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1.
J Korean Med Sci ; 39(34): e278, 2024 Sep 02.
Article in English | MEDLINE | ID: mdl-39228188

ABSTRACT

This report presents the latest statistics on the stroke population in South Korea, sourced from the Clinical Research Collaborations for Stroke in Korea-National Institute for Health (CRCS-K-NIH), a comprehensive, nationwide, multicenter stroke registry. The Korean cohort, unlike western populations, shows a male-to-female ratio of 1.5, attributed to lower risk factors in Korean women. The average ages for men and women are 67 and 73 years, respectively. Hypertension is the most common risk factor (67%), consistent with global trends, but there is a higher prevalence of diabetes (35%) and smoking (21%). The prevalence of atrial fibrillation (19%) is lower than in western populations, suggesting effective prevention strategies in the general population. A high incidence of large artery atherosclerosis (38%) is observed, likely due to prevalent intracranial arterial disease in East Asians and advanced imaging techniques. There has been a decrease in intravenous thrombolysis rates, from 12% in 2017-2019 to 10% in 2021, with no improvements in door-to-needle and door-to-puncture times, worsened by the coronavirus disease 2019 pandemic. While the use of aspirin plus clopidogrel for non-cardioembolic stroke and direct oral anticoagulants for atrial fibrillation is well-established, the application of direct oral anticoagulants for non-atrial fibrillation cardioembolic strokes in the acute phase requires further research. The incidence of early neurological deterioration (13%) and the cumulative incidence of recurrent stroke at 3 months (3%) align with global figures. Favorable outcomes at 3 months (63%) are comparable internationally, yet the lack of improvement in dependency at 3 months highlights the need for advancements in acute stroke care.


Subject(s)
Ischemic Attack, Transient , Ischemic Stroke , Registries , Humans , Republic of Korea/epidemiology , Female , Ischemic Attack, Transient/epidemiology , Ischemic Stroke/epidemiology , Male , Aged , Risk Factors , COVID-19/epidemiology , Atrial Fibrillation/epidemiology , Atrial Fibrillation/drug therapy , Atrial Fibrillation/complications , Middle Aged , Anticoagulants/therapeutic use , Incidence , Stroke/epidemiology , Aged, 80 and over , SARS-CoV-2 , Hypertension/epidemiology , Hypertension/complications , Prevalence
2.
Support Care Cancer ; 32(10): 645, 2024 Sep 09.
Article in English | MEDLINE | ID: mdl-39251492

ABSTRACT

PURPOSE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.


Subject(s)
Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Erlotinib Hydrochloride , Gefitinib , Lung Neoplasms , Protein Kinase Inhibitors , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Male , Female , Prospective Studies , Middle Aged , Aged , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Gefitinib/administration & dosage , Gefitinib/therapeutic use , Gefitinib/pharmacology , Erlotinib Hydrochloride/administration & dosage , Erlotinib Hydrochloride/pharmacology , Erlotinib Hydrochloride/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Afatinib/administration & dosage , Afatinib/therapeutic use , Afatinib/pharmacology , Cohort Studies , Aged, 80 and over , Adult
3.
J Hazard Mater ; 478: 135359, 2024 Oct 05.
Article in English | MEDLINE | ID: mdl-39126856

ABSTRACT

Polyhexamethylene guanidine (PHMG) is a positively charged polymer used as a disinfectant that kills microbes but can cause pulmonary fibrosis if inhaled. After the long-term risks were confirmed in South Korea, it became crucial to measure toxicity through diverse surrogate biomarkers, not only proteins, especially after these hazardous chemicals had cleared from the body. These biomarkers, identified by their biological functions rather than simple numerical calculations, effectively explained the imbalance of pulmonary surfactant caused by fibrosis from PHMG exposure. These long-term studies on children exposed to PHMG has shown that blood protein indicators, primarily related to apolipoproteins and extracellular matrix, can distinguish the degree of exposure to humidifier disinfectants (HDs). We defined the extreme gradient boosting models and computed reflection scores based on just ten selected proteins, which were also verified in adult women exposed to HD. The reflection scores successfully discriminated between the HD-exposed and unexposed groups in both children and adult females (AUROC: 0.957 and 0.974, respectively) and had a strong negative correlation with lung function indicators. Even after an average of more than 10 years, blood is still considered a meaningful specimen for assessing the impact of environmental exposure to toxic substances, with proteins providing in identifying the pathological severity of such conditions.


