Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival.

Previous experiments suggest a connection between the N-alpha-acetylation of proteins and sensitivity of cells to apoptotic signals. Here, we describe a biochemical assay to detect the acetylation status of proteins and demonstrate that protein N-alpha-acetylation is regulated by the availability of acetyl-CoA. Because the antiapoptotic protein Bcl-xL is known to influence mitochondrial metabolism, we reasoned that Bcl-xL may provide a link between protein N-alpha-acetylation and apoptosis. Indeed, Bcl-xL overexpression leads to a reduction in levels of acetyl-CoA and N-alpha-acetylated proteins in the cell. This effect is independent of Bax and Bak, the known binding partners of Bcl-xL. Increasing cellular levels of acetyl-CoA by addition of acetate or citrate restores protein N-alpha-acetylation in Bcl-xL-expressing cells and confers sensitivity to apoptotic stimuli. We propose that acetyl-CoA serves as a signaling molecule that couples apoptotic sensitivity to metabolism by regulating protein N-alpha-acetylation.

Periodontitis promotes bacterial extracellular vesicle-induced neuroinflammation in the brain and trigeminal ganglion.

Gram-negative bacteria derived extracellular vesicles (EVs), also known as outer membrane vesicles, have attracted significant attention due to their pathogenic roles in various inflammatory diseases. We recently demonstrated that EVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) can cross the blood-brain barrier (BBB) and that their extracellular RNA cargo can promote the secretion of proinflammatory cytokines, such as IL-6 and TNF-α, in the brain. To gain more insight into the relationship between periodontal disease (PD) and neuroinflammatory diseases, we investigated the effect of Aa EVs in a mouse model of ligature-induced PD. When EVs were administered through intragingival injection or EV-soaked gel, proinflammatory cytokines were strongly induced in the brains of PD mice. The use of TLR (Toll-like receptor)-reporter cell lines and MyD88 knockout mice confirmed that the increased release of cytokines was triggered by Aa EVs via TLR4 and TLR8 signaling pathways and their downstream MyD88 pathway. Furthermore, the injection of EVs through the epidermis and gingiva resulted in the direct retrograde transfer of Aa EVs from axon terminals to the cell bodies of trigeminal ganglion (TG) neurons and the subsequent activation of TG neurons. We also found that the Aa EVs changed the action potential of TG neurons. These findings suggest that EVs derived from periodontopathogens such as Aa might be involved in pathogenic pathways for neuroinflammatory diseases, neuropathic pain, and other systemic inflammatory symptoms as a comorbidity of periodontitis.

Functional modulation of lysophosphatidic acid type 2 G-protein coupled receptor facilitates alveolar bone formation.

Lipid biosynthesis is recently studied its functions in a range of cellular physiology including differentiation and regeneration. However, it still remains to be elucidated in its precise function. To reveal this, we evaluated the roles of lysophosphatidic acid (LPA) signaling in alveolar bone formation using the LPA type 2 receptor (LPAR2) antagonist AMG-35 (Amgen Compound 35) using tooth loss without periodontal disease model which would be caused by trauma and usually requires a dental implant to restore masticatory function. In this study, in vitro cell culture experiments in osteoblasts and periodontal ligament fibroblasts revealed cell type-specific responses, with AMG-35 modulating osteogenic differentiation in osteoblasts in vitro. To confirm the in vivo results, we employed a mouse model of tooth loss without periodontal disease. Five to 10 days after tooth extraction, AMG-35 facilitated bone formation in the tooth root socket as measured by immunohistochemistry for differentiation markers KI67, Osteocalcin, Periostin, RUNX2, transforming growth factor beta 1 (TGF-ß1) and SMAD2/3. The increased expression and the localization of these proteins suggest that AMG-35 elicits osteoblast differentiation through TGF-ß1 and SMAD2/3 signaling. These results indicate that LPAR2/TGF-ß1/SMAD2/3 represents a new signaling pathway in alveolar bone formation and that local application of AMG-35 in traumatic tooth loss can be used to facilitate bone regeneration and healing for further clinical treatment.

Frailty is not an independent risk factor for worse clinical outcomes in lumbar spinal surgery: a prospective cohort study.

