Dynamic bidirectional regulation of NLRC3 and gammaherpesviruses during viral latency in B lymphocytes.

While most NOD-like receptors (NLRs) are predominately expressed by innate immune cells, NLRC3, an inhibitory NLR of immune signaling, exhibits the highest expression in lymphocytes. The role of NLRC3 or any NLRs in B lymphocytes is completely unknown. Gammaherpesviruses, including human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV-68), establish latent infection in B lymphocytes, which requires elevated NF-κB. This study shows that during latent EBV infection of human B cells, viral-encoded latent membrane protein 1 (LMP1) decreases NLRC3 transcript. LMP1-induced-NF-κB activation suppresses the promoter activity of NLRC3 via p65 binding to the promoter. Conversely, NLRC3 inhibits NF-κB activation by promoting the degradation of LMP1 in a proteasome-dependent manner. In vivo, MHV-68 infection reduces Nlrc3 transcripts in splenocytes, and Nlrc3-deficient mice show greater viral latency than controls. These results reveal a bidirectional regulatory circuit in B lymphocytes, where viral latent protein LMP1 reduces NLRC3 expression, while NLRC3 disrupts gammaherpesvirus latency, which is an important step for tumorigenesis.

Feasibility of intraoperative pathologic examination for sentinel lymph nodes during sentinel node navigation surgery in early gastric cancer: results of pathologic protocol for SENORITA trial.

BACKGROUND: During sentinel node navigation surgery in patients with gastric cancer, intraoperative pathologic examination of sentinel nodes is crucial in determining the extent of surgery. In this study, we evaluated the feasibility and accuracy of intraoperative pathologic protocols using data from a prospective, multicenter, randomized trial. METHODS: A retrospective analysis was conducted using data from the SEntinel Node ORIented Tailored Approach trials from 2013 to 2016. All sentinel lymph nodes were evaluated during surgery with hematoxylin-eosin (HE) staining using a representative section at the largest plane for lymph nodes. For permanent histologic evaluation, sentinel basin nodes were stained with HE and cytokeratin immunohistochemistry in formalin-fixed, paraffin-embedded (FFPE) sections and examined with HE for three deeper-step sections at 200-µm intervals. The failure rate of identification by frozen section and the metastasis rate in non-sentinel basins were investigated. RESULTS: Of the 237 patients who underwent sentinel node basin dissection, 30 had lymph node metastases on permanent pathology. Thirteen patients had macrometastasis confirmed in frozen sections as well as FFPE sections (failure rate: 0%). Patients with negative sentinel nodes in frozen sections but micrometastasis in FFPE sections had no lymph node recurrence during the follow-up period (0%, 0/6). However, in cases with tumor-positive nodes in frozen sections, metastases in non-sentinel basins were detected in the paraffin blocks (8.3%, 2/24). CONCLUSIONS: The single-section HE staining method is sufficient for detecting macrometastasis via intraoperative pathological examination. If a negative frozen-section result is confirmed, sentinel basin dissection can be performed safely. Otherwise, standard surgery is required.

Patient-Reported Adverse Events Among Elderly Patients Receiving Novel Oral COVID-19 Antivirals: A Nationwide Sampled Survey in Korea.

BACKGROUND: There is a dearth of research on the factors linked with adverse events (AEs) associated with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL), particularly in the elderly. Therefore, this study aimed to investigate self-reported AEs and identify factors associated with the occurrence of AEs following NMVr or MOL treatment among survey participants aged 60 years or older in South Korea. METHODS: This nationwide survey was conducted through in-person interviews using structured questionnaires, from July 24 to August 31, 2023. Eligible participants included individuals aged 60 years or older who had been diagnosed with coronavirus disease 2019 (COVID-19) and received NMVr or MOL. The study outcomes included self-reported demographic, lifestyle, and health characteristics associated with the occurrence of AEs. Multivariate logistic regression analysis was used to estimate the adjusted odds ratio (aOR) and 95% confidence interval (CI) of each characteristic in participants with and without AEs. RESULTS: Of the 520 participants, 123 (23.7%) experienced at least one AE with oral COVID-19 treatment: 21.0% (96/458) for NMVr and 43.5% (27/62) for MOL. None of the participants reported any serious AEs. Increased odds of AE occurrence were observed in participants treated with MOL compared to those treated with NMVr (aOR, 3.05; 95% CI, 1.67-5.57), a history of two or more compared to one COVID-19 diagnosis (1.93; 1.03-3.62), and self-reported health status as "Unhealthy" compared to "Healthy" (2.65; 1.31-5.36). CONCLUSION: No AEs required further evaluation to change treatment strategies in elderly patients on NMVr or MOL. Several factors, including the use of MOL, history of COVID-19, and reported health status, were associated with an increased incidence of AEs. Both treatments may still be useful choices for patients with non-severe COVID-19 aged 60 years or older. However, close monitoring of unidentified potential harm and further investigation of the factors associated with the occurrence of AEs are needed.

