Serum periostin levels correlate with severity of intervertebral disc degeneration.

PURPOSE: Periostin, an extracellular matrix protein closely related to mechanical stress, inflammation, and ageing, has been implicated in intervertebral disc degeneration (IVDD) in basic research. However, it has not been examined in clinical cases. This study aimed to evaluate the association between IVDD severity and serum periostin concentration as well as to analyse potential associations between IVDD and clinical and demographic factors. METHODS: This retrospective cohort study included 198 patients who underwent lumbar disc herniation and lumbar canal stenosis between January 2020 and December 2022. The severity of IVDD was evaluated using the Pfirrmann grading, whereas serum periostin levels were measured using ELISA kits. Clinical demographics, including age, sex, body mass index, comorbidities, psoas muscle index, and spinal disease, were also recorded. RESULTS: This study demonstrated a significant correlation between high serum periostin levels and IVDD severity, as indicated by a high cumulative Pfirrmann score. Serum periostin levels were identified as an independent risk factor for IVDD in a multivariate regression model. Correlation analysis showed a correlation between periostin levels and Pfirrmann grade at each lumbar level (ρ = 0.458-0.550, p < 0.001) and a strong correlation with cumulative Pfirrmann score (ρ = 0.690, p < 0.001). CONCLUSION: The higher the serum periostin level, the higher the cumulative Pfirrmann score. Multivariate analysis showed that serum periostin was an independent risk factor for IVDD. Periostin levels may be a clinically suitable and useful biomarker for diagnosing IVDD, estimating disease progression and activity, providing prognostic information, and evaluating treatment options.

How long will it take to reach the gender diversity goal for orthopaedics in Japan?

BACKGROUND: In Japan, orthopaedics is one of the medical fields with the lowest proportion of women. This study analyses the change in gender diversity over the past decade and estimates the time required to achieve the 30% gender diversity goal, according to the critical mass in Japan in 2020. METHODS: We investigated the demographic composition of orthopaedic surgeons in 2020 by age group, the gender ratio of the main clinical fields from 2010 to 2020, and estimated the time required for the bottom 10 (i.e., least diverse) medical departments in Japan to reach the proportion of 30% women. We used simple linear regression analyses to clarify the number of years. RESULTS: In 2020, the population pyramid of orthopaedic surgeons showed that those in their 50s were the largest component with 24.1%, followed by those in their 40s and 30s with 22.3% and 19.4%, respectively. The percentage of women orthopaedic surgeons increased slightly from 4.1% in 2010 to 5.7% in 2020. This means that to achieve the proportion of 30% women at the current annual increase rate, orthopaedics would require up to 160 years, cardiovascular 149 years, and neurosurgery 135 years. CONCLUSION: Contrary to the recent increase in the number of women physicians, there has been only a slight increase in the number of women orthopaedic surgeons over the past decade. Moreover, the number of young male orthopaedic surgeons has decreased. As current orthopaedic surgeons age and retire, Japan will soon face an overall shortage of orthopaedic surgeons. Issues that must still be addressed in Japanese orthopaedics include educating men and women about gender diversity and bias, changing stereotypes about surgical lifestyles, improving work-life balance, and diligent and collaborative efforts at both the individual and community levels.

Cardiopulmonary Cement Embolism Following Cement-Augmented Pedicle Screw Fixation: A Narrative Review.

Fixation using cement-augmented pedicle screws (CAPS) is being increasingly performed. However, CAPS-associated cement leakage is a critical problem that can lead to cardiopulmonary cement embolism (CPCE). This narrative review aimed to explore the incidence of and risk factors and treatment strategies for CPCE and cement leakage-related complications after CAPS fixation. Data were extracted from each article, including characteristics of CPCE after CAPS fixation (incidence, location, diagnostic method and criteria, treatment, and outcome and prognosis). Overall, 28 case series and 14 case reports that met the inclusion criteria were included. Of the 1974 cases included in the review, CPCE was noted in 123, symptomatic CPCE in 35, and death in six, respectively. The frequencies of PCE and symptomatic PCE after CAPS fixation were 6% (range: 0-28.6%) and 1.3% (range: 0-26%), respectively. The range of frequencies of PCE and symptomatic PCE after CAPS fixation may have been wide because the definition of CPCE and data collection methods differed among the reports analyzed. Since PCE due to large cement emboli may be primarily related to the surgical technique, improved technique, such as minimizing the number of CAPSs by injecting low-volume high-viscosity cement at low velocity and pressure, and careful observation of cement leakage during CAPS insertion may reduce PCE associated with cement leakage. Spinal surgeons should pay more attention to the occurrence of CPCE during and after CAPS insertion, which can cause serious complications in some patients.

