Ginsenosides from Panax ginseng as Key Modulators of NF-κB Signaling Are Powerful Anti-Inflammatory and Anticancer Agents.

Nuclear factor kappa B (NF-κB) signaling pathways progress inflammation and immune cell differentiation in the host immune response; however, the uncontrollable stimulation of NF-κB signaling is responsible for several inflammatory illnesses regardless of whether the conditions are acute or chronic. Innate immune cells, such as macrophages, microglia, and Kupffer cells, secrete pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1ß, via the activation of NF-κB subunits, which may lead to the damage of normal cells, including neurons, cardiomyocytes, hepatocytes, and alveolar cells. This results in the occurrence of neurodegenerative disorders, cardiac infarction, or liver injury, which may eventually lead to systemic inflammation or cancer. Recently, ginsenosides from Panax ginseng, a historical herbal plant used in East Asia, have been used as possible options for curing inflammatory diseases. All of the ginsenosides tested target different steps of the NF-κB signaling pathway, ameliorating the symptoms of severe illnesses. Moreover, ginsenosides inhibit the NF-κB-mediated activation of cancer metastasis and immune resistance, significantly attenuating the expression of MMPs, Snail, Slug, TWIST1, and PD-L1. This review introduces current studies on the therapeutic efficacy of ginsenosides in alleviating NF-κB responses and emphasizes the critical role of ginsenosides in severe inflammatory diseases as well as cancers.

The Preventive Effect of Specific Collagen Peptides against Dexamethasone-Induced Muscle Atrophy in Mice.

Muscle atrophy, also known as muscle wasting, is the thinning of muscle mass due to muscle disuse, aging, or diseases such as cancer or neurological problems. Muscle atrophy is closely related to the quality of life and has high morbidity and mortality. However, therapeutic options for muscle atrophy are limited, so studies to develop therapeutic agents for muscle loss are always required. For this study, we investigated how orally administered specific collagen peptides (CP) affect muscle atrophy and elucidated its molecular mechanism using an in vivo model. We treated mice with dexamethasone (DEX) to induce a muscular atrophy phenotype and then administered CP (0.25 and 0.5 g/kg) for four weeks. In a microcomputed tomography analysis, CP (0.5 g/kg) intake significantly increased the volume of calf muscles in mice with DEX-induced muscle atrophy. In addition, the administration of CP (0.25 and 0.5 g/kg) restored the weight of the gluteus maximus and the fiber cross-sectional area (CSA) of the pectoralis major and calf muscles, which were reduced by DEX. CP significantly inhibited the mRNA expression of myostatin and the phosphorylation of Smad2, but it did not affect TGF-ß, BDNF, or FNDC5 gene expression. In addition, AKT/mTOR, a central pathway for muscle protein synthesis and related to myostatin signaling, was enhanced in the groups that were administered CP. Finally, CP decreased serum albumin levels and increased TNF-α gene expression. Collectively, our in vivo results demonstrate that CP can alleviate muscle wasting through a multitude of mechanisms. Therefore, we propose CP as a supplement or treatment to prevent muscle atrophy.

Prognostic Impact of Atrial Fibrillation in Patients with Heavily Calcified Coronary Artery Disease Receiving Rotational Atherectomy.

Background and Objectives: Although both rotational atherectomy (RA) and atrial fibrillation (AF) have a high thrombotic risk, there have been no previous studies on the prognostic impact of AF in patients who undergo percutaneous coronary intervention (PCI) using RA. Thus, the aim of the present study was to determine the prognostic impact of AF in patients undergoing PCI using RA. Materials and Methods: A total of 540 patients who received PCI using RA were enrolled between January 2010 and October 2019. Patients were divided into AF and sinus rhythm groups according to the presence of AF. The primary endpoint was net adverse clinical events (NACEs) defined as a composite outcome of all-cause death, myocardial infarction, target vessel revascularization, cerebrovascular accident, or total bleeding. Results: Although in-hospital adverse events showed no difference between those with AF and those without AF (in-hospital events, 54 (11.0%) vs. 6 (12.2%), p = 0.791), AF was strongly associated with an increased risk of NACE at 3 years (NACE: hazard ratio, 1.880; 95% confidence interval, 1.096-3.227; p = 0.022). Conclusions: AF in patients who underwent PCI using RA was strongly associated with poor clinical outcomes. Thus, more attention should be paid to thrombotic and bleeding risks.

