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Non-human primates are most suitable for generating cervical experimental models, and it is necessary to study the anatomy of the cervical spine in non-human primates when generating the models. The purpose of this study was to provide the anatomical parameters of the cervical spine and spinal cord in long-tailed macaques (Macaca fascicularis) as a basis for cervical spine-related experimental studies. Cervical spine specimens from 8 male adult subjects were scanned by micro-computed tomography, and an additional 10 live male subjects were scanned by magnetic resonance imaging. The measurements and parameters from them were compared to those of 12 male adult human subjects. Additionally, 10 live male subjects were scanned by magnetic resonance imaging, and the width and depth of the spinal cord and spinal canal and the thickness of the anterior and posterior cerebrospinal fluid were measured and compared to the relevant parameters of 10 male adult human subjects. The tendency of cervical parameters to change with segmental changes was similar between species. The vertebral body, spinal canal, and spinal cord were significantly flatter in the human subjects than in the long-tailed macaques. The cerebrospinal fluid space in the long-tailed macaques was smaller than that in the human subjects. The anatomical features of the cervical vertebrae of long-tailed macaques provide a reference for establishing a preclinical model of cervical spinal cord injury.

Ketogenic diet (KD) has been shown to be beneficial in a range of neurological disorders, with ketone metabolite β-hydroxybutyrate (βOHB) reported to block the nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in bone marrow-derived macrophages. In this study, we show that pretreatment with KD or in situ βOHB suppressed macrophages/microglia activation and the overproduction of inflammatory cytokines, while KD downregulated the expression of NLRP3 inflammasome. Moreover, KD promoted macrophages/microglia transformation from the M1 phenotype to the M2a phenotype following spinal cord injury (SCI) in the in vivo study. Rats in the KD group demonstrated improved behavioral and electrophysiological recovery after SCI when compared to those rats in the standard diet group. The in vitro study performed on BV2 cells indicated that βOHB inhibited an LPS+ATP-induced inflammatory response and decreased NLRP3 protein levels. Our data demonstrated that pretreatment with KD attenuated neuroinflammation following SCI, probably by inhibiting NLRP3 inflammasome and shifting the activation state of macrophages/microglia from the M1 to the M2a phenotype. Therefore, the ketone metabolite βOHB might provide a potential future therapeutic strategy for SCI.

Non-human primate (NHP) spinal cord injury (SCI) models can be informative in the evaluation of treatments that show promise in rodent models prior to translation to humans. In the present study, w...

To investigate the clinical characteristics of Bechet’s disease (BD) with respect to gender and age in China. Clinical data of 489 BD patients admitted to Peking Union Medical College Hospital (PUMCH) and registered by the BD registry database established by PUMCH from March 2014 to January 2019 were collected and analyzed in this study. Demographics, medical histories, clinical manifestations, laboratory test results, imaging findings, assessment of disease activity, treatment regimen, as well as the outcomes were reviewed. A total of 489 BD patients were included in this study, among them 286 males (58.5%) and 203 females (41.5%) with a male-to-female ratio of 1.41 and a median age of 34 years (interquartile range 28–44 years old). The results revealed that ocular lesions (P = 0.005), vascular lesions(P

The aim was to investigate the effectiveness of colour duplex ultrasound (CDU) plus contrast enhanced ultrasound (CEUS) vs. computed tomography angiography (CTA) for surveillance in patients with isolated mesenteric artery dissection (IMAD).Patients who underwent CDU, CEUS, and CTA for surveillance of IMAD between January 2012 and May 2019 were included in the study. The accuracy of CDU, CEUS, and CTA for determining the morphological characteristics of IMAD was analysed.A total of 42 patients undergoing 76 total imaging examinations during follow up were included. Both CTA and CDU plus CEUS demonstrated the thrombosed false lumen for 28 (36.8%) examinations and the dissecting aneurysm for 20 (26.3%) examinations (both κ = 1.0). The diameter of the dissecting aneurysm was 5.03 ± 1.25 mm using CDU and CEUS vs. 5.27 ± 1.23 mm on CTA (coefficient of consistency, 0.997; p .001). The entry points were visualised by CDU and CEUS for 20 (26.3%) examinations and by CTA for 14 (18.4%) examinations (κ = 0.769); no re-entry points were visualised by CDU and CEUS for any examinations but re-entry points were visualised by CTA for two (2.6%) examinations. The minimum inner diameter was 2.80 ± 1.30 mm on CDU and CEUS vs. 2.52 ± 1.29 mm on CTA (coefficient of consistency, 0.999; p .001). The peak systolic velocities were 128.2 ± 13.0 cm/s at diagnosis and 98.7 ± 4.9 cm/s after one month (p .001).The combination of CDU and CEUS can be used in place of CTA for the surveillance of IMAD.

Systemic vasculitis is diverse group of autoimmune disorders which are characterized by inflammation of blood vessel walls with deep aching and burning pain. Their underlying etiology and pathophysiology still remain poorly understood. Extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, are membrane vesicular structures that are released either during cell activation, or when cells undergo programmed cell death, including apoptosis, necroptosis, and pyroptosis. Although EVs were thought as cell dusts, but now they have been found to be potently active since they harbor bioactive molecules, such as proteins, lipids, nucleic acids, or multi-molecular complexes. EVs can serve as novel mediators for cell-to-cell communications by delivery bioactive molecules from their parental cells to the recipient cells. Earlier studies mainly focused on MVs budding from membrane surface. Recent studies demonstrated that EVs may also carry molecules from cytoplasm or even from nucleus of their parental cells, and these EVs may carry autoantigens and are important in vasculitis. EVs may play important roles in vasculitis through their potential pathogenic involvements in inflammation, autoimmune responses, procoagulation, endothelial dysfunction/damage, angiogenesis, and intimal hyperplasia. EVs have also been used as specific biomarkers for diagnostic use or disease severity monitoring. In this review, we have focused on the aspects of EV biology most relevant to the pathogenesis of vasculitis, discussed their perspective insights, and summarized the exist literature on EV relevant studies in vasculitis, therefore provides an integration of current knowledge regarding the novel role of EVs in systemic vasculitis.

