RESUMEN
BACKGROUND: Cryptogenic new-onset refractory status epilepticus (cNORSE) currently lacks comprehensive knowledge regarding its clinical dynamics, prognostic factors and treatment guidance. Here we present the longitudinal clinical profiles, predictive factors for outcomes and the optimal duration of immunotherapy in patients with cNORSE. METHODS: This retrospective secondary endpoint analysis investigated patients with cNORSE identified from a prospective autoimmune encephalitis cohort at a national referral centre in Korea. The main outcomes included longitudinal functional scales, seizure frequency and the number of antiseizure medications. Measures encompassed NORSE-related clinical parameters such as the duration of unconsciousness, immunotherapy profiles, cytokine/chemokine analysis, and serial MRI scans. RESULTS: A total of 74 patients with cNORSE were finally analysed (mean age: 38.0±18.2; 36 (48.6%) male). All patients received first-line immunotherapy, and 91.9% (68/74) received second-line immunotherapy. A total of 83.8% (62/74) regained consciousness within a median duration of 30 days (14-56), and 50% (31/62) achieved good outcome (mRS ≤2) at 2 years. Poor 1-year outcomes (mRS ≥3) were predicted by the presence of mesial temporal lobe (mTL) and extra-mTL lesions at 3-month MRI, and prolonged unconsciousness (≥60 days). Those with mTL atrophy exhibited a higher seizure burden post-NORSE. The optimal duration of immunotherapy appeared to be between 18 weeks and 1-year post-NORSE onset. CONCLUSIONS: This study elucidates longitudinal clinical dynamics, functional outcomes, prognostic factors and immunotherapy response in patients with cNORSE. These findings might contribute to a more standardised understanding and clinical decision-making for cNORSE.
RESUMEN
STUDY OBJECTIVES: Isolated rapid-eye movement behavior disorder (iRBD) is a prodromal synucleinopathy, but its conversion rate and subtypes can vary among different cohorts. We report the clinical characteristics and phenoconversion rate of the large single-center iRBD cohort in Korea and compared it to the Montreal cohort. METHODS: This prospective cohort study examined 238 patients with polysomnography confirmed iRBD from Seoul National University Hospital (SNUH) who completed at least one follow-up evaluation. We compared the baseline and phenoconversion data of the SNUH cohort to those of 242 iRBD patients in the Montreal cohort. RESULTS: In the SNUH cohort, age at RBD diagnosis was similar (66.4±7.8 vs 65.6±8.4, p=0.265), but the proportion of men was lower (63.0% vs. 74.0%, p=0.001), and the duration of follow-up was shorter than that in the Montreal cohort (3.7±2.0 vs. 4.8±3.6 years, p<0.001). During follow-up, 34 (11.8%) patients in the SNUH cohort converted to neurodegenerative disease: 18 (52.9%) to Parkinson's disease, 9 (26.5%) to dementia with Lewy bodies (DLB), and 7 (20.6%) to multiple system atrophy. The conversion rate in the SNUH cohort was 15% after 3 years, 22% after 5 years, and 32% after 7 years, which was significantly lower than that of the Montreal cohort (log-rank test, p=0.002). Among phenoconversion subtype, fewer subjects in the SNUH group than in the Montreal group converted to DLB (Gray's test p=0.001). CONCLUSIONS: Through a comparative analysis between the SNUH and Montreal cohorts, we identified a significant difference in phenoconversion rates, particularly for DLB patients. These findings underscore the importance of further research into the underlying factors, such as racial and geographical factors contributing to such disparities.
RESUMEN
Skin aging results from complex interactions of intrinsic and extrinsic factors, leading to structural and biochemical changes such as wrinkles and dryness. Ultraviolet (UV) irradiation leads to the degradation of hyaluronic acid (HA) in the skin, and the with fragmented HA contributes to inflammation. This study revealed that the synergistic combination of carnosine and retinol (ROL) increases HA production in normal human epidermal keratinocytes (NHEKs) by upregulating hyaluronan synthase 2 (HAS2) gene transcription. Simultaneously, the combined treatment of carnosine and ROL significantly attenuates UVB-induced prostaglandin E2 (PGE2) synthesis in NHEKs. A significant correlation exists between the increase of HA synthesis and the inhibition of PGE2 production. This study suggested that combined treatment of carnosine and ROL can improve skin aging phenotypes associated with UVB irradiation.