Application of contralateral osteotomy for the en bloc resection of paraspinal and spinal tumours: a report of three cases.

We herein report the effectiveness of contralateral osteotomy of the pedicle and posterolateral elements for en bloc resection (COPPER) of paraspinal and spinal tumours. This surgical method allows for complete resection of the localized tumour in the lateral posterior lesion without removing the entire vertebral body, as in total en bloc spondylectomy. Complete resection of paraspinal and spinal tumours is challenging for spinal surgeons because of anatomical complexities. Although the COPPER method has been introduced as a less invasive surgical procedure for wide resection of spinal tumours, no studies have reported the usefulness of this technique. We identified three patients with paraspinal or spinal tumours who underwent wide resection using the COPPER method and reviewed their clinical, radiological, and pathological outcomes. In all cases, we resected the spinal and paraspinal tumours extending to the anterior column and extravertebral component using the modified COPPER method. All patients underwent en bloc resection with a negative margin. We report three cases of spinal and paraspinal tumours extending to the anterior column and extravertebral component.

Development of Silver-Containing Hydroxyapatite-Coated Antimicrobial Implants for Orthopaedic and Spinal Surgery.

The prevention of surgical site infections is directly related to the minimization of surgical invasiveness, and is in line with the concept of minimally invasive spine therapy (MIST). In recent years, the incidence of postoperative infections has been increasing due to the increased use of spinal implant surgery in patients at high risk of infection, including the elderly and easily infected hosts, the limitations of poor bone marrow transfer of antibiotics, and the potential for contamination of surgical gloves and instruments. Thus, the development of antimicrobial implants in orthopedic and spinal surgery is becoming more and more popular, and implants with proven antimicrobial, safety, and osteoconductive properties (i.e., silver, iodine, antibiotics) in vitro, in vivo, and in clinical trials have become available for clinical use. We have developed silver-containing hydroxyapatite (Ag-HA)-coated implants to prevent post-operative infection, and increase bone fusion capacity, and have successfully commercialized antibacterial implants for hip prostheses and spinal interbody cages. This narrative review overviews the present status of available surface coating technologies and materials; describes how the antimicrobial, safety, and biocompatibility (osteoconductivity) of Ag-HA-coated implants have been demonstrated for commercialization; and reviews the clinical use of antimicrobial implants in orthopedic and spinal surgery, including Ag-HA-coated implants that we have developed.

Digital Transformation Will Change Medical Education and Rehabilitation in Spine Surgery.

The concept of minimally invasive spine therapy (MIST) has been proposed as a treatment strategy to reduce the need for overall patient care, including not only minimally invasive spine surgery (MISS) but also conservative treatment and rehabilitation. To maximize the effectiveness of patient care in spine surgery, the educational needs of medical students, residents, and patient rehabilitation can be enhanced by digital transformation (DX), including virtual reality (VR), augmented reality (AR), mixed reality (MR), and extended reality (XR), three-dimensional (3D) medical images and holograms; wearable sensors, high-performance video cameras, fifth-generation wireless system (5G) and wireless fidelity (Wi-Fi), artificial intelligence, and head-mounted displays (HMDs). Furthermore, to comply with the guidelines for social distancing due to the unexpected COVID-19 pandemic, the use of DX to maintain healthcare and education is becoming more innovative than ever before. In medical education, with the evolution of science and technology, it has become mandatory to provide a highly interactive educational environment and experience using DX technology for residents and medical students, known as digital natives. This study describes an approach to pre- and intraoperative medical education and postoperative rehabilitation using DX in the field of spine surgery that was implemented during the COVID-19 pandemic and will be utilized thereafter.

