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1.
JMIR Res Protoc ; 13: e56632, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39353191

RESUMO

BACKGROUND: Chronic neck pain (CNP) needs attention to its physical, cognitive, and social dimensions. OBJECTIVE: We aimed to design a health education program (HEP) with a biopsychosocial approach for patients with CNP. METHODS: A literature search on CNP, health education, and biopsychosocial models was carried out. Seven physiotherapists with expertise in HEPs and chronic pain participated in three teams that evaluated the literature and prepared a synthesis document in relation to the three target topics. Experts compiled the information obtained and prepared a proposal for an HEP with a biopsychosocial approach aimed at patients with CNP. This proposal was tested in the physiotherapy units of primary care health centers belonging to the East Assistance Directorate of Madrid, and suggestions were included in the final program. RESULTS: The HEP for CNP with a biopsychosocial approach consists of 5 educational sessions lasting between 90 and 120 minutes, carried out every other day. Cognitive, emotional, and physical dimensions were addressed in all sessions, with particular attention to the psychosocial factors associated with people who have CNP. CONCLUSIONS: The proposed HEP with a biopsychosocial approach emphasizes emotional management, especially stress, without neglecting the importance of physical and recreational exercises for the individual's return to social activities. The objective of this program was to achieve a clinically relevant reduction in perceived pain intensity and functional disability as well as an improvement in quality of life in the short and medium term. TRIAL REGISTRATION: ClinicalTrials.gov NCT02703506; https://clinicaltrials.gov/study/NCT02703506. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56632.


Assuntos
Dor Crônica , Cervicalgia , Humanos , Cervicalgia/terapia , Cervicalgia/reabilitação , Dor Crônica/terapia , Dor Crônica/psicologia , Educação em Saúde/métodos , Educação de Pacientes como Assunto/métodos
2.
J Surg Res ; 303: 173-180, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39357348

RESUMO

INTRODUCTION: Leadership development programs are the key for engaging physicians as partners in health-care administration. These programs have become common; however, one potential consequence of leadership training is attrition. METHODS: Using a prospectively collected database, Kaplan-Meier curves were used to analyze attrition of physician faculty following an intramural leadership program at an academic health center. RESULTS: Six cohorts totaling 165 faculty successfully completed our leadership program. Sixty-one faculty (37%) were from surgical departments (Group A) and 104 (63%) from nonsurgical departments (Group B). Thirty-six program graduates (21.8%) departed the institution at a mean follow-up of 68 mo for an annualized attrition rate of 3.6%. Attrition rates for Group B were significantly greater than for Group A (P = 0.05). Most faculty left for career advancement opportunities elsewhere. CONCLUSIONS: Our annualized attrition rate for leadership trained faculty was 3.6%, well below the attrition rate of our academic health center (5.3%) over a similar time period, and the 2018 national physician attrition rate of 7.8%. Strategies to improve retention are discussed.

3.
Gastroenterology ; 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39393543

RESUMO

BACKGROUND AND AIMS: Therapy failure in patients with metastatic colorectal cancer (mCRC, ∼80% occur in the liver) remains an overarching challenge. Preclinical studies demonstrated that HER3 promotes CRC cell survival, but therapies blocking the neuregulin-induced canonical HER3 signaling have made little impact in the clinic. Recent studies suggest that the liver microenvironment promotes CRC growth by activating HER3 in a neuregulin-independent fashion, thus elucidation of these mechanisms may reveal new strategies for treating patients with mCRC. METHODS: Patient-derived primary liver endothelial cells (ECs) were used to interrogate EC-CRC crosstalk. We conducted proteomic analysis to identify EC-secreted factor(s) that triggers non-canonical HER3 activation in CRC, and determined the subsequent effects on mCRC using diverse murine mCRC models. In vitro studies with genetic and pharmacological interventions were used to map the non-canonical HER3 pathway. RESULTS: We demonstrated that EC-secreted leucine-rich alpha-2-glycoprotein 1 (LRG1) directly binds and activates HER3 and promotes CRC growth distinct from neuregulin, the canonical HER3 ligand. Blocking host-derived LRG1 by gene knockout or a neutralizing antibody impaired mCRC outgrowth in the liver and prolonged mouse survival. We identified protein synthesis activated by the PI3K-PDK1-RSK-eIF4B axis as the biologically relevant signaling cascade downstream of the LRG1-HER3 interaction, which was not blocked by conventional HER3-specific antibodies that failed in prior clinical trials. CONCLUSIONS: LRG1 is a novel HER3 ligand and mediates liver-mCRC crosstalk. The LRG1-HER3 signaling axis is distinct from canonical HER3 signaling and represents a new therapeutic opportunity to treat patients with mCRC, and potentially other types of liver metastases.

