RESUMO
Anxiety is a remarkably common condition among patients with pharyngitis, but the relationship between these disorders has received little research attention, and the underlying neural mechanisms remain unknown. Here, we show that the densely innervated pharynx transmits signals induced by pharyngeal inflammation to glossopharyngeal and vagal sensory neurons of the nodose/jugular/petrosal (NJP) superganglia in mice. Specifically, the NJP superganglia project to norepinephrinergic neurons in the nucleus of the solitary tract (NTSNE). These NTSNE neurons project to the ventral bed nucleus of the stria terminalis (vBNST) that induces anxiety-like behaviors in a murine model of pharyngeal inflammation. Inhibiting this pharynxâNJPâNTSNEâvBNST circuit can alleviate anxiety-like behaviors associated with pharyngeal inflammation. This study thus defines a pharynx-to-brain axis that mechanistically links pharyngeal inflammation and emotional response.
Assuntos
Faringite , Faringe , Humanos , Animais , Camundongos , Ansiedade , Encéfalo , Células Receptoras Sensoriais , InflamaçãoRESUMO
Numerous molecular and physiological processes in the skeletal muscle undergo circadian time-dependent oscillations in accordance with daily activity/rest cycles. The circadian regulatory mechanisms underlying these cyclic processes, especially at the post-transcriptional level, are not well defined. Previously, we reported that the circadian E3 ligase FBXL21 mediates rhythmic degradation of the sarcomere protein TCAP in conjunction with GSK-3ß, and Psttm mice harboring an Fbxl21 hypomorph allele show reduced muscle fiber diameter and impaired muscle function. To further elucidate the regulatory function of FBXL21 in skeletal muscle, we investigated another sarcomere protein, Myozenin1 (MYOZ1), that we identified as an FBXL21-binding protein from yeast 2-hybrid screening. We show that FBXL21 binding to MYOZ1 led to ubiquitination-mediated proteasomal degradation. GSK-3ß co-expression and inhibition were found to accelerate and decelerate FBXL21-mediated MYOZ1 degradation, respectively. Previously, MYOZ1 has been shown to inhibit calcineurin/NFAT signaling important for muscle differentiation. In accordance, Fbxl21 KO and MyoZ1 KO in C2C12 cells impaired and enhanced myogenic differentiation respectively compared with control C2C12 cells, concomitant with distinct effects on NFAT nuclear localization and NFAT target gene expression. Importantly, in Psttm mice, both the levels and diurnal rhythm of NFAT2 nuclear localization were significantly diminished relative to wild-type mice, and circadian expression of NFAT target genes associated with muscle differentiation was also markedly dampened. Furthermore, Psttm mice exhibited significant disruption of sarcomere structure with a considerable excess of MYOZ1 accumulation in the Z-line. Taken together, our study illustrates a pivotal role of FBXL21 in sarcomere structure and muscle differentiation by regulating MYOZ1 degradation and NFAT2 signaling.
Assuntos
Proteínas F-Box , Ubiquitina-Proteína Ligases , Camundongos , Animais , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Sarcômeros/metabolismo , Diferenciação Celular/genética , Ubiquitinação , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Proteínas F-Box/genética , Proteínas F-Box/metabolismoRESUMO
Background Blood-brain barrier (BBB) permeability change is a possible pathologic mechanism of autoimmune encephalitis. Purpose To evaluate the change in BBB permeability in patients with autoimmune encephalitis as compared with healthy controls by using dynamic contrast-enhanced (DCE) MRI and to explore its predictive value for treatment response in patients. Materials and Methods This single-center retrospective study included consecutive patients with probable or possible autoimmune encephalitis and healthy controls who underwent DCE MRI between April 2020 and May 2021. Automatic volumetric segmentation was performed on three-dimensional T1-weighted images, and volume transfer constant (Ktrans) values were calculated at encephalitis-associated brain regions. Ktrans values were compared between the patients and controls, with adjustment for age and sex with use of a nonparametric approach. The Wilcoxon rank sum test was performed to compare Ktrans values of the good (improvement in modified Rankin Scale [mRS] score of at least two points or achievement of an mRS score of ≤2) and poor (improvement in mRS score of less than two points and achievement of an mRS score >2) treatment response groups among the patients. Results Thirty-eight patients with autoimmune encephalitis (median age, 38 years [IQR, 29-59 years]; 20 [53%] female) and 17 controls (median age, 71 years [IQR, 63-77 years]; 12 [71%] female) were included. All brain regions showed higher Ktrans values in patients as compared with controls (P < .001). The median difference in Ktrans between the patients and controls was largest in the right parahippocampal gyrus (25.1 × 10-4 min-1 [95% CI: 17.6, 43.4]). Among patients, the poor treatment response group had higher baseline Ktrans values in both cerebellar cortices (P = .03), the left cerebellar cortex (P = .02), right cerebellar cortex (P = .045), left cerebral cortex (P = .045), and left postcentral gyrus (P = .03) than the good treatment response group. Conclusion DCE MRI demonstrated that BBB permeability was increased in all brain regions in patients with autoimmune encephalitis as compared with controls, and baseline Ktrans values were higher in patients with poor treatment response in the cerebellar cortex, left cerebral cortex, and left postcentral gyrus as compared with the good response group. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Filippi and Rocca in this issue.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Encefalite , Doença de Hashimoto , Humanos , Feminino , Adulto , Idoso , Masculino , Permeabilidade Capilar , Estudos Retrospectivos , Encefalite/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
Lung-resident neutrophils need to be tightly regulated to avoid degranulation- and cytokine-associated damage to fragile alveolar structures that can lead to fatal outcomes. Here we show that lung neutrophils (LNs) express distinct surface proteins and genes that distinguish LNs from bone marrow and blood neutrophils. Functionally, LNs show impaired migratory activity toward chemoattractants and produce high levels of interleukin-6 (IL-6) at steady state and low levels of tumor necrosis factor-α in response to lipopolysaccharide (LPS) challenge. Treating bone marrow neutrophils with bronchoalveolar lavage fluid or prostaglandin E2 induces LN-associated characteristics, including the expression of transglutaminase 2 (Tgm2) and reduced production of inflammatory cytokines upon LPS challenge. Neutrophils from Tgm2-/- mice release high levels of inflammatory cytokines in response to LPS. Lung damage is significantly exacerbated in Tgm2-/- mice in an LPS-induced acute respiratory distress syndrome model. Collectively, we demonstrate that prostaglandin E2 is a key factor for the generation of LNs with unique immune suppressive characteristics, acting through protein kinase A and Tgm2, and LNs play essential roles in protection of the lungs against pathogenic inflammation.
Assuntos
Dinoprostona , Neutrófilos , Animais , Líquido da Lavagem Broncoalveolar/química , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Lipopolissacarídeos , Pulmão/patologia , Camundongos , Neutrófilos/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: To characterize the circadian features of the trigeminal ganglion in a mouse model of headache. BACKGROUND: Several headache disorders, such as migraine and cluster headache, are known to exhibit distinct circadian rhythms of attacks. The circadian basis for these rhythmic pain responses, however, remains poorly understood. METHODS: We examined trigeminal ganglion ex vivo and single-cell cultures from Per2::LucSV reporter mice and performed immunohistochemistry. Circadian behavior and transcriptomics were investigated using a novel combination of trigeminovascular and circadian models: a nitroglycerin mouse headache model with mechanical thresholds measured every 6 h, and trigeminal ganglion RNA sequencing measured every 4 h for 24 h. Finally, we performed pharmacogenomic analysis of gene targets for migraine, cluster headache, and trigeminal neuralgia treatments as well as trigeminal ganglion neuropeptides; this information was cross-referenced with our cycling genes from RNA sequencing data to identify potential targets for chronotherapy. RESULTS: The trigeminal ganglion demonstrates strong circadian rhythms in both ex vivo and single-cell cultures, with core circadian proteins found in both neuronal and non-neuronal cells. Using our novel behavioral model, we showed that nitroglycerin-treated mice display circadian rhythms of pain sensitivity which were abolished in arrhythmic Per1/2 double knockout mice. Furthermore, RNA-sequencing analysis of the trigeminal ganglion revealed 466 genes that displayed circadian oscillations in the control group, including core clock genes and clock-regulated pain neurotransmitters. In the nitroglycerin group, we observed a profound circadian reprogramming of gene expression, as 331 of circadian genes in the control group lost rhythm and another 584 genes gained rhythm. Finally, pharmacogenetics analysis identified 10 genes in our trigeminal ganglion circadian transcriptome that encode target proteins of current medications used to treat migraine, cluster headache, or trigeminal neuralgia. CONCLUSION: Our study unveiled robust circadian rhythms in the trigeminal ganglion at the behavioral, transcriptomic, and pharmacogenetic levels. These results support a fundamental role of the clock in pain pathophysiology. PLAIN LANGUAGE SUMMARY: Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24-hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day.
