Enpp1 mutations promote upregulation of hedgehog signaling in heterotopic ossification with aging.

INTRODUCTION: Heterotopic ossification of the tendon and ligament (HOTL) is a chronic progressive disease that is usually accompanied by thickening and ossification of ligaments and high osteogenic activity of the surrounding ligament tissue. However, the molecular mechanism of maintaining the cellular phenotype of HOTL remains unclear. MATERIALS AND METHODS: We first constructed a model of HOTL, Enpp1flox/flox/EIIa-Cre mice, a novel genetic mouse system. Imaging, histological, and cell-level analyses were performed to investigate the progressive ossification of the posterior longitudinal ligament, Achilles tendons, and degeneration joints caused by Enpp1 deficiency. RESULTS: The results indicate that Enpp1 deficiency led to markedly progressive heterotopic ossification (HO), especially spine, and Achilles tendons, and was associated with progressive degeneration of the knees. The bone mass was decreased in the long bone. Furthermore, fibroblasts from Enpp1flox/flox/EIIa-Cre mice had greater osteogenic differentiation potential following induction by osteogenesis, accompanied by enhanced hedgehog (Hh) signaling. In addition, fibroblast cells show senescence, and aggravation of the senescence phenotype by further osteogenic induction. CONCLUSION: Our study indicated that with increasing age, mutations in Enpp1 promote ectopic ossification of spinal ligaments and endochondral ossification in tendons and further aggravate knee degeneration by upregulating hedgehog signaling.

Microwave-assisted extraction of bioactive components from Angelica dahurica using the tailor-made natural deep eutectic solvents.

In the present study, a new, green, efficient, and sustainable microwave-assisted extraction method combined with a deep eutectic solvent was successfully established for the extraction of five important coumarins from Angelica dahurica, namely bergapten, oxypeucedanin, imperatorin, cnidilin, and isoimperatorin. Compared with the conventional extraction method, the extraction efficiency of this method was improved by 10.74%. With increasingly serious global environmental pollution, this green method will be a solution for mainstream sustainable development and lead to a stable improvement in fine industries such as food, medicine, and cosmetics. The findings of this study may provide valuable clues and a scientific basis for further research of A. dahurica and other pharmaceutical components.

Potential of intraoperative ultrasonographic assessment of the spinal cord central echo complex in predicting postoperative neurological recovery of degenerative cervical myelopathy.

BACKGROUND AND PURPOSE: The spinal cord central echo complex (SCCEC) is a special ultrasonography-based intramedullary structure, but its clinical significance in degenerative cervical myelopathy (DCM) is undefined. This study aimed to explore the potential of the SCCEC in predicting postoperative neurological recovery in DCM. METHODS: Thirty-two DCM patients who underwent intraoperative ultrasonography-guided French-door laminoplasty were prospectively enrolled. The modified Japanese Orthopaedic Association (mJOA) score was evaluated preoperatively and 12 months postoperatively. SCCEC width (SCCEC-W), and anteroposterior diameter (APD) and transverse diameter (TD) of the spinal cord were measured on transverse ultrasonographic images, while the tissue widths from anterior and posterior borders of the spinal cord to the SCCEC were measured on sagittal ultrasonographic images. The APD of the spinal cord and occupying rate of the spinal canal were measured on preoperative magnetic resonance imaging (MRI). RESULTS: All patients achieved improvements in mJOA scores, with an average recovery rate (RR) of 68.69 ± 20.22%. Spearman correlation analysis revealed that SCCEC-W, and ratios between the SCCEC-W and APD/TD based on ultrasonography, correlated moderately with mJOA score RR, with coefficients of -0.527, -0.605 and -0.514, respectively. The ratio between SCCEC-W and ultrasonographic TD correlated moderately with preoperative APD of the spinal cord. The MRI measurements and ultrasonography-based tissue widths showed no significant correlation with mJOA score RR. CONCLUSIONS: The SCCEC may have predictive potential as an intraoperative indicator of neurological recovery in treating DCM. SCCEC-W may be related to spinal cord compression in DCM.

Comparative intra- and inter-observer reliability of two methods for evaluating intraoperative ultrasonography-based spinal cord hyperechogenicity intensity in degenerative cervical myelopathy.