Antioxidant, Anti-Inflammatory, Anti-Menopausal, and Anti-Cancer Effects of Lignans and Their Metabolites.

Since chronic inflammation can be seen in severe, long-lasting diseases such as cancer, there is a high demand for effective methods to modulate inflammatory responses. Among many therapeutic candidates, lignans, absorbed from various plant sources, represent a type of phytoestrogen classified into secoisolariciresionol (Seco), pinoresinol (Pino), matairesinol (Mat), medioresinol (Med), sesamin (Ses), syringaresinol (Syr), and lariciresinol (Lari). Lignans consumed by humans can be further modified into END or ENL by the activities of gut microbiota. Lignans are known to exert antioxidant and anti-inflammatory activities, together with activity in estrogen receptor-dependent pathways. Lignans may have therapeutic potential for postmenopausal symptoms, including cardiovascular disease, osteoporosis, and psychological disorders. Moreover, the antitumor efficacy of lignans has been demonstrated in various cancer cell lines, including hormone-dependent breast cancer and prostate cancer, as well as colorectal cancer. Interestingly, the molecular mechanisms of lignans in these diseases involve the inhibition of inflammatory signals, including the nuclear factor (NF)-κB pathway. Therefore, we summarize the recent in vitro and in vivo studies evaluating the biological effects of various lignans, focusing on their values as effective anti-inflammatory agents.

Anti-Melanogenesis Effects of a Cyclic Peptide Derived from Flaxseed via Inhibition of CREB Pathway.

Linosorbs (Los) are cyclic peptides from flaxseed oil composed of the LO mixture (LOMIX). The activity of LO has been reported as being anti-cancer and anti-inflammatory. However, the study of skin protection has still not proceeded. In particular, there are poorly understood mechanisms of melanogenesis to LO. Therefore, we investigated the anti-melanogenesis effects of LOMIX and LO, and its activity was examined in mouse melanoma cell lines. The treatment of LOMIX (50 and 100 µg/mL) and LO (6.25-50 µM) suppressed melanin secretion and synthesis, which were 3-fold increased, in a dose-dependent manner, up to 95%. In particular, [1-9-NαC]-linusorb B3 (LO1) and [1-9-NαC]-linusorb B2 (LO2) treatment (12.5 and 25 µM) highly suppressed the synthesis of melanin in B16F10 cell lines up to 90%, without toxicity. LOMIX and LOs decreased the 2- or 3-fold increased mRNA levels, including the microphthalmia-associated transcription factor (MITF), Tyrosinase, tyrosinase-related protein 1 (TYRP1), and tyrosinase-related protein 2 (TYRP2) at the highest concentration (25 µM). Moreover, the treatment of 25 µM LO1 and LO2 inhibited the expression of MITF and phosphorylation of upper regulatory proteins such as CREB and PKA. Taken together, these results suggested that LOMIX and its individual LO could inhibit melanin synthesis via downregulating the CREB-dependent signaling pathways, and it could be used for novel therapeutic materials in hyperpigmentation.

Connarus semidecandrus Jack Exerts Anti-Alopecia Effects by Targeting 5α-Reductase Activity and an Intrinsic Apoptotic Pathway.

There is a growing demand for hair loss treatments with minimal side effects and recurrence potential. Connarus semidecandrus Jack has been used as a folk medicine for fever in tropical regions, but its anti-alopecia effects remain unclear. In this study, the anti-androgenic alopecia effect of an ethanol extract of Connarus semidecandrus Jack (Cs-EE) was demonstrated in a testosterone-induced androgenic alopecia (AGA) model, in terms of the hair-skin ratio, hair type frequency, and hair thickness. The area of restored hair growth and thickened hair population after Cs-EE treatment showed the hair-growth-promoting effect of Cs-EE. Histological data support the possibility that Cs-EE could reduce hair loss and upregulate hair proliferation in mouse skin by shifting hair follicles from the catagen phase to the anagen phase. Western blotting indicated that Cs-EE reduced the expression of the androgenic receptor. Cs-EE treatment also inhibited programmed cell death by upregulating Bcl-2 expression at the mRNA and protein levels. The anti-alopecia effect of Cs-EE was confirmed by in vitro experiments showing that Cs-EE had suppressive effects on 5-α reductase activity and lymph node carcinoma of the prostate proliferation, and a proliferative effect on human hair-follicle dermal papilla (HDP) cells. Apoptotic pathways in HDP cells were downregulated by Cs-EE treatment. Thus, Cs-EE could be a potential treatment for AGA.