Effect of age and gender in rates of achieving minimal clinically important difference and patient-acceptable symptom state 2 years after arthroscopic superior capsular reconstruction.

PURPOSE: This study aimed to evaluate patient-reported outcome measures (PROMs) and the effects of gender and age on achieving clinically significant outcomes in patients undergoing arthroscopic superior capsular reconstruction (ASCR) with a minimum 2-year follow-up. METHODS: Patients undergoing ASCR for irreparable rotator cuff tear between 2013 and 2020 were reviewed. Preoperative and minimum 2-year postoperative PROMs were collected, including American Shoulder and Elbow Surgeons (ASES), Constant, single assessment numeric evaluation (SANE), and visual analog scale (VAS) scores. Minimal clinically important difference (MCID) and patient-acceptable symptomatic state (PASS) were calculated for each functional score and analyzed according to age and gender. The percentages of patients achieving MCID and PASS were recorded. RESULTS: The study included 83 patients, with a mean follow-up of 3.5 ± 1.4 years. Significant improvements were found in ASES, Constant, SANE, and VAS for all groups based on gender and age. Based on receiver-operating characteristic curves, all scores had acceptable areas under the curve for PASS. Values for PASS and MCID were 81.5 and 10.3 for ASES; 61.5 and 6.2 for Constant; 82.5 and 11.5 for SANE and 1.5 and 1.1 for VAS, respectively. Analysis of achieving MCID and PASS showed no difference between the groups in the majority of outcome measures. However, female patients achieved the SANE thresholds for PASS at significantly higher rates than male patients. Patients ≥65 years old achieved ASES and Constant thresholds for MCID at significantly higher rates than patients ˂65 years old. CONCLUSION: Most patients achieved MCID and PASS at a 2-year follow-up. Patients showed comparable rates of MCID and PASS achievement on most outcome tools based on age and gender. Female patients achieved PASS on SANE at significantly higher rates than male patients and older patients achieved MCID on ASES and Constant at higher rates than young patients. Thus, age is a stronger factor for achieving MCID than gender. LEVEL OF EVIDENCE: Level II.

Preoperative magnetic resonance imaging rotator cuff tendon stump classification correlates with the surgical outcomes following superior capsular reconstruction.

HYPOTHESIS: This study aimed to investigate the correlation between rotator cuff stump classification and postoperative outcomes after superior capsular reconstruction (SCR). METHODS: A total of 75 patients who underwent SCR between June 2013 and May 2021 were included in this study. Based on stump classification using the signal intensity ratio of the tendon rupture site to the deltoid muscle in the coronal view of preoperative T2-weighted, fat-suppressed magnetic resonance imaging scans, the patients were classified into types 1, 2, and 3 with ratios of <0.8, 0.8-1.3, and >1.3 (44, 17, and 14 patients, respectively). The American Shoulder and Elbow Surgeons (ASES), Constant, and visual analog scale (VAS) scores for pain and range of motion were evaluated at a minimum of 1 year of follow-up postoperatively. The acromiohumeral distance and rotator cuff arthropathy according to the Hamada classification were assessed on plain radiography. The graft integrity was evaluated by magnetic resonance imaging at 3 and 12 months postoperatively and annually thereafter. RESULTS: Clinical and radiological outcomes were significantly improved after SCR. In comparison with type 2 and 3 patients, type 1 patients had significantly higher ASES scores (type 1, 2, and 3 = 84 ± 10, 75 ± 15, and 76 ± 14; all P = .014), Constant scores (type 1, 2, and 3 = 65 ± 5, 61 ± 9, and 56 ± 13; all P = .005), and forward flexion (type 1, 2, and 3 = 155 ± 10, 154 ± 15, and 145 ± 13; all P = .013). However, these statistical differences between groups were below the established minimum clinically important difference values for the ASES and Constant scores after rotator cuff repair. The graft failure rate after surgery was lower in the type 1 group than that in the other 2 groups; however, the difference was not statistically significant (P = .749). CONCLUSION: Patients with stump classification type 1 showed significantly better functional scores (ASES and VAS scores) and forward flexion; however, the clinical importance of these differences may be limited. Stump classification may be useful for predicting postoperative clinical outcomes.

