Joint-preserving effect and patient-reported outcomes of transtrochanteric curved varus osteotomy for osteonecrosis of the femoral head.

BACKGROUND: This study assessed the hip survival rate and patient-reported outcome measures (PROMs) of transtrochanteric curved varus osteotomy (CVO) for osteonecrosis of the femoral head (ONFH) compared with those of conservative management. METHODS: The CVO group comprised 32 consecutive patients (39 hips) who underwent CVO for ONFH between 2000 and 2011. The conservative group consisted of 36 consecutive patients (37 hips) who were managed conservatively for at least 1 year after collapse and who had ONFH classified by the Japanese Investigation Committee of Health and Welfare as type B or C1, for which CVO is indicated. Kaplan-Meier analysis of hip survival used any ONFH-related therapeutic surgery as the endpoint. PROMs were evaluated for all patients with surviving hips and radiographs available at the latest follow-up. RESULT: The 10-year hip survival rate in the CVO group was 86.7%, which was significantly higher than the 51.0% 5-year survival rate in the conservative group (p < 0.0001). The Oxford Hip Score and UCLA Activity Score were significantly better in the CVO group without joint space narrowing than in the conservative group, with no significant differences between the CVO group with joint space narrowing and the conservative group. CONCLUSION: CVO could preserve hip joints more effectively than conservative follow-up after collapse, although the presence of joint space narrowing could reduce satisfaction levels even in patients with long-term hip survival.

Life Course Epidemiology of Hip Osteoarthritis in Japan: A Multicenter, Cross-Sectional Study.

BACKGROUND: The incidence of developmental dysplasia of the hip (DDH) in Japanese newborns has reduced drastically following a primary prevention campaign initiated around 1972 to 1973; this perinatal education campaign promoted maintaining the hips of newborns in the naturally flexed-leg position. The purpose of the present study was to describe the life course epidemiology of hip osteoarthritis (OA) in adolescent and adult patients and to assess its association with exposure to the primary prevention campaign for DDH. METHODS: We included new patients with hip OA diagnosed from January 1, 2022, to December 31, 2022, at 12 core hospitals (8 special-function hospitals and 4 regional medical care support hospitals). The trend in the percentage of hips with a history of DDH treatment in childhood was estimated with use of a centered moving average using the birth year of the patient. We compared the prevalence of severe subluxation (Crowe type II, III, or IV) between patients with secondary hip OA due to hip dysplasia who were born in or before 1972 and those who were born in or after 1973. RESULTS: Overall, 1,095 patients (1,381 hips) were included. The mean age at the time of the survey was 63.5 years (range, 15 to 95 years). A total of 795 patients (1,019 hips; 73.8% of hips) were diagnosed with secondary OA due to hip dysplasia. Approximately 13% to 15% of hips among patients born from 1963 to 1972 had a history of DDH treatment in childhood; however, the percentage decreased among patients born in or after 1973. The prevalence of severe subluxation (Crowe type II, III, or IV) among patients born in or after 1973 was 2.4%, which was significantly less than that among patients born in or before 1972 (11.1%; odds ratio, 0.20; p < 0.001). CONCLUSIONS: As of 2022, secondary hip OA due to hip dysplasia is still responsible for most new cases of adolescent and adult hip OA seen in core hospitals in Japan. However, the perinatal education campaign initiated 50 years ago, which utilized a population approach and advocated for maintaining the hips of newborns in the naturally flexed-leg position, may have improved the environmental factors of DDH, as indicated by the apparently reduced need for treatment of DDH in childhood and the associated severe subluxation. This may result in a reduced need for challenging hip surgery later in life. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Sex differences of NF-κB-targeted therapy for mitigating osteoporosis associated with chronic inflammation of bone.

Aims: Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice. Methods: We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR). Results: Local delivery of NF-κB decoy ODN in vivo increased osteogenesis in males, but not females, in the presence of chronic inflammation induced by cPE. Bone resorption activity was decreased in both sexes. In vitro osteogenic and osteoclastic differentiation assays during inflammatory conditions did not reveal differences among the groups. Receptor activator of nuclear factor kappa Β ligand (Rankl) gene expression by osteoblasts was significantly decreased only in males when treated with ODN. Conclusion: We demonstrated that NF-κB decoy ODN increased osteogenesis in male mice and decreased bone resorption activity in both sexes in preclinical models of chronic inflammation. NF-κB signalling could be a therapeutic target for chronic inflammatory diseases involving bone, especially in males.

