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BACKGROUND: Ferroptosis of keratinocytes is closely associated with amplification of skin inflammation in psoriasis. This study focuses on unlocking the role of caffeic acid (CA), a polyphenol compound, in keratinocyte ferroptosis and understanding the underlying mechanistic basis. METHODS: The interaction between early growth response protein 1 (EGR1) and chac glutathione specific γglutamylcyclotransferase 1 (CHAC1) was predicted by bioinformatics and validated via chromatin immunoprecipitation and dual-luciferase reported assays. Their expressions in primary human epidermal keratinocytes were altered by transfection of EGR1/CHAC1 overexpression or knockdown plasmids, and then keratinocytes were followed by CA treatment and Erastin (ferroptosis inducer). Keratinocyte viability was determined by CCK-8 assay, and the ferroptotic effect was evaluated using colorimetric assay and flow cytometry. Proinflammatory cytokine secretion by keratinocytes was detected via ELISA. Expressions of EGR1 and CHAC1 in keratinocytes were analyzed by qRT-PCR or Western blot. RESULTS: Increased expressions of EGR1 and CHAC1 were detected in keratinocytes with Erastin treatment. CA (100 µM) antagonized Erastin (10 µM)-induced decrease in viability, increases in EGR1 and CHAC1 expressions, upregulation of MDA, ROS, and Fe2+, downregulation of GSH and SOD, and secretion of proinflammatory cytokines from keratinocytes. EGR1 overexpression potentiated Erastin-induced effects. Moreover, EGR1 overexpression and CA mutually counteracted their effects on Erastin-induced keratinocytes. EGR1 transcriptionally activated and positively regulated CHAC1. The above Erastin-induced effects were neutralized by EGR1 knockdown but potentiated by CHAC1 overexpression. Moreover, EGR1 knockdown and CHAC1 overexpression reversed each other's effects. CONCLUSION: CA reduces ferroptosis by inhibiting EGR1-induced activation of CHAC1 to dampen inflammation of keratinocytes in psoriasis. This study providing new compounds and candidate targets for the clinical treatment of psoriasis.
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BACKGROUND: While sleep disorders are implicated in atrial fibrillation (AF), the interplay of physiologic alterations and symptoms remains unclear. Sleep-based phenotypes can account for this complexity and translate to actionable approaches to identify at-risk patients and therapeutic interventions. OBJECTIVES: This study hypothesized discrete phenotypes of symptoms and polysomnography (PSG)-based data differ in relation to incident AF. METHODS: Data from the STARLIT (sleep Signals, Testing, And Reports LInked to patient Traits) registry on Cleveland Clinic patients (≥18 years of age) who underwent PSG from November 27, 2004, to December 30,2015, were retrospectively examined. Phenotypes were identified using latent class analysis of symptoms and PSG-based measures of sleep-disordered breathing and sleep architecture. Phenotypes were included as the primary predictor in a multivariable-adjusted Cox proportional hazard models for incident AF. RESULTS: In our cohort (N = 43,433, age 51.8 ± 14.5 years, 51.9% male, 74.9% White), 7.3% (n = 3,166) had baseline AF. Over a 7.6- ± 3.4-year follow-up period, 8.9% (n = 3,595) developed incident AF. Five phenotypes were identified. The hypoxia subtype (n = 3,245) had 48% increased incident AF (HR: 1.48; 95% CI: 1.34-1.64), the apneas + arousals subtype (n = 4,592) had 22% increased incident AF (HR: 1.22; 95% CI: 1.10-1.35), and the short sleep + nonrapid eye movement subtype (n = 6,126) had 11% increased incident AF (HR: 1.11; 95% CI: 1.01-1.22) compared with long sleep + rapid eye movement (n = 26,809), the reference group. The hypopneas subtype (n = 2,661) did not differ from reference (HR: 0.89; 95% CI: 0.77-1.03). CONCLUSIONS: Consistent with prior evidence supporting hypoxia as an AF driver and cardiac risk of the sleepy phenotype, this constellation of symptoms and physiologic alterations illustrates vulnerability for AF development, providing potential value in enhancing our understanding of integrated sleep-specific symptoms and physiologic risk of atrial arrhythmogenesis.
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Interferon-alpha (IFN-α) is a first-line drug for treating chronic hepatitis B (CHB). Guanylate-binding protein 1 (GBP1) is one of the interferon-stimulating factors, which participates in the innate immunity of the host and plays an antiviral and antibacterial role. In this study, we explored how GBP1 is involved in IFN-α antiviral activity against HBV. Before being gathered, HepG2-NTCP and HepG2 2.15 cells were transfected with the wild-type hGBP1 plasmid or si-GBP1, respectively, and followed by stimulation with Peg-IFNα-2b. We systematically explored the role of GBP1 in regulating HBV infection in cell models. Additionally, we also examined GBP1 levels in CHB patients. GBP1 activity increased, and its half-life was prolonged after HBV infection. Overexpression of GBP1 inhibited the production of HBsAg and HBeAg, as well as HBs protein and HBV total RNA levels, whereas silencing of GBP1 inhibited its ability to block viral infections. Interestingly, overexpressing GBP1 co-treatment with Peg-IFNα-2b further increased the antiviral effect of IFN-α, while GBP1 silencing co-treatment with Peg-IFNα-2b partly restored its inhibitory effect on HBV. Mechanistically, GBP1 mediates the anti-HBV response of Peg-IFNα-2b by targeting HBs. Analysis of clinical samples revealed that GBP1 was elevated in CHB patients and increased with Peg-IFNα-2b treatment, while GBP1 showed good stability in the interferon response group. Our study demonstrates that GBP1 inhibits HBV replication and promotes HBsAg clearance. It is possible to achieve antiviral effects through the regulation of IFN-α induced immune responses in response to HBV.
