Pectoralis Muscle Area as a Predictor of Mortality in Patients Hospitalized with Bronchiectasis Exacerbation.

INTRODUCTION: Data on factors related to mortality in patients with bronchiectasis exacerbation are insufficient. Computed tomography (CT) can measure the pectoralis muscle area (PMA) and is a useful tool to diagnose sarcopenia. This study aimed to evaluate whether PMA can predict mortality in patients with bronchiectasis exacerbation. METHODS: Patients hospitalized due to bronchiectasis exacerbation at a single center were retrospectively divided into survivors and non-survivors based on 1-year mortality. Thereafter, a comparison of the clinical and radiologic characteristics was conducted between the two groups. RESULTS: A total of 66 (14%) patients died at 1 year. In the multivariate analysis, age, BMI <18.4 kg/m2, sex-specific PMA quartile, ≥3 exacerbations in the previous year, serum albumin <3.5 g/dL, cystic bronchiectasis, tuberculosis-destroyed lung, and diabetes mellitus were independent predictors for the 1-year mortality in patients hospitalized with bronchiectasis exacerbation. A lower PMA was associated with a lower overall survival rate in the survival analysis according to sex-specific quartiles of PMA. PMA had the highest area under the curve during assessment of prognostic performance in predicting the 1-year mortality. The lowest sex-specific PMA quartile group exhibited higher disease severity than the highest quartile group. CONCLUSIONS: CT-derived PMA was an independent predictor of 1-year mortality in patients hospitalized with bronchiectasis exacerbation. Patients with lower PMA exhibited higher disease severity. These findings suggest that PMA might be a useful marker for providing additional information regarding prognosis of patients with bronchiectasis exacerbation.

Clinical characteristics and course of pulmonary artery stump thrombosis following lung cancer surgery: A retrospective study from tertiary care hospital.

The data regarding pulmonary artery stump thrombosis (PAST) after lung cancer surgery are insufficient. The aim of the present study was to evaluate the incidence, clinical characteristics, and prognosis of PAST. We retrospectively investigated the incidence and clinical characteristics of PAST among patients who underwent lung resection for lung cancer at 2 institutions. We compared the clinical parameters between PAST and pulmonary embolism (PE) and examined the clinical course of patients with PAST. Of the 1885 patients, PAST was found in 36 patients (1.9%). Right lower lobectomy (n = 13) and middle-lower bilobectomy (n = 9) were the most common types of surgery. The median time interval from lung resection to the detection of PAST was 3.8 months. Immobilization and a history of cerebrovascular disease were not observed in the PAST group. Most of the patients with PAST (91.7%) were diagnosed incidentally, whereas many patients with PE (75.9%) were symptomatic at the time of diagnosis. During the follow-up, one patient (2.8%) had contralateral PE complications. However, no patients in the PAST group experienced pulmonary thromboembolism-related in-hospital death or adverse outcomes. There was no difference in the prognosis of patients with PAST according to the administration of anticoagulation. PAST was rarely detected in lung cancer patients on follow-up chest computed tomography after lung resection. Patients with PAST were asymptomatic in most cases and had relatively favorable clinical outcomes. However, these patients are at risk of contralateral PE, despite its rarity.

Persistent enhancement of basolateral amygdala-dorsomedial striatum synapses causes compulsive-like behaviors in mice.

Compulsive behaviors are observed in a range of psychiatric disorders, however the neural substrates underlying the behaviors are not clearly defined. Here we show that the basolateral amygdala-dorsomedial striatum (BLA-DMS) circuit activation leads to the manifestation of compulsive-like behaviors. We revealed that the BLA neurons projecting to the DMS, mainly onto dopamine D1 receptor-expressing neurons, largely overlap with the neuronal population that responds to aversive predator stress, a widely used anxiogenic stressor. Specific optogenetic activation of the BLA-DMS circuit induced a strong anxiety response followed by compulsive grooming. Furthermore, we developed a mouse model for compulsivity displaying a wide spectrum of compulsive-like behaviors by chronically activating the BLA-DMS circuit. In these mice, persistent molecular changes at the BLA-DMS synapses observed were causally related to the compulsive-like phenotypes. Together, our study demonstrates the involvement of the BLA-DMS circuit in the emergence of enduring compulsive-like behaviors via its persistent synaptic changes.