OBJECTIVES: During French-door laminoplasty, a linear array transducer of IOUS was used to observe and record the spinal cord decompression. To acquire a higher-reliability method, and compare the in-observer and inter-observer reliability of two methods in evaluating the hyperechoic intensity of spinal cord ultrasound in degenerative cervical myelopathy (DCM). BACKGROUND: The intensity of spinal cord hyperechogenicity is considered as a potential predictor of neurological recovery in DCM after decompression, but the accuracy of gray value ratio (GVR) is affected by many factors. METHODS: Totally 28 patients (20 males and 8 females) who had been followed up for 12 months were included. Their mean age at surgery was 61.2 ± 10.8 years and the average symptom duration was 23.36 ± 22.11 months. The gray values of circles 1, 2 and 3 were recorded as Gcompression, Gnorml and Gsac, respectively. Circle 1 was drawn with the maximum brightness point within the spinal cord as the center, circle 2 with the same area was plotted on the spinal cord with uniform echogenicity, without compression and at least 1 cm away from the circle 1, and circle 3 was drawn on the dorsal dural sac at the same segment as circle 1. GVR was calculated as follows: GVR-A = Gcompression/Gnorml (method A), and GVR-B = Gcompression/Gsac (method B). The in-observer and inter-observer reliabilities of the two methods were compared. It is generally believed a reliability coefficient < 0.40 and > 0.75 indicate poor and good reliability respectively. The images-based GVR-B using this protocol demonstrates higher inter- and intraobserver reliabilities than GVR-A, and can be used as the basis for prognostic prediction and future studies. RESULTS: All examination acquisitions were successfully completed. GVR-A averaged 2.043 (0.318-5.56), and GVR-B averaged 0.578(0.06-1.41). GVR-B has better repeatability of gray value measurement, smaller relative standard deviation (RSD%) (0.298 vs. 0.32) and larger inter-group correlation coefficient compared with GVR-A. The mean value (MD) of the GVR difference calculated by GVR-B between the two clinicians was closer to 0. CONCLUSIONS: For DCM patients routinely using ultrasound for real-time cord visualization during spinal cord decompression by French-door laminoplasty, the images-based GVR-B using this protocol demonstrates better inter- and intraobserver reliabilities compared with GVR-A.

Overexpression of Rictor in the injured spinal cord promotes functional recovery in a rat model of spinal cord injury.

Rictor is an essential component that directly activates the mammalian target of rapamycin (mTOR) activity, which contributes to the intrinsic axon growth capacity of adult sensory neurons after injury. However, whether its action also applies to regeneration after spinal cord injury (SCI) remains unknown. In this study, rats were given spinal cord contusion at the T9-10 level to establish the SCI model and were subsequently treated with intraspinal cord injection of a Rictor overexpression lentiviral vector to locally upregulate the Rictor expression in the injured spinal cord. Thereafter, we investigated the therapeutic effects of Rictor overexpression in the injured spinal cords of SCI rats. Rictor overexpression not only significantly attenuated the acute inflammatory response and cell death after SCI but also markedly increased the shift in macrophages around the lesion from the M1 to M2 phenotype compared to those of the control lentiviral vector injection-treated group. Furthermore, Rictor overexpression dramatically increased neurogenesis in the lesion epicenter, subsequently promoting the tissue repair and functional recovery in SCI rats. Interestingly, the mechanism underlying the beneficial effects of Rictor overexpression on SCI may be associated with the Rictor overexpression playing a role in the anti-inflammatory response and driving macrophage polarization toward the M2 phenotype, which benefits resident neuronal and oligodendrocyte survival. Our findings demonstrate that Rictor is an effective target that affects the generation of molecules that inhibit spinal cord regeneration. In conclusion, localized Rictor overexpression represents a promising potential strategy for the repair of SCI.

Inadequate spinal cord expansion in intraoperative ultrasound after decompression may predict neurological recovery of degenerative cervical myelopathy.