The angioarchitecture of the spinal cord and microvascular changes after acute and subacute spinal cord injury (SCI) have been reported in rodents. Microvascular changes after chronic SCI have not been explored. We characterized three-dimensional microvascular changes during the chronic phase of cervical hemicontusion SCI in rats.At 12 weeks after 1.2-mm hemicontusion injury, microvascular parameters, including vascular volume, ratio of vascular volume to tissue volume, vascular number, and vascular separation, were measured at the epicenter and each cord segment, and the percentage and volume of spinal vessels with different diameters were measured by micro computed tomography at the injury segment.The 1.2-mm hemicontusion injury applied a compressive force of 1.050 ± 0.103 N to the cord, resulting in a cavity and a significant decrease in microvasculature at the epicenter. The vascular volume, ratio of vascular volume to tissue volume, and vascular number of the C5 cord decreased by 40%, 38%, and 36% at 12 weeks after SCI, whereas vascular separation increased by 54% compared with the control group. In the chronic phase after SCI, the percentage and volume of spinal microvessels at the contusion segment decreased significantly (especially vessels with diameters40 μm).Blood supply to the cervical spinal cord is insufficient during the chronic phase of cervical hemicontusion SCI, especially in microvessels with diameters40 μm. These results may provide a basis to explore microvascular changes of SCI during the chronic phase.

A ketogenic diet (KD) is composed of low-carbohydrate, high-fat and adequate levels of protein. It has been used for decades as a method to treat pediatric refractory epilepsy. However, recently, its side effects on the bones have received increasing attention. In order to comprehensively evaluate the effect of KD on the microstructures and mechanical properties of the skeleton, 14 male Sprague-Dawley rats were equally divided into two groups and fed with a KD (ratio of fat to carbohydrate and protein, 3:1) or a standard diet for 12 weeks. Body weight, as well as blood ketone and glucose levels, were monitored during the experiment. Bone morphometric analyses via micro-computerized tomography were performed on cortical and trabecular bone at the middle L4 vertebral body, the proximal humerus and tibia. The compressive stiffness and strength of scanned skeletal areas were calculated using micro-finite element analysis. The KD led to higher ketone levels and lower glucose levels, with reduced body weight and total bone mineral density (TBMD). After 12 weeks, the diet reduced the bone volume fraction, the trabecular number of cancellous bone, cortical thickness, total cross-sectional area inside the periosteal envelope and the bone area of cortical bone in the tibia and humerus, while increasing trabecular separation. However, KD may not affect the L4 vertebral body. The serum calcium or phosphate concentrations in the blood remained unchanged. In addition, bone stiffness and strength were clearly decreased by the KD, and significantly correlated with the BMD and bone area at all scanned sites. In conclusion, KD led to significant bone loss and reduced biomechanical function in appendicular bones, with a lesser impact on axial bones.

Ketogenic diet (KD) has been used in epilepsy for decades, but previous studies found it may cause severe bone loss. Every-other-day ketogenic diet (EODKD), the combination of KD with intermittent fasting, showed better potential for seizure control recently, while its effects on bone remain unknown. This study aims to establish different ketogenic rat models and compare the influence of EODKD with KD on bone microstructure and metabolism. Thirty male Sprague-Dawley rats were divided into Control, KD and EODKD groups, fed with standard diet, continuous and intermittent ketogenic diet respectively. After 12 weeks, bone mineral density (BMD) and body fat percentage were obtained by dual energy X-ray absorptiometry. Micro-CT and three-point bending test were used to evaluate the bone microstructure and mechanical properties. Activities of serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) were measured, together with the osteogenic capabilities of bone marrow stromal cells (BMSCs) tested by ALP activities and alizarin red stain in different osteogenic stage. Both EODKD and KD induced higher ketone and more fat percentage, but led to lower body weight compared with Control group. They both compromised bone mass and mechanical properties. Compared with KD, EODKD demonstrated higher ketone levels, but it also inhibited osteoclastic process as well as early osteogenic differentiation. In general, EODKD accelerated ketosis, but may not deteriorate bone microstructure and strength than KD.

Systemic vasculitis is a heterogeneous group of multisystem autoimmune disorders characterized by inflammation of blood vessels. Although many progresses in diagnosis and immunotherapies have been achieved over the past decades, there are still many unanswered questions about vasculitis from pathological understanding to more advanced therapeutics. Extracellular vesicles (EVs) are double-layer phospholipid membrane vesicles harboring various cargoes. EVs can be classified into exosomes, microvesicles (MVs), and apoptotic bodies depending on their size and origin of cellular compartment. EVs can be released by almost all cell types and may be involved in physical and pathological processes including, inflammation and autoimmune responses. In systemic vasculitis, EVs may have pathogenic involvement in inflammation, autoimmune responses, thrombosis, endothelium injury, angiogenesis and intimal hyperplasia. EV-associated redox reaction may also be involved in vasculitis pathogenesis by inducing inflammation, endothelial injury and thrombosis. Additionally, EVs may serve as specific biomarkers for diagnosis or monitoring of disease activity and therapeutic efficacy, i.e. AAV-associated renal involvement. In this review, we have discussed the recent advances of EVs, especially their roles in pathogenesis and clinical involvements in vasculitis.

The significance of the microbiota-gut-brain axis has been increasingly recognized as a major modulator of autoimmunity. Here, we aim to characterize the gut microbiota of a large cohort of treatment-naïve anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis patients relative to that of healthy controls (HCs). Relative to HCs, anti-NMDAR encephalitis patients had a decreased microbiome alpha-diversity index, marked disturbances of gut microbial composition and intestinal permeability damage. Disturbed microbiota in anti-NMDAR encephalitis patients might be linked with different clinical characteristics. Imputed KEGG analysis revealed perturbations of functional modules in the gut microbiomes of anti-NMDAR encephalitis. Compared to HCs, microbiota-depleted mice receiving fecal microbiota transplantation (FMT) from anti-NMDAR encephalitis patients had hypersensitivity and cognitive impairment. Furthermore, anti-NMDAR encephalitis FMT mice showed altered T cells in the spleen and small intestine lamina propria with an increased Th17 cells. Overall, this study first suggests that the anti-NMDAR encephalitis microbiome itself can influence neurologic, Th17 response and behavioral function. The gut microbiota is a potential therapeutic target for anti-NMDAR encephalitis.

