Association of resistance training and moderate-to-vigorous physical activity with clinical outcomes in men with airflow limitation: a nationwide population-based study.

Aerobic moderate-to-vigorous physical activity (MVPA) is recommended for individuals with chronic diseases. However, the association between resistance training (RT) in addition to moderate to vigorous physical activity (MVPA) and sleep duration, as well as respiratory symptoms, in patients with chronic obstructive pulmonary disease has not been thoroughly investigated. This population-based cross-sectional study used data from the Korea National Health and Nutrition Examination Survey between 2014 and 2019. A total of 61,754 individuals were identified and men with airflow limitation (FEV1/FVC < 0.7) who engaged in aerobic MVPA were selected (n = 794). Weighted percentages and odds ratio (OR) of sleep problems (≤ 5 or ≥ 9 h), chronic cough, and chronic sputum were estimated. A multivariate-adjusted complex sample logistic regression model was used to calculate ORs and 95% confidence intervals (CI). Subgroup analyses were conducted using the forced expiratory volume (FEV1) % of the predicted value (%pred) ≥ 80 vs. < 80. The percentages of sleep problems, chronic cough, and chronic sputum production were lower in men who underwent aerobic MVPA + RT than in those who underwent aerobic MVPA alone. The multivariable-adjusted OR of sleep problems was 0.44 (95% CI 0.25-0.77) in individuals undergoing aerobic MVPA + RT compared to aerobic MVPA alone. The ORs of chronic cough and sputum were 0.35 (95% CI 0.13-0.94) and 0.51 (95% CI 0.30-0.87), respectively. These associations were only significant in individuals with FEV1 < 80% pred. Compared with aerobic MVPA alone, aerobic MVPA + RT was associated with appropriate sleep duration and a decrease in chronic cough and sputum in male with airflow limitation. This was more pronounced in individuals with a FEV1 < 80% pred.

Ambulatory Status at Discharge Predicts Six-Month Mortality in Patients with COVID-19: A Retrospective Cohort Study.

This retrospective cohort study aimed to evaluate the association between ambulatory status at discharge and six-month post-discharge mortality among adults with coronavirus disease (COVID-19). We analyzed data from 398 patients aged over 18 admitted to a tertiary hospital in South Korea between December 2019 and June 2022. Patients were classified into two groups based on their ambulatory status at discharge: ambulatory (able to walk independently, n = 286) and non-ambulatory (unable to walk independently, requiring wheelchair or bed-bound, n = 112). Our analysis revealed that six-month survival rates were significantly higher in the ambulatory group (94.2%) compared to the non-ambulatory group (84.4%). Multivariate analysis identified ambulatory status at discharge (p = 0.047) and pre-existing malignancy (p = 0.007) as significant prognostic factors for post-discharge survival. This study highlights that the ability to walk independently at discharge is a crucial predictor of six-month survival in COVID-19 patients. These findings emphasize the need for interventions to improve the physical performance of non-ambulatory patients, potentially enhancing their survival prospects. This underscores the importance of targeted rehabilitation and physical therapy for the comprehensive care of COVID-19 survivors.

An Exploration of Tri-Axial Accelerometers in Assessing the Therapeutic Efficacy of Constraint-Induced Movement Therapy in Children with Unilateral Cerebral Palsy.

This study aimed to elucidate the role of tri-axial accelerometers in assessing therapeutic interventions, specifically constraint-induced movement therapy (CIMT), in children with unilateral cerebral palsy (UCP). The primary focus was understanding the correlation between the actigraphy metrics recorded during CIMT sessions and the resultant therapeutic outcomes. Children with UCP, aged between 4 and 12 years, participated in this study from July 2021 to December 2022. In conjunction with in-clinic sessions, during which participants wore tri-axial accelerometers on both limbs, we analyzed actigraphy data over three days of routine activities pre- and post-CIMT. While not all metrics derived from the accelerometers indicated significant improvements post-intervention, there was a clear trend towards a more balanced usage of both limbs, particularly evident in Axis 3, associated with vertical movement (p = 0.017). Additionally, a discernible correlation was observed between changes in the magnitude ratio derived from actigraphy data during CIMT (Δweek3-week1) and variations in traditional assessments pre- and post-intervention (ΔT0-T1), specifically the Assisting Hand Assessment grasp and release. Using tri-axial accelerometers has helped clarify the potential impacts of CIMT on children with UCP. The preliminary results suggest a possible link between actigraphy metrics taken during CIMT and the subsequent therapeutic outcomes determined by standardized tests.