The relationship between pelvic incidence and anatomical acetabular anteversion in female Japanese patients with hip osteoarthritis: a retrospective iconographic study.

PURPOSE: This study aimed (1) to investigate the relationship between pelvic incidence (PI) and the anatomical acetabular anteversion (AA) relative to the spino-pelvic tilt (SPT) plane (anatomical AASPT), relative to the anterior pelvic plane (anatomical AAAPP), and functional standing AA; and (2) to compare AA and the sagittal spino-pelvic parameters of lumbo-pelvic complex types 1 (PI ≤ 30°) and 2 (PI > 30°), in Japanese females with hip osteoarthritis. METHODS: We conducted a retrospective study on 110 Japanese females with unilateral hip osteoarthritis. PI, standing lumbar lordosis (LL), standing SPT, anatomical AASPT, anatomical AAAPP, and functional standing AA were measured and calculated using radiographs and computed tomography. The PI-LL difference was defined as the mathematical difference between the PI and standing LL angles. Pearson's correlation test was used to measure the relationship between the PI and AA. Student's t test was used to compare spino-pelvic parameters between lumbo-pelvic complex type 1 (n = 24) and type 2 (n = 86). RESULTS: There was a significant relationship between the PI and anatomical AASPT (r = -0.532, p < 0.001), but no significant relationship between the PI and anatomical AAAPP (r = -0.021, p = 0.824) or functional standing AA (r = 0.104, p = 0.299). Lumbo-pelvic complex type 1 had a higher anatomical AASPT (22.4° ± 9.1° vs. 5.4° ± 15.1°, p < 0.001), similar anatomical AAAPP (15.0° ± 10.6° vs. 15.1° ± 15.3°, p = 0.981) and functional standing AA (12.4° ± 8.0° vs. 15.0° ± 14.1°, p = 0.254), a lower standing SPT (- 14.3° ± 11.0° vs. 13.7° ± 12.6°, p < 0.001), and a lower PI-LL difference (- 14.4° ± 18.5° vs. 6.4° ± 17.1°, p < 0.001) in comparison to lumbo-pelvic complex type 2. CONCLUSION: Our findings will help to improve the understanding of hip anatomy and its relationship with the standing spino-pelvic alignment in Japanese females with hip osteoarthritis.

Cross-Talk between Transforming Growth Factor-ß and Periostin Can Be Targeted for Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to learn whether the cross-talk between TGF-ß (transforming growth factor-ß), a central mediator in pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether inhibitors for integrin αVß3, a periostin receptor, can block pulmonary fibrosis in model mice and the TGF-ß signals in fibroblasts from patients with IPF. We found that cross-talk exists between TGF-ß and periostin signals via αVß3/ß5 converging into Smad3. This cross-talk is necessary for the expression of TGF-ß downstream effector molecules important for pulmonary fibrosis. Moreover, we identified several potent integrin low-molecular-weight inhibitors capable of blocking cross-talk with TGF-ß signaling. One of the compounds, CP4715, attenuated bleomycin-induced pulmonary fibrosis in vivo in mice and the TGF-ß signals in vitro in fibroblasts from patients with IPF. These results suggest that the cross-talk between TGF-ß and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block this cross-talk.

