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In pancreatic cancer, postoperative complications (POCs) are associated with disease outcomes. The geriatric nutritional risk index (GNRI) is known to predict POCs after pancreatoduodenectomy (PD) or distal pancreatectomy (DP) in patients with hepatobiliary pancreatic tumors, including pancreatic cancer. Through POC occurrence risk, we aimed to determine whether GNRI could predict prognosis in patients who underwent PD or DP for resectable pancreatic cancer. This retrospective study examined 139 patients who underwent radical pancreatectomy for resectable pancreatic cancer at Ehime University. All patients were subjected to nutritional screening using GNRI and were followed up for POC diagnosis and patient outcomes such as overall survival (OS). Patients were divided based on the GNRI value of 99 (Low group: N = 74, GNRI < 99; High group: N = 65, GNRI ≥ 99), which was determined by receiver operating characteristic curve analysis. Multivariate analysis showed that GNRI < 99 was statistically correlated with POCs after curative pancreatic resection (p = 0.02). Univariate and multivariate analyses confirmed that GNRI < 99 was significantly associated with long OS (p = 0.04). GNRI could be a potential prognostic marker for resectable pancreatic cancer after curative pancreatic resection despite being a simple and noninvasive approach.

Background In osteonecrosis of the femoral head, appositional bone formation occurs in the reparative zone, where new trabeculae surround necrotic bone, leading to trabecular thickening. However, the underlying molecular mechanisms remain unclear. We previously demonstrated a significant correlation between trabecular thickening and nerve growth factor (NGF) expression in the reparative zone of stage 3 osteonecrosis of the femoral head. This study explored NGF’s molecular relationship with appositional bone formation. Methods RNA sequencing was performed on reparative zone samples from four stage 3 osteonecrosis of the femoral head femoral heads. One to three cylindrical samples (6 mm in diameter) were harvested per head. As controls, three samples were collected from the reparative zone of a single stage 1 osteonecrosis of the femoral head without histological evidence of appositional bone formation. Differentially expressed genes were identified using the DESeq2. Enrichment analysis was performed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases via DAVID. NGF expression was evaluated using immunohistochemistry. Results Stage 3 samples showed the upregulation of bone formation–related genes, including COL1A1 , RUNX2 , BMP2 , BGLAP , and NGF . KEGG analysis revealed the enrichment of bone-related signaling pathways, such as Wnt, TGF-β, and PI3K-Akt. NGF expression was observed in the reparative zone of stage 3 femoral heads, which exhibited appositional bone formation, but not in stage 1. Conclusion These findings indicate that the reparative zone exhibiting appositional bone formation shows transcriptional activation of bone formation, accompanied by increased NGF expression. NGF may be involved in the molecular mechanisms underlying appositional bone formation in osteonecrosis of the femoral head, and serve as a potential regulator of this process.

Background Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified MSCs that over-express specific cytokines, growth factors, or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. However, exposure to IL-4 prematurely inhibits osteogenesis of MSCs in vitro; furthermore, IL-4 overexpressing MSCs inhibit osteogenesis in vivo during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect. Methods In this study, we generated a lentiviral vector that produces PDGF-BB under a weak promoter (phosphoglycerate kinase, PGK) and lentiviral vector producing IL-4 under a strong promoter (cytomegalovirus, CMV). We infected MSCs with PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate cell proliferation and viability, protein expression, and the capability for osteogenesis. Results PDGF-BB and IL-4 co-overexpression was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone. Conclusions Overexpression of PDGF-BB together with IL-4 mitigates the inhibitory effect of IL-4 on osteogenesis by IL-4 overexpressing MSCS. PDGF-BB and IL-4 overexpressing MSCs may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation.

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.

Otitis media (OM) is common among young children and is related to hearing loss. We investigated the association between maternal insecticide use, from conception to the first and second/third trimesters, and OM events in children in the first year of age. Data from Japan Environment and Children's Study were used in this prospective cohort study. Characteristics of patients with and without history of OM during the first year of age were compared. The association between history of OM in the first year and insecticide use was evaluated using logistic regression analysis. The study enrolled 98,255 infants. There was no significant difference in the frequency of insecticide use between groups. Insecticide use of more than once a week from conception to the first trimester significantly increased the occurrence of OM in children in the first year (odds ratio [OR] = 1.30, 95% confidence interval [CI] 1.01–1.67). The association between OM in the first year and insecticide use from conception to the first trimester was only significant in the group without daycare attendance (OR 1.76, 95% CI 1.30–2.38). Maternal insecticide use more than once a week from conception to the first trimester significantly increased OM risk in offspring without daycare attendance.

