Beyond Growth Hormone: Association of Short Stature Types and Growth Hormones With Scoliosis.

STUDY DESIGN: Cross-sectional and retrospective cohort study. OBJECTIVE: We investigated the effect of 3 types of short stature [partial growth hormone deficiency (GHD), GHD, and idiopathic short stature (ISS)] and recombinant human growth hormone (rhGH) therapy on scoliosis. SUMMARY OF BACKGROUND DATA: In short stature, rhGH is widely used and the concentration of growth hormone varies among types. The epidemiologic characteristics of scoliosis and the role of rhGH in scoliosis remain unclear. PATIENTS AND METHODS: A cross-sectional study was conducted among 3896 patients with short stature (partial GHD, GHD, and ISS), and a 1:1 age and sex-matched control group with preexisting whole-spine radiographs. The cohort study included 2605 subjects who underwent radiography more than twice to assess scoliosis development, progression, and the need for bracing and surgery. Adjusted logistic regression was used to assess differences in the prevalence of scoliosis among patients with partial GHD, GHD, ISS, and controls. The Kaplan-Meier method was used to analyze the time course of scoliosis development and progression. Cox regression was applied to assess the independent factors related to scoliosis development and progression. Mendelian randomization analyses were also performed. RESULTS: Compared with controls, patients with short stature had a higher incidence of scoliosis (34.47% in partial GHD, 31.85% in GHD, 32.94% in ISS vs . 8.83% in control, P < 0.001), a higher risk of scoliosis development [hazard ratio (HR) = 1.964 in partial GHD, P < 0.001; HR = 1.881 in GHD, P = 0.001; HR = 1.706 in ISS, P = 0.001), but not a higher risk of progression, brace, or surgery. Among the 3 types of short stature, there were no differences in the incidence, development, and progression of scoliosis or the need for bracing or surgery. RhGH treatment increased the risk of scoliosis development in each short-stature group (HR = 2.673 in partial GHD, P < 0.001; HR = 1.924 in GHD, P = 0.049; HR = 1.564 in ISS, P = 0.004). Vitamin D supplementation was protective against scoliosis development (HR = 0.456 in partial GHD, P = 0.003; HR = 0.42 in GHD, P = 0.013; HR = 0.838 in ISS, P = 0.257). CONCLUSIONS: More attention should be paid to the spinal curve in patients with partial GHD, GHD, or ISS. For short stature treated with rhGH, the risk of scoliosis development was increased. Vitamin D supplementation may be beneficial for prevention. LEVEL OF EVIDENCE: Level III.

A targeted antibody-based array reveals a serum protein signature as biomarker for adolescent idiopathic scoliosis patients.

BACKGROUND: Evident adolescent idiopathic scoliosis (AIS) incurs high treatment costs, low quality of life, and many complications. Early screening of AIS is essential to avoid progressing to an evident stage. However, there is no valid serum biomarker for AIS for early screening. METHODS: Antibody-based array is a large-scale study of proteins, which is expected to reveal a serum protein signature as biomarker for AIS. There are two segments of the research, including biomarkers screening and validation. In the biomarkers screening group, a total of 16 volunteers participated in this study, and we carried out differentially expressed proteins screening via protein array assay between No-AIS group and the AIS group, through which GeneSet enrichment analysis was performed. In the validation group with a total of 62 volunteers, the differentially expressed proteins from screening group were verified by Enzyme-Linked immunosorbent assay (ELISA), and then multiple regression analysis. RESULTS: In our study, there were twenty-nine differentially expressed proteins in AIS, through Protein array assay and GeneSet enrichment analysis in the biomarkers screening group. Then the expression of FAP, CD23 and B2M decreased as the degree of AIS increased via ELISA in validation group (FAP, p < 0.0001; CD23, p = 0.0002; B2M, p < 0.0001). Further, the results of multiple regression analysis showed that FAP, CD23 are linked to Cobb angle, whereas B2M were excluded because of multicollinearity. CONCLUSIONS: Altogether, we found that serum protein FAP and CD23 are intimately related to AIS, suggesting FAP and CD23 are expected to serve as the serum biomarkers, which significantly facilitate frequent longitudinal monitoring as to keep track of disease progression and tailor treatment accordingly.