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Antivirais , Proteínas de Ligação ao GTP , Vírus da Hepatite B , Hepatite B Crônica , Interferon-alfa , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Antivirais/farmacologia , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/imunologia , Células Hep G2 , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Hepatite B Crônica/imunologia , Masculino , Antígenos de Superfície da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/metabolismo , Feminino , Adulto , Replicação Viral/efeitos dos fármacos , Hepatite B/virologia , Hepatite B/imunologia , Hepatite B/tratamento farmacológicoRESUMO
BACKGROUND: Aerobic exercise (AEx) has many potential benefits; however, it is unknown whether individuals with multiple sclerosis (MS) can attain the optimal intensity and duration to harness its effects. Forced-rate exercise (FE) is a novel paradigm in which the voluntary pedaling rate during cycling is supplemented to achieve a higher exercise intensity. The aim of this pilot trial was to investigate the feasibility and initial efficacy of a 12-week FE or voluntary exercise (VE) cycling intervention for individuals with MS. METHODS: Twenty-two participants with MS (Expanded Disability Severity Scale [EDSS] 2.0-6.5) were randomly assigned to FE (n = 12) or VE (n = 10), each with twice weekly 45-minute sessions at a prescribed intensity of 60% to 80% of maximum heart rate (HR). RESULTS: Eighteen individuals (FE = 11; VE = 7) completed the intervention, however, adaptations were required in both groups to overcome barriers to cycling. Overall, participants exercised for an average of 42.2 ± 2.3 minutes at an aerobic intensity of 65% ± 7% of maximum HR and a pedaling cadence of 67.3 ± 13.3 RPM. Cycling led to improved treadmill walking speed (0.61 to 0.68 m/sec, P = .010), with somewhat greater improvement with FE compared to VE (increase of 0.09 vs 0.03 m/s, respectively, P = .17) post intervention. Notably, the participant with the highest disability level (EDSS 6.5) tolerated FE but not VE. CONCLUSIONS: Aerobic exercise is feasible for individuals with MS, although those with increased disability may require novel paradigms such as FE to achieve targeted intensity. Further trials are warranted to investigate the effects of FE across the MS disability spectrum.
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BACKGROUND: Although routine antiviral therapy has been implemented in HCC patients, the risk of HBV reactivation (HBVr) remains with the use of programmed cell death-1(PD-1) blockade-based combination immunotherapy and the relevant risk factors are also unclear. Therefore, we aimed to identify the incidence and risk factors of HBVr in HCC patients undergoing combination therapy of PD-1 inhibitors and angiogenesis inhibitors and concurrent first-line antivirals. METHODS: We included a total of 218 HBV-related HCC patients with first-line antivirals who received PD-1 inhibitors alone or together with angiogenesis inhibitors. According to the anti-tumor therapy modalities, patients were divided into PD-1 inhibitors monotherapy group (anti-PD-1 group) and combination therapy group (anti-PD-1 plus angiogenesis inhibitors group). The primary study endpoint was the incidence of HBVr. RESULTS: HBVr occurred in 16 (7.3%) of the 218 patients, 2 cases were found in the anti-PD-1 group and the remaining 14 cases were in the combination group. The Cox proportional hazard model identified 2 independent risk factors for HBVr: combination therapy (hazard ratio [HR], 4.608, 95%CI 1.010-21.016, P = 0.048) and hepatitis B e antigen (HBeAg) positive (HR, 3.695, 95%CI 1.246-10.957, P = 0.018). Based on the above results, we developed a simple risk-scoring system and found that the high-risk group (score = 2) developed HBVr more frequently than the low-risk group (score = 0) (Odds ratio [OR], 17.000, 95%CI 1.946-148.526, P = 0.01). The area under the ROC curve (AUC-ROC) was 7.06 (95%CI 0.581-0.831, P = 0.006). CONCLUSION: HBeAg-positive patients receiving combination therapy have a 17-fold higher risk of HBVr than HBeAg-negative patients with PD-1 inhibitors monotherapy.
