Elevated Triglycerides to High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio Predicts Long-Term Mortality in High-Risk Patients.

BACKGROUND: Elevated triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been utilised as a predictor of outcomes in patients with adverse cardiometabolic risk profiles. In this study, we examined the prognostic value of elevated TG/HDL-C level in an Australian population of patients with high clinical suspicion of coronary artery disease (CAD) presenting for coronary angiography. METHODS: Follow-up data was collected for 482 patients who underwent coronary angiography in a prospective cohort study. The primary endpoint was all-cause mortality and the secondary endpoint was a major adverse cardiac event (MACE). Patients were stratified into two groups according to their baseline TG/HDL-C ratio, using a TG/HDL-C ratio cut point of 2.5. RESULTS: The mean follow-up period was 5.1 ± 1.2 years, with 49 all-cause deaths. Coronary artery disease on coronary angiography was more prevalent in patients with TG/HDL-C ratio ≥2.5 (83.6% vs. 69.4%, p = 0.03). On the Kaplan-Meier analysis, patients with TG/HDL-C ratio ≥2.5 had worse long-term prognosis (p = 0.04). On multivariate Cox regression adjusting for established cardiovascular risk factors and CAD on coronary angiography, TG/HDL-C ratio ≥2.5 was an independent predictor of long-term all-cause mortality (hazard ratio [HR] 2.10, 95% confidence interval [CI] 1.04-4.20, p = 0.04). On multivariate logistic regression adjusting for known cardiovascular risk factors and CAD on coronary angiography, TG/HDL-C ratio ≥2.5 was strongly associated with an increased risk of long-term MACE (odds ratio [OR] 2.72, 95% CI 1.42-5.20, p = 0.002). CONCLUSIONS: Elevated TG/HDL-C ratio is an independent predictor of long-term all-cause mortality and is strongly associated with an increased risk of MACE.

Methylobacterium currus sp. nov., isolated from a car air conditioning system.

A novel bacterial strain, designated PR1016AT, was isolated from a car air conditioning system. This rod-shaped strain showed catalase and oxidase activities, was aerobic and methylotrophic, and had a reddish pink colour. The genomic DNA G+C content of strain PR1016AT was 70.2 mol%, as determined by genome sequencing. Phylogenetic analysis based on 16S rRNA gene sequence similarity showed that strain PR1016AT was most closely related to Methylobacterium aquaticum GR16T (98.86 %), M. variabile GR3T (98.43 %), M. platani PMB 02T (98.36 %) and M. tarhaniae N4211T (98.14 %). The average nucleotide identity and digital DNA-DNA hybridization values between strain PR1016AT and M. aquaticum GR16T, M. platani PMB02T and M. variabile GR3T were 88.61, 88.14 and 87.88 %, and 36.4, 35.8 and 34.7 %, respectively. Numerous insertion sequences are present in the genome of strain PR1016AT, which has a larger genome than the four Methylobacterium species described above. Cells grew at 18-42 °C (optimum, 30 °C), at pH 4.0-9.0 (optimum, pH 7.0) and in the presence of 0-1.0 % (w/v) NaCl (optimum, 0 %). The major respiratory quinone was Q10. Fatty acid methyl ester analysis revealed that summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c) was the predominant cellular fatty acid in strain PR1016AT. Two-dimensional TLC indicated that the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. The genotypic and phenotypic characteristics indicate that strain PR1016AT represents a novel species of the genus Methylobacterium, for which the name Methylobacterium currus sp. nov. is proposed. The type strain is PR1016AT (=KACC 19662T=JCM 32670T).

Current challenges and future directions for bacterial self-healing concrete.

Microbially induced calcium carbonate precipitation (MICP) has been widely explored and applied in the field of environmental engineering over the last decade. Calcium carbonate is naturally precipitated as a byproduct of various microbial metabolic activities. This biological process was brought into practical use to restore construction materials, strengthen and remediate soil, and sequester carbon. MICP has also been extensively examined for applications in self-healing concrete. Biogenic crack repair helps mitigate the high maintenance costs of concrete in an eco-friendly manner. In this process, calcium carbonate precipitation (CCP)-capable bacteria and nutrients are embedded inside the concrete. These bacteria are expected to increase the durability of the concrete by precipitating calcium carbonate in situ to heal cracks that develop in the concrete. However, several challenges exist with respect to embedding such bacteria; harsh conditions in concrete matrices are unsuitable for bacterial life, including high alkalinity (pH up to 13), high temperatures during manufacturing processes, and limited oxygen supply. Additionally, many biological factors, including the optimum conditions for MICP, the molecular mechanisms involved in MICP, the specific microorganisms suitable for application in concrete, the survival characteristics of the microorganisms embedded in concrete, and the amount of MICP in concrete, remain unclear. In this paper, metabolic pathways that result in conditions favorable for calcium carbonate precipitation, current and potential applications in concrete, and the remaining biological challenges are reviewed.