RESUMEN
OBJECTIVE: Low-intensity transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation modality with high spatial selectivity and the ability to reach deep brain areas. The present study aimed to investigate the safety and effectiveness of low-intensity tFUS in treating major depressive disorder. METHODS: Participants were recruited in an outpatient clinic and randomly assigned to either the verum tFUS or sham stimulation group. The intervention group received six sessions of tFUS stimulation to the left dorsolateral prefrontal cortex over two weeks. Neuropsychological assessments were conducted before and after the sessions. Resting-state functional magnetic resonance imaging (rsfMRI) was also performed to evaluate changes in functional connectivity (FC). The primary outcome measure was the change in depressive symptoms, assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: The tFUS stimulation sessions were well tolerated without any undesirable side effects. The analysis revealed a significant main effect of session sequence on the MADRS scores and significant interactions between the session sequences and groups. The rsfMRI analysis showed a higher FC correlation between the right superior part of the subgenual anterior cingulate cortex (sgACC) and several other brain regions in the verum group compared with the sham group. CONCLUSION: Our results reveal that tFUS stimulation clinically improved MADRS scores with network-level modulation of a sgACC subregion. This randomized, sham-controlled clinical trial, the first study of its kind, demonstrated the safety and probable efficacy of tFUS stimulation for the treatment of depression.
RESUMEN
OBJECTIVE: The purpose of this study was to establish an oral health activity assessment tool for older people and evaluate its validity. BACKGROUND: To provide reasonable and efficient oral health promotion services with limited medical resources, a tool including categories and items of oral health promotion activities for older people should be prepared. MATERIALS AND METHODS: The tool initially consisted of 76 items on oral health promotion activities for older people classified into assessment-performance-evaluation stages. Topics for each stage included general and oral health, daily health, oral health status, behaviour, and awareness. In addition, two Delphi surveys were conducted on 10 experts who met the selection criteria, and the final items were derived based on the review opinions. RESULTS: As a result of the first and second Delphi surveys, the content validity for all items was ≥0.60 and the content validity index was ≥0.80. In the first survey, the degree of convergence in some items was 0-0.88. After modifying the contents according to expert opinions, the degree of convergence was improved from 0 to 0.50 in the second survey. The degree of agreement ranged from 0.75 to 1.00, indicating that experts agreed. Finally, a total of 65 items were derived. CONCLUSION: A 65-item tool was derived through two Delphi surveys for the assessment of oral health activities for older people. The use of the tool developed in this study would likely contribute to better prevention of oral diseases and the promotion of oral health among older people.
RESUMEN
Microglia are primarily involved in inflammatory reactions and oxidative stress in the brain; as such reducing microglial activation has been proposed as a potential therapeutic strategy for neurodegenerative disorders. Herein, we investigated the anti-inflammatory and antioxidant activities of coniferaldehyde (CFA), a naturally occurring cinnamaldehyde derivative, on activated microglia to evaluate its therapeutic potential. CFA inhibited the production of nitric oxide (NO) and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. CFA also inhibited intracellular reactive oxygen species levels and oxidative stress markers such as 4-HNE and 8-OHdG. Detailed mechanistic studies showed that CFA exerted anti-inflammatory effects by inhibiting TAK1-mediated MAP kinase/NF-κB activation and upregulating AMPK signaling pathways. In addition, CFA exerted antioxidant effects by inhibiting the NADPH oxidase subunits and by increasing the expression of antioxidant enzymes such as HO-1, NQO1, and catalase by upregulating Nrf2 signaling. Finally, we confirmed the effects of CFA on the brains of the LPS-injected mice. CFA inhibited microglial activation and the expression of proinflammatory markers and increased Nrf2-driven antioxidant enzymes. Furthermore, CFA inhibited the production of 4-HNE and 8-OHdG in the brains of LPS-injected mice. As a result, CFA's significant anti-inflammatory and antioxidant properties may have therapeutic applications in neuroinflammatory disorders related with oxidative stress and microglial activation.