Long-term efficacy of encapsulated xenogeneic islet transplantation: Impact of encapsulation techniques and donor genetic traits.

AIMS/INTRODUCTION: To investigate the long-term efficacy of various encapsulated xenogeneic islet transplantation, and to explore the impact of different donor porcine genetic traits on islet transplantation outcomes. MATERIALS AND METHODS: Donor porcine islets were obtained from wild-type, α1,3-galactosyltransferase knockout (GTKO) and GTKO with overexpression of membrane cofactor protein genotype. Naked, alginate, alginate-chitosan (AC), alginate-perfluorodecalin (A-PFD) and AC-perfluorodecalin (AC-PFD) encapsulated porcine islets were transplanted into diabetic mice. RESULTS: In vitro assessments showed no differences in the viability and function of islets across encapsulation types and donor porcine islet genotypes. Xenogeneic encapsulated islet transplantation with AC-PFD capsules showed the most favorable long-term outcomes, maintaining normal blood glucose levels for 180 days. A-PFD capsules showed comparable results to AC-PFD capsules, followed by AC capsules and alginate capsules. Conversely, blood glucose levels in naked islet transplantation increased to >300 mg/dL within a week after transplantation. Naked islet transplantation outcomes showed no improvement based on donor islet genotype. However, alginate or AC capsules showed delayed increases in blood glucose levels for GTKO and GTKO with overexpression of membrane cofactor protein porcine islets compared with wild-type porcine islets. CONCLUSION: The AC-PFD capsule, designed to ameliorate both hypoxia and inflammation, showed the highest long-term efficacy in xenogeneic islet transplantation. Genetic modifications of porcine islets with GTKO or GTKO with overexpression of membrane cofactor protein did not influence naked islet transplantation outcomes, but did delay graft failure when encapsulated.

Eucommia ulmoides Leaves Alleviate Cognitive Dysfunction in Dextran Sulfate Sodium (DSS)-Induced Colitis Mice through Regulating JNK/TLR4 Signaling Pathway.

Ulcerative colitis (UC) is one of the inflammatory bowel diseases (IBD) that is characterized by systemic immune system activation. This study was performed to assess the alleviative effect of administering an aqueous extract of Eucommia ulmoides leaves (AEEL) on cognitive dysfunction in mice with dextran sulfate sodium (DSS)-induced colitis. The major bioactive compounds of AEEL were identified as a quinic acid derivative, caffeic acid-O-hexoside, and 3-O-caffeoylquinic acid using UPLC Q-TOF/MSE. AEEL administration alleviated colitis symptoms, which are bodyweight change and colon shortening. Moreover, AEEL administration protected intestinal barrier integrity by increasing the tight junction protein expression levels in colon tissues. Likewise, AEEL improved behavioral dysfunction in the Y-maze, passive avoidance, and Morris water maze tests. Additionally, AEEL improved short-chain fatty acid (SCFA) content in the feces of DSS-induced mice. In addition, AEEL improved damaged cholinergic systems in brain tissue and damaged mitochondrial and antioxidant functions in colon and brain tissues caused by DSS. Also, AEEL protected against DSS-induced cytotoxicity and inflammation in colon and brain tissues by c-Jun N-terminal kinase (JNK) and the toll-like receptor 4 (TLR4) signaling pathway. Therefore, these results suggest that AEEL is a natural material that alleviates DSS-induced cognitive dysfunction with the modulation of gut-brain interaction.

Evaluating the validity and reliability of the Korean version of Scales for Outcomes in Parkinson's Disease-Cognition.

Objective: The Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) was developed to screen for cognition in PD. In this study, we aimed to evaluate the validity and reliability of the Korean version of the SCOPA-cog. Methods: We recruited 129 PD patients from 31 clinics with movement disorders in South Korea. The original version of the SCOPA-cognition was translated into Korean using the translation-retranslation method. The test-rest method with an intraclass correlation coefficient (ICC) and Cronbach's alpha coefficient were used to assess reliability. The Spearman's Rank correlation analysis with Montreal Cognitive Assessment-Korean version (MOCA-K) and Korean Mini-Mental State Examination (K-MMSE) were used to assess concurrent validity. Results: The Cronbach's alpha coefficient was 0.797, and the ICC was 0.887. Spearman's rank correlation analysis showed a significant correlation with the K-MMSE and MOCA-K scores (r = 0.546 and r = 0.683, respectively). Conclusions: Our results demonstrate that K-SCOPA-Cog exhibits good reliability and validity.

