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Alzheimer's & Dementia : the Journal of... May 2024Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age-related Nr4a1 reduction and...
INTRODUCTION
Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age-related Nr4a1 reduction and cognitive decline is undefined.
METHODS
Nr4a1 expressions were evaluated by quantitative PCR and immunochemical approaches. The cognition of mice was examined by multiple behavioral tests. Patch-clamp experiments were conducted to investigate the synaptic function.
RESULTS
NR4A1 in peripheral blood mononuclear cells decreased with age in humans. In the mouse brain, age-dependent Nr4a1 reduction occurred in the hippocampal CA1. Deleting Nr4a1 in CA1 pyramidal neurons (PyrNs) led to the impairment of cognition and excitatory synaptic function. Mechanistically, Nr4a1 enhanced TrkB expression via binding to its promoter. Blocking TrkB compromised the cognitive amelioration with Nr4a1-overexpression in CA1 PyrNs.
DISCUSSION
Our results elucidate the mechanism of Nr4a1-dependent TrkB regulation in cognition and synaptic function, indicating that Nr4a1 is a target for the treatment of cognitive decline.
HIGHLIGHTS
Nr4a1 is reduced in PBMCs and CA1 PyrNs with aging. Nr4a1 ablation in CA1 PyrNs impaired cognition and excitatory synaptic function. Nr4a1 overexpression in CA1 PyrNs ameliorated cognitive impairment of aged mice. Nr4a1 bound to TrkB promoter to enhance transcription. Blocking TrkB function compromised Nr4a1-induced cognitive improvement.
Topics: Animals; Cognitive Dysfunction; Nuclear Receptor Subfamily 4, Group A, Member 1; Mice; Humans; Aging; Male; CA1 Region, Hippocampal; Pyramidal Cells; Receptor, trkB; Leukocytes, Mononuclear; Aged; Female; Mice, Inbred C57BL
PubMed: 38605605
DOI: 10.1002/alz.13819 -
The World Allergy Organization Journal Apr 2024There are limited data regarding the characteristics and management of drug hypersensitivity reactions (DHR) in hospitalized children. This study aims to determine the...
INTRODUCTION
There are limited data regarding the characteristics and management of drug hypersensitivity reactions (DHR) in hospitalized children. This study aims to determine the prevalence, clinical features, and management of DHRs in pediatric inpatients.
METHODS
Children who had pediatric allergy consultation for suspected DHR during hospitalization in Ankara Bilkent City Hospital between August 1, 2020, and July 30, 2021, were included. Patient and reaction characteristics, culprit drugs, and management strategies were recorded. When possible, diagnostic tests (skin or provocation tests) were performed after discharge.
RESULTS
Among the 14,090 hospitalized children, 165 (72% male, median age: 106 months) underwent consultation for 192 suspected DHRs with 246 drugs. Cutaneous eruptions were the most common (94.3%). There was anaphylaxis in 40 patients and severe cutaneous adverse drug reaction in 4 patients (drug rash with eosinophilia and systemic symptoms in 3, acute generalized exanthematous pustulosis in 1). Antimicrobials were the leading cause (78.4%, n = 193/246). In 48 reactions, 60 (24%) culprit drugs could be readministered with close follow-up or desensitization (n = 12). In total, 186 suspected drugs were discontinued, and 115 were replaced with alternative drugs. After discharge, 38 provocation tests (2 positives) and 36 skin tests (1 positive prick test, 1 positive intradermal test, and 1 positive patch test) were performed.
DISCUSSION/CONCLUSIONS
The incidence of suspected DHR among pediatric inpatients was approximately 1.1%. Skin symptoms were the most common manifestation. Twenty-four percent of suspected drugs could be continued during hospitalization. Patients with DHR during hospitalization should be evaluated with a drug allergy work-up unless there are contraindications to testing.