Impact of chronic outward force on arterial responses of proximal and distal of long superficial femoral artery stent.

BACKGROUND: Self-expanding nitinol stent (SENS) implantation is commonly oversized in the superficial femoral artery (SFA), and leads to chronic outward force (COF) and in-stent restenosis (ISR). This study aimed to investigate the impact of COF of oversizing SENS on ISR of SFA. METHODS: In patients with implanted SENS in SFA, intimal hyperplasia especially between proximal segment and distal segment was evaluated by quantitative angiography, and the impact of COF on mid-term angiographic outcomes was investigated. In addition, porcine model with implanted SENS was used to evaluate the impact of COF on angiographic and histopathologic outcomes at 1 month. Excised stented arteries were evaluated by histopathologic analysis. RESULTS: We analyzed 65 SENS in 61 patients with follow-up angiography at 6 months to 1 year. The baseline diameter was 6.8 ± 0.71 mm and length were 97.0 ± 33.8 mm for the SENS. The ratio of the diameter of the stent to the reference vessel was 1.3 ± 0.24 at the proximal portion and 1.53 ± 0.27 at the distal portion (P < 0.001). In the long SFA stent, stent-to-vessel ratio was significantly higher in the distal stent than in the proximal stent (1.3 ± 0.2 vs. 1.55 ± 0.25, P = 0.001). ISR incidence was higher at the distal stent (37.3% vs 52.6%, P = 0.029). All 11 pigs survived for 4 weeks after SENS implantation. The vessel diameter was 4.04 ± 0.40 mm (control group) vs 4.45 ± 0.63 mm (oversized group), and the implanted stent diameter was 5.27 ± 0.46 mm vs. 7.18 ± 0.4 mm (P = 0.001). The stent-to-vessel diameter ratio was 1.31 ± 0.12 versus 1.63 ± 0.20 (P < 0.001). After 4 weeks, restenosis % was 29.5 ± 12.9% versus 46.8 ± 21.5% (P = 0.016). The neointimal area was 5.37 ± 1.15 mm2 vs. 8.53 ± 5.18 mm2 (P = 0.05). The restenosis % was 39.34 ± 8.53% versus 63.97 ± 17.1% (P = 0.001). CONCLUSIONS: COF is an important cause of restenosis in the distal portion of the SFA stent. Optimal sizing of the SFA stent is important to reduce the incidence of restenosis. Therefore, COF was an important factor of restenosis following distal SFA stenting.

Enzymatic characterization of a novel recombinant 1,3-α-3,6-anhydro-L-galactosidase specific for neoagarobiose hydrolysis into monosaccharides.

Two GH117 family α-neoagarobiose hydrolases (GH117A α-NABH and GH117B α-NABH) from the freshwater agar-degrading Cellvibrio sp. KY-GH-1 were expressed and purified as recombinant His-tagged proteins using an Escherichia coli expression system to compare activities. The amino acid sequence of GH117A α-NABH (364 amino acids, 40.9 kDa) showed 35% identity with that of GH117B α-NABH (392 amino acids, 44.2 kDa). GH117A α-NABH, but not GH117B α-NABH, could hydrolyze neoagarobiose (NA2) into monosaccharides 3,6-anhydro-L-galactose (L-AHG) and D-galactose. The presence of GH117A α-NABH homologues in all of the agar-degrading bacteria aligned suggests that GH117A α-NABH hydrolyzing NA2 into L-AHG and D-galactose is an essential component of the agar-degrading enzyme machinery. For GH117A α-NABH-catalyzed hydrolysis, NA2 was the sole substrate among various neoagaro-oligosaccharides (NA2~NA18). GH117A α-NABH appeared to exist as a dimer, and optimal enzymatic temperature and pH were 35 °C and 7.5, respectively. GH117A α-NABH was stable up to 35 °C and at pH 7.5 and unstable beyond 35 °C and outside pH 7.0~7.5. The kinetic parameters Km, Vmax, kcat, and kcat/Km for NA2 were 16.0 mM, 20.8 U/mg, 14.2 s-1, and 8.9 × 102 s-1 M-1, respectively. Combined addition of 5 mM MnSO4 and 10 mM tris(2-carboxyethyl)phosphine enhanced the enzyme activity by 2.4-fold. The enzyme-mediated hydrolysis of 5.0% NA2 into monosaccharide and purification of L-AHG from hydrolysis products by Sephadex G-10 column chromatography recovered ~ 192 mg L-AHG from 400 mg NA2 (~ 92% of the theoretical maximum yield). These results indicate that the recombinant GH117A α-NABH is NA2-specific and useful to produce L-AHG from NA2. KEY POINTS: • Recombinant GH117A α-NABH (364 aa, 40.9 kDa) purified from E. coli forms a dimer. • The enzyme hydrolyzes only NA2 among various neoagaro-oligosaccharides (NA2~NA18). • The enzyme completely hydrolyzes up to 5% NA2 into monomers under optimal conditions.