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Antiinflamatorios , Antioxidantes , Lipopolisacáridos , Quinasas Quinasa Quinasa PAM , Microglía , Factor 2 Relacionado con NF-E2 , FN-kappa B , Transducción de Señal , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , FN-kappa B/metabolismo , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Masculino , Quinasas Quinasa Quinasa PAM/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular , Estrés Oxidativo/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Acroleína/análogos & derivados , Acroleína/farmacología , Citocinas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Acute renal dysfunction is defined by the maximum increase in serum creatinine (sCr) without considering the pattern of change in sCr. We aimed to identify longitudinal patterns (trajectories) of postoperative sCr concentrations and investigate their association with long-term outcomes in patients undergoing valvular heart surgery. MATERIALS AND METHODS: In this retrospective review of 3,436 patients who underwent valvular heart surgery, we applied trajectory projection cluster analysis to identify the trajectories of sCr changes from baseline during the seven postoperative days. Primary and secondary endpoints were to investigate the associations of sCr trajectories with mortality using Kaplan-Meier curves and Cox proportional hazards regression analysis, and a composite of major adverse kidney events (MAKEs) at one year after surgery, respectively. RESULTS: Four clusters were identified: Clusters 1 and 2, a minimal change in sCr (90.1% of patients); Cluster 3, a significant and persistent increase in sCr (4.1% of patients); and Cluster 4, a significant but transient increase in sCr (5.8% of patients). The one-year postoperative mortality rate was higher in Cluster 3 (18.4%) and Cluster 4 (11.6%) than in Cluster 1+2 (2.7%). The Kaplan-Meier survival curve demonstrated significant differences in mortality rates among the clusters (log-rank test, P<0.001). In the multivariable Cox analysis, the sCr trajectory cluster was an independent prognostic factor for mortality. Cluster 3 had a higher prevalence of MAKEs (37.6%) compared with Cluster 1+2 (6.8%, P<0.001) and Cluster 4 (24.1%, P=0.045). The cluster was an independent prognostic factor for MAKEs. CONCLUSION: The sCr trajectory clusters exhibited significantly different risks of mortality and MAKEs at one year after surgery. Through these sCr trajectories, we confirmed that both the extent of sCr increase and its sustainability during the first seven postoperative days were closely associated with the long-term prognosis after valvular heart surgery.
RESUMEN
The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity.
Asunto(s)
Amelogénesis , Proteínas de Homeodominio , Ratones Noqueados , Células Madre , Factores de Transcripción , Animales , Humanos , Ratones , Amelogénesis/genética , Diferenciación Celular/genética , Epitelio/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Células Madre/metabolismo , Células Madre/citología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Vía de Señalización WntRESUMEN
Cytokinins regulate plant growth, development, and responses to environmental stresses such as cold via phosphorelay from cytokinin receptors to the ARABIDOPSIS RESPONSE REGULATORs (ARRs). However, the molecular mechanisms underlying the activation of type-B ARR transcriptional activity in Arabidopsis (Arabidopsis thaliana) remain unclear. Here, we show that the E3 SUMO ligase HIGH PLOIDY2 SUMOylates ARR1, a type-B ARR, at K236, triggering its activation. Cold- or cytokinin-induced phosphorylation of ARR1 at D89 is crucial for its interaction with HPY2. Lysine 236 is critical for ARR1's transactivation without compromising its DNA-binding ability, while D89 is crucial for ARR1's binding to target gene promoters. Cytokinin enhances ARR1's chromatin binding, but cold does not. ARR1 K236 plays a critical role in promoting histone H3 acetylation in response to both cytokinin and cold without affecting chromatin binding. The K236R mutation in ARR1 reduces target gene expression and alters cytokinin and cold response phenotypes. This study unveils a mechanism of ARR1 activation wherein phosphorylated ARR1 interacts with HPY2 and binds to chromatin in response to cytokinin. Cold triggers a phosphorelay targeting chromatin-bound ARR1. HPY2 then catalyzes ARR1 SUMOylation at K236, enhancing histone H3 acetylation and leading to transcriptional activation of ARR1 in response to both cold and cytokinin.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Unión al ADN , Regulación de la Expresión Génica de las Plantas , Transducción de Señal , Sumoilación , Factores de Transcripción , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Fosforilación , Citocininas/metabolismo , Histonas/metabolismo , Histonas/genética , Cromatina/metabolismo , Cromatina/genética , Acetilación , Mutación/genéticaRESUMEN