Assuntos
Cefaleia Histamínica , Transtornos de Enxaqueca , Neuralgia do Trigêmeo , Camundongos , Animais , Gânglio Trigeminal , Transcriptoma , Neuralgia do Trigêmeo/genética , Nitroglicerina , Cefaleia , Perfilação da Expressão Gênica , Dor , Ritmo Circadiano/genética , Camundongos KnockoutRESUMO
OBJECTIVE: To determine if insomnia-related factors differ depending on the presence of depression in patients with epilepsy. METHODS: This cross-sectional multicenter study collected data on depressive symptoms, insomnia symptoms, and excessive daytime sleepiness, which were defined as a Patient Health Questionnaire-9 (PHQ-9) score of ≥ 10, an Insomnia Severity Index (ISI) score of ≥ 15, and an Epworth Sleepiness Scale (ESS) of ≥ 11, respectively. Further, uncontrolled seizures were defined as one or more seizures per month during antiseizure medications treatment. A stepwise logistic regression analysis was conducted, with a logistic regression with interaction terms performed to identify differences in insomnia-related factors depending on depressive symptoms. RESULTS: Of 282 adults with epilepsy (men, 58 %; mean age, 40.4 ± 13.9 years), a PHQ-9 score ≥ 10, an ISI score ≥ 15, an ESS score ≥ 11 were noted in 23.4 % (n = 66), 20.2 % (n = 57), and 12.8 % (n = 36), respectively. More patients with depressive symptoms had an ISI score ≥ 15 (56.1 % vs. 9.3 %; p < 0.001) than those without. In multiple logistic regression, uncontrolled seizures (odds ratio [OR], 4.896; p < 0.01), daytime sleepiness (OR, 5.369; p < 0.05), and a history of psychiatric disorders (OR, 3.971; p < 0.05) were identified as significant factors that were more likely to be associated with an ISI score ≥ 15; however, this was only true in patients without depressive symptoms. In contrast, use of perampanel (OR, 0.282; p < 0.05) was less likely associated, while female sex (OR, 3.178; p < 0.05) was more likely associated with an ISI score ≥ 15 only in patients with depressive symptoms. CONCLUSIONS: Insomnia-related factors in patients with epilepsy may differ between patients with and without depression. Our findings of different insomnia-related factors based on the presence of depression may facilitate the management of patients with epilepsy.
Assuntos
Depressão , Epilepsia , Distúrbios do Início e da Manutenção do Sono , Humanos , Masculino , Feminino , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/psicologia , Adulto , Epilepsia/complicações , Epilepsia/psicologia , Estudos Transversais , Pessoa de Meia-Idade , Depressão/epidemiologia , Depressão/complicações , Adulto Jovem , Modelos Logísticos , Anticonvulsivantes/uso terapêutico , Inquéritos e Questionários , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Cigarette smoking is commonly reported among chronic pain patients in the clinic. Although chronic nicotine exposure is directly linked to nociceptive hypersensitivity in rodents, underlying neurobiological mechanisms remain unknown. METHODS: Multi-tetrode recordings in freely moving mice were used to test the activity of dopaminergic projections from the ventral tegmental area (VTA) to pyramidal neurones in the anterior cingulate cortex (ACC) in chronic nicotine-treated mice. The VTAâACC dopaminergic pathway was inhibited by optogenetic manipulation to detect chronic nicotine-induced allodynia (pain attributable to a stimulus that does not normally provoke pain) assessed by von Frey monofilaments (force units in g). RESULTS: Allodynia developed concurrently with chronic (28-day) nicotine exposure in mice (0.36 g [0.0141] vs 0.05 g [0.0018], P<0.0001). Chronic nicotine activated dopaminergic projections from the VTA to pyramidal neurones in the ACC, and optogenetic inhibition of VTA dopaminergic terminals in the ACC alleviated chronic nicotine-induced allodynia in mice (0.06 g [0.0064] vs 0.28 g [0.0428], P<0.0001). Moreover, optogenetic inhibition of Drd2 dopamine receptor signalling in the ACC attenuated nicotine-induced allodynia (0.07 g [0.0082] vs 0.27 g [0.0211], P<0.0001). CONCLUSIONS: These findings implicate a role of Drd2-mediated dopaminergic VTAâACC pathway signalling in chronic nicotine-elicited allodynia.