Decoding the Prevalent High-Risk Breast Cancers: Demographics, Pathological, Imaging Insights, and Long-Term Outcome.

Objective: To investigate the features and outcomes of breast cancer in high-risk subgroups. Materials and Methods: REB approved an observational study of women diagnosed with breast cancer from 2010 to 2019. Three radiologists, using the BI-RADS lexicon, blindly reviewed mammogram and MRI screenings without a washout period. Consensus was reached with 2 additional reviewers. Inter-rater agreement was measured by Fleiss Kappa. Statistical analysis included Mann-Whitney U, Chi-square tests for cohort analysis, and Kaplan-Meier for survival rates, with a Cox model for comparative analysis using gene mutation as a reference. Results: The study included 140 high-risk women, finding 155 malignant lesions. Significant age differences noted: chest radiation therapy (median age 44, IQR: 37.0-46.2), gene mutation (median age 49, IQR: 39.8-58.0), and familial risk (median age 51, IQR: 44.5-56.0) (P = .007). Gene mutation carriers had smaller (P = .01), higher-grade tumours (P = .002), and more triple-negative ER- (P = .02), PR- (P = .002), and HER2- (P = .02) cases. MRI outperformed mammography in all subgroups. Substantial to near-perfect inter-rater agreement observed. Over 10 years, no deaths occurred in chest radiation group, with no significant survival difference between gene mutation and familial risk groups, HR = 0.93 (95% CI: 0.27, 3.26), P = .92. Conclusion: The study highlights the importance of age and specific tumour characteristics in identifying high-risk breast cancer subgroups. MRI is confirmed as an effective screening tool. Despite the aggressive nature of cancers in gene mutation carriers, early detection is crucial for survival outcomes. These insights, while necessitating further validation with larger studies, advocate for a move toward personalized medical care, strengthening the existing healthcare guidelines.

Determination of lysophosphatidylcholine using peroxidase-mimic PVP/PtRu nanozyme.

Lysophosphatidylcholine (LPC) can be used as a biomarker for diseases such as cancer, diabetes, atherosclerosis, and sepsis. In this study, we demonstrated the ability of nanozymes to displace the natural derived enzyme in enzyme-based assays for the measurement of LPC. Synthesized polyvinylpyrrolidone-stabilized platinum-ruthenium nanozymes (PVP/PtRu NZs) had a uniform size of 2.48 ± 0.24 nm and superb peroxidase-mimicking activity. We demonstrated that the nanozymes had high activity over a wide pH and temperature range and high stability after long-term storage. The LPC concentration could be accurately analyzed through the absorbance and fluorescence signals generated by the peroxidation reaction using the synthesized nanozyme with substrates such as 3,3',5,5'-tetramethylbenzidine (TMB) and 10-acetyl-3,7-dihydroxyphenoxazine (Ampliflu™ Red). LPC at a concentration of 0-400 µM was used for the analysis, and the coefficient of determination (R2) was 0.977, and the limit of detection (LOD) was 23.1 µM by colorimetric assay. In the fluorometric assay, the R2 was 0.999, and the LOD was 8.97 µM. The spiked recovery values for the determination of LPC concentration in human serum samples were 102-115%. Based on these results, we declared that PVP/PtRu NZs had an ability comparable to that of the native enzyme horseradish peroxidase (HRP) in the enzyme-based LPC detection method.

Life-threatening esophageal perforation due to blister pack ingestion.