Subject(s)
Aerosols , Blood Proteins , Guanidines , Humans , Guanidines/toxicity , Guanidines/chemistry , Female , Adult , Blood Proteins/analysis , Lung Injury/chemically induced , Biomarkers/blood , Disinfectants/toxicity , Child , Humidifiers , Inhalation Exposure/adverse effects
4.
PLoS One ; 19(7): e0305832, 2024.
Article in English | MEDLINE | ID: mdl-39024311

ABSTRACT

Understanding the mechanisms that underlie de novo mutations (DNMs) can be essential for interpreting human evolution, including aspects such as rapidly diverging genes, conservation of non-coding regulatory elements, and somatic DNA adaptation, among others. DNM accumulation in Homo sapiens is often limited to evaluation of human trios or quads across a single generation. Moreover, human SNPs in exons, pseudogenes, or other non-coding elements can be ancient and difficult to date, including polymorphisms attributable to founder effects and identity by descent. In this report, we describe multigenerational evolution of a human coding locus devoid of natural selection, and delineate patterns and principles by which DNMs have accumulated over the past few thousand years. We apply a data set comprising cystic fibrosis transmembrane conductance regulator (CFTR) alleles from 2,393 individuals homozygous for the F508del defect. Additional polymorphism on the F508del background diversified subsequent to a single mutational event during recent human history. Because F508del CFTR is without function, SNPs observed on this haplotype are effectively attributable to factors that govern accumulating de novo mutations. We show profound enhancement of transition, synonymous, and positionally repetitive polymorphisms, indicating appearance of DNMs in a manner evolutionarily designed to protect protein coding DNA against mutational attrition while promoting diversity.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator , Mutation , Polymorphism, Single Nucleotide , Humans , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Evolution, Molecular , Haplotypes , Genomics/methods , Genome, Human , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism
5.
Sci Rep ; 14(1): 15678, 2024 07 08.
Article in English | MEDLINE | ID: mdl-38977785

ABSTRACT

Aging and lack of exercise are the most important etiological factors for muscle loss. We hypothesized that new factors that contribute to muscle loss could be identified from ones commonly altered in expression in aged and exercise-limited skeletal muscles. Mouse gastrocnemius muscles were subjected to mass spectrometry-based proteomic analysis. The muscle proteomes of hindlimb-unloaded and aged mice were compared to those of exercised and young mice, respectively. C1qbp expression was significantly upregulated in the muscles of both hindlimb-unloaded and aged mice. In vitro myogenic differentiation was not affected by altering intracellular C1qbp expression but was significantly suppressed upon recombinant C1qbp treatment. Additionally, recombinant C1qbp repressed the protein level but not the mRNA level of NFATc1. NFATc1 recruited the transcriptional coactivator p300, leading to the upregulation of acetylated histone H3 levels. Furthermore, NFATc1 silencing inhibited p300 recruitment, downregulated acetylated histone H3 levels, and consequently suppressed myogenic differentiation. The expression of C1qbp was inversely correlated with that of NFATc1 in the gastrocnemius muscles of exercised or hindlimb-unloaded, and young or aged mice. These findings demonstrate a novel role of extracellular C1qbp in suppressing myogenesis by inhibiting the NFATc1/p300 complex. Thus, C1qbp can serve as a novel therapeutic target for muscle loss.


Subject(s)
Muscle Development , Muscle, Skeletal , NFATC Transcription Factors , Animals , Male , Mice , Acetylation , Cell Differentiation , Histones/metabolism , Mice, Inbred C57BL , Muscle Development/genetics , Muscle, Skeletal/metabolism , NFATC Transcription Factors/metabolism , NFATC Transcription Factors/genetics
6.
Int J Mol Sci ; 25(13)2024 Jun 30.
Article in English | MEDLINE | ID: mdl-39000341

