What Is the Revision-free Survival of Resurfaced Allograft-prosthesis Composites for Proximal Humerus Reconstruction in Children With Bone Tumors?

BACKGROUND: Reconstruction of the proximal humerus in children who undergo bone tumor resection is challenging because of patients' small bone size and possible limb length discrepancy at the end of skeletal growth due to loss of the physis. There are several options for proximal humerus reconstruction in children, such as clavicula pro humero, free vascularized fibula grafting, massive bone osteoarticular allografting, endoprostheses, and allograft-prosthesis composites, but no consensus exists on the best method for reconstruction. Resurfaced allograft-prosthesis composites could be an alternative surgical option, but little is known about the results of this surgical technique. QUESTIONS/PURPOSES: (1) What are the complications and what is the survivorship free from reconstruction failure associated with resurfaced allograft-prosthesis composites in a small, single-center case series? (2) What Musculoskeletal Tumor Society scores do patients achieve after reconstructions with resurfaced allograft-prosthesis composites? METHODS: This study was a retrospective, single-arm case analysis in a single institution. We generally considered resurfaced allograft-prosthesis composites in children with malignant bone tumors involving the metaepiphysis of the proximal humerus in whom there was no evidence of joint contamination and in whom axillary nerve preservation was possible. Between 2003 and 2021, we treated 100 children (younger than 15 years) with bone tumors of the humerus. Thirty children (30%) with diaphyseal tumors (21 children) or distal tumors (9 children) were excluded. Among the potentially eligible children, 52 were not analyzed because they were treated with other procedures such as amputation, modular prostheses, cement spacers, free vascularized fibula grafting, and massive bone osteoarticular allografts. We included 18 children (26% of the potentially eligible children) who were treated with resurfaced allograft-prosthesis composites. There were 9 boys and 9 girls, with a median age of 10 years (range 4 to 15 years) at the time of diagnosis. A long stem (≥ 6 cm) in the resurfaced allograft-prosthesis composite was used in 9 children and a short stem (< 6 cm) was used in the remaining 9. One of the 18 children had a follow-up of less than 2 years. The median follow-up of the remaining 17 children was 4.7 years (range 2 to 19 years). The children' medical records were reviewed for clinical and functional outcomes. We performed a competing risk analysis to calculate the reconstruction failure-free survival of resurfaced allograft-prosthesis composites. Reconstruction failure was defined as removal of the implant or allograft because of implant loosening or breakage and allograft fracture or resorption. We analyzed the children's postoperative complications and functional outcomes at the end of the follow-up period using the Musculoskeletal Tumor Society functional scoring system. RESULTS: The competing risk analysis revealed that reconstruction failure was 25% (95% confidence interval 7% to 40%) at 3 years, reaching a plateau. Four of 18 children underwent surgical revision with a new reconstruction. The reasons for reconstruction revision were resorption of the allograft at the proximal part (2 children) and fracture of the allograft (2 children). Reconstruction revision was performed in 3 of 9 children who underwent reconstruction with a short stem and in 1 of 9 children who underwent reconstruction with a long stem. Several children had other complications that did not result in removal of the allograft. Allograft resorption was observed in 4 of 18 children, but no additional surgical treatment was performed. Shoulder instability or subluxation was observed in 4 of 18 children, but only 1 child underwent surgery with a reverse shoulder arthroplasty without removal of the resurfaced allograft-prosthesis composite. Limited elbow motion because of plate impingement was observed in 1 child who underwent surgical cutting of the protruding distal part of the plate. Incomplete radial nerve palsy after surgery occurred in 1 child, with spontaneous resolution after 2 months. Screw loosening occurred in 2 children who underwent surgery with removal of loose screws. Two children had a nonunion at the graft-host bone junction; 1 child underwent surgery with bone grafting and refixation of the graft-host bone junction, and the other child with both nonunion and plate breakage was treated with bone grafting and refixation of the graft-host bone junction with a new plate. Among 17 children who had a follow-up longer than 2 years, the median Musculoskeletal Tumor Society functional score at the last follow-up interval was 23 of 30 (range 20 to 26); 1 child was considered to have an excellent result (functional score ≥ 26), 15 children were considered to have a good result (functional score 21 to 25), and 1 child was considered to have a fair result (functional score ≤ 20). The Musculoskeletal Tumor Society functional score did not change after excluding 4 children who underwent replacement of resurfaced allograft-prosthesis composites (24 of 30 [range 20 to 26]). The median angle of flexion of the shoulder was 40° (range 20º to 90°), and the median angle of abduction was 30° (range 20º to 90°). CONCLUSION: Resurfaced allograft-prosthesis composites showed a high risk of complications, but not all complications resulted in removal of the reconstructed allograft. We used this technique mainly for very young children with small bones and for older children who underwent axillary nerve preservation. Although its success may be limited owing to a high risk of complications, a resurfaced allograft-prosthesis composite could be an alternative surgical option in order to preserve the bone stock and achieve good functional outcomes in very young children. We recommend using a long-stem resurfaced allograft-prosthesis composite, which may reduce the risk of complications. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Malawer type I/V proximal humerus reconstruction after tumor resection: a systematic review.