Hemoptysis as the presenting manifestation of bronchiectasis-associated hospitalization in Korea.

Background: Patients with bronchiectasis commonly experience disease exacerbations, which cause significant morbidity and mortality. However, data regarding the clinical features of bronchiectasis patients hospitalized with hemoptysis are scarce. Methods: We retrospectively collected the data of patients with bronchiectasis-associated hospitalization at a tertiary referral center in Korea, and classified them into the hemoptysis and infective exacerbation (IE) groups. The presence of hemoptysis was defined as a volume of expectorated blood larger than 10 mL per 24 hours. The clinical, radiological, and laboratory parameters were compared between the two groups. Results: Patients were classified into the hemoptysis [267 (54.5%)] and IE [223 (45.5%)] groups. Among the 44 patients of the hemoptysis group, 37 (84.1%) presented with hemoptysis than with IE at the recurrent episode. The hemoptysis group had a significantly lower 30-day mortality than that of the IE group. Previous pulmonary tuberculosis (TB), mycetoma, and bronchial artery hypertrophy were independently associated with the hemoptysis group. In contrast, male sex, poor performance status, colonization of Pseudomonas aeruginosa, ≥3 involved lobes, cystic bronchiectasis, and emphysema were inversely associated with the hemoptysis group. The absence of hemoptysis was one of the independent predictors of 30-day mortality in patients with bronchiectasis-associated hospitalization. Conclusions: In Korea, bronchiectasis patients hospitalized with hemoptysis exhibit a distinct phenotype, and are more likely to have previous pulmonary TB, mycetoma, and bronchial artery hypertrophy. Hemoptysis is associated with a lower risk of short-term mortality compared to IE in bronchiectasis-associated hospitalization.

ß-COP Suppresses the Surface Expression of the TREK2.

K2P channels, also known as two-pore domain K+ channels, play a crucial role in maintaining the cell membrane potential and contributing to potassium homeostasis due to their leaky nature. The TREK, or tandem of pore domains in a weak inward rectifying K+ channel (TWIK)-related K+ channel, subfamily within the K2P family consists of mechanical channels regulated by various stimuli and binding proteins. Although TREK1 and TREK2 within the TREK subfamily share many similarities, ß-COP, which was previously known to bind to TREK1, exhibits a distinct binding pattern to other members of the TREK subfamily, including TREK2 and the TRAAK (TWIK-related acid-arachidonic activated K+ channel). In contrast to TREK1, ß-COP binds to the C-terminus of TREK2 and reduces its cell surface expression but does not bind to TRAAK. Furthermore, ß-COP cannot bind to TREK2 mutants with deletions or point mutations in the C-terminus and does not affect the surface expression of these TREK2 mutants. These results emphasize the unique role of ß-COP in regulating the surface expression of the TREK family.

Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice.

Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic L-amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivity of VTA dopaminergic neurons.

Clinical relevance of bronchiectasis in patients with community-acquired pneumonia.

BACKGROUND: Data regarding the clinical characteristics and treatment outcomes of patients with community-acquired pneumonia (CAP) and bronchiectasis (BE) are rare. This study aims to elucidate the clinical relevance of BE in patients with CAP. METHODS: Patients hospitalized with CAP in a single center were retrospectively analyzed and divided into significant BE (BE with ≥ 3 lobes or cystic BE on computed tomography) and control groups. Clinical and microbiological characteristics were compared between the two groups. RESULTS: In the final analysis, 2112 patients were included, and 104 (4.9%) had significant BE. The significant BE group exhibited a higher prevalence of sputum production, dyspnea, and complicated parapneumonic effusion or empyema than the control group. Pseudomonas aeruginosa was more frequently isolated in the significant BE group than in the control group, whereas Mycoplasma pneumoniae was less commonly identified. Length of hospital stay (LOS) was significantly longer in the significant BE group than the control group (12 [8-17] days vs. 9 [6-13] days, p < 0.001). In contrast, 30-day and in-hospital mortality rates did not significantly differ between the two groups. Furthermore, significant BE was an independent predictor of prolonged hospitalization in two models based on CURB-65 and pneumonia severity index. CONCLUSIONS: Significant BE occurred in approximately 5% of patients with CAP and was more likely to be associated with sputum, dyspnea, complicated parapneumonic effusion or empyema, and isolation of P. aeruginosa. Significant BE was an independent predictor of LOS in patients with CAP.