Case report: Suspecting guanine nucleotide-binding protein beta 1 mutation in dyskinetic cerebral palsy is important.

Herein, we describe the case of a 43-month-old girl who presented with clinical manifestations of dyskinetic cerebral palsy (CP), classified as the Gross Motor Function Classification System (GMFCS) V. The patient had no family history of neurological or perinatal disorders. Despite early rehabilitation, serial assessments using the Gross Motor Function Measure (GMFM) showed no significant improvements in gross motor function. Brain magnetic resonance imaging showed nonspecific findings that could not account for developmental delay or dystonia. Whole-genome sequencing identified a heterozygous NM_002074.5(GNB1):c.239T>C (p.Ile80Thr) mutation in guanine nucleotide-binding protein beta 1 (GNB1) gene. Considering this case and previous studies, genetic testing for the etiology of dyskinetic CP is recommended for children without relevant or with nonspecific brain lesions.

Multichannel Transcranial Direct Current Stimulation Combined With Treadmill Gait Training in Patients With Parkinson's Disease: A Pilot Study.

Background: Gait problems are critical impairments in Parkinson's disease (PD) and are related to increased risk of fall and negatively impact activities of daily life. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that can modify the cortical excitability of gait-related brain regions. In this study, we investigated whether multichannel tDCS with simultaneous treadmill gait training could improve gait in PD. Methods: Twenty-four patients with PD were assigned randomly to a real or sham tDCS group. Before intervention, one patient of the real tDCS group was dropped out, leaving 23 patients to be analyzed in this study. Each patient underwent 30 min of treadmill gait training for 10 sessions over four consecutive weeks. Multichannel 4x1 tDCS was applied using five 6-cm-diameter round electrodes. One anode was placed on the CZ, and four cathodes were positioned symmetrically over the FZ, C5, C6, and PZ. Anodal tDCS (2mA) and sham tDCS were delivered for 20 min. The secondary outcomes were gait performance, as measured by the timed up and go test (TUG) and freezing of gait questionnaire (FOG-Q), and balance was assessed using the dynamic gait index (DGI), Berg balance scale (BBS), and functional reach test (FRT). Motor and non-motor performance of patients with PD were assessed using the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Participants were assessed before the intervention, immediately after the intervention, and 4 weeks after completion of the intervention. Results: The real tDCS group showed a significant improvement in the 10-m walk test, but the sham group did not. Among the secondary outcome measures, MDS-UPDRS part II, TUG, and BBS were improved only in the real tDCS group. Particularly, MDS-UPDRS part II showed a significant group*time interaction effect, indicating that real tDCS demonstrated a better effect on the activities of daily living patients with PD. Conclusions: The results of this pilot study suggest that multichannel tDCS applied on the leg motor cortex during treadmill gait training is a safe and effective means to improve gait velocity in patients with PD. Additional rigorous, large-sample, multicenter, randomized controlled trials are needed to confirm the effect of tDCS as a therapeutic adjunct for gait rehabilitation of patients with PD.

Development of in vitro three-dimensional drug screening system for obesity-related metabolic syndrome.