Impact of chronic total occlusion lesions on clinical outcomes in patients receiving rotational atherectomy: results from the ROCK registry.

The aim of this study was to investigate the impact of chronic total occlusion (CTO) on clinical outcomes in patients with calcified coronary lesions receiving rotational atherectomy (RA). This multi-center registry enrolled consecutive patients with calcified coronary artery disease who underwent RA during percutaneous coronary intervention (PCI) from 9 tertiary centers in Korea between January 2010 and October 2019. The primary outcome was target-vessel failure (TVF) which included the composite of cardiac death, target-vessel myocardial infarction (TVMI), and target-vessel revascularization (TVR). A total of 583 lesions were enrolled in this registry and classified as CTO (n = 42 lesions, 7.2%) and non-CTO (n = 541 lesions, 92.8%). The CTO group consisted of younger patients who were more likely to have a history of previous percutaneous coronary intervention or coronary artery bypass graft surgery. The incidence of the primary outcome was 14.1% and 16.7% for the non-CTO group and CTO group, respectively. The primary outcomes observed in the two groups were not significantly different (log-rank p = 0.736). The 18-month clinical outcomes of the CTO group were comparable to those of the non-CTO group in multivariate analysis. About 7% of patients requiring RA have CTO lesions and these patients experience similar clinical outcomes compared with those having non-CTO lesions. Use of RA for CTO lesions was safe despite higher procedural complexity.

Impact of Sleep-Disordered Breathing on Functional Outcomes in Ischemic Stroke: A Cardiopulmonary Coupling Analysis.

BACKGROUND AND PURPOSE: Cardiopulmonary coupling (CPC) analysis is an easily assessable method to evaluate sleep-disordered breathing (SDB); however, its prognostic impact in patients with acute ischemic stroke needs to be investigated. We performed a CPC analysis using Holter monitoring at the early stage of noncardioembolic ischemic stroke to investigate the prognostic effect of SDB on functional impairment at the 3-month follow-up. METHODS: A total 615 patients with acute noncardioembolic ischemic stroke who underwent Holter monitoring within 30 days of stroke onset were enrolled from a multicenter, prospective, all-comer cohort. CPC analysis was conducted, and SDB was defined by the presence of narrow-band coupling during sleep time. We investigated the association between SDB and functional impairment at 3 months as measured by the modified Rankin Scale. RESULT: Narrow-band coupling was present in 191 (31.1%) of 615 patients (mean age 64.5±12.6 years). The narrow-band group showed a significantly higher rate of severe functional impairment (modified Rankin Scale score >2; 45.5% versus 12.9%, P<0.001) and persistent disability (Δmodified Rankin Scale score ≤0; 53.9% versus 39.8%, P<0.001) at the 3-month follow-up. In multivariate analysis, narrow-band coupling was an independent predictor of higher risk of severe and persistent functional impairment at 3 months (odds ratio, 3.98 [95% CI, 2.34-6.78]; P<0.001; and odds ratio, 1.81 [95% CI, 1.23-2.66]; P<0.001, respectively). The results remained consistent after propensity-score matched analysis with 157 patient pairs (C-statistic=0.770). CONCLUSIONS: SDB assessed by CPC analysis at the early stage of ischemic stroke could predict severe and prolonged functional impairment at 3 months. CPC analysis using Holter monitoring can help predicting functional impairment in acute ischemic stroke.

Cilostazol-based triple versus potent P2Y12 inhibitor-based dual antiplatelet therapy in patients with acute myocardial infarction undergoing percutaneous coronary intervention.