14-3-3γ haploinsufficiency leads to altered dopamine pathway and Parkinson's disease-like motor incoordination in mice.

The 14-3-3 protein family with seven isoforms found in mammals is widely expressed in the brain and plays various roles in cellular processes. Several studies have reported that 14-3-3γ, one of the 14-3-3 protein isoforms, is associated with neurological and psychiatric disorders, but the role of 14-3-3γ in the pathophysiology of brain diseases is unclear. Although studies have been conducted on the relationship between 14-3-3γ protein and Parkinson's disease (PD), a common neurodegenerative disorder with severe motor symptoms such as bradykinesia and rigidity, a direct connection remains to be elucidated. We recently showed that adult heterozygous 14-3-3γ knockout mice are hyperactive and exhibit anxiety-like behavior. In this study, we further characterized the molecular and behavioral changes in aged 14-3-3γ heterozygous mice to investigate the role of 14-3-3γ in the brain. We observed decreased dopamine levels and altered dopamine metabolism in the brains of these mice, including changes in the phosphorylation of proteins implicated in PD pathology. Furthermore, we confirmed that they displayed PD symptom-like behavioral deficits, such as impaired motor coordination and decreased ability to the nest-building activity. These findings suggest an association between 14-3-3γ dysfunction and PD pathophysiology.

Biomimetically Engineered Amyloid-Shelled Gold Nanocomplexes for Discovering α-Synuclein Oligomer-Degrading Drugs.

The assembly of α-synuclein (αS) oligomers is recognized as the main pathological driver of synucleinopathies. While the elimination of toxic αS oligomers shows promise for the treatment of Parkinson's disease (PD), the discovery of αS oligomer degradation drugs has been hindered by the lack of proper drug screening tools. Here, we report a drug screening platform for monitoring the efficacy of αS-oligomer-degrading drugs using amyloid-shelled gold nanocomplexes (ASGNs). We fabricate ASGNs in the presence of dopamine, mimicking the in vivo generation process of pathological αS oligomers. To test our platform, the first of its kind for PD drugs, we use αS-degrading proteases and various small molecular substances that have shown efficacy in PD treatment. We demonstrate that the ASGN-based in vitro platform has strong potential to discover effective αS-oligomer-targeting drugs, and thus it may reduce the attrition problem in drug discovery for PD treatment.

Potential of γ-Aminobutyric Acid-Producing Leuconostoc mesenteroides Strains Isolated from Kimchi as a Starter for High-γ-Aminobutyric Acid Kimchi Fermentation.

γ-Aminobutyric acid (GABA)-producing Leuconostoc mesenteroides K1501 and K1627, isolated from kimchi, exhibited the highest GABA production in 1% monosodium glutamic acid. Both strains showed high survival rates of approximately 87% in artificial gastric juice (pH 3.0) and >80% in 0.1% artificial bile salt fluid. The survival rate was approximately 28% in 0.3% artificial bile salt fluid and 0% in 0.5% artificial bile salts. Both strains showed excellent adhesion to intestinal epithelial cells (>99%). Furthermore, it was observed that growth was not inhibited at 2% salt concentration; however, it was slightly retarded at salt concentrations of 3% and 4%. Moreover, L. mesenteroides K1501 and K1627 inhibited the growth of certain species of Lactobacillus, whose presence in kimchi fermentation is undesirable. Therefore, L. mesenteroides K1501 and K1627 have the potential to be used as starter organisms for functional GABA-rich kimchi.

Caspase-dependent apoptosis induces reactivation and gliogenesis of astrocytes in adult mice.