Idiopathic short stature and scoliosis in children treated with growth hormone.

The prevalence of scoliosis is not known in patients with idiopathic short stature, and the impact of treatment with recombinant human growth hormone on those with scoliosis remains controversial. We investigated the prevalence of scoliosis radiologically in children with idiopathic short stature, and the impact of treatment with growth hormone in a cross-sectional and retrospective cohort study. A total of 2,053 children with idiopathic short stature and 4,106 age- and sex-matched (1:2) children without short stature with available whole-spine radiographs were enrolled in the cross-sectional study. Among them, 1,056 with idiopathic short stature and 790 controls who had radiographs more than twice were recruited to assess the development and progression of scoliosis, and the need for bracing and surgery. In the cross-sectional study, there was an unexpectedly higher prevalence of scoliosis (33.1% (681/2,053) vs 8.52% (350/4,106)) in children with idiopathic short stature compared with controls (odds ratio 3.722; p < 0.001), although most cases were mild. In the longitudinal study, children with idiopathic short stature had a higher risk of the development and progression of scoliosis than the controls. Among children with idiopathic short stature without scoliosis at baseline, treatment with growth hormone significantly increased the risk of developing scoliosis (p = 0.015) and the need for bracing (p < 0.001). Among those with idiopathic short stature and scoliosis at baseline, treatment with growth hormone did not increase the risk of progression of the scoliosis, the need for bracing, or surgery. The impact of treatment with growth hormone on scoliosis in children with idiopathic short stature was considered controllable. However, physicians should pay close attention to the assessment of spinal curves in these children.

CASMART, a one-step CRISPR Cas12a-mediated isothermal amplification for rapid and high-resolution digital detection of rare mutant alleles.

Convenient, ultrasensitive, and accurate detection of rare variants is essential for early cancer diagnosis and precision medicine, however, despite years of efforts, tools that have all these qualities remain elusive. Here, we developed a one-step CRISPR/Cas12a-based digital diagnostic platform for accurately quantifying mutant alleles, referred to as the CRISPR ASsoaciated Mutation Allele Rapid Test (CASMART). The platform accurately quantifies the variant allele frequency of EGFR L858R within 1 h at 42 °C and can detect mutant targets as low as 0.3 copies/µL (0.498 aM) in mock multiplex cfDNA samples. We further investigated the applicability of CASMART using human genomic samples with confirmed EGFR L858R mutations previously measured variant allele frequency by next-generation sequencing. Comparison across platforms revealed equivalent detection performance (Pearson's correlation coefficient, R2 = 0.9208) and high quantification accuracy for mutation allele frequency (intraclass correlation coefficient = 0.959). Our one-step approach enables easy and accurate variant allele frequency measurement of rare mutant alleles without PCR instrumentation, while the assay time was reduced by approximately half compared to the digital PCR with the shortest turnaround. The CASMART is an alternative to conventional single nucleotide polymorphism detection methods with great potential as a next-generation biosensor for rapidly quantifying the variant allele fraction, especially in resource-limited settings.

Assessment of Neck Imbalance in Adolescent Idiopathic Scoliosis Patients: A Cross-Section Study Based on Body Image of 115 Patients with Main or Double Thoracic Curve.