Assuntos
Giro do Cíngulo , Nicotina , Humanos , Camundongos , Animais , Nicotina/farmacologia , Hiperalgesia/induzido quimicamente , Dopamina/metabolismo , DorRESUMO
BACKGROUND: This study aimed to examine the outcomes of open surgery techniques involving sacotomy and suturing of the feeding vessels in patients with aneurysm sac expansion after endovascular aneurysm repair (EVAR). METHODS: Fourteen consecutive patients treated with sacotomy and suturing of feeding vessels for expanding aneurysm sacs with type II endoleaks following EVAR, between January 2018 and December 2022, were retrospectively included. All patients underwent preoperative digital subtraction angiography, and attempts were made to embolize the thick feeding vessels to reduce intraoperative bleeding. Age, sex, comorbidities, clinical presentation, aneurysm sac increase, morbidity, mortality, and follow-up were recorded. RESULTS: The median age of the patients was 72.89 ± 5.13 years old, and 13 (92.9%) patients were male. The sac size at the time of the open procedure was 107.89 ± 22.58 mm, and the extent of sac growth at the time of the open procedure was 37.50 ± 18.29 mm. The initial technical success rate of laparotomy and open ligation of the culprit arteries causing type II endoleaks was 92.9% (13/14). Among the patients, 5 (35.7%) had been treated with interventional embolization before the open procedure. One endograft was removed and replaced by a bifurcated Dacron graft because of distal dislocation in one patient. All patients recovered, and no deaths were recorded postoperatively. No patients had an eventful postoperative course or any subsequent graft-related complications during follow-up. CONCLUSIONS: Open surgical repair involving sacotomy and suturing of the feeding vessels appeared to have good outcomes in the treatment of patients with aneurysm sac expansion caused by type II endoleaks after EVAR. Preoperative embolization of feeding vessels can thus effectively reduce intraoperative bleeding.
Assuntos
Aneurisma da Aorta Abdominal , Embolização Terapêutica , Endoleak , Correção Endovascular de Aneurisma , Aneurisma Ilíaco , Idoso , Feminino , Humanos , Masculino , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Prótese Vascular , Embolização Terapêutica/efeitos adversos , Endoleak/etiologia , Endoleak/prevenção & controle , Correção Endovascular de Aneurisma/efeitos adversos , Aneurisma Ilíaco/cirurgia , Aneurisma Ilíaco/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco , Técnicas de Sutura/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Phlegm is prevalent symptom in patients with chronic obstructive pulmonary disease (COPD). Few studies have investigated the effectiveness of N-acetylcysteine (NAC) nebulizer therapy in COPD patients. We evaluated the effect of nebulized NAC on the improvement of phlegm symptom in COPD patients. METHODS: This was a 12-week, prospective, single-arm, open-label, phase IV multi-center trial (NCT05102305, Registration Date: 20-October-2021). We enrolled patients aged ≥ 40 years with post bronchodilator forced expiratory volume in one second/forced vital capacity (FEV1/FVC) < 0.7 and COPD assessment test (CAT) phlegm score ≥ 2; the patients were current or ex-smoker with smoking pack-years ≥ 10. The primary endpoint was to determine the change in CAT phlegm score at 12 weeks compared to the baseline. Patients were assessed at baseline, 4, 8, and 12 weeks of treatment using the CAT score. RESULTS: In total, 100 COPD patients were enrolled from 10 hospitals. The mean age of the patients was 71.42 ± 8.20 years, with 19.78% being current-smokers and 80.22% being ex-smokers. The mean smoking pack-years was 40.32 ± 35.18. The mean FVC, FEV1, and FEV1/FVC were 3.94 L (75.44%), 2.22 L (58.50%), and 0.53, respectively. The CAT phlegm score at baseline was 3.47 ± 1.06, whereas after 12 weeks of nebulized NAC it significantly decreased to 2.62 ± 1.30 (p < 0.01). More than half (53.5%) of the patients expressed satisfaction with the effects of nebulized NAC therapy. Adverse events occurred in 8 (8.0%) patients. Notably, no serious adverse drug reactions were reported. CONCLUSION: In this study, we have established the effectiveness and safety of nebulized NAC over 12 weeks.