Astrocytes play an important role in increasing synaptic plasticity, regulating endogenous homeostasis, and contributing to neuroprotection but become overactivated or apoptotic in persistent neuroinflammatory responses or pathological conditions. Although gliogenesis under these conditions may be essential for neuronal protection, much remains unknown. Here, we generated new conditional transgenic mice (cTg) that can induce apoptosis via Cre-dependent active caspase-3 (taCasp3-2A-TEVp) without pathological conditions. We induced apoptosis of hippocampal CA1 astrocytes in cTg mice using GFAP promoter-driven adeno-associated virus (AAV) containing Cre recombinase. Activated caspase-3 was detected in astrocytes of the hippocampal CA1, and the number of astrocytes decreased sharply at 1 week but recovered at 2 weeks and was maintained until 4 weeks. Nuclear factor 1A (NF1A) mRNA, an important transcription factor for hippocampal reactive astrocytes, was significantly increased only at week 1. Interestingly, all reactive markers (pan, A1, A2) increased despite the decreased number of astrocytes at week 1, and there was no change in monoamine oxidase B (MAOB) observed in astrocytes of animal models of degenerative brain disease. Extensive CA1 astrocyte depletion at week 1 induced cognitive deficits; however, both recovered at weeks 2 and 4. Overall, transient hippocampal astrocyte depletion caused by apoptosis restored cell number and function within 2 weeks and did not induce significant neurotoxicity. Therefore, cTg mice are valuable as an in vivo animal model for studying gliogenesis in multiple regions of the adult brain.

Clinical Features and Treatment of Intra-Tendinous Suture Reaction Following Achilles Tendon Repair Using Nonabsorbable Suture Material: A Retrospective Case Series Study.

We aimed to investigate the clinical manifestations, radiological findings, and therapeutic outcome of treatment for patients with surgically confirmed foreign body reaction following an Achilles tendon repair using non-absorbable suture material. Eight consecutive patients who were confirmed as having an intra-tendinous suture foreign body reaction in the histopathological report were enrolled in this study. Medical records of all patients in terms of clinical and radiological features were retrieved. Also, the outcome of treatment was evaluated at a follow-up of at least 12 months. All the patients complained of pain and a palpable mass around a previous surgical site at mean 25.1 months (range, 4-72 months) after the initial surgery. Magnetic resonance imaging (MRI) or ultrasound were used to detect the lesion. All the patients underwent surgical excision of foreign body reaction tissue and primary repair using absorbable suture material. After the treatment, the wounds were healed completely in all, and the average FAOS (foot and ankle outcome score) was 91.32 at mean follow-up for 22.4 months. In conclusion, intra-tendinous suture reaction is a rare complication following an Achilles tendon repair using nonabsorbable suture material, but it can be treated adequately with only surgical excision of foreign body reaction tissue and primary repair using absorbable suture material.

ß-COP Regulates TWIK1/TREK1 Heterodimeric Channel-Mediated Passive Conductance in Astrocytes.

Mature astrocytes are characterized by a K+ conductance (passive conductance) that changes with a constant slope with voltage, which is involved in K+ homeostasis in the brain. Recently, we reported that the tandem of pore domains in a weak inward rectifying K+ channel (TWIK1 or KCNK1) and TWIK-related K+ channel 1 (TREK1 or KCNK2) form heterodimeric channels that mediate passive conductance in astrocytes. However, little is known about the binding proteins that regulate the function of the TWIK1/TREK1 heterodimeric channels. Here, we found that ß-coat protein (COP) regulated the surface expression and activity of the TWIK1/TREK1 heterodimeric channels in astrocytes. ß-COP binds directly to TREK1 but not TWIK1 in a heterologous expression system. However, ß-COP also interacts with the TWIK1/TREK1 heterodimeric channel in a TREK1 dependent manner and enhances the surface expression of the heterodimeric channel in astrocytes. Consequently, it regulates TWIK1/TREK1 heterodimeric channel-mediated passive conductance in astrocytes in the mouse brain. Taken together, these results suggest that ß-COP is a potential regulator of astrocytic passive conductance in the brain.

TTYH3 Modulates Bladder Cancer Proliferation and Metastasis via FGFR1/H-Ras/A-Raf/MEK/ERK Pathway.