Objective To investigate the effects of ketogenic metabolism on macrophage polarization, inflammation inhibition, and function recovery after acute spinal cord injury (SCI) in rats. Methods Sixty-four adult male Sprague-Dawley rats were randomly and equally divided into sham, standard diet (SD), ketone diet (KD), and 1, 3-butanediol (BD) groups. All animals underwent C5 unilateral laminectomy, whereas the SD, KD, and BD groups underwent C5 spinal cord hemi-contusion. The impact rod with a diameter of 1.5 mm was aligned 22.5° to the left and 1.4 mm to the midline, and then triggered to deliver a set displacement of 1.5 mm at a speed of 100 mm/s. The gene expression of inflammatory factors as well as the protein expression of inducible nitric oxide synthase, arginase-1, and inflammatory factors were measured at 1 week post-injury. Serum ketone and behavior were evaluated every second week for 12 weeks. Then, histological analyses of the gray and white matter at the epicenter were conducted at 12 weeks post-injury. Results The serum ketone levels of the KD and BD groups were significantly increased when compared with the SD group. The gene and protein expression of TNF-α and IL-1β tended to increase after the SCI, but were inhibited in the KD and BD groups. The protein expression of inducible nitric oxide synthase, marker of M1 macrophage, was inhibited in the KD and BD groups; on the other hand, the expression of arginase-1, marker of M2 macrophage, was boosted in the KD and BD groups. The usage of the ipsilateral forelimb was higher in the KD group than in the SD group. The hemi-contusive injury resulted in an obvious ipsilateral lesion area at the epicenter, and there was no significant difference between groups regarding the lesion size. However, the spared gray matter area was significantly greater in the KD group than in the SD and BD groups. Conclusion The present study suggests that ketogenic metabolism promotes macrophage polarization to M2, inhibits an inflammatory response, and alleviates the loss of gray matter after SCI. A higher ketone level, such as that induced by the ketogenic diet, seems to benefit function recovery after SCI.

Protecting white matter is one of the key treatment strategies for spinal cord injury (SCI), including alleviation of myelin loss and promotion of remyelination. Rapamycin has been shown neuroprotective effects against SCI and cardiotoxic effects while enhancing autophagy. However, specific neuroprotection of rapamycin for the white matter after cervical SCI has not been reported. Therefore, we aim to evaluate the role of rapamycin in neuroprotection after hemi-contusion SCI in mice. Forty-six 8-week-old mice were randomly assigned into the rapamycin group (n = 16), vehicle group (n = 16), and sham group (n = 10). All mice of the rapamycin and vehicle groups received a unilateral contusion with 1.2-mm displacement at C5 followed by daily intraperitoneal injection of rapamycin or dimethyl sulfoxide solution (1.5 mg⋅kg–1⋅day–1). The behavioral assessment was conducted before the injury, 3 days and every 2 weeks post-injury (WPI). The autophagy-related proteins, the area of spared white matter, the number of oligodendrocytes (OLs) and axons were evaluated at 12 WPI, as well as the glial scar and the myelin sheaths formed by Schwann cells at the epicenter. The 1.2 mm contusion led to a consistent moderate–severe SCI in terms of motor function and tissue damage. Rapamycin administration promoted autophagy in spinal cord tissue after injury and reduced the glial scar at the epicenter. Additionally, rapamycin increased the number of OLs and improved motor function significantly than in the vehicle group. Furthermore, the rapamycin injection resulted in an increase of Schwann cell-mediated remyelination and weight loss. Our results suggest that rapamycin can enhance autophagy, promote Schwann cell myelination and motor function recovery by preserved neural tissue, and reduce glial scar after hemi-contusive cervical SCI, indicating a potential strategy for SCI treatment.

Background: Liver injury commonly occurs in patients with COVID-19. There is limited data describing the course of liver injury occurrence in patients with different disease severity, and the causes and risk factors are unknown. We aim to investigate the incidence, characteristics, risk factors, and clinical outcomes of liver injury in patients with COVID-19.Methods: This retrospective observational study was conducted in three hospitals (Zhejiang, China). From January 19, 2020 to February 20, 2020, patients confirmed with COVID-19 (≥18 years) and without liver injury were enrolled and divided into non-critically ill and critically ill groups. The incidence and characteristics of liver injury were compared between the two groups. Demographics, clinical characteristics, treatments, and treatment outcomes between patients with or without liver injury were compared within each group. The multivariable logistic regression model was used to explore the risk factors for liver injury.Results: The mean age of 131 enrolled patients was 51.2 years (standard deviation [SD]: 16.1 years), and 70 (53.4%) patients were male. A total of 76 patients developed liver injury (mild, 40.5%; moderate, 15.3%; severe, 2.3%) with a median occurrence time of 10.0 days. Critically ill patients had higher and earlier occurrence (81.5 vs. 51.9%, 12.0 vs. 5.0 days; p < 0.001), greater injury severity (p < 0.001), and slower recovery (50.0 vs. 61.1%) of liver function than non-critically ill patients. Multivariable regression showed that the number of concomitant medications (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.05–1.21) and the combination treatment of lopinavir/ritonavir and arbidol (OR: 3.58, 95% CI: 1.44–9.52) were risk factors for liver injury in non-critically ill patients. The metabolism of arbidol can be significantly inhibited by lopinavir/ritonavir in vitro (p < 0.005), which may be the underlying cause of drug-related liver injury. Liver injury was related to increased length of hospital stay (mean difference [MD]: 3.2, 95% CI: 1.3–5.2) and viral shedding duration (MD: 3.0, 95% CI: 1.0–4.9).Conclusions: Critically ill patients with COVID-19 suffered earlier occurrence, greater injury severity, and slower recovery from liver injury than non-critically ill patients. Drug factors were related to liver injury in non-critically ill patients. Liver injury was related to prolonged hospital stay and viral shedding duration in patients with COVID-19.Clinical Trial Registration: World Health Organization International Clinical Trials Registry Platform, ChiCTR2000030593. Registered March 8, 2020.

