Antiepileptic and Neuroprotective Effects of Rheum tanguticum Root Extract on Trimethyltin-Induced Epilepsy and Neurodegeneration: In Vivo and in Silico Analyses.

BACKGROUND: Rheum tanguticum root, cataloged as "Daehwang" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations containing Daehwang are traditionally employed for treating neurological conditions. This study aimed to substantiate the antiepileptic and neuroprotective efficacy of R. tanguticum root extract (RTE) against trimethyltin (TMT)-induced epileptic seizures and hippocampal neurodegeneration. METHODS: The constituents of RTE were identified by ultra-performance liquid chromatography (UPLC). Experimental animals were grouped into the following five categories: control, TMT, and three TMT+RTE groups with dosages of 10, 30, and 100 mg/kg. Seizure severity was assessed daily for comparison between the groups. Brain tissue samples were examined to determine the extent of neurodegeneration and neuroinflammation using histological and molecular biology techniques. Network pharmacology analysis involved extracting herbal targets for Daehwang and disease targets for epilepsy from multiple databases. A protein-protein interaction network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and pivotal targets were determined by topological analysis. Enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool to elucidate the underlying mechanisms. RESULTS: The RTE formulation was found to contain sennoside A, sennoside B, chrysophanol, emodin, physcion, (+)-catechin, and quercetin-3-O-glucuronoid. RTE effectively inhibited TMT-induced seizures at 10, 30, and 100 mg/kg dosages and attenuated hippocampal neuronal decay and neuroinflammation at 30 and 100 mg/kg dosages. Furthermore, RTE significantly reduced mRNA levels of tumor necrosis factor (TNF-α), glial fibrillary acidic protein (GFAP), and c-fos in hippocampal tissues. Network analysis revealed TNF, Interleukin-1 beta (IL-1ß), Interleukin-6 (IL-6), Protein c-fos (FOS), RAC-alpha serine/threonine-protein kinase (AKT1), and Mammalian target of rapamycin (mTOR) as the core targets. Enrichment analysis demonstrated significant involvement of R. tanguticum components in neurodegeneration (p = 4.35 × 10-5) and TNF signaling pathway (p = 9.94 × 10-5). CONCLUSIONS: The in vivo and in silico analyses performed in this study suggests that RTE can potentially modulate TMT-induced epileptic seizures and neurodegeneration. Therefore, R. tanguticum root is a promising herbal treatment option for antiepileptic and neuroprotective applications.

DNA methylation-based organ tissue identification: Marker identification, SNaPshot multiplex assay development, and interlaboratory comparison.

Identifying body fluids and organ tissues is highly significant as they can offer crucial evidence in criminal investigations and aid the court in making informed decisions, primarily through evaluating the biological source and possibly at the activity level up to death or fatal damage. In this study, organ tissue-specific CpG markers were identified from Illumina's methylation EPIC array data of nine organ tissues, including epidermis, dermis, heart, skeletal muscle, blood, kidney, brain, lung, and liver, from autopsies of 10 Koreans. Through the validation test using 43 samples, 18 hypomethylation markers, with two markers for each organ tissue type, were selected to construct a SNaPshot assay. Two multiplex assays involving forward and reverse SBE primers were designed to help investigators accurately determine the organ origin of the analyzed tissue samples through repeated analysis of the same PCR products for markers. The developed multiplex demonstrated high accuracy, achieving 100.0 % correct detection of the presence of nine organ tissue types in 88 samples from autopsies of 10 Asians. However, two lung samples showed additional positive indications of the presence of blood. An interlaboratory comparison using 80 autopsy samples (heart, skeletal muscle, blood, kidney cortex, kidney medulla, brain, lung, and liver) from 10 individuals in Germany revealed overall comparable results with correct detection of the presence of eight organ tissue types in 92.5 % samples (74 of 80 samples). In the case of six samples, it was impossible to determine the correct tissue successfully due to drop-outs of unmethylation signals at target tissue marker loci. One of these lung samples revealed only non-intended off-target signals for blood. The observed differences might be due to differences in sample collection during routine autopsy, technical differences due to the PCR cycler, and the threshold used for signal calling. Indicating the presence of additional tissue type and off-target unmethylation signals seems alleviated by applying more stringent hypomethylation thresholds. Therefore, the developed SNaPshot multiplex assays will be valuable for forensic investigators dealing with organ tissue identification, as well as for prosecutors and defense aiming to establish the circumstances that occurred at the crime scene.

A novel approach of kinship determination based on the physical length of genetically shared regions of chromosomes.