Tweety family member 3 (TTYH3) is a calcium-activated chloride channel with a non-pore-forming structure that controls cell volume and signal transduction. We investigated the role of TTYH3 as a cancer-promoting factor in bladder cancer. The mRNA expression of TTYH3 in bladder cancer patients was investigated using various bioinformatics databases. The results demonstrated that the increasingly greater expression of TTYH3 increasingly worsened the prognosis of patients with bladder cancer. TTYH3 knockdown bladder cancer cell lines were constructed by their various cancer properties measured. TTYH3 knockdown significantly reduced cell proliferation and sphere formation. Cell migration and invasion were also significantly reduced in knockdown bladder cancer cells, compared to normal bladder cancer cells. The knockdown of TTYH3 led to the downregulation of H-Ras/A-Raf/MEK/ERK signaling by inhibiting fibroblast growth factor receptor 1 (FGFR1) phosphorylation. This signaling pathway also attenuated the expression of c-Jun and c-Fos. The findings implicate TTYH3 as a potential factor regulating the properties of bladder cancer and as a therapeutic target.

Pulmonary vein stump thrombosis after lung resection for lung cancer: clinical features and outcome.

Pulmonary vein stump thrombosis (PVST) is uncommonly encountered postoperative in-situ thrombosis in the stump of pulmonary veins after lung resection. Data regarding the incidence and clinical behaviour of PVST are scarce. Thus, this study aims to investigate the incidence, clinical characteristics and outcome of PVST after lung resection in patients with lung cancer. Follow-up enhanced chest computed tomography (CT) scans acquired after the surgery were retrospectively reviewed to determine PVST presence for patients with lung cancer who underwent lung resection in two tertiary referral centres. Out of the 1885 patients with lung cancer who underwent lobectomy or more extensive lung resection, PVST was observed in 37 patients (2.0%) on their follow-up chest CT. Most stump thrombi were observed in the left superior pulmonary vein [35 (94.6%)] and in patients who underwent left upper lobectomy [34 (91.9%)]. At the last CT follow-up of each patient, 33 (89.2%) exhibited complete resolution, three partial resolution and one stabilization. Eleven (29.7%) patients received anticoagulant therapy after the diagnosis. The rate of complete PVST resolution did not differ significantly between the anticoagulation and nonanticoagulation groups. None of the PVST patients experienced systemic embolic events, regardless of anticoagulation. The PVST incidence diagnosed at routine chest CT follow-up following lung cancer surgery was 2%. PVST was characterized by a benign clinical course without progression and systemic embolization, regardless of anticoagulation. However, further studies are required to determine individualized therapeutic strategies, including anticoagulation.

Deficiency of TTYH1 Expression Reduces the Migration and Invasion of U2OS Human Osteosarcoma Cells.

The Tweety homolog (TTYH) chloride channel family is involved in oncogenic processes including cell proliferation, invasion, and colonization of cancers. Among the TTYH family, TTYH1 is highly expressed in several cancer cells, such as glioma, breast, and gastric cancer cells. However, the role of TTYH1 in the progression of osteosarcoma remains unknown. Here, we report that deficient TTYH1 expression results in the inhibition of the migration and invasion of U2OS human osteosarcoma cells. We found that TTYH1 was endogenously expressed at both mRNA and protein levels in U2OS cells and that these channels were located at the plasma membrane of the cells. Moreover, we found that silencing of the TTYH1 with small interfering RNA (siRNA) resulted in a decrease in the migration and invasion of U2OS cells, while the proliferation of the cells was not affected. Additionally, treatment with TTYH1 siRNA significantly suppressed the mRNA expression of epithelial−mesenchymal transition (EMT)-regulated transcription factors such as Zinc E-Box Binding Homeobox 1 (ZEB1) and SNAIL. Most importantly, the expression of matrix metalloproteinase (MMP)-2, MPP-9, and N-cadherin was dramatically reduced following the silencing of TTYH1. Taken together, our findings suggest that silencing of TTYH1 expression reduces migration and invasion of U2OS cells and that TTYH1 may act as a potential molecular target for osteosarcoma treatment.