OBJECTIVE: To compare the neurological recovery between patients with adequate and inadequate immediate spinal cord expansion after sufficient decompression in degenerative cervical myelopathy (DCM). METHODS: Twenty-seven patients subjected to French-door laminoplasty underwent the guidance of intraoperative ultrasound (IOUS) and were prospectively included. The modified Japanese Orthopedic Association (mJOA) score was evaluated before surgery and at 12 months postoperatively. The maximum spinal cord compression (MSCC) after sufficient decompression was calculated on the IOUS image; patients were divided into adequate (MSCC ≥ 0.95) and inadequate (MSCC < 0.95) expansion groups according to the MSCC. The mJOA score, spinal cord hyperechogenicity, age at surgery, symptom duration, occupational rate of the spinal canal, and the minimum anteroposterior diameter of the spinal cord between the two groups were compared. RESULTS: Initially, 2 cases showed residual compression on IOUS; after further decompression, all patients acquired sufficient decompression. All patients achieved improvements in mJOA scores with an average recovery rate of 68.6 ± 20.3%. The recovery rate of the mJOA score of the inadequate expansion group was significantly inferior to that of the adequate expansion group (59.2 ± 21.7% versus 76.2 ± 16.2%, p = 0.028). The spinal cord hyperechogenicity was more common in the inadequate expansion group, while the spinal cord anteroposterior diameter of the inadequate expansion group was significantly smaller than that of the adequate expansion group. CONCLUSIONS: The application of IOUS in French-door laminoplasty could help to confirm sufficient decompression for the treatment of DCM. Inadequate spinal cord expansion after sufficient decompression had the high possibility of predicting less satisfactory neurological recovery of DCM. KEY POINTS: • The intraoperative ultrasound revealed that not all degenerative cervical myelopathy patients acquired adequate spinal cord expansion after sufficient decompression. • Patients who failed to acquire adequate spinal cord expansion commonly combined with spinal cord hyperechogenicity and trended to achieve less satisfactory neurological recovery after surgical decompression. • Inadequate spinal cord expansion after sufficient decompression had the high possibility of predicting less satisfactory neurological recovery of patients with degenerative cervical myelopathy.

Effect of teriparatide on ligamentum flavum mesenchymal stem cells isolated from patients with ossification of the posterior longitudinal ligament.

Ossification of the posterior longitudinal ligament (OPLL) within the spinal canal sometimes leads to severe myelopathy. Teriparatide (TPD) is a recombinant human parathyroid hormone (PTH) (1-34), which promotes osteogenesis of mesenchymal stem cells (MSCs) via PTH 1 receptor (PTH1R). Although ligamentum flavum (LF)-MSCs from patients with OPLL have a high osteogenic potency, the effect of TPD on them remains unknown. In this study, we determined PTH1R expression in LF-MSCs from patients with OPLL and investigated whether TPD promotes osteogenic differentiation in them. First, LF-MSCs were isolated from patients with OPLL and cervical spondylotic myelopathy (CSM) (controls). Cultured LF-MSCs were treated with different concentrations of TPD on days 0, 7, and 14. On day 21, osteogenic gene expression was quantified. Mineralization was measured based on optical density after Alizarin Red S staining. LF-MSCs from both groups expressed PTH1R at the same level. TPD did not enhance osteogenic gene expression and mineralization in LF-MSCs from both groups. TPD did not promote the osteogenic differentiation of LF-MSCs from patients with OPLL. Thus, it may be safe for patients with OPLL. However, further confirmation of our results with in vivo studies is necessary.

Short-term predictive potential of quantitative assessment of spinal cord impairment in patients undergoing French-door Laminoplasty for degenerative cervical myelopathy: preliminary results of an exploratory study exploiting intraoperative ultrasound data.

BACKGROUND: To study the correlation of neurological function in degenerative cervical myelopathy (DCM) patients with quantitative assessment of spinal cord compression and impairment by intraoperative ultrasound imaging (IOUSI). METHODS: Twenty-three patients who underwent French-Door laminoplasty for multilevel DCM were followed for 6 months. Modified Japanese Orthopaedic Association (mJOA) score and cervical MRI were assessed before surgery and at postoperative 6 months. IOUS, used to guide decompression, were recorded. The anteroposterior diameter (APD) and the gray values of the IOUSI hyperechogenicity of the midsagittal IOUSI at the narrowest level and at the lesion-free level, and the APD and traverse diameter at the traverse maximum compression level of IOUSI were measured. Maximum spinal cord compression (MSCC), compression rate (CR), and IOUSI gray value ratio (Rgray) were calculated. The appearance of preoperative T2W MRI increased signal intensity (ISI), and the signal change rate (SCR) on postoperative T2W MRI of 9 patients were also measured and calculated, and compared with that of IOUSI hyperechogenicity. RESULTS: Average mJOA score increased significantly from 11.57 ± 2.67 before surgery to 15.39 ± 1.50 at 6 months after surgery, with an average recovery rate (RR) of 71.11 ± 22.81%. The difference between the appearance of preoperative T2W MRI ISI and IOUSI hyperechogenicity was not significant. Spearman correlation analysis found that the IOUSI Rgray were negatively correlated with the RR of mJOA score with a coefficient of - 0.77, and the IOUSI Rgray was not correlated with the postoperative MRI SCR. CONCLUSIONS: In DCM patients, the gray values of IOUSI can be measured accurately. The IOUSI Rgray correlated with postoperative neurological recovery significantly.