BACKGROUND: Determination of genetic relatedness between individuals plays a crucial role in resolving numerous civil cases involving familial relationships and in forensic investigation concerning missing persons. Short tandem repeats (STRs), known for their high degree of DNA polymorphism, have traditionally been the primary choice of DNA markers in genetic testing, but their application for kinships testing is limited to cases involving close kinship. SNPs have emerged as promising supplementary markers for kinship determination. Nevertheless, the challenging remains in discriminating between third-degree or more distant relatives, such as first cousins, using SNPs. OBJECTIVE: To investigate a kinship analysis method for distant degree of familial relationships using high-density SNP data. METHODS: A high-density SNP data from 337 individuals of Korean families using Affymetrix Axiom KORV1.0-96 Array was obtained for this study. SNPs were aligned by chromosomal positions, and identity-by-state (IBS) was determined, and then shared regions as consecutive SNPs with IBS of 1 or 2 were investigated. The physical lengths of these IBS segments were measured and summed them to create an Index, as a measure of kinship. RESULTS: The kinship was determined by the physical length of shared chromosomal regions that are distinguished by each kinship. Using this method, the relationship was able be distinguished up to the fourth degree of kinship, and non-relatives were clearly distinguished from true relatives. We also found a potential for this approach to be used universally, regardless of microarray platforms for SNP genotyping and populations. CONCLUSION: This method has a potential to determine the different degree of kinship between individuals and to distinguish non-relatives from true relatives, which can be of great help for practical applications in kinship determination.

Duration of osteoporosis treatment to reduce the risk of subsequent osteoporotic fracture and all-cause mortality in elderly hip fracture patients in a Korean real-world study.

This study aimed to evaluate the association between treatment duration of osteoporosis medications and clinical outcomes of patients with hip fracture. We found that the risk of subsequent osteoporotic fractures and all-cause mortality showed a decreasing trend as the treatment duration of osteoporosis medications increased. PURPOSE: To assess the risk of subsequent osteoporotic fracture (SOF) and all-cause mortality (ACM) in elderly patients with hip fracture in South Korea and to evaluate the potential reduction in the risk of SOF and ACM with varying durations of osteoporosis treatment. METHODS: Newly diagnosed patients with hip fracture (age ≥ 60 years) who initiated osteoporosis medication within 3 months after the hip fracture from 2003-2014 were identified from the National Health Insurance Service-Senior cohort. The risk of SOF and ACM was estimated after the 1-year exposure-measurement period. Adjusted hazard ratios (aHRs) were calculated for treatment duration of osteoporosis medications categorized as short-term treatment (ST, < 3 months), early discontinuation (ED, ≥ 3- < 6 months), late discontinuation (LD, ≥ 6- < 12 months), and treatment continuation (TC, ≥ 12 months). RESULTS: A total of 4,421 patients were included in the analysis. The 3-year cumulative incidence of SOF was 22.4%, 22.0%, 23.9%, and 21.6%, and that of 3-year ACM was 29.8%, 27.0%, 19.7%, and 18.9% in the ST, ED, LD, and TC groups, respectively. Compared with the ST group, the risk of SOF showed a decreasing trend in the TC group (aHR [95% CI], 0.77 [0.58-1.00]). The risk of ACM was significantly reduced in the LD (aHR 0.68 [0.57-0.82]) and TC (aHR 0.65 [0.50-0.84]) groups. CONCLUSION: These findings underscore the importance of early and continuous osteoporosis treatment for elderly patients with hip fracture to improve health outcomes. The benefits of long-term osteoporosis treatment should be discussed in clinical practice to improve overall health outcomes.

Application of array-based age prediction models to post-mortem tissue samples.

Since DNA methylation at specific CpG sites exhibits a strong age association, researchers have developed numerous age prediction models based on the methylation BeadChip array. These models harness epigenetic clocks that hold the potential to narrow down the search range for unknown suspects and unidentified victims. This study collected 180 post-mortem tissue samples comprising nine tissue types (blood, brain, heart, lung, liver, kidney, muscle, epidermis, and dermis) from autopsies of 20 Koreans aged 18-78. Subsequently, DNA methylation profiling was conducted using the Infinium MethylationEPIC array. We tested several array-based age prediction models using the data obtained from various tissues. The pan-tissue clock exhibited a moderately accurate prediction across all nine tissue types (MAE = 8.7 years, r = 0.88). Notably, the DNAm ages of the Hannum clock, the skin & blood clock, and the Zhang clock strongly correlated with the actual age in blood samples (MAE < approximately 5 years, r > 0.9). PhenoAge yielded an MAE of 10.1 years and an r-value of 0.92. The muscle-specific epigenetic clock, the MEAT package, demonstrated high prediction accuracy in muscle samples (MAE = 4.7 years, r = 0.93). Those previously reported array-based age prediction models were mainly constructed in Europeans but performed well in Koreans. In addition, tests involving various quantities of DNA and fragmented DNA have shown that DNA quantity and quality affected methylation measurements and age prediction results. However, robust age prediction models exist under low amounts of DNA and fragmented DNA conditions.

