Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications.

Calcium-activated potassium (KCa) channels are ubiquitously expressed throughout the body and are able to regulate membrane potential and intracellular calcium concentrations, thereby playing key roles in cellular physiology and signal transmission. Consequently, it is unsurprising that KCa channels have been implicated in various diseases, making them potential targets for pharmaceutical interventions. Over the past two decades, numerous studies have been conducted to develop KCa channel-targeting drugs, including those for disorders of the central and peripheral nervous, cardiovascular, and urinary systems and for cancer. In this review, we synthesize recent findings regarding the structure and activating mechanisms of KCa channels. We also discuss the role of KCa channel modulators in therapeutic medicine. Finally, we identify the major reasons behind the delay in bringing these modulators to the pharmaceutical market and propose new strategies to promote their application.

Atmospheric environment and persistence of pediatric asthma: A population-based cohort study.

BACKGROUND: Asthma is a heterogeneous disease with different outcomes. For children with asthma at the age of 7 years, 67-75% are symptom-free as adults. Data on the important link between childhood and adult asthma are sparse. OBJECTIVE: We aimed to investigate factors associated with persistence of childhood asthma over three years of follow-up by linking data between Korea childhood Asthma Study (KAS) and their matched claims data from Health Insurance Review and Assessment Service (HIRA). METHODS: We analyzed data from 450 preadolescent children aged 7 to 10 years and classified them into remission or persistence groups. Baseline clinical characteristics and exposure to air pollution materials including PM2.5 and PM10 during three years of follow-up were compared. The main outcome was asthma persistence which was defined as the presence of asthma episodes with healthcare utilization and prescription of asthma medications within three years after KAS enrollment. RESULTS: At the third year of follow-up, after stepwise regression analysis, lower age at enrollment (adjusted odds ratio (aOR): 0.79; 95% confidence interval (CI): 0.64-0.96), male sex (aOR: 1.66; 95%CI: 1.05-2.63), proximity from an air-polluting facility (aOR: 2.4; 95%CI: 1.34-4.29), higher level outdoor PM2.5 (aOR: 1.1; 95%CI: 1.02-1.20), and higher rate of doctor-diagnosed food allergy (FA) (aOR: 2.33; 95%CI: 1.06-5.12) were significantly associated with persistence. CONCLUSION: We discovered various independent risk factors for the persistence of childhood asthma. By linking HIRA claims data, we could clarify risk factors for persistence in a well-defined study population.

Inhibition of Ca2+-permeable TRPV3 and inflammatory cytokine release by honokiol and magnolol in human epidermal keratinocytes.

Transient receptor potential vanilloid-3 (TRPV3) ion channels are prominently expressed in keratinocytes, playing a vital role in skin functions. Honokiol and magnolol (H&M) the primary bioactive constituents in Magnolia officinalis extract, demonstrate anti-inflammatory and skin-protective properties. Nevertheless, the underlying mechanism regarding their effect on Ca2+-permeable ion channels remain unclear. Our purpose in this study is to investigate the effect of H&M on TRPV3 and cytokine release in normal human epidermal keratinocytes (NHEKs), including its gain-of-function (GOF) mutants (G573S and G573C) associated with Olmstead syndrome. We performed whole-cell patch-clamp, fura-2 spectrofluorimetry to investigate channels activity, CCK-8 assay to analyze cell death and enzyme-linked immunosorbent assay to assess the cytokine release from NHEKs. H&M inhibited the TRPV3 current (ITRPV3) and cytosolic calcium increase in NHEKs, HEK293T cells overexpressing hTRPV3 and its GOF mutants. Moreover, the release of pro-inflammatory cytokines (interleukin-6 and -8) from keratinocytes stimulated by TRPV3 agonist was effectively suppressed by H&M. Our findings provide insights into the mechanism underlying the anti-inflammatory effects of H&M, highlighting their potential in treating skin diseases.