Opicapone to Treat Early Wearing-off in Parkinson's Disease Patients: The Korean ADOPTION Trial.

BACKGROUND: Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients. OBJECTIVES: To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients. METHODS: ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change. RESULTS: The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied. CONCLUSIONS: Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off.

Preoperative phenotype has no significant impact on the clinical outcomes and long-term survival of mechanically aligned total knee arthroplasty in Asian patients with osteoarthritis.

Aims: The aim of this study was to investigate the distribution of phenotypes in Asian patients with end-stage osteoarthritis (OA) and assess whether the phenotype affected the clinical outcome and survival of mechanically aligned total knee arthroplasty (TKA). We also compared the survival of the group in which the phenotype unintentionally remained unchanged with those in which it was corrected to neutral. Methods: The study involved 945 TKAs, which were performed in 641 patients with primary OA, between January 2000 and January 2009. These were classified into 12 phenotypes based on the combined assessment of four categories of the arithmetic hip-knee-ankle angle and three categories of actual joint line obliquity. The rates of survival were analyzed using Kaplan-Meier methods and the log-rank test. The Hospital for Special Surgery score and survival of each phenotype were compared with those of the reference phenotype with neutral alignment and a parallel joint line. We also compared long-term survival between the unchanged phenotype group and the corrected to neutral alignment-parallel joint line group in patients with Type IV-b (mild to moderate varus alignment-parallel joint line) phenotype. Results: The most common phenotype was Type I-b (mild to moderate varus alignment-medial joint line; 27.1% (n = 256)), followed by Type IV-b (23.2%; n = 219). There was no significant difference in the clinical outcomes and long-term survival between the groups. In Type IV-b phenotypes, the neutrally corrected group showed higher 15-year survival compared with the unchanged-phenotype group (94.9% (95% confidence interval (CI) 92.0 to 97.8) vs 74.2% (95% CI 98.0 to 100); p = 0.020). Conclusion: Constitutional varus was confirmed in more than half of these patients. Mechanically aligned TKA can achieve consistent clinical outcomes and long-term survival, regardless of the patient's phenotype. The neutrally corrected group had better long-term survival compared with the unchanged phenotype group.

Fermented Protaetia brevitarsis Larvae Improves Neurotoxicity in Chronic Ethanol-Induced-Dementia Mice via Suppressing AKT and NF-κB Signaling Pathway.

This study was investigated to examine the neuroprotective effect of fermented Protaetia brevitarsis larvae (FPB) in ethanol-induced-dementia mice. Consumption of FPB by mice resulted in improved memory dysfunction in the Y-maze, passive avoidance, and Morris water maze tests. FPB significantly decreased oxidative stress by regulating levels of malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) in brain tissues. In addition, FPB restored cerebral mitochondrial dysfunction by modulating levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP. In addition, FPB enhanced the cholinergic system via the regulation of acetylcholine (ACh) content, acetylcholinesterase (AChE) activity, and expressions of AChE and choline acetyltransferase (ChAT) in brain tissues. FPB ameliorated neuronal apoptosis through modulation of the protein kinase B (AKT)/B-cell lymphoma (BCL)-2 signaling pathway. Also, FPB improved inflammation response by down-regulating the toll-like receptor (TLR)-4/nuclear factor (NF)-κB pathway. Additionally, FPB ameliorated synaptic plasticity via the increase of the expressions of synaptophysin (SYP), postsynaptic density protein (PSD)-95, and growth-associated protein (GAP)-43. Treatment with FPB also reinforced the blood-brain barrier by increasing tight junctions including zonula occludens (ZO)-1, occludin, and claudin-1. In conclusion, these results show that FPB can improve cognitive impairment via AKT/NF-κB pathways in ethanol-induced-dementia mice.

Intraoperative Brainstem Auditory Evoked Potentials and Postoperative Nausea and Vomiting After Microvascular Decompression.