Effects of the location of both anterior and lateral boundaries of the necrotic lesion on collapse progression in osteonecrosis of the femoral head.

BACKGROUND: The location of the lateral boundary of the necrotic lesion to the weight-bearing portion of the acetabulum (Type classification) is an important factor for collapse in osteonecrosis of the femoral head (ONFH). Recent studies also reported the significance of the location of the anterior boundary of the necrotic lesion on the occurrence of collapse. We aimed to assess the effects of the location of both anterior and lateral boundaries of the necrotic lesion on collapse progression in ONFH. METHODS: We recruited 55 hips with post-collapse ONFH from 48 consecutive patients, who were conservatively followed for more than one year. Using a plain lateral radiograph (Sugioka's lateral view), the location of the anterior boundary of the necrotic lesion to the weight-bearing portion of the acetabulum was classified as follows: Anterior-area I (two hips) occupying the medial one-third or less; Anterior-area II (17 hips) occupying the medial two-thirds or less; and Anterior-area III (36 hips) occupying greater than the medial two-thirds. The amount of femoral head collapse was measured by biplane radiographs at the onset of hip pain and each follow-up period, and Kaplan-Meier survival curves with collapse progression (≥1 mm) as the endpoint were produced. The probability of collapse progression was also assessed by the combination of Anterior-area and Type classifications. RESULTS: Collapse progression was observed in 38 of the 55 hips (69.0%). The survival rate of hips with Anterior-area III/Type C2 was significantly lower. Among hips with Type B/C1, collapse progression occurred more frequently in hips with Anterior-area III (21 of 24 hips) than in hips with Anterior-area I/II (3 of 17 hips, P < 0.0001). CONCLUSIONS: Adding the location of the anterior boundary of the necrotic lesion to Type classification was useful to predict collapse progression especially in hips with Type B/C1.

Effects of bone mineral density at the lateral sclerotic boundary on the femoral head collapse onset in osteonecrosis of the femoral head: A preliminary study.

BACKGROUND: In the natural course of osteonecrosis of the femoral head, sclerotic changes at the boundary of necrotic lesion gradually occur until femoral head collapse. This study aims to examine the effects of bone mineral density at the lateral boundary of necrotic lesion on a subsequent femoral head collapse. METHODS: We developed patient-specific finite element models of 9 hips with subsequent collapse and 10 hips without subsequent collapse. Cubic regions of interest were selected at both subchondral areas of the lateral boundary and the adjacent necrotic lesion. Bone mineral density values of the regions of interest were quantitatively measured, and a ratio of bone mineral density values (lateral boundary/necrotic lesion) was calculated. Stress values at the lateral boundary were also evaluated. FINDINGS: The ratio of bone mineral density values was significantly higher in hips with subsequent collapse than that without subsequent collapse (p = 0.0016). The median equivalent stress and shear stress were significantly higher in hips with subsequent collapse than that without subsequent collapse (p = 0.0071, and p = 0.0143, respectively). The ratio of bone mineral density values showed a promising value in predicting the occurrence of subsequent femoral head collapse (AUC = 0.97). INTERPRETATION: Our results indicated that bone mineral density value at the lateral boundary of necrotic lesion may be associated with the occurrence of subsequent femoral head collapse in pre-collapse stage osteonecrosis of the femoral head.

Radiological factors associated with posterior dislocation after total hip arthroplasty for osteonecrosis of the femoral head - A retrospective study.