ABSTRACT

Poly L-lactic acid (PLLA) fillers stimulate collagen synthesis by activating various immune cells and fibroblasts. Piezo1, an ion channel, responds to mechanical stimuli, including changes in extracellular matrix stiffness, by mediating Ca2+ influx. Given that elevated intracellular Ca2+ levels trigger signaling pathways associated with fibroblast proliferation, Piezo1 is a pivotal regulator of collagen synthesis and tissue fibrosis. The aim of the present study was to investigate the impact of PLLA on dermal collagen synthesis by activating Piezo1 in both an H2O2-induced cellular senescence model in vitro and aged animal skin in vivo. PLLA elevated intracellular Ca2+ levels in senescent fibroblasts, which was attenuated by the Piezo1 inhibitor GsMTx4. Furthermore, PLLA treatment increased the expression of phosphorylated ERK1/2 to total ERK1/2 (pERK1/2/ERK1/2) and phosphorylated AKT to total AKT (pAKT/AKT), indicating enhanced pathway activation. This was accompanied by upregulation of cell cycle-regulating proteins (CDK4 and cyclin D1), promoting the proliferation of senescent fibroblasts. Additionally, PLLA promoted the expression of phosphorylated mTOR/S6K1/4EBP1, TGF-ß, and Collagen I/III in senescent fibroblasts, with GsMTx4 treatment mitigating these effects. In aged skin, PLLA treatment similarly upregulated the expression of pERK1/2/ERK1/2, pAKT/AKT, CDK4, cyclin D1, mTOR/S6K1/4EBP1, TGF-ß, and Collagen I/III. In summary, our findings suggest Piezo1's involvement in PLLA-induced collagen synthesis, mediated by heightened activation of cell proliferation signaling pathways such as pERK1/2/ERK1/2, pAKT/AKT, and phosphorylated mTOR/S6K1/4EBP1, underscoring the therapeutic potential of PLLA in tissue regeneration.


Subject(s)
Collagen , Fibroblasts , Polyesters , Animals , Polyesters/pharmacology , Polyesters/chemistry , Fibroblasts/metabolism , Fibroblasts/drug effects , Collagen/metabolism , Collagen/biosynthesis , Ion Channels/metabolism , Mice , Skin/metabolism , Skin/drug effects , Skin Aging/drug effects , Cellular Senescence/drug effects , Cell Proliferation/drug effects , Calcium/metabolism , Signal Transduction/drug effects , Humans
7.
Int J Stroke ; : 17474930241265652, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38907672

ABSTRACT

BACKGROUND: Multiple attempts of thrombectomy have been linked to a higher risk of intracerebral hemorrhage and worsened functional outcomes, potentially influenced by blood pressure (BP) management strategies. Nonetheless, the impact of intensive BP management following successful recanalization through multiple attempts remains uncertain. AIMS: This study aimed to investigate whether conventional and intensive BP managements differentially affect outcomes according to multiple-attempt recanalization (MAR) and first-attempt recanalization (FAR) groups. METHODS: In this secondary analysis of the OPTIMAL-BP trial, which was a comparison of intensive (systolic BP target: <140 mm Hg) and conventional (systolic BP target = 140-180 mm Hg) BP managements during the 24 h after successful recanalization, we included intention-to-treat population of the trial. Patients were divided into the MAR and the FAR groups. We examined a potential interaction between the number of thrombectomy attempts (MAR and FAR groups) and the effect of BP managements on clinical and safety outcomes. The primary outcome was functional independence at 3 months. Safety outcomes were symptomatic intracerebral hemorrhage within 36 h and mortality within 3 months. RESULTS: Of the 305 patients (median = 75 years), 102 (33.4%) were in the MAR group and 203 (66.6%) were in the FAR group. The intensive BP management was significantly associated with a lower rate of functional independence in the MAR group (intensive, 32.7% vs conventional, 54.9%, adjusted odds ratio (OR) = 0.33, 95% confidence interval (CI) = 0.12-0.90, p = 0.03). In the FAR group, the proportion of patients with functional independence was not significantly different between the BP managements (intensive, 42.5% vs conventional, 54.2%, adjusted OR = 0.73, 95% CI = 0.38-1.40). Incidences of symptomatic intracerebral hemorrhage and mortality rates were not significantly different according to the BP managements in both MAR and FAR groups. CONCLUSIONS: Among stroke patients who received multiple attempts of thrombectomy, intensive BP management for 24 h resulted in a reduced chance of functional independence at 3 months and did not reduce symptomatic intracerebral hemorrhage following successful reperfusion.