5.
Am J Occup Ther ; 78(6)2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39331565

RESUMO

IMPORTANCE: One primary function of occupational therapy state licensure boards (SLBs) is the discipline of ethical misconduct by licensed occupational therapy practitioners. However, SLB sanctioning is poorly understood by practitioners, regulators, and the public. OBJECTIVE: To identify predictors of occupational therapy practitioner sanctioning outcomes in the United States. DESIGN: Retrospective study; all public final consent orders and database entries provided online by SLBs were analyzed. Supervised gradient boosting machine learning, logistic regression, and contingency tables were used to generate odds ratios for variables associated with each sanctioning outcome. Multinomial testing was used to identify attribute overrepresentation among cases and national practitioner distributions. PARTICIPANTS: A total of 2,400 cases were analyzed across 47 states and Washington, DC. INTERVENTION: None. OUTCOMES AND MEASURES: Numerous complaint and respondent attribute variables were collected from final consent orders and database entries. RESULTS: Complaint reason, practice setting, and complaint source had the highest influence on predicting sanction outcome; geographic region, number of complaints in a given case, and length of investigation in months were secondarily influential. Being male or a certified occupational therapy assistant was associated with higher odds of severe sanctioning outcomes. CONCLUSIONS AND RELEVANCE: Disciplinary actions against occupational therapy practitioners were determined by numerous contextual factors; however, the most influential factors were complaint reason, practice setting, and complaint source. These results provide direction for exploring factors that predict sanctioning outcomes in the United States and also provide occupational therapy practitioners and SLBs a basis of applied outcomes that may improve implementation and education regarding clinical practice ethics. Plain-Language Summary: Occupational therapy state licensure boards (SLBs) are responsible for disciplining licensed occupational therapy practitioners for ethical misconduct. SLB sanctioning is poorly understood by practitioners, regulators, and the public. In this study, we identify the factors that predict the sanctioning outcomes of occupational therapy practitioners. The results may help state regulators, educators, and national associations more effectively act in a way that protects the public faith in occupational therapy services by providing contextualized information on practitioner behaviors that result in specific sanctioning outcomes. The study findings also provide occupational therapy practitioners and SLBs a basis of applied outcomes that may improve the implementation of and education regarding clinical practice ethics.


Assuntos
Licenciamento , Terapia Ocupacional , Má Conduta Profissional , Humanos , Estados Unidos , Estudos Retrospectivos , Masculino , Feminino
6.
Sci Data ; 11(1): 1040, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39333175

RESUMO

G-protein coupled receptors (GPCRs) are encoded by nonabundant mRNAs, and it is difficult to detect them reliably with the highly parallel methods that are in general use. Because of this, we developed and validated a sensitive, specific, semi-quantitative method for detecting these transcripts. We have used the method to profile GPCR transcripts in white blood cells (WBCs)-B, CD4, CD8, NK, and dendritic cells; monocytes, and macrophage-like monocytes treated with granulocyte-macrophage colony-stimulating factor-as well as platelets. On average, the white cells studied expressed 160 receptor mRNAs (range, 123-206). Platelets made 69. Some, but far from all, of the receptors we found have been detected earlier. We believe our data should stimulate studies of receptor function and contribute to drug development.