Licochalcone D Inhibits Skin Epidermal Cells Transformation through the Regulation of AKT Signaling Pathways.

Cell transformation induced by epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) is a critical event in cancer initiation and progression, and understanding the underlying mechanisms is essential for the development of new therapeutic strategies. Licorice extract contains various bioactive compounds, which have been reported to have anticancer and anti-inflammatory effects. This study investigated the cancer preventive efficacy of licochalcone D (LicoD), a chalcone derivative in licorice extract, in EGF and TPA-induced transformed skin keratinocyte cells. LicoD effectively suppressed EGF-induced cell proliferation and anchorage-independent colony growth. EGF and TPA promoted the S phase of cell cycle, while LicoD treatment caused G1 phase arrest and down-regulated cyclin D1 and up-regulated p21 expression associated with the G1 phase. LicoD also induced apoptosis and increased apoptosis-related proteins such as cleaved-caspase-3, cleaved-caspase-7, and Bax (Bcl-2-associated X protein). We further investigated the effect of LicoD on the AKT signaling pathway involved in various cellular processes and found decreased p-AKT, p-GSK3ß, and p-NFκB expression. Treatment with MK-2206, an AKT pharmacological inhibitor, suppressed EGF-induced cell proliferation and transformed colony growth. In conclusion, this study demonstrated the potential of LicoD as a preventive agent for skin carcinogenesis.

Comparison of Two Variant Analysis Programs for Next-Generation Sequencing Data of Whole Mitochondrial Genome.

BACKGROUND: With advance of next-generation sequencing (NGS) techniques, the need for mitochondrial DNA analysis is increasing not only in the forensic area, but also in medical fields. METHODS: Two commercial programs, Converge Software (CS) and Torrent Variant Caller for variant calling of NGS data, were compared with a considerable amount of sequence data of 50 samples with a homogeneous ethnicity. RESULTS: About 2,300 variants were identified and the two programs showed about 90% of consistency. CS, a dedicated analysis program for mitochondrial DNA, showed some advantages for forensic use. By additional visual inspection, several causes of discrepancy in variant calling results were identified. Application of different notation rules for mitochondrial sequence and the minor allele frequency close to detection threshold were the two most significant reasons. CONCLUSION: With prospective improvement of each program, researchers and practitioners should be aware of characteristics of the analysis program they use and prepare their own strategies to determine variants.

Ceramic-on-Ceramic or Metal-on-Polyethylene: The Bearing of Choice after Ceramic Component Fracture in Total Hip Arthroplasty along with Concise Follow-Up of the Previous Cohort.

OBJECTIVE: We previously reported the questionable result of reoperation using metal-on-polyethylene (MoP) bearing after the fracture of the ceramic component. After the report, we abandoned the use of MoP; instead, we used ceramic-on-ceramic (CoC) bearing. This report aimed to present the outcome of reoperation to CoC bearing after ceramic component failures along with the longer-term outcome of the previously reported cohort with an MoP bearing. RESULTS: The mean follow-up of the MoP cohort was extended from 4.3 years to 8.8 years. Metallosis had occurred in three of nine patients of the previous cohort, which all required re-reoperations. Two hips from 11 patients with revision to CoC had re-reoperations due to ceramic liner fracture and non-union of the osteotomized fragment, respectively. No metallosis and wear occurred in the cohort revised with CoC articulation. Otherwise, there were no adverse changes in radiographs and no impairment in functions. METHODS: We conducted an extended prospective evaluation of a previous cohort consisting of six head fractures and three liner fractures. In this cohort, the patients underwent a bearing change to metal-on-polyethylene. Additionally, we retrospectively analyzed 11 cases of third-generation ceramic bearing fractures, comprising nine head fractures and two liner fractures. These cases were subsequently treated with a bearing change to fourth-generation CoC. We assessed clinical and radiological outcomes, including complication rates, in both groups. CONCLUSION: We recommend the latest CoC as the bearing of choice in reoperation after the fracture of ceramic components. In the case of an MoP bearing after the ceramic component fracture, the risk of metallosis seemed high in the early postoperative period.