PURPOSE: Recently, many studies revealed that frailty affects unfavorably on postoperative outcomes in lumbar spinal diseases. This study aimed to investigate the relationship between frailty and clinical outcomes while identifying risk factors associated with worse clinical outcomes following lumbar spinal surgery. METHODS: From March 2019 to February 2021, we prospectively enrolled eligible patients with degenerative lumbar spinal diseases requiring surgery. Frailty was assessed preoperatively. To identify the impact of frailty on lumbar spinal diseases, clinical outcomes, which were measured with patient-reported outcomes (PROs) and postoperative complications, were compared according to the frailty. PROs were assessed preoperatively and one year postoperatively. In addition, risk factors for preoperative and postoperative worse clinical outcomes were investigated. RESULTS: PROs were constantly lower in the frail group than in the non-frail group before and after surgery, and the change of PROs between before and after surgery and postoperative complications were not different between the groups. In addition, frailty was a persistent risk factor for postoperative worse clinical outcome before and after surgery in lumbar spinal surgery. CONCLUSION: Frailty persistently affects the clinical outcome negatively before and after surgery in lumbar spinal surgery. However, as the change of the clinical outcome is not different between the frail group and the non-frail group, it is difficult to interpret whether the frail patients are vulnerable to the surgery. In conclusion, frailty is not an independent risk factor for worse clinical outcome in lumbar spinal surgery.

Depression of Synaptic N-methyl-D-Aspartate Responses by Xenon and Nitrous Oxide.

In "synapse bouton preparation" of rat hippocampal CA3 neurons, we examined how Xe and N2O modulate N-methyl-D-aspartate (NMDA) receptor-mediated spontaneous and evoked excitatory post-synaptic currents (sEPSCNMDA and eEPSCNMDA). This preparation is a mechanically isolated single neuron attached with nerve endings (boutons) preserving normal physiologic function and promoting the exact evaluation of sEPSCNMDA and eEPSCNMDA responses without influence of extrasynaptic, glial, and other neuronal tonic currents. These sEPSCs and eEPSCs are elicited by spontaneous glutamate release from many homologous glutamatergic boutons and by focal paired-pulse electric stimulation of a single bouton, respectively. The s/eEPSCAMPA/KA and s/eEPSCNMDA were isolated pharmacologically by their specific antagonists. Thus, independent contributions of pre- and postsynaptic responses could also be quantified. All kinetic properties of s/eEPSCAMPA/KA and s/eEPSCNMDA were detected clearly. The s/eEPSCNMDA showed smaller amplitude and slower rise and 1/e decay time constant (τ Decay) than s/eEPSCAMPA/KA Xe (70%) and N2O (70%) significantly decreased the frequency and amplitude without altering the τ Decay of sEPSCNMDA They also decreased the amplitude but increased the Rf and PPR without altering the τ Decay of the eEPSCNMDA These data show clearly that "synapse bouton preparation" can be an accurate model for evaluating s/eEPSCNMDA Such inhibitory effects of gas anesthetics are primarily due to presynaptic mechanisms. Present results may explain partially the powerful analgesic effects of Xe and N2O. SIGNIFICANCE STATEMENT: We could record pharmacologically isolated NMDA receptor-mediated spontaneous and (action potential-evoked) excitatory postsynaptic currents (sEPSCNMDA and eEPSCNMDA) and clearly detect all kinetic parameters of sEPSCNMDA and eEPSCNMDA at synaptic levels by using "synapse bouton preparation" of rat hippocampal CA3 neurons. We found that Xe and N2O clearly suppressed both sEPSCNMDA and eEPSCNMDA. Different from previous studies, present results suggest that Xe and N2O predominantly inhibit the NMDA responses by presynaptic mechanisms.

Protein Kinase A Is Responsible for the Presynaptic Inhibition of Glycinergic and Glutamatergic Transmissions by Xenon in Rat Spinal Cord and Hippocampal CA3 Neurons.