Most ingested foreign bodies do not cause serious complications. In rare cases, elderly people with cognitive decline may unintentionally swallow a blister pack while trying to take medicine. When a blister pack is separated into individual parts, the separated parts have sharp edges that can cause serious damage if ingested. We report a case of an elderly patient who unintentionally ingested a blister pack, which led to esophageal perforation and ultimately his death.

Prevalence of anterolateral ligament injuries and lateral meniscus tear on MR imaging in patients with both-bundle tear vs. selective bundle incomplete tear of the anterior cruciate ligament.

OBJECTIVES: We investigated the prevalence of anterolateral ligament (ALL) injury and lateral meniscus (LM) tear in cases with both-bundle tear and selective bundle incomplete tear of the anterior cruciate ligament (ACL). METHODS: A total of 174 cases of magnetic resonance (MR) images that had an ACL tear and underwent arthroscopic ACL reconstruction were retrospectively reviewed. ACL injury was classified into both bundle, anteromedial bundle, and posterolateral bundle (PL) on arthroscopic finding. The ALL was divided into three portions: femoral, meniscal, and tibial. ALL injury was scored into three groups: grade 0 is intact; grade 1 is stranding and edema surrounds the expected location of the ALL; grade 2 is clear discontinuity of the ALL consistent with rupture. Traumatic LM tear was also assessed on MR images. RESULTS: The total prevalence of ALL injury was 36.2% (reader 1) and 42.0% (reader 2). ALL injury was statistically related to the selective bundle tear (p = 0.002 and 0.004, readers 1 and 2). PL bundle tear was significantly correlated with the ALL injury (p value < 0.001, readers 1 and 2, both). The location and grade of ALL injury were not significantly correlated with the type of ACL injury. LM tear was not significantly related to the types of ACL tear (p = 0.208 and 0.907, readers 1 and 2) and ALL injury (p value = 0.096 and 0.383, readers 1 and 2). CONCLUSIONS: ALL injury was significantly related to the PL bundle tear of the ACL. LM tear was not significantly correlated with the types of ACL injury and ALL injury. KEY POINTS: • Anterolateral ligament (ALL) injury was significantly related to the posterolateral bundle (PL) tear of the anterior cruciate ligament (ACL). • Lateral meniscus (LM) tear was not significantly correlated with the types of ACL injury and ALL injury. • Clinicians and radiologists should be aware of these relationships and scrutinize ALL injury in cases with PL bundle tears, even with an incomplete ACL injury.

Double tract reconstruction versus double flap technique: short-term clinical outcomes after laparoscopic proximal gastrectomy for early gastric cancer.

BACKGROUND: Laparoscopic proximal gastrectomy (LPG) is increasingly preferred for operative management of early gastric cancer, although there is no consensus on a standard reconstruction method after resection. Two popular methods used after LPG are double tract reconstruction (DTR) and double flap technique (DFT). This study assessed comprehensive clinical outcomes including quality of life (QoL) and body composition change 1 year after DFT and DTR. METHODS: We retrospectively reviewed prospectively collected data from 51 to 18 patients who underwent DTR and DFT, respectively, between September 2014 and December 2018. Short-term surgical outcomes, presence of reflux esophagitis, nutritional supplementation, medications, nutritional status (laboratory results and body composition analysis), and QoL measured preoperatively and at 1 year postoperatively were compared between both groups. RESULTS: Both groups did not differ significantly in clinicopathological characteristics. The DFT as compared to the DTR group required significantly longer time for anastomosis (79.4 vs. 60.9 min, p < 0.001) and use of fewer staplers (3.39 vs. 6.86, p < 0.001). While the presence of endoscopic reflux esophagitis and iron/vitamin B12 replacement were comparable, the DTR group showed a higher tendency of taking anti-reflux medications for reflux symptoms (DTR: 13.7% vs. DFT: 0.0%, p = 0.177). The DTR group lost significantly more weight (p = 0.038) and body fat (p = 0.009). QoL analysis showed significant deterioration in diarrhea, eating restriction, and taste problems in both groups (DTR group: p = 0.008, p < 0.001, p = 0.010, respectively, and DFT group: p = 0.017, p = 0.024, p = 0.034, respectively). However, only the DTR group showed significant deterioration in physical function (p = 0.009), role function (p = 0.033), nausea/vomiting (p = 0.041), appetite loss (p = 0.019), dysphagia (p = 0.001), pain (p = 0.025), and body image (p = 0.004). CONCLUSIONS: Despite requiring a longer anastomosis time, performing DFT after LPG was shown to be an ideal reconstruction method in terms of better 1-year QoL and nutritional outcome. Further larger studies over longer postoperative periods are necessary to confirm our findings.

