RESUMEN
PURPOSE: Primary conjunctival molluscum contagiosum (MC) is rare and usually reported in patients with acquired immunodeficiency syndrome. In this study, we present a case of bilateral primary conjunctival MC in a patient with ocular graft-versus-host disease (oGVHD). METHODS: This is a case report study. Clinical evaluation, in vivo confocal microscopy imaging, and histopathology were used to confirm the diagnosis. RESULTS: A 38-year-old woman with a history of allogeneic bone marrow transplant and secondary chronic oGVHD presented with ocular discomfort, redness, and dryness. On examination, clusters of white gelatinous nodular lesions, stained with fluorescein and Lissamine green, were observed on the bulbar conjunctiva, along with similar solitary nodular lesions in all quadrants of both eyes. In vivo confocal microscopy revealed nests of epithelial cells with bright inclusions measuring approximately 30-35 µm. Excisional biopsy confirmed the diagnosis of MC. A 6-month post-operative follow-up showed healed conjunctiva with no recurrence and improved ocular comfort. CONCLUSIONS: Molluscum contagiosum should be considered in the differential diagnosis of conjunctival lesions in patients with impaired immunity such as oGVHD. In diagnosing MC lesions, in vivo confocal microscopy proves to be valuable. In the absence of topical antiviral treatment, surgical excision is warranted.
RESUMEN
BACKGROUND: Implementation science scholars have made significant progress identifying factors that enable or obstruct the implementation of evidence-based interventions, and testing strategies that may modify those factors. However, little research sheds light on how or why strategies work, in what contexts, and for whom. Studying implementation mechanisms-the processes responsible for change-is crucial for advancing the field of implementation science and enhancing its value in facilitating equitable policy and practice change. The Agency for Healthcare Research and Quality funded a conference series to achieve two aims: (1) develop a research agenda on implementation mechanisms, and (2) actively disseminate the research agenda to research, policy, and practice audiences. This article presents the resulting research agenda, including priorities and actions to encourage its execution. METHOD: Building on prior concept mapping work, in a semi-structured, 3-day, in-person working meeting, 23 US-based researchers used a modified nominal group process to generate priorities and actions for addressing challenges to studying implementation mechanisms. During each of the three 120-min sessions, small groups responded to the prompt: "What actions need to be taken to move this research forward?" The groups brainstormed actions, which were then shared with the full group and discussed with the support of facilitators trained in structured group processes. Facilitators grouped critical and novel ideas into themes. Attendees voted on six themes they prioritized to discuss in a fourth, 120-min session, during which small groups operationalized prioritized actions. Subsequently, all ideas were collated, combined, and revised for clarity by a subset of the authorship team. RESULTS: From this multistep process, 150 actions emerged across 10 priority areas, which together constitute the research agenda. Actions included discrete activities, projects, or products, and ways to shift how research is conducted to strengthen the study of implementation mechanisms. CONCLUSIONS: This research agenda elevates actions to guide the selection, design, and evaluation of implementation mechanisms. By delineating recommended actions to address the challenges of studying implementation mechanisms, this research agenda facilitates expanding the field of implementation science, beyond studying what works to how and why strategies work, in what contexts, for whom, and with which interventions.
