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Camel milk is a nutrient-rich diet and fermentation affects its nutritional value and probiotic function. In this study, sour camel milk and oat jujube sour camel milk were prepared using fermentation bacteria agent TR1, and the metabolites of camel milk, sour camel milk and oat jujube sour camel milk were detected using a non-targeted metabolomics approach using liquid chromatography-mass spectrometry (LC-MS).The results showed that the partial least squares discriminant analysis (PLS-DA) with 100 % accuracy and good predictive power detected 343 components in positive ion mode and 220 components in negative ion mode. The differential metabolites were mainly organic acids, amino acids, esters, vitamins and other substances contained in camel milk.It showed that there were significant differences in the metabolites of camel milk, sour camel milk and oat jujube sour camel milk. Based on the pathway enrichment analysis of the three dairy products in the KEGG database, 12 metabolic pathways mainly involved in the positive ion mode and 20 metabolic pathways mainly involved in the negative ion mode were identified. The main biochemical metabolic pathways and signal transduction pathways of the differential metabolites of the three dairy products were obtained. This study provides theoretical support for improving the nutritional quality and probiotic function of camel milk and fermented camel milk products and provides a basis for the development of relevant processing technologies and products for camel milk and fermented camel milk.
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In this article, we discuss new findings which suggest that type I regulatory T (Tr1) cells can interfere with cancer vaccine efficacy in mice by exerting strong regulatory control over antitumor immune responses.
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The THαß host immunological pathway contributes to the response to infectious particles (viruses and prions). Furthermore, there is increasing evidence for associations between autoimmune diseases, and particularly type 2 hypersensitivity disorders, and the THαß immune response. For example, patients with systemic lupus erythematosus often produce anti-double stranded DNA antibodies and anti-nuclear antibodies and show elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 throughout the disease course. These cytokines and antibody isotypes are associated with the THαß host immunological pathway. Similarly, the type 2 hypersensitivity disorders myasthenia gravis, Graves' disease, graft-versus-host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjögren's syndrome have also been linked to the THαß pathway. Considering the potential associations between these diseases and dysregulated THαß immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferon α/ß could be explored for effective management.
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Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/complicaciones , Síndrome de Sjögren/inmunología , Enfermedad Injerto contra Huésped/inmunología , Enfermedades Autoinmunes/inmunología , Citocinas/inmunología , Miastenia Gravis/inmunología , Anemia Hemolítica Autoinmune/inmunología , Enfermedad de Graves/inmunología , Enfermedad de Graves/complicaciones , Dermatomiositis/inmunologíaRESUMEN
Background: The preoperative predictors of residual or recurrent tricuspid regurgitation (TR) after cone reconstruction (CR) remains unclear in patients with Ebstein anomaly (EA). We aimed to determine the predictive value of right ventricular longitudinal strain, assessed using cardiac magnetic resonance (CMR) imaging, for residual or recurrent TR after CR in patients with EA. Methods: This single-centre, retrospective study analysed data from 48 patients with EA [mean ± standard deviation (SD), age, 35.0±13.6 years; 13 males] who underwent CMR before CR between January 2017 and February 2023. Two-dimensional colour Doppler echocardiography was performed before CR and mid-term (>6 months) after CR to evaluate the degree of TR in patients with EA. Thirty healthy volunteers served as controls. Univariate and multivariate logistic regression analyses were performed to identify CMR predictors of moderate or severe TR >6 months after CR. Results: Mid-term postoperative results revealed severe, moderate, and mild TR in 8 (17%), 7 (15%), and 33 (69%) patients, respectively. For patients with EA and moderate or severe TR after CR, left ventricular global longitudinal strain (GLS), left ventricular ejection fraction, right ventricular global longitudinal strain (RVGLS), and right ventricular ejection fraction (RVEF) were significantly worse compared to patients with mild TR (all P<0.05). Multivariate logistic regression analyses revealed that RVGLS was independently associated with moderate or severe TR >6 months after CR [odds ratio (OR) 1.193, 95% confidence interval (CI): 1.025-1.388; P=0.02]. Conclusions: RVGLS was a significant predictor of moderate or severe TR >6 months after CR. This finding emphasizes that early and accurate measurement of RV function may help to identify patients at high risk for severe residual or recurrent TR.