Anti-Inflammatory Effects of Alphitolic Acid Isolated from Agrimonia coreana Nakai Extracts Are Mediated via the Inhibition of ICRAC Activity in T Cells.

Agrimonia pilosa Ledeb., an important medicinal herb in traditional East Asian medicine, is primarily used to treat abdominal pain, dysentery, and hemostasis. There are ten other reported species of Agrimonia plants, including Agrimonia coreana Nakai-a naturally growing species in South Korea-and Agrimonia eupatoria Linn. Although recent studies have isolated numerous active constituents and investigated their effects, the medicinal utility of this herb is not yet fully explored. Through patch-clamp recording, a previous study reported that Agrimonia plant extracts inhibit the function of Ca2+ release-activated Ca2+ channels (CRACs). Herein, we aimed to identify and isolate the main compounds in A. coreana responsible for CRAC inhibition while assessing the anti-inflammatory effects mediated by this inhibition. We demonstrated for the first time that alphitolic acid isolated from A. coreana has a dose-dependent inhibitory effect on CRAC activity and, thus, an inhibitory effect on intracellular calcium increase. Furthermore, analysis of human CD4+ T cell proliferation via the carboxyfluorescein diacetate succinimidyl ester method revealed that alphitolic acid inhibited T cell proliferation in a concentration-dependent manner. Our findings provide a theoretical basis for the potential therapeutic use of alphitolic acid in the treatment of inflammatory diseases.

Treatment Outcome of the Brain Metastases in Peri-Rolandic Area: Comparison Between Surgery and Stereotactic Radiosurgery.

BACKGROUND: Brain metastases of peri-Rolandic area is crucial as it directly impacts the quality of life for cancer patients. Surgery or stereotactic radiosurgery (SRS) is considered for peri-Rolandic brain metastases as for other brain metastases. However, the benefit of each treatment modality on functional outcome has not been clearly defined for this tumor. The purpose of this study is to compare the functional course of each treatment and to suggest an effective treatment for patients' quality of life. METHODS: Fifty-two patients who had undergone SRS or surgery for brain metastasis confirmed by enhanced MRI were enrolled retrospectively. Overall survival (OS), progression free survival (PFS), and functional outcomes were estimated using the Kaplan-Meier method, univariate, multivariate analysis, and Cox proportional hazards regression. RESULTS: Median OS and PFS were 13.3 months and 8.9 months in our study population. Treatment modalities were not significant factors for OS and PFS. Extracranial systemic cancer progression was significant factor for both parameters (p=0.030 for OS and p=0.040 for PFS). Median symptom improvement (improvement of at least 1 grade after surgery compared to preoperative state) time was significantly shorter in surgery group than in the SRS group (10.5 days vs. 37.5 days, p=0.034). CONCLUSION: Surgery for brain metastases can contribute to a positive quality of life for the remaining duration of the patient's life.

Alpha-Mangostin: A Potent Inhibitor of TRPV3 and Pro-Inflammatory Cytokine Secretion in Keratinocytes.

The TRPV3 calcium ion channel is vital for maintaining skin health and has been associated with various skin-related disorders. Since TRPV3 is involved in the development of skin inflammation, inhibiting TRPV3 could be a potential treatment strategy. Alpha-mangostin isolated from Garcinia mangostana L. extract exhibits diverse positive effects on skin health; however, the underlying mechanisms remain obscure. This study investigated the TRPV3-inhibitory properties of alpha-mangostin on TRPV3 hyperactive mutants associated with Olmsted syndrome and its impact on TRPV3-induced cytokine secretion and cell death. Our findings demonstrate that alpha-mangostin effectively inhibits TRPV3, with an IC50 of 0.077 ± 0.013 µM, showing inhibitory effects on both wild-type and mutant TRPV3. TRPV3 inhibition with alpha-mangostin decreased calcium influx and cytokine release, protecting cells from TRPV3-induced death. These results indicate that alpha-mangostin reduced inflammation in TRPV3-activated skin keratinocytes, suggesting that alpha-mangostin could be potentially used for improving inflammatory skin conditions such as dermatitis.