BACKGROUND: Several reconstruction methods exist for Malawer type I/V proximal humerus reconstruction after bone tumor resection; however, no consensus has been reached regarding the preferred methods. METHODS: We conducted a literature search on various types of proximal humerus oncologic reconstruction methods. We collected data on postoperative functional outcomes assessed based on Musculoskeletal Tumor Society (MSTS) scores, 5-year reconstruction survival rates, and complications. We calculated each reconstruction's weighted mean based on the sample size and standard errors. Complications were categorized based on the Henderson classification. Based on these integrated data, our primary objective is to propose an optimal strategy for proximal humerus reconstruction after bone tumor resection. RESULTS: We examined various reconstruction techniques, including modular prosthesis (752 patients in 21 articles), osteoarticular allograft (142 patients in 6 articles), allograft prosthesis composites (APCs) (236 patients in 12 articles), reverse shoulder total arthroplasty (141 patients in 10 articles), composite reverse shoulder total arthroplasty (33 patients in 4 articles), claviculo-pro-humero (CPH) technique (51 patients in 6 articles), and cement spacer (207 patients in 4 articles). Weighted mean MSTS scores were: modular prosthesis (73.8%), osteoarticular allograft (74.4%), APCs (79.2%), reverse shoulder total arthroplasty (77.0%), composite reverse shoulder total arthroplasty (76.1%), CPH technique (75.1%), and cement spacer (69.1%). Weighted 5-year reconstruction survival rates were modular prosthesis (85.4%), osteoarticular allograft (67.6%), APCs (85.2%), reverse shoulder total arthroplasty (84.1%), and cement spacer (88.0%). Reconstruction survival data was unavailable for composite reverse shoulder total arthroplasty and CPH technique. Major complications included shoulder joint instability: modular prosthesis (26.2%), osteoarticular allograft (41.5%), APCs (33.9%), reverse shoulder total arthroplasty (17%), composite reverse shoulder total arthroplasty (6.1%), CPH technique (2.0%), and cement spacer (8.7%). Aseptic loosening of the prosthesis occurred: modular prosthesis (3.9%) and reverse shoulder total arthroplasty (5.7%). Allograft fracture was observed in 54.9% of patients with osteoarticular allograft. CONCLUSION: The complication profiles differed among reconstruction methods. Weighted mean MSTS scores exceeded 70% in all methods except cement spacer, and the 5-year reconstruction survival rate surpassed 80% for all methods except osteoarticular allograft. Proximal humerus reconstruction after bone tumor resection should consider potential complications and patients' individual factors.

Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

Clinical characteristics of primary cutaneous and subcutaneous Ewing sarcoma.

