Association of remnant cholesterol with risk of dementia: a nationwide population-based cohort study in South Korea.

BACKGROUND: The association between remnant cholesterol (remnant-C) and cardiovascular disease risk is well established, but its association with dementia remains unclear. We aimed to examine this association using a large-scale population dataset. METHODS: We did a nationwide, population-based cohort study in which we identified participants aged 40 years and older who underwent the national health examination in 2009 from South Korea's National Health Insurance Service. We excluded people who were younger than 40 years and those with a triglyceride concentration of 400 mg/dL or higher due to concerns regarding the accuracy of calculated low-density lipoprotein cholesterol concentration in individuals with extremely high triglyceride concentrations. People who were previously diagnosed with dementia before the index date, and those who had any missing variables were also excluded. To minimise the influence of possible reverse causation, we excluded individuals who had developed any type of dementia within 1 year of the baseline measurements. We calculated hazard ratios (HRs) for all-cause dementia, Alzheimer's disease, and vascular dementia in each quartile of remnant-C using the Cox proportional hazards model adjusted for age, sex, body-mass index, estimated glomerular filtration rate, income level, smoking status, alcohol consumption, regular exercise, diabetes, hypertension, statin and fibrate use, and total cholesterol concentrations. We also did subgroup analyses to investigate the association between remnant-C and the risk of dementia stratified by age, sex, obesity, glycaemic status (normoglycaemia, impaired fasting glucose, new-onset type 2 diabetes, type 2 diabetes with a duration of less than 5 years, and type 2 diabetes with a duration of 5 years or more), hypertension, chronic kidney disease, and dyslipidaemia, using likelihood ratio tests. FINDINGS: 4 234 415 individuals who underwent the national health examination in 2009 were deemed eligible for inclusion. We excluded 1 612 819 individuals on the basis of age, triglyceride concentration, missing variables, or having dementia at baseline. We identified 2 621 596 participants aged 40 years and older (1 305 556 men and 1 316 040 women) who underwent the national health examination and followed them up until the date of any incident of dementia or the end of the study period of Dec 31, 2020. During a median follow-up of 10·3 years (IQR 10·1-10·6), 146 991 (5·6%) participants developed all-cause dementia, 117 739 (4·5%) developed Alzheimer's disease, and 14 536 (0·6%) developed vascular dementia. The risk of dementia increased progressively with higher remnant-C concentrations. Compared with the lowest quartile of remnant-C (quartile 1), HRs in the highest quartile (quartile 4) were 1·11 (95% CI 1·09-1·13) for all-cause dementia, 1·11 (1·08-1·13) for Alzheimer's disease, and 1·15 (1·09-1·21) for vascular dementia. Subgroup analyses revealed that the risk of dementia associated with high remnant-C concentrations was higher in middle-aged people aged 40-59 years than in older people. The risk of dementia associated with high concentrations of remnant-C was notably more pronounced in individuals with diabetes compared with those without diabetes, and the risk increased steeply with a longer duration of diabetes. INTERPRETATION: Results showed that higher remnant-C concentrations were independently associated with increased risks of all-cause dementia, Alzheimer's disease, and vascular dementia. More research is needed to determine the mechanisms underlying this finding. Monitoring and managing higher concentrations of remnant-C might have important implications for reducing the risk of dementia. FUNDING: None.

Pioglitazone as Add-on THERAPY in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial.

Background: This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin. Methods: In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135). Results: At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (-0.47%; 95% confidence interval, -0.61 to -0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, highdensity lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%). Conclusion: Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin.

Triglyceride-Rich Lipoproteins and Remnant Cholesterol in Cardiovascular Disease.

Despite the well-established benefits of statin treatments in lowering low-density lipoprotein cholesterol (LDL-C), a significant residual risk for atherosclerotic cardiovascular disease (ASCVD) remains. Triglycerides (TGs) have long been recognized as potential residual risk factors in this context, but recent studies now disclose the substantial role of TG-rich lipoproteins (TRLs) and cholesterol components of metabolized TRLs (commonly referred to as remnant cholesterol) in atherogenesis, not just TGs alone. Evidence derived through diverse sources, including preclinical studies of pathogenic mechanisms, epidemiologic investigations, and genetic research, has consistently supported the considerable contribution of TRLs and remnant cholesterol in predicting occurrences of ASCVD. As emerging biomarkers for predicting atherosclerosis, they have thus become prioritized therapeutic targets, meant to augment LDL-C lowering efforts in individuals at high risk of ASCVD. However, routine clinical testing for remnant cholesterol and TRLs is still in question, necessitating further research into appropriate treatment plans if levels are elevated. New therapies targeting proteins in TG metabolic pathways, particularly angiopoietin-like protein 3 and apolipoprotein C-III, have shown potential advantages in patients with mild-to-moderate hypertriglyceridemia by reducing blood levels of TGs and remnant cholesterol. The aim of this review is to summarize existing evidence linking elevated TRLs and remnant cholesterol with development of ASCVD and to explore additional guidance for clinical therapy.