Assuntos
Plaquetas , Leucócitos , RNA Mensageiro , Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/genética , Plaquetas/metabolismo , Leucócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Monócitos/metabolismo
7.
JAMA Netw Open ; 7(9): e2432927, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39264626

RESUMO

Importance: Patients with locally advanced rectal cancer and persistent lymph node metastases (PLNM) after neoadjuvant treatment are at high risk of developing locoregional and distant metastasis, yet optimal postsurgical treatment of these patients is limited. Objective: To analyze the association of PLNM with pretreatment clinical parameters, intensity of neoadjuvant treatment, and long-term oncological outcomes. Design, Setting, and Participants: This cohort study is a post-hoc analysis of 3 randomized clinical trials (Surgical Oncology Working Group of Germany [CAO], Radiological Oncology Working Group of Germany [ARO], and Working Group for Internal Oncology in the German Cancer Society [AIO]) conducted in Germany in 1994, 2004, and 2012 that included 1948 patients with locally advanced rectal cancer recruited between February 1995 and January 2018. Statistical analysis was conducted between September 2023 and February 2024. Exposures: Receiving preoperative fluorouracil-based chemoradiotherapy (CRT, comprising the preoperative group of CAO/ARO/AIO-94 and the control group of CAO/ARO/AIO-04), fluorouracil-based CRT plus oxaliplatin (experimental group of CAO/ARO/AIO-04), or total neoadjuvant treatment (TNT) with fluorouracil-based CRT plus oxaliplatin with induction or consolidation leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin chemotherapy within the CAO/ARO/AIO-12 trial. Main Outcome and Measures: The associations of PLNM with clinical parameters, intensity of neoadjuvant treatment, and cumulative incidences of LR, DM, and overall survival were assessed. Results: A total of 1888 patients (1333 male participants [70.6%]; median [range] age, 62 [19-84] years) with locally advanced rectal adenocarcinoma (clinical tumor stage 3 to 4 and/or clinically node-positive) treated within 3 consecutive clinical trials were analyzed. A total of 522 (29%) experienced PLNM; 378 had lymph node stage (ypN) 1 (20%) after neoadjuvant treatment (ypN) 1 (20%), and 174 had ypN2 (9%). Age, clinical T-stage, N-stage, grading, carcinoembryonic antigen levels, and time interval from completion of CRT to surgery were significantly associated with PLNM, whereas sex and tumor location were not. The percentage of patients with ypN2 stage was almost halved after TNT (18 of 293 patients [6%]) compared with patients treated with fluorouracil-based CRT (114 of 1009 patients [11.3%]; χ26 = 16.693; P = .01). After a median (IQR) follow-up of 54 (37-62) months, 5-year overall survival was 86.1% (95% CI, 83.9%-88.4%) for ypN0, 74.0% (95% CI, 83.9%-88.4%) for ypN1, and 43% for ypN2 (95% CI, 35.4%-52.2%) (P < .001). The 5-year cumulative incidences of locoregional and distant metastases were, respectively, 3% (95% CI, 2.1%-4.2%) and 20% (95% CI, 18%-23%) for ypN0, 6% (95% CI, 3.4%-8.8%) and 40% (95% CI, 34%-46%) for ypN1, and 19% (95% CI, 13%-26%) and 72% (95% CI, 63%-79%) for ypN2 (both P < .001). Conclusions and Relevance: In this cohort study, PLNM unmasked an unfavorable phenotype of rectal cancer at high risk for treatment failure. More aggressive adjuvant treatment might be considered; however, risk-adapted surveillance strategies and early recurrence-directed surgery, if feasible, are important strategies in this group of patients with CRT- and/or chemotherapy-resistant disease.


Assuntos
Metástase Linfática , Terapia Neoadjuvante , Neoplasias Retais , Humanos , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Masculino , Feminino , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Idoso , Adulto , Estudos de Coortes , Alemanha/epidemiologia , Quimiorradioterapia/métodos , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem
8.
medRxiv ; 2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39252896

