GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer's disease mouse model.

GV1001 protects neural cells from amyloid-ß (Aß) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer's disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aß oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aß oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.

Predicting cognitive stage transition using p-tau181, Centiloid, and other measures.

BACKGROUND: A combination of plasma phospho-tau (p-tau), amyloid beta (Aß)-positron emission tomography (PET), brain magnetic resonance imaging, cognitive function tests, and other biomarkers might predict future cognitive decline. This study aimed to investigate the efficacy of combining these biomarkers in predicting future cognitive stage transitions within 3 years. METHODS: Among the participants in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE-V) study, 49 mild cognitive impairment (MCI) and 113 cognitively unimpaired (CU) participants with Aß-PET and brain imaging data were analyzed. RESULTS: Older age, increased plasma p-tau181, Aß-PET positivity, and decreased semantic fluency were independently associated with cognitive stage transitions. Combining age, p-tau181, the Centiloid scale, semantic fluency, and hippocampal volume produced high predictive value in predicting future cognitive stage transition (area under the curve = 0.879). CONCLUSIONS: Plasma p-tau181 and Centiloid scale alone or in combination with other biomarkers, might predict future cognitive stage transition in non-dementia patients. HIGHLIGHTS: -Plasma p-tau181 and Centiloid scale might predict future cognitive stage transition. -Combining them or adding other biomarkers increased the predictive value. -Factors that independently associated with cognitive stage transition were demonstrated.

Fairness-Based Multi-AP Coordination Using Federated Learning in Wi-Fi 7.

Federated learning is a type of distributed machine learning in which models learn by using large-scale decentralized data between servers and devices. In a short-range wireless communication environment, it can be difficult to apply federated learning because the number of devices in one access point (AP) is small, which can be small enough to perform federated learning. Therefore, it means that the minimum number of devices required to perform federated learning cannot be matched by the devices included in one AP environment. To do this, we propose to obtain a uniform global model regardless of data distribution by considering the multi-AP coordination characteristics of IEEE 802.11be in a decentralized federated learning environment. The proposed method can solve the imbalance in data transmission due to the non-independent and identically distributed (non-IID) environment in a decentralized federated learning environment. In addition, we can also ensure the fairness of multi-APs and determine the update criteria for newly elected primary-APs by considering the learning training time of multi-APs and energy consumption of grouped devices performing federated learning. Thus, our proposed method can determine the primary-AP according to the number of devices participating in the federated learning in each AP during the initial federated learning to consider the communication efficiency. After the initial federated learning, fairness can be guaranteed by determining the primary-AP through the training time of each AP. As a result of performing decentralized federated learning using the MNIST and FMNIST dataset, the proposed method showed up to a 97.6% prediction accuracy. In other words, it can be seen that, even in a non-IID multi-AP environment, the update of the global model for federated learning is performed fairly.

L-Type Ca2+ Channel Inhibition Rescues the LPS-Induced Neuroinflammatory Response and Impairments in Spatial Memory and Dendritic Spine Formation.

Ca2+ signaling is implicated in the transition between microglial surveillance and activation. Several L-type Ca2+ channel blockers (CCBs) have been shown to ameliorate neuroinflammation by modulating microglial activity. In this study, we examined the effects of the L-type CCB felodipine on LPS-mediated proinflammatory responses. We found that felodipine treatment significantly diminished LPS-evoked proinflammatory cytokine levels in BV2 microglial cells in an L-type Ca2+ channel-dependent manner. In addition, felodipine leads to the inhibition of TLR4/AKT/STAT3 signaling in BV2 microglial cells. We further examined the effects of felodipine on LPS-stimulated neuroinflammation in vivo and found that daily administration (3 or 7 days, i.p.) significantly reduced LPS-mediated gliosis and COX-2 and IL-1ß levels in C57BL/6 (wild-type) mice. Moreover, felodipine administration significantly reduced chronic neuroinflammation-induced spatial memory impairment, dendritic spine number, and microgliosis in C57BL/6 mice. Taken together, our results suggest that the L-type CCB felodipine could be repurposed for the treatment of neuroinflammation/cognitive function-associated diseases.

Development of peptide aptamers as alternatives for antibody in the detection of amyloid-beta 42 aggregates.