Fetal growth rather than prematurity determines lung function in children with asthma.

BACKGROUND AND OBJECTIVE: Preterm birth or fetal growth has been associated with reduced lung function and asthma during childhood in the general population. We aimed to elucidate whether prematurity or fetal growth has a significant influence on lung function or symptoms in children with stable asthma. METHODS: We included children with stable asthma who participated in the Korean childhood Asthma Study cohort. Asthma symptoms were determined by asthma control test (ACT). Percent predicted values of pre- and post-bronchodilator (BD) lung function including forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), and forced expiratory flow at 25%-75% of FVC (FEF25%-75% ) were measured. Lung function and symptoms were compared according to the history of preterm birth and birth weight (BW) for gestational age (GA). RESULTS: The study population consisted of 566 children (age range: 5-18 years). There were no significant differences in lung function and ACT between preterm and term subjects. We observed no significant difference in ACT but significant differences were observed in pre- and post-BD FEV1 , pre- and post-BD FVC, and post-BD FEF25%-75% according to BW for GA in total subjects. Two-way ANOVA revealed that BW for GA rather than prematurity was a significant determining factor for pre- and post-BD lung function. After regression analysis, BW for GA was still a significant determining factor of pre- and post-BD FEV1 and pre- and post-BD FEF25%-75% . CONCLUSION: Fetal growth rather than prematurity appears to have a significant effect on lung function in children with stable asthma.

Frequency of exacerbation and degree of required asthma medication can characterize childhood longitudinal asthma trajectories.

BACKGROUND: To the best of our knowledge, there have been no investigations of longitudinal asthma trajectories based on asthma exacerbation frequency and medications required for asthma control in children. OBJECTIVE: To investigate longitudinal asthma trajectories based on the exacerbation frequency throughout childhood and asthma medication ranks. METHODS: A total of 531 children aged 7 to 10 years were enrolled from the Korean childhood Asthma Study. Required asthma medications for control of asthma from 6 to 12 years of age and asthma exacerbation frequency from birth to 12 years of age were obtained from the Korean National Health Insurance System database. Longitudinal asthma trajectories were identified on the basis of asthma exacerbation frequency and asthma medication ranks. RESULTS: Four asthma clusters were identified: lesser exacerbation with low-step treatment (8.1%), lesser exacerbations with middle-step treatment (30.7%), highly frequent exacerbations in early childhood with small-airway dysfunction (5.7%), and frequent exacerbations with high-step treatment (55.6%). The frequent exacerbations with high-step treatment cluster were characterized by a high prevalence of male sex, increased blood eosinophil (counts) with fractional exhaled nitric oxide, and high prevalence of comorbidities. The highly frequent exacerbation in early childhood with small-airway dysfunction cluster was characterized by recurrent wheeze in preschool age, with high prevalence of acute bronchiolitis in infancy and a greater number of family members with small-airway dysfunction at school age. CONCLUSION: The present study identified 4 longitudinal asthma trajectories on the basis of the frequency of asthma exacerbation and asthma medication ranks. These results would help clarify the heterogeneities and pathophysiologies of childhood asthma.

Multi-target modulation of ion channels underlying the analgesic effects of α-mangostin in dorsal root ganglion neurons.