BACKGROUND: We performed this study to investigate the effect of intraoperative brainstem auditory evoked potential (IBAEP) changes on the development of postoperative nausea and vomiting (PONV) after microvascular decompression (MVD) for neurovascular cross compression. METHODS: A total of 373 consecutive cases were treated with MVD. The use of rescue antiemetics after surgery was used as an objective indicator of PONV. IBAEP monitoring was routinely performed in all. RESULTS: The use of rescue antiemetics was significantly associated with female sex (OR = 3.427; 95% CI, 2.077-5.654; P < 0.001), PCA use (OR = 3.333; 95% CI, 1.861-5.104; P < 0.001), and operation time (OR = 1.017; 95% CI, 1.008-1.026; P < 0.001). A Wave V peak delay of more than 1.0 milliseconds showed a significant relation with the use of rescue antiemetics (OR = 1.787; 95% CI, 1.114-2.867; P = 0.016) and a strong significant relation with the use of rescue antiemetics more than 5 times (OR = 2.426; 95% CI, 1.372-4.290; P = 0.002). CONCLUSIONS: A wave V peak delay of more than 1.0 milliseconds might have value as a predictor of PONV after MVD. More detailed neurophysiological studies will identify the exact pathophysiology underlying PONV after MVD.

Hepatoprotective Effect of Allium ochotense Extracts on Chronic Alcohol-Induced Fatty Liver and Hepatic Inflammation in C57BL/6 Mice.

This study was performed to investigate the protective effects of Allium ochotense on fatty liver and hepatitis in chronic alcohol-induced hepatotoxicity. The physiological compounds of a mixture of aqueous and 60% ethanol (2:8, w/w) extracts of A. ochotense (EA) were identified as kestose, raffinose, kaempferol and quercetin glucoside, and kaempferol di-glucoside by UPLC Q-TOF MSE. The EA regulated the levels of lipid metabolism-related biomarkers such as total cholesterol, triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)-cholesterol in serum. Also, EA ameliorated the levels of liver toxicity-related biomarkers such as glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and total bilirubin in serum. EA improved the antioxidant system by reducing malondialdehyde contents and increasing superoxide dismutase (SOD) levels and reduced glutathione content. EA improved the alcohol metabolizing enzymes such as alcohol dehydrogenase, acetaldehyde dehydrogenase, and cytochrome P450 2E1 (CYP2E1). Treatment with EA alleviated lipid accumulation-related protein expression by improving phosphorylation of AMP-activated protein kinase (p-AMPK) expression levels. Especially, EA reduced inflammatory response by regulating the toll-like receptor-4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR-4/NF-κB) signaling pathway. EA showed an anti-apoptotic effect by regulating the expression levels of B-cell lymphoma 2 (BCl-2), BCl-2-associated X protein (BAX), and caspase 3. Treatment with EA also ameliorated liver fibrosis via inhibition of transforming growth factor-beta 1/suppressor of mothers against decapentaplegic (TGF-ß1/Smad) pathway and alpha-smooth muscle actin (α-SMA). Therefore, these results suggest that EA might be a potential prophylactic agent for the treatment of alcoholic liver disease.

Long-term control of diabetes by tofacitinib-based immunosuppressive regimen after allo islet transplantation in diabetic rhesus monkeys that rejected previously transplanted porcine islets.

Porcine islet xenotransplantation has been highlighted as an alternative to allo islet transplantation. Despite the remarkable progress that has been made in porcine-islet pre-clinical studies in nonhuman primates, immunological tolerance to porcine islets has not been achieved to date. Therefore, allo islet transplantation could be required after the failure of porcine islet xenotransplantation. Here, we report the long-term control of diabetes by allogeneic pancreatic islet transplantation in diabetic rhesus monkeys that rejected previously transplanted porcine islets. Four diabetic male rhesus monkeys received the porcine islets and then allo islets (5700-19 000 IEQ/kg) were re-transplanted for a short or long period after the first xeno islet rejection. The recipient monkeys were treated with an immunosuppressive regimen consisting of ATG, humira, and anakinra for induction, and sirolimus and tofacitinib for maintenance therapy. The graft survival days of allo islets in these monkeys were >440, 395, >273, and 127, respectively, similar to that in allo islet transplanted cynomolgus monkeys that received the same immunosuppressive regimen without xeno sensitization. Taken together, it is likely that prior islet xenotransplantation does not affect the survival of subsequent allo islets under clinically applicable immunosuppressants.