Purpose: The dislocation rate after total hip arthroplasty for osteonecrosis of the femoral head is higher than that after total hip arthroplasty for osteoarthritis. However, few reports have investigated the factors contributing to dislocation after total hip arthroplasty for osteonecrosis of the femoral head. The aim of this study was to assess radiological factors associated with posterior dislocation after total hip arthroplasty for osteonecrosis of the femoral head. Methods: We retrospectively reviewed 179 cementless total hip arthroplasties for osteonecrosis of the femoral head using a posterolateral approach between 2002 and 2020 with a minimum follow-up period of 24 months. The following radiological factors were examined for a possible association with posterior dislocation after total hip arthroplasty: cup anteversion angle, cup inclination angle, femoral offset, and stem anteversion angle. Results: Posterior dislocation occurred in seven hips (3.9 %). Compared to hips without posterior dislocation, those with posterior dislocation exhibited a significantly smaller cup anteversion angle (p = 0.045) and a nonsignificantly greater decrease in femoral offset (p = 0.089). Based on receiver operating characteristic curve analyses, the cutoff values for predicting posterior dislocation were 9.9° for the cup anteversion angle and 8.1 mm for the decrease in femoral offset. Logistic regression analysis showed a significantly higher risk of posterior dislocation among hips with a cup anteversion angle less than 9.9° (odds ratio = 7.1, p = 0.022) or with a decrease in femoral offset over 8.1 mm (odds ratio = 5.0, p = 0.040). Conclusions: A small cup anteversion angle and a decreased femoral offset are suggested to be associated with posterior dislocation after total hip arthroplasty in patients with osteonecrosis of the femoral head.

Zinc deficiency impairs axonal regeneration and functional recovery after spinal cord injury by modulating macrophage polarization via NF-κB pathway.

Background: Spinal cord injury (SCI) is a devastating disease that results in permanent paralysis. Currently, there is no effective treatment for SCI, and it is important to identify factors that can provide therapeutic intervention during the course of the disease. Zinc, an essential trace element, has attracted attention as a regulator of inflammatory responses. In this study, we investigated the effect of zinc status on the SCI pathology and whether or not zinc could be a potential therapeutic target. Methods: We created experimental mouse models with three different serum zinc concentration by changing the zinc content of the diet. After inducing contusion injury to the spinal cord of three mouse models, we assessed inflammation, apoptosis, demyelination, axonal regeneration, and the number of nuclear translocations of NF-κB in macrophages by using qPCR and immunostaining. In addition, macrophages in the injured spinal cord of these mouse models were isolated by flow cytometry, and their intracellular zinc concentration level and gene expression were examined. Functional recovery was assessed using the open field motor score, a foot print analysis, and a grid walk test. Statistical analysis was performed using Wilcoxon rank-sum test and ANOVA with the Tukey-Kramer test. Results: In macrophages after SCI, zinc deficiency promoted nuclear translocation of NF-κB, polarization to pro-inflammatory like phenotype and expression of pro-inflammatory cytokines. The inflammatory response exacerbated by zinc deficiency led to worsening motor function by inducing more apoptosis of oligodendrocytes and demyelination and inhibiting axonal regeneration in the lesion site compared to the normal zinc condition. Furthermore, zinc supplementation after SCI attenuated these zinc-deficiency-induced series of responses and improved motor function. Conclusion: We demonstrated that zinc affected axonal regeneration and motor functional recovery after SCI by negatively regulating NF-κB activity and the subsequent inflammatory response in macrophages. Our findings suggest that zinc supplementation after SCI may be a novel therapeutic strategy for SCI.

The sourcil roundness index is a useful measure for quantifying acetabular concavity asphericity.

This study aimed to clarify the clinical utility of the sourcil roundness index (SRI), a novel index for quantifying the asphericity of the acetabular concavity, by determining (1) the difference in the SRI between dysplastic and normal hips and (2) the correlation between the SRI and radiographic parameters of hip dysplasia. We reviewed standing anteroposterior pelvic radiographs of 109 dysplastic and 40 normal hips. The SRI was determined as the ratio of the distance from the medial edge of the sourcil to the most concave point of the acetabular sourcil (A) to the distance from the medial to the lateral edge of the sourcil (B). The formula for SRI is (A/B) × 100-50 (%), with an SRI of 0% indicating a perfectly spherical acetabulum, and higher SRI values indicating a more aspherical shape. The median SRI was greater in patients with hip dysplasia than in normal hips (5.9% vs. - 1.4%; p < 0.001). Furthermore, the median SRI was greater in the severe dysplasia subgroup (18.9%) than in the moderate (3.5%) and borderline-to-mild (- 1.3%) dysplasia subgroups (p < 0.05). Quantification of acetabular concavity asphericity by the SRI showed that dysplastic hips had a more lateral acetabular concave point than normal hips, and that the severity of hip dysplasia had an effect on the acetabular concavity asphericity.