BACKGROUND: α-Mangostin is a xanthone isolated from the pericarps of mangosteen fruit with, and has analgesic properties. Although the effects suggest an interaction of α-mangostin with ion channels in the nociceptive neurons, electrophysiological investigation of the underlying mechanism has not been performed. HYPOTHESIS: We hypothesized that α-Mangostin exerts its analgesic effects by modulating the activity of various ion channels in dorsal root ganglion (DRG) neurons. METHODS: We performed a whole-cell patch clamp study using mouse DRG neurons, HEK293T cells overexpressing targeted ion channels, and ND7/23 cells. Molecular docking (MD) and in silico absorption, distribution, metabolism, and excretion (ADME) analyses were conducted to obtain further insights into the binding sites and pharmacokinetics, respectively. RESULTS: Application of α-mangostin (1-3 µM) hyperpolarized the resting membrane potential (RMP) of small-sized DRG neurons by increasing background K+ conductance and thereby inhibited action potential generation. At micromolar levels, α-mangostin activates TREK-1, TREK-2, or TRAAK, members of the two-pore domain K+ channel (K2P) family known to be involved in RMP formation in DRG neurons. Furthermore, capsaicin-induced TRPV1 currents were potently inhibited by α-mangostin (0.43 ± 0.27 µM), and partly suppressed tetrodotoxin-sensitive voltage-gated Na+ channel (NaV) currents. MD simulation revealed that multiple oxygen atoms in α-mangostin may form stable hydrogen bonds with TREKs, TRAAK, TRPV1, and NaV channels. In silico ADME tests suggested that α-mangostin may satisfy the drug-likeness properties without penetrating the blood-brain barrier. CONCLUSION: The analgesic properties of α-mangostin might be mediated by the multi-target modulation of ion channels, including TREK/TRAAK activation, TRPV1 inhibition, and reduction of the tetrodotoxin-sensitive NaV current. The findings suggest that the phytochemical can be a multi-ion channel-targeting drug and an alternative drug for effective pain management.

The therapeutic effects on U87 and SAS cells using Proton Linac based Boron Neutron Capture Therapy in Korea.

A proton linac based boron neutron capture therapy system (A-BNCT, 10MeV, 4mA) was successfully developed in Korea. We performed in vitro experiments with U87 and SAS cells and revealed the efficacy of a binary therapy BNCT using epithermal neutrons and boronophenylalanine (BPA). The results revealed that BNCT showed cancer cell selectivity and caused cell death. Further in vitro studies can be a valuable method to characterize an A-BNCT system. We expect BNCT to become a treatment option for cancer patients.

Comparison of Long-Term Follow-Up Outcomes Between Minimally Invasive and Open Surgery for Single-Level Lumbar Fusion.

AIM: To evaluate, and to compare the clinical outcomes of minimally invasive surgery (MIS), and open surgery for single-level lumbar fusion over a minimum of 10-year follow-up. MATERIAL AND METHODS: We included 87 patients who underwent spinal fusion at the L4 - L5 level between January 2004 and December 2010. Based on the surgical method, the patients were divided into the open surgery (n=44) and MIS groups (n=43). We evaluated baseline characteristics, perioperative comparisons, postoperative complications, radiologic findings, and patientreported outcomes. RESULTS: The mean follow-up period was > 10 years in both groups (open surgery, 10.50 years; MIS, 10.16 years). The operative time was longer in the MIS group (4.37 h) than that in the open surgery group (3.34 h) (p=0.001). Estimated blood loss was lower in the MIS group (281.40 mL) than in the open surgery group (440.23 mL) (p < 0.001). Postoperative complications, including surgical site infection, adjacent segment disease, and pseudoarthrosis, did not differ between the groups. Plain radiographic findings of the lumbar spine did not differ between the two groups. Visual scores for back/leg pain and the Oswestry disability index did not differ between the two groups, preoperatively and at 6 months, 1, 5, and 10 years after surgery. CONCLUSION: After a minimum of the 10-year follow-up, postoperative complications and clinical outcomes did not differ significantly between patients who underwent open fusion and MIS fusion at the L4 - L5 level.

Quantification and Validation of an HPLC Method for Low Concentrations of Apigenin-7-O-Glucuronide in Agrimonia pilosa Aqueous Ethanol Extract Topical Cream by Liquid-Liquid Extraction.