Behcet's disease (BD) patients have abnormal FcγR polymorphisms, the implication of which remains elusive. We examined FcγRIIb expression on neutrophils, monocytes, B cells, natural killer cells, dendritic cells and T cells, and FcγRI and FcγRIII expression on monocytes in BD patients and healthy controls using flow cytometry. We further stimulated monocytes with IgG and (or) lipopolysaccharide (LPS) and measured IL-6 and TNF-α production by enzyme-linked immunosorbent assay. We found that BD monocytes expressed a lower level of FcγRIIb and a higher level of FcγRIII, which were correlated with erythrocyte sedimentation rate and C-reactive protein and were rescued after treatment. Furthermore, LPS- and IgG-stimulated BD monocytes produced higher levels of IL-6 and TNF-α than HC monocytes. In summary, we found that BD monocytes downregulated FcγRIIb expression and upregulated FcγRIII expression, which were correlated with disease activity and potentially contributed to monocyte hyperactivation in BD.

Dihydroartemisinin (DHA), an active metabolite and derivative of artemisinin, is the most effective antimalarial drug and has strong antitumor activity in various tumor types. It has recently been reported that DHA can induce autophagy and has significant effects on multiple myeloma (MM), but the mechanisms and the relationship between the autophagy and apoptosis induced by DHA remain to be elucidated. Herein, we demonstrated that DHA significantly induces cell death in a dose- and time-dependent manner via the extrinsic and intrinsic apoptosis pathways. Moreover, DHA-induced autophagy, which plays a prodeath role in MM, can regulate canonical apoptosis and vice versa. Furthermore, the P38/MAPK signaling pathway is responsible for decreased autophagy and increased apoptosis. DHA induces autophagy and apoptosis also through the inhibition of the Wnt/β-catenin signaling pathway. In addition, DHA shows a strong effect in a xenograft mouse model. Collectively, these findings reveal that DHA, as an artemisinin-based drug, could be an effective and safe therapeutic agent for MM.

STUDY DESIGN Retrospective analysis of computed tomographic images of 92 normal pediatric cervical vertebrae. OBJECTIVE The aim of this study was to ascertain the feasibility of the pedicle, intralaminar, and lateral mass screws fixation in children. SUMMARY OF BACKGROUND DATA Fixation techniques of C7 vertebrae are technically challenging in the pediatric population. Although the techniques offer alternatives to screws placement at C7 spine in adult, there is no consensus to apply these screws in children. METHODS A total of 92 patients (59 males and 33 females) from 3- to 16-year old divided into three groups (group 1, 1-6 years; group2, 7-10 years; group 3, 11-16 years) were included. Measurements were taken through computed tomography (CT) imaging without evidence of spinal trauma. Length, width, and angle of lamina and pedicle were measured, and lateral mass length was also assessed. RESULTS There was no statistical difference between the left and right sides, as well as the sexes. In 1 to 6 years' age group, 83.3% of the laminas and 87.5% of the pedicles measured have thicknesses of >3.5 mm. In 7 to 10 years' age group, 84.0% of the laminas and all the pedicles observed have thicknesses of >3.5 mm. In 11 to 16 years' age group, 88.4% of the laminas and 97.7% of the pedicles measured have thicknesses of >3.5 mm. Most of the spinolaminar angles were between 42.5° and 56°. There are three cases (3.3%) having lateral mass length >12 mm. CONCLUSION It is feasible to insert a screw (O 3.5 mm) in C7 lamina in children, and the intralaminar screw fixation is a safe and reliable technique. Around 49°, the spinolaminar angle with axial position, can be used as reference for placing screws in the C7 lamina. Preoperative CT scan will help surgeons to insert the laminar screw safely and accurately. LEVEL OF EVIDENCE N/A.

Kanglai Li,1,* Jiong Tao,2,* Yuemei Li,3 Minhua Chen,2 Xiuhua Wu,2 Yingtao Liao,2 Xiaolan Lin,4 Zhaoyu Gan2 1Department of Very Important Patient, the 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Psychiatry, the 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Obstetrics, Wuzhou Gongren Hospital, Wuzhou, People’s Republic of China; 4Department of Infectious Diseases, the 3rd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: The aim of the study was to describe and compare the patterns of medication persistence among patients with unipolar depression (UD) or bipolar depression in a 5-year follow-up, and explore their impact on long-term outcome. Patients and methods: A total of 333 eligible patients with current major depressive episode were observed and followed up from the first index prescription for 5 years. Lack of persistence or treatment interruption was defined as a gap of at least 2 consecutive months without taking any medication. Time to lack of persistence in the first (TLP1) and the second (TLP2) episode of treatment, number of visits before the first treatment interruption (NV) and number of treatment interruptions (NTI) were measured. Results: During the 5-year follow-up, nearly 50% of patients experienced at least two times of treatment interruption. Pattern of medication persistence did not significantly differ between UD and bipolar disorder (BD) patients. TLP1 was positively associated with TLP2. Shorter TLP1 predicted a higher possibility of subsequent visits because of recurrence or relapse and more NTI meant a lower likelihood of achieving full remission in the fifth year for both UD and BD patients. For UD patients, shorter TLP1 or less NV predicted a lower chance of achieving remission, while for BD patients, shorter TLP1 meant an earlier subsequent visit and more NTI predicted a lower possibility of achieving remission. Conclusion: Pattern of medication persistence was similar but its impact on the long-term outcome was quite different between UD and BD. Keywords: adherence, pharmacotherapy, bipolar disorder, depression, rehabilitation

To clarify osteoporotic effects of ketogenic diet (KD) on cancellous and cortical bone compared with ovariectomy (OVX) in mice. Forty female C57BL/6J 8-week-old mice were randomly divided into SD+Sham, SD+OVX, KD+Sham, and KD+OVX groups, and fed for 12 weeks. The distal femur of trabecular bone and the middle femur of cortical bone were evaluated with Micro-CT scanning. The maximum bending force and stiffness of the tibia were calculated using a three-point bending test. Osteoblast and osteoclast expression of femur were identified using tartrate-resistant acid phosphatase (TRAP), collagen type I (CoLI), and osteocalcin (OCN) staining. A 2-factor analysis of variance was used to evaluate effects of KD and OVX on radiological, biomechanical, and histological parameters. KD resulted in not only remarkable cancellous bone decline comparable to OVX, but also unique cortical bone reduction. The maximum bending force and stiffness decreased in the KD+Sham and KD+OVX groups but did not change in the SD+OVX group. The KD+OVX led to significantly higher expression in TRAP and noticeably lower expression in CoLI when compared with other groups. Both KD+Sham and SD+OVX prominently increased expression in TRAP, but decreased expression in CoLI. There was no significant difference in OCN among the four groups. The present results suggest that KD compromises both the cancellous and cortical bone architecture of long bones while OVX only in cancellous bone architecture. A combination of KD and OVX may lead to more bone loss.