Alzheimer's disease (AD) causes cognitive impairment and serious social isolation. However, there are no effective treatments and even no established confirmatory diagnostic tools for the disease. Amyloid beta (Aß) aggregation in the brain is the best-known pathognomonic mechanism of AD, so various methods for Aß detection have been developed for the diagnosis of this disease. We synthesized two novel, ultra-sensitive peptide probes specialized in detecting Aß aggregates, and examined their potential for future diagnostic application. The peptides are produced through phage high-throughput screening (HTS) and amplified through a serial process called biopanning, which is a repeating method of elution and amplification of probes. We picked phages specific for amyloid from two kinds of phage display. The synthesized peptides were confirmed to have excellent binding affinity to Aß aggregates, by immunohistochemical staining and western blotting using the brains of 3X transgenic (Tg) AD mice at different stages (5-7, 12-17 months old) of AD severity. In the present study, it was confirmed that newly developed amyloid-binding peptides could be used as novel probes for the detection of Aß aggregates, which can be used for clinical diagnosis of AD in the future.

Micro-RNAs in the aqueous humour of patients with diabetic macular oedema.

IMPORTANCE: Micro-RNAs (miRNAs) have been studied as new biomarkers or mediators in various diseases, but the value of aqueous humour (AH) miRNAs in diabetic macular oedema (DMO) is still not known. BACKGROUND: To compare AH miRNAs and related cytokine expression in DMO patients and healthy controls. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Twenty naïve DMO patients and 13 control subjects, who were scheduled for intravitreal injection and cataract surgery, respectively. METHODS: AH samples were collected at the beginning of each procedure and analysed using a miRNA polymerase chain reaction (PCR) array composed of 84 miRNAs, reverse transcripase-quantitative PCR (qPCR) for verifying selected differentially expressed miRNAs, and a cytokine assay, the results of which were compared with bioinformatics conducted to find out genes associated with DMO-related miRNAs. MAIN OUTCOMES MEASURES: AH expression of miRNAs and cytokines and the bioinformatics results. RESULTS: Five miRNAs (hsa-miR-185-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-15b-5p and hsa-miR-15a-5p) showing a fold change greater than -50 in log2 values in the miRNA PCR array were selected, all significantly down-regulated in the DMO group compared to the control group (P < .05), and showed a direct relationship with tumour necrosis factor, nuclear factor kappa B subunit 1 and interleukin-6 (IL-6) in bioinformatics analysis, all of which were related to vascular endothelial growth factor (VEGF). In the cytokine assay, the aqueous concentrations of VEGF, placental growth factor, IL-6 and IL-8 were significantly higher in the DMO group compared to the control group. CONCLUSIONS AND RELEVANCE: This study is the first to perform miRNA profiling of the AH of DMO patients. We identified differentially expressed miRNAs in DMO AH, which may be used as potential biomarkers or novel therapeutic targets for DMO.

Ultrasensitive Fluorescence Detection of Alzheimer's Disease Based on Polyvalent Directed Peptide Polymer Coupled to a Nanoporous ZnO Nanoplatform.

Amyloid-beta 42 (Aß42), the key biomarker of Alzheimer's disease (AD), aggregates to form neurotoxic amyloid plaques. In this work, we modified two fluorescein isothiocyanate-labeled Aß42-targeting peptides and designed an Aß42-specific ultrasensitive polyvalent-directed peptide polymer (PDPP) to enhance AD diagnosis sensitivity. The dissociation constant of Aß42 by PDPP was 103-fold higher than the single-site-directed peptide. The improved binding was due to the ability of PDPP to detect multiple receptors on the target. The power of the PDPP diagnostic probe was verified in its application to detect Aß42 in cerebrospinal fluid (CSF), which showed a lower limit of detection (LOD) in the fg mL-1 range that is more sensitive than detection by antibodies or single peptides. In addition, we present a novel ultrasensitive diagnostic system using an array of nanoporous ZnO nanoparticles, which play a role in fluorescence signal amplification, to further improve AD diagnosis sensitivity. We enhanced the signal on the basis of the properties of nanoporous ZnO nanoparticles and measured and quantified an ultralow concentration (ag mL-1 range) of Aß42. This PDPP coupled to the nanoporous ZnO-based system is a novel approach to AD diagnosis that might also be useful for the detection of other target biomarkers and clinical applications.

Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling.

BACKGROUND: The FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML). However, the effects of dasatinib on microglial and/or astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail. METHODS: BV2 microglial cells, primary astrocytes, or primary microglial cells were treated with dasatinib (100 or 250 nM) or vehicle (1% DMSO) for 30 min or 2 h followed by lipopolysaccharide (LPS; 200 ng/ml or 1 µg/ml) or PBS for 5.5 h. RT-PCR, real-time PCR; immunocytochemistry; subcellular fractionation; and immunohistochemistry were subsequently conducted to determine the effects of dasatinib on LPS-induced neuroinflammation. In addition, wild-type mice were injected with dasatinib (20 mg/kg, intraperitoneally (i.p.) daily for 4 days or 20 mg/kg, orally administered (p.o.) daily for 4 days or 2 weeks) or vehicle (4% DMSO + 30% polyethylene glycol (PEG) + 5% Tween 80), followed by injection with LPS (10 mg/kg, i.p.) or PBS. Then, immunohistochemistry was performed, and plasma IL-6, IL-1ß, and TNF-α levels were analyzed by ELISA. RESULTS: Dasatinib regulates LPS-induced proinflammatory cytokine and anti-inflammatory cytokine levels in BV2 microglial cells, primary microglial cells, and primary astrocytes. In BV2 microglial cells, dasatinib regulates LPS-induced proinflammatory cytokine levels by regulating TLR4/AKT and/or TLR4/ERK signaling. In addition, intraperitoneal injection and oral administration of dasatinib suppress LPS-induced microglial/astrocyte activation, proinflammatory cytokine levels (including brain and plasma levels), and neutrophil rolling in the brains of wild-type mice. CONCLUSIONS: Our results suggest that dasatinib modulates LPS-induced microglial and astrocytic activation, proinflammatory cytokine levels, and neutrophil rolling in the brain.

Red Ginseng Attenuates Aß-Induced Mitochondrial Dysfunction and Aß-mediated Pathology in an Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aß) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aß-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aß-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aß accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aß-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aß deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

International Nursing: Use of a Commercially Available Smartphone Application to Solve Information Needs of Orthopedic Scrub Nurses.

The purpose of this article is to describe the use of a commercially available smartphone application to solve information needs of scrub nurses in orthopedic surgery. A semistructured, focus group interview was conducted with orthopedic scrub nurses. These nurses had solved their information needs about orthopedic surgery by using a commercially available smartphone application. Because of smartphone technology's convenience, accessibility, mobility, ease of use, and use at no charge, it is worth considering in nursing practice, education, and research.

Effects of aspirin and clopidogrel on neural stem cells.

Cerebral infarction causes severe morbidity and mortality. Most patients with cerebral infarction should take antiplatelet drugs daily, so the effects of those drugs on the regeneration of the brain need to be investigated. Aspirin and clopidogrel are the most widely used antiplatelet drugs for the prevention of ischemic stroke. We investigated the effects of aspirin and clopidogrel on neural stem cells (NSCs). NSCs were dissociated from fetal rat cortex and cultured with basic fibroblast growth factor and N2 medium. To measure the effects of aspirin and clopidogrel on NSCs, NSCs were treated with several concentrations of aspirin, clopidogrel bisulfate, and clopidogrel resinate for 24 h. After the treatment, we measured cell viability by cell counting kit-8, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, flow cytometry, and lactate dehydrogenase assay. To evaluate their effects on NSC proliferation, we performed BrdU cell proliferation assay and colony-forming unit assay. We compared the intracellular protein level in the NSCs treated with aspirin and two types of clopidogrel, by proteomics analysis. Various viability tests showed that clopidogrel resinate and clopidogrel bisulfate did not affect the viability and proliferation of NSCs whereas aspirin decreased them even at low concentrations which are clinically relevant. Moreover, through the proteomics, it was confirmed that the toxicity of aspirin to NSCs might be associated with the alteration of several intracellular proteins. Taken together, these results suggest that clopidogrel resinate and clopidogrel bisulfate are safe but aspirin could be toxic to NSCs. Therefore, when these antiplatelet agents are prescribed over the long-term, the finding that aspirin could be toxic to NSCs should be considered.

Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal.

Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca(2+) concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca(2+) levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death.