RESUMEN
Wet clothing is less insulative than dry clothing and increases heat loss in cold air. Tactical necessity can render removal of wet clothing impossible and/or require Warfighters to remain static to avoid detection, limiting heat production and posing a threat of hypothermia (core temperature <35°C). This study aimed to characterize body temperatures and evaluate hypothermia risk while statically exposed to 5°C air wearing three wet military uniforms. Further, low-speed loaded walking was evaluated as a strategy to raise end-static temperatures. Twelve adults (11M, 1F) randomly completed three wet-cold trials wearing either the Improved Hot Weather Combat Uniform (IHWCU), Army Combat Uniform (ACU), or ACU with silk-weight base layer (ACU+). Each trial involved 180 minutes of cold air (5.3±0.3°C, 0.8 m·s-1) exposure after a clothed 2-minute head-out immersion (34.0 ± 0.2°C). Volunteers were static for 60 minutes followed by 120 minutes of loaded walking. Rectal temperature (Tre) area under the curve did not differ among the three wet uniforms when static (p=0.431) with Tre increasing, rather than decreasing, across the 60 minutes (IHWCU: +0.26±0.19°C, ACU: +0.37±0.21°C, ACU+: +0.36±0.20°C). Hypothermia risk with 60-minute static wet-cold exposure therefore appears minimal, regardless of the military uniform worn. End-static finger temperatures (IHWCU: 9.48±2.30°C, ACU: 9.99±1.82°C, ACU+: 9.27±1.66°C, p >0.999) were reduced by ~20-23°C posing a considerable dexterity concern. Heat production of ~210 W·m2 appeared sufficient to begin to reverse negative cumulative heat storage and initiate slight elevation of rectal and peripheral temperatures, although finger temperatures increased < 2°C after 120 minutes. ClinicalTrials.gov ID:NCT05409937.
RESUMEN
The effectiveness of school-based universal prevention programs is frequently diminished due to low-quality implementation. Organizational factors support high-quality implementation because of their broad influence across implementers. Conceptually, implementation leadership (i.e., behaviors that prioritize, reward, and support evidence-based practice [EBP] implementation) works to embed a favorable implementation climate (i.e., implementers' collective perceptions that their organization prioritizes, rewards, and support EBP implementation) leading to improved implementation citizenship behavior and attitudes toward EBP. This organizational implementation process model has some empirical support but has not been tested in a multilevel framework or related to hypothesized attitudinal and behavioral outcomes. The sample included 319 teachers across 39 US public elementary schools; all were implementing Schoolwide Positive Behavior Interventions and Supports. Multilevel mediation (level 1 = teacher, level 2 = school) was used to test the indirect association of implementation leadership on implementation-related attitudes and behaviors via implementation climate across two time points (fall and spring). At the school level, the organizational implementation process model was validated related to implementation citizenship behavior, but not attitudes toward EBP. At the teacher level, the process model was validated related to both outcomes, and there was a significant direct effect of implementation leadership on attitudes toward EBP. Developing strong leaders for implementation seems key to achieving high-quality EBP implementation. Implications for schools, principal training, and research are discussed.
RESUMEN
Forensic case samples collected in sexual assaults typically contain DNA from multiple sources, which complicates short-tandem repeat (STR) profiling. These samples are typically sent to a laboratory to separate the DNA from sperm and non-sperm sources prior to analysis. Here, the automation and miniaturization of these steps using digital microfluidics (DMF) is reported, which may eventually enable processing sexual assault samples outside of the laboratory, at the point of need. When applied to vaginal swab samples collected up to 12 h post-coitus (PC), the new method identifies single-source (male) STR profiles. When applied to samples collected 24-72 h PC, the method identifies mixed STR profiles, suggesting room for improvement and/or potential for data deconvolution. In sum, an automated, miniaturized sample pre-processing method for separating the DNA contained in sexual assault samples is demonstrated. This type of automated processing using DMF, especially when combined with Rapid DNA Analysis, has the potential to be used for processing of sexual assault samples in hospitals, police offices, and other locations outside of the laboratory.