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Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular , Proteína Potenciadora del Homólogo Zeste 2 , Meduloblastoma , Hormonas Tiroideas , Meduloblastoma/patología , Meduloblastoma/metabolismo , Meduloblastoma/genética , Humanos , Diferenciación Celular/efectos de los fármacos , Animales , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Ratones , Hormonas Tiroideas/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/tratamiento farmacológico , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Platelet-rich fibrin (PRF), originally used to support soft tissue healing, is also considered a therapeutic option for treating oral lichen planus and leukoplakia. The progression from the two premalignant lesions to the aggressive malignant oral squamous cell carcinoma involves an inflammatory process linked to chemokine expression. Thus, there is a rationale for studying how PRF modulates the expression of chemokines in oral squamous carcinoma cells. To this aim, we expose the oral squamous carcinoma cell line HSC2 to IL1ß and TNFα either alone or in the presence of lysates obtained from solid PRF membranes. We report here that in HSC2 cells, PRF lysates significantly reduce the forced transcription of chemokines, e.g., CXCL1, CXCL2, CXCL8, CXCL10, and CCL5. Moreover, PRF lysates attenuate the nuclear translocation of p65 in HSC2 oral epithelial cells when exposed to IL1ß and TNFα. PRF lysates further reduce chemokine expression provoked by poly:IC HMW. Even though less pronounced, PRF lysates reduce IL1ß- and TNFα-induced chemokine expression in TR146 cells. In primary oral epithelial cells, however, PRF lysates increase the basal expression of CXCL1, CXCL2 and CXCL8. Thus, PRF can exert a biphasic effect on chemokine expression in oral squamous cell carcinoma cell lines and primary oral epithelial cells. These findings suggest that PRF may reduce inflammation in a malignant environment while provoking an immunological response in healthy oral epithelium.
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Introduction: Functional magnetic resonance imaging (fMRI) has become a fundamental tool for studying brain function. However, the presence of serial correlations in fMRI data complicates data analysis, violates the statistical assumptions of analyses methods, and can lead to incorrect conclusions in fMRI studies. Methods: In this paper, we show that conventional whitening procedures designed for data with longer repetition times (TRs) (>2 s) are inadequate for the increasing use of short-TR fMRI data. Furthermore, we comprehensively investigate the shortcomings of existing whitening methods and introduce an iterative whitening approach named "IDAR" (Iterative Data-adaptive Autoregressive model) to address these shortcomings. IDAR employs high-order autoregressive (AR) models with flexible and data-driven orders, offering the capability to model complex serial correlation structures in both short-TR and long-TR fMRI datasets. Results: Conventional whitening methods, such as AR(1), ARMA(1,1), and higher-order AR, were effective in reducing serial correlation in long-TR data but were largely ineffective in even reducing serial correlation in short-TR data. In contrast, IDAR significantly outperformed conventional methods in addressing serial correlation, power, and Type-I error for both long-TR and especially short-TR data. However, IDAR could not simultaneously address residual correlations and inflated Type-I error effectively. Discussion: This study highlights the urgent need to address the problem of serial correlation in short-TR (< 1 s) fMRI data, which are increasingly used in the field. Although IDAR can address this issue for a wide range of applications and datasets, the complexity of short-TR data necessitates continued exploration and innovative approaches. These efforts are essential to simultaneously reduce serial correlations and control Type-I error rates without compromising analytical power.