OBJECTIVE: Given the rarity of cutaneous/subcutaneous Ewing sarcoma, their clinical characteristics remain poorly understood. In this study, we aimed to analyse the clinical characteristics of patients with cutaneous/subcutaneous Ewing sarcoma and review the treatment strategy. METHODS: We reviewed the clinical data of 154 patients with Ewing sarcoma who were treated at our hospital between 2005 and 2019. Amongst these patients, 21 patients with cutaneous/subcutaneous Ewing sarcoma were analysed. As a basic strategy, patients with localized disease received intensive chemotherapy (vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide), followed by definitive surgery with or without radiotherapy. In total, 15 patients underwent pre-diagnostic resection with macroscopic residue (seven patients) or non-macroscopic residue (eight patients) before intensive chemotherapy. RESULTS: The median tumour length of the measurable lesions was 3.2 cm, and the ratio of metastasis was significantly lower than the Ewing sarcoma of other anatomical sites (10% vs. 37%, P = 0.013). Despite the pre-diagnostic resection, local recurrence after additional resection and/or adjuvant radiotherapy did not occur in any of the patients with localized disease. Overall survival was significantly higher in patients with cutaneous/subcutaneous Ewing sarcoma than in patients with Ewing sarcoma of other anatomical sites (hazard ratio = 0.33, P = 0.013). The event-free survival rate of cutaneous/subcutaneous Ewing sarcoma was also superior to that of Ewing sarcoma of other anatomical sites (hazard ratio = 0.35, P = 0.01). CONCLUSIONS: Patients with cutaneous/subcutaneous Ewing sarcoma may have better prognosis than those with Ewing sarcoma at other anatomical sites. Although pre-diagnostic resection without appropriate investigations is not recommended, local control may be recovered by using a combination of additional resection, chemotherapy and radiotherapy.

Association of two-staged surgery with systemic perioperative complications in lateral lumbar interbody fusion for adult spinal deformity: a propensity score-weighted study.

PURPOSE: Adult spinal deformity (ASD) surgery carries a higher risk of perioperative systemic complications. However, evidence for the effect of planned two-staged surgery on the incidence of perioperative systemic complications is scarce. Here, we evaluated the effect of two-staged surgery on perioperative complications following ASD surgery using lateral lumbar interbody fusion (LLIF). METHODS: The study was conducted under a retrospective multi-center cohort design. Data on 293 consecutive ASD patients (107 in the two-staged group and 186 in the one-day group) receiving corrective surgery using LLIF between 2012 and 2021 were collected. Clinical outcomes included occurrence of perioperative systemic complications, reoperation, and intraoperative complications, operation time, intraoperative blood loss, transfusion, and length of hospital stay. The analysis was conducted using propensity score (PS)-stabilized inverse probability treatment weighting to adjust for confounding factors. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated in a PS-weighted cohort. RESULTS: In this cohort, 19 (18.4%) patients in the two-staged group and 43 (23.1%) patients in the one-day group experienced any systemic perioperative complication within 30 days following ASD surgery. In the PS-weighted cohort, compared with the patients undergoing one-day surgery, no association with the risk of systemic perioperative complications was seen in patients undergoing two-staged surgery (PS-weighted OR 0.78, 95% CI 0.37-1.63; p = 0.51). CONCLUSION: Our study suggested that two-staged surgery was not associated with risk for perioperative systemic complications following ASD surgery using LLIF.

Recurrence rate after posterior percutaneous screw fixation without anterior debridement for pyogenic spondylitis compared with conservative treatment: a propensity score-matched analysis.

PURPOSE: Previous studies have shown that percutaneous pedicle screw (PPS) posterior fixation without anterior debridement for pyogenic spondylitis can improve patient quality of life compared with conservative treatment. However, data on the risk of recurrence after PPS posterior fixation compared with conservative treatment is lacking. The aim of this study was to compare the recurrence rate of pyogenic spondylitis after PPS posterior fixation without anterior debridement and conservative treatment. METHODS: The study was conducted under a retrospective cohort design in patients hospitalized for pyogenic spondylitis between January 2016 and December 2020 at 10 affiliated institutions. We used propensity score matching to adjust for confounding factors, including patient demographics, radiographic findings, and isolated microorganisms. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence of pyogenic spondylitis during the follow-up period in the matched cohort. RESULTS: 148 patients (41 in the PPS group and 107 in the conservative group) were included. After propensity score matching, 37 patients were retained in each group. PPS posterior fixation without anterior debridement was not associated with an increased risk of recurrence compared with conservative treatment with orthosis (HR, 0.80; 95% CI, 0.18-3.59; P = 0.77). CONCLUSIONS: In this multi-center retrospective cohort study of adults hospitalized for pyogenic spondylitis, we found no association in the incidence of recurrence between PPS posterior fixation without anterior debridement and conservative treatment.

NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury.

Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1ß, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1ß prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1ß is a novel potential target for treating and preventing this disorder.

Case-control study of the correlation between the five times sit to stand and 6-min walk distance in patients with pancreatic cancer.

PURPOSE: Cases of pancreatic cancer are increasing, and the risk of developing this disease reportedly increases with age. In recent years, there has been an increasing number of reports on physical function in patients with pancreatic cancer. Methods such as the 6-min walk distance (6 MWD) should be established to evaluate physical function, as a decline in exercise capacity is an important index in these patients. Recently, the 6 MWD has also been used to evaluate physical function in patients with pancreatic cancer. In healthy older adults, a decrease in 6 MWD is reportedly associated with intrinsic capacity and health status. Such factors make assessing 6 MWD important. However, the measurement of 6 MWD requires a sizable measurement environment. The five times sit to stand (FTSTS) test is a simple method that can be performed using a chair. FTSTS is hypothesized to be a useful assessment scale in patients with pancreatic cancer because it is easy to estimate the decline in physical function in clinical practice if the decline in 6 MWD can be estimated by evaluating FTSTS. The study's purpose was to clarify this hypothesis and ascertain the cutoff required to determine the decrease in 6 MWD in clinical practice. METHODS: Sixty consecutive patients with preoperative pancreatic cancer who were assessed for physical function were studied. 6 MWD (< 400 m) was the objective variable, and binary logistic regression analysis was performed, with age, BMI, sex, FTSTS, and HGS as explanatory variables. Receiver-operating characteristic (ROC) curve analysis was performed for the explanatory variables, which were found to be significant based on logistic regression analysis. The area under the curve (AUC) was also calculated. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were evaluated. This study was approved by Hiroshima University Hospital's ethics committee (approval number: E808-1). RESULTS: Fifty-seven of the 60 patients were included in the analysis. Logistic regression analysis showed that FTSTS was a significant explanatory variable; ROC curve analysis showed an AUC of 0.872 and a cutoff value of 8.98 s. The sensitivity, specificity, PPV, and NPV were 82.4%, 80.0%, 63.6%, and 91.4%, respectively. CONCLUSIONS: A decrease in 6 MWD in preoperative pancreatic cancer patients can be identified by performing FTSTS.

Neurological severity evaluation using magnetic resonance imaging in acute spontaneous spinal epidural haematomas.

PURPOSE: This study aimed to elucidate the severity of neurological deficits in a large series of patients with acute spontaneous spinal epidural haematoma (SSEH) using magnetic resonance imaging (MRI). METHODS: We included 57 patients treated for acute SSEH at 11 institutions and retrospectively analysed their demographic and MRI data upon admission. We investigated MRI findings, such as the haematoma length and canal occupation ratio (COR). The neurological severity of SSEH was assessed based on the American Spinal Injury Association score on admission. RESULTS: Of the 57 patients, 35 (61%) presented with severe paralysis. The MRI analysis showed that SSEH was often located in the cervical spine, dorsal to the spinal cord, and spread over more than three vertebrae. No differences in age, sex, and aetiology were found between patients with and without severe paralysis. The hypo-intensity layer encircling the haematoma, intra-haematoma heterogeneity, and increased CORs were observed more frequently in the severe paralysis group. Furthermore, pathological examination of a dissected haematoma from one patient with a hypo-intensity layer revealed a collagen layer around the haematoma, and patients with intra-haematoma heterogeneity were more likely to have a bleeding predisposition. CONCLUSIONS: In this large series of patients with SSEH, we identified some MRI features associated with severe paralysis, such as the hypo-intensity layer, intra-haematoma heterogeneity, and increased COR. Accordingly, patients with these MRI characteristics should be considered for early surgical intervention.