OBJECTIVE: Neck imbalance negatively affects body aesthetics of adolescent idiopathic scoliosis (AIS) patients. The evaluation of neck imbalance is currently limited to radiographic parameters, but lacks visual indicators. Therefore, the purpose of this study was to establish indexes of neck imbalance based on body image and to investigate whether these indexes can truly reflect neck imbalance in AIS patients. METHODS: We performed a cross-sectional study at a single institution between June 2017 and September 2020 and there were 115 subjects involved in this research. All patients were diagnosed with adolescent idiopathic scoliosis, Lenke type I/II. Radiographic parameters measured included cervical axis tilt (CAT), T1 tilt, first rib angle (FRA), clavicle angle (CA), radiographic shoulder height (RSH), proximal thoracic curve (PTC), apical vertebra translation of proximal thoracic (AVT of PT), main thoracic curve (MTC), apical vertebra translation of main thoracic (AVT of MT) and coronal balance (CB/C7PL-CSVL). Neck imbalance indexes were obtained and measured following a standardized manner. Intra-class correlation coefficient (ICC) analysis was performed for neck imbalance indexes to determine their intra-observer and inter-observer reliability, and correlation tests were performed for neck imbalance indexes with the radiographic parameters mentioned above. RESULTS: Strong intraobserver and interobserver reliability were observed in neck imbalance index (NII) 1 (0.91 and 0.88), neck imbalance index 2 (0.85 and 0.81) and NII 3 (0.82 and 0.80), P < 0.05. Significant correlation was found in cervical axis tilt (R = 0.81 for NII 1, R = 0.77 for NII 2 and R = 0.78 for NII 3), T1 tilt (R = 0.43 for NII 1, R = 0.52 for NII 2 and R = 0.48 for NII 3), first rib angle (R = 0.41 for NII 1, R = 0.48 for NII 2 and R = 0.43 for NII 3), proximal thoracic curve (R = 0.36 for NII 2) and apical vertebra translation of proximal thoracic (R = -0.37 for NII 2 and R = -0.35 for NII 3) with neck imbalance indexes. Neck imbalance index 1 showed the highest correlation with cervical axis tilt (R = 0.81, P < 0.01). CONCLUSIONS: Neck imbalance indexes established in our study were in good correlation with cervical axis tilt (CAT), At the meantime, they showed significant correlations with T1 tilt and first rib angle (FRA). Our study provides a practical method for measurement of neck imbalance regarding realistic perspective and makes up for the lack of photographic indexes about neck imbalance.

The Potential Role of Cytokines in Diabetic Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is a major cause of low back pain. Diabetes mellitus is a chronic inflammatory disease that may cause or aggravate IVDD; however, the mechanism by which diabetes induce IVDD is currently unclear. Compared to non-diabetic individuals, diabetic patients have higher levels of plasma cytokines, especially TNF-α, IL-1ß, IL-5, IL-6, IL-7, IL-10, and IL-18. Due to the crucial role of cytokines in the process of intervertebral disc degeneration, we hypothesized that elevation of these cytokines in plasma of diabetic patients may be involved in the process of diabetes-induced IVDD. In this review, changes in plasma cytokine levels in diabetic patients were summarized and the potential role of elevated cytokines in diabetes-induced IVDD was discussed. Results showed that some cytokines such as TNF-α and IL-1ß may accelerate the development of IVDD, while others such as IL-10 is supposed to prevent its development. Apoptosis, senescence, and extracellular matrix metabolism were found to be regulated by these cytokines in IVDD. Further studies are required to validate the cytokines targeted strategy for diabetic IVDD therapy.

Immune-responsive gene 1/itaconate activates nuclear factor erythroid 2-related factor 2 in microglia to protect against spinal cord injury in mice.

The pathophysiology of spinal cord injury (SCI) involves primary injury and secondary injury. Secondary injury is a major target for SCI therapy, whereas microglia play an important role in secondary injury. The immunoresponsive gene 1 (Irg-1) has been recorded as one of the most significantly upregulated genes in SCI tissues in gene chip data; however, its role in SCI remains unclear. This study aims to illustrate the role of Irg-1 as well as its regulated metabolite itaconate in SCI. It was demonstrated that the expression of Irg-1 was increased in spinal cord tissues in mice as well as in microglia stimulated by lipopolysaccharides (LPS). It was also shown that overexpression of Irg-1 may suppress LPS-induced inflammation in microglia, while these protective effects were attenuated by Nrf2 silencing. In vivo, overexpression of Irg-1 was shown to suppress neuroinflammation and improve motor function recovery. Furthermore, treatment of microglia with itaconate demonstrated similar inflammation suppressive effects as Irg-1 overexpression in vitro and improved motor function recovery in vivo. In conclusion, the current study shows that Irg-1 and itaconate are involved in the recovery process of SCI, either Irg-1 overexpression or itaconate treatment may provide a promising strategy for the treatment of SCI.