Fully-automated multi-organ segmentation tool applicable to both non-contrast and post-contrast abdominal CT: deep learning algorithm developed using dual-energy CT images.

A novel 3D nnU-Net-based of algorithm was developed for fully-automated multi-organ segmentation in abdominal CT, applicable to both non-contrast and post-contrast images. The algorithm was trained using dual-energy CT (DECT)-obtained portal venous phase (PVP) and spatiotemporally-matched virtual non-contrast images, and tested using a single-energy (SE) CT dataset comprising PVP and true non-contrast (TNC) images. The algorithm showed robust accuracy in segmenting the liver, spleen, right kidney (RK), and left kidney (LK), with mean dice similarity coefficients (DSCs) exceeding 0.94 for each organ, regardless of contrast enhancement. However, pancreas segmentation demonstrated slightly lower performance with mean DSCs of around 0.8. In organ volume estimation, the algorithm demonstrated excellent agreement with ground-truth measurements for the liver, spleen, RK, and LK (intraclass correlation coefficients [ICCs] > 0.95); while the pancreas showed good agreements (ICC = 0.792 in SE-PVP, 0.840 in TNC). Accurate volume estimation within a 10% deviation from ground-truth was achieved in over 90% of cases involving the liver, spleen, RK, and LK. These findings indicate the efficacy of our 3D nnU-Net-based algorithm, developed using DECT images, which provides precise segmentation of the liver, spleen, and RK and LK in both non-contrast and post-contrast CT images, enabling reliable organ volumetry, albeit with relatively reduced performance for the pancreas.

Midterm Clinical and Radiological Outcomes of Revision Lateral Meniscal Allograft Transplantation.

Background: It is unknown whether the outcomes achieved in the early period after revision lateral meniscal allograft transplantation (RLMAT) are maintained through the midterm period. Purpose: To evaluate the midterm clinical and radiological results of patients who underwent RLMAT. Study Design: Case series; Level of evidence, 4. Methods: We reviewed the outcomes of 19 RLMATs in 18 patients with at least 5 years of follow-up data. The mean follow-up period was 6 ± 1.1 years (range, 5-8.5 years). Clinical outcomes were assessed using the modified Lysholm score, the International Knee Documentation Committee (IKDC) subjective score, and the Tegner activity level. Radiographic progression of arthritis was measured by the absolute and relative joint space widths on 45° of knee flexion posteroanterior radiographs preoperatively, 1 year postoperatively, and at the latest follow-up.Failure was defined as meniscocapsular separation, removal, or tear of more than half of the meniscal allograft on postoperative magnetic resonance imaging (MRI) or conversion to total knee arthroplasty. Of the 18 patients, 3 underwent ≥2 RLMATs. The survival rate was evaluated according to the number of revision surgeries. Results: For knees with an intact meniscus transplant at the final follow-up, the modified Lysholm and IKDC scores were significantly improved compared with preoperatively, but the Tegner activity level was unchanged. No significant differences were found in the absolute and relative joint space widths postoperatively. There were 6 failures within 3 years after RLMAT; the overall 5-year survival rate was 68.4% (13/19 knees). All failed knees showed bucket-handle tear patterns on MRI due to meniscocapsular healing failure. The survival rate decreased as the number of RLMATs increased-73.3% for a first RLMAT (n = 15 knees), 66.7% for a second RLMAT (n = 3 knees), and 0% for a third RLMAT (n = 1 knee). Midterm MRIs of 8 well-healed RLMATs showed evidence of meniscal degeneration; nonetheless, this did not affect clinical outcomes. Conclusion: The midterm results of RLMATs demonstrated a 5-year survival rate of 68.4% and positive clinical and radiological outcomes for failed MATs despite unimproved activity levels. Inadequate meniscocapsular healing was the leading cause of failure, and it needs to be carefully considered when performing RLMATs.