Development of a Metabolic Syndrome Classification and Prediction Model for Koreans Using Deep Learning Technology: The Korea National Health and Nutrition Examination Survey (KNHANES) (2013-2018).

The prevalence of metabolic syndrome (MetS) and its cost are increasing due to lifestyle changes and aging. This study aimed to develop a deep neural network model for prediction and classification of MetS according to nutrient intake and other MetS-related factors. This study included 17,848 individuals aged 40-69 years from the Korea National Health and Nutrition Examination Survey (2013-2018). We set MetS (3-5 risk factors present) as the dependent variable and 52 MetS-related factors and nutrient intake variables as independent variables in a regression analysis. The analysis compared and analyzed model accuracy, precision and recall by conventional logistic regression, machine learning-based logistic regression and deep learning. The accuracy of train data was 81.2089, and the accuracy of test data was 81.1485 in a MetS classification and prediction model developed in this study. These accuracies were higher than those obtained by conventional logistic regression or machine learning-based logistic regression. Precision, recall, and F1-score also showed the high accuracy in the deep learning model. Blood alanine aminotransferase (ß = 12.2035) level showed the highest regression coefficient followed by blood aspartate aminotransferase (ß = 11.771) level, waist circumference (ß = 10.8555), body mass index (ß = 10.3842), and blood glycated hemoglobin (ß = 10.1802) level. Fats (cholesterol [ß = -2.0545] and saturated fatty acid [ß = -2.0483]) showed high regression coefficients among nutrient intakes. The deep learning model for classification and prediction on MetS showed a higher accuracy than conventional logistic regression or machine learning-based logistic regression.

Recombinant human KAI1/CD82 attenuates M1 macrophage polarization on LPS-stimulated RAW264.7 cells via blocking TLR4/JNK/NF-κB signal pathway.

KAI1/CD82, a membrane tetraspanin protein, can prevent various cancers and retinal disorders through its anti-angiogenic and anti-metastatic capacity. However, little is known about its anti-inflammatory effect and molecular mechanism. Therefore, the present study aimed to inLPSvestigate effect of a recombinant protein of the large extracellular domain of human KAI1 (Gly 111-Leu 228, rhKAI1) on lipopolysaccharides (LPS)-stimulated RAW264.7 macrophage-like cells and mouse bone marrow-derived macrophages (BMDM) and to identify its underlying mechanism. Our data showed that rhKAI1 suppressed expression levels of classically macrophages (M1) phenotyperelated surface markers F4/80+CD86+ in LPS-stimulated BMDM and RAW264.7 cells. In addition, LPS markedly increased mRNA expression and release levels of pro-inflammatory cytokines and mediators such as interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, cyclooxygenase-2, nitric oxide and prostaglandin E2, whereas these increases were substantially down-regulated by rhKAI1. Furthermore, LPS strongly increased expression of NF-κB p65 in the nuclei and phosphorylation of ERK, JNK, and p38 MAPK. However, nuclear translocation of NF-κB p65 and phosphorylation of JNK were greatly reversed in the presence of rhKAI1. Especially, rhKAI1 markedly suppressed expression of toll-like receptor (TLR4) and prevented binding of LPS with TLR4 through molecular docking predict analysis. Importantly, Glu 214 of rhKAI1 residue strongly interacted with Lys 360 of TLR4 residue, with a binding distance of 2.9 Å. Taken together, these findings suggest that rhKAI1 has an anti-inflammatory effect on LPS-polarized macrophages by interacting with TLR4 and down-regulating the JNK/NF-κB signaling pathway. [BMB Reports 2023; 56(6): 359-364].

Long-term efficacy and safety of intravenous injection of clonal mesenchymal stem cells derived from bone marrow in five adults with moderate to severe atopic dermatitis.