Biomechanical evaluation of monosegmental pedicle instrumentation in a calf spine model and the role of fractured vertebrae in screw stability.

BACKGROUND: Monsegmental pedicle instrumentation (MSPI) has been used to treat thoracolumbar fractures. However, there are few reports about the biomechanical characteristics of MSPI compared with traditional short-segment pedicle instrumentation (SSPI) in management of unstable thoracolumbar fractures, and the influence of vertebral fracture on screw stability is still unclear. METHODS: This study was to compare the immediate stability between MSPI and SSPI in management of unstable L1 fracture, and to evaluate the role of fractured vertebrae in screw stability. Two studies were performed: in the first study, sixteen fresh calf spines (T11-L3) were divided into two groups, in which unstable fractures at L1 were produced and then instrumented with MSPI or SSPI respectively. The range of motion (ROM) and lax zone (LZ) of specimens were evaluated with pure moment of 6 Nm loaded. The second study measured and compared the pullout strength of screws inserted in to 16 intact and fractured vertebrae of calf spines (L1-3) respectively. The correlation of pullout strength with load sharing classification (LSC) of fractured vertebrae was analyzed. RESULTS: No significant difference in the ROM and LZ of the destabilized segments after fixation between MSPI and SSPI, except in axial rotation of ROM (P < 0.05). After fatigue cyclic loading, the MSPI showed a significant increase of ROM during lateral bending and axial rotation (P < 0.05); however, there were no significant differences in the LZ during all loading models between groups (P > 0.05). The mean pullout strength of pedicle screws in fractured vertebrae decreased by 13.7%, compared with that of intact vertebrae (P > 0.05), and had a low correlation with LSC of the fractured vertebrae (r = 0.293, P > 0.05). CONCLUSIONS: MSPI can provide effective immediate stability for management of unstable thoracolumbar fractures; however, it has less fatigue resistance during lateral bending and axial rotation compared with SSPI. LSC score of fractured vertebrae is not a major influence on the pullout strength of screws.

Improving Hybrid Tin Halide Films of Lead-Free Perovskite Solar Cells with a Volatile Additive of Dipropyl Sulfide.

Lead-free perovskite solar cells with hybrid tin halides (Sn-PVKs) as harvesters have attracted attention with respect to eliminating the contamination of conventional hybrid lead halides. However, Sn-PVK films usually have inferior performance due to rapid crystallization and uncontrollable morphology. Moreover, Sn2+ ions suffer from irreversible oxidation that results in self-doping and device instability. Additive engineering is a key strategy for improving the quality of Sn-PVK films, but solid residues of additives could degrade the transport-recombination process. In this work, dipropyl sulfide (DPS) was introduced as a volatile additive into the precursor solution, and no residue exists in the Sn-PVK films after thermal annealing. The coordinating ability of DPS molecules stabilized Sn2+ ions to form the intermediate complex, which retards the crystallization and oxidation of Sn-PVK films. Consequently, the power conversion efficiencies of devices increase from 11.0% to 12.9% with less recombination and a lower leakage current, and the stability of the devices is improved simultaneously.

Excellent Hole Mobility and Out-of-Plane Piezoelectricity in X-Penta-Graphene (X = Si or Ge) with Poisson's Ratio Inversion.