Risk Factor for Clinical Failure of Medial Meniscal Allograft Transplant: Early vs Late Graft Tear.

BACKGROUND: Graft tears are common postoperative findings in meniscal allograft transplant (MAT). Graft tear in medial MAT may be different from that of lateral MAT, considering the difference between medial meniscal tears and lateral meniscal tears. Moreover, medial MAT is frequently accompanied by ligament reconstruction, which is associated with graft tear. The effect of graft tear on the long-term survivorship of medial MAT has not been investigated. HYPOTHESIS: Graft tear would adversely affect the survivorship of medial MAT and the effect would be different according to the timing of graft tear. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 55 patients undergoing medial MAT between June 2019 and March 2000 were retrospectively reviewed. Postoperative magnetic resonance imaging (MRI) scans were reviewed to identify graft tears, and the timing of their occurrence was investigated. Postoperative MRI was performed routinely during the first postoperative year and every 2 years thereafter. The patients were classified into a no graft tear (NT) group, early graft tear (occurring within 1 year; ET) group, and late graft tear (occurring 1 year after surgery; LT) group. The survival rate of medial MAT was estimated according to graft tear, with a failure being defined as (1) reoperations including arthroplasty, realignment osteotomy, revision MAT, and meniscectomy (>50% of the graft or to the zone of the meniscocapsular junction) or (2) Lysholm score <65. Clinical scores were compared between the groups. RESULTS: The mean follow-up duration was 8.6 ± 5.3 years. During that period, clinical failures occurred in 6 (10.9%) patients. The overall survival rate at 5 years was 94.0% (95% CI, 90.6%-97.4%). Graft tears were seen in 18 patients: 6 patients in the ET group and 12 patients in the LT group. The median time when the graft tear was noted on MRI scans was 5.5 months (range, 1-11 months) postoperatively in the ET group and 99.5 months (range, 19-264 months) postoperatively in the LT group. Five patients in the ET group had root tears, whereas 9 patients in the LT group had complex or horizontal tears. The 5-year survival rate of the ET group was 62.5% (95% CI, 41.2%-83.8%), which was significantly lower than that of the NT group (96.8%; 95% CI, 93.6%-99.9%) and the LT group (85.7%; 95% CI, 72.5%-98.9%; P = .002). The mean postoperative Lysholm scores were 85.6 ± 17.9 in the NT group, 93.0 ± 2.8 in the ET group, and 79.3 ± 11.6 in the LT group, showing no significant difference between the groups (Kruskal-Wallis test, P = .058). CONCLUSION: Clinical relevance of graft tear that occurred after medial MAT was dependent upon its timing. ET was a risk factor for clinical failure, whereas LT did not adversely affect graft survivorship. Lysholm scores did not differ according to graft tear.

Limb length change after total knee arthroplasty for valgus deformity does not affect the clinical score and is not affected by fixed flexion deformity.

BACKGROUND: The limb length change (LLC) after total knee arthroplasty (TKA) is especially significant in valgus deformity. The higher LLC could cause higher incidences of lower limb length discrepancy (LLD) and low clinical score. However, studies about LLC after TKA for valgus deformity are limited, and there are none on the relationship between LLC and fixed flexion deformity (FFD) in valgus deformity. HYPOTHESIS: (1) The amount of LLC would affect the postoperative LLD, (2) the improvement of fixed flexion deformity (FFD) would affect the amount of LLC, (3) The amount of LLC would affect the improvement in the clinical score after TKA for valgus deformity. PATIENTS AND METHODS: Fifty knees of 50 patients who underwent primary unilateral TKA for valgus-type osteoarthritis between January 2000 and October 2021 were included. A radiological and clinical assessment were performed the day before the operation and at 12 months post-operatively. Full-length standing anteroposterior radiographs were used to measure HKA and LLC. FFD and Hospital for Special Surgery (HSS) score were measured in the outpatient department. RESULTS: The incidence of lengthening was 92.0% and the mean LLC was 18.85mm (SD, 19.60mm). Postoperative LLD over 10mm occurred in 26% and the mean of postoperative LLD was 4.21mm (SD, 7.96mm). The LLC was correlated with postoperative LLD (rs=0.357, p=0.011) and the HKA change (rs=0.375, p=0.007), but not with the FFD improvement (rs=0.164, p=0.255) and HSS improvement (rs=0.076, p=0.613) or postoperative HSS (rs=0.094, p=0.528). CONCLUSION: LLC was affected by HKA improvement but not by FFD improvement after TKA for patients with valgus deformity. Additionally, LLC did not affect the clinical score. LEVEL OF EVIDENCE: III; retrospective cohort study.