Although potent P2Y12 inhibitor-based dual antiplatelet therapy (DAPT) has replaced clopidogrel-based therapy as the standard treatment in patients with acute myocardial infarction (AMI), there is a concern about the risk of bleeding in East Asian patients. We compared the efficacy and safety of cilostazol-based triple antiplatelet therapy (TAT) with potent P2Y12 inhibitor-based DAPT in Korean patients. A total of 4152 AMI patients who underwent percutaneous coronary intervention (PCI) in the Korea Acute Myocardial Infarction Registry were analyzed retrospectively. Patients were divided into two groups: the TAT group (aspirin + clopidogrel + cilostazol, n = 3161) and the potent DAPT group (aspirin + potent P2Y12 inhibitors [ticagrelor or prasugrel], n = 991). Major clinical outcomes at 30 days and 2 years were compared between the two groups using propensity score matching (PSM) analysis. After PSM (869 pairs), there were no significant differences between the two groups in the incidence of total death, cardiac death, myocardial infarction (MI), target vessel revascularization, stent thrombosis, and stroke at 30 days and 2 years. However, the Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding rates were significantly lower in the TAT group compared with the potent DAPT group at 2 years (6.4% vs. 3.6%, p = 0.006). In Korean AMI patients undergoing PCI, TAT with cilostazol was associated with lower bleeding than the potent P2Y12 inhibitor-based DAPT without increased ischemic risk. These results could provide a rationale for the use of TAT in East Asian AMI patients.

Changes in Characteristics of Patients with Liver Cirrhosis Visiting a Tertiary Hospital over 15 Years: a Retrospective Multi-Center Study in Korea.

BACKGROUND: Liver cirrhosis has become a heavy burden not only for patients, but also for our society. However, little is known about the recent changes in clinical outcomes and characteristics of patients with cirrhosis-related complications in Korea. Therefore, we aimed to evaluate changes in characteristics of patients with liver cirrhosis in Daegu-Gyeongbuk province in Korea over the past 15 years. METHODS: We retrospectively reviewed the medical records of 15,716 liver cirrhotic patients from 5 university hospitals in Daegu-Gyeongbuk province from 2000 to 2014. The Korean Standard Classification of Diseases-6 code associated with cirrhosis was investigated through medical records and classified according to the year of first visit. RESULTS: A total of 15,716 patients was diagnosed with cirrhosis. A number of patients newly diagnosed with cirrhosis has decreased each year. In 2000, patients were most likely to be diagnosed with hepatitis B virus (HBV) cirrhosis, followed by alcoholic cirrhosis. There was a significant decrease in HBV (P < 0.001), but alcohol, hepatitis C virus (HCV), and non-alcoholic fatty liver disease (NAFLD) showed a significant increase during the study period (alcohol, P = 0.036; HCV, P = 0.001; NAFLD, P = 0.001). At the time of initial diagnosis, the ratio of Child-Turcotte-Pugh (CTP) class A gradually increased from 23.1% to 32.9% (P < 0.001). The most common cause of liver-related hospitalization in 2000 was hepatocellular carcinoma (HCC) (25.5%); in 2014, gastrointestinal bleeding with esophageal and gastric varices (21.4%) was the most common cause. Cases of hospitalization with liver-related complication represented 76.4% of all cases in 2000 but 70.9% in 2014. Incidence rate of HCC has recently increased. In addition, HCC-free survival was significantly lower in CTP class A than in classes B and C. Finally, there was significant difference in HCC occurrence according to causes (P < 0.001). HBV and HCV cirrhosis had lower HCC-free survival than alcoholic and NAFLD cirrhosis. CONCLUSION: In recent years, the overall number of cirrhosis patients has decreased. This study confirmed the recent trend in decrease of cirrhosis, especially of cirrhosis due to HBV, and the increase of HCV, alcoholic and NAFLD cirrhosis. Targeted screening for at-risk patients will facilitate early detection of liver diseases allowing effective intervention and may have decreased the development of cirrhosis and its complications.

Robotic versus conventional primary total knee arthroplasty: clinical and radiological long-term results with a minimum follow-up of ten years.