Recently, the application of two-dimensional (2D) piezoelectric materials has been seriously hindered because most of them possess only in-plane piezoelectricity but lack out-of-plane piezoelectricity. In this work, using first-principles calculation, by atomic substitution of penta-graphene (PG) with tiny out-of-plane piezoelectricity, we design and predict stable 2D X-PG (X = Si or Ge) semiconductors with excellent in-plane and out-of-plane piezoelectricity and extremely high in-plane hole mobility. Among them, Ge-PG exhibits better performance in all aspects with an in-plane strain piezoelectric coefficient d11 = 8.43 pm/V, an out-of-plane strain piezoelectric coefficient d33 = -3.63 pm/V, and in-plane hole mobility µh = 57.33 × 103 cm2 V-1 s-1. By doping Si and Ge atoms, the negative Poisson's ratio of PG approaches zero and reaches a positive value, which is due to the gradual weakening of the structure's mechanical strength. The bandgaps of Si-PG (0.78 eV) and Ge-PG (0.89 eV) are much smaller than that of PG (2.20 eV), by 2.82 and 2.47 times, respectively. This indicates that the substitution of X atoms can regulate the bandgap of PG. Importantly, the physical mechanism of the out-of-plane piezoelectricity of these monolayers is revealed. The super-dipole-moment effect proposed in the previous work is proved to exist in PG and X-PG, i.e., it is proved that their out-of-plane piezoelectric stress coefficient e33 increases with the super-dipole-moment. The e33-induced polarization direction is also consistent with the super-dipole-moment direction. X-PG is predicted to have prominent potential for nanodevices applied as electromechanical coupling systems: wearable, ultra-thin devices; high-speed electronic transmission devices; and so on.

Improving Hybrid Tin Halide Films by Tin Trifluoromethanesulfonate for Lead-Free Perovskite Solar Cells.

Tin-based perovskite solar cells (Sn-PSCs) without toxic lead ions outperform other types of lead-free PSCs in terms of photovoltaic performance. To avoid the oxidation of Sn2+ cations and the formation of vacancy defects, most reports involve the addition of SnF2 to the perovskite precursor solution, but hybrid tin halide (Sn-PVK) films still suffer from poor crystallinity and stability. In this work, we used an alternative additive of tin trifluoromethanesulfonate (Sn(OTF)2). Compared to SnF2, the solubility of Sn(OTF)2 in the precursor solution is greatly improved, and the crystal nucleation process is delayed, resulting in the enhancement of crystal growth. The coordination ability of the OTF- anions suppresses the oxidation of Sn2+ cations, which promotes the stability of Sn-PVK films. By replacing the conventional additive of SnF2 with Sn(OTF)2, the device achieves an increase in power conversion efficiency from 7.96% to 10.3%, while the stability of the devices is improved simultaneously.

Development of a mouse model of chronic ventral spinal cord compression: Neurobehavioral, radiological, and pathological changes.

Objectives: The main objective of this study was to establish a mouse model of spinal ligament ossification to simulate the chronic spinal cord compression observed in patients with ossification of the posterior longitudinal ligament (OPLL). The study also aimed to examine the mice's neurobiological, radiological, and pathological changes. Methods: In the previous study, a genetically modified mouse strain was created using Crispr-Cas9 technology, namely, Enpp1 flox/flox /EIIa-Cre (C57/B6 background), to establish the OPLL model. Wild-type (WT) mice without compression were used as controls. Functional deficits were evaluated through motor score assessment, inclined plate testing, and gait analysis. The extent of compression was determined using CT imaging. Hematoxylin and eosin staining, luxol fast blue staining, TUNEL assay, immunofluorescence staining, qPCR, and Western blotting were performed to evaluate levels of apoptosis, inflammation, vascularization, and demyelination in the study. Results: The results demonstrated a gradual deterioration of compression in the Enpp1 flox/flox /EIIa-Cre mice group as they aged. The progression rate was more rapid between 12 and 20 weeks, followed by a gradual stabilization between 20 and 28 weeks. The scores for spinal cord function and strength, assessed using the Basso Mouse Scale and inclined plate test, showed a significant decline. Gait analysis revealed a noticeable reduction in fore and hind stride lengths, stride width, and toe spread. Chronic spinal cord compression resulted in neuronal damage and activated astrocytes and microglia in the gray matter and anterior horn. Progressive posterior cervical compression impeded blood supply, leading to inflammation and Fas-mediated neuronal apoptosis. The activation of Bcl2 and Caspase 3 was associated with the development of progressive neurological deficits (p < 0.05). Conclusions: The study presents a validated model of chronic spinal cord compression, enabling researchers to explore clinically relevant therapeutic approaches for OPLL.