PubMed: 38601275
DOI: 10.1016/j.waojou.2024.100893 -
Indian Journal of Dermatology,... Feb 2024
PubMed: 38595025
DOI: 10.25259/IJDVL_812_2023 -
Indian Journal of Dermatology,... Apr 2024Background The International Contact Dermatitis Research Group (ICDRG) grading is the gold standard and is used to interpret patch test results in allergic contact...
Three-part scoring system (tripartite) for teledermatology versus International Contact Dermatitis Research Group criteria to interpret patch test readings: A comparative, observational study.
Background The International Contact Dermatitis Research Group (ICDRG) grading is the gold standard and is used to interpret patch test results in allergic contact dermatitis (ACD). The ICDRG readings include a combination of visual and palpation findings. Digital photography limits palpation. An alternative scoring system exists to analyse 2D images and interpret patch test readings in teledermatology (TD). Aims To compare tri-partite scoring system (TPSS) (TD) with ICDRG (face-to-face) and to assess the feasibility of TPSS by TD. Methods In this observational study, two investigators each scored the patch test readings for 78 patients at the 48th h, 96th h and on the 7th day. Results The TPSS has a sensitivity of 100%, specificity of 93.34%, positive predictive value of 91.67% and negative predictive value of 100%. At a confidence interval of 95%, Cohen's kappa (0.90) indicated excellent agreement between both investigators. The concordance between both scoring systems was at 93.2% for agreement and 6.82% for disagreement. Polysensitisation (6 patients with 16 allergens) was detected equally in both methods. Limitations A single centre study. Conclusion The readings obtained by TPSS were in agreement with ICDRG. TPSS can reduce the number of patient visits by 50% and may be used during COVID-19 times and beyond.
PubMed: 38594974
DOI: 10.25259/IJDVL_118_2023 -
Asia-Pacific Journal of Sports... Apr 2024Bridging repair has emerged as a promising and reliable treatment strategy for the massive rotator cuff tears (MRCTs). However, there remains a lack of evidence on which...
Histologic and biomechanical comparison of fascia lata autograft, acellular dermal xenograft, and synthetic patch for bridging massive rotator cuff tear in a rabbit model.
BACKGROUND
Bridging repair has emerged as a promising and reliable treatment strategy for the massive rotator cuff tears (MRCTs). However, there remains a lack of evidence on which bridging graft provides the better repair results, and a dearth of animal studies comparing bridging repairs with different grafts. The purpose of this study was to evaluate the histological and biomechanical outcomes of commonly used grafts (autologous fascia lata (FL), acellular dermal matrix graft (ADM), and polyethylene terephthalate (PET) patch).
METHODS
A total of 66 male New Zealand White Rabbits were used to mimic a model of unilateral chronic MRCTs. The rabbits were randomly divided into three groups: (1) FL group, which underwent bridging repair with autologous FL; (2) ADM group, which underwent bridging with ADM; and (3) PET group, which underwent bridging with PET patch. Tissue samples were collected and subjected to histological analysis using Hematoxylin and eosin, Picrosirius red, Safranin O/Fast green staining, and Immunostaining. Collagen diameter and fibril density in the regenerated tendon was analyzed with transmission electron microscopy (TEM). Additionally, biomechanical tests were performed at 6 and 12 weeks after repair.
RESULTS
The regenerated tendon successfully reattached to the footprint in all experimental groups. At 6 weeks after repair, the FL group had a significantly higher Modified Tendon Histological Evaluation (MTHE) score at the regenerated tendon than the PET group (13.2 ± 1.64 vs 9.6 ± 1.95, respectively; = 0.038). The picrosirius red staining results showed that the FL group had a significantly higher type I collagen content than the ADM and PET groups at 6 weeks, and this difference was sustained with the PET group at 12 weeks ( < 0.05). Immunofluorescence analysis against CD68 indicated that the number of macrophage infiltrates was significantly lower in the FL group than in the ADM and PET groups ( < 0.05). At 12 weeks after repair, the area of Safranin O metachromasia was significant greater in ADM group than that in the PET group ( = 0.01). The FL group showed a significantly larger collagen diameter in the regenerated tendon than the PET group ( < 0.05), as indicated by TEM results. Furthermore, the FL group resulted in a greater failure load (at 6 weeks; 118.40 ± 16.70 N vs 93.75 ± 9.06 N, respectively; = 0.019) and elastic modulus (at 6 weeks; 12.28 ± 1.94 MPa vs 9.58 ± 0.79 MPa, respectively; = 0.024; at 12 weeks; 15.02 ± 2.36 MPa vs 11.63 ± 1.20 MPa, respectively; = 0.032) than the ADM group.