PURPOSE: The aim of this study was (1) to compare the clinical and radiological outcomes of robotic and conventional total knee arthroplasty with a minimum follow-up of ten years, (2) to evaluate the survival rate, (3) and to estimate the accuracy of the two techniques by analyzing the outliers of the total knee arthroplasty (TKA) patients. METHODS: We evaluated 351 patients (390 knees), 155 patients undergoing robotic TKA, and 196 patients treated with conventional TKA with a mean follow-up of 11.0 years. HSS, KSS, WOMAC, and SF-12 questionnaires were used for clinical evaluation. Mechanical alignment, implant radiological measurements, and outliers were analyzed for radiological results. Kaplan-Meier survival analysis was performed for survival rate. RESULTS: All clinical assessments showed excellent improvements in both groups (all p < 0.05), without any significant difference between the groups (p > 0.05). The conventional TKA group showed a significantly higher number of outliers compared with the robotic TKA group (0 < 0.05). The cumulative survival rate was 98.8% in the robotic TKA group and 98.5% in the conventional TKA group with excellent survival (p = 0.563). CONCLUSION: Our study showed excellent survival with both robotic and conventional TKA and similar clinical outcomes at long-term follow-up. And, in terms of radiological outcome, robotic TKA showed better accuracy and consistency with fewer outliers compared with conventional TKA. With longer follow-up and larger cohort, the accuracy and effectiveness of robotic TKA on implant survival rate can be elucidated in the future.

Selective ß1-Blockers Are Not Associated With New-onset Diabetes Mellitus in Hypertensive Patients.

BACKGROUND: Although ß-blockers are known to increase new-onset diabetes mellitus (DM), previous evidence have been controversial. It has been suggested that newer vasodilatory ß-blockers yield better glycemic control than older nonselective agents. The aim of this study was to evaluate the diabetogenicity of currently used newer ß-blockers based on ß1 receptor selectivity in a series of Asian population. METHODS: We investigated a total of 65,686 hypertensive patients without DM from 2004 to 2014. Patients with hemoglobin (Hb) A1c ≤6.0%, fasting blood glucose ≤110 mg/dL, and no history of diabetes or diabetic treatment were enrolled for analysis. Patients were divided into the ß-blockers group and non-ß-blockers group. Propensity score matching (PSM) analysis using a logistic regression model was performed to adjust for potential confounders. The primary end point was the cumulative incidence of new-onset DM, defined as a fasting blood glucose ≥126 mg/dL or HbA1c ≥6.5%, and major adverse cardiac and cerebral events (MACCE), defined as a composite of total death, nonfatal myocardial infarction, and cerebrovascular accidents. We investigated predictors of new-onset DM and MACCE based on 2 models, including clinical risk factors and co-medications, respectively. RESULTS: Mean follow-up duration was 30.91 ± 23.14 months in the entire group before adjustment. The ß-blockers group had a significantly higher incidence of new-onset DM and MACCE than the non-ß-blockers group. After PSM, analysis of a total of 2284 patients (1142 pairs, C-statistic = 0.752) showed no difference between the 2 groups in new-onset DM or MACCE. In multivariate analysis after PSM, baseline HbA1c, stroke, heart failure, nonselective ß-blockers, and age were independent predictors of new-onset DM. Selective ß1-blockers did not increase new-onset DM after adjustment for other antihypertensive medication and statins. CONCLUSIONS: In the era of newer ß-blockers, selective ß1-blockers were not associated with new-onset DM. More evidence is needed to verify this relationship and the underlying mechanisms.

Hyperuricaemia and development of type 2 diabetes mellitus in Asian population.

Recently, meta-analysis studies reported that hyperuricaemia is associated with higher incidence of type 2 diabetes mellitus (T2DM), however, there are limited data on the Asian population. The aim of this observational study is to estimate the long-term impact of hyperuricaemia on the new-onset T2DM and cardiovascular events. This study is based on a single-centre, all-comers, and large retrospective cohort. Subjects that visited from January 2004 to February 2014 were enrolled using the electronic database of Korea University Guro Hospital. A total of 10 505 patients without a history of T2DM were analyzed for uric acid, fasting glucose and haemoglobin (Hb) A1c level. Inclusion criteria included both Hb A1c <5.7% and fasting glucose level <100 mg/dL without T2DM. Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dL in men, and ≥6.5 mg/dL in women. To adjust baseline confounders, a propensity score matching (PSM) analysis was performed. The impact of hyperuricaemia on the new-onset T2DM and cardiovascular events were compared with the non-hyperuricaemia during the 5-year clinical follow-up. After PSM, baseline characteristics of both groups were balanced. In a 5-year follow-up, the hyperuricaemia itself was a strong independent predictor of the incidence of new-onset T2DM (HR, 1.78; 95% CI, 1.12 to 2.8). Hyperuricaemia was a strong independent predictor of new-onset T2DM, which suggests a substantial implication for a correlation between uric acid concentration and insulin resistance (or insulin sensitivity). Also, hyperuricaemia is substantially implicated in cardiovascular risks and the further long-term cardiovascular events in the crude population, but it is not an independent predictor of long-term cardiovascular mortality in the matched population.