Metabolic syndrome is increasingly common, and closely related with overweight or obesity. In the obese state, macrophages infiltrate to the adipose tissue (AT), resulting in chronic inflammation and insulin resistance in the AT cells. Recently, attention has been paid to the role of AT macrophages in metabolic disorders should be applied to the initial drug screening step, but it was difficult to mimic the inflammatory adipocytes using the traditional 2-dimensional (2D) culture. In this study, we developed the 3-dimensional (3D) culture system to overcome this limitation. After adipogenic differentiation, lipid droplets were highly accumulated in cells, and differentiation of preadipocytes was not declined by macrophage co-culture. However, only co-cultured cells expressed the insulin resistance features. Compare to mono-cultured adipocytes, co-cultured adipocytes showed reduced glucose uptake and GLUT4 did not translocated to cell membrane even though treatment of high concentration of insulin. Using 3D co-culture model, we develop a microwell-scale drug screening protocol to test anti-obesity effect. 3D cultured cells reacted more sensitive to drugs, and PPARγ antagonist GW9662 (10, 20 µM) repressed adipogenic differentiation in a concentration-dependent manner in 3D co-cultured cells.

Synthesis of novel 1H-Pyrazolo[3,4-b]pyridine derivatives as DYRK 1A/1B inhibitors.

As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8 and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC50 Values of 3-287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory enzymatic activity (IC50 = 3 nM) and cell proliferation inhibitory activity (IC50 = 1.6 µM) towards HCT116 colon cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic interactions.

Optimal stimulation site for rTMS to improve motor function: Anatomical hand knob vs. hand motor hotspot.

Repetitive transcranial magnetic stimulation (rTMS) is used to modulate neuronal excitability of the human brain. Distant effects on contralateral corticomotor excitability can be exerted by interhemispheric modulation by low-frequency rTMS on ipsilateral hemisphere. To modulate corticospinal excitability, accurate determination of the stimulation site is important to maximize the effects of rTMS. In the present study, we investigated the difference in the distant effect of 1 Hz rTMS with respect to inducing functional improvement in the non-dominant hand by inhibiting the dominant hemisphere depending on cortical target areas. Ten healthy right-handed volunteers without any neurological disorders were enrolled. The anatomical hand knob (HK) identified from individual magnetic resonance imaging and the transcranial magnetic stimulation (TMS) induced hand motor hotspot (hMHS) by recording motor evoked potentials (MEPs) in the contralateral first dorsal interosseous muscle were determined. All participants underwent three conditions of 1 Hz rTMS on left hemisphere intervention; rTMS application over the HK, rTMS application over the hMHS, and sham-rTMS. Before and after each intervention, all participants undergone motor function assessments with their left hand. The cortical mapping showed that the hMHS was located anteriorly and laterally compared to the HK. Motor function tests showed the most significant improvements after the hMHS stimulation. When we compared the distant effects of target site on corticospinal excitability and motor behavior, delivering 1 Hz rTMS to the hMHS was more effective than delivering it to the HK for improving corticomotor excitability, motor skill, and dexterity. These results suggest that TMS-induced hMHS is an optimal target area to induce distant effect of low-frequency rTMS in motor function.

Comparison of hemodynamic changes after repetitive transcranial magnetic stimulation over the anatomical hand knob and hand motor hotspot: A functional near-infrared spectroscopy study.