Inhibition of Neural Stem Cell Necroptosis Mediated by RIPK1/MLKL Promotes Functional Recovery After SCI.

Endogenous neural stem cells (eNSCs) are a new therapeutic strategy for the noninvasive repair of spinal cord injury (SCI). Necroptosis is a necrosome-dependent cell death process that serves as a significant regulatory mechanism in SCI. Current research shows that neurons, oligodendrocytes, and astrocytes all undergo necroptosis after SCI. However, it is unclear whether eNSCs are associated with necroptosis after SCI. By performing immunofluorescence analysis, we found that eNSCs undergo necroptosis during spinal cord injury repair in mice. Our present work demonstrates that receptor-interacting protein kinase 1 (RIPK1)/mixed lineage kinase domain-like protein (MLKL) are involved in necroptosis pathway in SCI mice. In vitro, the necroptosis induced by TNF-α/Smac-mimetic/Z-VAD-FMK (TSZ) treatment regulates phenotype of NSCs. In detail, the proliferative capacity of NSCs was significantly decreased in the presence of continual TSZ treatment, and the transcription of proinflammatory genes was upregulated, while the transcription of neurotrophic factors was inhibited. NSCs exhibited an obvious tendency to differentiate into glial cells under short-duration TSZ stimulation (6 h and 12 h); as the stimulus duration increased (24 h), the differentiation ability of the NSCs was significantly inhibited. These phenotypic changes are not conducive to neural cell survival and neural repair. Moreover, we examined the effect of necroptosis inhibitors on TSZ-treated NSCs. Necrostatin-1 and necrosulfonamide significantly reduced the necroptosis of NSCs after TSZ treatment and improved the phenotypic function of NSCs under TSZ stimulation. In additional in vivo experiments, after 2 weeks of administration, the necroptosis inhibitors reduced the necroptosis of NSCs and improved functional recovery in SCI mice. Taken together, these data indicate that the inhibition of NSC necroptosis with necroptosis inhibitors facilitates survival and phenotype maintenance in vitro and contributes to neuroprotection and repair in vivo. Our findings suggest that blocking necroptosis of eNSCs may be a potential therapeutic strategy for treating SCI.

Efficacy and safety of novel biologics in the treatment of lupus nephritis based on registered clinical trials: a systematic review and network meta-analysis.

To compare the clinical effectiveness and safety of novel biologics for the treatment of lupus nephritis based on a reticulated meta-analysis approach. Registered clinical trials in 4 major databases (PubMed, Embase, Web of Science, The Cochrane Register of Clinical Trials) and ClinicalTrials.gov were systematically searched with a search time frame of build to June 2022. And we screened registered randomized controlled clinical trials of biologics for the treatment of lupus nephritis according to the protocol's nadir criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 and Review Manager 5.3 software to compare and rank differences in effectiveness and safety between the biologics. A total of 10 registered randomized controlled clinical trials involving 2148 subjects were included in this study. The interventions were ranked from best to worst in terms of the primary outcome indicator of effectiveness, renal complete remission: belimumab > anifrolumab (900 + 300) mg > obinutuzumab > ocrelizumab 400 mg > abatacept 30/10 mg/kg > belimumab + rituximab > abatacept 10/10 mg/kg > abatacept (30/10 + 10/10) mg/kg > placeo > ocrelizumab 1000 mg > rituximab > anifrolumab 300 mg, belimumab was superior to placebo [OR = 1.75, 95% CI (1.13, 2.70)] and anifrolumab 300 mg [OR = 3.27, 95% CI (1.05, 10.14)], anifrolumab (900 + 300) mg was superior to anifrolumab 300 mg [OR = 3.56, 95% CI (1.30, 9.76)], and all were statistically significant. The ranking of each intervention in terms of overall renal remission for secondary outcome indicators from best to worst was: obinutuzumab > belimumab + rituximab > anifrolumab (900 + 300) mg > ocrelizumab 1000 mg > ocrelizumab 400 mg > belimumab > rituximab 1000 mg > abatacept 30/10 mg/kg > abatacept (30/10 + 10/10) mg/kg > placeo > abatacept 10/10 mg/kg > anifrolumab 300 mg, obinutuzumab was superior to placebo [OR = 2.27, 95% CI (1.11, 4.67)] and belimumab was also superior to placebo [OR = 1.56, 95% CI (1.07, 2.27)], and all were statistically significant. In terms of safety, with a focus on serious adverse events and serious infections, the results were: Serious adverse events at 1 year of monitoring occurred better with ocrelizumab 1000 mg than ocrelizumab 400 mg [OR = 0.51, 95% CI (0.29, 0.89)] and were statistically different; serious adverse events at 2 years of monitoring infection adverse events occurred better with obinutuzumab than with abatacept (30/10 + 10/10) mg/kg [OR = 0.24, 95% CI (0.07, 0.81)] and were statistically different. The safety of the new biologics in combination with conventional standard therapies is generally good, but it is belimumab and obinutuzumab that are most effective in achieving complete and overall remission in the kidney. This study protocol has been registered with PROSPERO, with a registration number of CRD42021262498.