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.

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. 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. 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. 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.

Background Approximately one third of patients undergoing core decompression (CD) for early-stage osteonecrosis of the femoral head (ONFH) experience progression of the disease, and subsequently require total hip arthroplasty (THA). Thus, identifying adjunctive treatments to optimize bone regeneration during CD is an unmet clinical need. Platelet-derived growth factor (PDGF)-BB plays a central role in cell growth and differentiation. The aim of this study was to characterize mesenchymal stromal cells (MSCs) that were genetically modified to overexpress PDGF-BB (PDGF-BB-MSCs) in vitro and evaluate their therapeutic effect when injected into the bone tunnel at the time of CD in an in vivo rabbit model of steroid-associated ONFH. Methods In vitro studies : Rabbit MSCs were transduced with a lentivirus vector carrying the human PDGF-BB gene under the control of either the cytomegalovirus (CMV) or phosphoglycerate (PGK) promoter. The proliferative rate, PDGF-BB expression level, and osteogenic differentiation capacity of unmodified MSCs, CMV-PDGF-BB-MSCs, and PGK-PDGF-BB-MSCs were assessed. In vivo studies: Twenty-four male New Zealand white rabbits received an intramuscular (IM) injection of methylprednisolone 20 mg/kg. Four weeks later, the rabbits were divided into four groups: the CD group, the hydrogel [HG, (a collagen-alginate mixture)] group, the MSC group, and the PGK-PDGF-BB-MSC group. Eight weeks later, the rabbits were sacrificed, their femurs were harvested, and microCT, mechanical testing, and histological analyses were performed. Results In vitro studies : PGK-PDGF-BB-MSCs proliferated more rapidly than unmodified MSCs ( P  < 0.001) and CMV-PDGF-BB-MSCs ( P  < 0.05) at days 3 and 7. CMV-PDGF-BB-MSCs demonstrated greater PDGF-BB expression than PGK-PDGF-BB-MSCs ( P  < 0.01). However, PGK-PDGF-BB-MSCs exhibited greater alkaline phosphatase staining at 14 days ( P  < 0.01), and osteogenic differentiation at 28 days ( P  = 0.07) than CMV-PDGF-BB-MSCs. In vivo : The PGK-PDGF-BB-MSC group had a trend towards greater bone mineral density (BMD) than the CD group ( P  = 0.074). The PGK-PDGF-BB-MSC group demonstrated significantly lower numbers of empty lacunae ( P  < 0.001), greater osteoclast density ( P  < 0.01), and greater angiogenesis ( P  < 0.01) than the other treatment groups. Conclusion The use of PGK-PDGF-BB-MSCs as an adjunctive treatment with CD may reduce progression of osteonecrosis and enhance bone regeneration and angiogenesis in the treatment of early-stage ONFH.

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. Although the FDG PET/CT maximum standardized uptake value (SUVmax) of the tumor is a useful parameter, it is not an absolute value but a relative value, and it is affected by various factors such as equipment and imaging protocols. In order to make SUVmax more universal, the ratio of SUVmax of the tumor to SUV mean of the liver right lobe (TLR) was investigated. The present study showed that the TLR can be a useful predictor for differentiating benign from malignant IPMNs and may be associated with outcomes, such as postoperative recurrence.

A critical-size bone defect is a challenging clinical problem in which a gap between bone ends will not heal and will become a nonunion. The current treatment is to harvest and transplant an autologous bone graft to facilitate bone bridging. To develop less invasive but equally effective treatment options, one needs to first have a comprehensive understanding of the bone healing process. Therefore, it is imperative to leverage the most advanced technologies to elucidate the fundamental concepts of the bone healing process and develop innovative therapeutic strategies to bridge the nonunion gap. In this review, we first discuss the current animal models to study critical-size bone defects. Then, we focus on four novel analytic techniques and discuss their strengths and limitations. These four technologies are mass cytometry (CyTOF) for enhanced cellular analysis, imaging mass cytometry (IMC) for enhanced tissue special imaging, single-cell RNA sequencing (scRNA-seq) for detailed transcriptome analysis, and Luminex assays for comprehensive protein secretome analysis. With this new understanding of the healing of critical-size bone defects, novel methods of diagnosis and treatment will emerge.