DNA methylome profiling of blood to identify individuals in a pair of monozygotic twins.

BACKGROUND: Short tandem repeat (STR) markers cannot be used to distinguish between genetically identical monozygotic (MZ) twins, causing problems in a case with an MZ twin as a suspect. Many studies have shown that in older MZ twins, there are significant differences in overall content and genomic distribution of methylation. OBJECTIVE: In this study, we analyzed the DNA methylome profile of blood to identify recurrent differentially methylated CpG sites (DMCs) to discriminate between MZ twins. METHODS: Blood samples were collected from 47 paired MZ twins. We performed the DNA methylation profiling using the HumanMethylation EPIC BeadChip platform and identified recurrent DMCs between MZ twins. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and motif enrichment analyses were performed to reveal the biological functions of recurrent DMCs. We collected DNA methylome data from the Gene Expression Omnibus (GEO) public database to verify the recurrent DMCs between MZ twins. RESULTS: We identified recurrent DMCs between MZ twin samples and observed that they were enriched in immune-related genes. In addition, we verified our DMCs in a public dataset. CONCLUSION: Our results suggest that the methylation level at recurrent DMCs between MZ twins may serve as a valuable biomarker for identification of individuals in a pair of MZ twins.

Protective Effect of Bojungikki-Tang against Radiation-Induced Intestinal Injury in Mice: Experimental Verification and Compound-Target Prediction.

Bojungikki-tang (BJIT) is a traditional herbal medicine used in Korea, Japan, and China to treat gastrointestinal disorders. In this study, we aimed to investigate whether BJIT has protective effects against radiation-induced intestinal injury and to predict the underlying therapeutic mechanisms and related pathways via network pharmacological analyses. BJIT was injected intraperitoneally (50 mg/kg body weight) to C3H/HeN mice at 36 and 12 h before exposure to partial abdominal irradiation (5 Gy and 13 Gy) to evaluate the apoptotic changes and the histological changes and variations in inflammatory cytokine mRNA levels in the jejunum, respectively. Through in silico network analysis, we predicted the mechanisms underlying BJIT-mediated regulation of radiation-induced intestinal injury. BJIT reduced the level of apoptosis in the jejunal crypts 12 h post 5-Gy irradiation. Histological assessment revealed intestinal morphological changes in irradiated mice 3.5 days post 13-Gy irradiation. Furthermore, BJIT decreased inflammatory cytokine levels following radiation exposure. Apoptosis, TNF, p53, VEGF, toll-like receptor, PPAR, PI3K-Akt, and MAPK signaling pathways, as well as inflammatory bowel disease (IBD), were found to be linked to the radioprotective effects of BJIT against intestinal injury. According to our results, BJIT exerted its potential protective effects by attenuating histopathological changes in jejunal crypts and suppressing inflammatory mediator levels. Therefore, BJIT is a potential therapeutic agent that can treat radiation-induced intestinal injury and its associated symptoms.

Biogeographic origin and genetic characteristics of the peopling of Jeju Island based on lineage markers.

BACKGROUND: Jeju Island is the largest island of South Korea, located southwest far from the mainland of Korea, and has a unique history and its own cultures that are distinguished from those of the other regions of the Korean mainland. However, the Jeju population has not been deeply investigated to date to understand their genetic structure, which may reflect their historical and geographical background. OBJECTIVE: To identify the genetic characteristics and biogeographic origin of people of Jeju Island based on the statistical analysis of genetic data using lineage markers. METHODS: 17 Y-STRs data for 615 unrelated males and mitochondrial DNA haplogroup data for 799 unrelated individuals residing on Jeju Island were generated, and analyzed to investigate genetic diversity and genetic characteristics using statistical methods including pairwise Fst or Rst, Analysis of molecular variance (AMOVA) and Multidimensional scaling (MDS). RESULTS: For male individuals of Jeju Island, unique genetic characteristics were observed in the analysis of Y-STRs, including low haplotype diversity, strong association with surnames, genetic difference from other regions of Korea, and common genetic variation of the Y-STR loci known to be predominant in Northern populations, such as Mongolians. Statistical analysis of the mitochondrial DNA haplogroups also revealed similar results that showed low haplogroup diversity and high frequency of haplogroup Y prevalent mostly in ethnic populations around the Sea of Okhotsk in Northeastern Asia. All these results suggest that Jeju Island is genetically distinct from other regions of Korea, possibly being a subpopulation in Korea, and related closely to Northern Asian populations. CONCLUSION: The findings in the genetic approach could support understanding of the historical background of Jeju Island that is consistent with evidence from other multidisciplinary studies.