RESUMO

The OpenOximetry Repository is a structured database storing clinical and lab pulse oximetry data, serving as a centralized repository and data model for pulse oximetry initiatives. It supports measurements of arterial oxygen saturation (SaO2) by arterial blood gas co-oximetry and pulse oximetry (SpO2), alongside processed and unprocessed photoplethysmography (PPG) data and other metadata. This includes skin color measurements, finger diameter, vital signs (e.g., arterial blood pressure, end-tidal carbon dioxide), and arterial blood gas parameters (e.g., acid-base balance, hemoglobin concentration). Data contributions are encouraged. All data, from desaturation studies to clinical trials, are collected prospectively to ensure accuracy. A common data model and standardized protocols for consistent archival and interpretation ensure consistent data archival and interpretation. The dataset aims to facilitate research on pulse oximeter performance across diverse human characteristics, addressing performance issues and promoting accurate pulse oximeters. The initial release includes controlled lab desaturation studies (CLDS), with ongoing updates planned as further data from clinical trials and CLDS become available.

9.
J Oral Rehabil ; 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39305043

RESUMO

BACKGROUND: Physical therapy seems the most promising treatment for temporomandibular disorders (TMD), although their effectiveness is controversial in general, due to high heterogeneity regarding study designs, applied treatments and outcomes measures. OBJECTIVES: The aim of this scoping review is to analyse the methodological characteristics of clinical trials evaluating physical therapy treatments in subjects with TMD. METHODS: A systematic search was conducted in Medline/PubMed, SPORTDiscus, Scopus, Web of Science, SciELO, Cochrane, ScienceDirect and EMBASE databases on 31 October 2023. Clinical trials evaluating physical therapy interventions in patients older than 18 years with TMD, published in English or Spanish languages. Data regarding content reporting of study designs, sample characteristics, interventions and outcome measures was extracted. Descriptive summary statistics were reported. RESULTS: The search retrieved 15 322 records, and 136 were included. There were 107 randomised clinical trials, 5 non-randomised controlled trials and 24 non-controlled trials. Most studies had moderate to high risk of bias, small sample sizes (median, 44 subjects) and short follow-up periods (1-3 months). The most common diagnostic criteria used was the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) (48.9%). The most reported experimental interventions were manual therapy (40.4%), exercise (30.2%) and electrotherapy modalities (27.2%), and the most common outcome measure domains were pain (83.8%), range of movement (61.8%), disability (45.6%) and mechanosensitivity (29.4%). There was poor content reporting of experimental interventions. CONCLUSIONS: Current literature of clinical trials of physical therapy interventions for TMD has moderate to high risk of bias, poor content reporting, small sample size and short-term follow-ups which limit internal and external validity, as well as applicability into clinical practice.

10.
J Org Chem ; 89(19): 14228-14232, 2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39288304

RESUMO

We present the regio- and diastereoselective Barbier-type allenylation reaction of glyoxals mediated by indium to furnish highly valuable syn-bis(α-hydroxyallenes) and syn-α,α'-dihydroxyallenynes. The gold-catalyzed controlled cyclization of these unsaturated diols enables the divergent preparation of three types of oxacycles.

11.
bioRxiv ; 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39345363

RESUMO

Local adaptation may facilitate range expansion during invasions, but the mechanisms promoting destructive invasions remain unclear. Cheatgrass (Bromus tectorum), native to Eurasia and Africa, has invaded globally, with particularly severe impacts in western North America. We sequenced 307 genotypes and conducted controlled experiments. We found that diverse lineages invaded North America, where long-distance gene flow is common. Ancestry and phenotypic clines in the native range predicted those in the invaded range, indicating pre-adapted genotypes colonized different regions. Common gardens showed directional selection on flowering time that reversed between warm and cold sites, potentially maintaining clines. In the Great Basin, genomic predictions of strong local adaptation identified sites where cheatgrass is most dominant. Preventing new introductions that may fuel adaptation is critical for managing ongoing invasions.