Patchouli Alcohol Improves the Integrity of the Blood-Spinal Cord Barrier by Inhibiting Endoplasmic Reticulum Stress Through the Akt/CHOP/Caspase-3 Pathway Following Spinal Cord Injury.

Spinal cord injury (SCI) is a destructive and complex disorder of the central nervous system (CNS) for which there is no clinical treatment. Blood-spinal cord barrier (BSCB) rupture is a critical event in SCI that aggravates nerve injury. Therefore, maintaining the integrity of the BSCB may be a potential method to treat SCI. Here, we showed that patchouli alcohol (PA) exerts protective effects against SCI. We discovered that PA significantly prevented hyperpermeability of the BSCB by reducing the loss of tight junctions (TJs) and endothelial cells. PA also suppressed endoplasmic reticulum stress and apoptosis in vitro. Furthermore, in a rat model of SCI, PA effectively improved neurological deficits. Overall, these results prove that PA exerts neuroprotective effects by maintaining BSCB integrity and thus be a promising candidate for SCI treatment.

18ß-Glycyrrhetinic acid inhibits IL-1ß-induced inflammatory response in mouse chondrocytes and prevents osteoarthritic progression by activating Nrf2.

Osteoarthritis (OA) is presently the most prevalent form of chronic degenerative joint disease, which is characterized by erosion of articular cartilage, subchondral bone sclerosis and synovitis. Accumulating evidence has revealed that 18ß-glycyrrhetinic acid (18ß-GA), a major bioactive component derived from Glycyrrhiza glabra, exerts anti-inflammatory effects on several diseases. However, the anti-inflammatory effects of 18ß-GA on OA remain undetermined. The present study aimed to investigate the anti-inflammatory effects of 18ß-GA on chondrocytes and the therapeutic effects on destabilization of the medial meniscus destabilization (DMM) mouse models of OA. For the in vivo study, we randomly divided the mice into three groups: vehicle control (n = 15), sham (n = 15) and 18ß-GA (n = 15) groups, and treated them with similar doses (50 mg kg-1 day-1) of 18ß-GA or saline. Cartilage tissues were harvested from the mice for histological analyses eight weeks after operation. For the in vitro studies, mouse chondrocytes were administered with 10 ng mL-1 interleukin-1ß (IL-1ß) after being treated with 18ß-GA at various concentrations. In vitro assays revealed that treatment with 18ß-GA considerably suppressed the expression of pro-inflammatory mediators and cytokines, including prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), nitric oxide (NO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and interleukin-6 (IL-6), which were induced by IL-1ß. Furthermore, 18ß-GA decreased the expression of matrix-degrading proteases, including matrix metalloproteinase 13 (MMP13) and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), in a concentration-dependent manner, which mediated extracellular matrix (ECM) degradation. 18ß-GA reversed aggrecan and type II collagen degradation. Furthermore, we observed that 18ß-GA significantly suppressed IL-1ß-induced nuclear factor kappa B (NF-κB) activation by activating the nuclear factor erythroid-derived 2-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway in vitro and in vivo. Experiments demonstrated that 18ß-GA might alleviate the progression of OA in the DMM mouse model in vivo. The findings demonstrate that 18ß-GA reduces inflammation induced by IL-1ß in chondrocytes. Therefore, 18ß-GA could be a potential therapeutic agent for OA.

Promoting Nrf2/Sirt3-Dependent Mitophagy Suppresses Apoptosis in Nucleus Pulposus Cells and Protects against Intervertebral Disc Degeneration.