Evaluation of locomotive syndrome in patients receiving surgical treatment for degenerative musculoskeletal diseases: A multicentre prospective study using the new criteria.

OBJECTIVES: This study aimed to evaluate the condition of patients with locomotive syndrome (LS) and their improvement after undergoing surgery for degenerative musculoskeletal diseases using the new criteria, including stage 3. METHODS: In total, 435 patients aged ≥40 years (167 middle-aged and 268 older) were divided into four groups based on the disease location: the lumbar (n = 118), hip (n = 191), knee (n = 80), and foot and ankle (n = 46) groups. Patients were evaluated by pre- and 1 year postoperative LS risk tests, including the stand-up test, two-step test, and 25-Question Geriatric Locomotive Function Scale. RESULTS: The pre- and postoperative prevalence of LS stage 3 were 78% and 29%, respectively. The postoperative LS stage improved in 62% of patients (77% and 53% in the middle-aged and older groups, respectively). Overall, the knee group showed the worst results, and the foot and ankle groups showed the best pre- and postoperative results. The pre- and postoperative prevalence of LS stage 3 according to the 25-Question Geriatric Locomotive Function Scale were comparable to those based on the total assessment. CONCLUSIONS: The new LS stage criteria are appropriate, and the 25-Question Geriatric Locomotive Function Scale is a good option for evaluating patients requiring surgery.

Effects of assigning physical therapists exclusively to the acute-phase stroke patient ward.

[Purpose] In April 2014, an additional health insurance system aiming to maintain or improve activities of daily living levels was newly established by the Japanese government. The purpose of this study was to determine the influence of this new medical system for rehabilitation on patient management (e.g., activities of daily living level and length of hospital stay) in an acute-phase stroke patient ward. [Participants and Methods] All patients were admitted to the stroke patient ward in our hospital and were registered between January 2012 and December 2019. We assessed the differences in the time to initiation of rehabilitation, length of hospitalization, implementation rate of rehabilitation, and Barthel Index between the period before the start of the new medical system (Prior period) and after this system was started (Post period). [Results] Significant improvements were observed in the initiation of rehabilitation and the difference in the Barthel Index scores after the start of the new medical system. Although the length of hospitalization and implementation rate of rehabilitation did not differ significantly, both indicators gradually improved after the start of the new system. [Conclusion] Our results suggest that the new medical system for rehabilitation is beneficial for patient management in the acute-phase stroke patient ward.

Significant Improvement After Surgery for a Symptomatic Osteoblastoma in a Patient with Camurati-Engelmann Disease: Case Report and Literature Review.

Camurati-Engelmann disease (CED) is a rare, progressive diaphyseal dysplasia characterized as diaphyseal hyperostosis and sclerosis of the long bones. Corticosteroids, bisphosphonates, and losartan have been reported to be effective systemic medications used to reduce CED symptoms. There are no reports of osteoblastoma in patients with CED, and osteoblastoma in the distal radius is rare. We present a patient diagnosed with CED, based on radiological and histological examinations, at 11 years old. At 22 years old, she experienced severe pain in her right forearm and was treated with bisphosphonate, losartan, and prednisolone; however, the pain continued. An expansive and sclerotic lesion at the distal radius was observed on radiography. A follow-up plain radiograph indicated that the lesion was growing. Fluorodeoxyglucose positron emission tomography revealed solitary, intense radiotracer uptake, and a biopsy and surgical resection were performed due to suspected malignancy. Pathologic analysis showed anastomosing bony trabeculae rimmed by osteoblasts observed in a loose fibrovascular stroma. The lesion was diagnosed as an osteoblastoma. Following bone excision and artificial bone grafting, the patient's severe pain almost completely disappeared. At final follow-up, no evidence of osteoblastoma recurrence was noted. To our knowledge, this is the first case report of osteoblastoma arising in a patient with CED. Bone excision and artificial bone grafting may be a treatment option for local symptomatic osteoblastoma in patients with CED.

Inflammasome-Independent and Atypical Processing of IL-1ß Contributes to Acid Aspiration-Induced Acute Lung Injury.