The effects of a general anesthetic xenon (Xe) on spontaneous, miniature, electrically evoked synaptic transmissions were examined using the "synapse bouton preparation," with which we can clearly evaluate pure synaptic responses and accurately quantify pre- and postsynaptic transmissions. Glycinergic and glutamatergic transmissions were investigated in rat spinal sacral dorsal commissural nucleus and hippocampal CA3 neurons, respectively. Xe presynaptically inhibited spontaneous glycinergic transmission, the effect of which was resistant to tetrodotoxin, Cd2+, extracellular Ca2+, thapsigargin (a selective sarcoplasmic/endoplasmic reticulum Ca2+-ATPase inhibitor), SQ22536 (an adenylate cyclase inhibitor), 8-Br-cAMP (membrane-permeable cAMP analog), ZD7288 (an hyperpolarization-activated cyclic nucleotide-gated channel blocker), chelerythrine (a PKC inhibitor), and KN-93 (a CaMKII inhibitor) while being sensitive to PKA inhibitors (H-89, KT5720, and Rp-cAMPS). Moreover, Xe inhibited evoked glycinergic transmission, which was canceled by KT5720. Like glycinergic transmission, spontaneous and evoked glutamatergic transmissions were also inhibited by Xe in a KT5720-sensitive manner. Our results suggest that Xe decreases glycinergic and glutamatergic spontaneous and evoked transmissions at the presynaptic level in a PKA-dependent manner. These presynaptic responses are independent of Ca2+ dynamics. We conclude that PKA can be the main molecular target of Xe in the inhibitory effects on both inhibitory and excitatory neurotransmitter release. SIGNIFICANCE STATEMENT: Spontaneous and evoked glycinergic and glutamatergic transmissions were investigated using the whole-cell patch clamp technique in rat spinal sacral dorsal commissural nucleus and hippocampal CA3 neurons, respectively. Xenon (Xe) significantly inhibited glycinergic and glutamatergic transmission presynaptically. As a signaling mechanism, protein kinase A was responsible for the inhibitory effects of Xe on both glycine and glutamate release. These results may help understand how Xe modulates neurotransmitter release and exerts its excellent anesthetic properties.

Development and Verification of a Diagnostic Technology for Waste Battery Deterioration Factors.

We defined four major deterioration factors (electrolyte loss (EL), lithium loss (LL), lithium precipitation (LP), and compound deterioration (CD)). Then, we derived eleven key performance indicators (KPIs) for comparative analysis. After that, we fabricated three deteriorated cells for each of three deterioration factors (EL, LL, and LP) and one cell with CD (for verification) with four individual (dis)charging experiment manuals. The two major contributions of this study are the performance of 1) trend analysis to determine a suitable diagnostic metric by inspecting the eleven KPIs and 2) comparison analysis of V o c v , t ' ' ${{V}_{ocv,t}^{{ {^\prime} {^\prime}}}}$ and V o c v , t , s i m ' ' ${{V}_{ocv,t,sim}^{{ {^\prime} {^\prime}}}}$ to verify the effectiveness of utilizing V o c v , t ' ' ${{V}_{ocv,t}^{{ {^\prime} {^\prime}}}}$ as a real-time deterioration diagnostic factor using a concept of model-in-the-loop simulation. The results show that 1) V o c v , t ' ' ${{V}_{ocv,t}^{{ {^\prime} {^\prime}}}}$ has the most conspicuous trendline tendency among the eleven comparison targets for all four major deterioration factors, and 2) the angle difference between the two trends of V o c v , t ' ' ${{V}_{ocv,t}^{{ {^\prime} {^\prime}}}}$ and V o c v , t , s i m ' ' ${{V}_{ocv,t,sim}^{{ {^\prime} {^\prime}}}}$ lies within a minimum of 9° and a maximum of 43° (with a 10 4 ${{10}^{4}}$ sscale on the x-axis and a 10 - 7 ${{10}^{-7}}$ scale on the y-axis for a clear trend line analysis). From this, we can conclude that the trendline-based real-time deterioration analysis employing V o c v , t ' ' ${{V}_{ocv,t}^{{ {^\prime} {^\prime}}}}$ may be practically applicable to a limited extent.

Relationship between asthma and sarcopenia in the elderly: a nationwide study from the KNHANES.