Assuntos
Acetilcisteína , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica , Humanos , Acetilcisteína/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Masculino , Feminino , Idoso , Estudos Prospectivos , Pessoa de Meia-Idade , Volume Expiratório Forçado/efeitos dos fármacos , Administração por Inalação , Capacidade Vital/efeitos dos fármacos , Expectorantes/administração & dosagem , Expectorantes/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The treatment success rate for tuberculosis (TB) has stagnated at 80-81% in South Korea, indicating unsatisfactory outcomes. Enhancing treatment success rate necessitates the development of individualized treatment approaches for each patient. This study aimed to identify the risk factors associated with unfavorable treatment outcomes to facilitate tailored TB care. METHODS: We retrospectively analyzed the data of patients with active TB between January 2019 and December 2020 at a single tertiary referral center. We classified unfavorable treatment outcomes according to the 2021 World Health Organization guidelines as follows: "lost to follow-up" (LTFU), "not evaluated" (NE), "death," and "treatment failure" (TF). Moreover, we analyzed risk factors for each unfavorable outcome using Cox proportional hazard regression analysis. RESULTS: A total of 659 patients (median age 62 years; male 54.3%) were included in the study. The total unfavorable outcomes were 28.1%: 4.6% LTFU, 9.6% NE, 9.1% deaths, and 4.9% TF. Multivariate analysis showed that a culture-confirmed diagnosis of TB was associated with a lower risk of LTFU (adjusted hazard ratio [aHR], 0.25; 95% confidence interval [CI], 0.10-0.63), whereas the occurrence of adverse drug reactions (ADRs) significantly increased the risk of LTFU (aHR, 6.63; 95% CI, 2.63-16.69). Patients living far from the hospital (aHR, 4.47; 95% CI, 2.50-7.97) and those with chronic kidney disease (aHR, 3.21; 95% CI, 1.33-7.75) were at higher risk of being transferred out to other health institutions (NE). Higher mortality was associated with older age (aHR, 1.06; 95% CI, 1.04-1.09) and comorbidities. The ADRs that occurred during TB treatment were a risk factor for TF (aHR, 6.88; 95% CI, 2.24-21.13). CONCLUSION: Unfavorable outcomes of patients with TB were substantial at a tertiary referral center, and the risk factors for each unfavorable outcome varied. To improve treatment outcomes, close monitoring and the provision of tailored care for patients with TB are necessary.
Assuntos
Antituberculosos , Tuberculose , Humanos , Masculino , Pessoa de Meia-Idade , Antituberculosos/efeitos adversos , Estudos Retrospectivos , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Fatores de Risco , Resultado do Tratamento , República da Coreia/epidemiologia , Assistência Centrada no PacienteRESUMO
BACKGROUND: Coinfections with multiple nontuberculous mycobacterial (NTM) species have not been widely studied. We aimed to evaluate the clinical characteristics and treatment outcomes in patients with NTM-pulmonary disease (PD) caused by coinfection with multiple NTM species. METHODS: We retrospectively reviewed patients with NTM-PD at a tertiary referral hospital in Korea between March 2012 and December 2018. Coinfection was defined as two or more species of NTM pathogens isolated from the same respiratory specimen or different specimens within three months. RESULTS: Among 1,009 patients with NTM-PD, 147 (14.6%) NTM coinfections were observed (average age 64.7 years, 69.4% women). NTM species were identified more frequently (median 6 vs. 3 times, P < 0.001) in the coinfection group than in the single species group, and follow-up duration was also longer in the coinfection group (median 44.9 vs. 27.1 months, P < 0.001). Mycobacterium avium complex (MAC) and M. abscessus and M. massiliense (MAB) were the dominant combinations (n = 71, 48.3%). For patients treated for over six months in the MAC plus MAB group (n = 31), sputum culture conversion and microbiological cure were achieved in 67.7% and 41.9% of patients, respectively. We divided the MAC plus MAB coinfection group into three subgroups according to the target mycobacteria; however, no statistical differences were found in the treatment outcomes. CONCLUSION: In NTM-PD cases, a significant number of multiple NTM species coinfections occurred. Proper identification of all cultured NTM species through follow-up is necessary to detect multispecies coinfections. Further research is needed to understand the nature of NTM-PD in such cases.
Assuntos
Coinfecção , Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Micobactérias não Tuberculosas , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Idoso , Coinfecção/microbiologia , Micobactérias não Tuberculosas/isolamento & purificação , Resultado do Tratamento , Pneumopatias/microbiologia , Pneumopatias/complicações , Complexo Mycobacterium avium/isolamento & purificação , Antibacterianos/uso terapêutico , República da CoreiaRESUMO
Arrhythmias range from mild nuisances to potentially fatal conditions, detectable through electrocardiograms (ECGs). With advancements in wearable technology, ECGs can now be monitored on-the-go, although these devices often capture noisy data, complicating accurate arrhythmia detection. This study aims to create a new deep learning model that utilizes generative adversarial networks (GANs) for effective noise removal and ResNet for precise arrhythmia classification from wearable ECG data. We developed a deep learning model that cleans ECG measurements from wearable devices and detects arrhythmias using refined data. We pretrained our model using the MIT-BIH Arrhythmia and Noise databases. Least squares GANs were used for noise reduction, maintaining the integrity of the original ECG signal, while a residual network classified the type of arrhythmia. After initial training, we applied transfer learning with actual ECG data. Our noise removal model significantly enhanced data clarity, achieving over 30 dB in a signal-to-noise ratio. The arrhythmia detection model was highly accurate, with an F1-score of 99.10% for noise-free data. The developed model is capable of real-time, accurate arrhythmia detection using wearable ECG devices, allowing for immediate patient notification and facilitating timely medical response.