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BACKGROUND: Tricuspid regurgitation (TR) is associated with worse clinical outcomes after transcatheter aortic valve replacement (TAVR) and mitral transcatheter edge-to-edge repair (M-TEER), but little is known about its association with health status outcomes. OBJECTIVES: The aims of this study were to explore, using the Society of Thoracic Surgeons and American College of Cardiology TVT (Transcatheter Valve Therapy) Registry, the association between baseline TR and health status after TAVR and M-TEER and to determine if baseline TR was associated with clinical endpoints. METHODS: Health status was assessed using Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score in patients enrolled in the TVT Registry who underwent isolated TAVR or M-TEER between January 2019 and June 2021. The association among baseline TR and KCCQ-OS score, being alive and well, and clinical outcomes was examined. RESULTS: In total, 130,097 TAVR patients (13.1% with moderate TR, 2.3% with severe TR) and 19,593 M-TEER patients (33.2% with moderate TR, 14.7% with severe TR) were included. Mean KCCQ-OS scores were lower with severe vs moderate vs none to mild TR at baseline prior to TAVR (39.4 ± 24.2 vs 45.2 ± 24.7 vs 51.3 ± 25.3; P < 0.01) or M-TEER (38.1 ± 23.9 vs 41.9 ± 24.7 vs 45.4 ± 25.2; P < 0.01) and similarly at 30 days and 1 year. The odds of being alive and well at 1 year were lower with moderate or severe TR before TAVR (adjusted OR: 0.79 [95% CI: 0.74-0.85] and adjusted OR: 0.81 [95% CI: 0.70-0.94], respectively) and severe TR before M-TEER (adjusted OR: 0.53; 95% CI: 0.40-0.71). Furthermore, moderate or severe TR before TAVR was associated with higher 1-year mortality and readmission, whereas moderate or severe TR before M-TEER was associated with higher 1-year mortality. CONCLUSIONS: In a large cohort of U.S. patients who underwent TAVR or M-TEER, greater baseline TR was associated with worse health status and clinical outcomes. Understanding adverse outcomes of TR in patients with coexisting valvular abnormalities is important, especially with rapidly evolving transcatheter tricuspid valve interventions.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Estado de Salud , Válvula Mitral , Sistema de Registros , Reemplazo de la Válvula Aórtica Transcatéter , Insuficiencia de la Válvula Tricúspide , Humanos , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Femenino , Masculino , Resultado del Tratamiento , Insuficiencia de la Válvula Tricúspide/fisiopatología , Insuficiencia de la Válvula Tricúspide/diagnóstico por imagen , Insuficiencia de la Válvula Tricúspide/mortalidad , Insuficiencia de la Válvula Tricúspide/cirugía , Anciano , Factores de Tiempo , Anciano de 80 o más Años , Factores de Riesgo , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/mortalidad , Estenosis de la Válvula Aórtica/fisiopatología , Válvula Aórtica/cirugía , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/fisiopatología , Válvula Mitral/cirugía , Válvula Mitral/fisiopatología , Válvula Mitral/diagnóstico por imagen , Estados Unidos , Medición de Riesgo , Insuficiencia de la Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/fisiopatología , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/mortalidad , Índice de Severidad de la Enfermedad , Recuperación de la Función , Válvula Tricúspide/fisiopatología , Válvula Tricúspide/cirugía , Válvula Tricúspide/diagnóstico por imagen , Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/instrumentación , Cateterismo Cardíaco/mortalidadRESUMEN
The rapid growth of therapeutic monoclonal antibodies demands greater accessibility to scalable methods of evaluating antigen binding. Homogenous TR-FRET is ideal for preliminary screening but has not been reported to assay these interactions due to their high-affinity and complex solution-phase kinetics. Here we report the development of a competition assay to rank-order the relative affinities of these drugs for a common antigen. The assay is compatible with automation, requires no modification of the analytes, and measures affinities as low as single-digit picomolar. We further demonstrate applications to inform the development of antibody-drug conjugates. The assay may aid discovery and manufacturing of therapeutic antibodies as a low-cost, high-throughput alternative to existing technologies.
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Tryptophan is an essential amino acid and plays an important role in several metabolic processes relevant for the human health. As the main metabolic pathway for tryptophan along the kynurenine axis is involved in inflammatory responses, changed metabolite levels can be used to monitor inflammatory diseases such as ulcerative colitis. As a progenitor of serotonin, altered tryptophan levels have been related to several neurogenerative diseases as well as depression or anxiety. While tryptophan concentrations are commonly evaluated in serum, a non-invasive detection approach using saliva might offer significant advantages, especially during long-term treatments of patients or elderly. In order to estimate whether active transport processes for tryptophan might contribute to a potential correlation between blood and saliva tryptophan concentrations, we investigated tryptophan's transport across an established oral mucosa in vitro model. Interestingly, treatment with tryptophan revealed a concentration dependent secretion of tryptophan and the presence of a saturable transporter while transport studies with deuterated tryptophan displayed increased permeability from the saliva to the blood compartment. Protein analysis demonstrated a distinct expression of L-type amino acid transporter 1 (LAT1), the major transporter for tryptophan, and exposure to inhibitors (2 -amino-2-norbornanecarboxylic acid (BCH), L-leucine) led to increased tryptophan levels on the saliva side. Additionally, exposure to tryptophan in equilibrium studies resulted in a regulation of LAT1 at the mRNA level. The data collected in this study suggest the participation of active transport mechanisms for tryptophan across the oral mucosa epithelium. Future studies should investigate the transport of tryptophan across salivary gland epithelia in order to enable a comprehensive understanding of tryptophan exchange at the blood-saliva barrier.