Activation of the phosphatidylinositol 3-kinase pathway plays important roles in reduction of cerebral infarction by cilnidipine.

Cerebral infarction causes permanent neuronal loss inducing severe morbidity and mortality. Because hypertension is the main risk factor for cerebral infarction and most patients with hypertension take antihypertensive drugs daily, the neuroprotective effects and mechanisms of anti-hypertensive drugs need to be investigated. Cilnidipine, a long-acting, new generation 1,4-dihydropyridine inhibitor of both L- and N-type calcium channels, was reported to reduce oxidative stress. In this study, we investigated whether cilnidipine has therapeutic effects in an animal model of cerebral infarction. After determination of the most effective dose of cilnidipine, a total of 128 rats were subjected to middle cerebral artery occlusion. Neurobehavioral function test and brain MRI were performed, and rats with similar sized infarcts were randomized to either the cilnidipine group or the control group. Cilnidipine treatment was performed with reperfusion after 2-h occlusion. Western blots and immunohistochemistry were also performed after 24-h occlusion. Initial infarct volume on diffusion-weighted MRI was not different between the cilnidipine group and the control group; however, fluid-attenuated inversion recovery MRI at 24 h showed significantly reduced infarct volume in the cilnidipine group compared with the control group. Cilnidipine treatment significantly decreased the number of triphosphate nick end labeling-positive cells compared to the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3ß, and Bcl-2 and decreased expression of Bax and cleaved caspase-3. These results suggest that cilnidipine, which is used for the treatment of hypertension, has neuroprotective effects in the ischemic brain through activation of the PI3K pathway. We investigated whether cilnidipine has neuroprotective effects on ischemic stroke in an animal model. We have demonstrated that the neuroprotective effect of cilnidipine is associated with the activation of the PI3K pathway. Considering the daily use of antihypertensive drugs for patients with hypertension, cilnidipine could be beneficial for patients with ischemic stroke.

Increased VEGF and decreased SDF-1α in patients with silent brain infarction are associated with better prognosis after first-ever acute lacunar stroke.

BACKGROUND: Pre-existing silent brain infarctions (SBIs) have been reported to be associated with better outcomes after first-ever symptomatic ischemic stroke, although the mechanism of this remains unclear. We investigated the association between SBIs, outcomes of acute lacunar infarction, and biomarkers including vascular endothelial growth factor (VEGF), stromal cell-derived factor-1α (SDF-1α), macrophage migration inhibitory factor (MIF), and high-mobility group box-1 (HMGB1). METHODS: A total of 68 consecutive patients diagnosed with first-ever lacunar infarction (<20 mm) within 24 hours of symptom onset were included in this study. Clinical, laboratory, and imaging data were obtained. Plasma levels of VEGF, SDF-1α, MIF, and HMGB1 were assessed using Enzyme-Linked Immunosorbent Assay kits. RESULTS: SBIs were noted in 31 of the 68 patients. Although the initial National Institutes of Health Stroke Scale scores were not related with the presence of SBIs (P = .313), patients with SBIs had better outcomes at 3 months (P = .029). Additionally, plasma VEGF levels were higher (P = .035) and SDF-1α levels were lower (P < .001) in patients with SBIs. Logistic regression analysis indicated that VEGF and SDF-1α were independently associated with the presence of SBIs. CONCLUSIONS: SBIs are associated with favorable outcomes in patients with first-ever acute lacunar infarction and higher levels of VEGF, and lower levels of SDF-1α in these patients may contribute to their more favorable prognosis.

GV1001 reduces neurodegeneration and prolongs lifespan in 3xTg-AD mouse model through anti-aging effects.