BACKGROUND: Low-frequency rTMS can induce upregulation of excitability in the contralateral hemisphere by interhemispheric interaction. OBJECTIVE: The aim of this study was to compare the effects of interhemispheric modulation on hemodynamic changes after applying low-frequency rTMS over the anatomical hand knob (HK) and the hand motor hotspot (hMHS) in the dominant motor cortex. METHODS: Ten healthy right-handed participants without a history of neurological or psychiatric symptoms (five males; 29.8±2.8 years) participated in this single-blind, randomized, cross-over study. rTMS was applied under three conditions over the dominant (left) hemisphere for 20 minutes: 1) 1 Hz rTMS stimulation on the HK (HK-rTMS), 2) 1 Hz rTMS stimulation on the hMHS (hMHS-rTMS), and 3) sham stimulation (Sham-rTMS). For all participants, functional near-infrared spectroscopy (fNIRS) was applied for measurement of cerebral oxyhemoglobin (oxyHb) and deoxyhemoglobin (deoxyHb) concentration over the non-dominant (right) hemisphere during a serial reaction time task (SRTT) with the non-dominant (left) hand before and after each condition. RESULTS: The average coordinates of the hMHS (x = - 39.60 mm, y = - 17.11 mm, z = 66.40 mm) were anterior and lateral to the HK (x = - 36.72 mm, y = - 28.87 mm, z = 56.41 mm). In fNIRS time-series analysis, the integral value of oxyHb wassignificantly increased over the motor cortical region of the non-dominant hemisphere after the hMHS-rTMS compared with Sham-rTMS. The HK-rTMS also showed slight increment of oxyHb concentration but without statistical significance. The SPM group analysis showed greater magnitude of the activity in hMHS-rTMS than that of HK-rTMS after stimulation (p < 0.05). CONCLUSIONS: These results demonstrated an interhemispheric modulation effect of hemodynamic changes by 1 Hz rTMS. The hMHS produced a more robust modulation effect of 1 Hz rTMS on the contralateral hemisphere than did the HK. Therefore, the rTMS can be considered a better stimulation target than the HK.

A Novel Selective 11ß-HSD1 Inhibitor, (E)-4-(2-(6-(2,6-Dichloro-4-(Trifluoromethyl)Phenyl)-4-Methyl-1,1-Dioxido-1,2,6-Thiadiazinan-2-yl)Acetamido)Adamantan-1-Carboxamide (KR-67607), Prevents BAC-Induced Dry Eye Syndrome.

Dry eye syndrome is the most common eye disease and it is caused by various reasons. As the balance of the tear film that protects the eyes is broken due to various causes, it becomes impossible to properly protect the eyes. In this study, the protective effects and underlying mechanisms of topical (E)-4-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)adamantan-1-carboxamide (KR-67607), a novel selective 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) inhibitor, were investigated in benzalkonium chloride (BAC)-induced dry eye syndrome. BAC-treated rat eyes induced significant increases in ocular surface damage, decreased corneal thickness, corneal basement membrane destruction in the conjunctival epithelium, and expression of pro-inflammatory cytokines tumor necrosis factor-α and 11ß-HSD1. These effects of BAC were reversed by topical KR-67607 treatment. Furthermore, KR-67607 decreased 4-hydroxynonenal expression and increased antioxidant and mucus secretion in BAC-treated rat eyes. Taken together, a novel selective 11ß-HSD1 inhibitor can prevent BAC-induced dry eye syndrome by inhibiting pro-inflammatory cytokine and reactive oxygen species expression via the inhibition of both 11ß-HSD1 activity and expression.

Optimization of cyclic sulfamide derivatives as 11ß-hydroxysteroid dehydrogenase 1 inhibitors for the potential treatment of ischemic brain injury.

The 11ß-hydroxysteroiddehydrogenase type 1(11ß-HSD1), acortisolregenerating enzyme that amplifies tissue glucocorticoidlevels, plays an important role in diabetes, obesity, and glaucoma and is recognized as a potential therapeutic target for various disease conditions. Moreover, a recent study demonstrated that selective 11ß-HSD1 inhibitor can attenuate ischemic brain injury. This prompted us to optimize cyclic sulfamide derivative for aiming to treat ischemic brain injury. Among the synthesized compounds, 6e has an excellent in vitro activivity with an IC50 value of 1 nM toward human and mouse 11ß-HSD1 and showed good 11ß-HSD1 inhibition in ex vivo study using brain tissue isolated from mice. Furthermore, in the transient middle cerebral artery occlusion model in mice, 6e treatment significantly attenuated infarct volume and neurological deficit following cerebral ischemia/reperfusion injury. Additionally, binding modes of 6e for human and mouse 11ß-HSD1 were suggested.

