelle. The functional polyamino acids possessing the capacity of pH-responsive membrane destabilization allows smooth endosomal escape of the nanomicelle into the cytoplasm. After introduction into CNS, the nanomicelle successfully provided the sustained protein expression in the cerebrospinal fluid for almost a week. Immune responses after mRNA administration into CNS were effectively suppressed by the use of the nanomicelle compared with naked mRNA introduction. In vitro analyses using specific TLR-expressing HEK293 cells confirmed that the nanomicelle inclusion prevented mRNA from the recognition by TLRs. Thus, the polyplex nanomicelle is a promising system that simultaneously resolved the two major problems of in vivo mRNA introduction, the instability and immunogenicity, opening the door to various new therapeutic strategies using mRNA.