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BACKGROUND/AIMS: Congestion is prognostically relevant in cardiac transthyretin amyloidosis (ATTR-CA), but whether congestion has an incremental prognostic value beyond the well-established, congestion-sensitive NT-proBNP is unknown. Therefore, we aimed to comparatively evaluate the prognostic utility of several congestion surrogates over NT-proBNP. METHODS: We estimated hazard ratios by Cox proportional hazards regressions with time-varying covariates from a panel data set of the local amyloidosis cohort study AmyKoS. Different models were compared by using chi(χ)2-statistics measuring overall model significance. RESULTS/CONCLUSION: 131 ATTR-CA patients (wild-type 84.0%, hereditary 6.9%, without genetic testing 9.2%; median age 78.7 (quartiles 73.3, 82.1) years; 85.5% male) with 566 observations across a median follow-up of 38.2 (30.6; 48.2) months were analyzed. 83.2% received disease-modifying treatment; 20.6% participated concurrently in placebo-controlled gene silencer trials. Information on congestion improved biomarker-driven risk stratification and identified patients at the highest risk. Echocardiographic congestion markers performed better than clinical findings and daily diuretic use/dosage. Relevant adjusters were daily diuretic dosage, disease-modifying treatment, eGFR, and right atrial volume. NT-proBNP and the tricuspid regurgitation peak velocity (tr-vmax) provided an easy-to-use stratification with overall model performance similar to NAC and Mayo staging systems. Further analyses are necessary for validation and to identify the optimal cut points of the congestion markers.
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The photo-reaction of the LOV1 domain of the Chlamydomonas reinhardtii phototropin is investigated by room-temperature time-resolved serial crystallography. A covalent adduct forms between the C4a atom of the central flavin-mononucleotide chromophore and a protein cysteine. The structure of the adduct is very similar to that of LOV2 determined 23 years ago from the maidenhair fern Phy3.
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Chlamydomonas reinhardtii , Fototropinas , Sincrotrones , Chlamydomonas reinhardtii/química , Chlamydomonas reinhardtii/metabolismo , Cristalografía por Rayos X/métodos , Fototropinas/química , Fototropinas/metabolismo , Modelos Moleculares , Mononucleótido de Flavina/química , Dominios Proteicos , Chlamydomonas/química , Chlamydomonas/metabolismoRESUMEN
The spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) interaction has a major role in the normal innate and adaptive immune responses, but dysregulation of this interaction is implicated in several human diseases, including autoimmune disorders, hematological malignancies, and Alzheimer's Disease. Development of small molecule chemical probes could aid in studying this pathway both in normal and aberrant contexts. Herein, we describe the miniaturization of a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to measure the interaction between SYK and FCER1G in a 1536-well ultrahigh throughput screening (uHTS) format. The assay utilizes the His-SH2 domains of SYK, which are indirectly labeled with anti-His-terbium to serve as a TR-FRET donor and a FITC-conjugated phosphorylated ITAM domain peptide of FCER1G to serve as an acceptor. We have optimized the assay into a 384-well HTS format and further miniaturized the assay into a 1536-well uHTS format. Robust assay performance has been achieved with a Z' factor > 0.8 and signal-to-background (S/B) ratio > 15. The utilization of this uHTS TR-FRET assay for compound screening has been validated by a pilot screening of 2,036 FDA-approved and bioactive compounds library. Several primary hits have been identified from the pilot uHTS. One compound, hematoxylin, was confirmed to disrupt the SYK/FECR1G interaction in an orthogonal protein-protein interaction assay. Thus, our optimized and miniaturized uHTS assay could be applied to future scaling up of a screening campaign to identify small molecule inhibitors targeting the SYK and FCER1G interaction.