Association between maternal use of spray formulations and offspring urological anomalies: The Japan Environment and Children's Study.

OBJECTIVE: Concerns exist regarding the effects of maternal inhalation of household products on fetal health. This study aimed to clarify the impact of maternal exposure to household products, including spray formulations, on urological anomalies in offspring up to the age of 1 year. METHODS: This study included data from 84 237 children from the Japan Environment and Children's Study, an ongoing nationwide cohort study. Using maternal self-report questionnaires, information on the use of organic solvents, waterproof sprays, insect-repellent sprays, insecticide sprays, and herbicides from implantation until the second or third trimester of pregnancy and data on urological anomalies were collected 1 year after delivery. RESULTS: Urological anomalies occurred in 799 infants. Multivariate logistic regression analysis adjusted for maternal age, pregnancy body mass index, gestational diabetes, pre-existing maternal kidney disease, and preterm birth revealed no association between maternal exposure to organic solvents and the prevalence of offspring urological anomalies. Nevertheless, we observed significant associations between waterproof spray use during pregnancy and urological anomalies in boys (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.03-1.59) and between the use of insecticide spray during pregnancy and urological anomalies in girls (OR: 1.48, 95% CI: 0.98-2.22). Sub-analysis revealed significant associations between waterproof spray use during pregnancy and vesicoureteral reflux in boys (OR: 2.14, 95% CI: 1.02-4.49) and between the use of insecticide spray during pregnancy and hydronephrosis in girls (OR: 2.23, 95% CI: 1.11-4.47). CONCLUSION: Spray formulation use during pregnancy might increase the risk of urological anomalies in the offspring.

Simple Symptom-Based Prediction of COVID-19: A Single-Center Study of Outpatient Fever Clinic in Japan.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) symptoms are not fully understood in non-hospitalized individuals in Japan, and COVID-19 differentiation by symptoms alone remained challenging. Therefore, this study aimed to examine COVID-19 prediction from symptoms using real-world data in an outpatient fever clinic. METHODS: We compared the symptoms of COVID-19-positive and negative patients who visited the outpatient fever clinic at Imabari City Medical Association General Hospital and tested for COVID-19 from April 2021 to May 2022. This retrospective single-center study enrolled 2,693 consecutive patients. RESULTS: COVID-19-positive patients had a higher frequency of close contact with COVID-19-infected patients compared with COVID-19-negative patients. Moreover, patients with COVID-19 had high-grade fever at the clinic compared with patients without COVID-19. Additionally, the most common symptom in patients with COVID-19 was sore throat (67.3%), followed by cough (62.0%), which was approximately twice as common in patients without COVID-19. COVID-19 was more frequently identified in patients having a fever (≥37.5℃) with a sore throat, a cough, or both. The positive COVID-19 rate reached approximately half (45%) when three symptoms were present. CONCLUSION: These results suggested that COVID-19 prediction by combinations of simple symptoms and close contact with COVID-19-infected patients might be useful and lead to recommendations for testing of COVID-19 in symptomatic individuals.

Relationship between the degree of subchondral collapse and articular surface irregularities in osteonecrosis of the femoral head.

Articular surface irregularities are often observed in collapsed femoral heads with osteonecrosis, while the effects of the degree of collapse on the articular surface are poorly understood. We first macroscopically assessed the articular surface irregularities on 2-mm coronal slices obtained using high-resolution microcomputed tomography of 76 surgically resected femoral heads with osteonecrosis. These irregularities were observed in 68/76 femoral heads, mainly at the lateral boundary of the necrotic region. The mean degree of collapse was significantly larger for femoral heads with articular surface irregularities than for those without (p < 0.0001). Receiver operating characteristic analysis showed that the cutoff value for the degree of collapse in femoral heads with articular surface irregularities at the lateral boundary was 1.1 mm. Next, for femoral heads with <3-mm collapse (n = 28), articular surface irregularities were quantitatively assessed based on the number of automatically counted negative curvature points. Quantitative evaluation showed that the degree of collapse was positively correlated with the presence of articular surface irregularities (r = 0.95, p < 0.0001). Histological examination of articular cartilage above the necrotic region (n = 8) revealed cell necrosis in the calcified layer and abnormal cellular arrangement in the deep and middle layers. In conclusion, articular surface irregularities of the necrotic femoral head depended on the degree of collapse, and articular cartilage was already altered even in the absence of macroscopically determined gross irregularities.