RESUMEN
INTRODUCTION: Placing ureteral stents at the uretero-ileal anastomosis for radical cystectomy with ileal conduit (RCIC) has long been common practice. Recently, some providers have begun omitting stents. We sought to investigate differences in perioperative and 30-day outcomes between patients who underwent radical cystectomy with ileal conduit (RCIC) with and without stents placed at the uretero-ileal anastomosis. METHODS: We identified RCICs performed between 2019 to 2021 in the National Surgical Quality Improvement Program database and corresponding Cystectomy-Targeted Participant Use File. Baseline demographics, comorbidities, and operative parameters were compared via Pearson's chi-square and t-tests between stented and stent-less RCICs. Outcomes of interest, including rates of urinary tract infections (UTIs), acute kidney injury (AKI), renal failure requiring dialysis, ileoileal anastomotic leaks, ureteral obstruction, urinary leak or fistula formation, reoperations, and 30-day hospital readmissions were compared using Pearson's chi-square. All statistical tests were 2 tailed with P < .05 considered significant. RESULTS: Five Thousand Four Hundred Eighteen RCICs were identified. Four hundred ninety-eight (9.2%) were stent-less. There were no differences in baseline demographics or comorbidities. Significantly fewer stented patients had robotic-assisted operations (23% vs 29%, P < .01). Stented patients had lower rates of urinary leak or fistula formation (3.1% vs 4.8%, P = .04). There was no significant difference in 30-day rates of UTIs, AKIs, renal failure, ileoileal anastomotic leaks, ureteral obstruction, reoperations, and readmissions. Limitations include retrospective design and lack of longitudinal tracking past 30 days. CONCLUSIONS: Stent-less patients had non-inferior outcomes compared to stented patients in most important 30-day outcomes. Our analysis suggests that stents may not be necessary in ileal conduit urinary diversion procedures.
RESUMEN
Numerous genes including sarcospan (SSPN) have been designated as obesity-susceptibility genes by human genome-wide association studies. Variants in the SSPN locus have been linked with sex-dependent obesity-associated traits, however this association has not been investigated in vivo. To delineate the role SSPN plays in regulating metabolism with potential to impact cardiac function we subjected young and aged global SSPN-deficient (SSPN-/-) male and female mice to obesogenic conditions (60% fat diet). We hypothesized that loss of SSPN combined with metabolic stress would increase susceptibility of mice to cardiometabolic disease. Baseline and endpoint assessments of several anthropometric parameters were performed including weight, glucose tolerance, and fat distribution of mice fed control (CD) and high fat diet (HFD). Doppler echocardiography was used to monitor cardiac function. White adipose and cardiac tissues were assessed for inflammation utilizing histological, gene expression and cytokine analysis. Overall, SSPN deficiency protected both sexes and ages from diet-induced obesity with a greater effect in females. While SSPN-/- HFD mice gained less weight than WT cohorts, SSPN-/- CD groups increased weight. Furthermore, aged SSPN-/- mice developed glucose intolerance regardless of diet. Echocardiography showed preserved systolic function for all groups, however aged SSPN-/- males (CD) exhibited significant increases in LVmass and (HFD) signs of diastolic dysfunction. Cytokine analysis revealed significantly increased IL-1α and IL-17A in white adipose tissue from young SSPN-/- male mice that may be protective from diet-induced obesity. Overall, these studies suggest several sex-dependent mechanisms influence the role SSPN plays in metabolic responses that become evident with age.
RESUMEN
Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (~3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.
RESUMEN
The retinoid fenretinide (FENR) is a promising compound for preventing breast cancer recurrence but faces challenges due to poor solubility and low bioavailability. This study explores the development of dissolving microneedles (MNs) containing FENR-loaded ethosomes for minimally invasive breast cancer chemoprevention, aiming to enhance local drug distribution. Ethosomes were formulated using ethanol, propylene glycol, soya lecithin, water, and polysorbate 80 micelles. MNs were created from poly(vinyl alcohol) and poly(vinylpyrrolidone) hydrogels by adding polymer powder directly into ethosomes suspensions, reducing manufacturing time and cost. Two methods were used to load ethosomes into high-density moulds: 1) only in the needle area, and 2) in both the needle area and baseplate. Dynamic light scattering confirmed nanostructures in the hydrogels and MNs. Micelle-based ethosomes dissolved MNs in 15 min, compared to 30 min for other MNs. Skin deposition studies showed greater drug deposition (up to 10 µg/patch) and enhanced skin permeation of FENR (up to 40 µg) with Method 2. In-vivo studies in rats demonstrated that oral administration resulted in plasma FENR levels below 10 ng/g in the first three hours, whereas MN administration delayed delivery, reaching a maximum plasma concentration of 52 ng/g at 48 h. Skin deposition of FENR from MNs decreased from 3 µg/g on day 1 to <0.3 µg/g by the last day. This study indicates that MNs are a potential minimally invasive dosage form for delivering FENR, offering a new approach for breast cancer chemoprevention.