Objective quantification of ligament balancing using VERASENSE in measured resection and modified gap balance total knee arthroplasty.

BACKGROUND: Soft tissue balancing which is above all most important factor of total knee arthroplasty, has been performed by subjective methods. Recently objective orthosensor has been developed for compartment pressure measurement. The purpose of this study was: (1) to quantify the compartment pressure of the joint throughout the range of motion during TKA using orthosensor, (2) to determine the usefulness of orthosensor by analyzing correlation between the pressure in both compartment with initial trial and after final implantation, and (3) to evaluate the types and effectiveness of additional ligament balancing procedures to compartment pressure. METHODS: Eighty-four patients underwent total knee arthroplasty (TKA) using VERASENSE Knee System. TKA was performed by measured resection and modified gap balance technique. Compartment pressure was recorded on full extension, 30°, 60°, 90° and full flexion at initial (INI), after each additional procedure, and after final (FIN) implantation. "Balanced" knees were defined as when the compartment pressure difference was less than 15 pounds. RESULTS: Thirty patients (35.7%) showed balanced knee initially and 79 patients (94.0%) showed balance after final implantation. The proportion of balanced knee after initial bony resection, modified gap balancing TKAs showed significantly higher proportion than measured resection TKAs (P = 0.004) On both compartment, the pressure was generally decreased throughout the range of motion. Linear correlation on both compartment showed statistically significant throughout the range on motion, with higher correlation value on the lateral compartment. Total 66 additional ligament balancing procedures were performed. CONCLUSION: Using orthosensor, we could obtain 94% quantified balance knee, consequently. And between the techniques, measured resection TKA showed less balanced knee and also required more additional procedures compared to modified gap balancing TKA. Furthermore, with the acquired quantified data during appropriate ligament balancing, the surgeon could eventually reduce the complications associated with soft tissue imbalance in the future.

Inhibition of JNK2 and JNK3 by JNK inhibitor IX induces prometaphase arrest-dependent apoptotic cell death in human Jurkat T cells.

Exposure of human Jurkat T cells to JNK inhibitor IX (JNKi), targeting JNK2 and JNK3, caused apoptotic DNA fragmentation along with G2/M arrest, phosphorylation of Bcl-2, Mcl-1, and Bim, Δψm loss, and activation of Bak and caspase cascade. These JNKi-induced apoptotic events were abrogated by Bcl-2 overexpression, whereas G2/M arrest, cyclin B1 up-regulation, Cdk1 activation, and phosphorylation of Bcl-2 family proteins were sustained. In the concomitant presence of the G1/S blocking agent aphidicolin and JNKi, the cells underwent G1/S arrest and failed to induce all apoptotic events. The JNKi-induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by the Cdk1 inhibitor. Immunofluorescence microscopic analysis revealed that mitotic spindle defect and prometaphase arrest were the underlying factors for the G2/M arrest. These results demonstrate that JNKi-induced mitochondrial apoptosis was caused by microtubule damage-mediated prometaphase arrest, prolonged Cdk1 activation, and phosphorylation of Bcl-2 family proteins in Jurkat T cells.

Extracellular production of a thermostable Cellvibrio endolytic ß-agarase in Escherichia coli for agarose liquefaction.