In this study, we aimed to develop and validate a pretreatment method for separating and analyzing the small amounts of biomarkers contained in topical cream formulations. Analyzing semisolid formulations that contain low concentrations of active ingredients is difficult. Cream formulations containing an aqueous ethanol extract of 0.1% Agrimonia pilosa is an example. Approximately 0.0013% of apigenin-7-O-glucuronide(A7OG) was contained as a biomarker in the cream. To determine the A7OG content present in the cream formulation, liquid-liquid extraction using dichlormethane was applied. In addition, the volume of the distribution liquid was measured using the peak ratios of the indicator component, A7OG, and an internal standard, baicalin. Subsequently, the A7OG content in the cream formulation was calculated. Using this time-saving method, A7OG can be simply analyzed without additional pretreatment steps, such as evaporation and reconstitution. Moreover, the validation results confirmed that this analytical method met all of the criteria. Consequently, A7OG was successfully isolated from the cream, analyzed, and quantified using the developed method.

Automatically Diagnosing Skull Fractures Using an Object Detection Method and Deep Learning Algorithm in Plain Radiography Images.

OBJECTIVE: Deep learning is a machine learning approach based on artificial neural network training, and object detection algorithm using deep learning is used as the most powerful tool in image analysis. We analyzed and evaluated the diagnostic performance of a deep learning algorithm to identify skull fractures in plain radiographic images and investigated its clinical applicability. METHODS: A total of 2026 plain radiographic images of the skull (fracture, 991; normal, 1035) were obtained from 741 patients. The RetinaNet architecture was used as a deep learning model. Precision, recall, and average precision were measured to evaluate the deep learning algorithm's diagnostic performance. RESULTS: In ResNet-152, the average precision for intersection over union (IOU) 0.1, 0.3, and 0.5, were 0.7240, 0.6698, and 0.3687, respectively. When the intersection over union (IOU) and confidence threshold were 0.1, the precision was 0.7292, and the recall was 0.7650. When the IOU threshold was 0.1, and the confidence threshold was 0.6, the true and false rates were 82.9% and 17.1%, respectively. There were significant differences in the true/false and false-positive/false-negative ratios between the anteriorposterior, towne, and both lateral views (p=0.032 and p=0.003). Objects detected in false positives had vascular grooves and suture lines. In false negatives, the detection performance of the diastatic fractures, fractures crossing the suture line, and fractures around the vascular grooves and orbit was poor. CONCLUSION: The object detection algorithm applied with deep learning is expected to be a valuable tool in diagnosing skull fractures.

Comparison of Outcomes at Trauma Centers versus Non-Trauma Centers for Severe Traumatic Brain Injury.

OBJECTIVE: Traumatic brain injury (TBI) is one of the most common injuries in patients with multiple trauma, and it associates with high post-traumatic mortality and morbidity. A trauma center was established to provide optimal treatment for patients with severe trauma. This study aimed to compare the treatment outcomes of patients with severe TBI between non-trauma and trauma centers based on data from the Korean Neuro-Trauma Data Bank System (KNTDBS). METHODS: From January 2018 to June 2021, 1122 patients were enrolled in the KNTDBS study. Among them, 253 patients from non-traumatic centers and 253 from trauma centers were matched using propensity score analysis. We evaluated baseline characteristics, the time required from injury to hospital arrival, surgery-related factors, neuromonitoring, and outcomes. RESULTS: The time from injury to hospital arrival was shorter in the non-trauma centers (110.2 vs. 176.1 minutes, p=0.012). The operation time was shorter in the trauma centers (156.7 vs. 128.1 minutes, p0.003). Neuromonitoring was performed in nine patients (3.6%) in the non-trauma centers and 67 patients (26.5%) in the trauma centers (p<0.001). Mortality rates were lower in trauma centers than in non-trauma centers (58.5% vs. 47.0%, p=0.014). The average Glasgow coma scale (GCS) at discharge was higher in the trauma centers (4.3 vs. 5.7, p=0.011). For the Glasgow outcome scale-extended (GOSE) at discharge, the favorable outcome (GOSE 5-8) was 17.4% in the non-trauma centers and 27.3% in the trauma centers (p=0.014). CONCLUSION: This study showed lower mortality rates, higher GCS scores at discharge, and higher rates of favorable outcomes in trauma centers than in non-trauma centers. The regional trauma medical system seems to have a positive impact in treating patients with severe TBI.