RESUMEN
An issue for molecular dynamics simulations is that events of interest often involve timescales that are much longer than the simulation time step, which is set by the fastest timescales of the model. Because of this timescale separation, direct simulation of many events is prohibitively computationally costly. This issue can be overcome by aggregating information from many relatively short simulations that sample segments of trajectories involving events of interest. This is the strategy of Markov state models (MSMs) and related approaches, but such methods suffer from approximation error because the variables defining the states generally do not capture the dynamics fully. By contrast, once converged, the weighted ensemble (WE) method aggregates information from trajectory segments so as to yield unbiased estimates of both thermodynamic and kinetic statistics. Unfortunately, errors decay no faster than unbiased simulation in WE as originally formulated and commonly deployed. Here, we introduce a theoretical framework for describing WE that shows that the introduction of an approximate stationary distribution on top of the stratification, as in nonequilibrium umbrella sampling (NEUS), accelerates convergence. Building on ideas from MSMs and related methods, we generalize the NEUS approach in such a way that the approximation error can be reduced systematically. We show that the improved algorithm can decrease the simulation time required to achieve the desired precision by orders of magnitude.
RESUMEN
Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts - including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 - associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology.
Asunto(s)
Enfermedad de Alzheimer , Corteza Entorrinal , Ratones Transgénicos , Isoformas de Proteínas , Proteínas tau , Corteza Entorrinal/metabolismo , Corteza Entorrinal/patología , Animales , Humanos , Proteínas tau/metabolismo , Proteínas tau/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Femenino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratones , Modelos Animales de Enfermedad , Empalme Alternativo/genética , Regulación de la Expresión GénicaRESUMEN
Recent advances in nonparametric contrast sensitivity function (CSF) estimation have yielded a new tradeoff between accuracy and efficiency not available to classical parametric estimators. An additional advantage of this new framework is the ability to independently tune multiple aspects of the estimator to seek further improvements. Machine learning CSF estimation with Gaussian processes allows for design optimization in the kernel, acquisition function, and underlying task representation, to name a few. This article describes a novel kernel for CSF estimation that is more flexible than a kernel based on strictly functional forms. Despite being more flexible, it can result in a more efficient estimator. Further, trial selection for data acquisition that is generalized beyond pure information gain can also improve estimator quality. Finally, introducing latent variable representations underlying general CSF shapes can enable simultaneous estimation of multiple CSFs, such as from different eyes, eccentricities, or luminances. The conditions under which the new procedures perform better than previous nonparametric estimation procedures are presented and quantified.