A high-fat, low–carbohydrate diet (KD) or calorie restriction in the form of every-other-day fasting (EODF) results in ketone body metabolism with an increasing β-hydroxybutyrate (βOHB) level. Previous studies have supported that a KD and EODF have a neuroprotective effect. However, the βOHB levels in the cerebrospinal fluid (CSF) resulting from a KD and EODF remain unknown. The aim of this study was to detect βOHB levels in rats fed a KD, EODF diet, and every-other-day ketogenic diet (EODKD) and to compare the serum βOHB level with the CSF βOHB level. Twenty-four male Sprague-Dawley rats were randomly divided into KD, EODF, EODKD, and standard diet (SD) groups. A customized food with a ratio of carbohydrates to fats of 1:4 was used in the KD and EODKD groups. The βOHB level was measured using ELISA kits in 200 µl serum and 100 µl CSF samples for each rat after feeding for 2 weeks. The KD, EODF, and EODKD resulted in a significant increase in βOHB levels in both the serum and CSF. The βOHB levels in the EODKD group were the highest. The CSF βOHB level was, on average, 69% of the serum βOHB level. There was a positive correlation between the overall βOHB levels in serum and that in cerebrospinal fluid. This study demonstrated that the KD, EODF, and EODKD resulted in ketone body metabolism, as the βOHB levels increased significantly compared with those resulting from the standard diet. Our results suggested that the serum βOHB level was an indicator of the CSF βOHB level, and that the EODKD was an effective diet to enhance ketogenic metabolism.

Prostheses and implants have been widely utilized in the orthopedic and dental fields. Nowadays, significant advances have been made in the structural and functional connection between living bone and prostheses, especially in the presence of compromised bone quantity/quality. Despite improvement in the treatment outcomes after augmentation, there are still challenges to meet the clinical demands due to limited materials available. In the current study, we investigated the effects of nano-nacre particles as an alternative material on stimulating bone cell differentiation and formation. Mouse osteoblastic cells (MC3T3-E1) were cultured on nano-nacre/type I collagen composite scaffold (NN-ICS) and type I collagen scaffold (ICS). Generated nano-nacre particles showed controlled release of protein and calcium for a period of 36 days. NN-ICS significantly contributed to the proliferation and differentiation of preosteoblasts compared to ICS controls. Our data showed that nano-nacre particles could serve as a candidate of bone substitution material, which potentially contributed to treatment outcomes in cases with compromised bone quality and/or quality.

Background To investigate the diagnostic value of the interferon-γ release assay (IGRA) for detecting tuberculosis (TB) infection in patients with Behçet’s disease (BD). Methods We retrospective analyzed the data collected from 173 BD patients hospitalized between 2010 and 2015. Ninety-nine healthy volunteers were enrolled as a control group. IGRA was performed using T-SPOT.TB. The diagnosis of active TB (ATB) was based on clinical, radiological, microbiological, histopathological information and the response to anti-TB therapy. Latent TB (LTB) infection was defined as asymptomatic patients with positive T-SPOT.TB. Results TB infection was documented in 59 BD patients (34.1%). The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio of T-SPOT.TB for the diagnosis of ATB were 88.9%, 74.8%, 29.1%, 98.3%, 3.53 and 0.15, respectively. The receiver-operating-characteristic curve demonstrated that spot-forming cells (SFCs) of 70/106 PBMC was the optimal cutoff for diagnosing ATB, with an area under the curve of 0.891. Furthermore, the median SFCs in ATB group was significantly higher than those in LTB infection (466/106 PBMC vs. 68/106 PBMC, p = 0.007) or previous TB infection (466/106 PBMC vs. 96/106 PBMC, p = 0.018). A significant discrepancy between T-SPOT.TB and tuberculin skin test was noted (kappa coefficient = 0.391, p = 0.002). Conclusions T-SPOT.TB, an IGRA, may assist in the diagnosis of ATB in BD patients, and the higher SFCs suggest ATB in BD patients.

Objective. To investigate the clinical features and potential risk factors of aneurysmal lesions in Behcet’s disease (BD). Methods. We retrospectively reviewed the clinical data of BD patients with aneurysmal lesions in our institute from 1997 to 2017 and compared them with 207 BD patients without aneurysmal lesions. The treatment and outcome of these patients were also analyzed. Results. Sixty-nine patients were included with 117 aneurysmal lesions. The average period between BD onset and diagnosis of aneurysmal lesion was 5.4±5.5 years. Thirty-three patients (47.8%) had multiple aneurysmal lesions. Ten patients developed 20 pulmonary artery aneurysms alone. For the other 97 aortic and/or peripheral artery aneurysms in 59 patients, the most commonly affected vessels were abdominal aorta (27/97, 27.8%), coronary artery (10/97, 10.3%), and superficial femoral artery (8/97, 8.2%). Multivariate analysis revealed pathergy reaction (OR=3.78 (1.70-8.41)), arterial stenosis or occlusion (OR=44.12 (11.56-168.35)), and arterial thrombosis (OR=9.27 (2.33-36.93)) as independent predictors of aneurysmal lesions in BD. With a mean follow-up of 5.5±4.0 years, 40 patients (58.0%) achieved clinical improvements, 15 patients (21.7%) relapsed, and 10 patients (14.5%) died. The respective estimated cumulative 1- and 5-year relapse-free rates were 91.3% and 76.3%, and the respective estimated 1- and 5-year survival rates were 95.0% and 87.2%. Conclusion. Aneurysmal lesions are severe complications in BD. Pathergy reaction, arterial stenosis or occlusion, and arterial thrombosis are the risk factors of aneurysmal lesions in BD. Achieving BD remission and performing surgical or interventional procedures are both important in the treatment of these patients.