Four GH16 family ß-agarases (GH16A, GH16B, GH16C, and GH16D), originated from an agarolytic bacterium Cellvibrio sp. KY-GH-1, were expressed in an Escherichia coli system and their activities were compared. Only GH16B (597 amino acids, 63.8 kDa), with N-terminal 22-amino acid signal sequence, was secreted into the culture supernatant and demonstrated a robust endolytic agarose hydrolyzing activity for producing neoagarotetraose (NA4) and neoagarohexaose (NA6) as end products. The optimal temperature and pH for the enzyme activity were 50 °C and 7.0, respectively. The enzyme was stable up to 50 °C and over a pH range of 5.0-8.0. The kinetic parameters, including Km, Vmax, kcat, and kcat/Km, of GH16B ß-agarases for agarose were 14.40 mg/mL, 542.0 U/mg, 576.3 s-1, and 4.80 × 106 s-1 M-1, respectively. The addition of 1 mM MnCl2 and 15 mM tris(2-carboxyethyl)phosphine enhanced the enzymatic activity. When agarose or neoagaro-oligosaccharides were used as substrates, the end products of enzymatic catalysis were NA4 and NA6, whereas agaropentaose was produced along with NA4 and NA6 when agaro-oligosaccharides were used as substrates. Treatment of 9%[w/v] melted agarose with the enzyme (1.6 µg/mL) under continuous magnetic stirring at 50 °C for 14 h resulted in efficient agarose liquefaction into NA4 and NA6. Purification of NA4 and NA6 from the enzymatic hydrolysate (9%[w/v] agarose, 20 mL) via Sephadex G-15 column chromatography yielded ~ 650 mg NA4/~ 900 mg NA6 (i.e., ~ 85.3% of the theoretical maximum yield). These findings suggest that the recombinant thermostable GH16B ß-agarase is useful for agarose liquefaction to produce NA4 and NA6.

Surgical Excision for Refractory Ischiogluteal Bursitis: A Consecutive Case Series of 21 Patients.

Purpose: A response to conservative treatment is usually obtained in cases of ischiogluteal bursitis. However, the time required to achieve relief of symptoms can vary from days to weeks, and there is a high recurrence rate, thus invasive treatment in addition to conservative treatment can occasionally be effective. Therefore, the aim of this study was to examine surgical excision in cases of refractory ischiogluteal bursitis and to evaluate patients' progression and outcome. Materials and Methods: A review of 21 patients who underwent surgical excision for treatment of ischiogluteal bursitis between February 2009 and July 2020 was conducted. Of these patients, seven patients were male, and 14 patients were female. Injection of steroid and local anesthetic into the ischial bursa was administered at outpatient clinics in all patients, who and they were refractory to conservative treatment, including aspiration and prescription drugs. Therefore, surgery was considered necessary. Excisions were performed by two orthopedic specialists using a direct vertical incision on the ischial area. A review of each patient was performed after excision, and quantification of the outcomes recorded using clinical scoring systems was performed. Results: The results of radiologic evaluation showed that the mean lesion size was 6.2 cm×4.5 cm×3.6 cm. The average disease course after excision was 21.6 days (range, 15-48 days). Measurement of clinical scores, including the visual analog scale and Harris hip scores, was performed during periodic visits, with scores of 0.7 (range, 0-2) and 98.1 (range, 96-100) at one postoperative month, respectively. Conclusion: Surgical excision, with an expectation of favorable results, could be considered for treatment of ischiogluteal bursitis that is refractory to therapeutic injections, aspirations, and medical prescriptions, particularly in moderate-to-severe cases.

Long-Term Clinical Impact of Patients with Multi-Vessel Non-Obstructive Coronary Artery Disease.

BACKGROUND: Non-obstructive coronary artery disease (CAD) is a disease commonly diagnosed in patients undergoing coronary angiography. However, little is known regarding the long-term clinical impact of multi-vessel non-obstructive CAD. Therefore, the object of this study was to investigate the long-term clinical impact of multi-vessel non-obstructive CAD. METHOD: A total of 2083 patients without revascularization history and obstructive CAD were enrolled between January 2010 and December 2015. They were classified into four groups according to number of vessels involved in non-obstructive CAD (25% ≤ luminal stenosis < 70%): zero, one, two, or three diseased vessels (DVs). We monitored the patients for 5 years. The primary outcome was major cardiovascular and cerebrovascular events (MACCEs), defined as a composite of cardiac death, stroke, and myocardial infarction (MI). RESULT: The occurrence of MACCEs increased as the number of non-obstructive DVs increased, and was especially high in patients with three DVs. After adjustment, patients with three DVs still showed significantly poorer clinical outcomes of MACCEs, stroke, and MI compared those with zero DVs. CONCLUSION: Multi-vessel non-obstructive CAD, especially in patients with non-obstructive three DVs, is strongly associated with poor long-term clinical outcomes. This finding suggests that more intensive treatment may be required in this subset of patients.