Periostin plays a critical role in the cell cycle in lung fibroblasts.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a median survival of only three to 5 years. Fibroblast proliferation is a hallmark of IPF as is secretion of extracellular matrix proteins from fibroblasts. However, it is still uncertain how IPF fibroblasts acquire the ability to progressively proliferate. Periostin is a matricellular protein highly expressed in the lung tissues of IPF patients, playing a critical role in the pathogenesis of pulmonary fibrosis. However, it remains undetermined whether periostin affects lung fibroblast proliferation. METHODS: In this study, we first aimed at identifying periostin-dependently expressed genes in lung fibroblasts using DNA microarrays. We then examined whether expression of cyclins and CDKs controlling cell cycle progression occur in a periostin-dependent manner. We next examined whether downregulation of cell proliferation-promoting genes by knockdown of periostin or integrin, a periostin receptor, using siRNA, is reflected in the cell proliferation of lung fibroblasts. We then looked at whether lung fibroblasts derived from IPF patients also require periostin for maximum proliferation. We finally investigated whether CP4715, a potent inhibitor against integrin αVß3 (a periostin receptor), which we have recently found blocks TGF-ß signaling, followed by reduced BLM-induced pulmonary fibrosis in mice, can block proliferation of lung fibroblasts derived from IPF patients. RESULTS: Many cell-cycle-related genes are involved in the upregulated or downregulated genes by periostin knockdown. We confirmed that in lung fibroblasts, periostin silencing downregulates expression of several cell-cycle-related molecules, including the cyclin, CDK, and, E2F families, as well as transcription factors such as B-MYB and FOXM1. Periostin or integrin silencing slowed proliferation of lung fibroblasts and periostin silencing increased the distribution of the G0/G1 phase, whereas the distribution of the G2/M phase was decreased. Lung fibroblasts derived from IPF patients also required periostin for maximum proliferation. Moreover, CP4715 downregulated proliferation along with expression of cell-cycle-related genes in IPF lung fibroblasts as well as in normal lung fibroblasts. CONCLUSIONS: Periostin plays a critical role in the proliferation of lung fibroblasts and the present results provide us a solid basis for considering inhibitors of the periostin/integrin αVß3 interaction for the treatment of IPF patients.

Periostin forms a functional complex with IgA in human serum.

BACKGROUND: Periostin is a matricellular protein belonging to the fasciclin family, playing a role for the pathogenesis of allergic diseases by binding to integrins on cell surfaces. Serum periostin is elevated in various allergic diseases reflecting type 2 inflammation and tissue remodeling so that for allergic diseases, periostin is expected to be a novel biomarker for diagnosis, assessing severity or prognosis, and predicting responsiveness to treatments. We have previously shown that most serum periostin exists in the oligomeric form by intermolecular disulfide bonds. METHODS: In this study, we examined how periostin forms a complex in serum, whether the periostin complex in serum is functional, and whether the complex formation interferes with reactivity to anti-periostin Abs. RESULTS: We found that periostin formed a complex with IgA1 at a 1:1 ratio. The periostin in the serum complex contained at least five different isoforms. However, IgA was not essential for the oligomeric formation of periostin in mouse serum or in IgA-lacking serum. The periostin-IgA complex in human serum was functional, sustaining the ability to bind to αVß3 integrin on cell surfaces. Moreover, periostin formed the complex with IgA broadly, which interferes the binding of the Abs recognizing all of the domains except the R4 domain to periostin. CONCLUSIONS: Periostin is a novel member of the IgA-associated molecules. These results are of great potential use to understand the pathological roles of periostin in allergic diseases and, from a practical standpoint, to develop diagnostics or therapeutic agents against periostin.

Hierarchical control of interleukin 13 (IL-13) signals in lung fibroblasts by STAT6 and SOX11.

Interleukin (IL)-13 is a signature cytokine of type 2 inflammation important for the pathogenesis of various diseases, including allergic diseases. Signal transducer and activator of transcription (STAT) 6 is a critical transcriptional factor for the IL-13 signals; however, it remains unknown how expression of the IL-13-induced genes is differentiated by the transcriptional machineries. In this study, we identified IL-13-induced transcriptional factors in lung fibroblasts using DNA microarrays in which SOX11 was included. Knockdown of SOX11 down-regulated expression of periostin and CCL26, both of which are known to be downstream molecules of IL-13, whereas enforced expression of SOX11 together with IL-13 stimulation enhanced expression of periostin. Moreover, we found that in DNA microarrays combining IL-13 induction and SOX11 knockdown there exist both SOX11-dependent and -independent molecules in IL-13-inducible molecules. In the former, many inflammation-related and fibrosis-related molecules, including periostin and CCL26, are involved. These results suggest that SOX11 acts as a trans-acting transcriptional factor downstream of STAT6 and that in lung fibroblasts the IL-13 signals are hierarchically controlled by STAT6 and SOX11.