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Carcinoma Hepatocelular , Hepatite B , Neoplasias Hepáticas , Humanos , Vírus da Hepatite B , Hepatite B/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Antígenos E da Hepatite B/farmacologia , Antígenos E da Hepatite B/uso terapêutico , Angiogênese , Neoplasias Hepáticas/tratamento farmacológico , Ativação Viral , Antivirais/uso terapêuticoRESUMO
Background: Cognitive impairment (CI) is a distinctive characteristic of schizophrenia, with evidence suggesting that childhood and adolescence onset schizophrenia (CAOS), representing severe but rare forms of schizophrenia, share continuity with adult-onset conditions. While relationships between altered brain function and CI have been identified in adults with schizophrenia, the extent of brain function abnormalities in CAOS remains largely unknown. In this study, we employed resting-state functional magnetic resonance imaging (rs-fMRI) to investigate functional alterations in brain areas among patients with CAOS. To assess CI across multiple cognitive domains, we utilized the Stroop Color and Word Tests (SCWT) and MATRICS Consensus Cognitive Battery (MCCB) tests. Our objective was to explore the associations between functional CI and the amplitude of low-frequency fluctuation (ALFF) levels in these patients. Methods: We enrolled 50 patients diagnosed with CAOS and 33 healthy controls (HCs) matched for sex and age. Cognitive functions were assessed using the MCCB and SCWT methods. Rs-fMRI data were acquired using gradient-echo echo-planar imaging sequences. Voxel-based ALFF group maps were compared through two-sample t-tests in SPM8. Subsequently, correlation analyses were conducted to identify associations between ALFF levels and cognitive scores. Results: In comparison to HCs, patients exhibited significantly increased ALFF levels in the right fusiform gyrus, frontal lobe, and caudate, as well as the left frontal lobe and caudate. Conversely, reduced ALFF levels were observed in the temporal and left medial frontal lobes. Significant differences were identified between HCs and patients in terms of total cognitive scores, ALFF levels, and domain scores. All test scores were decreased, except for TMA. Correlation analyses between ALFF levels and cognitive functions in patients with CAOS differed from those in HCs. Pearson correlation analyses revealed positive associations between Brief Visuospatial Memory Test - Revised (BVMT-R) scores and ALFF levels in the left medial frontal gyrus. Digital Span Test (DST) scores were negatively correlated with ALFF levels in the right caudate, and Maze Test values were negatively correlated with levels in the left caudate. However, Pearson correlation analyses in HCs indicated that color and Hopkins Verbal Learning Test (HVLT-R) scores positively correlated with ALFF levels in the left frontal lobe, while color-word and symbol coding scores negatively correlated with levels in the right caudate. Conclusions: Altered ALFF levels in the brain may be linked to cognitive impairment (CI) in patients with CAOS. We highlighted the pathophysiology of schizophrenia and provide imaging evidence that could potentially aid in the diagnosis of CAOS.
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BACKGROUND: Following COVID-19 infection, as many as a third of patients have long-term symptoms, known as post-acute sequelae (PASC). The mechanisms contributing to PASC remain largely unknown and, due to the heterogeneity of symptoms, treating PASC provides unique challenges. OBJECTIVE: Our study sought to (1) identify clinical symptom profiles based on PROMIS Global Health (GH) items, (2) evaluate demographic and clinical differences across profiles, and (3) identify predictors of change in health-related quality of life (HRQL) over time. DESIGN: This was an observational cohort study of patients with PASC who completed PROMIS-GH between 2/11/21 and 12/3/21 as part of routine care, with data extracted from the electronic health record. PARTICIPANTS: There were 1407 adult patients (mean age 49.6 ± 13.7, 73% female, 81% White race) with PASC seen in the recovery clinic between 2/11/21 and 12/3/21, with 1129 (80.2%) completing PROMIS-GH as routine care. MAIN MEASURES: HRQL was measured with PROMIS-GH at initial visit and after 12 months. KEY RESULTS: Latent profile analysis identified symptom classes based on five PROMIS-GH items (mental health, ability to carry out physical activities, pain, fatigue, and emotional problems). Four latent profiles were identified: (1) "Poor HRQL" (n = 346), (2) "Mixed HRQL: good mental/poor physical" (n = 232), (3) "Mixed HRQL: poor mental/good physical" (n = 324), and (4) "Good HRQL" (n = 227). Demographics and comorbidities varied significantly across profile with patients with more severe COVID-19 infection more likely to be in profiles 1 and 2. Overall, patients improved 2 T-score points on PROMIS-GH after 12 months, with differences by profile. Predictors of improved HRQL included profile, lower body mass index, and fewer COVID symptoms. CONCLUSIONS: Patients with PASC have distinct HRQL symptom profiles which were able to differentiate across COVID-19 severity and symptoms. Improvement over 12 months differed by profile. These profiles may be used to better understand the mechanisms behind PASC. Future research should evaluate their ability to guide treatment decisions to improve HRQL.