12.
Strahlenther Onkol ; 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39325141

RESUMO

PURPOSE: Recent data suggest an impact of extracellular vesicles (EVs) and their micro(mi)RNA cargo on cell-cell interactions to contribute to pathophysiology of leukaemia and radiation response. Here, we investigated differential miRNA cargo of EVs from serum derived from patients with leukaemia (n = 11) before and after total body irradiation with 2â€¯× 2 Gy as compared to healthy donors (n = 6). METHODS: RNA was isolated from EVs and subjected to next generation sequencing of miRNAs. Analysis of sequencing data was performed with miRDeep29 software and differentially expressed miRNAs were filtered using R package edgeR10,11. Signaling pathways were identified using Kyoto Encyclopedia of Genes and Genomes database (KEGG) pathway analysis. RESULTS: Flow cytometric and Western blot analyses confirmed the presence of characteristic EV markers TSG-101, CD­9 and CD-81. miRNA sequencing revealed a differential cargo in serum of patients with leukaemia in comparison to healthy donors with 23 significantly upregulated and 16 downregulated miRNAs affecting hedgehog, estrogen, glutathione metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathways amongst others. Whole body irradiation of patients with leukaemia significantly increased 11 miRNAs, involved in cell cycle regulation and platinum drug resistance, and decreased 15 miRNAs, contributing to apoptosis or cytokine-receptor interactions. CONCLUSION: As compared to healthy controls and following irradiation, we have identified differentially regulated miRNAs in serum-derived EVs from patients with leukaemia that may serve as possible biomarkers of leukaemic disease and treatment and radiation exposure.

13.
IMA Fungus ; 15(1): 27, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39215368

RESUMO

OBJECTIVES: Cryptococcosis remains a severe global health concern, underscoring the urgent need for rapid and reliable diagnostic solutions. Point-of-care tests (POCTs), such as the cryptococcal antigen semi-quantitative (CrAgSQ) lateral flow assay (LFA), offer promise in addressing this challenge. However, their subjective interpretation poses a limitation. Our objectives encompass the development and validation of a digital platform based on Artificial Intelligence (AI), assessing its semi-quantitative LFA interpretation performance, and exploring its potential to quantify CrAg concentrations directly from LFA images. METHODS: We tested 53 cryptococcal antigen (CrAg) concentrations spanning from 0 to 5000 ng/ml. A total of 318 CrAgSQ LFAs were inoculated and systematically photographed twice, employing two distinct smartphones, resulting in a dataset of 1272 images. We developed an AI algorithm designed for the automated interpretation of CrAgSQ LFAs. Concurrently, we explored the relationship between quantified test line intensities and CrAg concentrations. RESULTS: Our algorithm surpasses visual reading in sensitivity, and shows fewer discrepancies (p < 0.0001). The system exhibited capability of predicting CrAg concentrations exclusively based on a photograph of the LFA (Pearson correlation coefficient of 0.85). CONCLUSIONS: This technology's adaptability for various LFAs suggests broader applications. AI-driven interpretations have transformative potential, revolutionizing cryptococcosis diagnosis, offering standardized, reliable, and efficient POCT results.

14.
Psychol Sport Exerc ; 76: 102726, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39216683

RESUMO

Acute stress is frequent in sports and rehabilitation contexts and can impact cognitive processes essential for motor learning. This study aimed to investigate the influence of induced acute stress on the learning of a precise manual task, examining its effect on five key parameters of fine motor control: trajectory error, trajectory error direction, time error, tracing accuracy, and task accuracy. A double-masked, randomized clinical trial with 62 participants (average age 20.65 ± 2.54 years; 39 females; 23 males) was conducted. To examine the effects of stress, participants were assigned to either a stress or a control group through stratified randomization by sex. Initially, all participants underwent the Maastricht Acute Stress Test (in its acute stress and control versions, respectively). Subsequently, they performed the precise manual task on a graphic tablet at three stages of the learning process: acquisition, short-term retrieval, and long-term retrieval. Electrodermal activity and heart rate variability were recorded to assess stress induction. Data analysis from 30 stress group participants and 25 control group participants revealed no statistically significant differences between groups in any of the variables studied at the three learning stages. Both groups exhibited statistically significant improvements in time error, trajectory error direction, and tracing accuracy during both short-term and long-term retrieval compared to acquisition. Our findings suggest that acute physical and psychological stress does not markedly impair learning a precise manual task of adhering to a specific trajectory and pace among young adults.