Inflammation plays a pivotal role in the pathophysiology of gastric aspiration-induced acute lung injury (ALI). However, its mechanism remains unclear. In this study, we investigated the role of NLRP3 inflammasome-driven IL-1ß production in a mouse model of acid aspiration-induced inflammation and ALI. Acid aspiration-induced inflammatory responses and ALI in wild-type mice were significantly attenuated in IL-1ß-/- mice, but not NLRP3-/- mice. In vitro experiments revealed that severe acidic stress (pH 1.75) induced the processing of pro-IL-1ß into its 18-kDa mature form (p18-IL-1ß), which was different from the caspase-1-processed 17-kDa form (p17-IL-1ß), in human THP-1 macrophages and primary murine macrophages. Deficiency of NLRP3 and caspase-1 had no effect on acidic stress-produced IL-1ß. The production of IL-1ß by severe acidic stress was prevented by inhibitors of serine proteases [4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride], but not of cysteine proteases (E-64), cathepsin G, or inflammasome. The cathepsin D inhibitor pepstatin A inhibited IL-1ß production induced by mild acidic stress (pH 6.2) or lactic acid, but not severe acidic stress. Using mass spectrometry and processing-site mutants of pro-IL-1ß, we identified D109 as a novel cleavage site of pro-IL-1ß in response to severe acidic stress and calculated the theoretical molecular mass of the mature form to be 18.2 kDa. The bioactivity of acidic stress-produced IL-1ß was confirmed by its ability to promote p38 phosphorylation and chemokine upregulation in alveolar epithelial cells. These findings demonstrate a novel mechanism of acid-induced IL-1ß production and inflammation independent of NLRP3 inflammasome and provide new insights into the therapeutic strategies for aspiration pneumonitis and ALI.

The International Classification of Functioning, Disabilities, and Health categories rated as necessary for care planning for older patients with heart failure: a survey of care managers in Japan.

BACKGROUND: Establishing an information-sharing system between medical professionals and welfare/care professionals may help prevent heart failure (HF) exacerbations in community-dwelling older adults. Therefore, we aimed to identify the ICF categories necessary for care managers to develop care plans for older patients with HF. METHODS: A questionnaire was administered to 695 care managers in Hiroshima, Japan, on ICF items necessary for care planning. We compared the care managers according to their specialties (medical qualifications and welfare or care qualifications). Furthermore, we created a co-occurrence network using text mining, regarding the elements necessary for collaboration between medical and care professionals. RESULTS: There were 520 valid responses (74.8%). Forty-nine ICF items, including 18 for body functions, one for body structure, 21 for activities and participation, and nine for environmental factors, were classified as "necessary" for making care plans for older people with HF. Medical professionals more frequently answered "necessary" than care professionals regarding the 11 items for body functions and structure and three items for activities and participation (p < 0.05). Medical-welfare/care collaboration requires (1) information sharing with related organisations; (2) emergency response; (3) a system of cooperation between medical care and non-medical care; (4) consultation and support for individuals and families with life concerns, (5) management of nutrition, exercise, blood pressure and other factors, (6) guidelines for consultation and hospitalisation when physical conditions worsen. CONCLUSIONS: Our findings showed that 49 ICF categories were required by care managers for care planning, and there was a significant difference in perception between medical and welfare or care qualifications qualifications.

Changes in motor function and quality of life after surgery in patients with pancreatic cancer.

OBJECTIVE: To determine the changes in motor function and health-related quality of life after pancreatectomy and identify factors influencing postoperative physical functioning in health-related quality of life. METHODS: This single-centre, prospective, observational study measured 6-min walking distance, grip strength, knee extension strength and health-related quality of life variables in patients with pancreatic cancer, before and after surgery. Paired t- and Wilcoxon signed-rank tests were used to compare pre- and postoperative motor function and health-related quality-of-life variables. Factors associated with postoperative physical functioning scores of health-related quality of life were assessed using multiple regression analysis. RESULTS: Fifty-nine individuals were enrolled. Motor function values decreased significantly postoperatively, including 6-min walking distance (mean ± standard deviation: 402.5 ± 95.4 vs. 497.7 ± 80.4 m, p < 0.001), knee extensor strength (0.42 ± 0.10 vs. 0.47 ± 0.10 kgf/kg, p < 0.001) and grip strength (22.0 ± 8.9 vs. 24.5 ± 9.2 kg, p = 0.001). Multiple regression analysis showed significant association between 6-min walking distance change and postoperative physical functioning scores of health-related quality of life (p = 0.036). CONCLUSION: The results suggest that motor function decreases postoperatively, and a decrease in 6-min walking distance after surgery is associated with postoperative physical functioning in patients with pancreatic cancer.