One of the causes of intervertebral disc degeneration (IVDD) is nucleus pulposus cell (NPC) death, possibly apoptosis. In this study, we explored the role of the Nrf2/Sirt3 pathway and tert-butylhydroquinone (t-BHQ) in IVDD and elucidated the potential working mechanism. Reactive oxygen species (ROS) assay kits and malondialdehyde (MDA) assay kits were used to assess oxidative stress. Western blot and TUNEL staining were used to examine apoptosis. After siRNA against Nrf2 or lentivirus against Sirt3 was transfected into NPCs, the mechanism of the effect of the Nrf2/Sirt3 pathway on NPCs was assessed. The interaction between t-BHQ and its potential interacting protein NRF2 was further investigated through protein docking analysis. ChIP examined the binding affinity between Nrf2 and Sirt3 promoter. In vivo experiments, X-ray, hematoxylin-eosin (HE) staining, Safranin O staining, and immunohistochemistry were used to evaluate IVDD grades. The results demonstrated that activation of the Nrf2/Sirt3 pathway inhibited tert-butyl hydroperoxide- (TBHP-) induced apoptosis and mitochondrial dysfunction in vitro. In addition to apoptosis, upregulation of the Nrf2/Sirt3 pathway induced by t-BHQ restored TBHP-induced autophagic flux disturbances. However, its protective effect was reversed by chloroquine and Si-ATG5. Furthermore, t-BHQ ameliorated IVDD development in a rat model. In conclusion, our findings indicate that the Nrf2/Sirt3 pathway and its agonist represent a potential candidate for treating IVDD.

Cardamonin protects nucleus pulposus cells against IL-1ß-induced inflammation and catabolism via Nrf2/NF-κB axis.

Intervertebral disc degeneration (IVDD) is one of the major causes of low back pain, but effective therapies are still lacking because of its complicated pathology. It has been demonstrated that increased levels of interleukin-1ß (IL-1ß) may promote the development of IVDD. Cardamonin (CAR) is a chalcone extracted from Alpinia katsumadai and other plants. It exhibits an anti-inflammatory effect in multiple diseases. In the present study, we investigated the protective effects of CAR on rat nucleus pulposus (NP) cells under IL-1ß stimulation in vitro and in a puncture-induced rat IVDD model in vivo. We explored the CAR treatment's inhibition of the expression of inflammatory factors such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in rat NP cells. Moreover, the up-regulation of matrix metalloproteinase-13 (MMP-13) and thrombospondin motifs 5 (ADAMTS-5) and the degradation of aggrecan and collagen II induced by IL-1ß were reversed by CAR. Mechanistically, we demonstrated that CAR inhibited nuclear factor kappa B (NF-κB) signaling by activating the nuclear factor erythroid-derived 2-like 2 (Nrf2) in IL-1ß-induced rat NP cells. Furthermore, the protective effect of CAR was shown in the IVDD model through persistent intragastric administration. Taken together, our results revealed that CAR could activate the Nrf2/HO-1 signaling axis and be a novel agent for IVDD therapy.

Puerarin suppresses inflammation and ECM degradation through Nrf2/HO-1 axis in chondrocytes and alleviates pain symptom in osteoarthritic mice.

Osteoarthritis (OA) is the most common degenerative joint disorder with no effective drugs. Puerarin is a dietary supplement that has wide-ranging pharmacological effects. This study aimed to investigate the effects of Puerarin on OA. The effects of Puerarin on apoptosis, extracellular matrix (ECM) metabolism, and inflammation-related factors were assessed; also, the nuclear factor-κB (NF-κB) signaling pathway and Nrf2/HO-1 (nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1) axis were evaluated to elucidate the working mechanism of Puerarin. Mice were fed with Puerarin to evaluate the therapeutic effect of Puerarin on Osteoarthritis in vivo. The results showed that Puerarin suppressed inflammatory mediators and apoptosis induced by IL-1ß treatment in chondrocytes, it may also suppress ECM degradation in IL-1ß treated chondrocytes. The mechanism study revealed that Nrf2/HO-1 pathway is involved in Puerarin induced inhibition of NF-κB signaling pathway. Finally, in vivo study demonstrated that Puerarin could postpone the progression of OA in mice and relieve the symptoms of pain. In conclusion, Puerarin may potentially alleviate OA progression, and the mechanism may relate to the Nrf2/HO-1 pathway regulation.