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COVID-19 , Síndrome de COVID-19 Pós-Aguda , Qualidade de Vida , Humanos , Feminino , Masculino , COVID-19/psicologia , COVID-19/epidemiologia , Pessoa de Meia-Idade , Adulto , Estudos de Coortes , Idoso , SARS-CoV-2RESUMO
BACKGROUND: The potential for aerobic exercise (AE) to enhance neuroplasticity post-stroke has been theorized but not systematically investigated. Our aim was to determine the effects of forced-rate AE (FE) paired with upper extremity (UE) repetitive task practice (FE + RTP) compared to time-matched UE RTP (RTP only) on motor recovery. METHODS: A single center randomized clinical trial was conducted from April 2019 to December 2022. Sixty individuals ≥6 months post-stroke with UE hemiparesis were randomized to FE + RTP (N = 30) or RTP only (N = 30), completing 90-minute sessions, 3×/week for 8 weeks. The FE + RTP group underwent 45-minute of FE (5-minute warm-up, 35-minute main set, and 5-minute cool down) followed by 45-minute of UE RTP. The RTP only group completed 90-minute of RTP. Primary outcomes were the Fugl-Meyer Assessment (FMA) and Action Research Arm Test (ARAT). The 6-minute Walk Test (6MWT, secondary outcome) assessed walking capacity. RESULTS: Sixty individuals enrolled and 56 completed the study. The RTP only group completed more RTP in terms of repetitions (411.8 ± 44.4 vs 222.8 ± 28.4, P < .001) and time (72.7 ± 6.7 vs 37.8 ± 2.4 minutes, P < .001) versus FE + RTP. There was no significant difference between groups on the FMA (FE + RTP, 36.2 ± 10.1-44.0 ± 11.8 and RTP only, 34.4 ± 11.0-41.2 ± 13.4, P = .43) or ARAT (FE + RTP, 32.5 ± 16.6-37.7 ± 17.9 and RTP only, 32.8 ± 18.6-36.4 ± 18.5, P = .88). The FE + RTP group demonstrated greater improvements on the 6MWT (274.9 ± 122.0-327.1 ± 141.2 m) versus RTP only (285.5 ± 160.3-316.9 ± 170.0, P = .003). CONCLUSIONS: There was no significant difference between groups in the primary outcomes. The FE + RTP improved more on the 6MWT, a secondary outcome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03819764.
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Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/complicações , Extremidade Superior , Exercício Físico , Caminhada , Recuperação de Função Fisiológica , Resultado do TratamentoRESUMO
OBJECTIVE: To examine the cardiorespiratory effects of a forced-rate aerobic exercise (FE) intervention among individuals with chronic stroke compared with an upper extremity repetitive task practice (UE RTP) control group. DESIGN: Secondary analysis of data from a randomized controlled trial. SETTING: Research laboratory. PARTICIPANTS: Individuals with chronic stroke (N=60). INTERVENTIONS: Participants completed 24 sessions of FE followed by RTP (FE+RTP, N=30) or time matched RTP alone (N=30). The FE+RTP group was prescribed exercise at 60%-80% of heart rate reserve on a motorized stationary cycle ergometer for 45 minutes followed by 45 minutes of RTP. The control group completed 90 minutes of RTP. MAIN OUTCOME MEASURES: Metabolic exercise stress tests on a cycle ergometer were conducted at baseline and post-intervention. Outcomes included peak oxygen consumption (peak VÌo2) and anaerobic threshold (AT). RESULTS: Fifty participants completed the study intervention and pre/post stress tests. The FE+RTP group demonstrated significantly greater improvements in peak VÌo2 from 16.4±5.7 to 18.3±6.4 mL/min/kg compared with the RTP group (17.0±5.6 to 17.2±5.6 mL/min/kg, P=.020) and significantly greater improvements in AT from 10.3±2.8 to 11.5±3.6 mL/min/kg compared with the RTP group (10.8±3.9 to 10.4±3.2 mL/min/kg, P=.020). In analyzing predictors of post-intervention peak VÌo2, the multivariable linear regression model did not reveal a significant effect of age, sex, body mass index, or beta blocker usage. Similarly, bivariate linear regression models for the FE group only did not find any exercise variables (aerobic intensity, power, or cycling cadence) to be significant predictors of peak VÌo2. CONCLUSIONS: While the aerobic exercise intervention was integrated into rehabilitation to improve UE motor recovery, it was also effective in eliciting significant and meaningful improvements in cardiorespiratory fitness. This novel rehabilitation model may be an effective approach to improve motor and cardiorespiratory function in persons recovering from stroke.
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Aptidão Cardiorrespiratória , Terapia por Exercício , Consumo de Oxigênio , Reabilitação do Acidente Vascular Cerebral , Humanos , Masculino , Reabilitação do Acidente Vascular Cerebral/métodos , Aptidão Cardiorrespiratória/fisiologia , Feminino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Terapia por Exercício/métodos , Idoso , Doença Crônica , Teste de Esforço , Limiar Anaeróbio/fisiologia , Ciclismo/fisiologia , Acidente Vascular Cerebral/fisiopatologiaRESUMO
OBJECTIVE: Quantify cognitive deficits in patients with postacute sequelae of COVID-19 (PASC) and identify key variables related to cognitive impairment in PASC. METHOD: Patients with polymerase chain reaction-confirmed COVID-19 underwent a comprehensive neuropsychological evaluation. The comparison group included patients without neurological disorders determined by the neuropsychologist to be cognitively intact. Cognitive impairment was defined as impairment (Composite T ≤35) in 1 of 6 cognitive domains. The PASC group was split into impaired or intact based on the above criteria. Multivariable logistic regression models assessed predictors including demographics, COVID-19 severity, clinical characteristics, and mood. RESULTS: There were 210 patients with PASC, predominantly female (73.3%, P < .001), without other demographic differences when compared with 369 normal controls. Patients with PASC were more likely to have cognitive impairment (odds ratio 3.61; 95% confidence interval, 2.36-5.54; P < .001) compared with controls, with significantly lower scores in domains of memory, language, processing speed, visuospatial function, executive function (P < .001), and higher depressive (P = .004) and anxiety symptoms (P = .003). Patients with PASC who demonstrated cognitive impairment (n = 93) had higher body mass index compared with those with PASC without cognitive impairment (n = 117), without differences in other predictors. CONCLUSION: Patients with PASC are almost 4 times more likely to evidence cognitive dysfunction compared with normal controls. Forty-four percent of patients with PASC demonstrated cognitive deficits about 7 months from infection. Estimated premorbid intelligence significantly correlated with impairment. Higher body mass index was the only metric shown to differentiate those with PASC and cognitive impairment from those with PASC who were cognitively intact.