Assuntos
Arritmias Cardíacas , Eletrocardiografia , Processamento de Sinais Assistido por Computador , Razão Sinal-Ruído , Dispositivos Eletrônicos Vestíveis , Arritmias Cardíacas/diagnóstico , Humanos , Eletrocardiografia/métodos , Algoritmos , Aprendizado Profundo , Redes Neurais de ComputaçãoRESUMO
This study investigated the correlation between the individual chemical constituents of particulate matter 2.5 µm (PM2.5) and respiratory parameters as well as the living environment and daily behaviors in patients with chronic obstructive pulmonary disease (COPD). Data were obtained from prospective COPD panel conducted in South Korea. Following collection via a microPEM, 18 metallic elements were determined using energy-dispersive X-ray fluorescence spectroscopy. All participants completed detailed questionnaires on living environments and lifestyle practices. Eighty-nine stable COPD patients (mean age 68.1 years; 94.4% male) were analyzed. Several constituents (titanium, aluminum, bromine, and silicone) were significantly associated with respiratory outcomes. Copper and manganese concentrations were significantly associated with the living environment. Increased ventilation time and air purifier operation were associated with lower concentrations of copper, silicone, barium, and titanium. These findings suggest varying relationships between PM2.5 constituents and clinical parameters in COPD patients, providing a basis for personalized interventions and future research.
RESUMO
Background Active surveillance (AS) is an accepted strategy for patients with low-risk papillary thyroid microcarcinoma (PTMC). While previous studies have evaluated the prognostic value of US features, results have been inconsistent. Purpose To determine if US features can help predict tumor progression in patients with low-risk PTMC undergoing AS. Materials and Methods This prospective study enrolled 1177 participants with PTMC from three hospitals between June 2016 and January 2021. Participants were self-assigned to either immediate surgery or AS, and those with two or more US examinations in the absence of surgery were included in the analysis. A χ2 test was used to compare estimated tumor progression rate at 4 years between participants stratified according to US features. Multivariable Cox regression analysis was used to assess the association of clinical and US features with overall tumor progression and specific progression criteria. Results Among 699 participants included in the analysis, 68 (mean age, 49 years ± 12 [SD]; 40 female participants) showed tumor progression (median follow-up, 41.4 months ± 16 [SD]). Tumor progression was associated with the US features of diffuse thyroid disease (DTD) (hazard ratio [HR], 2.3 [95% CI: 1.4, 3.7]; P = .001) and intratumoral vascularity (HR, 1.7 [95% CI: 1.0, 3.0]; P = .04) and the participant characteristics of male sex (HR, 2.8 [95% CI: 1.7, 4.6]; P < .001), age less than 30 years (HR, 2.9 [95% CI: 1.2, 6.8]; P = .01), and thyroid-stimulating hormone level of 7 µU/mL or higher (HR, 6.9 [95% CI: 2.7, 17.4]; P < .001). The risk of tumor progression was higher for participants with DTD (14%, P = .001) or intratumoral vascularity (14%, P = .02) than for participants without these features (6%). DTD and intratumoral vascularity were associated with tumor enlargement (HR, 2.7 [95% CI: 1.4, 5.1]; P = .002) and new lymph node metastasis (HR, 5.0 [95% CI: 1.3, 19.4]; P = .02), respectively. Conclusion DTD and intratumoral vascularity were associated with an increased risk of tumor progression in participants with PTMC undergoing AS. Clinical trial registration no. NCT02938702 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Reuter and the review "International Expert Consensus on US Lexicon for Thyroid Nodules" by Durante et al in this issue.
Assuntos
Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Conduta Expectante , Estudos Prospectivos , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer , accounting for approximately 85% of lung cancers. For more than 40 years, platinum (Pt)-based drugs are still one of the most widely used anticancer drugs even in the era of precision medicine and immunotherapy. However, the clinical limitations of Pt-based drugs, such as serious side effects and drug resistance, have not been well solved. This study constructs a new albumin-encapsulated Pt(IV) nanodrug (HSA@Pt(IV)) based on the Pt(IV) drug and nanodelivery system. The characterization of nanodrug and biological experiments demonstrate its excellent drug delivery and antitumor effects. The multi-omics analysis of the transcriptome and the ionome reveals that nanodrug can activate ferroptosis by affecting intracellular iron homeostasis in NSCLC. This study provides experimental evidence to suggest the potential of HSA@Pt(IV) as a nanodrug with clinical application.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Ferroptose , Neoplasias Pulmonares , Nanopartículas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Albuminas , Ferro/farmacologia , Linhagem Celular TumoralRESUMO
BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC. METHODS: This was a largescale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC. RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy. CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients. TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .
Assuntos
Canais de Cálcio , Estudo de Associação Genômica Ampla , Neoplasias Nasofaríngeas , Humanos , Quimiorradioterapia , Variação Genética , Genótipo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Canais de Cálcio/genéticaRESUMO
BACKGROUND: The longitudinal relationship between adiposity and lung function is controversial. We aimed to investigate the long-term association between adiposity changes and lung function in a middle-aged general Asian population. METHODS: In total, 5011 participants (average age, 54 years; 45% men) were enrolled from a community-based prospective cohort. During the follow-up period (median 8 years), both spirometry and bio-electrical impedance analysis were performed biannually. Individual slopes of the fat mass index (FMI; fat mass divided by the square of height in meters) and waist-to-hip ratio (WHR) were calculated using linear regression analysis. Multivariate linear mixed regression analysis was used to determine the long-term association between adiposity changes and lung function. RESULTS: The FMI was inversely associated with forced vital capacity (FVC) (estimated: - 31.8 mL in men, - 27.8 mL in women) and forced expiratory volume in 1 s (FEV1) (estimated: - 38.2 mL in men, - 17.8 mL in women) after adjusting for baseline age, height, residential area, smoking exposure (pack-years, men only), initial adiposity indices, and baseline lung function. The WHR was also inversely associated with FVC (estimated = - 1242.2 mL) and FEV1 (estimated = - 849.8 mL) in men. The WHR-increased group showed a more rapid decline in lung function than the WHR-decreased group in both the fat-gain and fat-loss groups. CONCLUSION: Adiposity was associated with the long-term impairment of lung function. Central obesity was the main driver of lung function impairment in the middle-aged general Asian population, regardless of fat mass changes.
Assuntos
Adiposidade , Pulmão , Masculino , Pessoa de Meia-Idade , Humanos , Feminino , Estudos Prospectivos , Índice de Massa Corporal , Obesidade/epidemiologia , Capacidade Vital , Volume Expiratório ForçadoRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease that causes joint swelling and inflammation and can involve the entire body. RA is characterized by the increase of pro-inflammatory cytokines such as interleukin (IL) and tumor necrosis factor, and the over-activation of T lymphocytes and B lymphocytes, which may lead to severe chronic inflammation of joints. However, despite numerous studies the pathogenesis and treatment of RA remain unresolved. This study investigated the use of small heterodimer partner-interacting leucine zipper protein (SMILE) overexpression to treat a mouse model of RA. SMILE is an insulin-inducible corepressor through adenosine monophosphate-activated kinase (AMPK) signaling pathway. The injection of a SMILE overexpression vector to mice with collagen induced-arthritis resulted in a milder clinical pathology and a reduced incidence of arthritis, less joint tissue damage, and lower levels of Th17 cells and plasma B cells in the spleen. Immunohistochemistry of the joint tissue showed that SMILE decreased B-cell activating factor (BAFF) receptor (BAFF-R), mTOR, and STAT3 expression but increased AMPK expression. In SMILE-overexpressing transgenic mice with collagen antibody-induced arthritis (CAIA), a decrease in the arthritis score and reductions in tissue damage, the number of B cells, and antibody production were observed. The treatment of immune cells in vitro with curcumin, a known SMILE-inducing agent, led to decreases in plasma B cells, germinal center B cells, IL-17-producing B cells, and BAFF-R-positive B cells. Taken together, our findings demonstrate the therapeutic potential of SMILE in RA, based on its inhibition of B cell activation mediated by the AMPK/mTOR and STAT3 signaling pathway and BAFF-R expression. Video abstract.