CONCLUSIONS
This study demonstrated that all three grafts could successfully bridging chronic MRCTs in a rabbit model. However, autologous FL promoted tendon regeneration and maturation, and enhanced the tensile properties of the tendon-to-bone complex when compared with ADM and PET grafts.
PubMed: 38584973
DOI: 10.1016/j.asmart.2024.01.007 -
Frontiers in Pharmacology 2024Pain is a clinically relevant health care issue with limited therapeutic options, creating the need for new and improved analgesic strategies. The amygdala is a limbic...
Pain is a clinically relevant health care issue with limited therapeutic options, creating the need for new and improved analgesic strategies. The amygdala is a limbic brain region critically involved in the regulation of emotional-affective components of pain and in pain modulation. The central nucleus of amygdala (CeA) serves major output functions and receives nociceptive information via the external lateral parabrachial nucleus (PB). While amygdala neuroplasticity has been linked causally to pain behaviors, non-neuronal pain mechanisms in this region remain to be explored. As an essential part of the neuroimmune system, astrocytes that represent about 40-50% of glia cells within the central nervous system, are required for physiological neuronal functions, but their role in the amygdala remains to be determined for pain conditions. In this study, we measured time-specific astrocyte activation in the CeA in a neuropathic pain model (spinal nerve ligation, SNL) and assessed the effects of astrocyte inhibition on amygdala neuroplasticity and pain-like behaviors in the pain condition. Glial fibrillary acidic protein (GFAP, astrocytic marker) immunoreactivity and mRNA expression were increased at the chronic (4 weeks post-SNL), but not acute (1 week post-SNL), stage of neuropathic pain. In order to determine the contribution of astrocytes to amygdala pain-mechanisms, we used fluorocitric acid (FCA), a selective inhibitor of astrocyte metabolism. Whole-cell patch-clamp recordings were performed from neurons in the laterocapsular division of the CeA (CeLC) obtained from chronic neuropathic rats. Pre-incubation of brain slices with FCA (100 µM, 1 h), increased excitability through altered hyperpolarization-activated current (I) functions, without significantly affecting synaptic responses at the PB-CeLC synapse. Intra-CeA injection of FCA (100 µM) had facilitatory effects on mechanical withdrawal thresholds (von Frey and paw pressure tests) and emotional-affective behaviors (evoked vocalizations), but not on facial grimace score and anxiety-like behaviors (open field test), in chronic neuropathic rats. Selective inhibition of astrocytes by FCA was confirmed with immunohistochemical analyses showing decreased astrocytic GFAP, but not NeuN, signal in the CeA. Overall, these results suggest a complex modulation of amygdala pain functions by astrocytes and provide evidence for beneficial functions of astrocytes in CeA in chronic neuropathic pain.
PubMed: 38576475
DOI: 10.3389/fphar.2024.1368634 -
International Journal of Telemedicine... 2024Users of homecare services are often excluded from clinical trials due to advanced age, multimorbidity, and frailty. Atrial fibrillation (AF) is a common and frequently...
AIMS
Users of homecare services are often excluded from clinical trials due to advanced age, multimorbidity, and frailty. Atrial fibrillation (AF) is a common and frequently undiagnosed arrhythmia in the elderly and is associated with severe mortality, morbidity, and healthcare costs. Timely identification prevents associated complications through evidence-based treatment. This study is aimed at assessing the feasibility of AF screening using new digital health technology in older people in a homecare setting.