Intramuscular Adipose Tissue Content as a Predictor of Incisional Hernia after Hepatic Resection.

BACKGROUND: Incisional hernia (IH) is a common surgical complication, with an incidence of 6-31% following major abdominal surgery. This study aimed to investigate the impact of intramuscular adipose tissue content (IMAC) on the incidence of IH in patients who underwent hepatic resection. METHODS: Data of 205 patients who underwent open hepatic resection between 2007 and 2019 at Ehime University Hospital were retrospectively analyzed. Patient characteristics, perioperative findings, and body composition were compared between patients with IH and those without IH. The quantity and quality of skeletal muscle, calculated as skeletal muscle index and IMAC, were evaluated using preoperative computerized tomography images. RESULTS: Forty (19.5%) patients were diagnosed with IH. The cumulative incidence rates were 15.6% at 1 year and 19.6% at 3 years. On univariate analysis, body mass index, areas of subcutaneous and visceral fat, and IMAC were significantly higher in the IH group than in the non-IH group (p = 0.0023, 0.0070, 0.0047, and 0.0080, respectively). No significant difference in skeletal muscle index was found between the groups (p = 0.3548). The incidence of diabetes mellitus, intraoperative transfusion, and postoperative wound infection was significantly higher in the IH group than in the non-IH group (p = 0.0361, 0.0078, and 0.0299, respectively). On multivariate analysis, a high IMAC and wound infection were independent risk factors for IH (adjusted odds ratio, 2.83 and 4.52, respectively; p = 0.0152 and 0.0164, respectively). CONCLUSION: IMAC can predict the incidence of IH in patients undergoing hepatic resection.

Therapeutic effects of MSCs, genetically modified MSCs, and NFĸB-inhibitor on chronic inflammatory osteolysis in aged mice.

The number of total joint replacements is increasing, especially in elderly patients, and so too are implant-related complications such as prosthesis loosening. Wear particles from the prosthesis induce a chronic inflammatory reaction and subsequent osteolysis, leading to the need for revision surgery. This study investigated the therapeutic effect of NF-ĸB decoy oligodeoxynucleotides (ODN), mesenchymal stem cells (MSCs), and genetically-modified NF-ĸB sensing interleukin-4 over-secreting MSCs (IL4-MSCs) on chronic inflammation in aged mice. The model was generated by continuous infusion of contaminated polyethylene particles into the intramedullary space of the distal femur of aged mice (15-17 months old) for 6 weeks. Local delivery of ODN showed increased bone mineral density (BMD), decreased osteoclast-like cells, increased alkaline phosphatase (ALP)-positive area, and increased M2/M1 macrophage ratio. Local injection of MSCs and IL4-MSCs significantly decreased osteoclast-like cells and increased the M2/M1 ratio, with a greater trend for IL4-MSCs than MSCs. MSCs significantly increased ALP-positive area and BMD values compared with the control. The IL4-MSCs demonstrated higher values for both ALP-positive area and BMD. These findings demonstrated the therapeutic effects of ODN, MSCs, and IL4-MSCs on chronic inflammatory osteolysis in aged mice. The two MSC-based therapies were more effective than ODN in increasing the M2/M1 macrophage ratio, reducing bone resorption, and increasing bone formation. Specifically, MSCs were more effective in increasing bone formation, and IL4-MSCs were more effective in mitigating inflammation. This study suggests potential therapeutic strategies for treating wear particle-associated inflammatory osteolysis after arthroplasty in the elderly.

[A Case of Unresectable Hepatocellular Carcinoma Treated using Lenvatinib and Conversion Surgery].

A 57-year-old man was treated with lenvatinib for unresectable hepatocellular carcinoma(HCC). Thereafter, the tumor marker levels decreased, and the tumor became resectable. The patient underwent portal vein embolization followed by laparoscopic extended left lobectomy. The patient's postoperative course was uneventful, and the tumor marker levels remained within the normal range. No recurrence was observed 3 months after surgery. In recent years, the use of systemic chemotherapy with drugs, such as lenvatinib, followed by conversion surgery has been reported in some cases of unresectable HCC. The present case reports successful conversion surgery following lenvatinib treatment.