Assuntos
Artrite Experimental , Doenças Autoimunes , Animais , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Colágeno , Inflamação , Zíper de Leucina , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVE: To compare the image quality and diagnostic performance between standard turbo spin-echo MRI and accelerated MRI with deep learning (DL)-based image reconstruction for degenerative lumbar spine diseases. MATERIALS AND METHODS: Fifty patients who underwent both the standard and accelerated lumbar MRIs at a 1.5-T scanner for degenerative lumbar spine diseases were prospectively enrolled. DL reconstruction algorithm generated coarse (DL_coarse) and fine (DL_fine) images from the accelerated protocol. Image quality was quantitatively assessed in terms of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) and qualitatively assessed using five-point visual scoring systems. The sensitivity and specificity of four radiologists for the diagnosis of degenerative diseases in both protocols were compared. RESULTS: The accelerated protocol reduced the average MRI acquisition time by 32.3% as compared to the standard protocol. As compared with standard images, DL_coarse and DL_fine showed significantly higher SNRs on T1-weighted images (T1WI; both p < .001) and T2-weighted images (T2WI; p = .002 and p < 0.001), higher CNRs on T1WI (both p < 0.001), and similar CNRs on T2WI (p = .49 and p = .27). The average radiologist assessment of overall image quality for DL_coarse and DL_fine was higher on sagittal T1WI (p = .04 and p < .001) and axial T2WI (p = .006 and p = .01) and similar on sagittal T2WI (p = .90 and p = .91). Both DL_coarse and DL_fine had better image quality of cauda equina and paraspinal muscles on axial T2WI (both p = .04 for cauda equina; p = .008 and p = .002 for paraspinal muscles). Differences in sensitivity and specificity for the detection of central canal stenosis and neural foraminal stenosis between standard and DL-reconstructed images were all statistically nonsignificant (p ≥ 0.05). CONCLUSION: DL-based protocol reduced MRI acquisition time without degrading image quality and diagnostic performance of readers for degenerative lumbar spine diseases. CLINICAL RELEVANCE STATEMENT: The deep learning (DL)-based reconstruction algorithm may be used to further accelerate spine MRI imaging to reduce patient discomfort and increase the cost efficiency of spine MRI imaging. KEY POINTS: ⢠By using deep learning (DL)-based reconstruction algorithm in combination with the accelerated MRI protocol, the average acquisition time was reduced by 32.3% as compared with the standard protocol. ⢠DL-reconstructed images had similar or better quantitative/qualitative overall image quality and similar or better image quality for the delineation of most individual anatomical structures. ⢠The average radiologist's sensitivity and specificity for the detection of major degenerative lumbar spine diseases, including central canal stenosis, neural foraminal stenosis, and disc herniation, on standard and DL-reconstructed images, were similar.
Assuntos
Aprendizado Profundo , Humanos , Constrição Patológica , Vértebras Lombares/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , AceleraçãoRESUMO
OBJECTIVE: This study aimed to evaluate the outcomes of physician-modified endografts (PMEGs) for the treatment of thoracic aortic pathologies involving the aortic arch. METHODS: A retrospective single-center study was performed on consecutive patients with thoracic aortic pathologies treated by PMEGs between February 2018 and May 2022. Data on baseline characteristics, operative procedure, and follow-up information were collected. The endpoints included technical success, complications, mortality, overall survival, re-intervention, and target vessel instability. RESULTS: This study comprised 173 patients (mean age=58±13, range=28-83, 148 men) with thoracic aortic pathologies, including 44 thoracic aortic aneurysms, 113 aortic dissections (9 type A, 4 residual type A, 75 type B, 32 non-A non-B), 3 aortic intramural hematomas, and 13 penetrating aortic ulcers. Thirty-five of the patients had PMEGs with 3 fenestrations, 32 had 2 fenestrations, and 106 had 1 single fenestration. Technical success was 98% (170/173), and the 30-day mortality was 2% (3/173). Perioperative complications included stroke (n=3, 2%), retrograde type A dissection (RTAD; n=3, 2%) and renal injury (n=3, 2%). Seven deaths (4%) were noted during a median follow-up of 11 (range=1-52) months. Eleven cases of re-intervention were stent-related. There were 5 type Ia endoleaks (3%), 2 type III endoleaks (1%) from the innominate artery (IA), and 3 type Ic endoleaks (2%) from the left subclavian arteries. One case of IA stent-graft (SG) stenosis was noted because of mural thrombus. Estimate rates of overall survival, freedom from secondary intervention, and freedom from target vessel instability at 2 years were 93.4% (95% confidence interval [CI]=88.7%-98.1%), 80.7% (95% CI=73.3%-88.1%), and 89.0% (95% CI=80.4%-97.6%), respectively. CONCLUSIONS: Physician-modified endografts showed promising immediate therapeutic results in the treatment of thoracic aortic pathologies involving the aortic arch. Our study demonstrates that the technique is feasible and produces acceptable results. Long-term outcomes are required for further refinement of this technical approach to confirm technical success and durability over time as a valuable option for endovascular aortic arch repair in specialized centers. CLINICAL IMPACT: Our short- and mid-term outcomes of physician-modified endografts in 173 patients showed promising results compared to other branched/fenestrated techniques and backed up the endovascular repair of the aortic arch. Meanwhile, the technical expertise pointed out in our manuscript, including preloaded guidewire, diameter-reducing wire and inner mini-cuffs, provided reference and technical guidance for our peers. Most importantly, it demonstrated that the PMEG, as a device whose components were all commercially available, might be a better option for emergency surgery and for centers who had no access to custom-made devices.