METHODS
Users of homecare services ≥ 65 years old with at least one additional risk factor for stroke in two Norwegian municipalities were assessed for study participation by nurses. Participants performed a continuous prolonged ECG recording using a patch ECG device (ECG247 Smart Heart Sensor).
RESULTS
A total of 144 individuals were assessed for study participation, but only 18 (13%) were included. The main reasons for noninclusion were known AF and/or anticoagulation therapy (25%), severe cognitive impairment (26%), and lack of willingness to participate (36%). The mean age of participants performing the ECG test was 81 (SD ± 7) years, and 9 (50%) were women. All ECG tests were interpretable; the mean ECG monitoring time was 104 hours (IQR 34-338 hours). AF was detected in one individual (6%).
CONCLUSION
This feasibility study highlights the challenges of enrolling older people receiving homecare services in clinical trials. However, all included participants performed an interpretable and prolonged continuous ECG recording with a digital ECG patch device. This trial is registered with NCT04700865.
PubMed: 38567031
DOI: 10.1155/2024/4080415 -
Molecular Autism Apr 2024Glutamatergic synapse dysfunction is believed to underlie the development of Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) in many individuals....
BACKGROUND
Glutamatergic synapse dysfunction is believed to underlie the development of Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) in many individuals. However, identification of genetic markers that contribute to synaptic dysfunction in these individuals is notoriously difficult. Based on genomic analysis, structural modeling, and functional data, we recently established the involvement of the TRIO-RAC1 pathway in ASD and ID. Furthermore, we identified a pathological de novo missense mutation hotspot in TRIO's GEF1 domain. ASD/ID-related missense mutations within this domain compromise glutamatergic synapse function and likely contribute to the development of ASD/ID. The number of ASD/ID cases with mutations identified within TRIO's GEF1 domain is increasing. However, tools for accurately predicting whether such mutations are detrimental to protein function are lacking.
METHODS
Here we deployed advanced protein structural modeling techniques to predict potential de novo pathogenic and benign mutations within TRIO's GEF1 domain. Mutant TRIO-9 constructs were generated and expressed in CA1 pyramidal neurons of organotypic cultured hippocampal slices. AMPA receptor-mediated postsynaptic currents were examined in these neurons using dual whole-cell patch clamp electrophysiology. We also validated these findings using orthogonal co-immunoprecipitation and fluorescence lifetime imaging (FLIM-FRET) experiments to assay TRIO mutant overexpression effects on TRIO-RAC1 binding and on RAC1 activity in HEK293/T cells.
RESULTS
Missense mutations in TRIO's GEF1 domain that were predicted to disrupt TRIO-RAC1 binding or stability were tested experimentally and found to greatly impair TRIO-9's influence on glutamatergic synapse function. In contrast, missense mutations in TRIO's GEF1 domain that were predicted to have minimal effect on TRIO-RAC1 binding or stability did not impair TRIO-9's influence on glutamatergic synapse function in our experimental assays. In orthogonal assays, we find most of the mutations predicted to disrupt binding display loss of function but mutants predicted to disrupt stability do not reflect our results from neuronal electrophysiological data.
LIMITATIONS
We present a method to predict missense mutations in TRIO's GEF1 domain that may compromise TRIO function and test for effects in a limited number of assays. Possible limitations arising from the model systems employed here can be addressed in future studies. Our method does not provide evidence for whether these mutations confer ASD/ID risk or the likelihood that such mutations will result in the development of ASD/ID.
CONCLUSIONS
Here we show that a combination of structure-based computational predictions and experimental validation can be employed to reliably predict whether missense mutations in the human TRIO gene impede TRIO protein function and compromise TRIO's role in glutamatergic synapse regulation. With the growing accessibility of genome sequencing, the use of such tools in the accurate identification of pathological mutations will be instrumental in diagnostics of ASD/ID.