BACKGROUND: The lack of association between serum testosterone levels and symptoms suggestive of hypogonadism is a significant barrier in the determination of late-onset hypogonadism (LOH) in men. This study explored whether testosterone levels increase after morning awakening, likewise the cortisol awakening response (CAR) in the hypothalamic-pituitary-adrenal (HPA) axis, and whether testosterone levels during the post-awakening period are associated with age and symptoms suggestive of late-onset hypogonadism (LOH) in men. METHODS: Testosterone and cortisol levels were determined in saliva samples collected immediately upon awakening and 30 and 60 min after awakening, and scores of the Aging Males' Symptoms (AMS) questionnaire were obtained from 225 healthy adult men. RESULTS: A typical CAR (an increase in cortisol level ≥ 2.5 nmol/L above individual baseline) was observed in 155 participants (the subgroup exhibiting typical CAR). In the subgroup exhibiting CAR, testosterone levels sharply increased during the post-awakening period, showing a significant negative correlation with age, total AMS score, and the scores of 11 items on the somatic, psychological, and sexual AMS subscales. Of these items, three sexual items (AMS items #15-17) were correlated with age. Meanwhile, there was no notable increase in testosterone levels and no significant correlation of testosterone levels with age and AMS score in the subgroup exhibiting no typical CAR (n = 70). CONCLUSIONS: The results indicate that the hypothalamus-pituitary-gonad (HPG) axis responds to morning awakening, and determining testosterone levels during the post-awakening period in men with typical CAR may be useful for assessing HPG axis function and LOH.
The present study found that the HPG axis in healthy adult men responds to the morning awakening, characterized by increased salivary testosterone levels after the awakening period.The levels of salivary testosterone during the first hour after awakening are negatively associated with age and the severity of symptoms suggestive of LOH in adult men with typical CAR.
Asunto(s)
Hidrocortisona , Hipogonadismo , Sistema Hipotálamo-Hipofisario , Saliva , Testosterona , Humanos , Masculino , Testosterona/análisis , Testosterona/sangre , Testosterona/metabolismo , Saliva/química , Saliva/metabolismo , Hipogonadismo/metabolismo , Hipogonadismo/sangre , Hipogonadismo/diagnóstico , Persona de Mediana Edad , Adulto , Hidrocortisona/metabolismo , Hidrocortisona/sangre , Hidrocortisona/análisis , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Anciano , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Envejecimiento/metabolismo , Envejecimiento/fisiología , Encuestas y Cuestionarios , Factores de Edad , Adulto Joven , Vigilia/fisiologíaRESUMEN
Background and study aims The Plan-Do-Study Act (PDSA) ramp is a framework that uses initial small changes to build consensus and momentum for subsequent, iterative process improvement. Our aim was to study its impact on endoscopy unit efficiency and throughput. Methods Following a granular time-and-motion analysis to evaluate baseline performance (phase 1) we instituted successive interventions and measured their impact on core efficiency metrics including procedure volume and turnover time (phases 2-3). Results We identified that inefficiency in turnover of anesthesia-supported endoscopy was the most crucial issue. Implementation of a pre-procedure anesthesia visit in phase 2 reduced turnover time by 15.5 minutes (95% confidence interval 3.9-27.1 minutes). Subsequent changes (phase 3) including front-loaded procedure scheduling and parallel in-room preparation resulted in an 18% increase in procedure volume. Conclusions The PDSA ramp model is an effective means of assessing operational processes, developing novel interventions, and building consensus to improve the real-world productivity in a resource-conscious manner.