Inhibiting tau protein improves the recovery of spinal cord injury in rats by alleviating neuroinflammation and oxidative stress.

After spinal cord injury, the concentrations of total and hyperphosphorylated tau in cerebrospinal fluid increase, and levels of both correlate with injury severity. Tau inhibition is considered effective therapy for many central nervous system diseases, including traumatic brain injury and Alzheimer's disease. However, whether it can play a role in the treatment of spinal cord injury remains unclear. In this study, the therapeutic effects of tau inhibition were investigated in a rat model of transection spinal cord injury by injecting the rats with a lentivirus encoding tau siRNA that inhibits tau expression. We found that tau inhibition after spinal cord injury down-regulated the levels of inflammatory mediators, including tumor necrosis factor-α, interleukin-6 and interleukin-1ß. It also led to a shift of activated microglial polarization from the M1 pro-inflammatory phenotype to the M2 anti-inflammatory phenotype, and reduced the amount of reactive oxygen species in the acute phase. Furthermore, the survival of residual neural cells around the injury epicenter, and neuronal and axonal regeneration were also markedly enhanced, which promoted locomotor recovery in the model rats. Collectively, our findings support the conclusion that tau inhibition can attenuate neuroinflammation, alleviate oxidative stress, protect residual cells, facilitate neurogenesis, and improve the functional recovery after spinal cord injury, and thus suggest that tau could be a good molecular target for spinal cord injury therapy.

Identification of immunodiagnostic blood biomarkers associated with spinal cord injury severity.

Blood always shows some immune changes after spinal cord injury (SCI), and detection of such changes in blood may be helpful for diagnosis and treatment of SCI. However, studies to date on blood immune changes after SCI in humans are not comprehensive. Therefore, to obtain the characteristics of blood immune changes and immunodiagnostic blood biomarkers of SCI and its different grades, a human blood transcriptome sequencing dataset was downloaded and analyzed to obtain differentially expressed immune-related genes (DEIGs), related functions and signaling pathways related to SCI and its various grades. Characteristic biomarkers of SCI and its different grades were identified by using weighted gene coexpression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) logistic regression. Expression of biomarkers was verified through experiments. The area under the curve (AUC) of biomarkers was calculated to evaluate their diagnostic value, and differences in immune cell content were examined. In this study, 17 kinds of immune cells with different contents between the SCI group and healthy control (HC) group were identified, with 7 immune cell types being significantly increased. Differences in the content of immune cells between different grades of SCI and the HC group were also discovered. DEIGs were identified, with alteration in some immune-related signaling pathways, vascular endothelial growth factor signaling pathways, and axon guidance signaling pathways. The SCI biomarkers identified and those of American Spinal Injury Society Impairment Scale (AIS) A and AIS D of SCI have certain diagnostic sensitivity. Analysis of the correlation of immune cells and biomarkers showed that biomarkers of SCI, AIS A grade and AIS D grade correlated positively or negatively with some immune cells. CKLF, EDNRB, FCER1G, SORT1, and TNFSF13B can be used as immune biomarkers for SCI. Additionally, GDF11and HSPA1L can be used as biomarkers of SCI AIS A grade; PRKCA and CMTM2 can be used as biomarkers of the SCI AIS D grade. Detecting expression of these putative biomarkers and changes in related immune cells may be helpful for predicting the severity of SCI.