Protective effect of a novel selective 11ß-HSD1 inhibitor on eye ischemia-reperfusion induced glaucoma.

Glaucoma is one of the leading causes of preventable blindness, affecting > 2 million people in the United States. Recently, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors were found to exert preventive effects against glaucoma. However, there is no evidence for the role of 11ß-HSD1 inhibitors against glaucoma. Here, we developed a novel 11ß-HSD1 inhibitor, (1R,2S,3S,5R,6S,7S)-6-(2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamido)-adamantane-2-carboxamide (KR-67607) and showed its protective effects against ischemia-reperfusion-induced eye injury. We demonstrate that KR-67607 effectively reduced cortisol levels in mouse eyes and maintained the trabecular meshwork (TM) structure in the presence of transient ischemic stress. Furthermore, KR-67607 reversed the elevation of intra-ocular pressure (IOP), suggesting that the TM structure maintained by KR-67607 prevented the excessive rise in IOP that exacerbates glaucoma. KR-67607 was shown to have a higher specificity for 11ß-HSD1 than carbenoxolone (CBX) in vitro. Moreover, KR-67607 reduced apoptosis and the structural disruption of TM cells. Antioxidation was the major protective pathway of KR-67607 against chemically-induced ischemia-reperfusion in TM cells and the glucocorticoid receptor (GR) was closely associated with this pathway. When TM cells undergo ischemic stress, GR is activated and then translocates to the cell nucleus where it interferes with Nrf-2-mediated antioxidant gene expression. However, when KR-67607 inhibited GR translocation, Nrf-2 was able to induce antioxidant gene transcription, which consequently, enhanced the antioxidant capacity of the cells. In conclusion, our current work describes a novel selective 11ß-HSD1 inhibitor for glaucoma treatment and provides evidence of its physiological role in anti-oxidative pathways in the TM.

Protective effects of carbenoxolone, an 11ß-HSD1 inhibitor, against chemical induced dry eye syndrome.

Dry eye syndrome (DES) is a disorder of the eye due to tear deficiency or excessive evaporation that causes damage to the eye and is associated with discomfort and dryness. 11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) is an enzyme that converts inactive cortisone to active cortisol. Recently, 11ß-HSD1 has been expressed in human and rodent eyes and has been recognized as a target of glaucoma. In this study, the therapeutic effects and underlying mechanisms of topical carbenoxolone, an 11ß-HSD1 inhibitor, were investigated in benzalkonium chloride (BAC)-treated human conjunctival epithelial cells and a rat DES model. In the in vitro study, carbenoxolone dose-dependently inhibited cell death and 11ß-HSD1 activity in BAC-treated human conjunctival epithelial cells. For the in vivo study, carbenoxolone or a solvent was administered to the BAC-induced DES model twice daily. BAC-treated rat eyes showed significant increases in ocular surface damage, a reduction of tears, decrease corneal thickness, corneal basement membrane destruction, apoptosis in the conjunctival epithelium, and expression of pro-inflammatory cytokines (TNF-α and IL-6) and 11ß-HSD1. These effects of BAC were reversed by topical carbenoxolone treatment. These results demonstrate that carbenoxolone can prevent DES by inhibiting pro-inflammatory cytokine expression and cell death of the corneal and conjunctival epithelium via inhibition of both 11ß-HSD1 activity and expression in the eyes of BAC-treated rats. It is suggested that topical 11ß-HSD1 inhibitors may provide a new therapeutic window in the prevention and/or treatment of DES.

Carbenoxolone prevents chemical eye ischemia-reperfusion-induced cell death via 11ß-hydroxysteroid dehydrogenase type 1 inhibition.