OBJECTIVE: Few studies have investigated the relationship between asthma and sarcopenia. We aimed to examine the relationship between asthma and sarcopenia in a community-dwelling geriatric population, especially regarding lung function and asthma control. METHODS: A cross-sectional dataset from the Korean National Health and Nutrition Examination Survey 2008-2011 was utilized. Data regarding asthma history, age at asthma onset, recent asthma exacerbations, and hospitalization for asthma exacerbations were obtained using structured questionnaires. Appendicular skeletal muscle was calculated as the sum of the skeletal muscle mass, and physical activity was assessed using the International Physical Activity Questionnaire. RESULTS: Asthma presented an estimated incidence of 6.17 ± 0.37% in the elderly. Groups were divided and analyzed according to asthma, muscle mass, and physical activity. Sarcopenia was associated with aging, male sex, smoking history, low body mass index (BMI), and reduced lung function with or without asthma. Sarcopenic asthma had a younger onset and reduced physical activity than non-sarcopenic asthma. Obstructive patterns were more frequent in asthmatics exhibiting low or moderate physical activity levels than in those with high activity, but asthma control was not associated with sarcopenia and physical activity. Multivariate logistic regression analyses showed that compared with control, sarcopenic asthma was associated with FEV1 < 60%, and airway obstruction, and with aging, male, and lower BMI, compared with non-sarcopenic asthma. CONCLUSIONS: Our findings suggest that decreased muscle mass and physical activity levels contribute to reduced lung function in elderly asthmatics. Furthermore, sarcopenic asthma was associated with aging, low BMI, and reduced lung function in the elderly.

Trichloroethanol, an active metabolite of chloral hydrate, modulates tetrodotoxin-resistant Na+ channels in rat nociceptive neurons.

BACKGROUND: Chloral hydrate is a sedative-hypnotic drug widely used for relieving fear and anxiety in pediatric patients. However, mechanisms underlying the chloral hydrate-mediated analgesic action remain unexplored. Therefore, we investigated the effect of 2',2',2'-trichloroethanol (TCE), the active metabolite of chloral hydrate, on tetrodotoxin-resistant (TTX-R) Na+ channels expressed in nociceptive sensory neurons. METHODS: The TTX-R Na+ current (INa) was recorded from acutely isolated rat trigeminal ganglion neurons using the whole-cell patch-clamp technique. RESULTS: Trichloroethanol decreased the peak amplitude of transient TTX-R INa in a concentration-dependent manner and potently inhibited persistent components of transient TTX-R INa and slow voltage-ramp-induced INa at clinically relevant concentrations. Trichloroethanol exerted multiple effects on various properties of TTX-R Na+ channels; it (1) induced a hyperpolarizing shift on the steady-state fast inactivation relationship, (2) increased use-dependent inhibition, (3) accelerated the onset of inactivation, and (4) retarded the recovery of inactivated TTX-R Na+ channels. Under current-clamp conditions, TCE increased the threshold for the generation of action potentials, as well as decreased the number of action potentials elicited by depolarizing current stimuli. CONCLUSIONS: Our findings suggest that chloral hydrate, through its active metabolite TCE, inhibits TTX-R INa and modulates various properties of these channels, resulting in the decreased excitability of nociceptive neurons. These pharmacological characteristics provide novel insights into the analgesic efficacy exerted by chloral hydrate.

Clinical and Radiological Outcomes of a Comparative Study of Anterior Cervical Decompression and Fusion with Partial Pediculotomy, Partial Vertebrotomy (PPPV) Posterior Endoscopic Cervical Decompression (PECD) for Cervical Foraminal Pathology.

Background and Objectives: The purpose was to compaSre medium-term clinical and radiological outcomes of Partial Pediculotomy, Partial Vertebrotomy (PPPV) Posterior Endoscopic Cervical Decompression (PECD) surgery versus Anterior Cervical Discectomy and Fusion (ACDF) for patients with cervical disc herniations and foraminal pathologies. Materials and Methods: A prospective registry of patients who had undergone either PPPV PECD surgery or ACDF surgery for cervical disc herniation or foraminal pathologies under a single fellowship-trained spine surgeon was performed. The baseline characteristics and operative details including complications were recorded for all included patients. The clinical outcomes evaluated include VAS, MJOA, motor score, and NDI and MacNab's score. The radiological parameters in neutral-measured facet length, facet area, disc height, C2-C7 angle, neck tilt angle, T1 slope and thoracic inlet angle were also evaluated. Results: A total of 55 patients (29 PPPV PECD, 26 ACDF) were included, with mean follow-up periods of 21.9 and 32.3 months, respectively. Each cohort was noted to have a single case of surgical complication. Statistically significant changes of facet area (49.05 ± 14.50%) and facet length (52.71 ± 15.11%) were noted in the PPPV PECD group. At neutral alignment of the neck on a lateral X-ray, compared to ACDF, PPPV PECD had a statistically significant change in neck tilt angle (-11.68 ± 17.35°) and T1 slope angle (-11.69 ± 19.58°). Whilst both PPPV PECD and ACDF had significant improvements in VAS, MJOA and NDI postoperatively, PPPV PECD was found to be superior across all above scores at various follow-up timepoints compared to its ACDF counterparts. Conclusions: PPPV PECD surgery achieved a satisfactory radiological correction of neck alignment and significantly improved clinical outcomes at medium-term follow-up for our cohort of patients, highlighting its feasibility in treating patients with cervical disc herniations and foraminal pathologies.