Maternal Posttraumatic Stress Symptoms and Psychological Burden in Mothers of Korean Children With Anaphylaxis.

PURPOSE: Anaphylaxis is a severe allergic reaction that is potentially life-threatening, but post-traumatic stress symptoms (PTSS) in the caregivers of children with anaphylaxis have not been evaluated. This study aimed to investigate the psychological burden on mothers of children with recent anaphylaxis. METHODS: A total of 188 children with recent anaphylaxis was recruited from 13 hospitals in Korea. Validated questionnaires, including the Korean versions of the Beck Anxiety Inventory (K-BAI), the Beck Depression Inventory (K-BDI), and the Impact of Event Scale Revised-Korean version (IES-R-K), were used to evaluate maternal anxiety, depression, and PTSS. RESULTS: The median ages of children and their mothers were 4 and 36 years, respectively. PTSS (IES-R-K ≥ 25) were identified in 56.9% of mothers, and 57.9% of them showed severe PTSS. The proportions of mothers who had anxiety (K-BAI ≥ 22) and depression (K-BDI ≥ 17) were 18.6% and 33.0%, respectively. Multivariable logistic regression analysis indicated that the patient's history of asthma (adjusted odds ratio [aOR], 5.46; 95% CI, 1.17-25.59) and the presence of central nervous symptoms (aOR, 3.27; 95% CI, 1.07-9.96) were associated with PTSS. Age of 2 or older (aOR, 2.87; 95% CI, 1.10-7.52) and eggs, milk, or wheat as the cause of anaphylaxis (aOR, 2.87; 95% CI, 1.10-7.52) increased the risk of severe PTSS. CONCLUSIONS: The rate of PTSS among mothers of children with recent anaphylaxis was high at 56.9%. Clinicians who care for pediatric anaphylaxis patients should be aware of the psychological burden on their caregivers.

The Relationship Between Trauma Scoring Systems and Outcomes in Patients With Severe Traumatic Brain Injury.

Objective: This study investigated the relationship between trauma scoring systems and outcomes in patients with severe traumatic brain injury (TBI). Methods: From January 2018 to June 2021, 1,122 patients with severe TBI were registered in the Korean Neuro-Trauma Data Bank System. Among them, 697 patients with data on trauma scoring systems were included in the study. According to the Glasgow Outcome Scale-Extended score, the patients were divided into unfavorable and favorable outcome groups. The abbreviated injury scale (AIS), injury severity score (ISS), revised trauma score (RTS), and trauma and injury severity score (TRISS) were evaluated. Results: The AIS head score was higher in the unfavorable outcome group than in the favorable outcome group (4.39 vs. 4.06, p<0.001). ISS was also higher in the unfavorable outcome group (27.27 vs. 24.22, p=0.001). The RTS and TRISS were higher in the favorable outcome group (RTS, 4.74 vs. 5.45, p<0.001; TRISS, 48.05 vs. 71.02, p<0.001). In comparing the survival and death groups, the ISS was lower in the survival group (25.76 vs. 27.29, p=0.036). Furthermore, RTS was higher in the survival group (5.26 vs. 4.54, p<0.001), as was TRISS (62.11 vs. 44.91, p<0.001). Conclusion: Trauma scoring systems, including ISS, RTS, and TRISS, provide tools for quantifying posttraumatic risk and can be used to predict prognosis. Among these, TRISS is an indicator of the predicted survival rate and is considered a clinically useful tool for predicting unfavorable and favorable outcomes in patients with severe TBI.