8.
Int J Mol Sci ; 25(10)2024 May 15.
Article in English | MEDLINE | ID: mdl-38791435

ABSTRACT

Naturally derived essential oils and their active components are known to possess various properties, ranging from anti-oxidant, anti-inflammatory, anti-bacterial, anti-fungal, and anti-cancer activities. Numerous types of essential oils and active components have been discovered, and their permissive roles have been addressed in various fields. In this comprehensive review, we focused on the roles of essential oils and active components in skin diseases and cancers as discovered over the past three decades. In particular, we opted to highlight the effectiveness of essential oils and their active components in developing strategies against various skin diseases and skin cancers and to describe the effects of the identified essential-oil-derived major components from physiological and pathological perspectives. Overall, this review provides a basis for the development of novel therapies for skin diseases and cancers, especially melanoma.


Subject(s)
Oils, Volatile , Skin Neoplasms , Skin , Oils, Volatile/pharmacology , Oils, Volatile/therapeutic use , Oils, Volatile/chemistry , Humans , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Skin Neoplasms/metabolism , Skin/drug effects , Skin/metabolism , Skin/pathology , Animals , Skin Diseases/drug therapy
9.
J Am Heart Assoc ; 13(10): e033611, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38761083

ABSTRACT

BACKGROUND: Recent clinical trials established the benefit of dual antiplatelet therapy with aspirin and clopidogrel (DAPT-AC) in early-presenting patients with minor ischemic stroke. However, the impact of these trials over time on the use and outcomes of DAPT-AC among the patients with nonminor or late-presenting stroke who do not meet the eligibility criteria of these trials has not been delineated. METHODS AND RESULTS: In a multicenter stroke registry, this study examined yearly changes from April 2008 to August 2022 in DAPT-AC use for stroke patients ineligible for CHANCE/POINT (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events/Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) clinical trials due to National Institutes of Health Stroke Scale >4 or late arrival beyond 24 hours of onset. A total of 32 118 patients (age, 68.1±13.1 years; male, 58.5%) with National Institutes of Health Stroke Scale of 4 (interquartile range, 1-7) were analyzed. In 2008, DAPT-AC was used in 33.0%, other antiplatelets in 62.7%, and no antiplatelet in 4.3%. The frequency of DAPT-AC was relatively unchanged through 2013, when the CHANCE trial was published, and then increased steadily, reaching 78% in 2022, while other antiplatelets decreased to 17.8% in 2022 (Ptrend<0.001). From 2011 to 2022, clinical outcomes nonsignificantly improved, with an average relative risk reduction of 2%/y for the composite of stroke, myocardial infarction, and all-cause mortality, both among patients treated with DAPT-AC and patients treated with other antiplatelets. CONCLUSIONS: Use of DAPT-AC in stroke patients with stroke ineligible for recent DAPT clinical trials increased markedly and steadily after CHANCE publication in 2013, reaching deployment in nearly 4 of every 5 patients by 2022. The secondary prevention in patients with ischemic stroke seems to be gradually improving, possibly due to the enhancement of risk factor control.


Subject(s)
Aspirin , Clopidogrel , Dual Anti-Platelet Therapy , Ischemic Stroke , Platelet Aggregation Inhibitors , Registries , Humans , Clopidogrel/therapeutic use , Aspirin/therapeutic use , Male , Aged , Female , Ischemic Stroke/drug therapy , Ischemic Stroke/mortality , Ischemic Stroke/diagnosis , Ischemic Stroke/prevention & control , Dual Anti-Platelet Therapy/adverse effects , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/adverse effects , Middle Aged , Treatment Outcome , Aged, 80 and over , Time Factors , Japan/epidemiology , Secondary Prevention/methods , Secondary Prevention/trends , Drug Therapy, Combination , Risk Factors
10.
Int J Mol Sci ; 25(8)2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38673775

ABSTRACT

Solute carrier family 26 member 4 (SLC26A4) is a member of the SLC26A transporter family and is expressed in various tissues, including the airway epithelium, kidney, thyroid, and tumors. It transports various ions, including bicarbonate, chloride, iodine, and oxalate. As a multiple-ion transporter, SLC26A4 is involved in the maintenance of hearing function, renal function, blood pressure, and hormone and pH regulation. In this review, we have summarized the various functions of SLC26A4 in multiple tissues and organs. Moreover, the relationships between SLC26A4 and other channels, such as cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and sodium chloride cotransporter, are highlighted. Although the modulation of SLC26A4 is critical for recovery from malfunctions of various organs, development of specific inducers or agonists of SLC26A4 remains challenging. This review contributes to providing a better understanding of the role of SLC26A4 and development of therapeutic approaches for the SLC26A4-associated hearing loss and SLC26A4-related dysfunction of various organs.