Astrocyte-derived adenosine excites sleep-promoting neurons in the ventrolateral preoptic nucleus: Astrocyte-neuron interactions in the regulation of sleep.

Although ATP and/or adenosine derived from astrocytes are known to regulate sleep, the precise mechanisms underlying the somnogenic effects of ATP and adenosine remain unclear. We selectively expressed channelrhodopsin-2 (ChR2), a light-sensitive ion channel, in astrocytes within the ventrolateral preoptic nucleus (VLPO), which is an essential brain nucleus involved in sleep promotion. We then examined the effects of photostimulation of astrocytic ChR2 on neuronal excitability using whole-cell patch-clamp recordings in two functionally distinct types of VLPO neurons: sleep-promoting GABAergic projection neurons and non-sleep-promoting local GABAergic neurons. Optogenetic stimulation of VLPO astrocytes demonstrated opposite outcomes in the two types of VLPO neurons. It led to the inhibition of non-sleep-promoting neurons and excitation of sleep-promoting neurons. These responses were attenuated by blocking of either adenosine A1 receptors or tissue-nonspecific alkaline phosphatase (TNAP). In contrast, exogenous adenosine decreased the excitability of both VLPO neuron populations. Moreover, TNAP was expressed in galanin-negative VLPO neurons, but not in galanin-positive sleep-promoting projection neurons. Taken together, these results suggest that astrocyte-derived ATP is converted into adenosine by TNAP in non-sleep-promoting neurons. In turn, adenosine decreases the excitability of local GABAergic neurons, thereby increasing the excitability of sleep-promoting GABAergic projection neurons. We propose a novel mechanism involving astrocyte-neuron interactions in sleep regulation, wherein endogenous adenosine derived from astrocytes excites sleep-promoting VLPO neurons, and thus decreases neuronal excitability in arousal-related areas of the brain.

A focus group interview with health professionals: establishing efficient transition care plan for older adult patients in Korea.

BACKGROUND: Although transition care planning can affect the functional status and quality of life after acute hospitalization in older adults, little is known on problems associated with discharge planning in acute care hospitals in Korea. We aimed to investigate barriers and possible solutions on transfer planning of complex older patients in this study. METHODS: We used focus group interviews with the application of framework analysis. Twelve physicians providing inpatient care from 6 different institutions in Korea participated in the interview. Facilitating questions were extracted from 2 roundtable meetings prior to the primary interview. From transcribed verbatim, themes were constructed from corresponding remarks by participants. RESULTS: We revealed two main domains of the barrier, which included multiple subdomains for each of them. The first domain was a patient factor barrier, a composite of misperception of medical providers' intentions, incomprehension of the healthcare system, and communication failure between the caregivers or decision-makers. The second domain, institutional factors included different fee structures across the different levels of care, high barrier to accessing health service in tertiary hospitals or to be referred to, the hardship of communication between institutions, and insufficient subacute rehabilitation service across the country. CONCLUSIONS: Through the interview, physicians in the field recognized barriers to a smooth transition care process from tertiary level hospitals to community care, especially for older adults. Participants emphasized both the patients and hospital sides of adjustment on behaviors, communication, and greater attention for the individuals during the transition period.

Outcome of pallidal deep brain stimulation for treating isolated orofacial dystonia.