Inhibition of LRRK2 restores parkin-mediated mitophagy and attenuates intervertebral disc degeneration.

OBJECTIVE: To elucidate the role of LRRK2 in intervertebral disc degeneration (IDD) as well as its mitophagy regulation mechanism. METHODS: The expression of LRRK2 in human degenerative nucleus pulposus tissues as well as in oxidative stress-induced rat nucleus pulposus cells (NPCs) was detected by western blot. LRRK2 was knocked down in NPCs by lentivirus (LV)-shLRRK2 transfection; apoptosis and mitophagy were assessed by western blot, TUNEL assay, immunofluorescence staining and mitophagy detection assay in LRRK2-deficient NPCs under oxidative stress. After knockdown of Parkin in NPCs with siRNA transfection, apoptosis and mitophagy were further assessed. In puncture-induced rat IDD model, X-ray, MRI, hematoxylin-eosin (HE) and Safranin O-Fast green (SO) staining were performed to evaluate the therapeutic effects of LV-shLRRK2 on IDD. RESULTS: We found that the expression of LRRK2 was increased in degenerative NPCs both in vivo and in vitro. LRRK2 deficiency significantly suppressed oxidative stress-induced mitochondria-dependent apoptosis in NPCs; meanwhile, mitophagy was promoted. However, these effects were abolished by the mitophagy inhibitor, suggesting the effect of LRRK2 on apoptosis in NPCs is mitophagy-dependent. Furthermore, Parkin knockdown study showed that LRRK2 deficiency activated mitophagy by recruiting Parkin. In vivo study demonstrated that LRRK2 inhibition ameliorated IDD in rats. CONCLUSIONS: The results revealed that LRRK2 is involved in the pathogenesis of IDD, while knockdown of LRRK2 inhibits oxidative stress-induced apoptosis through mitophagy. Thus, inhibition of LRRK2 may be a promising therapeutic strategy for IDD.

No evidence of a correlation between lumbar spinal subtypes and intervertebral disc degeneration among asymptomatic middle-aged and aged patients.

The aim of the present study was to identify whether lumbar spinal subtypes (LSS) were associated with lumbar disc degeneration (LDD) among asymptomatic middle-aged and aged subjects. A cohort of 158 asymptomatic Chinese adults aged >40 years was recruited and 97 volunteers that met the inclusion criteria with complete information available were selected for inclusion. According to spinal morphology, volunteers were divided into four subtypes based on the classification of Roussouly. After baseline information was collected and spinopelvic parameters were measured, the data were compared among the four groups. According to the Pfirrmann classification, the degree of LDD was evaluated at each level on the MRI. For grades I-V, LDD at each level was effectively compared. Each of the four LSS from I to IV according to Roussouly classification from types I to IV were comprised of 25 (25.8%), 19 (19.6%), 38 (39.2%) and 15 (15.5%) of volunteers, respectively. Lumbar lordosis, sacral slope and pelvic incidence were significantly different among the four sub-types (P<0.001 for each), but no difference in pelvic tilt was observed (P=0.21). From types I to IV LSS, the proportion of disc degeneration was found to be 44, 52, 50 and 48%, respectively, which exhibited no statistically significant difference among LSS. No correlation between LSS and intervertebral disc degeneration was obtained among the asymptomatic middle-aged and aged subjects. The present study provides a reference for spinal surgery and indicated that additional risk factors should be assessed in the asymptomatic population of this age group, particularly in terms of differentially expressed genes.

Risk factors for postoperative residual back pain after percutaneous kyphoplasty for osteoporotic vertebral compression fractures.