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Transferencia Resonante de Energía de Fluorescencia , Ensayos Analíticos de Alto Rendimiento , Quinasa Syk , Quinasa Syk/antagonistas & inhibidores , Quinasa Syk/metabolismo , Transferencia Resonante de Energía de Fluorescencia/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Unión ProteicaRESUMEN
Light-oxygen-voltage (LOV) domains are small photosensory flavoprotein modules that allow the conversion of external stimuli (sunlight) into intracellular signals responsible for various cell behaviors (e.g. phototropism and chloroplast relocation). This ability relies on the light-induced formation of a covalent thioether adduct between a flavin chromophore and a reactive cysteine from the protein environment, which triggers a cascade of structural changes that result in the activation of a serine/threonine (Ser/Thr) kinase. Recent developments in time-resolved crystallography may allow the activation cascade of the LOV domain to be observed in real time, which has been elusive. In this study, we report a robust protocol for the production and stable delivery of microcrystals of the LOV domain of phototropin Phot-1 from Chlamydomonas reinhardtii (CrPhotLOV1) with a high-viscosity injector for time-resolved serial synchrotron crystallography (TR-SSX). The detailed process covers all aspects, from sample optimization to data collection, which may serve as a guide for soluble protein preparation for TR-SSX. In addition, we show that the crystals obtained preserve the photoreactivity using infrared spectroscopy. Furthermore, the results of the TR-SSX experiment provide high-resolution insights into structural alterations of CrPhotLOV1 from Δt = 2.5â ms up to Δt = 95â ms post-photoactivation, including resolving the geometry of the thioether adduct and the C-terminal region implicated in the signal transduction process.
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Chlamydomonas reinhardtii , Sincrotrones , Chlamydomonas reinhardtii/metabolismo , Chlamydomonas reinhardtii/química , Cristalografía por Rayos X/métodos , Luz , Fototropinas/química , Fototropinas/metabolismo , Fototropinas/genética , Dominios ProteicosRESUMEN
INTRODUCTION: This study was conducted to analyze and compare the intraocular pressure (IOP) treatment effect of the slow-eluting (SE) travoprost intracameral implant to the IOP treatment effect of topical prostaglandin analog (PGA) monotherapy in a subgroup of subjects who were on pre-study PGA monotherapy prior to enrollment in the two pivotal phase 3 trials of the travoprost intracameral implant. METHODS: A combined study population of 133 subjects from two phase 3 trials, who were on topical PGA monotherapy at screening, subsequently underwent a washout period from their topical PGA, and then were randomized and administered an SE travoprost intracameral implant. The subjects were analyzed for the IOP treatment effects of the pre-study topical PGA monotherapy and the in-study SE travoprost intracameral implant. Paired t-tests were used to compare the difference in screening minus post-washout baseline IOP versus month 3 minus post-washout baseline IOP. The IOP-lowering efficacy in eyes administered an SE travoprost intracameral implant was compared to the IOP lowering in the same eyes while on a topical PGA monotherapy prior to study entry. RESULTS: Pre-study topical PGA monotherapy and the SE travoprost intracameral implant demonstrated IOP treatment effects of -5.76 mmHg and -7.07 mmHg, respectively. The IOP-lowering treatment effect was significantly greater by 1.31 mmHg for the SE travoprost intracameral implant relative to pre-study PGA monotherapy (95% confidence interval: -2.01, -0.60; P = 0.0003). CONCLUSIONS: The SE travoprost intracameral implant demonstrated superior IOP-lowering treatment effect versus pre-study topical PGA monotherapy with a superiority margin that was both statistically significant and clinically meaningful. The greater IOP reduction from baseline while on the SE implant versus pre-study topical PGA monotherapy may be a reflection of the optimized adherence and continuous elution of PGA therapy into the anterior chamber achieved with the SE travoprost intracameral implant. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03519386 and NCT03868124.
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Skeletal muscle aging in rats is a reduction in skeletal muscle mass caused by a decrease in the number or volume of skeletal muscle myofibers. Apoptosis has been recognized to play a key role in accelerating the process of skeletal muscle aging in rats. The thioredoxin (Trx) system is a widely expressed oxidoreductase system that controls the cellular reduction/oxidation state and has both potent anti-free radical damage and important pro-growth and apoptosis inhibitory functions. Previous studies have shown that exercise delays skeletal muscle aging. However, it is unclear whether exercise attenuates skeletal muscle aging via the Trx system. Therefore, the present study used the Trx system as an entry point to explore the effect of aerobic exercise to improve skeletal muscle aging in rats and its possible mechanisms, and to provide a theoretical basis for exercise to delay skeletal muscle aging in rats. It was shown that aerobic exercise in senescent rats resulted in increased gastrocnemius index, decreased body weight, increased endurance, decreased skeletal muscle cell apoptosis, increased activity and protein expression of the Trx system, and decreased expression of p38 and ASK1. Based on these findings, we conclude that 10 weeks of aerobic exercise may enhance the anti-apoptotic effect of Trx by up-regulating Trx and Trx reductase (TR) protein expression, which in turn increases Trx activity in rat skeletal muscle, and ultimately alleviates apoptosis in senescent skeletal muscle cells.