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BACKGROUND AND OBJECTIVES: Longitudinal outcomes in anti-NMDA receptor encephalitis (anti-NMDARe) are still not fully understood and may not be adequately captured with the modified Rankin Scale (mRS), often the sole reported outcome. We aim to characterize longitudinal outcomes in anti-NMDARe using multiple outcome measures. METHODS: This single-center, retrospective, observational study examined outcome measures (mRS and Clinical Assessment Scale in Autoimmune Encephalitis [CASE]) in adults with NMDA receptor-IgG in CSF at short- and long-term follow-ups using linear and logistic regression modeling. Patients with evaluations for cognitive impairment (Montreal Cognitive Assessment/Mini-Mental State Examination), depression (Patient Health Questionnaire-9), and anxiety (General Anxiety Disorder-7) >6 months from symptom onset were correlated with final CASE scores. RESULTS: Thirty-eight patients (76% female, median disease onset age = 28 years, range = 1-75 years) were included. The majority received first-line immunosuppressants (97%) at a median of 3.9 weeks (interquartile range [IQR] = 2.1-9.7) from symptom onset and 68% received second-line therapies. At baseline, median/mean mRS and CASE were 4 (IQR = 3-5) and 12.9 (SD = 7.2), respectively. At short-term follow-up (median = 10 weeks, IQR = 6-17), factors associated with higher CASE and mRS included dysautonomia, coma/lethargy, seizures/status epilepticus, and intensive care unit admission (p < 0.05). At long-term follow-up (median = 70 weeks, IQR = 51-174), median/mean mRS and CASE were 2 (IQR = 1-3) and 4.4 (SD = 4.2), respectively. Only weakness at symptom onset predicted higher mRS scores (odds ratio = 5.6, 95% confidence interval 1.02-30.9, p = 0.047). Despite both mRS and CASE improving from baseline (p < 0.001), only 9 patients (31%) returned to their premorbid function. Among patients with cognitive and mood evaluations >6 months from onset, moderate-severe cognitive impairment (42%), depression (28%), and anxiety (30%) were frequent. Cognitive and depression measures were associated with final CASE subscores (including memory, language, weakness, and psychiatric). DISCUSSION: Multiple clinical factors influenced short-term outcomes, but only onset weakness influenced long-term mRS, highlighting that mRS is predominantly affected by global motor function. Although mRS and CASE improved over time for most patients, these outcome measures did not capture the full extent of long-term functional impairment in terms of mood, cognition, and the ability to return to premorbid function. This emphasizes the need for increased utilization of more nuanced cognitive and mood outcome measures.
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Encefalite Antirreceptor de N-Metil-D-Aspartato , Disfunção Cognitiva , Encefalite , Doença de Hashimoto , Adulto , Humanos , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Masculino , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Transtornos de Ansiedade , Disfunção Cognitiva/etiologiaRESUMO
BACKGROUND: We aimed to investigate the prognostic factors associated with clinical outcomes in CV2/Collapsin response-mediator protein 5 (CRMP5)-IgG paraneoplastic neurologic disorders (PND). METHODS: This is a retrospective study of patients with CV2/CRMP5-IgG PND evaluated between 2002-2022. We examined the association of clinical variables (including age, clinical phenotype [autoimmune encephalopathy, myelopathy, polyneuropathy/radiculopathy, MG, cerebellar ataxia, chorea, optic neuropathy], cancer) with three clinical outcomes (wheelchair dependence, modified Rankin Scale [mRS], mortality) using univariate logistic regression and Cox proportional hazards modeling. Kaplan-Meier estimates were used to determine the probability of survival. RESULTS: Twenty-seven patients (56% female) with CV2/CRMP5-IgG PND were identified with a median follow-up of 54 months (IQR = 11-102). An underlying tumor was identified in 15 patients (56%) including small cell lung cancer (SCLC) (8, [53%]), thymoma (4, [27%]), and other histologies (3, [20%]). At last follow-up, 10 patients (37%) needed a wheelchair for mobility and this outcome was associated with myelopathy (HR = 7.57, 95% CI = 1.87-30.64, P = 0.005). Moderate-severe mRS = 3-5 was associated with CNS involvement (encephalopathy, myelopathy, or cerebellar ataxia) (OR = 7.00, 95% CI = 1.18-41.36, P = 0.032). The probability of survival 4 years after symptom onset was 66%. Among cancer subtypes, SCLC (HR = 18.18, 95% CI = 3.55-93.04, P < 0.001) was significantly associated with mortality, while thymoma was not. INTERPRETATION: In this retrospective longitudinal study of CV2/CRMP5-IgG PND, patients with CNS involvement, particularly myelopathy, had higher probability of disability. SCLC was the main determinant of survival in this population.