Clinical Outcome of Patients Diagnosed Traumatic Intracranial Epidural Hematoma With Severe Brain Injury (Glasgow Coma Scale ≤8) Who Undergo Surgery: A Report From the Korean Neuro-Trauma Data Bank System.

Objective: To evaluate the clinical outcomes and prognostic factors in surgically treated patients with severe brain injury (Glasgow Coma Scale [GCS] score ≤8) diagnosed with traumatic epidural hematoma (EDH). Methods: From January 2018 to June 2021, 1,122 patients with an initial GCS score ≤8 were retrospectively enrolled in the Korean Neuro-Trauma Data Bank System. Clinical data of 79 surgically treated patients with EDH were compared between the unfavorable (scores of 1-4 on the Glasgow Outcome Scale-Extended [GOSE]) and favorable (score of 5-8 on the GOSE) outcome groups. Results: The overall mortality rate was 13.9%, and 60.8% of the patients had good outcomes at six months post-trauma. In the univariate analysis, increasing age (p=0.010), lower initial GCS score (p=0.001), higher Rotterdam computed tomography (CT) score (p=0.012), craniotomy rather than craniectomy (p=0.032), larger EDH volume (p=0.007), and loss of pupillary reactivity (unilateral unreactive pupil, p=0.026; bilateral unreactive pupils, p<0.001), were significantly correlated with unfavorable outcomes. Of these factors, increasing age (p=0.011) and bilateral unreactive pupils (p=0.002) were the most significant risk factors in the multivariate logistic regression analysis. The interval from admission to the brain CT scan was not correlated with the outcome; however, it was significantly longer in the unfavorable outcome group. Conclusion: Despite severe brain injury, more than half of the patients with EDH had favorable outcomes after surgical treatment. Our findings suggest that prompt diagnosis and surgical treatment should be considered for such cases.

Age-related Huntington's disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy.

Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals. We observed age-associated alterations in chromatin accessibility between HD-MSNs and pre-HD-MSNs and identified miR-29b-3p, whose age-associated upregulation promotes HD-MSN degeneration by impairing autophagic function through human-specific targeting of the STAT3 3' untranslated region. Reducing miR-29b-3p or chemically promoting autophagy increased the resilience of HD-MSNs against neurodegeneration. Our results demonstrate miRNA upregulation with aging in HD as a detrimental process driving MSN degeneration and potential approaches for enhancing autophagy and resilience of HD-MSNs.

Learning curve for minimally invasive transforaminal lumbar interbody fusion: a systematic review.

PURPOSE: Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is commonly used to treat degenerative lumbar spinal disorders. It facilitates a full-scale spinal decompression and interbody fusion with minimal neural retraction using the tubular retractor system. Despite the benefits of surgical efficiency and minimalism, this technique requires a long learning curve. There is currently no consensus on the learning curve characteristics and proper training methods for MI-TLIF. Thus, this systematic review aimed to discuss the cutoff point at which technical proficiency is achieved and ways to enhance the learning process. METHODS: Major databases, including PubMed, Embase, and Cochrane Library, were searched for learning curve studies that have evaluated the clinical outcome and learning progress of MI-TLIF using quantitative data. The qualities of the selected studies were assessed using the Newcastle‒Ottawa scale. The plateau points in the "learning curve" were analyzed according to various outcome measures. RESULTS: Nine full-text articles, representing 753 cases, were included from 9743 screened studies. The most commonly used outcome measures were the operative time, followed by the complication rate. The mean cutoff point for the operative time was 31.33 ± 11.98 (range 13‒45) cases. CONCLUSION: The plateau point in the learning curve for MI-TLIF may differ according to the outcome measures used. Most studies have demonstrated the learning progress based on simple task efficiency, rather than patient outcomes. Moreover, the learning rate may be affected by the patients' and technical conditions. Therefore, great care is required in interpreting the learning curve and cutoff point for MI-TLIF proficiency.