Constitutive overexpression of periostin delays wound healing in mouse skin.

Periostin is a matricellular protein involved in development, maintenance, and regulation of tissues and organs via by binding to cell surface integrin receptors. Pathologically, periostin plays an important role in the process of wound healing: as a deficiency of the Postn gene delays wound closure and periostin is consistently up-regulated in response to injury and skin diseases. However, the functional role of elevated periostin in the process of wound healing has not been tested. In this study, we generated Postn-transgenic mice under the control of the CAG promoter/enhancer to investigate the effects of constitutive overexpression of full length periostin during its pathophysiological roles. Transgenic mice showed significant overexpression of periostin in skin, lung, and heart, but no morphological changes were observed. However, when these transgenic mice were injured, periostin overexpression delayed the closure of excisional wounds. Expression of IL-1ß and TNFα, pro-inflammatory cytokines important for wound healing, was significantly decreased in the transgenic mice, prior to delayed healing. Infiltration of neutrophils and macrophages, the main sources of IL-1ß and TNFα, was also down-regulated in the transgenic wound sites. From these data, we conclude that enforced expression of periostin delays wound closure due to reduced infiltration of neutrophils and macrophages followed by down-regulation of IL-1ß and TNFα expression. This suggests that regulated spatiotemporal expression of periostin is important for efficient wound healing and that constitutive periostin overexpression interrupts the normal process of wound closure.

Periostin in inflammation and allergy.

We found for the first time that IL-4 and IL-13, signature type 2 cytokines, are able to induce periostin expression. We and others have subsequently shown that periostin is highly expressed in chronic inflammatory diseases-asthma, atopic dermatitis, eosinophilc chronic sinusitis/chronic rhinosinusitis with nasal polyp, and allergic conjunctivitis-and that periostin plays important roles in the pathogenesis of these diseases. The epithelial/mesenchymal interaction via periostin is important for the onset of allergic inflammation, in which periostin derived from fibroblasts acts on epithelial cells or fibroblasts, activating their NF-κB. Moreover, the immune cell/non-immune cell interaction via periostin may be also involved. Now the significance of periostin has been expanded into other inflammatory or fibrotic diseases such as scleroderma and pulmonary fibrosis. The cross-talk of periostin with TGF-ß or pro-inflammatory cytokines is important for the underlying mechanism of these diseases. Because of its pathogenic importance and broad expression, diagnostics or therapeutic drugs can be potentially developed to target periostin as a means of treating these diseases.

Sagittal spino-pelvic alignment in rapidly destructive coxarthrosis.

PURPOSE: To investigate the sagittal spino-pelvic alignment (SSPA) in patients with rapidly destructive coxarthrosis (RDC). METHODS: SSPA was investigated in 44 patients with RDC and 70 patients with hip osteoarthritis (HOA). The study included only female patients over the age of 70 years because epidemiological reports indicate that RDC most commonly occurs in this group of patients. The SSPA parameters that were analyzed included lumbar lordosis (LL), lumbar range of motion (ΔLL), sacral slope (SS), pelvic incidence (PI), and pelvic tilt (PT). The pelvic inclination angle (PIA) in the supine position and the change in the PIA from the supine to the standing position (ΔPIA) were measured using anteroposterior pelvic radiographs. The values of these parameters were compared between the two groups. The levels of the SRS-Schwab classification modifiers were used to investigate the degree of sagittal malalignment. RESULTS: The RDC group showed significant lower LL, ΔLL and SS values, and significantly higher PT and ΔPIA values than the HOA group (P < 0.01). With regard to the sagittal modifiers in the SRS-Schwab classifications of the patients, the PI-LL and PT levels of the RDC group were significantly worse than those in the HOA group (P < 0.01). CONCLUSIONS: The present study suggests that the static factors of a reduction in the lumbar lordotic angle and greater posterior pelvic tilt, the dynamic factors of small ΔLL values and large ΔPIA values and the complex interaction of these two types of factors, may play important roles in the development of RDC.