Asunto(s)
Sensibilidad de Contraste , Sensibilidad de Contraste/fisiología , Humanos , Aprendizaje AutomáticoRESUMEN
As of 2023, more than 200 million people worldwide are living with osteoporosis. Oral bisphosphonates (BPs) are the primary treatment but can cause gastrointestinal (GI) side effects, reducing patient compliance. Microarray (MAP) technology has the potential to overcome GI irritation by facilitating the transdermal delivery of BPs. This study examines the delivery of alendronic acid (ALN) and risedronate sodium (RDN) using dissolving and hydrogel-forming MAPs for osteoporosis treatment. In vivo testing on osteoporotic female Sprague Dawley rats demonstrated the efficacy of MAPs, showing significant improvements in mean serum and bone alkaline phosphatase levels, bone volume, and porosity compared to untreated bilateral ovariectomy (OVX) controls. Specifically, MAP treatment increased mean bone volume to 55.04 ± 2.25 % versus 47.16 ± 1.71 % in OVX controls and reduced porosity to 44.30 ± 2.97 % versus 52.84 ± 1.70 % in the distal epiphysis of the femur. In the distal metaphysis, bone volume increased to 43.32 ± 3.24 % in MAP-treated rats compared to 24.31 ± 3.21 % in OVX controls, while porosity decreased to 55.39 ± 5.81 % versus 75.69 ± 3.21 % in OVX controls. This proof-of-concept study indicates that MAP technology has the potential to be a novel, patient-friendly alternative for weekly osteoporosis management.
RESUMEN
PURPOSE: Immune gene expression signatures are emerging as potential biomarkers for immunotherapy (IO). VIGex is a 12-gene expression classifier developed in both nCounter (Nanostring) and RNA sequencing (RNA-seq) assays and analytically validated across laboratories. VIGex classifies tumor samples into hot, intermediate-cold (I-Cold), and cold subgroups. VIGex-Hot has been associated with better IO treatment outcomes. Here, we investigated the performance of VIGex and other IO biomarkers in an independent data set of patients treated with pembrolizumab in the INSPIRE phase II clinical trial (ClinicalTrials.gov identifier: NCT02644369). MATERIALS AND METHODS: Patients with advanced solid tumors were treated with pembrolizumab 200 mg IV once every 3 weeks. Tumor RNA-seq data from baseline tumor samples were classified by the VIGex algorithm. Circulating tumor DNA (ctDNA) was measured at baseline and start of cycle 3 using the bespoke Signatera assay. VIGex-Hot was compared with VIGex I-Cold + Cold and four groups were defined on the basis of the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). RESULTS: Seventy-six patients were enrolled, including 16 ovarian, 12 breast, 12 head and neck cancers, 10 melanoma, and 26 other tumor types. Objective response rate was 24% in VIGex-Hot and 10% in I-Cold/Cold. VIGex-Hot subgroup was associated with higher overall survival (OS) and progression-free survival (PFS) when included in a multivariable model adjusted for tumor type, tumor mutation burden, and PD-L1 immunohistochemistry. The addition of ΔctDNA improved the predictive performance of the baseline VIGex classification for both OS and PFS. CONCLUSION: Our data indicate that the addition of ΔctDNA to baseline VIGex may refine prediction for IO.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Biomarcadores de Tumor , ADN Tumoral Circulante , Neoplasias , Transcriptoma , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/sangre , Anticuerpos Monoclonales Humanizados/uso terapéutico , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/análisis , Femenino , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Masculino , Persona de Mediana Edad , Antineoplásicos Inmunológicos/uso terapéutico , Anciano , Resultado del Tratamiento , AdultoRESUMEN
Loss of function mutations in the X-linked PIGA gene lead to PIGA-CDG, an ultra-rare congenital disorder of glycosylation (CDG), typically presenting with seizures, hypotonia, and neurodevelopmental delay. We identified two brothers (probands) with PIGA-CDG, presenting with epilepsy and mild developmental delay. Both probands carry PIGA S132C , an ultra-rare variant predicted to be damaging. Strikingly, the maternal grandfather and a great-uncle also carry PIGA S132C , but neither presents with symptoms associated with PIGA-CDG. We hypothesized genetic modifiers may contribute to this reduced penetrance. Using whole genome sequencing and pedigree analysis, we identified possible susceptibility variants found in the probands and not in carriers and possible protective variants found in the carriers and not in the probands. Candidate variants included heterozygous, damaging variants in three genes also involved directly in GPI-anchor biosynthesis and a few genes involved in other glycosylation pathways or encoding GPI-anchored proteins. We functionally tested the predicted modifiers using a Drosophila eye-based model of PIGA-CDG. We found that loss of CNTN2 , a predicted protective modifier, rescues loss of PIGA in Drosophila eye-based model, like what we predict in the family. Further testing found that loss of CNTN2 also rescues patient-relevant phenotypes, including seizures and climbing defects in Drosophila neurological models of PIGA-CDG. By using pedigree information, genome sequencing, and in vivo testing, we identified CNTN2 as a strong candidate modifier that could explain the incomplete penetrance in this family. Identifying and studying rare disease modifier genes in human pedigrees may lead to pathways and targets that may be developed into therapies.