Modulation of calcium carbonate precipitation by exopolysaccharide in Bacillus sp. JH7.

Extracellular polymeric substance (EPS) is proposed to facilitate calcium ion supersaturation through its nucleation effect during the microbially induced calcium carbonate precipitation (MICP) process. However, the supersaturation effect of Ca2+ via EPS in MICP has not been clearly demonstrated. Enhanced exopolysaccharide production of the alkali- and halotolerant MICP-capable bacteria, Bacillus sp. JH7, was achieved through glycerol addition. This was demonstrated by measuring cellular precipitation and Congo red binding. Interestingly, field emission scanning electron microscopy and energy-dispersive X-ray spectrometry analysis demonstrated that there was no MICP under glycerol-amended conditions. Although glycerol promoted exopolysaccharide capture of Ca2+ ions, Ca2+ embedded onto EPS did not participate in MICP formation. The pH was reduced in glycerol-added media, which led us to analyze high acetate production under our test conditions. Purified glycerol-induced exopolysaccharide showed a higher capacity of Ca2+ capture than the control. Quantitative RT-PCR analysis showed that three genes involved in exopolysaccharide production were highly upregulated by glycerol. The amounts of three detected monosaccharides (arabinose, glucose, and mannose) were altered by glycerol. Cell hydrophobicity measurements indicated that glycerol could confer more hydrophilic characteristics to cells, which might enhance Ca2+ binding onto EPS. Unexpectedly, our data demonstrated, for the first time, that glycerol could promote exopolysaccharide and acetate production under our test condition, which could inhibit MICP by reducing the availability of free Ca2+.

Is giving or receiving psychologically beneficial to older mothers in South Korea? Importance of marital status.

In order to understand intergenerational financial transfers and subjective well-being for older mothers, this study argues that marital status is an important factor to be considered. Using the first wave of the Korean Longitudinal Study of Aging (KLoSA), this study finds that married older mothers report higher levels of life satisfaction when they provide economic support but widowed older mothers feel higher levels of life satisfaction when they receive economic support. Also, regular or irregular financial support appears to also matter in the associations between financial support and life satisfaction. These findings suggest that married and widowed older mothers have different viewpoints about the parent-children relationship.

Living arrangements and suicidal ideation among the Korean older adults.

OBJECTIVES: This study examines how living arrangements are associated with suicidal ideation for older adults in South Korea, which has the highest suicide rate among OECD countries, and a particularly high suicide rate for older persons. METHODS: Analyzing a sample of 5795 women and 3758 men aged 65 and older from a nationwide representative cross-sectional data-set, we examined how many older adults think about suicide over a one-year period, why they think about suicide, and whether living arrangements are associated with suicidal ideation. RESULTS: About 1 out of 12 respondents in our sample reported suicidal ideation. While women and men did not differ in the prevalence of suicidal ideation, women attributed their suicidal feelings to health problems, while men attributed theirs to economic difficulties. Logistic regression results indicated that living arrangements are associated with suicidal ideation for men but not women. Older men living with a spouse were less likely to have suicidal ideation than older men with other living arrangements (i.e., living alone, living with children without spouse, living with spouse, and others). CONCLUSIONS: Our results highlight the importance of living arrangements to older men's suicidal ideation. We discuss gender differences in the implications of living arrangements to suicidal ideation within the context of Confucian culture.

2-Phenylbenzofuran derivatives alleviate mitochondrial damage via the inhibition of ß-amyloid aggregation.

To obtain modulators for reducing mitochondrial damage by the inhibition of Aß oligomer formation, 2-phenylbenzofuran derivatives were designed and prepared. Their inhibitory activity against Aß fibril formation was screened using ThT fluorescence assay, and the effect of derivatives on mitochondrial function was evaluated using JC-1 and MTT assay. 2-Phenylbenzofuran derivatives with dimethylamino group at p-position had an excellent inhibitory activity against Aß fibril formation. Particularly, compound 19m alleviated mitochondrial damage remarkably and possessed protective effects against Aß-induced cytotoxicity.

Synthesis and structure-activity relationships of tri-substituted thiazoles as RAGE antagonists for the treatment of Alzheimer's disease.