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Ataxia Cerebelar , Neoplasias Pulmonares , Doenças do Sistema Nervoso , Carcinoma de Pequenas Células do Pulmão , Doenças da Medula Espinal , Timoma , Neoplasias do Timo , Humanos , Feminino , Masculino , Estudos Retrospectivos , Proteínas do Tecido Nervoso , Proteínas Associadas aos Microtúbulos , Estudos Longitudinais , Autoanticorpos , Doenças do Sistema Nervoso/etiologia , Timoma/complicações , Neoplasias do Timo/complicações , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Imunoglobulina GRESUMO
The purpose of this study was to reveal the antibacterial activity and mechanism of Polygonatum sibiricum extract (PSE) against Bacillus cereus and further analyze the application of PSE in pasteurized milk (PM). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values and growth curve analysis were used to evaluate the antibacterial activity of PSE against B. cereus. The changes in contents of intracellular adenosine 5'-triphosphate (ATP) and reactive oxygen species (ROS), activities of ß-galactosidase, adenosine triphosphatase (ATPase) and alkaline phosphatase (AKP), cell membrane potential, protein and nucleic acid leakage, and cell morphology were used to reveal the antibacterial mechanism. The effects of PSE on viable count and sensory evaluation of PM during storage were analyzed. The results showed that the MIC and MBC values of PSE against B. cereus were 2 and 4 mg/mL, respectively. Growth curve analysis showed that PSE with a concentration of 2 MIC could completely inhibit the growth of B. cereus. After treatments with PSE, the levels of intracellular ATP and ROS, and activities of ß-galactosidase, ATPase and AKP of B. cereus were significantly reduced (p < 0.05). Cell membrane was depolarized, amounts of protein and nucleic acid leakage were significantly increased (p < 0.05), and cell morphology was destroyed. Furthermore, PSE significantly reduced the viable count of B. cereus in PM and improved the sensory quality of PM during storage (p < 0.05). Together, our findings suggested that PSE had the desired effect as a natural preservative applied in PM.
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Ácidos Nucleicos , Polygonatum , Animais , Leite/microbiologia , Bacillus cereus , Espécies Reativas de Oxigênio/farmacologia , Antibacterianos/farmacologia , beta-Galactosidase/farmacologia , Extratos Vegetais/farmacologia , Adenosina Trifosfatases/farmacologia , Trifosfato de AdenosinaRESUMO
OBJECTIVE: Currently, there is no validated patient-reported outcome measure (PROM) applicable to all esophageal diseases. Our objective was to create a psychometrically robust, validated universal esophageal PROM that can also objectively assess patients' quality of life (QoL). METHODS: The pilot PROM constructed based on expert opinions, literature review, and previous unpublished institutional research had 27 items covering 8 domains. It was completed by 30 patients in the outpatient clinic followed by a structured debriefing interview, which allowed for refining the PROM. The final PROM: Cleveland Clinic Esophageal Questionnaire (CEQ) included 34 items across 6 domains (Dysphagia, Eating, Pain, Reflux & Regurgitation, Dyspepsia, Dumping), each accompanied by a corresponding QoL component. Further psychometric assessment of the PROM was conducted by evaluating (1) acceptability, (2) construct validity, (3) reliability, and (4) responsiveness. RESULTS: Five hundred forty-six unique patients (median 63.7 years [54.3-71.7], 53% male [287], 86% White) completed CEQ at >90% completion within 5 minutes. Construct validity was demonstrated by differentiating scores across esophageal cancer (n = 146), achalasia (n = 170), hiatal hernia (n = 160), and other diagnoses (n = 70). Internal reliability (Cronbach alpha 0.83-0.89), and test-retest reliability (intraclass correlation coefficients 0.63-0.85) were strong. Responsiveness was demonstrated through CEQ domains improving for 53 patients who underwent surgery for achalasia or hiatal hernia (Cohen d 0.86-2.59). CONCLUSIONS: We have constructed a psychometrically robust, universal esophageal PROM that allows concise, consistent, objective quantification of symptoms and their effect on the patient. The CEQ is valuable in prognostication and tracking of longitudinal outcomes in both benign and malignant esophageal diseases.