Subject(s)
Sulfate Transporters , Humans , Sulfate Transporters/metabolism , Sulfate Transporters/genetics , Animals , Kidney/metabolism , Chloride-Bicarbonate Antiporters/metabolism , Chloride-Bicarbonate Antiporters/genetics , Organ Specificity , Chlorides/metabolism , Ion Transport
11.
Public Health Nurs ; 41(4): 723-735, 2024.
Article in English | MEDLINE | ID: mdl-38588062

ABSTRACT

OBJECTIVE: To analyze duties, tasks, and task elements of health workers in charge of vaccination at public health centers in South Korea. DESIGN: Descriptive study using a survey. SAMPLE: Health workers in charge of vaccination for more than 1 year at 254 public health centers in South Korea. Of 631 health workers, 401 responded to the questionnaire, and 379 responses were included in the analysis after excluding 22 incomplete responses. MEASUREMENTS: The Developing A Curriculum (DACUM) workshop was conducted to identify the frequency, importance, and difficulty of duties, tasks, and task elements. RESULTS: Four duties (vaccination promotion, vaccination administration and symptom management, execution of vaccination, and vaccination education), 18 tasks, and 81 task elements were identified. "Execution of vaccination" exhibited the highest determinant coefficient. "Implementing the budget" exhibited the highest determinant coefficient among tasks, and "dealing with an emergency in the case of adverse events" exhibited the highest determinant coefficient among task elements. CONCLUSIONS: Duty, task, and task elements with high determinant coefficients have high educational needs. Education demands was higher for administrative work than for direct vaccination. Developing an educational curriculum based on DACUM results could contribute to the professional education of vaccine workers.


Subject(s)
Vaccination , Humans , Republic of Korea , Vaccination/statistics & numerical data , Surveys and Questionnaires , Male , Female , Adult , Curriculum , Health Personnel , Task Performance and Analysis , Middle Aged , Job Description
12.
JAMA Netw Open ; 7(4): e246878, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38630474

ABSTRACT

Importance: The associations between blood pressure (BP) decreases induced by medication and functional outcomes in patients with successful endovascular thrombectomy remain uncertain. Objective: To evaluate whether BP reductions induced by intravenous BP medications are associated with poor functional outcomes at 3 months. Design, Setting, and Participants: This cohort study was a post hoc analysis of the Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control trial, a comparison of intensive and conventional BP management during the 24 hours after successful recanalization from June 18, 2020, to November 28, 2022. This study included 302 patients who underwent endovascular thrombectomy, achieved successful recanalization, and exhibited elevated BP within 2 hours of successful recanalization at 19 stroke centers in South Korea. Exposure: A BP decrease was defined as at least 1 event of systolic BP less than 100 mm Hg. Patients were divided into medication-induced BP decrease (MIBD), spontaneous BP decrease (SpBD), and no BP decrease (NoBD) groups. Main Outcomes and Measures: The primary outcome was a modified Rankin scale score of 0 to 2 at 3 months, indicating functional independence. Primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and mortality due to index stroke within 3 months. Results: Of the 302 patients (median [IQR] age, 75 [66-82] years; 180 [59.6%] men), 47 (15.6%)were in the MIBD group, 39 (12.9%) were in the SpBD group, and 216 (71.5%) were in the NoBD group. After adjustment for confounders, the MIBD group exhibited a significantly smaller proportion of patients with functional independence at 3 months compared with the NoBD group (adjusted odds ratio [AOR], 0.45; 95% CI, 0.20-0.98). There was no significant difference in functional independence between the SpBD and NoBD groups (AOR, 1.41; 95% CI, 0.58-3.49). Compared with the NoBD group, the MIBD group demonstrated higher odds of mortality within 3 months (AOR, 5.15; 95% CI, 1.42-19.4). The incidence of symptomatic intracerebral hemorrhage was not significantly different among the groups (MIBD vs NoBD: AOR, 1.89; 95% CI, 0.54-5.88; SpBD vs NoBD: AOR, 2.75; 95% CI, 0.76-9.46). Conclusions and Relevance: In this cohort study of patients with successful endovascular thrombectomy after stroke, MIBD within 24 hours after successful recanalization was associated with poor outcomes at 3 months. These findings suggested lowering systolic BP to below 100 mm Hg using BP medication might be harmful.