Atopic dermatitis is a chronic and relapsing inflammatory skin disease that is treated with immunosuppressants. However, long-term use of immunosuppressants may cause toxicity and severe side-effects. To confirm the long-term efficacy and safety of clonal mesenchymal stem cell therapy, we performed investigator-initiated clinical trials and long-term observation in five adult patients with moderate to severe atopic dermatitis that was refractory to conventional treatments. The clinical response assessment values such as Eczema Area and Severity Index (EASI) improved significantly at 16 weeks, and 80% (4/5) of the patients achieved EASI-50 after one or two treatment cycles. Patients were observed for long-term efficacy and safety for an average of 38 weeks (range, 16-86) and showed no serious side-effects. Among the cytokines tested, CCL-17, interleukin (IL)-13, and IL-22 significantly decreased at the end-point of the five participants, two patients who maintained good clinical response over 84 weeks showed increased IL-17 cytokine levels in the blood.

Acrosyringeal variant of extragenital lichen sclerosus et atrophicus.

Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory dermatosis of the anogenital area, and approximately 15% to 20% of patients with LSA have extragenital lesions. Here, we report the case of an 18-year-old Korean man presenting with multiple asymptomatic punctated hypopigmented atrophic macules on the dorsa of both feet. Dermoscopic examination revealed hypopigmented atrophic macules with several central keratotic plugs. The histopathologic findings indicated LSA but were confined to the acrosyringium. Based on the clinical and histopathological findings, the patient was diagnosed with an acrosyringeal variant of extragenital LSA. The patient in this case showed a unique histopathological finding in which the typical features of LSA were confined to the acrosyringium, as well as an unusual clinical presentation of non-coalescing atrophic punctate macules on the dorsum of the feet.

Significant relationship between temporal hair loss and other scalp areas in female pattern hair loss.

Female pattern hair loss affects the central scalp, sparing the frontal hairline. The temporal area can also be affected by hair loss. We investigated the degree of temporal hair loss and correlation of other sites of scalp hair loss in Korean female pattern hair loss patients. A total of 109 women with female pattern hair loss were enrolled in this retrospective analysis. We measured hair density and thickness in five scalp sites including the frontal, vertex, occipital and bilateral temporal areas by phototrichogram. Frontal and vertex area hair loss were classified according to the Basic and Specific (BASP) classification, and temporal scalp and occiput areas were also assessed. Eighty-nine patients showed temporal hair loss. The mean of the hair density was lowest in the temporal area among all scalp areas. Total and thick hair densities of the frontal scalp were correlated with those of the vertex, temporal scalp and occiput in descending order, and hair thickness of the frontal scalp was more related with that of the temporal scalp than the vertex. In this study, temporal involvement is evident in female pattern hair loss. We suggest that temporal involvement should be added to pattern hair loss classification, especially BASP classification.

Intraindividual comparison of psychophysical parameters between perimodiolar and lateral-type electrode arrays in patients with bilateral cochlear implants.

OBJECTIVE: Perimodiolar electrode arrays were developed to improve stimulation of specific neuronal populations and to decrease power consumption; however, they can damage the cochlear structure. We examined and compared psychophysical parameters of perimodiolar and lateral-type electrode arrays in patients who received a different type of bilateral cochlear implant (CI) in each ear. STUDY DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENTS: Eight child patients (three males, five females) received a different CI in each ear (perimodiolar array and lateral array). They received the CIs sequentially (n = 7) or simultaneously (n = 1). INTERVENTIONS: Diagnostic, therapeutic, and rehabilitative. MAIN OUTCOME MEASURES: Electrically evoked compound action potential, threshold level, comfort level, and dynamic range (DR) of the basal, mid, and apical electrodes were compared. We also surveyed battery consumption for each device. RESULTS: Electrically evoked compound action potential threshold, threshold level, and comfort level were lower for the perimodiolar-type electrode array than for the lateral-type electrode array in most patients. However, the DR for the perimodiolar array was narrower than for the lateral array. For most patients, there was little difference in battery life. CONCLUSION: Although the level of electrical energy required for auditory stimulation seems to be lower for the perimodiolar electrode array than for the laterally placed array, the DR was wider and the amount of battery consumption was similar. The electrode array should be chosen by considering various patient factors, such as residual hearing.

Identification of differentially expressed genes by gabapentin in cultured dorsal root ganglion in a rat neuropathic pain model.

Neuropathic pain is a chronic pain disorder caused by nervous system lesions as a direct consequence of a lesion or by disease of the portions of the nervous system that normally signal pain. The spinal nerve ligation (SNL) model in rats that reflect some components of clinical pain have played a crucial role in the understanding of neuropathic pain. To investigate the direct effects of gabapentin on differential gene expression in cultured dorsal root ganglion (DRG) cells of SNL model rats, we performed a differential display reverse transcription-polymerase chain reaction analysis with random priming approach using annealing control primer. Genes encoding metallothionein 1a, transforming growth factor-ß1 and palmitoyl-protein thioesterase-2 were up-regulated in gabapentin-treated DRG cells of SNL model rats. The functional roles of these differentially expressed genes were previously suggested as neuroprotective genes. Further study of these genes is expected to reveal potential targets of gabapentin.