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Acalasia Esofágica , Doenças do Esôfago , Hérnia Hiatal , Humanos , Masculino , Feminino , Qualidade de Vida , Reprodutibilidade dos Testes , Inquéritos e Questionários , Doenças do Esôfago/diagnóstico , Instituições de Assistência Ambulatorial , Medidas de Resultados Relatados pelo PacienteRESUMO
INTRODUCTION: Attempted suicide among older adults represents a significant mental health concern that has witnessed a rising incidence within this demographic in recent years. Research indicates that attempted suicide among the older population serves as a primary risk factor for completed suicide. Consequently, the objective of this study is to provide a comprehensive overview of the prevailing factors that influence suicide attempts among older adults, thereby offering evidence to guide healthcare professionals in designing targeted interventions. METHODS AND ANALYSIS: This study will adhere to the Joanna Briggs Institute framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. We will synthesise qualitative studies using a comprehensive and inclusive bibliographic search strategy. The following databases will be searched: PubMed, Embase, Web of Science, CINAHL and the Cochrane Library. The quality of the articles will be assessed using the 10-item Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research. At the same time, data extraction will be performed using the Qualitative Assessment and Review Instrument data extraction form proposed by the Joanna Briggs Institute for Evidence-Based Practice. The synthesis of findings will adhere to the principles and procedures of Thomas and Hardens' three-stage thematic synthesis approach. ETHICS AND DISSEMINATION: Ethical approval will not be required for this study, as it solely encompasses data derived from previously published research. The findings will be disseminated through publication in a peer-reviewed journal. Moreover, the results will be presented at relevant academic conferences to guarantee that the study's outcomes reach pertinent stakeholders. This protocol is registered with the PROSPERO prospective database for systematic review. PROSPERO REGISTRATION NUMBER: CRD42023408385.
Assuntos
Cuidadores , Tentativa de Suicídio , Humanos , Idoso , Tentativa de Suicídio/psicologia , Projetos de Pesquisa , Pessoal de Saúde , Atenção à Saúde , Literatura de Revisão como AssuntoRESUMO
The triglyceride-glucose (TyG) index is an accessible and reliable surrogate indicator of insulin resistance and is strongly associated with diabetes. However, its relationship with diabetic retinopathy (DR) remains controversial. This meta-analysis aimed to assess the relationship between the TyG index and the prevalence of DR. Initial studies were searched from PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) electronic databases. The retrieval time range was from the establishment of the database to June 2023. Pooled estimates were derived using a random-effects model and reported as odds ratio (OR) with 95% confidence intervals (CIs). Two researchers independently assessed the methodological quality of the included studies. The Newcastle-Ottawa Quality Scale (NOS) was utilized to assess cohort studies or case-control studies. The Agency for Healthcare Research and Quality (AHRQ) methodology checklist was applied to assess cross-sectional studies. Ten observational studies encompassing 13716 patients with type 2 diabetes were included in the meta-analysis. The results showed that a higher TyG index increased the risk of DR compared with a low TyG index (OR: 2.34, 95% CI: 1.31-4.19, P < 0.05). When the index was analyzed as a continuous variable, consistent results were observed (OR: 1.48, 95% CI: 1.12-1.97, P < 0.005). There was no significant effect on the results of the sensitivity analyses excluding one study at a time (P all < 0.05). A higher TyG index may be associated with an increased prevalence of DR in patients with type 2 diabetes. However, high-quality cohort or case-control studies are needed to further substantiate this evidence. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023432747.
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Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Humanos , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Glucose , Triglicerídeos , Estados Unidos , Estudos Observacionais como AssuntoRESUMO
Fatigue and pain are prevalent in persons with multiple sclerosis (PwMS), negatively impacting quality of life (QoL). Clinical management is challenging due to their multiple underlying causes. Aerobic exercise elicits central and peripheral effects, which may effectively manage MS-related symptoms. Our aim was to determine the effects of an aerobic cycling intervention on symptoms impacting QoL. Eighteen participants completed a 12-week moderate- to high-intensity aerobic cycling intervention. Participants reported significant improvements in physical fatigue, overall fatigue, pain intensity, and pain interference. Aerobic exercise should be considered as part of a multi-faceted approach to improve fatigue and pain in PwMS.
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Terapia por Exercício , Fadiga , Esclerose Múltipla , Qualidade de Vida , Humanos , Exercício Físico , Fadiga/etiologia , Fadiga/terapia , Esclerose Múltipla/complicações , Esclerose Múltipla/terapia , Dor/etiologia , Ciclismo/fisiologiaRESUMO
BACKGROUND: Diabetic retinopathy (DR) is a common diabetic neurodegenerative disease that affects vision in severe cases. Current therapeutic drugs are ineffective for some patients with severe side effects, and ginsenoside-Rg1 (GRg1) has been shown to protect against DR and may serve as a new potential drug for DR. This study aimed to confirm the protective effect of GRg1 against DR and its molecular mechanism. METHODS: Human retinal microvascular endothelial cells (hRMECs) and rats were used to construct DR models in vitro and in vivo. Cell proliferation was detected by BrdU assays, the cell cycle was detected by flow cytometry, and TNF-α, IL-6 and IL-1ß levels were detected by ELISA. qRTâPCR, Western blotting and immunohistochemistry were used to detect the expression of related genes and proteins, and angiogenesis assays were used to assess angiogenesis. RIP and RNA pull down assays were used to determine the relationship between miR-216a-5p and TLR4; retinal structure and changes were observed by HE staining and retinal digestive spread assays. RESULTS: GRg1 effectively inhibited HG-induced hRMEC proliferation, cell cycle progression and angiogenesis and reduced the levels of intracellular inflammatory cytokines and growth factors. HG downregulated the expression of miR-216a-5p and upregulated the expression of TLR4/NF-kB signaling pathway-related proteins. Importantly, GRg1 inhibited TLR4/NF-kB signaling pathway activation by upregulating miR-216a-5p, thereby inhibiting HG-induced cell proliferation, cell cycle progression, angiogenesis, and the production of inflammatory cytokines and growth factors. In addition, animal experiments confirmed the results of the cell experiments. CONCLUSIONS: GRg1 inhibits TLR4/NF-kB signaling by upregulating miR-216a-5p to reduce growth factors and inflammatory cytokines in DR, providing a potential therapeutic strategy for DR.