Subject(s)
Hypertension , Stroke , Aged , Female , Humans , Male , Blood Pressure , Cerebral Hemorrhage , Cohort Studies , Hypertension/epidemiology , Pressure , Stroke/surgery , Aged, 80 and over
13.
Nat Commun ; 15(1): 2957, 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38580646

ABSTRACT

Nonsense mutations - the underlying cause of approximately 11% of all genetic diseases - prematurely terminate protein synthesis by mutating a sense codon to a premature stop or termination codon (PTC). An emerging therapeutic strategy to suppress nonsense defects is to engineer sense-codon decoding tRNAs to readthrough and restore translation at PTCs. However, the readthrough efficiency of the engineered suppressor tRNAs (sup-tRNAs) largely varies in a tissue- and sequence context-dependent manner and has not yet yielded optimal clinical efficacy for many nonsense mutations. Here, we systematically analyze the suppression efficacy at various pathogenic nonsense mutations. We discover that the translation velocity of the sequence upstream of PTCs modulates the sup-tRNA readthrough efficacy. The PTCs most refractory to suppression are embedded in a sequence context translated with an abrupt reversal of the translation speed leading to ribosomal collisions. Moreover, modeling translation velocity using Ribo-seq data can accurately predict the suppression efficacy at PTCs. These results reveal previously unknown molecular signatures contributing to genotype-phenotype relationships and treatment-response heterogeneity, and provide the framework for the development of personalized tRNA-based gene therapies.


Subject(s)
Codon, Nonsense , RNA, Transfer , Codon, Nonsense/genetics , RNA, Transfer/genetics , RNA, Transfer/metabolism , Codon/genetics , Ribosomes/metabolism , Genetic Therapy , Protein Biosynthesis/genetics , Codon, Terminator
14.
World J Surg ; 48(3): 713-722, 2024 03.
Article in English | MEDLINE | ID: mdl-38501549

ABSTRACT

BACKGROUND: The da Vinci single-port system (SPS) (Intuitive Surgical, Sunnyvale, CA, USA) was designed for single-port (SP) surgery. Although we have reported our clinical outcomes using the SPS for a simple procedure in general thoracic surgery, major pulmonary resection had been performed only in cadaveric experiments to date. This study evaluated the feasibility of SP subcostal robotic major pulmonary resection using the SPS. Here, we present our initial clinical experience of SP subcostal robotic major pulmonary resection at our institution. METHODS: Twenty-five patients with lung cancer underwent SP major subcostal pulmonary resection using the SPS between March and November 2022. Patient characteristics, intraoperative and perioperative outcomes were assessed. Questionnaires were used to evaluate patient satisfaction with the cosmetic results and quality of life through face-to-face or telephone interviews on postoperative day 30. RESULTS: All patients underwent major pulmonary resection with complete radical resection (R0). Nineteen patients underwent lobectomy, whereas six patients underwent segmentectomy. The mean docking time and total operative time were 4.16 ± 1.19 min (range, 2.3-7.8 min) and 197.6 ± 55.33 min (range, 130-313 min), respectively. No patients underwent conversion to open thoracotomy. One patient required an additional assistant port due to severe pleural adhesions. CONCLUSIONS: SP subcostal robotic major pulmonary resection using the SPS is feasible and safe. With the continuous development of robotic technology and surgical techniques, we believe that more complex general thoracic surgeries will be performed in the future using SPS.