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Envejecimiento , Apoptosis , Músculo Esquelético , Condicionamiento Físico Animal , Tiorredoxinas , Animales , Músculo Esquelético/fisiología , Músculo Esquelético/metabolismo , Masculino , Tiorredoxinas/metabolismo , Condicionamiento Físico Animal/fisiología , Envejecimiento/fisiología , Ratas , MAP Quinasa Quinasa Quinasa 5/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Ratas Sprague-Dawley , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Resistencia Física/fisiologíaRESUMEN
BACKGROUND: Individuals with Parkinson disease (PD) can improve their overall mobility and participation in daily activities as they engage in frequent exercise. Despite the need for individually tailored exercises, persons with PD often face barriers to accessing physical rehabilitation professionals who can provide them. Telerehabilitation (TR) may facilitate access to necessary and individually tailored rehabilitation for individuals with PD. OBJECTIVE: The purpose of this study was to assess the feasibility of TR for individuals with PD and explore clinical outcomes compared to in-person care. METHODS: This was a pilot randomized controlled trial conducted at 2 outpatient neurorehabilitation clinics with 3 study groups: clinic+TR, TR-only, and usual care (UC). TR was administered using a web-based application with a mobile app option. One-hour interventions were performed weekly for 4 weeks, in-person for the clinic+TR and UC groups and virtually for the TR-only group. Home exercises were provided on paper for the UC group and via the web-based platform for the clinic+TR and TR-only groups. Feasibility was assessed by recruitment and retention success and patient and therapist satisfaction, as rated in surveys. Clinical outcomes were explored using performance and patient-reported measures in between- and within-group analyses. RESULTS: Of 389 patients screened, 68 (17.5%) met eligibility criteria, and 20 (29.4% of those eligible) were enrolled (clinic+TR, n=6; TR-only, n=6; and UC, n=8). One patient (TR-only) was withdrawn due to a non-study-related injurious fall. Regardless of group allocation, both patients and therapists generally rated the mode of care delivery as "good" or "very good" across all constructs assessed, including overall satisfaction and safety. In the analysis of all groups, there were no differences in clinical outcomes at the discharge visit. Within-group differences (from baseline to discharge) were also generally not significant except in the UC group (faster 5-time sit-to-stand time and higher mini balance evaluation systems test balance score) and clinic+TR group (higher mini balance evaluation systems test balance score). CONCLUSIONS: High satisfaction amongst patients and clinicians regardless of group, combined with nonsignificant between-group differences in clinical outcomes, suggest that TR is feasible for individuals with PD in early-moderate stages. Future trials with a larger sample are necessary to test clinical effectiveness. As larger trials enroll patients with diverse characteristics (eg, in terms of age, disease progression, caregiver support, technology access and capacity, etc), they could begin to identify opportunities for matching patients to the optimal utilization of TR as part of the therapy episode. TRIAL REGISTRATION: ClinicalTrials.gov NCT06246747; https://clinicaltrials.gov/study/NCT06246747.
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The aim of this study was to evaluate different aspects of transition outcomes in groups of transgender and gender diverse (TGD) people based on their transition status. We divided the 70 TGD participants (19 individuals assigned male at birth and 51 assigned female at birth) into two groups: those who had completed their psychiatric and psychological evaluation (PPE), which is mandatory in Croatia, and those who had undergone gender-affirming medical treatment (GAMT) (both gender-affirming hormone treatment and gender-affirming surgery). The online survey included sociodemographic questions and a custom-designed nine-item scale. The items were specifically designed based on the DSM-5-TR criteria for gender dysphoria to assess subjectively perceived transition outcomes. We conducted a factor analysis of the scale followed by structural equation modeling for confirmation. Chi-squared and Mann-Whitney U tests were used to compare group differences. The following three-factor structure was confirmed: better functioning, reduced body dysphoria, and satisfaction with decision. A positive influence of better functioning on satisfaction with the decision was found. In addition, our results showed that TGD individuals who had undergone GAMT scored higher on better functioning than those who had just completed PPE. Both groups consistently scored high on satisfaction with the decision, with no statistically significant differences between them. Our findings suggest that TGD individuals view gender-affirming medical care as beneficial to their overall functioning.