Effect of Acute Static Stretching on the Activation Patterns Using High-Density Surface Electromyography of the Gastrocnemius Muscle during Ramp-Up Task.

This study aimed to evaluate motor unit recruitment during submaximal voluntary ramp contraction in the medial head of the gastrocnemius muscle (MG) by high-density spatial electromyography (SEMG) before and after static stretching (SS) in healthy young adults. SS for gastrocnemius was performed in 15 healthy participants for 2 min. Normalized peak torque by bodyweight of the plantar flexor, muscle activity at peak torque, and muscle activation patterns during ramp-up task were evaluated before and after SS. Motor unit recruitment during the submaximal voluntary contraction of the MG was measured using SEMG when performing submaximal ramp contractions during isometric ankle plantar flexion from 30 to 80% of the maximum voluntary contraction (MVC). To evaluate the changes in the potential distribution of SEMG, the root mean square (RMS), modified entropy, and coefficient of variation (CV) were calculated from the dense surface EMG data when 10% of the MVC force was applied. Muscle activation patterns during the 30 to 80% of MVC submaximal voluntary contraction tasks were significantly changed from 50 to 70% of MVC after SS when compared to before. The variations in motor unit recruitment after SS indicate diverse motor unit recruitments and inhomogeneous muscle activities, which may adversely affect the performance of sports activities.

Deletion of inflammasome adaptor protein ASC enhances functional recovery after spinal cord injury in mice.

BACKGROUND: Research has revealed the crucial roles of inflammasomes in various central nervous system disorders. However, the role of inflammasomes in secondary damage following spinal cord injury (SCI) remains incompletely understood. METHODS: Here, we investigated the role of apoptosis-associated speck-like protein (ASC), an adaptor protein for inflammasome formation, after contusion SCI in ASC homozygous knockout (ASC-/-) mice. Contusion SCI was induced using a force of 60 kdyn, and recovery of open-field locomotor performance was evaluated using the nine-point Basso Mouse Scale (BMS). Bone marrow transplantation (BMT) was performed to create mice chimeric for ASC expression in bone marrow cells. RESULTS: Western blot analysis revealed that protein expression of NLRP3, ASC, Caspase-1, and IL-ß were increased in injured spinal cords compared with sham-control spinal cords at 1 day post injury (dpi). Double immunostaining showed that ASC expression was co-localized to cellular constituents of the spinal cord, including NeuN+ neurons, CD11b+ microglia/macrophages, GFAP+ astrocytes, and MOG+ oligodendrocytes. ASC-/- mice had significantly better locomotor function assessed by BMS than wild-type (WT) mice. ASC-/- mice also had significantly reduced levels of Nlrp3, Casp1, IL1b, Il-6, Tnfa, Cxcl1, and Ly6g mRNA compared with WT mice. BMT (WT→ASC-/-) mice had significantly better BMS scores than BMT (WT→WT) mice. BMT (ASC-/-→WT) mice also had significantly better BMS scores than BMT (WT→WT) mice. However, the statistical significance was limited to time points between 7 and 21 dpi. CONCLUSIONS: These results suggest that ASC-dependent inflammasome formation, especially in resident cells of the spinal cord, plays a pivotal role in the progression of secondary damage following SCI.

Crucial role of NLRP3 inflammasome in a murine model of Kawasaki disease.