BACKGROUND: Isolated orofacial dystonia is a rare segmental neurological disorder that affects the eye, mouth, face, and jaws. Current literature on pallidal surgery for orofacial dystonia is limited to case reports and small-scale studies. This study was to investigate clinical outcomes of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with isolated orofacial dystonia. METHODS: Thirty-six patients who underwent GPi DBS at Incheon St. Mary's Hospital, The Catholic University of Korea, between 2014 and 2019 were included in this study. Burke-Fahn-Marsden Dystonia Rating Scale, Unified Dystonia Rating Scale, and Global Dystonia Severity Rating Scale were retrospectively retrieved for analysis before surgery, at 6-month follow-up as short-term outcome, and at follow-up over 1 year (12 months to 69 months) as long-term results. RESULTS: Mean total BFMDRS-M scores at the three time points (baseline, 6 months, and over 1 year follow-up) were 11.6 ± 4.9, 6.1 ± 5.2 (50.3 ± 29.9% improvement, p < 0.05), and 4.3 ± 4.2 (65.0 ± 24.2% improvement, p < 0.05), respectively. In terms of UDRS and GDS, improvement rates were 45.1% (p < 0.001) and 47.7% (p < 0.001) at 6 months, and 63.8% (p < 0.001) and 65.7% (p < 0.001) at over 1 year after surgery, respectively. CONCLUSIONS: Bilateral GPi DBS in isolated orofacial dystonia can be effective if conservative treatment option fails. Its benefit is not only observed in a short term, but also maintained in a long-term follow-up.

Contribution of tetrodotoxin-resistant persistent Na+ currents to the excitability of C-type dural afferent neurons in rats.

BACKGROUND: Growing evidence supports the important role of persistent sodium currents (INaP) in the neuronal excitability of various central neurons. However, the role of tetrodotoxin-resistant (TTX-R) Na+ channel-mediated INaP in the neuronal excitability of nociceptive neurons remains poorly understood. METHODS: We investigated the functional role of TTX-R INaP in the excitability of C-type nociceptive dural afferent neurons, which was identified using a fluorescent dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchloride (DiI), and a whole-cell patch-clamp technique. RESULTS: TTX-R INaP were found in most DiI-positive neurons, but their density was proportional to neuronal size. Although the voltage dependence of TTX-R Na+ channels did not differ among DiI-positive neurons, the extent of the onset of slow inactivation, recovery from inactivation, and use-dependent inhibition of these channels was highly correlated with neuronal size and, to a great extent, the density of TTX-R INaP. In the presence of TTX, treatment with a specific INaP inhibitor, riluzole, substantially decreased the number of action potentials generated by depolarizing current injection, suggesting that TTX-R INaP are related to the excitability of dural afferent neurons. In animals treated chronically with inflammatory mediators, the density of TTX-R INaP was significantly increased, and it was difficult to inactivate TTX-R Na+ channels. CONCLUSIONS: TTX-R INaP apparently contributes to the differential properties of TTX-R Na+ channels and neuronal excitability. Consequently, the selective modulation of TTX-R INaP could be, at least in part, a new approach for the treatment of migraine headaches.

Astrocytes in the Ventrolateral Preoptic Area Promote Sleep.

Although ventrolateral preoptic (VLPO) nucleus is regarded as a center for sleep promotion, the exact mechanisms underlying the sleep regulation are unknown. Here, we used optogenetic tools to identify the key roles of VLPO astrocytes in sleep promotion. Optogenetic stimulation of VLPO astrocytes increased sleep duration in the active phase in naturally sleep-waking adult male rats (n = 6); it also increased the extracellular ATP concentration (n = 3) and c-Fos expression (n = 3-4) in neurons within the VLPO. In vivo microdialysis analyses revealed an increase in the activity of VLPO astrocytes and ATP levels during sleep states (n = 4). Moreover, metabolic inhibition of VLPO astrocytes reduced ATP levels (n = 4) and diminished sleep duration (n = 4). We further show that tissue-nonspecific alkaline phosphatase (TNAP), an ATP-degrading enzyme, plays a key role in mediating the somnogenic effects of ATP released from astrocytes (n = 5). An appropriate sample size for all experiments was based on statistical power calculations. Our results, taken together, indicate that astrocyte-derived ATP may be hydrolyzed into adenosine by TNAP, which may in turn act on VLPO neurons to promote sleep.SIGNIFICANCE STATEMENT Glia have recently been at the forefront of neuroscience research. Emerging evidence illustrates that astrocytes, the most abundant glial cell type, are the functional determinants for fates of neurons and other glial cells in the central nervous system. In this study, we newly identified the pivotal role of hypothalamic ventrolateral preoptic (VLPO) astrocytes in the sleep regulation, and provide novel insights into the mechanisms underlying the astrocyte-mediated sleep regulation.