Preoperative C-Reactive Protein-to-Albumin Ratio Predicts Postoperative Pancreatic Fistula following Pancreatoduodenectomy: A Single-Center, Retrospective Study.

Postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD) is a potentially lethal complication, and it is clinically important to determine its risk preoperatively. Although C-reactive protein-to-albumin ratio (CAR) is reported to be a prognostic marker for postoperative complications in several cancers, no evidence is currently available regarding the association between preoperative CAR and POPF following PD for periampullary tumors. This study examined whether preoperative CAR could predict POPF following PD. Clinical data were retrospectively retrieved from Ehime University Hospital. The optimal cut-off value for CAR was determined using receiver operating characteristic (ROC) curve analysis. This study enrolled 203 consecutive patients undergoing PD for periampullary tumors. The CAR value was significantly higher in the POPF group than in the non-POPF group (p < 0.001). According to the ROC curve analysis, the optimal cut-off value for CAR was 0.09. Patients with CAR ≥ 0.09 had higher incidence rates of POPF than their counterparts. CAR ≥ 0.09 was a risk factor for POPF in the multivariate logistic regression analysis (odds ratio 34.5, 95% confidence interval 11.75-101.38, p < 0.001). This is the first report demonstrating an association between CAR and POPF following PD. Preoperative CAR is an independent predictive marker for POPF following PD.

The influence of bone marrow edema for the assessment of the boundaries of necrotic lesions in patients with osteonecrosis of the femoral head.

This study aimed to investigate the influence of bone marrow edema (BME) for the assessment of the boundaries of necrotic lesions using unenhanced and contrast-enhanced (CE) magnetic resonance (MR) images in patients with osteonecrosis of the femoral head (ONFH). We retrospectively reviewed 72 consecutive hips in 55 patients of ONFH that were Association Research Circulation Osseous (ARCO) stage III or higher and underwent both unenhanced and contrast-enhanced MR imaging between January 2005 and February 2016. The degree of extension of BMEs, and the boundaries of the necrotic lesions were compared using unenhanced and CE MR images on both mid coronal and mid oblique-axial slices. Forty-two percent of the coronal T1 images, 40% of the coronal fat-saturated T2 images, and 48% of the oblique-axial T1 images showed differences in the boundaries of necrotic lesion, by comparison with those of CET1-weighted MR images. The boundaries of necrotic lesions were clearly detected in all hips on CE coronal slices and 97% of all hips on CE oblique-axial slices. The BME grade in the difference group was significantly higher than in the non-difference group on the coronal plane (P = 0.0058). There were significant differences between the BME grade and duration from the onset of hip pain to MR imaging examination. Multivariate analyses revealed that the duration from the onset to MR imaging examination in both coronal (P = 0.0008) and oblique-axial slices (P = 0.0143) were independently associated with differences in the boundary of necrotic lesion between T1 and CET1-weighted MR images. Our findings suggest that unenhanced MR image may be insufficient for a precise assessment of the boundaries of the necrotic lesions for ONFH cases in the early phase of subchondral collapse due to the diffuse BME.

Sex differences in the therapeutic effect of unaltered versus NFκB sensing IL-4 over-expressing mesenchymal stromal cells in a murine model of chronic inflammatory bone loss.