RESUMEN
OBJECTIVE: This study evaluated the clinical effectiveness of Minds.NAVI, a depression screening kit combining psychometric measures and stress hormone biomarkers, in a prospective clinical trial. The objective was to assess its potential as a depression screening tool and investigate the associations between psychological assessments, salivary hormone staging, and depression severity. METHODS: Thirty-five participants with major depressive disorder and 12 healthy controls (HCs) were included. The Minds.NAVI software, utilizing the PROtective and Vulnerable factors battEry Test (PROVE) and salivary cortisol/dehydroepiandrosterone (DHEA) analysis, was employed. The PROVE test is a comprehensive self-report questionnaire that assesses depressive symptoms, suicide risk, attachment style, adverse childhood experiences, mentalization capacity, and resilience. In addition, salivary cortisol and DHEA levels were measured to evaluate the functional stage of the hypothalamic-pituitary-adrenal (HPA) axis. RESULTS: Minds.NAVI exhibited 100% sensitivity, 91.7% specificity, and 97.9% accuracy in distinguishing depression from HCs within an exploratory small group. Salivary stress hormone phases showed changes with depression stage (p=0.030), and the proportion of patients with "adrenal exhaustion stage" was higher in the moderate/severe depression group (p=0.038). Protective/vulnerable factors differed significantly between controls and depressed groups (p<0.001). Cortisol awakening response inversely correlated with depressive symptom severity (r=-0.31, p=0.034). CONCLUSION: This study suggested possible clinical effectiveness of Minds.NAVI, a depression screening tool that integrates psychometric measures and stress hormone biomarkers. The findings support the potential association between depression, chronic stress, and HPA axis hyporesponsiveness.
RESUMEN
The fighter pilots exposed to high gravitational (G) acceleration must perform anti-G maneuvers similar to the Valsalva maneuver. However, the effects of high-G acceleration and anti-G maneuvers on cardiac function have rarely been studied. This study aimed to investigate the effects of high-G forces on cardiac function of fighter pilots. Fighter pilots who underwent regular health check-ups and echocardiography were included (n = 29; 100% men, 41 ± 10 years old; mean flight time, 1821 ± 1186 h). Trainees who had not experienced any flights were included in the control group (n = 16; 100% men, 36 ± 17 years old). Echocardiographic data included left ventricular chamber size, systolic and diastolic functions, right ventricular systolic pressure (RVSP), inferior vena cava (IVC) collapsibility, and tricuspid annular plane systolic excursion (TAPSE). No significant differences in left ventricular ejection fraction, RVSP, or IVC collapsibility were observed between two groups. In the multivariate linear regression analysis with total flight time as an independent continuous variable for fighter pilots, TAPSE was positively correlated with total flight time. The experience of fighter pilots who were exposed to high-G acceleration forces and anti-G maneuvers did not cause cardiac structural changes, but the exposure might be associated with right heart function changes.
Asunto(s)
Hipergravedad , Pilotos , Masculino , Humanos , Adulto , Persona de Mediana Edad , Adulto Joven , Femenino , Volumen Sistólico , Función Ventricular Izquierda , Hipergravedad/efectos adversos , AceleraciónAsunto(s)
Entrenamiento de Intervalos de Alta Intensidad , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/complicaciones , Proyectos Piloto , Masculino , Femenino , Anciano , Persona de Mediana Edad , Terapia por Ejercicio/métodos , Resultado del TratamientoRESUMEN
Autonomic imbalance predicts worse clinical outcomes in patients with heart failure (HF). Managing the variables affecting heart rate variability (HRV) might improve the clinical outcomes of patients with HF. This study aimed to investigate variables affecting HRV. We assessed autonomic nervous system activity (low-frequency [Lf], high-frequency [Hf], and Lf/Hf ratio) in 60 patients with HF, employing standard measures to capture short-term HRV. To estimate the independent effects of variables such as well-known cardiac risk factors and psychosocial conditions on HRV, multivariate analyses were conducted. For psychosocial variables, we assessed depression and quality of life in patients and their family caregivers. We also assessed the self-care behavior of patients and their caregivers' burden. Depression in family caregivers and self-care behavior of patients were independently associated with a decreased Hf (ß-coefficientâ =â 0.309, Pâ =â .039 and ß-coefficientâ =â -0.029, Pâ =â .047, respectively). Depression of family caregivers and self-care behavior of patients may affect HRV in patients with HF.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo , Insuficiencia Cardíaca , Humanos , Calidad de Vida , Sistema Nervioso Autónomo , Frecuencia Cardíaca/fisiologíaRESUMEN