Conditional deletion of TMEM16A in cholinergic neurons of the medial habenula induces anhedonic-like behavior in mice.

The medial habenula (mHb), a subregion of the habenula, is involved in diverse brain functions, such as nicotine addiction, anxiety, and anhedonia. We recently reported that TMEM16A deficiency, a calcium-activated chloride channel, decreased the activity of mHb cholinergic neurons. Since downregulated activity in cholinergic neurons of the mHb is involved in anhedonia-like behavior, we here investigated whether conditional deletion of TMEM16A in mHb cholinergic neurons also displays anhedonia-like behavior. The conditional deletion of TMEM16A in the mHb cholinergic neurons of mice (TMEM16A cKO mice) was generated by crossing ChaT-Cre (+) with floxed TMEM16A f/f mice. TMEM16A cKO mice displayed significantly reduced social interaction, sucrose preference, female urine sniffing, and increased marble burying. These behavioral data suggest the potential role of TMEM16A in anhedonic-like behavior in mice. Taken together, the presented data suggest that TMEM16A-mediated mHb activity might be a therapeutic target for anhedonia-related symptoms.

Neuroinflammation Induced by Transgenic Expression of Lipocalin-2 in Astrocytes.

Transgenic mice are a useful tool for exploring various aspects of gene function. A key element of this approach is the targeted overexpression of specific genes in cells or tissues. Herein, we report for the first time, the generation and characterization of conditional transgenic (cTg) mice for lipocalin-2 (LCN2) expression. We generated the R26-LCN2-transgenic (LCN2-cTg) mice that carried a loxP-flanked STOP (neo) cassette, Lcn2 cDNA, and a GFP sequence. When bred with Tg mice expressing Cre recombinase under the control of various tissues or cell-specific promoters, Cre-mediated recombination deletes the STOP cassette and allows the expression of LCN2 and GFP. In this study, we achieved the recombination of loxP-flanked LCN2 in hippocampal astrocytes of cTg mouse brain, using a targeted delivery of adeno-associated virus (AAVs) bearing Cre recombinase under the control of a GFAP promoter (AAVs-GFAP-mCherry-Cre). These mice with localized LCN2 overexpression in astrocytes of the hippocampus developed neuroinflammation with enhanced glial activation and increased mRNA and protein levels of proinflammatory cytokines. Furthermore, mice showed impairment in cognitive functions as a typical symptom of hippocampal inflammation. Taken together, our study demonstrates the usefulness of LCN2-cTg mice in targeting specific cells at various organs for conditional LCN2 expression and for subsequent investigation of the functional role of cell-type-specific LCN2 within these sites. Moreover, the LCN2-cTg mice with targeted expression of LCN2 in hippocampal astrocytes are a new in vivo model of neuroinflammation.

The Effect of the Schroth Rehabilitation Exercise Program on Spinal and Feet Alignment in Adolescent Patients with Idiopathic Scoliosis: A Pilot Study.

BACKGROUND: This study investigated the therapeutic effects of 12-week Schroth rehabilitation exercises (SRE) in improving Cobb's angle, scoliometer readings, lumbar lordosis, and the calcaneal valgus angle of patients with idiopathic scoliosis. METHODS: This pilot study included 60 adolescent patients diagnosed with idiopathic scoliosis by a rehabilitation physician based on a Cobb's angle of ≥10° using total anteroposterior plain radiography. Patients were classified into groups with a Cobb's angle of 10-19° (G1), 20-29° (G2), and ≥30° (G3). Cobb's angle, scoliometer readings, lumbar lordosis, and calcaneal valgus angles were analyzed before and after the 12-week SRE. RESULTS: SRE improved Cobb's angle (-6.85), scoliometer readings (-2.80), lumbar lordosis (4.23), and calcaneal valgus angles (left, -3.76; right, -2.83) regardless of the initial scoliosis angle, and within-group changes were significant (p < 0.001). In this study, participants in all three groups had undergone SRE, regardless of initial scoliosis severity, and the findings were significant. CONCLUSION: SRE can be used for patients with idiopathic scoliosis to improve asymmetric musculoskeletal morphology and the patient's quality of life.