Whole Mitochondrial Genome Analysis in Non-Small Cell Lung Carcinoma Reveals Unique Tumor-Specific Somatic Mutations.

CONTEXT.­: Mitochondria and mitochondrial DNA have been suggested to play a role in cancer initiation and progression. Knowledge of mitochondrial DNA could provide a breakthrough to advance cancer management. OBJECTIVE.­: To identify the mitochondrial DNA landscape in non-small cell lung carcinoma. DESIGN.­: The adenocarcinoma set consisted of 365 pairs of adenocarcinomas and normal lung tissues, whereas the metastasis set included 12 primary non-small cell carcinomas, 15 metastatic tumors, and their normal counterparts. Tumor-specific somatic variants were identified, and if a variant showed heteroplasmy, the proportion of minor alleles was evaluated. Variants with greater than 10% change in allele frequency between tumor and normal pairs were identified as "heteroplasmic shifts." RESULTS.­: Tumor-specific variants appeared throughout the whole mitochondrial genome, without a common hot spot. Distinct variant profiles were seen in 289 (79.18%) of all individual adenocarcinomas. The presence of a unique profile and the number and loading of heteroplasmic shifts in tumors increased with higher stage or lymph node metastasis, and were related to shorter survival. In the metastasis set, the primary tumor variants were generally found in metastatic tumors. CONCLUSIONS.­: This study shows that somatic mitochondrial DNA mutations present with diverse locations and unique profiles in each individual tumor, implying their clinicopathologic utility.

Revealing Joseon period People's single nucleotide polymorphism associated with lactase gene by ancient DNA analysis of human remains from archaeological sites in Korea.

Lactase non-persistence (LNP), one of the causes of lactose intolerance, is related to lactase gene associated single nucleotide polymorphisms (SNPs). Since the frequency of LNP varies by ethnic group and country, the research to reveal the presence or absence of LNP for specific people has been conducted worldwide. However, in East Asia, the study of lactase gene associated SNPs have not been sufficiently examined so far using ancient human specimens from archaeological sites. In our study of Joseon period human remains (n=14), we successfully revealed genetic information of lactase gene associated SNPs (rs1679771596, rs41525747, rs4988236, rs4988235, rs41380347, rs869051967, rs145946881 and rs182549), further confirming that as for eight SNPs, the pre-modern Korean people had a lactase non-persistent genotype. Our report contributes to the establishment of LNP associated SNP analysis technique that can be useful in forthcoming studies on human bones and mummy samples from East Asian archaeological sites.

The effect of tranexamic acid in open reduction and internal fixation of pelvic and acetabular fracture: A systematic review and meta-analysis.

BACKGROUND: Pelvic bone fractures may cause extensive bleeding; however, the efficacy of tranexamic acid (TXA) usage in pelvic fracture surgery remains unclear. In this systematic review and meta-analysis, we aimed to evaluate the efficacy of TXA in open reduction and internal fixation surgery for pelvic and acetabular fracture. METHODS: MEDLINE, Embase, and Cochrane Library databases were systematically searched for studies published before April 22, 2020, that investigated the effect of TXA in the treatment of pelvic and acetabular fracture with open reduction and internal fixation. A pooled analysis was used to identify the differences between a TXA usage group and a control group in terms of estimated blood loss (EBL), transfusion rates, and postoperative complications. RESULTS: We included 6 studies involving 764 patients, comprising 293 patients who received TXA (TXA group) and 471 patients who did not (control group). The pooled analysis showed no differences in EBL between the groups (mean difference -64.67, 95% confidence interval [CI] -185.27 to -55.93, P = .29). The study period transfusion rate showed no significant difference between the groups (odds ratio [OR] 0.77, 95% CI 0.19-3.14, P = .71, I2 = 82%), nor in venous thromboembolism incidence (OR 1.53, 95% CI 0.44-5.25, P = .50, I2 = 0%) or postoperative infection rates (OR 1.15, 95% CI 0.13-9.98, P = .90, I2 = 48%). CONCLUSIONS: Despite several studies having recommended TXA administration in orthopedic surgery, our study did not find TXA usage to be more effective than not using TXA in pelvic and acetabular fracture surgery, especially in terms of EBL reduction, transfusion rates, and the risk of postoperative complications.

Neuroprotective effect of Geijigadaehwang-tang against trimethyltin-induced hippocampal neurodegeneration: An in vitro and in vivo study.