Wedging of vertebral bodies at the thoracolumbar spine in healthy individuals on whole body MRI screening: correlation with disc degeneration and disc herniation.

BACKGROUND: There have been no reports on the relationship between wedging of vertebral bodies at the thoracolumbar spine and disc herniation in healthy individuals on magnetic resonance imaging (MRI). PURPOSE: To investigate the degree of wedging of vertebral bodies at the thoracolumbar spine in healthy individuals who underwent whole-body (WB) MRI. We also assessed the correlation between wedging and adjacent disc pathology. MATERIAL AND METHODS: This retrospective study comprised 200 healthy patients who underwent WB MRI as part of a regular health check from January 2019 to February 2019. We measured anterior and posterior vertical heights of each vertebral body between T10 and L2. The ratio of anterior height to posterior height (APR) was calculated, and we evaluated disc degeneration or disc herniation using WB MRI. RESULTS: The APR of T10 was significantly higher than at the other levels (P < 0.05), and the APR of L1 was significantly lower (P < 0.05). Men had a significantly smaller APR than women at T12 to L2 (P < 0.05). Regarding the relationship between APR and disc degeneration, the group without disc degeneration had a higher APR, with statistical significance at T12, L1, and L2. Regarding the relationship between APR and disc herniation, the group without disc herniation had a higher APR, with statistical significance at T11, T12, L1, and L2. CONCLUSION: Wedging of vertebral bodies is most prominent at L1. Although the values were statistically significant only at some levels, the patients with disc degeneration or herniation had more prominent wedge deformity of thoracolumbar spine.

A finite element analysis and cyclic load experiment on an additional transcortical-type hole formed around the proximal femoral nail system's distal locking screw.

BACKGROUND: A complication associated with the distal locking screw used in the proximal femoral nail (PFN) system is the formation of accidental additional holes. We hypothesized that an increase in stress around additional holes is a relevant factor contributing to fractures. This study aimed to evaluate stress changes in the cortical bone around additional screw holes using finite element analysis. METHODS: Proximal femoral nail antirotation (PFNA)-II (Synthes, Solothurn, Switzerland) was inserted into a femur model. An additional 4.9-mm transcortical hole was made either anteriorly (anterior hole model) or posteriorly (posterior hole model) to the distal locking screw. Finite element analysis was used to calculate compression, tension, and load limits to investigate stress around additional holes with respect to the direction of screw penetration and degree of osteoporosis. The results were then compared with those of mechanical testing. A 31A-21 type intertrochanteric fracture was applied. As a control group, a model without additional holes (no-hole model) was developed. Repeated load-loading tests were performed on 10 model bones per model group. RESULTS: Tensile stress was significantly greater in the no-hole model when additional screw holes were present, and the anterior hole showed a higher maximum stress value than the posterior hole, suggesting that the anterior hole was more susceptible to fracture. The change in tensile stress first appeared in the hole around the lateral cortical bone and proceeded to the medial side. Biomechanical testing showed that fractures around the distal locking screw occurred in 0 cases of the no-hole, 10 of the anterior hole, and 9 of the posterior hole models. CONCLUSIONS: During PFN surgery for intertrochanteric fracture, holes with distal locking screws fixed and removed at the anterior and posterior of the nail can be a risk factor for fractures in the surrounding area.

Protein arginine methyltransferase 1 contributes to the development of allergic rhinitis by promoting the production of epithelial-derived cytokines.