Bimodal benefits on objective and subjective outcomes for adult cochlear implant users.

BACKGROUND AND OBJECTIVES: Given that only a few studies have focused on the bimodal benefits on objective and subjective outcomes and emphasized the importance of individual data, the present study aimed to measure the bimodal benefits on the objective and subjective outcomes for adults with cochlear implant. SUBJECTS AND METHODS: Fourteen listeners with bimodal devices were tested on the localization and recognition abilities using environmental sounds, 1-talker, and 2-talker speech materials. The localization ability was measured through an 8-loudspeaker array. For the recognition measures, listeners were asked to repeat the sentences or say the environmental sounds the listeners heard. As a subjective questionnaire, three domains of Korean-version of Speech, Spatial, Qualities of Hearing scale (K-SSQ) were used to explore any relationships between objective and subjective outcomes. RESULTS: Based on the group-mean data, the bimodal hearing enhanced both localization and recognition regardless of test material. However, the inter- and intra-subject variability appeared to be large across test materials for both localization and recognition abilities. Correlation analyses revealed that the relationships were not always consistent between the objective outcomes and the subjective self-reports with bimodal devices. CONCLUSIONS: Overall, this study supports significant bimodal advantages on localization and recognition measures, yet the large individual variability in bimodal benefits should be considered carefully for the clinical assessment as well as counseling. The discrepant relations between objective and subjective results suggest that the bimodal benefits in traditional localization or recognition measures might not necessarily correspond to the self-reported subjective advantages in everyday listening environments.

Rapid and direct detection of apolipoprotein E genotypes using whole blood from humans.

Polymerase chain reaction (PCR) is a powerful molecular biological tool in the field of toxicity testing and diagnostics. The use of PCR for large-scale genetic testing requires an effective method of sample processing. Unfortunately, isolation of PCR-quality DNA is time-consuming. PCR performed directly on whole blood is preferred because of time efficiency, cost of the procedure, and possible automation for large-scale toxicity evaluation and diagnosis. The apolipoprotein E (APOE) gene contains two single-nucleotide polymorphisms (SNP) located at codons 112 and 158, producing three APOE protein isoforms known to be associated with the risks of developing cardiovascular disease and susceptibility to Alzheimer's disease. In the present study, an attempt was made to use the AnyDirect solution for APOE genotyping by PCR using whole blood directly without DNA purification. Results for two PCR methods, (1) conventional PCR using purified DNA and conventional buffer and (2) direct PCR using whole blood and AnyDirect solution, were compared in four different PCR-based APOE genotyping methods including PCR restriction-fragment-length polymorphism (PCR-RFLP), allele-specific PCR, SNaPshot mini-sequencing, and multiplex tetra-primer amplification refractory mutation system (T-ARMS) PCR. There was complete concordance in the APOE genotypes between conventional PCR and direct PCR, in all four different PCR-based APOE genotyping methods. Data demonstrated that the four different PCR-based APOE genotyping methods are able to determine the APOE genotypes successfully using whole blood directly with the use of AnyDirect solution. The direct multiplex T-ARMS PCR using whole blood may be the most rapid, simple, and inexpensive method for detecting APOE genotypes among four different APOE genotyping methods.

Identification of differentially expressed genes in human mesenchymal stem cell-derived neurons.

Mesenchymal stem cells (MSCs) have greater potential for immediate clinical and toxicological applications, due to their ability to self-renew, proliferate, and differentiate into a variety of cell types. To identify novel candidate genes that were specifically expressed during transdifferentiation of human MSCs to neuronal cells, we performed a differential expression analysis with random priming approach using annealing control primer-based differential display reverse transcription-polymerase chain reaction approach. We identified genes for acyl-CoA thioesterase, tissue inhibitor of metalloproteinases-1, brain glycogen phosphorylase, ubiquitin C-terminal hydrolase and aldehyde reductase were up-regualted, whereas genes for transgelin and heparan sulfate proteoglycan were down-regulated in MSC-derived neurons. These differentially expressed genes may have potential role in regulation of neurogenesis. This study could be applied to environmental toxicology in the field of testing the toxicity of a chemical or a physical agent.