Topics: Humans; Autism Spectrum Disorder; HEK293 Cells; Intellectual Disability; Mutation; Mutation, Missense; Neurons
PubMed: 38566250
DOI: 10.1186/s13229-024-00590-9 -
Scientific Reports Mar 2024The consumption of water constitutes the physical health of most of the living species and hence management of its purity and quality is extremely essential as...
The consumption of water constitutes the physical health of most of the living species and hence management of its purity and quality is extremely essential as contaminated water has to potential to create adverse health and environmental consequences. This creates the dire necessity to measure, control and monitor the quality of water. The primary contaminant present in water is Total Dissolved Solids (TDS), which is hard to filter out. There are various substances apart from mere solids such as potassium, sodium, chlorides, lead, nitrate, cadmium, arsenic and other pollutants. The proposed work aims to provide the automation of water quality estimation through Artificial Intelligence and uses Explainable Artificial Intelligence (XAI) for the explanation of the most significant parameters contributing towards the potability of water and the estimation of the impurities. XAI has the transparency and justifiability as a white-box model since the Machine Learning (ML) model is black-box and unable to describe the reasoning behind the ML classification. The proposed work uses various ML models such as Logistic Regression, Support Vector Machine (SVM), Gaussian Naive Bayes, Decision Tree (DT) and Random Forest (RF) to classify whether the water is drinkable. The various representations of XAI such as force plot, test patch, summary plot, dependency plot and decision plot generated in SHAPELY explainer explain the significant features, prediction score, feature importance and justification behind the water quality estimation. The RF classifier is selected for the explanation and yields optimum Accuracy and F1-Score of 0.9999, with Precision and Re-call of 0.9997 and 0.998 respectively. Thus, the work is an exploratory analysis of the estimation and management of water quality with indicators associated with their significance. This work is an emerging research at present with a vision of addressing the water quality for the future as well.
PubMed: 38553492
DOI: 10.1038/s41598-024-56775-y -
Acta Dermato-venereologica Mar 2024Allergic contact dermatitis is reported among individuals using continuous glucose monitoring systems and insulin pumps. The aim of this study was to describe contact...
Contact Allergy to Allergens in the Swedish Baseline Series Overrepresented in Diabetes Patients with Skin Reactions to Medical Devices - A Retrospective Study from Southern Sweden.
Allergic contact dermatitis is reported among individuals using continuous glucose monitoring systems and insulin pumps. The aim of this study was to describe contact allergy patterns for allergens in the Swedish baseline series and medical device-related allergens among users. Contact allergy to baseline series allergens and isobornyl acrylate was compared between diabetes patients and dermatitis patients patch-tested at the Department of Occupational and Environmental Dermatology during 2017 to 2020. Fifty- four diabetes patients and 2,567 dermatitis patients were included. The prevalence of contact allergy to fragrance mix II and sesquiterpene lactone mix was significantly higher in diabetes patients compared with dermatitis patients. Of the diabetes patients 13.0% and of the dermatitis patients 0.5% tested positive to sesquiterpene lactone mix (p < 0.001). Of the diabetes patients 7.4% and of the dermatitis patients 2.3% tested positive to fragrance mix II (p = 0.041). Of the diabetes patients 70.4% tested positive to medical device-related allergens. Of the diabetes patients 63.0% and of the dermatitis patients 0.2% were allergic to isobornyl acrylate (p < 0.001). In conclusion, not only medical device-related contact allergies, but also contact allergy to baseline series allergens (fragrance mix II and sesquiterpene lactone mix), is overrepresented in diabetes patients who use medical devices.
Topics: Humans; Allergens; Retrospective Studies; Sweden; Blood Glucose Self-Monitoring; Blood Glucose; Dermatitis, Allergic Contact; Diabetes Mellitus; Patch Tests; Lactones; Sesquiterpenes; Acrylates; Camphanes
PubMed: 38551376
DOI: 10.2340/actadv.v104.19676