BACKGROUND: Arginine methylation is a posttranslational modification mediated by protein arginine methyltransferases (PRMTs). Although previous studies have shown that PRMT1 contributes to the severity of allergic airway inflammation or asthma, the underlying mechanism is poorly understood. OBJECTIVE: This study aimed to explore the role of PRMT1 and its relevant mechanism in the development of allergic rhinitis (AR). METHODS: The expression levels of PRMTs and cytokines were determined by RT-PCR, and the localization of PRMT1 was determined by immunohistochemistry and confocal microscopy. The levels of house dust mite (HDM)-specific immunoglobulins in serum and of cytokines in nasal lavage fluids were determined by ELISA. PRMT1 inhibition was achieved by siRNA and treatment with the pan PRMT inhibitor arginine N-methyltransferase inhibitor-1. RESULTS: PRMT1 expression was significantly increased in the nasal mucosa of patients and mice with AR. The degree of eosinophilic infiltration in the nasal mucosa was reduced in PRMT1+/- AR mice compared with wild-type mice. PRMT1 haploinsufficiency reduced the levels of HDM-specific immunoglobulins in serum and those of TH2 (IL-4, IL-5, and IL-13) and epithelial (thymic stromal lymphopoietin [TSLP], IL-25, and IL-33) cytokines in the nasal lavage fluids of AR mice. In nasal epithelial cells, HDM and IL-4 cooperate to enhance PRMT1 expression through a mitogen-activated protein kinase-dependent pathway. In addition, PRMT1 was essential for the production of TSLP, IL-25, and IL-33 in response to HDM and IL-4. Arginine N-methyltransferase inhibitor-1 treatment alleviated AR in the mouse model. CONCLUSIONS: PRMT1 plays an important role in AR development by regulating epithelial-derived cytokine production and might be a new therapeutic target for AR.

Subscapularis-sparing deltopectoral approach in reverse total shoulder arthroplasty.

PURPOSE: This study compared the clinical and radiologic results of reverse shoulder arthroplasty (RSA) using either the subscapularis-sparing deltopectoral approach (SSDA) or traditional deltopectoral approach (TDA) in cuff tear arthropathy patients. MATERIALS AND METHOD: We retrospectively evaluated 71 patients who underwent RSA for cuff tear arthropathy between July 2014 and December 2018. Patients were divided into two groups according to the surgical approach: TDA (34 cases) and SSDA (37 cases). The mean patient age was 78.6 years, and the mean (range) follow-up period was 23.5 (12-48) months. Clinical results were assessed using the Visual Analogue pain Scale (VAS), American Shoulder and Elbow Surgeon score (ASES), Korean Shoulder Scoring System (KSS), and Constant score. Radiographic indicators prosthesis-scapular neck angle (PSNA), peg-glenoid rim distance (PGRD), inferior overhang, acromion-greater tuberosity (AT) distance, and glenoid-greater tuberosity (GT) distance) were assessed, and notching severity was assessed according to the Nerot-Sirveaux classification. RESULTS: The radiographic indicator results of the TDA and SSDA groups were as follows: PSNA (131.4° ± 17.2°, 136.1° ± 7.7°), PGRD (18.7 mm ± 2.9 mm, 21.4 mm ± 2.0 mm), AT distance (38.3 mm ±6.9 mm, 37.5 mm ± 6.8 mm), GT distance (51.6 mm ± 6.3 mm, 51.4 mm ± 5.3 mm), and inferior overhang (4.4 mm ± 2.2 mm, 2.9 mm ± 1.3 mm). PGRD and inferior overhang showed statistically significant differences between groups, but the clinical results showed no significant differences. There were no complications such as neurovascular injury, implant loosening, surgical site infection, or acromion fracture in either group. CONCLUSION: SSDA for RSA showed no significant differences in clinical and radiological results compared with TDA. Therefore, SSDA is a viable alternative for RSA in cuff tear arthropathy.

Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte Dedifferentiation During Pressure Overload.