The role of muscle depletion and visceral adiposity in HCC patients aged 65 and over undergoing TACE.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has been increasing among the elderly populations. Trans-arterial chemoembolization (TACE), a widely used first-line non-curative therapy for HCCs is an issue in geriatrics. We investigated the prognosis of elderly HCC patients treated with TACE and determined the factors that affect the overall survival. METHODS: We included 266 patients who were older than 65 years and had received TACE as initial treatment for HCC. We analyzed the skeletal muscle index (SMI) and visceral-to-subcutaneous fat ratio (VSR) around the third lumbar vertebrae using computed tomography scans. Muscle depletion with visceral adiposity (MDVA) was defined by falling below the median SMI and above the median VSR value sex-specifically. We evaluated the overall survival in association with MDVA and other clinical factors. RESULTS: The mean age was 69.9 ± 4.5 years, and 70.3% of the patients were men. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, 29, 136, and 101 patients were classified as BCLC 0, A, and B stages, respectively, and 79 (29.7%) had MDVA. During the median follow-up of 4.1 years, patients with MDVA had a shorter life expectancy than those without MDVA (P = 0.007) even though MDVA group had a higher objective response rate after the first TACE (82.3% vs. 75.9%, P = 0.035). Multivariate analysis revealed that MDVA (Hazard ratio [HR] 1.515) age (HR 1.057), liver function (HR 1.078), tumor size (HR 1.083), serum albumin level (HR 0.523), platelet count (HR 0.996), tumor stage (stage A, HR 1.711; stage B, HR 2.003), and treatment response after the first TACE treatment (HR 0.680) were associated with overall survival. CONCLUSIONS: MDVA is a critical prognostic factor for predicting survival in the elderly patients with HCC who have undergone TACE.

Higher frailty burden in older adults with chronic constipation.

BACKGROUND: Despite constipation being a common clinical condition in older adults, the clinical relevance of constipation related to frailty is less studied. Hence, we aimed to investigate the association between chronic constipation (CC) and frailty in older adults. METHODS: This is a cross-sectional analysis of a population-based, prospective cohort study of 1278 community-dwelling older adults in South Korea. We used the Rome criteria to identify patients with irritable bowel syndrome with predominant constipation (IBS-C) and functional constipation (FC). We investigated whether participants consistent with the criteria for IBS-C and FC had CC. Frailty was assessed using the Cardiovascular Health Study (CHS) frailty phenotype. RESULTS: In the study population with a mean age of 75.3 ± 6.3 years, 136 (10.7%) had CC. The participants with CC were older, had higher medication burdens, and had worse physical performances compared to those without CC (All P < .05). By association analysis, the prevalence of CC was associated with frailty by the CHS criteria (P < .001). The CHS frailty score was associated with the presence of CC by the univariate logistic regression analysis and the multivariate analysis adjusted for age, sex, and multimorbidity. CONCLUSIONS: Frailty was associated with CC in community-dwelling older people, suggesting that constipation should be considered as an important geriatric syndrome in clinical practice concerning frail older adults.

Characterization of antigenic variant infectious bursal disease virus strains identified in South Korea.