Wear particles from joint arthroplasties induce chronic inflammation associated with prolonged upregulation of nuclear factor kappa-B (NF-κB) signaling in macrophages and osteoclasts, which leads to osteolysis and implant loosening. Mesenchymal stromal cell (MSC)-based therapy showed great potential for immunomodulation and mitigation of osteolysis in vivo, especially in the chronic phase of inflammation. We previously generated genetically modified MSCs that secrete the anti-inflammatory cytokine interleukin 4 (IL-4) in response to NF-κB activation (NFκB-IL-4 MSCs). However, whether the impact of sexual difference in the internal environment can alter the therapeutic effects of IL-4 over-secreting MSCs that simultaneously mitigate prolonged inflammation and enhance bone formation remains unknown. This study investigated the therapeutic effects of unaltered MSCs versus NFκB-IL-4 MSCs in mitigating chronic inflammation and enhancing bone formation in male and female mice. The murine model was established by continuous infusion of polyethylene particles contaminated with lipopolysaccharide (cPE) into the medullary cavity of the distal femur for 6 weeks to induce chronic inflammation. Unaltered MSCs or NFκB-IL-4 MSCs were infused into the femoral intramedullary cavity in sex-matched groups beginning 3 weeks after primary surgery. Femurs were harvested at 6 weeks, and bone marrow density was measured with micro-computational tomography. Numbers of osteoclast-like cells, osteoblasts, and macrophages were evaluated with histochemical and immunofluorescence staining. cPE infusion resulted in severe bone loss at the surgery site, increased tartrate-resistant acid phosphatase positive osteoclasts and M1 pro-inflammatory macrophages, and decreased alkaline phosphatase expression. MSC-based therapy effectively decreased local bone loss and polarized M1 macrophages into an M2 anti-inflammatory phenotype. In females, unaltered MSCs demonstrated a larger impact in enhancing the osteogenesis, but they demonstrated similar anti-inflammatory effects compared to NFκB-IL-4 MSCs. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments in a sexually dimorphic manner, which could be an efficacious therapeutic strategy for treatment of periprosthetic osteolysis in both genders.

The tumor-to-liver ratio of the standardized uptake value is a useful FDG-PET/CT parameter for predicting malignant intraductal papillary mucinous neoplasm of the pancreas.

Background: The present study aimed to investigate the efficacy of positron emission tomography with 18Fluoro-deoxyglucose (FDG-PET/CT) for predicting malignant intraductal papillary mucinous neoplasm (IPMN). Methods: The records of 88 patients pathologically diagnosed with IPMN after surgery at Ehime University Hospital and Ehime Prefectural Central Hospital from April 2009 to December 2020 were retrospectively reviewed. The patients' characteristics, blood chemistry, and imaging examinations were evaluated as potential predictors of malignant IPMN. Of the PET/CT results, the maximum standardized uptake value (SUVmax) of the tumor, the tumor-to-blood pool ratio of the SUV (TBR), and the tumor-to-liver ratio of the SUV (TLR) were compared. Results: On pathology, the diagnosis was adenoma (IPMA) in 40 patients, high-grade dysplasia (HGD) in 26 patients, and carcinoma (IPMC) in 22 patients. HGD and IPMC were defined as malignant IPMN. On multivariate analyses, TLR ≥ 1.3 and high-risk stigmata were independent predictors of malignant IPMN (P = .001 and P = .007, respectively). When both HRS and TLR ≥ 1.3 were present, the positive predictive value for malignancy was 88.2%. Furthermore, TLR was significantly higher for patients with IPMC than with HGD (P = .039). Conclusion: TLR can be a useful predictor for differentiating benign from malignant IPMN and may be associated with postoperative outcomes.

Differential dynamics of bone graft transplantation and mesenchymal stem cell therapy during bone defect healing in a murine critical size defect.

Background: A critical size bone defect is a clinical scenario in which bone is lost or excised due to trauma, infection, tumor, or other causes, and cannot completely heal spontaneously. The most common treatment for this condition is autologous bone grafting to the defect site. However, autologous bone graft is often insufficient in quantity or quality for transplantation to these large defects. Recently, tissue engineering methods using mesenchymal stem cells (MSCs) have been proposed as an alternative treatment. However, the underlying biological principles and optimal techniques for tissue regeneration of bone using stem cell therapy have not been completely elucidated. Methods: In this study, we compare the early cellular dynamics of healing between bone graft transplantation and MSC therapy in a murine chronic femoral critical-size bone defect. We employ high-dimensional mass cytometry to provide a comprehensive view of the differences in cell composition, stem cell functionality, and immunomodulatory activity between these two treatment methods one week after transplantation. Results: We reveal distinct cell compositions among tissues from bone defect sites compared with original bone graft, show active recruitment of MSCs to the bone defect sites, and demonstrate the phenotypic diversity of macrophages and T cells in each group that may affect the clinical outcome. Conclusion: Our results provide critical data and future directions on the use of MSCs for treating critical size defects to regenerate bone.Translational Potential of this article: This study showed systematic comparisons of the cellular and immunomodulatory profiles among different interventions to improve the healing of the critical-size bone defect. The results provided potential strategies for designing robust therapeutic interventions for the unmet clinical need of treating critical-size bone defects.