A series of thiazole derivatives were designed, and prepared to develop RAGE antagonist for the treatment of Alzheimer's disease (AD). SAR studies were performed to optimize inhibitory activity on Aß-RAGE binding. SAR studies showed that introducing an amino group at part A was essential for inhibitory activity on Aß-RAGE binding. Compounds selected from Aß-RAGE binding screening displayed inhibitory activity on Aß transport across BBB. They also showed inhibitory activity against Aß-induced NF-κB activation. These results indicated that our derivatives had a potential as therapeutic agent for the treatment of AD.

Discovery of potent and selective rhodanine type IKKß inhibitors by hit-to-lead strategy.

Regulation of NF-κB activation through the inhibition of IKKß has been identified as a promising target for the treatment of inflammatory and autoimmune disease such as rheumatoid arthritis. In order to develop novel IKKß inhibitors, we performed high throughput screening toward around 8000 library compounds, and identified a hit compound containing rhodanine moiety. We modified the structure of hit compound to obtain potent and selective IKKß inhibitors. Throughout hit-to-lead studies, we have discovered optimized compounds which possess blocking effect toward NF-κB activation and TNFα production in cell as well as inhibition activity against IKKß. Among them, compound 3q showed the potent inhibitory activity against IKKß, and excellent selectivity over other kinases such as p38α, p38ß, JNK1, JNK2, and JNK3 as well as IKKα.

Small molecules that protect against ß-amyloid-induced cytotoxicity by inhibiting aggregation of ß-amyloid.

Aggregated ß-amyloid (Aß) plays crucial roles in Alzheimer's disease (AD) pathogenesis, therefore blockade of Aß aggregation is considered as a potential therapeutic target. We designed and synthesized small molecules to reduce Aß-induced cytotoxicity by inhibiting Aß aggregation. The small molecules were screened via ThT, MTT, and cell-based cytotoxicity assay (Aß burden assay). Selected compounds 1c, 1d, 1e, and 1f were then investigated by evaluating their effects on cognitive impairment of acute AD mice model. Learning and memory dysfunction by injection of Aß(1-42) was recovered by administration of these molecules. Especially, 1d showed the best recovery activity in Y-maze task, object recognition task, and passive avoidance task with dose dependent manner. These results suggest that 1d has high potential as a therapeutic agent for AD.

Synthesis and biological evaluation of 4-piperidinecarboxylate and 4-piperidinecyanide derivatives for T-type calcium channel blockers.

To obtain selective and potent inhibitor for T-type calcium channel by ligand based drug design, 4-piperidinecarboxylate and 4-piperidinecyanide derivatives were prepared and evaluated for in vitro and in vivo activity against α(1G) calcium channel. Among them, several compounds showed good T-type calcium channel inhibitory activity and minimal off-target activity over hERG channel (% inhibition at 10 µM=61.85-71.99, hERG channel IC(50)=1.57 ± 0.14-4.98 ± 0.36 µM). Selected compound 31a was evaluated on SNL model of neuropathic pain and showed inhibitory effect on mechanical allodynia.

Synthesis and biological evaluation of 3-substituted-benzofuran-2-carboxylic esters as a novel class of ischemic cell death inhibitors.

A series of 3-substituted-benzofuran-2-carboxylic esters was synthesized and evaluated for biological activity as ischemic cell death inhibitors in H9c2 cells and rat primary cardiac myocytes under conditions of oxygen and glucose deprivation. The introduction of a sulfur atom at the three-position substituent of the benzofuran ring markedly improved ischemic cell death inhibitory potency. In particular, 3-[2-(4-nitro-phenylsulfanyl)-acetylamino]-benzofuran-2-carboxylic acid ester (10) (EC(50)=0.532 µM, cell death=6.18%) and 4-chloro-3-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzofuran-2-carboxylic ester (18) (EC(50)=0.557 µM, cell death=7.02%) were shown to be the most potent in this series of benzofuran analogs.

Enhanced calcium carbonate-biofilm complex formation by alkali-generating Lysinibacillus boronitolerans YS11 and alkaliphilic Bacillus sp. AK13.