GV1001, which mimics the activity of human telomerase reverse transcriptase, protects neural cells from amyloid beta (Aß) toxicity and other stressors through extra-telomeric function, as noted in our prior in vitro studies. As per a recent phase II clinical trial, it improves cognitive function in patients with moderate to severe dementia. However, the underlying protective mechanisms remain unclear. This study aimed to investigate the effects of GV1001 on neurodegeneration, senescence, and survival in triple transgenic Alzheimer's disease (3xTg-AD) mice. GV1001 (1 mg/kg) was subcutaneously injected into old 3xTg-AD mice thrice a week until the endpoint for sacrifice, and survival was analysed. Magnetic resonance imaging (MRI) and Prussian blue staining (PBS) were performed to evaluate entry of GV1001 entrance into the brain. Diverse molecular studies were performed to investigate the effect of GV1001 on neurodegeneration and cellular senescence in AD model mice, with a particular focus on BACE, amyloid beta1-42 (Aß1-42), phosphorylated tau, volume of dentate gyrus, ß-galactosidase positive cells, telomere length, telomerase activity, and ageing-associated proteins. GV1001 crossed the blood-brain barrier, as confirmed by assessing the status of ferrocenecarboxylic acid-conjugated GV1001 using magnetic resonance imaging and PBS. GV1001 increased the survival of 3xTg-AD mice. It decreased BACE and Aß1-42 levels, neurodegeneration (i.e., reduced CA1, CA3 and dentate gyrus volume, decreased levels of senescence-associated ß-galactosidase positive cells, and increased telomere length and telomerase activity), and levels of ageing-associated proteins. We suggest that GV1001 exerts anti-ageing effects in 3xTg-AD mice by reducing neurodegeneration and senescence, which contributes to improved survival.

Association between osteoporosis and the rate of telomere shortening.

A shorter leukocyte telomere length (LTL) is reported to be associated with age-related diseases, including osteoporosis. Many studies have tried identifying the association between LTL and osteoporosis, although it remains controversial. This study aimed to determine whether osteoporosis is independently associated with LTL shortening in a prospective longitudinal cohort. The KBASE study is an independent multicenter prospective cohort in South Korea, which began in 2014. We compared the LTL values for each participant at baseline and over a 2-year follow-up period. Boxplots were used to demonstrate the differences in the change in LTL over a 2-year follow-up according to osteoporosis. Multivariable linear regression was conducted to identify whether osteoporosis is independently associated with the rate of telomere shortening. A total of 233 subjects (from 55 to 88 years) from the KBASE cohort were finally enrolled in the study. We observed that the LTL decreased by approximately 1.2 kbp over 2 years. While the LTL decreased as age increased, the rate of LTL shortening did not increase with age. Multivariable linear regression analysis indicated that only osteoporosis was independently associated with rapid LTL shortening over 2 years (B, -8.08; p = 0.038). We sought to identify an association between osteoporosis and LTL shortening in an independent prospective cohort. We found that participants with osteoporosis had significantly faster LTL shortening over 2 years than those without osteoporosis. We hope this study will help elucidate the underlying mechanisms in the relationship between LTL and osteoporosis in the future.

Development of the Korean construction job exposure matrix (KoConJEM) based on experts' judgment using the 60 consolidated occupations for construction workers.

BACKGROUND: This study was conducted as an effort to develop a Korean construction job exposure matrix (KoConJEM) based on 60 occupations recently consolidated by the construction workers mutual aid association for use by the construction industry. METHODS: The probability, intensity, and prevalence of exposure to 26 hazardous agents for 60 consolidated occupations were evaluated as binary (Yes/No) or four categories (1 to 4) by 30 industrial hygiene experts. The score for risk was calculated by multiplying the exposure intensity by the prevalence of exposure. Fleiss' kappa for each hazardous agent and occupation was used to determine agreement among the 30 experts. The JEM was expressed on a heatmap and a web-based dashboard to facilitate comparison of factors affecting exposure according to each occupation and hazardous agent. RESULTS: Awkward posture, heat/cold, heavy lifting, and noise were hazardous agents regarded as exposure is probable by at least one or more experts in all occupations, while exposure to asphalt fumes was considered hazardous in the smallest number of occupations (n = 5). Based on the degree of agreement among experts, more than half of the harmful factors and most occupations showed fair to good results. The highest risk value was 16 for awkward posture for most occupations other than safety officer. CONCLUSIONS: The KoConJEM provides information on the probability, intensity, and prevalence of exposure to harmful factors, including most occupations employing construction workers; therefore, it may be useful in the conduct of epidemiological studies on assessment of health risk for construction workers.

Relationship between telomere shortening and early subjective depressive symptoms and cognitive complaints in older adults.