Subject(s)
Robotic Surgical Procedures , Robotics , Humans , Robotic Surgical Procedures/methods , Quality of Life , Operative Time , Patient Satisfaction
15.
Comput Inform Nurs ; 42(5): 343-353, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38453464

ABSTRACT

New nurses must acquire accurate knowledge of medication administration, as it directly affects patient safety. This study aimed to develop a microlearning-based self-directed learning chatbot on medication administration for novice nurses. Furthermore, the study had the objective of evaluating the chatbot feasibility. The chatbot covered two main topics: medication administration processes and drug-specific management, along with 21 subtopics. Fifty-eight newly hired nurses on standby were asked to use the chatbot over a 2-week period. Moreover, we evaluated the chatbot's feasibility through a survey that gauged changes in their confidence in medication administration knowledge, intrinsic learning motivation, satisfaction with the chatbot's learning content, and usability. After using the chatbot, participants' confidence in medication administration knowledge significantly improved in all topics ( P < .001) except "Understanding a concept of 5Right" ( P = .077). Their intrinsic learning motivation, satisfaction with the learning content, and usability scored above 5 out of 7 in all subdomains, except for pressure/tension (mean, 2.12; median, 1.90). They scored highest on ease of learning (mean, 6.69; median, 7.00). A microlearning-based chatbot can help new nurses improve their knowledge of medication administration through self-directed learning.


Subject(s)
Feasibility Studies , Humans , Female , Adult , Surveys and Questionnaires , Male , Self-Directed Learning as Topic , Clinical Competence
17.
Int J Mol Sci ; 25(5)2024 Feb 29.
Article in English | MEDLINE | ID: mdl-38474091

ABSTRACT

Ubiquitin-like modifier-activating enzyme 6 (UBA6) is a member of the E1 enzyme family, which initiates the ubiquitin-proteasome system (UPS). The UPS plays critical roles not only in protein degradation but also in various cellular functions, including neuronal signaling, myocardial remodeling, immune cell differentiation, and cancer development. However, the specific role of UBA6 in cellular functions is not fully elucidated in comparison with the roles of the UPS. It has been known that the E1 enzyme is associated with the motility of cancer cells. In this study, we verified the physiological roles of UBA6 in lung cancer cells through gene-silencing siRNA targeting UBA6 (siUBA6). The siUBA6 treatment attenuated the migration of H1975 cells, along with a decrease in lysosomal Ca2+ release. While autophagosomal proteins remained unchanged, lysosomal proteins, including TRPML1 and TPC2, were decreased in siUBA6-transfected cells. Moreover, siUBA6 induced the production of multivesicular bodies (MVBs), accompanied by an increase in MVB markers in siUBA6-transfected H1975 cells. Additionally, the expression of the exosomal marker CD63 and extracellular vesicles was increased by siUBA6 treatment. Our findings suggest that knock-down of UBA6 induces lysosomal TRPML1 depletion and inhibits endosomal trafficking to lysosome, and subsequently, leads to the accumulation of MVBs and enhanced exosomal secretion in lung cancer cells.


Subject(s)
Lung Neoplasms , Humans , Lung Neoplasms/metabolism , Lysosomes/metabolism , Multivesicular Bodies/metabolism , Proteasome Endopeptidase Complex/metabolism , Signal Transduction , Ubiquitin/metabolism , Ubiquitin-Activating Enzymes/metabolism
18.
Medicina (Kaunas) ; 60(3)2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38541075

ABSTRACT

Background and Objectives: Therapeutic hypothermia (TH) shows promise as an approach with neuroprotective effects, capable of reducing secondary brain damage and intracranial pressure following successful mechanical thrombectomy in the acute phase. However, its effect on cognitive impairment remains unclear. This study investigated whether TH can improve cognitive impairment in a mouse model of transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R). Materials and Methods: Nine-week-old C57BL/6N mice (male) were randomly assigned to three groups: sham, tMCAO/R, and tMCAO/R with TH. Cognitive function was assessed 1 month after model induction using the Y-maze test, and regional cerebral glucose metabolism was measured through positron emission tomography with fluorine-18 fluorodeoxyglucose. Results: tMCAO/R induced cognitive impairment, which showed improvement with TH. The TH group exhibited a significant recovery in cerebral glucose metabolism in the thalamus compared to the tMCAO/R group. Conclusions: These findings indicate that TH may hold promise as a therapeutic strategy for alleviating ischemia/reperfusion-induced cognitive impairment.