15.
Healthcare (Basel) ; 12(15)2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39120215

RESUMO

A cross-sectional study was conducted with three aims: (1) to determine the degree of compliance with physical activity recommendations among adolescents according to sex and place of residence, (2) to determine the perceived support of family and friends for physical activity among adolescents according to sex and place of residence, and (3) to analyse the influence of family and friends support on compliance with physical activity recommendations among adolescents according to sex and place of residence. A total of 694 adolescents from an inland area of Spain (14.06 ± 1.27 years) participated. Four one-day physical activity questionnaires were administered to assess physical activity and the Parental Support Scale and Peer Support to measure perceived support from family and friends regarding physical activity. Chi-square, Crammer's V and Student's tests were calculated to identify differences between variables according to sex and municipality of residence. Moreover, the initial binary logistic regression model was constructed to predict the physical activity compliance. Differences in adherence to physical activity recommendations were found according to the sex of the students (rural area: x2 = 4.192, p < 0.05; V = 0.106, p < 0.05; urban area: x2 = 8.999, p < 0.05; V = 0.167, p < 0.01). There were also sex differences in rural areas on items related to families providing transport (t = 3.878, p ≤ 0.001; d = 0.40) and doing physical activity together (t = 4.974, p ≤ 0.001; d = 0.50). It is concluded that most adolescents do not comply with physical activity recommendations. In addition, 30.4% of urban girls' compliance was predicted by the perception that their family members saw them doing physical activity and doing it with friends.

16.
J ECT ; 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121009

RESUMO

AIMS: To explore knowledge and attitudes of medical students before and after exposure to a technology-enhanced learning and teaching (TELT) session about electroconvulsive therapy (ECT). BACKGROUND: Adequate knowledge of and attitudes toward ECT is essential for medical students. However, the impact of teaching on knowledge and attitudes is infrequently studied. METHODS: Fourth- and fifth year medical students at the University of Glasgow were provided with an online questionnaire before and after engaging in a remote TELT session, led by a consultant psychiatrist with expertise in ECT. The online teaching session used resources developed by a multidisciplinary team who specialize in ECT. The teaching session lasted around 1 hour. The questionnaire contained 3 sections: baseline demographics, knowledge of ECT, and attitudes toward ECT. Changes in scores were analyzed. RESULTS: Sixty-seven students completed the teaching session. Response rate to the precourse questionnaire was 68.7% (n = 46), and the postcourse questionnaire was 44.8% (n = 30). Prior to engaging with the learning materials, 9 students reported no knowledge of ECT and a third believed that ECT did not cause a seizure. In general, students who had personal experience of mental illness (friend, relative, or self) had more positive attitudes toward ECT and higher knowledge scores. In general, an increase in knowledge and attitude scores was found in the postcourse questionnaire. CONCLUSIONS: Exposing medical students to a TELT session focused on ECT during their psychiatric placement appeared to improve knowledge and attitudes surrounding ECT.

17.
Nat Commun ; 15(1): 7584, 2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39217171

RESUMO

Heparan sulfate (HS) regulation of FGFR function, which is essential for salivary gland (SG) development, is determined by the immense structural diversity of sulfated HS domains. 3-O-sulfotransferases generate highly 3-O-sulfated HS domains (3-O-HS), and Hs3st3a1 and Hs3st3b1 are enriched in myoepithelial cells (MECs) that produce basement membrane (BM) and are a growth factor signaling hub. Hs3st3a1;Hs3st3b1 double-knockout (DKO) mice generated to investigate 3-O-HS regulation of MEC function and growth factor signaling show loss of specific highly 3-O-HS and increased FGF/FGFR complex binding to HS. During development, this increases FGFR-, BM- and MEC-related gene expression, while in adult, it reduces MECs, increases BM and disrupts acinar polarity, resulting in salivary hypofunction. Defined 3-O-HS added to FGFR pulldown assays and primary organ cultures modulates FGFR signaling to regulate MEC BM synthesis, which is critical for secretory unit homeostasis and acinar function. Understanding how sulfated HS regulates development will inform the use of HS mimetics in organ regeneration.