RATIONALE: The Hippo pathway plays an important role in determining organ size through regulation of cell proliferation and apoptosis. Hippo inactivation and consequent activation of YAP (Yes-associated protein), a transcription cofactor, have been proposed as a strategy to promote myocardial regeneration after myocardial infarction. However, the long-term effects of Hippo deficiency on cardiac function under stress remain unknown. OBJECTIVE: We investigated the long-term effect of Hippo deficiency on cardiac function in the presence of pressure overload (PO). METHODS AND RESULTS: We used mice with cardiac-specific homozygous knockout of WW45 (WW45cKO), in which activation of Mst1 (Mammalian sterile 20-like 1) and Lats2 (large tumor suppressor kinase 2), the upstream kinases of the Hippo pathway, is effectively suppressed because of the absence of the scaffolding protein. We used male mice at 3 to 4 month of age in all animal experiments. We subjected WW45cKO mice to transverse aortic constriction for up to 12 weeks. WW45cKO mice exhibited higher levels of nuclear YAP in cardiomyocytes during PO. Unexpectedly, the progression of cardiac dysfunction induced by PO was exacerbated in WW45cKO mice, despite decreased apoptosis and activated cardiomyocyte cell cycle reentry. WW45cKO mice exhibited cardiomyocyte sarcomere disarray and upregulation of TEAD1 (transcriptional enhancer factor) target genes involved in cardiomyocyte dedifferentiation during PO. Genetic and pharmacological inactivation of the YAP-TEAD1 pathway reduced the PO-induced cardiac dysfunction in WW45cKO mice and attenuated cardiomyocyte dedifferentiation. Furthermore, the YAP-TEAD1 pathway upregulated OSM (oncostatin M) and OSM receptors, which played an essential role in mediating cardiomyocyte dedifferentiation. OSM also upregulated YAP and TEAD1 and promoted cardiomyocyte dedifferentiation, indicating the existence of a positive feedback mechanism consisting of YAP, TEAD1, and OSM. CONCLUSIONS: Although activation of YAP promotes cardiomyocyte regeneration after cardiac injury, it induces cardiomyocyte dedifferentiation and heart failure in the long-term in the presence of PO through activation of the YAP-TEAD1-OSM positive feedback mechanism.

TLR2 and the NLRP3 inflammasome mediate IL-1ß production in Prevotella nigrescens-infected dendritic cells.

Prevotella nigrescens is an oral pathogen that is frequently observed in the subgingival plaque of periodontitis patients. Interleukin-1ß (IL-1ß) is known to be involved in the immunopathology of periodontal diseases and has been implicated in the destruction of bone. In this study, we investigated the mechanism of IL-1ß production by P. nigrescens in murine bone marrow-derived dendritic cells (BMDCs). Our results showed that a host receptor, Toll-like receptor 2 (TLR2), but not TLR4 is required for pro-IL-1ß induction and nucleotide-binding oligomerization domain like receptor pyrin domain containing 3 (NLRP3) priming in BMDCs in response to P. nigrescens and activation of the NLRP3 inflammasome is necessary for processing of pro-IL-1ß into mature IL-1ß. In addition, an inhibitor assay revealed that production of reactive oxygen species, P2X7R activity, and release of cathepsin B are involved in IL-1ß production in BMDCs in response to P. nigrescens.

Conventional versus helical blade screw insertion following the removal of the femoral head screw: a biomechanical evaluation using trochanteric gamma 3 locking nail versus PFN antirotation.

OBJECTIVE: When a hip screw needs to be changed, choosing between the conventional (C-type) and helical blade (H-type) types is difficult. In this biomechanical study, we compared these two screw types relative to the type of the initial screw used. METHODS: C- or H-type screws were inserted (leading screw) in three types of polyurethane bone models (Sawbone, Pacific Research Laboratories, Inc., Washington, USA: 130 × 180 × 40 mm) of different bone mineral densities (pounds per cubic feet [PCF] 5, 80 kg/m3; PCF 10, 160 kg/m3; and PCF 15, 240 kg/m3), and then successively or alternately inserted (following screw) after the leading screw removal. An original model (original C and H) of a leading screw without removal was created as a control. The strengths of resistance to pullout (PO) and rotational stress were measured. For each experimental condition, there were 30 experimental models. RESULTS: The original C screw was superior in PO strength, and the original H-type screw was superior in rotational strength. When the C- or H-type screw was the leading screw, using the C-type screw again as the following screw (C1-C2, H1-C2) showed the greatest resistance to PO, and using the H-type screw as the following screw (C1-H2, H1-H2) showed superior resistance to rotational strength. However, the rotational strength of the C2 screw decreased by more than 50% compared with that of the original C screw. Moreover, the PO and rotational strengths of the H2 screw decreased to less than 30% overall compared with those of the original H screw. CONCLUSION: The H-type screw should be used for second-time screw insertion procedures in cases where it is difficult to choose between PO and rotational strengths.