Increased blood flow of spinal cord lesion after decompression improves neurological recovery of degenerative cervical myelopathy: an intraoperative ultrasonography-based prospective cohort study.

INTRODUCTION: Surgical decompression is a highly effective therapy for degenerative cervical myelopathy (DCM), but the mechanisms of neurological recovery following decompression remain unclear. This study aimed to evaluate the spinal cord blood flow status after sufficient decompression by intraoperative contrast-enhanced ultrasonography (CEUS) and to analyze the correlation between neurological recovery and postdecompressive spinal cord blood perfusion in DCM. MATERIALS AND METHODS: Patients with multilevel DCM were treated by ultrasound-guided modified French-door laminoplasty using a self-developed rongeur. Neurological function was evaluated using the modified Japanese Orthopaedic Association (mJOA) score preoperatively and at 12 months postoperatively. Spinal cord compression and cervical canal enlargement before and after surgery were assessed by magnetic resonance imaging and computerized tomography. The decompression status was evaluated in real time by intraoperative ultrasonography, while the spinal cord blood flow after sufficient decompression was assessed by CEUS. Patients were categorized as favourable (≥50%) or unfavourable (<50%) recovery according to the recovery rate of the mJOA score at 12 months postoperatively. RESULTS: Twenty-nine patients were included in the study. The mJOA scores were significantly improved in all patients from 11.2±2.1 preoperatively to 15.0±1.1 at 12 months postoperatively, with an average recovery rate of 64.9±16.2%. Computerized tomography and intraoperative ultrasonography confirmed adequate enlargement of the cervical canal and sufficient decompression of the spinal cord, respectively. CEUS revealed that patients with favourable neurological recovery had a greater increased blood flow signal in the compressive spinal cord segment after decompression. CONCLUSIONS: In DCM, intraoperative CEUS can clearly reflect spinal cord blood flow. Patients with increased blood perfusion of the spinal cord lesion immediately after surgical decompression tended to achieve greater neurological recovery.

Identification of novel gene signatures and immune cell infiltration in intervertebral disc degeneration using bioinformatics analysis.

Background: Intervertebral disc degeneration (IDD) is the leading cause of lower back pain, and an overall understanding of the molecular mechanisms related to IDD is still lacking. The purpose of this study was to explore gene signatures and immune cell infiltration related to IDD via bioinformatics analysis. Methods: A total of five expression profiles of mRNA and non-coding RNA were downloaded from the Gene Expression Omnibus (GEO) database. The potentially involved lncRNA/circRNA-miRNA-mRNA networks and protein-protein interaction networks were constructed by miRNet, circBank, STRING, and the Cytoscape database. Gene ontology, Kyoto Encyclopaedia of Genes and Genomes Analysis, Gene Set Enrichment Analysis, Gene Set Variation Analysis, Immune Infiltration Analysis, and Drug-Gene Interaction were used to analyse the top 20 hub genes. RT-qPCR was conducted to confirm the 12 differential expressions of genes both in the nucleus pulposus and annulus fibrosus tissues Results: There were 346 differentially expressed mRNAs, 12 differentially expressed miRNAs, 883 differentially expressed lncRNAs, and 916 differentially expressed circRNAs in the GEO database. Functional and enrichment analyses revealed hub genes associated with platelet activation, immune responses, focal adhesion, and PI3K-Akt signalling. The apoptotic pathway, the reactive oxygen species pathway, and oxidative phosphorylation play an essential role in IDD. Immune infiltration analysis demonstrated that the Treg cells had significant infiltration, and three levels of immune cells, including dendritic cells, Th2 cells, and tumour-infiltrating lymphocytes, were inhibited in IDD. Drug-gene interaction analysis showed that COL1A1 and COL1A2 were targeted by collagenase clostridium histolyticum, ocriplasmin, and PDGFRA was targeted by 66 drugs or molecular compounds. Finally, 24 cases of IDD tissues and 12 cases of normal disc tissues were collected, and the results of RT-qPCR were consistent with the bioinformatics results. Conclusion: Our data indicated that the 20 hub genes and immune cell infiltration were involved in the pathological process of IDD. In addition, the PDGFRA and two potential drugs were found to be significant in IDD development.