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Retinopatia Diabética , Ginsenosídeos , MicroRNAs , Doenças Neurodegenerativas , Humanos , Ratos , Animais , NF-kappa B/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Células Endoteliais/metabolismo , Citocinas/genética , Citocinas/metabolismo , Ginsenosídeos/metabolismo , Doenças Neurodegenerativas/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Purpose: The accurate prediction of non-cirrhotic hepatocellular carcinoma (NCHCC) risk facilitates improved surveillance strategy and decreases cancer-related mortality. This study aimed to explore the correlation between immunogenic cell death (ICD) and NCHCC prognosis using The Cancer Genome Atlas (TCGA) datasets, and the potential prognostic value of ICD-related genes in NCHCC. Methods: Clinical and transcriptomic data of patients with NCHCC patients were retrieved from TCGA database. Weighted gene co-expression network analysis was performed to obtain the NCHCC phenotype-related module genes. Consensus clustering analysis was performed to classify the patients into two clusters based on intersection genes among differentially expressed genes (DEGs) between cancer and adjacent tissues, NCHCC phenotype-related genes, and ICD-related genes. NCHCC-derived tissue microarray was used to evaluate the correlation of the expression levels of key genes with NCHCC prognosis using immunohistochemical staining. Results: Cox regression analyses were performed to construct a prognostic risk score model comprising three genes (TMC7, GRAMD1C, and GNPDA1) based on DEGs between two clusters. The model stratified patients with NCHCC into two risk groups. The overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. Univariable and multivariable Cox regression analyses revealed that these signature genes are independent predictors of OS. Functional analysis revealed differential immune status between the two risk groups. Next, a nomogram was constructed, which demonstrated the potent distinguishing ability of the developed model based on receiver operating characteristic curves. In vitro functional validation revealed that the migration and invasion abilities of HepG2 and Huh7 cells were upregulated upon GRAMD1C knockdown but downregulated upon TMC7 knockdown. Conclusion: This study developed a prognostic model comprising three genes, which can aid in predicting the survival of patients with NCHCC and guide the selection of drugs and molecular markers for NCHCC.
RESUMO
OBJECTIVE: To investigate whether the expression of triple motif protein 19/38 (TRIM19/38) mRNA in peripheral blood mononuclear cells (PBMCs) of HBeAg-negative chronic hepatitis B virus (HBV) carriers is associated with the response to pegylated interferon alpha (peg-IFN-α) treatment and HBsAg clearance. METHODS: In this prospective study, HBeAg-negative chronic HBV carriers treated with peg-IFN-α completed 48 weeks of follow-up. After treatment with peg-IFN-α, the patients were divided into responders (R group) and nonresponders (NR group) according to the changes in HBV DNA and HBsAg levels at week 48 of treatment. According to whether serum HBsAg loss or seroconversion occurred, the patients were divided into a serological response group (SR group) and a nonserological response group (NSR group). The level of TRIM19/38 mRNA in PBMCs was detected by real-time fluorescence quantitative PCR. The diagnostic performance of TRIM19/38 was analysed by calculating the receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). RESULTS: 43 HBeAg-negative chronic HBV carriers, 35 untreated CHB patients and 19 healthy controls were enrolled in this study. We found that TRIM19/38 mRNA levels were significantly lower in untreated CHB patients than in healthy controls. In HBeAg-negative chronic HBV carriers who underwent prospective follow-up, TRIM19/38 mRNA levels were negatively correlated with HBV DNA and ALT at baseline. Among the patients treated with peg-IFN-α, 16 patients achieved a treatment response (R group) and 27 patients did not achieve a treatment response (NR group). Compared with baseline, HBsAg levels in the R group decreased significantly at 12 and 24 weeks of treatment; at the early stage of peg-IFN-α treatment, the dynamic changes in TRIM19/38 mRNA levels in the R and NR groups were different, and the TRIM19/38 mRNA levels in the R group were significantly higher than those in the NR group, especially at 24 weeks of treatment. ROC curve analysis showed that the changes in mRNA levels of TRIM19 and TRIM38 predicted the treatment response, with AUCs of 0.694 and 0.757, respectively. Among the patients treated with peg-IFN-α, 11 patients achieved a serological response (SR group) and 32 patients did not achieve a serological response (NSR group). Compared with baseline, HBsAg levels in the SR group decreased significantly at 12 and 24 weeks of treatment; TRIM19/38 mRNA levels were significantly higher in the SR group than in the NSR group at week 24. CONCLUSION: The higher level of TRIM19/38 mRNA in PBMCs of HBeAg-negative chronic HBV carriers may be related to the early treatment effect of peg-IFN-α and HBsAg clearance. TRIM19 and TRIM38 have clinical significance in predicting virological response and guiding treatment regimens.