Purpose. Barium sulfate and lead oxide are commonly used for angiographic studies, but there is no report on the comparison of two contrast agents in angiography of cervical spinal cord. This study was aimed to compare the microvascular architecture of cervical spinal cord in rats after angiography with the barium sulfate agent to the lead oxide agent. Methods. Twelve adult Sprague-Dawley rats were randomly divided into the barium sulfate group (n=6) and the lead oxide group (n=6). Each rat was perfused under the same protocol using either two contrast agents. The angiography was evaluated with the vascular number at different ranks. The cervical spinal cord samples were scanned using micro-CT with low resolution and high resolution. The microvascular parameters, including ratio of vascular volume to tissue volume (VV/TV), vascular number (V.N), diameter (V.Dm), separation (V.Sp), connectivity density (Conn.D), structure model index (SMI), percentage, and volume of vessels at different diameters were measured. Results. The perfusion was better in the barium sulfate group, with more blood vessel trees of rank II and III visible compared to the lead oxide group. Low-resolution micro-CT analysis showed no difference in microvascular parameters except SMI between the two groups. High-resolution micro-CT analysis results showed that V.N and Conn.D of barium sulfate group were 60% and 290% more than those of the lead oxide group; however, V.Sp was 41% less than the lead oxide group. The percentage of vessels with diameter of 10 μm and 20 μm, and the volume of vessels with diameter of less than 100 μm was higher in the barium sulfate group than in the lead oxide group. The SMI index in the barium sulfate group was higher than that in the lead oxide group at both low resolution and high resolution. Conclusions. Compared with lead oxide, barium sulfate is more suitable for perfusion of cervical spinal cord microvessels, and cheap and nontoxic with high resolution.

ObjectivesTo survey anxiety and depression symptoms to COVID-19 outbreak in the public, medical staff and patients during the initial phase of the pandemic.DesignCross-sectional online survey administered through WeChat Mini Program using Chinese versions of Zung Self-rating Depression Scale and Zung Self-rating Anxiety Scale.SettingGuangzhou, China.Participants47 378 public, 1512 medical staff and 125 patients with COVID-19.ResultsHigher rates of depression (47.8%) and anxiety symptoms (48.7%) were shown by patients who were screened positive compared with those of the public (35.6%, 25.7%) or medical staff (15.4%, 13.3%). The professional identity of a nurse, conditions of ‘with an infected family member’ and ‘working at the frontline’ were risk factors to depression or anxiety symptoms for the medical staff. Younger age, lower educational level, female and not having adequate masks were the risk factors for the public.ConclusionThe COVID-19 outbreak increased people’s depression or anxiety emotion responses, which varied extensively among the patients, public and medical staff.

Dentin dysplasia type I (DDI) is an autosomal-dominant genetic disorder resulting from dentin defects. The molecular basis of DDI remains unclear. DDI exhibits unique characteristics with phenotypes featuring obliteration of pulp chambers and diminutive root, thus providing a useful model for understanding the genetics of tooth formation. Using a large Chinese family with 14 DDI patients, we mapped the gene locus responsible for DDI to 3p26.1-3p24.3 and further identified a missense mutation, c.353C>A (p.P118Q) in the SSUH2 gene on 3p26.1, which co-segregated with DDI. We showed that SSUH2 (p.P118Q) perturbed the structure and significantly reduced levels of mutant (MT) protein and mRNA compared with wild-type SSUH2. Furthermore, MT P141Q knock-in mice (+/- and -/-) had a unique partial obliteration of the pulp cavity and upregulation or downregulation of six major genes involved in odontogenesis: Dspp, Dmp1, Runx2, Pax9, Bmp2, and Dlx2. The phenotype of missing teeth was determined in zebrafish with morpholino gene knockdowns and rescued by injection of normal human mRNA. Taken together, our observations demonstrate that SSUH2 disrupts dental formation and that this novel gene, together with other odontogenesis genes, is involved in tooth development.

Background Ventral defect caused by resection of the lesions involving the upper cervical spine commonly has been reconstructed with a fabricated mesh cage. Recently, a clival screw and plate fitted to the osseous anatomy of the craniovertebral junction was developed for this pathologic status. Objective To evaluate the stability a clivus plate system fixation (CPSF) for the craniovertebral junction and compare it with a conventional fashioned mesh cage fixation (FMCF). Methods Seven human fresh cadaveric specimens (occiput [Oc], atlas [C1], axis [C2], third cervical vertebra [C3], fourth cervical vertebra [C4]) were tested with intact and destabilization-reconstruction conditions. FMCF and CPSF were applied randomly to the clivus to the C3 segment combined with posterior occipitocervical fixation applied from the occiput to C4 segment, respectively. Specimens were subjected to a pure moment of 1.5 Nm in flexion, extension, lateral bending, and axial rotation, respectively. The range of motion (ROM) and neutral zone (NZ) from the occiput to C3 were calculated and compared between two anterior fixations. Results Motions were reduced significantly in all directions following FMCF and CPSF fixations when compared with the intact. The CPSF resulted in smaller ROM in lateral bending (0.3° vs. 0.6°, P = 0.015), axial rotation (0.6° vs. 1.2°, P = 0.023) and flexion (0.1° vs. 0.3°, P = 0.019), but similar ROM in extension (0.2° vs. 0.4°, P = 0.273) when compared with the FMCF. NZs with the CPSF were 0.1° in flexion-extension, 0.1° in lateral bending and 0.2° in axial rotation, respectively, and similar to NZs with the FMCF. Conclusions The clivus plate system fixation is biomechanically superior to the conventional fashioned mesh cage fixation in flexion, lateral bending and axial rotation, but equavalent in extension.