Infectious bursal disease (IBD) is one of the most important immunosuppressive diseases of young chickens, causing considerable economic losses to the poultry industry. More than 30 years ago, an antigenic variant (av) pathotype of the IBD virus (IBDV) was reported to originate in, and subsequently spread among, poultry farms in the USA. Recently, a novel avIBDV lineage was identified in China and was shown to exhibit clear differences in its pathogenicity as well as molecular characteristics compared with the previously isolated variant strains. In this study, we conducted a passive surveillance of chicken carcasses submitted to our research division from June-December 2019, and detected the IBDV strains by reverse transcription PCR. Five avIBDV strains were isolated, and their pathogenicity was determined by necropsy and molecular analysis. Additionally, a coinfection field case involving an avIBDV strain and a very virulent IBDV (vvIBDV) strain was identified. Multiple sequence alignment and phylogenetic analysis of partial viral protein 1 (VP1) and hypervariable region (hv) VP2 genes revealed that those strains originated from two different avIBDV lineages. The co-occurrence of two sub-groups of avIBDVs in South Korea confirms for the first time the evolution of antigenic variant IBDV strains, and highlights the urgency for the development of new strategies for IBDV intervention in South Korea.RESEARCH HIGHLIGHTS Five avIBDV strains were identified in South Korea by passive surveillance test in 2019.A coinfection between two IBDV strains from different genogroups was reported in a field case.By phylogenetic analysis, Korean avIBDVs belonged to two distinct lineages of antigenic variant genogroup.

Long-term effect of a 24-week multicomponent intervention on physical performance and frailty in community-dwelling older adults.

INTRODUCTION: Multicomponent interventions improve physical function and frailty in older adults, but their long-term benefit remains uncertain. METHODS: This prospective non-randomised study was conducted in 383 older Koreans (mean age, 76.8 years; female 72.3%) who were living alone or receiving medical aid. Of these, 187 individuals chose to receive a 24-week intervention that consisted of group exercise, nutritional supplements, depression management, deprescribing and home hazard reduction. The remaining 196 individuals received usual care. We compared the short physical performance battery (SPPB) score (0-12 points), frailty phenotype scale (0-5 points) and deficit-accumulation frailty index (0-1) at baseline, 6, 18 and 30 months. RESULTS: After 1:1 propensity score matching (n = 117 per group), the mean SPPB scores for the intervention and comparison groups were 7.6 versus 7.6 at baseline, 10.7 versus 7.1 at 6 months (mean difference, 3.5; 95% confidence interval [CI], 2.8-4.2), 9.1 versus 7.8 at 18 months (1.3; 95% CI, 0.6-2.0) and 8.6 versus 7.5 at 30 months (1.1; 95% CI, 0.4-1.8). The intervention group had lower frailty phenotype scale (1.1 versus 1.8; difference, -0.7; 95% CI -1.0 to -0.3) and frailty index (0.22 versus 0.27; difference, -0.04; -0.06 to -0.02) at 6 months, but similar scores at 18 and 30 months. The 30-month mean institutionalisation-free survival time was 28.5 months in the intervention group versus 23.3 months in the comparison group (difference, 5.2 months; 95% CI, 3.1-7.4). CONCLUSIONS: The 24-week multicomponent intervention showed sustained improvement in physical function, temporary reduction in frailty and longer institutionalisation-free survival over 30 months.

Serum GDF15 Level Is Independent of Sarcopenia in Older Asian Adults.

BACKGROUND: Growth differentiation factor 15 (GDF15), induced by tissue inflammation and mitochondrial stress, has received significant attention as a biomarker of mitochondrial dysfunction and has been implicated in various age-related diseases. However, the association between circulating GDF15 and sarcopenia-associated outcomes in older adults remains to be established. AIM: To validate previous experimental data and to investigate the possible role of GDF15 in aging and muscle physiology in humans, this study examined serum GDF15 levels in relation to sarcopenia-related parameters in a cohort of older Asian adults. METHODS: Muscle mass and muscle function-related parameters, such as grip strength, gait speed, chair stands, and short physical performance battery score were evaluated by experienced nurses in 125 geriatric participants with or without sarcopenia. Sarcopenia was diagnosed using the Asian-specific cutoff points. Serum GDF15 levels were measured using an enzyme immunoassay kit. RESULTS: Serum GDF15 levels were not significantly different according to sarcopenia status, muscle mass, muscle strength, and physical performance and were not associated with the skeletal muscle index, grip strength, gait speed, time to complete 5 chair stands, and short physical performance battery score, regardless of adjustments for sex, age, and BMI. CONCLUSIONS: These findings indicate that the definite role of GDF15 on muscle metabolism observed in animal models might not be evident in humans and that elevated GDF15 levels might not predict the risk for sarcopenia, at least in older Asian adults.