Cytokine storm syndrome after anti-thymoglobulin infusion in a cynomolgus monkey with systemic lymphadenopathy caused by follicular hyperplasia: A case report.

Nonhuman primates are widely used in transplantation research as preclinical xeno- or allo-transplantation models. Rabbit anti-thymoglobulin (ATG) is often used for T-cell depletion as an immunosuppressant. T-cell depletion can cause a secondary cytokine storm syndrome that can be minimized/prevented by a prophylactic administration of systemic corticosteroids and antihistamines. We report a case of death due to CSS in a cynomolgus monkey with follicular hyperplasia-induced systemic lymphadenopathy after ATG administration. A 6-year-old female cynomolgus monkey was rendered diabetic and then transplanted with a genetically modified porcine pancreatic islets (PPI) (50 000 IEQ/kg) through the portal vein 22 days later without immunosuppressant. Because graft function was not comparable, we planned re-transplantation of PPI. For re-transplantation of the PPI, we performed an intravenous (IV) ATG infusion for inductive immunosuppression. The monkey died 3 h and 30 min after ATG administration despite cardiopulmonary resuscitation. Systemic lymphadenopathy was observed on submandibular, axillary, inguinal, foregut, colic, and hilar lymph nodes, and splenomegaly was also observed on necropsy. Histopathologic examination of the lymph node revealed follicular hyperplasia. The IL-6 level was higher after ATG infusion compared to before ATG infusion (before vs. after ATG infusion; 14.9 vs. >5000 pg/mL). The death of the cynomolgus monkey was caused by severe CSS because of apoptosis of B cells in the systemic lymph nodes caused by the ATG administration. A thorough physical examination of palpable lymph nodes and pre-ATG sonographic or computed tomographic screening could have identified lymphadenopathy, potentially preventing its infusion and reducing mortality risk.

Lateral Distance From the Osteotomy Hinge Point to the Tibial Cortex Is Associated With Lateral Hinge Fracture Type and Fracture Occurrence Time After Medial Open-Wedge High Tibial Osteotomy.

PURPOSE: To verify whether the distance from the hinge point to the tibial cortex affects the occurrence time and characteristics of the lateral hinge fracture (LHF) in medial open-wedge high tibial osteotomy. METHODS: We retrospectively reviewed 171 knees in 171 patients (121 women, 50 men; mean age, 53.9 years; range, 36-67 years) who had undergone medial open-wedge high tibial osteotomy with locking plate fixation between January 2011 and December 2020. Osteotomy hinge point and LHFs were identified on intraoperative fluoroscopy and immediate postoperative radiographs. LHF type was classified as suggested by Takeuchi et al. Acute fracture was defined as a fracture that occurred during surgery, and delayed fracture was defined as a fracture observed after 1 month postoperatively. The nearest distances from osteotomy hinge point to lateral, distal, and proximal cortex were measured on postoperative radiographs. We compared the distance between the different types and between acute and delayed LHFs. RESULTS: There were 55 LHFs (32%) (type I, 40 knees; type II, 14 knees; type III, 1 knee) that occurred acutely in 41 knees and were found as delayed fractures in 14 knees. The patient demographics were not significantly different between non-LHFs and each type of LHFs. Proximal and distal distances were not statistically different among fracture types and between occurrence times. However, lateral distances were significantly shorter in type I LHFs (6.2 ± 1.8 mm) and longer in type II LHFs (9.3 ± 2.3 mm) than in non-LHFs (7.1 ± 2.7 mm) (P = .020 and .004, respectively). The lateral cortical distances were also different between acute LHFs (6.4 ± 1.9 mm) and delayed LHF (9.0 ± 2.7 mm) (P < .001). In the case of fracture type, the frequency of type I decreases with increase in the lateral distance, whereas that of type II increases with increase in the lateral cortical distance. In acute fracture, type I was dominant (85.4%), whereas in delayed fracture, type II was dominant (57.2%). CONCLUSIONS: The lateral cortical distance from the hinge point was significantly associated with LHF occurrence. Shorter distance increased the risk for acute type I LHF, whereas longer distance increased the risk for delayed type II LHFs. LEVEL OF EVIDENCE: Level III, retrospective comparative prognostic trial.