Impact of Palliative Gastrectomy in Patients with Incurable Gastric Cancer.

Background and Objectives: The prognosis of metastatic or unresectable gastric cancer is dismal, and the benefits of the palliative resection of primary tumors with noncurative intent remain controversial. This study aimed to evaluate the impact of palliative gastrectomy (PG) on overall survival in gastric cancer patients. Materials and Methods: One hundred forty-eight gastric cancer patients who underwent PG or a nonresection (NR) procedure between January 2011 and 2017 were retrospectively reviewed to select and analyze clinicopathological factors that affected prognosis. Results: Fifty-five patients underwent primary tumor resection with palliative intent, and 93 underwent NR procedures owing to the presence of metastatic or unresectable disease. The PG group was younger and more female dominant. In the PG group, R1 and R2 resection were performed in two patients (3.6%) and 53 patients (96.4%), respectively. The PG group had a significantly longer median overall survival than the NR group (28.4 vs. 7.7 months, p < 0.001). Multivariate analyses revealed that the overall survival was significantly better after palliative resection (hazard ratio (HR), 0.169; 95% confidence interval (CI), 0.088-0.324; p < 0.001) in patients with American Society of Anesthesiologists Physical Status (ASA) scores ≤1 (HR, 0.506; 95% CI, 0.291-0.878; p = 0.015) and those who received postoperative chemotherapy (HR, 0.487; 95% CI, 0.296-0.799; p = 0.004). Among the patients undergoing palliative resection, the presence of <15 positive lymph nodes was the only significant predictor of better overall survival (HR, 0.329; 95% CI, 0.121-0.895; p = 0.030). Conclusions: PG might lead to the prolonged survival of certain patients with incurable gastric cancer, particularly those with less-extensive lymph-node metastasis.

High-Quality Genome Assembly of Peronospora destructor, the Causal Agent of Onion Downy Mildew.

Peronospora destructor is an obligate biotrophic oomycete that causes downy mildew on onion (Allium cepa). Onion is an important crop worldwide, but its production is affected by this pathogen. We sequenced the genome of P. destructor using the PacBio sequencing platform, and de novo assembly resulted in 74 contigs with a total contig size of 29.3 Mb and 48.48% GC content. Here, we report the first high-quality genome sequence of P. destructor and its comparison with the genome assemblies of other oomycetes. The genome is a very useful resource to serve as a reference for analysis of P. destructor isolates and for comparative genomic studies of the biotrophic oomycetes.

Tendril extract of Cucurbita moschata suppresses NLRP3 inflammasome activation in murine macrophages and human trophoblast cells.

Inflammation is the root cause of many diseases that pose a serious threat to human health. Excessive inflammation can also result in preterm birth or miscarriage in pregnant women. Pumpkin (Cucurbita moschata Duchesne, CMD) is a well-known traditional health food and medicinal herb used in many countries to treat diabetes, obesity, osteoporosis, cancer and other diseases. In this study, we investigated the effects of hot water extract derived from the tendrils of C. moschata Duchesne (TCMD) on NLRP3 inflammasome activation in murine macrophages and human trophoblast cells. The TCMD treatment of LPS-primed bone marrow-derived macrophages (BMDMs) and human trophoblast cells attenuated NLRP3 inflammasome activation induced by inflammasome activators such as ATP, nigericin, and monosodium urate (MSU). TCMD treatment suppressed IL-1ß secretion in a dose-dependent manner, without affecting IL-6 secretion. In addition, TCMD inhibited NLRP3-dependent pyroptosis in BMDMs. TCMD also suppressed the release of mature IL-1ß and activation of cleaved-caspase-1 via limited ASC oligomerization. Furthermore, TCMD significantly inhibited IL-1ß secretion and pyroptotic cell death in human trophoblast cells. These results suggest that TCMD exhibits anti-inflammatory effects mediated via inhibition of NLRP3 inflammasome activation suggesting therapeutic potential against inflammatory diseases, preterm birth, and miscarriage.