Microbially induced calcium carbonate (CaCO3) precipitation (MICP) is a process where microbes induce condition favorable for CaCO3 formation through metabolic activities by increasing the pH or carbonate ions when calcium is near. The molecular and ecological basis of CaCO3 precipitating (CCP) bacteria has been poorly illuminated. Here, we showed that increased pH levels by deamination of amino acids is a driving force toward MICP using alkalitolerant Lysinibacillus boronitolerans YS11 as a model species of non-ureolytic CCP bacteria. This alkaline generation also facilitates the growth of neighboring alkaliphilic Bacillus sp. AK13, which could alter characteristics of MICP by changing the size and shape of CaCO3 minerals. Furthermore, we showed CaCO3 that precipitates earlier in an experiment modifies membrane rigidity of YS11 strain via upregulation of branched chain fatty acid synthesis. This work closely examines MICP conditions by deamination and the effect of MICP on cell membrane rigidity and crystal formation for the first time.

Micro and ultrastructural changes monitoring during decellularization for the generation of a biocompatible liver.

Decellularization of a whole organ is an attractive process that has been used to create 3D scaffolds structurally and micro-architecturally similar to the native one. Currently used decellularization protocols exhibit disrupted extracellular matrix (ECM) structure and denatured ECM proteins. Therefore, maintaining a balance between ECM preservation and cellular removal is a major challenge. The aim of this study was to optimize a multistep Triton X-100 based protocol (either using Triton X-100/ammonium hydroxide mixture alone or after its modification with DNase, sodium dodecyl sulfate or trypsin) that could achieve maximum decellularization with minimal liver ECM destruction suitable for subsequent organ implantation without immune rejection. Based on our findings, Triton X-100 multistep protocol was insufficient for whole liver decellularization and needed to be modified with other detergents. Among all Triton X-100 modified protocols, a Triton X-100/DNase-based one was considered the most suitable. It maintains a gradual but sufficient removal of cells to generate decellularized biocompatible liver scaffolds without any significant alteration to ECM micro- and ultra-structure.

Higher long-term adherence to statins in rural patients at high atherosclerotic risk.

BACKGROUND: Rural patients with atherosclerotic cardiovascular disease (ASCVD) experience greater cardiovascular morbidity and mortality than their urban counterparts. Statin therapy is a key component of ASCVD treatment. The extent to which there may be regional differences in long-term adherence to statins is unknown. OBJECTIVE: To assess long-term rates of adherence to statins in a high-risk ASCVD cohort, and whether regional differences exist between rural and urban patients. METHODS: Follow-up was conducted in patients who underwent coronary angiography at a single tertiary center between 2009 and 2013. Adherence was defined as consumption of prescribed statin ≥6 days per week. Patients were divided into remoteness areas (RAs), classified as RA1 (major city), RA2 (inner regional), and RA3 (outer regional) based on the Australian Standard Geographical Classification. RESULTS: Five hundred twenty-five patients (69% male, mean age 64 ± 11 years) were followed-up after a median of 5.3 years. Baseline characteristics were similar between RAs. Overall adherence was 83%; however, rural patients were significantly more adherent to their statin therapy (80% in RA1, 83% in RA2, and 93% in RA3, P = .04). Living in RA3 independently predicted greater statin adherence than living in RA1 (odds ratio: 2.75, 95% CI: 1.1-7.8, P = .03). All-cause mortality was significantly higher in RA3 than other regional areas (6% RA1, 12% RA2, and 18% RA3, P = .01). CONCLUSIONS: Despite higher all-cause mortality, rural patients with ASCVD demonstrate significantly greater long-term adherence to statins than urban patients. Other factors, such as reduced access to health care and delayed diagnosis may explain the gap in outcomes between rural and urban patients.

Synthesis and evaluation of alpha,alpha'-disubstituted phenylacetate derivatives for T-type calcium channel blockers.

We have synthesized and evaluated alpha,alpha'-disubstituted phenylacetate derivatives that were designed as T-type calcium channel blockers. Among them, compound 10e (IC(50)=8.17+/-0.48nM) showed the most potent T-type calcium current blocking activity and higher potency than Mibefradil (IC(50)=1.34+/-0.49microM). The PK profile and subtype selectivity over L-type calcium channel were satisfied for further animal assay using disease model.

Usefulness of Platelet-to-Lymphocyte Ratio to Predict Long-Term All-Cause Mortality in Patients at High Risk of Coronary Artery Disease Who Underwent Coronary Angiography.