Assuntos
Membrana Basal , Diferenciação Celular , Células Epiteliais , Heparitina Sulfato , Camundongos Knockout , Glândulas Salivares , Transdução de Sinais , Sulfotransferases , Animais , Heparitina Sulfato/metabolismo , Membrana Basal/metabolismo , Glândulas Salivares/metabolismo , Glândulas Salivares/citologia , Sulfotransferases/metabolismo , Sulfotransferases/genética , Camundongos , Células Epiteliais/metabolismo , Células Epiteliais/citologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Masculino , Fatores de Crescimento de Fibroblastos/metabolismo
18.
NIHR Open Res ; 4: 23, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39145107

RESUMO

Background: MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients. Aim: The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify in-vivo surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the 'reactive species interactome') to differentiate between groups of conservative and usual oxygen targets. Methods and design: After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg methyl-D 9-choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTNISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838.

19.
Interv Neuroradiol ; : 15910199241276676, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39166279

RESUMO

BACKGROUND AND OBJECTIVE: Cerebrospinal fluid (CSF) diversion is typically performed with an external ventricular drain (EVD) for symptomatic hydrocephalus (HCP) following subarachnoid hemorrhage (SAH). Lumbar drain (LD) has also been studied to reduce the incidence of vasospasm after SAH but not HCP. We performed a single center retrospective analysis to evaluate the safety of LD versus EVD for symptomatic HCP following aneurysmal SAH in a naturally randomized patient population. METHODS: Patients admitted for aneurysmal SAH who developed symptomatic HCP were treated with EVD or LD depending on neurosurgeon on call. Of the 10 neurosurgeons on call, five would place EVD in all patients while the other five would request LD be placed by interventional neuroradiology; however, the distribution on call was not evenly distributed. We retrospectively compared these two groups for drain complications and outcomes with Modified Rankin Scale (mRS). RESULTS: From 2018 to 2021, there were a total of 77 patients with aneurysmal SAH requiring CSF diversion for HCP. There were 56 cases of EVD placement and 21 cases of LD placement. Overall drain complications were 32.0% of cases with EVD and 9.5% with LD, p = .0773. EVD versus LD complications consisted of hemorrhage (1.8% vs 0%, p = 1.0000), infection (7.1 vs 0%, p = .5698), clogged (25% vs 0%, p = .008), dislodgement (1.8% vs 4.6%, p = .4737) and replacement (16% vs 4.8%, p = .2698). No case of cerebellar tonsillar herniation occurred. mRS between EVD versus LD obtained at baseline (0.3 vs 0.3, p = .3943), discharge (3.8 vs 2.7, p = .047), 90 days (2.9 vs 2.0, p = .060), and 1 year (2.6 vs 1.6, p = .081). One year mortality rates between EVD versus LD (26.8% vs 19.0%, p = .483). CONCLUSION: Symptomatic HCP after aneurysmal SAH can be effectively and safely treated with LD. LD had lower overall complications than EVD with no hemorrhage, infection or malfunction. Further prospective randomized control study may be helpful in elucidating optimal CSF diversion for patients with symptomatic HCP.

20.
Phys Rev E ; 110(1-1): 014130, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39160970

RESUMO

We present a mean-field solution of the dynamics of a Greenberg-Hastings neural network with both excitatory and inhibitory units. We analyze the dynamical phase transitions that appear in the stationary state as the model parameters are varied. Analytical solutions are compared with numerical simulations of the microscopic model defined on a fully connected network. We found that the stationary state of this system exhibits a first-order dynamical phase transition (with the associated hysteresis) when the fraction of inhibitory units f is smaller than some critical value f_{t}≲1/2, even for a finite system. Moreover, any solution for f<1/2 can be mapped to a solution for purely excitatory systems (f=0). In finite systems, when the system is dominated by inhibition (f>f_{t}), the first-order transition is replaced by a pseudocritical one, namely a continuous crossover between regions of low and high activity that resembles the finite size behavior of a continuous phase transition order parameter. However, in the thermodynamic limit (i.e., infinite-system-size limit), we found that f_{t}→1/2 and the activity for the inhibition dominated case (f≥f_{t}) becomes negligible for any value of the parameters, while the first-order transition between low- and high-activity phases for f

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