Subject(s)
Cognitive Dysfunction , Hypothermia, Induced , Neuroprotective Agents , Reperfusion Injury , Mice , Animals , Male , Neuroprotective Agents/pharmacology , Mice, Inbred C57BL , Infarction, Middle Cerebral Artery/drug therapy , Reperfusion Injury/complications , Cognitive Dysfunction/therapy , Cognitive Dysfunction/complications , Glucose
19.
J Neurol ; 271(5): 2684-2693, 2024 May.
Article in English | MEDLINE | ID: mdl-38376545

ABSTRACT

BACKGROUND: The effectiveness of endovascular treatment for in-hospital stroke remains debatable. We aimed to compare the outcomes between patients with in-hospital stroke and community-onset stroke who received endovascular treatment. METHODS: This prospective registry-based cohort study included consecutive patients who underwent endovascular treatment from January 2013 to December 2022 and were registered in the Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy study and Yonsei Stroke Cohort. Functional outcomes at day 90, radiological outcomes, and safety outcomes were compared between the in-hospital and community-onset groups using logistic regression and propensity score-matched analysis. RESULTS: Of 1,219 patients who underwent endovascular treatment, 117 (9.6%) had in-hospital stroke. Patients with in-hospital onset were more likely to have a pre-stroke disability and active cancer than those with community-onset. The interval from the last known well to puncture was shorter in the in-hospital group than in the community-onset group (155 vs. 355 min, p<0.001). No significant differences in successful recanalization or safety outcomes were observed between the groups; however, the in-hospital group exhibited worse functional outcomes and higher mortality at day 90 than the community-onset group (all p<0.05). After propensity score matching including baseline characteristics, functional outcomes after endovascular treatment did not differ between the groups (OR: 1.19, 95% CI 0.78-1.83, p=0.4). Safety outcomes did not significantly differ between the groups. CONCLUSION: Endovascular treatment is a safe and effective treatment for eligible patients with in-hospital stroke. Our results will help physicians in making decisions when planning treatment and counseling caregivers or patients.


Subject(s)
Endovascular Procedures , Propensity Score , Registries , Stroke , Humans , Male , Female , Aged , Middle Aged , Stroke/therapy , Aged, 80 and over , Treatment Outcome , Prospective Studies , Cohort Studies , Hospitalization/statistics & numerical data , Thrombolytic Therapy , Outcome Assessment, Health Care , Thrombectomy/methods
20.
Med Sci Monit ; 30: e942574, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38297827

ABSTRACT

BACKGROUND Ketamine, a compelling candidate for neuropathic pain management, has attracted interest for its potential to elevate brain-derived neurotrophic factor (BDNF) levels. We aimed to assess the effects of intrathecally administered ketamine on the cerebrospinal fluid (CSF) levels of BDNF(c-BDNF) and allodynia in a rat model of traumatic brain injury (TBI). MATERIAL AND METHODS Forty-five rats were divided into 3 groups: sham operation (Group S), untreated TBI (Group T), and ketamine-treated TBI (Group K), with 15 rats in each group. Rats were anesthetized, and their skulls were secured in a stereotactic frame before undergoing craniotomy. A controlled cortical impact (CCI) was induced, followed by injection of ketamine (3.41 µg/g) into the CSF in Group K. In Group T, no drug was injected after CCI delivery. On postoperative days (POD) 1, 7, and 14, the 50% mechanical withdrawal threshold (50% MWT) and c-BDNF levels were assessed. RESULTS Groups T and K exhibited a significantly lower 50% MWT than Group S on POD 1(6.6 [5.7, 8.7] g, 10.0 [6.8, 11.6] g, and 18.7 [11.6, 18.7] g, respectively; P<0.001). The c-BDNF levels in Group K were significantly higher than those in Groups S and T on POD 1 (18.9 [16.1, 23.0] pg/ml, 7.3 [6.0, 8.8] pg/ml, and 11.0 [10.6, 12.3] pg/ml, respectively; P=0.006). CONCLUSIONS Intrathecal ketamine administration did not exhibit anti-allodynic effects following mild TBI. c-BDNF level is a promising potential indicator for predicting the expression of allodynia after mild TBI.


Subject(s)
Brain Concussion , Ketamine , Rats , Animals , Hyperalgesia/drug therapy , Ketamine/pharmacology , Ketamine/therapeutic use , Brain-Derived Neurotrophic Factor/metabolism , Rats, Sprague-Dawley
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