Kawasaki disease (KD) is a systemic febrile syndrome during childhood that is characterized by coronary arteritis. The etiopathogenesis of KD remains to be elucidated. NLRP3 inflammasome is a large multiprotein complex that plays a key role in IL-1ß-driven sterile inflammatory diseases. In the present study, we investigated the role of NLRP3 inflammasome in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS) and found that NLRP3 inflammasome is required for the development of CAWS-induced vasculitis. CAWS administration induced IL-1ß production, caspase-1 activation, leukocyte infiltration, and fibrotic changes in the aortic root and coronary arteries, which were significantly inhibited by a deficiency of IL-1ß, NLRP3, and ASC. In vitro experiments showed that among cardiac resident cells, macrophages, but not endothelial cells or fibroblasts, expressed Dectin-2, but did not produce IL-1ß in response to CAWS. In contrast, CAWS induced caspase-1 activation and IL-1ß production in bone marrow-derived dendritic cells (BMDCs), which were inhibited by a specific caspase-1 inhibitor and a deficiency of NLRP3, ASC, and caspase-1. CAWS induced NLRP3 and pro-IL-1ß expression through a Dectin-2/Syk/JNK/NF-κB pathway, and caspase-1 activation and cleavage of pro-IL-1ß through Dectin-2/Syk/JNK-mediated mitochondrial ROS generation, indicating that CAWS induces the priming and activation of NLRP3 inflammasome in BMDCs. These findings provide new insights into the pathogenesis of KD vasculitis, and suggest that NLRP3 inflammasome may be a potential therapeutic target for KD.

Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages.

Although the intimate linkage between hypoxia and inflammation is well known, the mechanism underlying this linkage has not been fully understood. Nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates interleukin-1ß (IL-1ß) secretion and pyroptosis, and is implicated in the pathogenesis of sterile inflammatory diseases. Here, we investigated the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia in macrophages. Severe hypoxia (0.1% O2 ) induced the processing of pro-IL-1ß, pro-caspase-1, and gasdermin D, as well as the release of IL-1ß and lactate dehydrogenase in lipopolysaccharide (LPS)-primed murine macrophages, indicating that hypoxia induces NLRP3 inflammasome-driven inflammation and pyroptosis. NLRP3 deficiency and a specific caspase-1 blockade inhibited hypoxia-induced IL-1ß release. Hypoxia-induced IL-1ß release and cell death were augmented under glucose deprivation, and an addition of glucose in the media negatively regulated hypoxia-induced IL-1ß release. Under hypoxia and glucose deprivation, hypoxia-induced glycolysis was not driven and subsequently, the intracellular adenosine triphosphates (ATPs) were depleted. Atomic absorption spectrometry analysis showed a reduction of intracellular K+ concentrations, indicating the K+ efflux occurring under hypoxia and glucose deprivation. Furthermore, hypoxia and glucose deprivation-induced IL-1ß release was significantly prevented by inhibition of K+ efflux and KATP channel blockers. In vivo experiments further revealed that IL-1ß production was increased in LPS-primed mice exposed to hypoxia (9.5% O2 ), which was prevented by a deficiency of NLRP3, an apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1. Our results demonstrate that NLRP3 inflammasome can sense intracellular energy crisis as a danger signal induced by hypoxia and glucose deprivation, and provide new insights into the mechanism underlying hypoxia-induced inflammation.

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis.

Hepatic ischemia-reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living donor LT and found that a high serum ferritin level, a marker of iron overload, of the donor is an independent risk factor for liver damage after LT. Since ferroptosis has been recently discovered as an iron-dependent cell death that is triggered by a loss of cellular redox homeostasis, we investigated the role of ferroptosis in a murine model of hepatic I/R injury, and found that liver damage, lipid peroxidation, and upregulation of the ferroptosis marker Ptgs2 were induced by I/R, and all of these manifestations were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or α-tocopherol. Fer-1 also inhibited hepatic I/R-induced inflammatory responses. Furthermore, hepatic I/R injury was attenuated by iron chelation by deferoxamine and exacerbated by iron overload with a high iron diet. These findings demonstrate that iron overload is a novel risk factor for hepatic I/R injury in LT, and ferroptosis contributes to the pathogenesis of hepatic I/R injury.