BACKGROUND: We examined factors contributing to the transmission of an acute respiratory virus within multi-use facilities, focusing on an outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a movie theater in the Republic of Korea. METHODS: This retrospective cohort study involved a descriptive analysis of 48 confirmed cases. Logistic regression was applied to a cohort of 80 theater attendees to identify risk factors for infection. The infection source and transmission route were determined through gene sequencing data analysis. RESULTS: Of the 48 confirmed cases, 35 were theater attendees (72.9%), 10 were family members of attendees (20.8%), 2 were friends (4.2%), and 1 was an employee (2.1%). Among the 80 individuals who attended the 3rd to 5th screenings of the day, 35 became infected, representing a 43.8% attack rate. Specifically, 28 of the 33 third-screening attendees developed confirmed SARSCoV-2, constituting an 84.8% attack rate. Furthermore, 11 of the 12 cases epidemiologically linked to the theater outbreak were clustered monophyletically within the AY.69 lineage. At the time of the screening, 35 individuals (72.9%) had received 2 vaccine doses. However, vaccination status did not significantly influence infection risk. Multivariate analysis revealed that close contacts had a 15.9-fold higher risk of infection (95% confidence interval, 4.37-78.39) than casual contacts. CONCLUSION: SARS-CoV-2 transmission occurred within the theater, and extended into the community, via a moviegoer who attended the 3rd screening during the viral incubation period after contracting the virus from a family member. This study emphasizes the importance of adequate ventilation in theaters.
RESUMEN
BACKGROUND: Immune checkpoint inhibitors unleash inhibitory signals on T cells conferred by tumors and surrounding stromal cells. Despite the clinical efficacy of checkpoint inhibitors, the lack of target expression and persistence of immunosuppressive cells limit the pervasive effectiveness of the therapy. These limitations may be overcome by alternative approaches that co-stimulate T cells and the immune microenvironment. METHODS: We analyzed single-cell RNA sequencing data from multiple human cancers and a mouse tumor transplant model to discover the pleiotropic expression of the Interleukin 7 (IL-7) receptor on T cells, macrophages, and dendritic cells. RESULTS: Our experiment on the mouse model demonstrated that recombinant IL-7 therapy induces tumor regression, expansion of effector CD8 T cells, and pro-inflammatory activation of macrophages. Moreover, spatial transcriptomic data support immunostimulatory interactions between macrophages and T cells. CONCLUSION: These results indicate that IL-7 therapy induces anti-tumor immunity by activating T cells and pro-inflammatory myeloid cells, which may have diverse therapeutic applicability.
Asunto(s)
Interleucina-7 , Neoplasias , Humanos , Animales , Ratones , Interleucina-7/genética , Interleucina-7/farmacología , Inmunoterapia , Neoplasias/genética , Neoplasias/terapia , Linfocitos T , Análisis de Secuencia de ARN , Microambiente Tumoral/genética , Linfocitos T CD8-positivosRESUMEN
BACKGROUND: Rectal neuroendocrine tumors (NETs) have malignant potential, and lymph node (LN) or distant metastases can occur; however, treatment of NETs 1-2 cm in size is controversial. OBJECTIVE: This study aimed to identify predictive factors for LN metastasis and prognostic factors for recurrence of rectal NETs, especially tumors 1â2 cm in size. METHODS: Between October 2004 and November 2020, 453 patients underwent endoscopic or surgical treatment for rectal NETs in Seoul National University Hospital. The data on these patients were prospectively collected in our database and reviewed retrospectively. In cases of local excision, we evaluated LN metastasis with radiologic imaging, including computed tomography or magnetic resonance imaging before treatment and during the follow-up periods. RESULTS: LN metastasis was observed in 40 patients (8.8%). A higher rate of LN metastasis was observed in larger-sized tumors, advanced T stage, lymphovascular invasion (LVI), perineural invasion (PNI), and high tumor grade. In multivariable analysis, the significant risk factors for LN metastasis were tumor size (1 ≤ size < 2 cm: hazard ratio [HR] 64.07; size ≥2 cm: HR 102.37, p < 0.001) and tumor grade (G2: HR 3.63, p = 0.034; G3: HR 5.09, p = 0.044). In multivariable analysis for tumors 1-2 cm in size, the risk factor for LN metastasis was tumor grade (G2: HR 6.34, p = 0.013). CONCLUSIONS: Tumor grade and size are important predictive factors for LN metastasis. In NETs 2 cm in size, tumor grade is also important for LN metastasis, and radical resection should be considered.