To explore the associated risk factors of symptomatic knee osteonecrosis (KON) in patients with systemic lupus erythematosus (SLE), we conducted a retrospective case–control study to compare the clinical and laboratory features between SLE patients with and without symptomatic KON matched by age and gender. Univariate and multivariate regression analyses were used to evaluate possible associated risk factors. Twenty (one male, nineteen females) out of 3941 lupus patients were identified as symptomatic KON, which was confirmed by magnetic resonance imaging. The mean age at KON onset was 34.4 (range 12–67) years, and the median course of lupus at KON onset was 72.5 (range 8–123) months. Univariate and multivariate analyses identified that the prevalence of cutaneous vasculitis (OR 5.23; 95 % CI 1.11–24.70), hyperfibrinogenemia (OR 4.75; 95 % CI 1.08–20.85), and elevated IgG levels (OR 6.05; 95 % CI 1.58–23.16) were statistically higher in KON group, and hydroxychloroquine (HCQ) usage was statistically lower in KON group (OR 0.27; 95 % CI 0.07–0.97). Glucocorticoid usage, in terms of maximal dose, duration of treatment, and the percentage of receiving methylprednisolone pulse therapy, did not show statistical difference between the two groups (p > 0.05). Symptomatic KON is a relatively rare complication of SLE. Cutaneous vasculitis, hyperfibrinogenemia, and elevated IgG levels are possible risk factors, whereas HCQ may provide a protective effect. Our results suggest that lupus activity as well as hypercoagulation status may play a role in the pathogenesis of KON in lupus.

Cognitive impairment is one of the core symptoms of schizophrenia, and patients with schizophrenia are at increased risk of metabolic syndrome (MS). However, the role of MS in cognitive impairment of schizophrenia is not established. This study investigated the correlation between neurocognitive, social cognitive performance and MS with schizophrenia. One hundred and fifty eight (158) schizophrenia patients were divided into 3 groups with ① normal metabolism, ② metabolic disorder (only meeting 1 or 2 MS criteria), and ③ metabolic syndrome (meeting 3 or more MS criteria). MATRICS Consensus Cognitive Battery)MCCB(and the Brief Psychiatric Rating Scale)BPRS(were used to evaluate cognitive performance and clinical symptoms. Blood samples were obtained to detect glucose and lipid metabolic levels. Overall MCCB and subscale T scores in the normal metabolism and metabolic disorder groups were better than in the MS group. After controlling for the confounding factors including age, sex, the usage of hypolipidemic and hypoglycemic drugs, and disease duration, metabolic deficits had effects on the symbol coding and spatial span scores. The results suggest that a defective metabolic state might play a role in neurocognitive performance of schizophrenia patients.

Study design An experimental animal study of osteoporosis (OP) and intervertebral disc degeneration (IDD). Objective The aim of this study was to clarify the effects of estrogen deficiency and supplement on cervical IDD induced by bilateral facetectomy in rats. Summary of background data The relationship between IDD and OP is still controversy with the wide prevalence in aged people. Methods Seventy-two Sprague-Dawley female rats were randomly divided into ovariectomy (OVX) group, facet joints resection of C4-6 (FR), FR-OVX group, estrogen replacement therapy (ERT, based on the FR-OVX group) group, and sham group. Specimens of C4-6 segment were harvested at 12 and 24 weeks. The microstructures of C5 vertebrae, vertebral endplate lesions and calcification, and IDD of C5/6 disc were evaluated by micro-computed tomography (micro-CT) and histology. The protein and gene levels of aggrecan, Col2α1, matrix metalloprotease (MMP)-3, and MMP-13 in the C5/6 and C4/5 discs were measured. Results Microstructures of C5 vertebral body were weakened significantly after ovariectomy, while restored effectively with estradiol supplementation. The facetectomy led to significant IDD, and the IDD was aggravated when combined with OVX. The IDD of the ERT group was alleviated effectively and similar to that of the FR group in intervertebral disc height, vertebral endplate lesions and calcification, and disc degeneration scores. In addition, the estrogen supplement maintained the extracellular matrix by decreasing MMP-3 and MMP-13, and increasing aggrecan and Col2α1 expression. Conclusion The present study demonstrated that estrogen deficiency exacerbated IDD induced by spinal instability, while estrogen supplementation alleviated the progression of disc degeneration related to osteoporosis. Level of evidence N/A.

Variety of evidence suggests that low-grade inflammation may be involved in the pathophysiology of bipolar disorder (BD). However, the conclusion regarding the relationship between inflammation and BD has been inconsistent. In this study, we aimed to survey the prevalence of low-grade inflammation in a large Han Chinese population with BD and assess its impact on the clinical features of BD. 430 eligible cases were drawn from patients who were admitted or had ever been admitted for BD to the inpatient service of the psychiatric department of the Third Hospital of Sun Yat-sen University. Subjects with current active physical diseases or white blood count (WBC) >19.0 × 109/L (2 times the upper reference) were excluded. Serum C-reactive protein (CRP) levels and WBC were measured with fast blood sample. Low-grade inflammation was defined as CRP>3 mg/L or WBC > 9.5 × 109/L(the upper reference). Clinical features of BD were collected through semi-structural interview conducted by trained interviewers with background of psychiatric education. If defined as CRP>3 mg/L, the prevalence of low-grade inflammation among BD was 10.1% (41/404), it was positively associated with BMI (p = 0.012), comorbidity of glycolipid metabolic diseases(p = 0.018). After adjusting for BMI, it was found to be positively related to recent suicide attempt (p = 0.03), initiation with (hypo)manic episode(p = 0.047), leaden paralysis (p = 0.037) and family history of mental disorders(p = 0.012), while the association between comorbidity of glycolipid metabolic diseases and low-grade inflammation disappeared (p = 0.330). If defined as WBC > 9.5 × 109/L, the prevalence of low-grade inflammation was 8.1% (33/409), it was positively associated with psychotic features (p = 0.011) and adverse life events before the onset of illness(p A much lower prevalence of low-grade inflammation in BD is found among Han Chinese population than among western population. Low-grade inflammation of different definition impacts differentially on the clinical features of BD.