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Disforia de Género , Personas Transgénero , Humanos , Femenino , Masculino , Croacia , Adulto , Personas Transgénero/psicología , Personas Transgénero/estadística & datos numéricos , Estudios Transversales , Disforia de Género/psicología , Encuestas y Cuestionarios , Procedimientos de Reasignación de Sexo/psicología , Adulto Joven , Cirugía de Reasignación de Sexo/psicología , Persona de Mediana Edad , Satisfacción PersonalRESUMEN
BACKGROUND: Early identification of treatment non-response in first-episode psychosis (FEP) is essential to outcome. Despite indications that exposure to childhood trauma (CT) can have adverse effects on illness severity, its impact on treatment non-response and the interplay with other pre-treatment characteristics is sparsely investigated. We use a lack of clinical recovery as an early indicator of treatment resistance to investigate the relationship between CT and treatment resistance status at one-year follow-up and the potential mediation of this effect by other pre-treatment characteristics. METHODS: This prospective one-year follow-up study involved 141 participants recruited in their first year of treatment for a schizophrenia-spectrum disorder. We investigated clinical status, childhood trauma (CT), premorbid adjustment (PA), and duration of untreated psychosis (DUP) at baseline and clinical status at one-year follow-up. Ordinal regression analyses were conducted to investigate how PA and DUP affected the relationship between CT and one-year outcome in FEP. RESULTS: 45 % of the FEP sample reported moderate to severe CT, with significantly higher levels of CT in the early treatment resistant group compared to participants with full or partial early recovery. Ordinal regression analysis showed that CT was a significant predictor of being in a more severe outcome group (OR = 4.59). There was a partial mediation effect of PA and a full mediation effect of DUP on the effect of CT on outcome group membership. DISCUSSION: Our findings indicate that reducing treatment delays may mitigate the adverse effects of CT on clinical outcomes and support the inclusion of broad trauma assessment in FEP services.
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Trastornos Psicóticos , Humanos , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/fisiopatología , Femenino , Masculino , Adulto , Adulto Joven , Estudios de Seguimiento , Adolescente , Experiencias Adversas de la Infancia , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Estudios Prospectivos , Adultos Sobrevivientes de Eventos Adversos Infantiles/estadística & datos numéricosRESUMEN
Thyroid cancer is the most common endocrine cancer, with differentiated thyroid cancers (DTCs) accounting for 95% of diagnoses. While most DTC patients are diagnosed and treated with radioiodine (RAI), up to 20% of DTC patients become RAI refractory (RAI-R). RAI-R patients have significantly reduced survival rates compared to patients who remain RAI-avid. This study explores [89Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [89Zr]Zr-TR1402 was synthesized with a molar activity of 25.9 MBq/nmol by conjugating recombinant human TSH (rhTSH) analogue TR1402 to chelator p-SCN-Bn-deferoxamine (DFO) in a molar ratio of 3:1 (DFO/TR1402) and radiolabeling with 89Zr (t1/2 = 78.4 h, ß+ = 22.7%). As TSHR is absent in commonly available DTC-derived cell lines, TSHR was reintroduced via stable transduction by delivering a lentivirus containing the full-length coding region of the human TSHR gene. Receptor-mediated uptake of [89Zr]Zr-TR1402 was evaluated in vitro in stably transduced TSHR+ and wild-type TSHR- DTC cell lines. In vivo PET imaging was performed on Days 1-3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR- xenografts, along with ex vivo biodistribution on Day 3 postinjection. In vitro uptake of 1 nM [89Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T (P < 0.0001) and FTC133 (P < 0.01) cells than in TSHR- THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T (P < 0.0001) and TSHR+ FTC133 (P < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. In vivo PET imaging showed accumulation of [89Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, ex vivo biodistribution confirmed a significant difference (P < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133- (0.8 ± 0.1%ID/g) tumors. A significant difference (P < 0.05) in uptake was also seen in the male THJ529T xenograft model between THJ529T+ (1.8 ± 0.6%ID/g) and THJ529T- (0.8 ± 0.4%ID/g) tumors. The in vitro and in vivo accumulation of [89Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.