Platelet-to-lymphocyte ratio (PLR) has recently been studied as a biomarker in patients with established coronary artery disease (CAD). The association between PLR and long-term all-cause mortality is unclear in patients at high risk of CAD who undergo coronary angiography for various indications. Follow-up was completed for 514 patients who underwent coronary angiography in a prospective study cohort. The primary end point was all-cause mortality. Patients were classified into tertiles based on preangiography PLR and also dichotomized based on the optimal cutoff at a PLR of 137, determined from the receiver operating characteristic curve analysis. The mean follow-up period was 5.0 ± 1.3 years, with 50 all-cause deaths. On the Kaplan-Meier analysis, patients in Tertile 3 (PLR > 145) had worse prognosis than patients in Tertiles 1 (PLR ≤ 106) and 2 (PLR 106.1 to 145) (p = 0.0075), and patients with PLR ≥ 137 had a significantly higher rate of all-cause mortality than those with PLR < 137 (p = 0.0006). On multivariate Cox regression adjusting for known cardiovascular risk factors, PLR was a strong, independent predictor of long-term all-cause mortality on the tertile analysis (Tertile 3 vs Tertile 1: hazard ratio 2.52, 95% confidence interval 1.18 to 5.39, p = 0.017) and based on the cutoff at a PLR of 137 (PLR ≥ 137 vs <137: hazard ratio 2.25, 95% confidence interval 1.21 to 4.20, p = 0.011). In conclusion, elevated PLR is associated with long-term all-cause mortality in patients at high risk of CAD who undergo coronary angiography, and PLR may be a useful prognostic biomarker in this population.

Necroptosis Is a Mechanism of Death in Mouse Induced Hepatocyte-Like Cells Reprogrammed from Mouse Embryonic Fibroblasts.

Liver transplantation is recommended for patients with liver failure, but liver donors are limited. This necessitates the development of artificial livers, and hepatocytes are necessary to develop such artificial livers. Although induced hepatocyte-like cells are used in artificial livers, the characteristics of mouse induced hepatocyte-like cells (miHeps) reprogrammed with embryonic fibroblasts have not yet been clarified. Therefore, this study investigated the mechanisms underlying the survival, function, and death of miHeps. miHeps showed decreased cell viability, increased cytotoxicity, decreased hepatic function, and albumin and urea secretion at passage 14. Addition of necrostatin-1 (NEC-1) to miHeps inhibited necrosome formation and reactive oxygen species generation and increased cell survival. However, NEC-1 did not affect the hepatic function of miHeps. These results provide a basis for development of artificial livers using hepatocytes.

Silver nanoparticles improve structural stability and biocompatibility of decellularized porcine liver.

No ideal cross-linking agent has been identified for decellularized livers (DLs) yet. In this study, we evaluated structural improvements and biocompatibility of porcine DLs after cross-linking with silver nanoparticles (AgNPs). Porcine liver slices were decellularized and then loaded with AgNPs (100 nm) after optimization of the highest non-toxic concentration (5 µg/mL) using Human hepatocellular carcinoma (HepG2) and EAhy926 human endothelial cell lines. The cross-linking effect of AgNPs was evaluated and compared to that of glutaraldehyde and ethyl carbodiimide hydrochloride and N-hydroxysuccinimide. The results indicated that AgNPs improved the ultra-structure of DLs' collagen fibres with good porosity and increased DLs' resistance against in vitro degradation with good cytocompatibility. AgNPs decreased the host inflammatory reaction against implanted porcine DL slices in vivo and increased the polarization of M2 macrophages. Thus, structural and functional improvements of Porcine DLs could be achieved using AgNPs.

The association between the use of biomedical services and the holistic use of traditional East Asian medicine: a national survey of outpatients in South Korea.

OBJECTIVES: The holistic use of a system of complementary and alternative medicine (CAM) is potentially linked to its treatment outcomes. This paper examines how the use of biomedicine is associated with the holistic use of CAM, focusing on traditional East Asian medicine (EM) that is uniquely integrated in the medical system in South Korea. DESIGN/SETTINGS: A representative national sample of EM outpatients in South Korea. PARTICIPANTS: 3861 survey respondents. METHODS: By using the 2011 Korean National Survey of EM patients, ordered logistic regression models specify the relationship between EM outpatients' use of biomedicine and their holistic use of EM modalities. RESULTS: Among EM outpatients who used at least one EM modality in the past 3 months, people who used two (33.3%) or three (29.4%) modalities together are the two highest proportions, followed by users of four (18.1%), five (7.2%), six (2.1%) and seven (0.6%) modalities. The odds for EM users to use EM holistically are 17% greater among EM users who used biomedicine as well, compared with EM users who did not use biomedicine. CONCLUSIONS: The healthcare community should recognise that CAM use likely becomes holistic as people use biomedicine concomitantly, when the practice rights over a CAM system are comprehensively and exclusively entitled to a group of CAM professionals who are independent from practitioners of biomedicine.