ETHNOPHARMACOLOGICAL RELEVANCE: Patients with dementia are diagnosed with deficiency patterns and interior patterns in traditional Chinese medicine due to decreased physical strength, mental atrophy including cognitive function, and decreased motor function in the gastrointestinal tract. Since "greater yin symptom" in Shanghanlun has been interpreted as interior, deficiency, and cold pattern in traditional Chinese medicine, it is necessary to determine whether Geijigadaehwang-tang (GDT) has therapeutic effects on neurodegenerative diseases and the underlying mechanism if it has such effects. AIMS OF THE STUDY: Trimethyltin (TMT), a neurotoxic organotin compound, has been used to induce several neurodegenerative diseases, including epilepsy and Alzheimer's disease. This study aimed to evaluate the therapeutic efficacy of GDT for TMT-induced hippocampal neurodegeneration and seizures and to determine the mechanisms involved at the molecular level. MATERIALS AND METHODS: The main components of GDT were analyzed using ultra-performance liquid chromatography. TMT was used to induce neurotoxicity in microglial BV-2 cells and C57BL6 mice. GDT was administered at various doses to determine its neuroprotective and seizure inhibition effects. The inhibitory effects of GDT on TMT-induced apoptosis, inflammatory pathways, and oxidative stress pathways were determined in the mouse hippocampal tissues. RESULTS: GDT contained emodin, chrysophanol, albiflorin, paeoniflorin, 6-gingerol, and liquiritin apioside. In microglial BV-2 cells treated with TMT, GDT showed dose-dependent neuroprotective effects. Oral administration of GDT five times for 2.5 days before and after TMT injection inhibited seizures at doses of 180 and 540 mg/kg and inhibited neuronal death in the hippocampus. In hippocampal tissues extracted from mice, GDT inhibited the protein expression of ionized calcium binding adaptor molecule 1, glial fibrillary acidic protein, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3, and phosphorylated nuclear factor (NF)-κB/total-NFκB ratio. Additionally, GDT inhibited the messenger RNA levels of tumor necrosis factor-α, inducible nitric oxide synthase, apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, interleukin-1ß, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1. CONCLUSION: This study's results imply that GDT might have neuroprotective potential in neurodegenerative diseases through neuronal death inhibition and anti-inflammatory and antioxidant mechanisms.

High Risk of Neck-liner Impingement and Notching Observed with Thick Femoral Neck Implants in Ceramic-on-ceramic THA.

BACKGROUND: Recently, impingement between the femoral stem and ceramic liner, which appears as a notch in the stem neck on radiographs, has emerged as a new complication. However, the proportion of impingement, potential risk factors, and related complications are poorly elucidated. QUESTION/PURPOSES: In patients who underwent ceramic-on-ceramic (CoC) THA and had at least 10 years of follow-up, we asked: (1) What proportion had radiographic evidence of stem neck-ceramic liner impingement (notching of the stem), and what implant design, implantation factors, or complications such as ceramic fracture or metallosis are associated with impingement? (2) How common are the complications of noise and ceramic fracture? (3) What are the radiologic changes (including fixation of femoral and acetabular components, osteolysis, and heterotopic ossification) and clinical outcomes as determined by the modified Harris hip score (mHHS) for this cohort? (4) What is the survivorship with implant revision as the endpoint and with reoperation for any reason as the endpoint after CoC THA using a thick-neck stem design? METHODS: Between May 2003 and April 2010, 643 patients underwent primary THA at a tertiary referral hospital. After excluding patients with metal-on-polyethylene and with ceramic-on-polyethylene implants, 621 patients were considered eligible for this study. All patients received the same hemispherical titanium cup, a standard-length tapered titanium stem, and a CoC bearing. Of those, 19% (115) were lost to follow-up before 10 years, and 8% (50) were excluded because they died before the minimum follow-up duration of 10 years, leaving 73% (456) for analysis. Patients had a mean age of 50 ± 14 years and were followed for a median (range) of 13 years (10 to 17). The mean cup abduction was 38° ± 5°, and the mean cup anteversion was 26° ± 7°. To determine the proportion of patients with the neck-liner impingement, we analyzed the plain radiographs of every patient during follow-up to detect notches around the stem. The detection of stem neck notches on the radiographs was reliable (intraobserver reliability: κ = 0.963; p < 0.001 and interobserver reliability: κ = 0.975; p < 0.001). To evaluate factors related to notching, we compared the possible confounding factors including gender, age, BMI, implant position, neck length, and head diameter. Complications such as ceramic fracture, noise, dislocation, and periprosthetic joint infection were recorded. Noise was evaluated via interview and with the Hip Noise Assessment Questionnaire, which assessed the noise qualitatively. For clinical outcome, we assessed the mHHS, which includes pain and function scales (0 [worst] to 100 [best]), every visit. Tilting of at least 4° or migration of at least 4 mm was the criteria for cup loosening; subsidence more than 3 mm, any change in position, or a continuous radiolucent line greater than 2 mm was the criteria for stem loosening. To evaluate osteolysis, we performed CT scans in 57% (262 of 456) of patients. Kaplan-Meier survivorship analysis was performed using the endpoints of survivorship free from implant revision and survivorship free from reoperation for any cause. RESULTS: The proportion of stem neck notching was 11% (49 of 456). There were no differences in cup abduction and anteversion between hips with notches and those without notches. Notched hips were more likely to have 28-mm than 32-mm heads (90% [44 of 49] versus 70% [285 of 407]; odds ratio 3.77 [95% CI 1.46 to 9.73]; p = 0.004). None of the 49 notched hips had a ceramic head or liner fracture or evidence of metallosis. A ceramic head fracture was reported in 2% (9 of 456); all fractures occurred in 28-mm short neck heads. A ceramic liner fracture occurred in 0.2% (1 of 456), and noise was noted in 6% (27 of 456). Acetabular osteolysis developed in 2% (7 of 456). The mHHS was 91 ± 12 points at the final follow-up. The survivorship free from implant revision was 97% (95% CI 96% to 99%), and the survivorship free from reoperation for any cause was 96% (95% CI 95% to 98%) at 13 years. CONCLUSION: The proportion of stems with neck-ceramic liner impingement and ceramic component fracture were unacceptably high after the use of a thick-neck stem design, especially when a 28-mm head was used. We have discontinued the use of this stem design and we recommend that such stems should not be used when CoC bearings are used. As these findings might be generalized to other bearing couples, further studies focused on polyethylene liner wear and local metallosis due to thick stem neck are warranted. LEVEL OF EVIDENCE: Level III, therapeutic study.