Telomere length (TL) has been reported to be associated with depression and cognitive impairment in elderly. Early detection of depression and cognitive impairment is important to delay disease progression. Therefore, we aimed to identify whether TL is associated with early subjective depressive symptoms and cognitive complaints among healthy elderly subjects. This study was a multicenter, outcome assessor-blinded, 24-week, randomized controlled trial (RCT). Measurement of questionnaire and physical activity scores and blood sample analyses were performed at baseline and after six months of follow-up in all study participants. Linear regression analyses were performed to identify whether early subjective depressive symptoms, cognitive complaints, and several blood biomarkers are associated with TL. Altogether, 137 relatively healthy elderly individuals (60-79 years old) were enrolled in this prospective RCT. We observed an approximate decrease of 0.06 and 0.11-0.14 kbps of TL per one point increase in the geriatric depression scale and cognitive complaint interview scores, respectively, at baseline and after six months of follow-up. We also found an approximate decrease of 0.08-0.09 kbps of TL per one point increase in interleukin (IL)-6 levels at baseline and after six months of follow-up. Our study showed that both early subjective depressive symptoms and cognitive complaints were associated with a relatively shorter TL in relatively healthy elderly individuals. In addition, based on our findings, we believe that IL-6 plays an important role in the relationship between shortening TL and early subjective depressive symptoms and cognitive complaints.

Predicting amyloid PET positivity using plasma p-tau181 and other blood-based biomarkers.

Introduction: This study aimed to determine the efficacy of combining plasma phosphorylated tau (p-tau)181, amyloid beta (Aß)42/Aß40, neurofilament light (NfL), and apolipoprotein E (APOE) genotypes for detecting positive amyloid positron emission tomography (PET), which is little known in the Asian population, in two independent cohorts. Methods: Biomarkers were measured using a single-molecule array (Simoa) in a cohort study (Asan). All participants underwent amyloid PET. Significant changes in the area under the curve (AUC) and Akaike Information Criterion values were considered to determine the best model. The generalizability of this model was tested using another cohort (KBASE-V). Results: In the Asan cohort, after adjusting for age and sex, p-tau181 (AUC = 0.854) or APOE ε4 status (AUC = 0.769) distinguished Aß status with high accuracy. Combining them or adding NfL and Aß42/40 improved model fitness. The best-fit model included the plasma p-tau181, APOE ε4, NfL and Aß42/40. The models established from the Asan cohort were tested in the KBASE-V cohort. Additionally, in the KBASE-V cohort, these three biomarker models had similar AUC in cognitively unimpaired (AUC = 0.768) and mild cognitive impairment (MCI) (AUC = 0.997) participants. Conclusions: Plasma p-tau181 showed a high performance in determining Aß-PET positivity. Adding plasma NfL and APOE ε4 status improved the model fit without significant improvement in AUC.

Differential expression of aqueous humor microRNAs in central retinal vein occlusion and its association with matrix metalloproteinases: a pilot study.

The aim of this study is to investigate the differential expression of microRNAs (miRNAs) in the aqueous humor (AH) of patients with central retinal vein occlusion (CRVO), and their association with AH matrix metalloproteinase (MMP) activity. Eighteen subjects, including 10 treatment naïve patients with CRVO and 8 control subjects, scheduled for intravitreal injection and cataract surgery, respectively, were included. AH samples were collected at the beginning of the procedure. A microarray composed of 84 miRNAs was performed to identify differentially expressed miRNAs in CRVO AH, which were further analyzed using bioinformatic tools to identify directly related cytokines/proteins. Eight miRNAs (hsa-mir-16-5p, hsa-mir-142-3p, hsa-mir-19a-3p, hsa-mir-144-3p, hsa-mir-195-5p, hsa-mir-17-5p, hsa-mir-93-5p, and hsa-mir-20a-5p) were significantly downregulated in the CRVO group. Bioinformatic analysis revealed a direct relationship among downregulated miRNAs, CRVO, and the following proteins: MMP-2, MMP-9, tumor necrosis factor, transforming growth factor beta-1, caspase-3, interleukin-6, interferon gamma, and interleukin-1-beta. Activities of MMP-2 and -9 in AH were detected using gelatin zymography, showing significant increase in the CRVO group compared to the control group (p < 0.01). This pilot study first revealed that MMP-2 and -9 were directly related to downregulated miRNAs and showed significant increase in activity in AH of patients with CRVO. Therefore, the relevant miRNAs and MMPs in AH could serve as potential biomarkers or therapeutic targets for CRVO.