PURPOSE: To determine the incidence of and risk factors for residual back pain in osteoporotic vertebral compression fracture (OVCF) patients after percutaneous kyphoplasty (PKP) treatment, we performed a retrospective analysis of prospective data. METHODS: Patients who underwent bilateral PKP and met this study's inclusion criteria were retrospectively reviewed. Back pain intensity was assessed using a visual analogue scale (VAS) after surgery. Residual back pain was defined as the presence of postoperative moderate-severe pain (average VAS score ≥ 4), and the variables included patient characteristics, baseline symptoms, radiological parameters and surgical factors. Univariate and multivariate logistic regression analyses were performed to identify risk factors. RESULTS: A total of 809 patients were included, and residual back pain was identified in 63 (7.8%) patients. Of these patients, 52 patients had complete data for further analysis. Multivariate logistic regression analysis showed that risk factors for back pain included the presence of an intravertebral vacuum cleft (OR 2.93, P = 0.032), posterior fascia oedema (OR 4.11, P = 0.014), facet joint violations (OR 12.19, P < 0.001) and a separated cement distribution (OR 2.23, P = 0.043). CONCLUSION: The incidence of postoperative residual back pain was 7.8% among 809 OVCF patients following PKP. The presence of an intravertebral vacuum cleft, posterior fascia oedema, facet joint violations and a separated cement distribution were identified as independent risk factors for residual back pain.

Stabilization of HIF-1α alleviates osteoarthritis via enhancing mitophagy.

Mitochondrial dysfunction leads to osteoarthritis (OA) and disc degeneration. Hypoxia inducible factor-1α (HIF-1α) mediated mitophagy has a protective role in several diseases. However, the underlying mechanism of HIF-1α mediated mitophagy in OA remains largely unknown. This current study was performed to determine the effect of HIF-1α mediated mitophagy on OA. Therefore, X-ray and tissue staining including HE staining, safranin O-fast green (S-O) and Alcian Blue were used to assess imageology and histomorphology differences of mouse knee joint. Transcriptional analysis was used to find the possible targets in osteoarthritis. Western blot analysis, RT-qPCR and immunofluorescence staining were used to detect the changes in gene and protein levels in the vitro experiment. The expression of HIF-1α was increased in human and mouse OA cartilage. HIF-1α knockdown by siRNA further impair the hypoxia-induced mitochondrial dysfunction; In contrast, HIF-1α mediated protective role was reinforced by prolylhydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG). In addition, HIF-1α stabilization could alleviate apoptosis and senescence via mitophagy in chondrocytes under hypoxia condition, which could also ameliorate surgery-induced cartilage degradation in mice OA model. In conclusion, HIF-1α mediated mitophagy could alleviate OA, which may serve as a promising strategy for OA treatment.

Prevalence of the thoracic scoliosis in children and adolescents candidates for strabismus surgery: results from a 1935-patient cross-sectional study in China.

PURPOSE: No study so far has paid attention to strabismus-related spinal imbalance. This study aimed to determine the epidemiology of thoracic scoliosis in children and adolescents with strabismus and investigate the association of two diseases. METHODS AND DESIGN: A cross-sectional study. Study group consists of 1935 consecutive candidates for strabismus surgery (4-18 years); Control group consists of the age- and sex-matched patients with respiratory diseases. All subjects underwent a screening program based on chest plain radiographs using the Cobb method. Their demographic information, clinical variables and results of Cobb angle were recorded and analyzed. RESULTS: A significantly higher prevalence of thoracic scoliosis (289/1935, 14.94% versus 58/1935, 3.00%) was found in study group compared with control group. Among strabismic patients, the coronal thoracic scoliosis curve mainly distributed in right and in main thoracic (198/289) and in the curves 10°-19° (224/289); Age range 7-9 years (103/1935), female (179/1935) and concomitant exotropia patients (159/851) were more likely to have thoracic scoliosis. According to the logistic regression, thoracic scoliosis had no significant association with age, BMI, duration of illness and onset age (p > 0.05). However, gender, BCVA, type of strabismus and degree of strabismus showed a significant relationship with the prevalence of thoracic scoliosis (p < 0.05). CONCLUSIONS: With a pooled prevalence of 14.94%, strabismus patients showed a great higher risk of developing thoracic scoliosis. Screening for scoliosis in strabismus patients can be helpful to discover a high prevalence of potential coronal scoliosis. More attention should be paid to ophthalmological problems in patients with scoliosis. These slides can be retrieved under Electronic Supplementary Material.