RESUMEN
BACKGROUND: Sex- and age-dependent outcome differences have been observed in treatment of Major Depressive Disorder (MDD), including 10 Hz repetitive Transcranial Magnetic Stimulation (rTMS). We examined whether there are sex- and age-dependent differences in outcome with intermittent Theta Burst Stimulation (iTBS), another rTMS protocol. METHODS: The relationship between biological sex, age, and treatment outcome was retrospectively examined among 414 patients with MDD treated with 10 Hz or iTBS rTMS. Linear mixed-effects modeling was used to examine the association between treatment and change in the 30-item Inventory of Depressive Symptomatology Self-Report (IDS-SR30) score from baseline to treatments 10 and 30, with biological sex (M/F), protocol (iTBS/10 Hz), age (≥/<50 years old), and time (treatment 1/10/30) included as fixed effects. The three-way sex-protocol-time and age-protocol-time interactions were used to determine any differential relationships between protocol and outcome dependent on sex and age. Post-hoc t-tests were conducted to examine differences in improvement. RESULTS: There was a significant three-way sex-protocol-time interaction at treatments 10 (p = 0.016) and 30 (p = 0.031). Males showed significantly greater improvement with iTBS than females at treatments 10 (p = 0.041) and 30 (p = 0.035), while females showed numerically greater improvement with 10 Hz treatment. While there was not a significant three-way age-protocol-time interaction, there was a significant interaction between age (≥50 years old) and time at treatments 10 (p = 0.007) and 30 (p = 0.042), and among age, sex, and time at treatment 30 (p = 0.028). LIMITATIONS: Retrospective naturalistic treatment protocol. CONCLUSIONS: iTBS appeared less efficacious in females than in males, and rTMS overall was more efficacious in patients over fifty, particularly females.
Asunto(s)
Trastorno Depresivo Mayor , Estimulación Magnética Transcraneal , Humanos , Trastorno Depresivo Mayor/terapia , Estimulación Magnética Transcraneal/métodos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Factores Sexuales , Factores de Edad , Estudios Retrospectivos , Resultado del Tratamiento , AncianoRESUMEN
There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
Asunto(s)
Aterosclerosis , ADN Mitocondrial , Inflamación , Macrófagos , Proteínas de la Membrana , Placa Aterosclerótica , Molécula 1 de Adhesión Celular Vascular , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Animales , Molécula 1 de Adhesión Celular Vascular/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Macrófagos/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Ratones , Placa Aterosclerótica/patología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Masculino , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias/patología , Ratones Noqueados para ApoE , Transducción de Señal , Femenino , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismoRESUMEN
Hydrogel-forming microneedle array patches (HFMAPs) are microneedles that create microconduits upon insertion and swelling in the skin, potentially allowing prolonged drug delivery without generating sharps waste. Delivering hydrophobic drugs using HFMAPs poses challenges, which can be addressed using solubility enhancers such as cyclodextrins (CDs). This study aimed to deliver risperidone (RIS) transdermally using HFMAPs. To enhance the aqueous solubility of RIS hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and hydroxypropyl-gamma-cyclodextrin (HP-γ-CD) were utilised and their performance was tested using phase solubility studies. The aqueous solubility of RIS was enhanced by 4.75-fold and 2-fold using HP-ß-CD and HP-γ-CD, respectively. RIS-HP-ß-CD complex (CX) and physical mixture (PM) directly compressed tablets were prepared and combined with HFMAPs. Among the tested formulations, RIS-HP-ß-CD PM reservoirs with 11 x 11 PVA/PVP HFMAPs exhibited the best performance in ex vivo studies and were further evaluated in in vivo experiments using female Sprague Dawley rats. The extended wear time of the MAPs