Glaucoma is one of the leading causes of preventable blindness diseases, affecting more than 2 million people in the United States. Recently, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors were found to exert preventive effects against glaucoma. Therefore, we investigated whether carbenoxolone (CBX), an 11ß-HSD1 inhibitor, prevents chemical ischemia-reperfusion-induced cell death in human trabecular meshwork (HTM) cells. The present study demonstrated that CBX inhibited cell death caused by iodoacetic acid (IAA)-induced ischemia-reperfusion, and its effect was associated with the inhibition of 11ß-HSD1 expression and activity. Furthermore, CBX reversed the IAA-induced structural damage on filamentous actin in HTM cells. In IAA-treated cells, the levels of 11ß-HSD1 and the apoptosis-related factors Bax and FASL were increased throughout the reperfusion period, and CBX was able to attenuate the expression of 11ß-HSD1 and the apoptosis-related factors. CBX also effectively suppressed IAA-induced intracellular ROS formation and cytochrome c release, which are involved in the mitochondrial apoptosis pathway. In addition, IAA-induced chemical ischemia-reperfusion stimulated TNF-α expression and NF-κB p65 phosphorylation, and these effects were attenuated by CBX. 11ß-HSD1 RNAi also suppressed IAA-induced cell apoptosis via reduction of oxidative stress and inhibition of the pro-inflammatory pathway. Taken together, the present study demonstrated that the inhibition of 11ß-HSD1 protected the TM against chemical ischemia-reperfusion injury, suggesting that the use of 11ß-HSD1 inhibitors could be a useful strategy for glaucoma therapy.

Erratum to: Ganglioside GM1 influences the proliferation rate of mouse induced pluripotent stem cells.

The BMB Reports would like to correct in the ACKNOWLEDGEMENTS of BMB Rep. 45(12), 713-718 titled "Ganglioside GM1 influences the proliferation rate of mouse induced pluripotent stem cells".

Anti-inflammatory effect of a selective 11ß-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) converts inactive cortisone to the active cortisol. 11ß-HSD1 may be involved in the resolution of inflammation. In the present study, we investigate the anti-inflammatory effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), a selective 11ß-HSD1 inhibitor, in lipopolysaccharide (LPS)-activated C57BL/6J mice and macrophages. LPS increased 11ß-HSD1 activity and expression in macrophages, which was inhibited by KR-66344. In addition, KR-66344 increased survival rate in LPS treated C57BL/6J mice. HO-1 mRNA expression level was increased by KR-66344, and this effect was reversed by the HO competitive inhibitor, ZnPP, in macrophages. Moreover, ZnPP reversed the suppression of ROS formation and cell death induced by KR-66344. ZnPP also suppressed animal survival rate in LPS plus KR-66344 treated C57BL/6J mice. In the spleen of LPS-treated mice, KR-66344 prevented cell death via suppression of inflammation, followed by inhibition of ROS, iNOS and COX-2 expression. Furthermore, LPS increased NFκB-p65 and MAPK phosphorylation, and these effects were abolished by pretreatment with KR-66344. Taken together, KR-66344 protects against LPS-induced animal death and spleen injury by inhibition of inflammation via induction of HO-1 and inhibition of 11ß-HSD1 activity. Thus, we concluded that the selective 11ß-HSD1 inhibitor may provide a novel strategy in the prevention/treatment of inflammatory disorders in patients.

Ganglioside GM1 influences the proliferation rate of mouse induced pluripotent stem cells.

Gangliosides play important roles in the control of several biological processes, including proliferation and transmembrane signaling. In this study, we demonstrate the effect of ganglioside GM1 on the proliferation of mouse induced pluripotent stem cells (miPSCs). The proliferation rate of miPSCs was lower than in mouse embryonic stem cells (mESCs). Fluorescence activated cell sorting analysis showed that the percentage of cells in the G2/M phase in miPSCs was lower than that in mESCs. GM1 was expressed in mESCs, but not miPSCs. To confirm the role of GM1 in miPSC proliferation, miPSCs were treated with GM1. GM1-treated miPSCs exhibited increased cell proliferation and a larger number of cells in the G2/M phase. Furthermore, phosphorylation of mitogen-activated protein kinases was increased in GM1- treated miPSCs.