Safety of a single intra-articular injection of LBSA0103 hyaluronic acid in patients with osteoarthritis of the knee: a multicenter, single-arm, prospective, cohort study.

OBJECTIVE: LBSA0103 is a recently developed high-molecular-weight, cross-linked, non-animal hyaluronic acid (HA). The safety of LBSA0103 has been investigated only in a limited number of patients, therefore this prospective study was designed. This study sought to assess the safety including injection-site reactions and adverse drug reactions after a single intra-articular injection of LBSA0103 in patients with osteoarthritis (OA) of the knee joint. METHODS: This study was a multicenter, single-arm, prospective cohort study. After screening, eligible patients with OA of the knee joint (Kellgren-Lawrence grades I-III) were enrolled, received a single intra-articular HA (LBSA0103) injection, and were followed up for two weeks. Any adverse events including injection-site reactions and adverse drug reactions were evaluated by the investigators. RESULTS: A total of 1949 subjects (2976 knee joints) was enrolled, all of whom received a single intra-articular injection of LBSA0103. Injection-site reactions occurred in 5.59% of enrolled subjects (109/1949), and the most frequently reported injection-site reaction was pain (4.87%), followed by swelling (1.03%). Most of the injection-site reactions were transient and resolved within 14 days without additional treatment. The incidence of adverse drug reactions other than injection-site reactions was 0.67% (13/1949). Most adverse events were of mild severity. No serious adverse events related to the study drug were reported. CONCLUSIONS: A single intra-articular injection of LBSA0103 in patients with OA of the knee joint was safe, and no significant safety concerns were observed. As such, LBSA0103 could be safely applied as an intra-articular injection for the management of knee OA. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (identifier: NCT04369261).

Culture-Expanded Autologous Adipose-Derived Mesenchymal Stem Cell Treatment for Osteonecrosis of the Femoral Head.