Fermented Protaetia brevitarsis Larvae Ameliorates Chronic Ethanol-Induced Hepatotoxicity in Mice via AMPK and TLR-4/TGF-ß1 Pathways.

This study evaluated the hepatoprotective effect of fermented Protaetia brevitarsis larvae (FPB) in ethanol-induced liver injury mice. As a result of amino acids in FPB, 18 types of amino acids including essential amino acids were identified. In the results of in vitro tests, FPB increased alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities. In addition, FPB treatment increased cell viability on ethanol- and H2O2-induced HepG2 cells. FPB ameliorated serum biomarkers related to hepatoxicity including glutamic oxaloacetic transaminase, glutamine pyruvic transaminase, total bilirubin, and lactate dehydrogenase and lipid metabolism including triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Also, FPB controlled ethanol metabolism enzymes by regulating the protein expression levels of ADH, ALDH, and cytochrome P450 2E1 in liver tissue. FPB protected hepatic oxidative stress by improving malondialdehyde content, reduced glutathione, and superoxide dismutase levels. In addition, FPB reversed mitochondrial dysfunction by regulating reactive oxygen species production, mitochondrial membrane potential, and ATP levels. FPB protected ethanol-induced apoptosis, fatty liver, and hepatic inflammation through p-AMP-activated protein kinase and TLR-4/NF-κB signaling pathways. Furthermore, FPB prevented hepatic fibrosis by decreasing TGF-ß1/Smad pathway. In summary, these results suggest that FPB might be a potential prophylactic agent for the treatment of alcoholic liver disease via preventing liver injury such as fatty liver, hepatic inflammation due to chronic ethanol-induced oxidative stress.

Three-dimensional body composition parameters using automatic volumetric segmentation allow accurate prediction of colorectal cancer outcomes.

BACKGROUND: Parameters obtained from two-dimensional (2D) cross-sectional images have been used to determine body composition. However, data from three-dimensional (3D) volumetric body images reflect real body composition more accurately and may be better predictors of patient outcomes in cancer. This study aimed to assess the 3D parameters and determine the best predictive factors for patient prognosis. METHODS: Patients who underwent surgery for colorectal cancer (CRC) between 2010 and 2016 were included in this study. Preoperative computed tomography images were analysed using an automatic segmentation program. Body composition parameters for muscle, muscle adiposity, subcutaneous fat (SF) and abdominal visceral fat (AVF) were assessed using 2D images at the third lumbar (L3) level and 3D images of the abdominal waist (L1-L5). The cut-off points for each parameter were determined using X-tile software. A Cox proportional hazards regression model was used to identify the association between the parameters and the treatment outcomes, and the relative influence of each parameter was compared using a gradient boosting model. RESULTS: Overall, 499 patients were included in the study. At a median follow-up of 59 months, higher 3D parameters of the abdominal muscles and SF from the abdominal waist were found to be associated with longer overall survival (OS) and disease-free survival (all P < 0.001). Although the 3D parameters of AVF were not related to survival outcomes, patients with a high AVF volume and mass experienced higher rate of postoperative complications than those with low AVF volume (27.4% vs. 18.7%, P = 0.021, for mass; 27.1% vs. 19.0%, P = 0.028, for volume). Low muscle mass and volume (hazard ratio [HR] 1.959, P = 0.016; HR 2.093, P = 0.036, respectively) and low SF mass and volume (HR 1.968, P = 0.008; HR 2.561, P = 0.003, respectively), both in the abdominal waist, were identified as independent prognostic factors for worse OS. Along with muscle mass and volume, SF mass and volume in the abdominal waist were negatively correlated with mortality (all P < 0.001). Both AVF mass and volume in the abdominal waist were positively correlated with postoperative complications (P < 0.05); 3D muscle volume and SF at the abdominal waist were the most influential factors for OS. CONCLUSIONS: 3D volumetric parameters generated using an automatic segmentation program showed higher correlations with the short- and long-term outcomes of patients with CRC than conventional 2D parameters.