Asunto(s)
Tumores Neuroendocrinos , Neoplasias del Recto , Humanos , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/patología , Metástasis Linfática/patología , Estudios Retrospectivos , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Factores de Riesgo , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , PronósticoRESUMEN
Parkinson's disease (PD) is an incurable neurological disorder that causes typical motor deficits. In this study, we investigated the effects of creatine supplementation and exercise in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We found that 2% creatine supplementation and/or exercise intervention for 4 weeks elicited neurobehavioral recovery and neuroprotective effects regarding dopaminergic cell loss in MPTP-treated mice; this effect implies functional preservation of dopaminergic cells in the substantia nigra, as reflected by tyrosine hydroxylase expression recovery. Creatine and exercise reduced necroptotic activity in dopaminergic cells by lowering mixed lineage kinase domain-like protein (MLKL) modification to active phenotypes (phosphorylation at Ser345 and oligomerization) and phosphorylated receptor-interacting protein kinase 1 (RIPK1) (Ser166-p) and RIPK3 (Ser232-p) levels. In addition, creatine and exercise reduced the MPTP-induced increase in pathogenic α-synuclein forms, such as Ser129 phosphorylation and oligomerization. Furthermore, creatine and exercise had anti-inflammatory and antioxidative effects in MPTP mice, as evidenced by a decrease in microglia activation, NF-κB-dependent pro-inflammatory molecule expression, and increase in antioxidant enzyme expression. These phenotypic changes were associated with the exercise/creatine-induced AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) and sirtuin 3 (SIRT3)/forkhead box O3 (FoxO3a) signaling pathways. In all experiments, combining creatine with exercise resulted in considerable improvement over either treatment alone. Consequently, these findings suggest that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/tratamiento farmacológico , alfa-Sinucleína/metabolismo , Creatina/farmacología , Creatina/uso terapéutico , Necroptosis , Neuronas Dopaminérgicas/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Antiinflamatorios/farmacología , Suplementos Dietéticos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismoRESUMEN
Orthohantaviruses, etiological agents of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome, pose a critical public health threat worldwide. Hantaan orthohantavirus (HTNV) outbreaks are particularly endemic in Gyeonggi Province in northern area of the Republic of Korea (ROK). Small mammals were collected from three regions in the Gyeonggi Province during 2017 and 2018. Serological and molecular prevalence of HTNV was 25/201 (12.4%) and 10/25 (40%), respectively. A novel nanopore-based diagnostic assay using a cost-efficient Flongle chip was developed to rapidly and sensitively detect HTNV infection in rodent specimens within 3 h. A rapid phylogeographical surveillance of HTNV at high-resolution phylogeny was established using the amplicon-based Flongle sequencing. In total, seven whole-genome sequences of HTNV were newly obtained from wild rodents collected in Paju-si (Gaekhyeon-ri) and Yeoncheon-gun (Hyeonga-ri and Wangnim-ri), Gyeonggi Province. Phylogenetic analyses revealed well-supported evolutionary divergence and genetic diversity, enhancing the resolution of the phylogeographic map of orthohantaviruses in the ROK. Incongruences in phylogenetic patterns were identified among HTNV tripartite genomes, suggesting differential evolution for each segment. These findings provide crucial insights into on-site diagnostics, genome-based surveillance, and the evolutionary dynamics of orthohantaviruses to mitigate hantaviral outbreaks in HFRS-endemic areas in the ROK.