Anterior decompression through transoral axis slide and rotation osteotomy for salvage of failed posterior occipitocervical fusion: a novel technique note.

Atlantoaxial dislocation could be caused by odontoid fractures or Os odontoideum. The previous surgical techniques in treatment of atlantoaxial dislocation were based on arch remove decompression or anterior atlantoaxial release and atlantoaxial (occipital-cervical) screw fixation-based reduction and fusion. However, for some clinical situations, all of above techniques cannot be applied. In this study, a patient with atlantoaxial dislocation caused by Os odontoideum treated by posterior occipitocervical fusion 20 years ago and failed. We design a novel anterior decompression through transoral axis slide and rotation osteotomy for salvage of this failed posterior occipitocervical fusion case. The C2 body and odontoid process was ventrally slide and rotation at good position after operation as well as the position of plate and screws, the spinal canal was increased significantly after operation too. We suggest this anterior decompression through transoral "C2 slide and rotation" technique is good choice for salvage of failed posterior occipitocervical fusion and some irreducible atlantoaxial dislocation because of the anterior bony fusion, it could direct decompress the spinal cord anteriorly, avoid the odontoid resection, and is feasible and safe technique.

The Emerging Roles of the Gaseous Signaling Molecules NO, H2S, and CO in the Regulation of Stem Cells.

Stem cell technology can be used in tissue engineering and regenerative medicine to transplant stem cells of somatic, embryonic, or induced pluripotent origin, which have tremendous potential for the treatment of currently incurable diseases. Stem cells can maintain their stemness through their self-renewal capability while promoting tissue repair and regeneration through differentiation into various target tissue cells. These two major processes of stem cell biology are precisely regulated via extracellular and intracellular signals. Gaseous signaling molecules have recently been identified to play important roles in both physiology and pathophysiology, and inhalable nitric oxide (iNO) has even been applied as a therapeutic agent. Compared with chemical formulations, these molecules have lower molecular weights and are more likely to pass through the blood-brain barrier and between cells. Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), three major gaseous signaling molecules involved in biological functions, are emerging as regulators of stem cell processes such as self-renewal, differentiation, survival, anti-apoptotic effects, proliferation, and immune rejection. Although many reviews concerning the roles of gaseous signaling molecules in different diseases or systems are available, few have focused on the roles of these molecules in the regulation of stem cells. Therefore, the aim of this paper is to systematically review the current literature on the functions and mechanisms of the gaseous signaling molecules NO, H2S, and CO in different types of stem cells and to summarize the effects of these molecules on stem cell biology and in therapy.

Dual regulation of microglia and neurons by Astragaloside IV-mediated mTORC1 suppression promotes functional recovery after acute spinal cord injury.

Inflammation and neuronal apoptosis contribute to the progression of secondary injury after spinal cord injury (SCI) and are targets for SCI therapy; autophagy is reported to suppress apoptosis in neuronal cells and M2 polarization may attenuate inflammatory response in microglia, while both are negatively regulated by mTORC1 signalling. We hypothesize that mTORC1 suppression may have dual effects on inflammation and neuronal apoptosis and may be a feasible approach for SCI therapy. In this study, we evaluate a novel inhibitor of mTORC1 signalling, Astragaloside IV (AS-IV), in vitro and in vivo. Our results showed that AS-IV may suppress mTORC1 signalling both in neuronal cells and microglial cells in vitro and in vivo. AS-IV treatment may stimulate autophagy in neuronal cells and protect them against apoptosis through autophagy regulation; it may also promote M2 polarization in microglial cells and attenuate neuroinflammation. In vivo, rats were intraperitoneally injected with AS-IV (10 mg/kg/d) after SCI, behavioural and histological evaluations showed that AS-IV may promote functional recovery in rats after SCI. We propose that mTORC1 suppression may attenuate both microglial inflammatory response and neuronal apoptosis and promote functional recovery after SCI, while AS-IV may become a novel therapeutic medicine for SCI.