Induction of Airway Allergic Inflammation by Hypothiocyanite via Epithelial Cells.

Hypothiocyanite (OSCN-) serves as a potent innate defense system against microbes in the lungs. OSCN- is generated by the catalysis of peroxidases using thiocyanate transported via several anion transporters, including pendrin/SLC26A4 and hydrogen peroxide (H2O2) generated by Duox1 and Duox2. We previously demonstrated that expression of pendrin, peroxidases, and Duox1/Duox2 is up-regulated in bronchial asthma patients and/or asthma model mice and that these molecules are important in accelerating airway inflammation. However, it remained unclear how activating these molecules would lead to airway inflammation. In this study, we examined whether OSCN- produced via the pendrin/peroxidase/Duox pathway causes inflammation via airway epithelial cells. In an in vitro OSCN- production system, OSCN-, but not H2O2, activated NF-κB, a transcription factor critical for inflammatory responses, in the airway epithelial cells. OSCN- was sensed by protein kinase A (PKA) followed by formation of the dimerization of PKA. The dimerized PKA, the active form, was critical in activating NF-κB. Detoxifying H2O2, mainly by catalase, enabled the dominant abilities of OSCN- to dimerize PKA and activate NF-κB, compared with untreated H2O2 Furthermore, OSCN- in high doses caused necrosis of the cells, inducing release of IL-33, a trigger to initiate type 2 inflammation. These results demonstrate that OSCN- in low doses activates NF-κB via PKA in airway epithelial cells, whereas OSCN- in high doses causes necrosis, suggesting an important role in airway allergic inflammation for the production of OSCN- via the pendrin/peroxidase/Duox pathway.

Clarithromycin attenuates IL-13-induced periostin production in human lung fibroblasts.

BACKGROUND: Periostin is a biomarker indicating the presence of type 2 inflammation and submucosal fibrosis; serum periostin levels have been associated with asthma severity. Macrolides have immunomodulatory effects and are considered a potential therapy for patients with severe asthma. Therefore, we investigated whether macrolides can also modulate pulmonary periostin production. METHODS: Using quantitative PCR and ELISA, we measured periostin production in human lung fibroblasts stimulated by interleukin-13 (IL-13) in the presence of two 14-member-ring macrolides-clarithromycin or erythromycin-or a 16-member-ring macrolide, josamycin. Phosphorylation of signal transducers and activators of transcription 6 (STAT6), downstream of IL-13 signaling, was evaluated by Western blotting. Changes in global gene expression profile induced by IL-13 and/or clarithromycin were assessed by DNA microarray analysis. RESULTS: Clarithromycin and erythromycin, but not josamycin, inhibited IL-13-stimulated periostin production. The inhibitory effects of clarithromycin were stronger than those of erythromycin. Clarithromycin significantly attenuated STAT6 phosphorylation induced by IL-13. Global gene expression analyses demonstrated that IL-13 increased mRNA expression of 454 genes more than 4-fold, while decreasing its expression in 390 of these genes (85.9%), mainly "extracellular," "plasma membrane," or "defense response" genes. On the other hand, clarithromycin suppressed 9.8% of the genes in the absence of IL-13. Clarithromycin primarily attenuated the gene expression of extracellular matrix protein, including periostin, especially after IL-13. CONCLUSIONS: Clarithromycin suppressed IL-13-induced periostin production in human lung fibroblasts, in part by inhibiting STAT6 phosphorylation. This suggests a novel mechanism of the immunomodulatory effect of clarithromycin in asthmatic airway inflammation and fibrosis.

Traumatic atlanto-occipital dislocation with successfully bystander resuscitation after cardiopulmonary arrest: A case report.

This case report describes successful bystander cardiopulmonary resuscitation after a cardiopulmonary arrest due to a traffic accident, followed by early diagnosis and treatment of a traumatic atlanto-occipital dislocation, resulting in successful community reintegration.