Background The diagnosis of Behçet’s disease (BD) remains challenging due to the lack of diagnostic biomarkers. This study aims to identify potential serum metabolites associated with BD and its disease activity. Methods Medical records and serum samples of 24 pretreated BD patients, 12 post-treated BD patients, and age-matched healthy controls (HC) were collected for metabolomics and lipidomics profiling using UPLC-QTOF-MS and UPLC-QTOF-MSE approaches. Additionally, serum samples from an independent cohort of BD patients, disease controls including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Takayasu’s arteritis (TA), Crohn’s disease (CD) patients, and HC were collected for further validation of two potential biomarkers using UPLC-QTOFMS analysis. Results Unsupervised principal component analysis (PCA) showed a clear separation of metabolomics profiles of BD patients from HC. Statistical analysis of the data revealed differential metabolites between BD patients and HC. The serum levels of some phosphatidylcholines (PCs) were found to be significantly lower in BD patients, while the levels of several polyunsaturated fatty acids (PUFAs) were increased markedly in the BD group compared with HC. Furthermore, the serum level of two omega-6 PUFAs, linoleic acid (LA) and arachidonic acid (AA), were dramatically decreased in patients with remission. A validation cohort confirmed that the serum LA and AA levels in BD patients were significantly higher than those in HC and patients with RA, SLE, TA, and CD. In addition, receiver operating characteristic (ROC) analysis indicated good sensitivity and specificity. Conclusions The serum metabolomics profiles in BD patients are altered. Serum LA and AA are promising diagnostic biomarkers for BD.

The class III PI3-kinase (PIK3C3) is an enzyme responsible for the generation of phosphatidylinositol 3-phosphate (PI3P), a critical component of vesicular membrane. Here, we report that PIK3C3 deficiency in zebrafish results in intestinal injury and inflammation. In pik3c3 mutants, gut tube forms but fails to be maintained. Gene expression analysis reveals that barrier-function-related inflammatory bowel disease (IBD) susceptibility genes (e-cadherin, hnf4a, ttc7a) are suppressed, while inflammatory response genes are stimulated in the mutants. Histological analysis shows neutrophil infiltration into mutant intestinal epithelium and the clearance of gut microbiota. Yet, gut microorganisms appear dispensable as mutants cultured under germ-free condition have similar intestinal defects. Mechanistically, we show that PIK3C3 deficiency suppresses the formation of PI3P and disrupts the polarized distribution of cell-junction proteins in intestinal epithelial cells. These results not only reveal a role of PIK3C3 in gut homeostasis, but also provide a zebrafish IBD model., The functions of the class III PI3-kinase (PIK3C3) in gut homeostasis and innate immunity are poorly understood. Here the authors show that PIK3C3-deficient zebrafishes develop intestinal injury and inflammation due to mislocalization of cell junction proteins.

Metformin (Met), an anti-diabetes drug, has also shown therapeutic effects for ovariectomy-induced (OVX) osteoporosis. However, similar effects against bone loss induced by a ketogenic diet (KD) have not been tested. This study was aimed to evaluate the microarchitectures and biomechanics of KD-induced osteoporosis with and without administration of Met, and compare the effect of Met on bone loss induced by KD with OVX. Forty female C57BL/6J mice were randomly divided into Sham, OVX, OVX + Met (100 mg/kg/day), KD (3:1 ratio of fat to carbohydrate and protein), and KD + Met (100 mg/kg/day) groups. After 12 weeks, the bone mass and biomechanics were measured in distal cancellous bone and in mid-shaft cortical bone of the femur. The activities of serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), together with immunohistochemistry staining of osteocalcin (OCN) and TRAP, were evaluated. Both OVX and KD induced significant bone loss and compromised biomechanical properties in the cancellous bone, but no effect was found in cortical bone. The administration of Met increased the cancellous bone volume fraction (BV/TV) from 3.78 to 5.23% following the OVX and from 4.04 to 6.33% following the KD, it also enhanced the compressive stiffness from 47 to 160 N/mm following the OVX and from 35 to 340 N/mm with the KD. Met effectively increased serum ALP in the KD group while decreased serum TRAP in the OVX group, but up-regulated expression of OCN and down-regulated expression of TRAP in both OVX and KD groups. The present study demonstrated that Met effectively attenuated the cancellous bone loss induced by KD and maintained the biomechanical properties of long bones, providing evidence for Met as a treatment of by KD-induced osteoporosis in teenage skeleton.

The ketone metabolite β-hydroxybutyrate (βOHB), is reported to be neuroprotective after spinal cord injury (SCI) in rats, but the underlying mechanism remains unknown. The present study aims to investigate effects of βOHB on suppression of oxidative stress and inhibition of class I histone deacetylases (HDACs) in in vivo and in vitro models. Rats were fed with ketogenic diet (KD) or standard diet (SD) for 3 weeks. A C5 hemi-contusion injury was applied to these animals on the 14th day of experiment, and spinal cord samples were harvested on the 1st, 3rd and 7th days after SCI, respectively. The blood ketone levels were significantly higher in the KD groups. KD reduced oxidative stress markers and reactive oxygen species (ROS) products, downregulated the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)2 and NOX4, and upregulated the expression of forkhead box group O (FOXO)3a, mitochondrial superoxide dismutase (MnSOD), and catalase after SCI. The in vitro study, performed on PC12 cells, indicated that βOHB inhibited H

The aim of this study is to investigate the effect of ketogenic metabolism, induced by different diet interventions, on histone acetylation and its potential antioxidant capacity to injured spinal cord tissue in rats. 72 male Sprague–Dawley rats were randomly divided into 4 groups, fed with ketogenic diet (KD), every other day fasting (EODF), every other day ketogenic diet (EODKD) and standard diet (SD) respectively for 2 weeks. β-Hydroxybutyrate (βOHB) concentration was measured both in serum and cerebrospinal fluid (CSF). C5 spinal cord tissue was harvested before, at 3 h and 24 h after injury for analysis of HDAC activity, histone acetylation and oxidative makers. All three dietary interventions resulted in a significant increase of βOHB level in both serum and CSF, and inhibited HDAC activity by 31–43% in spinal cord. Moreover, the expressions of acetylated histone AcH3K9 and AcH3K14 were significantly increased. Anti-oxidative stress genes Foxo3a and Mt2 and related proteins, such as mitochondrial superoxide dismutase (SOD), FOXO3a, catalase were increased in dietary intervention groups. After SCI, high ketogenic metabolism demonstrated significant reduction of the expression of lipid peroxidation factors malondialdehyde (MDA), and this might contribute to the reported neuroprotection of the spinal cord from oxidative damage possibly mediated by increasing SOD. The result of this study suggested that by inhibiting HDAC activity and modifying related gene transcription, ketogenic metabolism, induced by KD, EODF or EODKD, might reduce oxidative damage in the spinal cord tissue after acute injury.