resulted in the sustained release of RIS and its active metabolite 9-hydroxyrisperidone (9-OH-RIS) in plasma samples, lasting from 3 to 5 days with a 1-day application and up to 10 days with a 5-day application. For a 1-day application, HFMAPs showed greater systemic exposure to RIS compared to intramuscular control (AUC0-t: 13330.05 ± 2759.95 ng/mL/hour versus 2706 ± 1472 ng/mL/hour). Moreover, RIS exposure was extended to 5 days (AUC0-t: 12292.37 ± 1801.94 ng/mL/hour). In conclusion, HFMAPs could serve as an alternative for delivering RIS in a sustained manner, potentially improving the treatment of schizophrenia.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina , Administración Cutánea , Sistemas de Liberación de Medicamentos , Hidrogeles , Risperidona , Solubilidad , Risperidona/administración & dosificación , Risperidona/farmacocinética , Risperidona/química , Animales , Hidrogeles/química , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/instrumentación , 2-Hidroxipropil-beta-Ciclodextrina/química , Ratas , Agujas , Ratas Sprague-Dawley , Absorción Cutánea , Ciclodextrinas/química , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacocinética , Femenino , Piel/metabolismoRESUMEN
Background: Research indicates that people with Parkinson's disease (PwPs) may experience challenges in both peripheral and central auditory processing, although findings are inconsistent across studies. Due to the diversity of auditory measures used, there is a need for standardized, replicable hearing assessments to clarify which aspects of audition are impacted in PWPs and whether they are linked to motor and non-motor symptoms. Objective: To characterize auditory processes and their possible alteration in PwPs. To address this, we collected a comprehensive set of standardized measures of audition using PART, a digital testing platform designed to facilitate replication. Additionally, we examined the relationship between auditory, cognitive, and clinical variables in PwPs. Methods: We included 44 PwPs and 54 age and education matched healthy controls. Assessments included detection of diotic and dichotic frequency modulation, temporal gaps, spectro-temporal broad-band modulation, and speech-on-speech masking. Results: We found no statistically significant differences in auditory processing measures between PwPs and the comparison group (psâ>â0.07). In PwPs, an auditory processing composite score showed significant medium size correlations with cognitive measures (0.39â<âr<0.41, psâ<â0.02) and clinical variables of motor symptom severity, quality of life, depression, and caretaker burden (0.33â<âr<0.52, psâ<â0.03). Conclusions: While larger datasets are needed to clarify whether PwPs experience more auditory difficulties than healthy controls, our results underscore the importance of considering auditory processing on the symptomatic spectrum of Parkinson's disease using standardized replicable methodologies.
It is unknown whether there exists a relationship between Parkinson's disease (PD) and hearing ability. While some studies have found hearing difficulties to be associated with PD, other studies failed to replicate these effects. We suggest that a possible reason for these differing findings are differences in how hearing is measured. To clarify the literature, we tested a group of people with Parkinson's (PwPs) on several aspects of hearing using a freely available tablet-based app. We compared PwPs hearing tests to those of an age and education matched group of people without PD. While we found no clear differences among the groups, we did find better hearing abilities were related to less motor symptom severity and depression, better reported quality of life, and less reported burden of the disease experienced by the caretaker. We conclude that while there is no solid evidence showing the hearing is necessarily impaired in PD, that measuring hearing in PwPs can provide valuable clinical information. This can inform new approaches to treatment for people living with PD such as those related with improving hearing.