BACKGROUD: Outcomes of traditional treatment for osteonecrosis of the femoral head (ONFH) are not always satisfactory. Hence, cell-supplementation therapy has been attempted to facilitate necrotic-tissue regeneration. Adipose-derived mesenchymal stem cell (ADMSC) transplantation is potentially advantageous over bone marrow-derived MSC implantation, but its outcomes for ONFH remain unclear. The aim of this study was to determine 2-year radiological and clinical outcomes of culture-expanded autologous ADMSC implantation for ONFH. METHODS: Eighteen hips with necrotic lesions involving ≥ 30% of the femoral head were included. ADMSCs were harvested by liposuction and culture expanded for 3 passages over 3 weeks. With a 6-mm single drilling, ADMSCs were implanted into the necrotic zone. All patients underwent magnetic resonance imaging (MRI), single-photon emission computed tomography/computed tomography (SPECT/CT) at screening and 6 months, 12 months, and 24 months postoperatively. The primary outcome was the change in the size of necrotic area on MRI. Secondary outcomes were changes in clinical scores and radioisotope uptake on SPECT/CT. Conversion total hip arthroplasty (THA) was defined as the endpoint. RESULTS: Preoperatively, the necrotic lesion extent was 63.0% (38.4%-96.7%) of the femoral head. The mean Harris hip score was 89.2, the University of California at Los Angeles (UCLA) score was 5.6, and Western Ontario and McMaster Universities Arthritis index (WOMAC) was 79.4. Three patients underwent THA and 1 patient died in an accident. Finally, 11 patients (14 hips) were available for ≥ 2-year follow-up. At the last follow-up, no surgery-related complications occurred, and 14 of 17 hips (82%) were able to perform daily activities without THA requirement. There was no significant decrease in lesion size between any 2 intervals on MRI. However, widening of high signal intensity bands on T2-weighted images inside the necrotic lesion was observed in 9 of 14 hips (64%); 11 of 14 hips (79%) showed increased vascularity on SPECT/CT at 2 years postoperatively. No significant differences were observed between preoperative and 24-month mean Harris hip score (89.2 vs. 88.6), WOMAC (79.4 vs. 75.7), and UCLA score (5.6 vs. 6.2). CONCLUSIONS: Our outcomes suggest that culture-expanded ADMSC implantation is a viable option for ONFH treatment without adverse events.

Incarcerated diaphragmatic hernia after right hepatectomy: an autopsy case with a review of 45 previous cases.

An iatrogenic diaphragmatic hernia after major hepatic resection is a rare complication. Incarceration of the abdominal organ through a diaphragmatic defect can have a fatal prognosis. Here, we report a case of incarcerated diaphragmatic hernia after right hepatectomy, which was diagnosed only after the autopsy. The deceased, who had right hepatectomy 1 year previously, complained of severe chest pain, and 4 days later was found dead. Localized decomposition in his chest and abdomen suggested a late complication of the surgery because the location was consistent with the prior surgical area. In the autopsy, there was a small defect in his right diaphragm, resulting in the herniation and incarceration of the small intestine. Gross and microscopic findings of the herniated small intestine were consistent with ischemic enteritis. Different from our case, most of the previously reported cases showed a good prognosis after surgical repair, except one lethal one. Even though its overall incidence is very low, an incarcerated diaphragmatic hernia is one of the critical complications of major hepatic resection. The clinicians should warn the patients to avoid preventable morbidity and mortality. Reviewing this fatal complication would be also helpful for forensic pathologists and death investigators.

Two-stage total hip arthroplasty following skeletal traction after extensive soft tissue release for severe limb-length discrepancy.

INTRODUCTION: To maximise limb-length discrepancy (LLD) resolution during total hip arthroplasty (THA) for untreated developmental hip dysplasia or septic hip sequelae, THA following limb lengthening was introduced using different methods. We aimed to evaluate 2-stage THA results following limb lengthening via skeletal traction after extensive soft tissue release. METHOD: In total, 24 hips with severe LLD in 10 men and 14 women (mean age, 49.6 ± 15.2 years) underwent 2-stage THA and were followed thereafter (mean 6.3 ± 3.7 years). The entire abductor muscle origin was subperiosteally released from the ilium, and the soft tissue around the hip joint, including the psoas tendon, short external rotator, joint capsule, and adductor tendon, was extensively released. 2-stage THA was performed after 2-week skeletal traction using proximal tibial pins. During the final THA, 7 hips necessitated subtrochanteric shortening osteotomy (STO) for hip joint reduction. We evaluated the clinical and radiological results and especially focused on LLD and neurological complications. RESULTS: The Harris Hip Score improved from 57.1 ± 9.6 to 88.3 ± 6.3 points. No patients showed worse abductor power. LLD improved from 5.0 ± 2.0 to 1.4 ± 1.0 cm. No permanent neurological complications occurred except for 1 transient peroneal nerve palsy during traction, which resolved fully after cessation of traction. There were 2 hips with STO nonunion treated with osteosynthesis and stem revision. CONCLUSION: 2-stage THA following skeletal traction after extensive soft tissue release showed favourable results in terms of neurologic complication prevention and LLD resolution. However, a large proportion of patients still necessitated shortening osteotomy with a risk for nonunion at the osteotomy site. Though surgical procedures might be complicated and necessitate longer hospital stays, 2-stage THA with extensive soft tissue release might be an alternative treatment option for patients with severe LLD willing to resolve their limb length discrepancy.