Is Autophagy a Prerequisite for Steroidogenesis in Leydig Cells?

We investigated the involvement of autophagy with steroidogenesis in testicular Leydig cells. Human chorionic gonadotropin (hCG)-stimulated T production in Leydig cells was not remarkably altered in the presence of an autophagy inhibitor 3-methyladenine (3-MA). Although pretreatment with 3-MA demonstrated a tendency to decrease hCG-induced T production, the differences were significant only at a higher time point of 24 h following hCG. Microtubule associated protein light chain 3 (LC3)-II was detectable in the control cells in all the experiments. The hCG-induced increase in steroidogenic acute regulatory protein (StAR) and cytochrome P450 side chain cleave (P450scc) protein levels were not significantly altered by 3-MA. Leydig cells isolated from immature rat testes 12 h following hCG treatment showed relatively increased levels of LC3-II protein compared to the control group. Furthermore, LC3-II levels shown in these cells reached almost the identical to those from normal adult testes. However, LC3-II protein levels were almost comparable or even slightly lower than the controls at 48 h following hCG. Expression of StAR and P450scc was upregulated at both 12 and 48 h after hCG. We also used MA-10 cells, the mouse Leydig cell line, in this experiment. When dibutyryl cyclic-AMP was treated with MA-10 cells, P4 levels were significantly increased in the cell culture medium. However, P4 levels tended to decrease in the presence of 3-MA, but the difference was not statistically significant. This was consistent with the results of the rat Leydig cell experiments. Together, we believe that although autophagy participates in steroidogenesis and enhances steroidogenic efficacy of Leydig cells, it may not be a decisive cellular process for steroidogenesis, specifically in the mature Leydig cells.

Early Graft Tear As a Major Risk Factor for the Clinical Failure of Lateral Meniscal Allograft Transplantation.

BACKGROUND: Graft tears are often observed on magnetic resonance imaging after lateral meniscal allograft transplantation (MAT). Their characteristics, such as the location and configuration, are likely to be different depending on the timing of the injury. However, the clinical relevance of early and late graft tears has not been investigated. HYPOTHESIS: (1) Both early and late graft tears would be associated with the clinical failure of lateral MAT, and (2) an early graft tear (ET) would lead to worse outcomes than a late graft tear (LT) or an intact graft. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 261 patients who had undergone lateral MAT between March 2000 and June 2019 were retrospectively reviewed. The graft tear was investigated using magnetic resonance imaging, which was performed routinely during the first postoperative year and every 2 years thereafter. The patients were classified according to the timing of the graft tear: no graft tear (NT) group, ET (≤1 year after surgery) group, and LT (>1 year after surgery) group. Clinical failure was defined as (1) reoperations including arthroplasty, realignment osteotomy, revision MAT, and meniscectomy (>50% of the graft or to the zone of the meniscocapsular junction) or (2) a Lysholm score of <65. Risk factors for a low survival rate were investigated using Cox regression analysis. A comparison of the Lysholm scores for each group was also performed. RESULTS: There were 24 (9.2%) patients who had clinical failure at a mean follow-up of 7.5 ± 4.3 years. The overall survival rate at 5 years was 92.8% (95% CI, 91.1%-94.5%). A graft tear was noted in 80 patients: 23 patients in the ET group and 57 patients in the LT group. The most common tear pattern was a meniscocapsular tear in the ET group and a complex tear in the LT group. The hazard ratios for clinical failure in the ET and LT groups were 30.7 (95% CI, 9.4-76.4; P < .001) and 4.0 (95% CI, 1.3-12.9; P = .013), respectively. The Lysholm score of the ET group (82.7 ± 14.8) was significantly lower than that of the other 2 groups (NT: 87.6 ± 11.7; LT: 90.7 ± 9.0; P = .024). CONCLUSION: An ET was a major risk factor for the clinical failure of lateral MAT. An LT was associated with a lower survival rate. An ET was also associated with worse clinical outcomes.