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ADAM17 Supports Disinhibition of Pre-sympathetic Glutamatergic Neurons Through Microglial Chemotaxis
No full textA disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound enzyme that cleaves cell-surface proteins. Here, we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub, located in the paraventricular nucleus of the hypothalamus (PVN), upon stimulation by angiotensin II (Ang-II). For Ang-II-induced disinhibition, targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons. Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17. Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II’s pressor response. Using conditional and targeted knockout models of ADAM17, an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension. Collectively, this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation
Prior adolescent oxycodone exposure enhances pain sensitivity following chronic intermittent ethanol in adult female mice
Get PDFThe opioid crisis remains a critical public health concern, with rising rates of overdose and opioid use disorder. While opioids are effective for managing pain, both chronic use and withdrawal are associated with increased pain sensitivity. Although most prior research has focused on adults, opioid use during adolescence is common and linked to a heightened risk for developing alcohol use disorder and other forms of substance misuse. Like opioids, acute alcohol use can be analgesic, but chronic alcohol exposure and withdrawal lead to increased pain sensitivity. However, the interactive effects of adolescent opioid and adult alcohol exposure on pain remain poorly understood. In this study, we investigated whether adolescent oxycodone exposure (AOE) alters the development of mechanical and thermal sensitivity following adult chronic intermittent ethanol (CIE) vapor exposure in male and female mice. AOE alone induced transient mechanical but not thermal hypersensitivity in both sexes, which resolved within six days of cessation. In adulthood, CIE exposure induced mechanical and thermal hypersensitivity in both sexes. Importantly, a prior history of AOE prolonged CIE-induced hypersensitivity in female, but not male mice. Additionally, females with combined AOE and CIE exposure exhibited enhanced hypersensitivity in the Randall–Selitto test compared to all other groups. These findings demonstrate that AOE increases vulnerability to pain-related effects of adult CIE exposure in females. This work highlights the importance of studying poly-drug interactions across developmental windows and underscores the need to include both sexes in preclinical models of pain and substance use
Integrated Systems Biology Identifies Disruptions in Mitochondrial Function and Metabolism as Key Contributors to HFpEF
Get PDFHeart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases. The ZSF1-obese rat model recapitulates clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and diastolic dysfunction. We utilized a systems-biology approach to define the metabolic and transcriptional signatures to gain mechanistic insight into pathways contributing to HFpEF development. Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14 weeks of age for extensive physiological phenotyping and left ventricle (LV) tissue harvesting for unbiased-metabolomics, RNA-sequencing, and mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes driving HFpEF pathology, versus hypertension + metabolic syndrome. Comparison of ZSF1-lean vs WKY (ie, hypertension-exclusive effects) revealed metabolic remodeling suggesting increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of most catabolic energy producing pathways, manifesting in a marked decrease in the energetic state (ie, reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Impaired mitochondrial function was demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling. Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential interventional target
Evaluation of the combination lenvatinib and pembrolizumab in endometrial cancer; a real world multi-institutional review of practice patterns, efficacy and tolerability
No full textObjective: KEYNOTE-775 defined lenvatinib/pembrolizumab as the new standard-of-care for patients with proficient mismatch repair (pMMR) recurrent EC. However, the regimen required dose reductions in 66.5 % of participants and the generalizability of these results was uncertain. We conducted an observational study to determine the prescribing patterns, outcomes and side effects in a real-world setting. Methods: A national multidisciplinary consortium was utilized to study treatment patterns of patients with advanced/recurrent EC treated with lenvatinib/pembrolizumab from 2019 through 2022. Treatment decisions were based on the physician\u27s recommendation. Results: 188 patients across 14 institutions were included. Histologic subtypes were 33 % endometrioid, 41 % serous, 9.6 % mixed, 10.1 % carcinosarcoma, and 2.1 % clear cell. 85.6 % were pMMR and 5.3 % were dMMR. Lenvatinib starting dose was 20 mg in 19.7 %, 18 mg in 14.9 %, 14 mg in 47.3 %, and 10 mg in 18.1 %. Median dose intensity of lenvatinib was 14 mg. Pembrolizumab dosing was 200 mg Q3W in 94.1 %. Grade ≥ 3 adverse events (AE) rates related to lenvatinib were similar across starting doses: 20 mg (13.5 %), 18 mg (17.9 %), 14 mg (7.9 %), 10 mg (17.6 %) (p = 0.31). Response rates in relation to lenvatinib starting dose were 20 mg (27 %), 18 mg (35.7 %), 14 mg (39.3 %), 10 mg (44.1 %) (p = 0.50). In relation to lenvatinib starting dose, PFS, OS and duration of therapy were not statistically different. Response rates (p = 0.24), PFS (p = 0.66) & OS (p = 0.22) were similar in White and Black patients. Conclusions: In a real-world analysis, the predominant starting dose was 14 mg lenvatinib and 200 mg pembrolizumab. Starting at varying doses does not appear to compromise response rates or survival and no new severe adverse events emerged
Handbook of Behavioral Neuroscience
No full textWe summarize the basic insights that mathematical and computational modeling has provided so far into how the intrinsic properties of midbrain dopamine neurons might contribute to their electrical activity in vivo, particularly with respect to the integration of their synaptic inputs. We emphasize modeling subpopulations with different responses to noise, depolarization, and hyperpolarization. Topics include conductance-based single-compartment models with Hodgkin-Huxley-type equivalent circuits and mass balances, bifurcation theory and fast/slow analyses, pacemaking, degeneracy, bursting, dynamic clamp, Markov models of ion channels, linking electrical and metabolic activity, synaptic integration in the balanced state in vivo, and multicompartmental models with spatially extended morphologies
Evaluation of the user experience for a point of care molecular test for causes of vaginitis
Get PDFBackground: Vaginitis is a major cause of healthcare visits in the US, costing over $1.2 billion annually. Point-of-care (POC) nucleic acid amplification tests (NAATs) could improve accuracy of diagnosis and treatment during initial visit for vaginitis compared to send-out NAATs. Methods: A secondary analysis of data was collected from test operators at POC testing sites where the Xpert Xpress Multiplex Vaginal Panel test (“MVP test”) was performed. Users completed a survey assessing their experience with the instrument system and the PCR-based MVP test. Results: The MVP test demonstrated consistent performance, measured by positive and negative percent agreement, across all user categories, including both trained and untrained staff. Performance was evaluated based on job function (clinicians, non-clinicians, support staff) and educational level (bachelor’s degree or higher, associate’s degree or some college, high school diploma/general educational development (GED) with technical certification), with no significant differences in performance (P \u3e 0.082 and P \u3e 0.050, respectively). User feedback from 19 operators showed that 15/19 (79%) of users found the GeneXpert Xpress Instrument System easy to set up, and 18/19 (96%) found the test instructions easy to follow. Users described the system as user-friendly with clear instructions and helpful videos. Overall, 19/19 (100%) agreed that the MVP test was easy to perform. Conclusions: Availability of accurate POC diagnostics will only be useful if the test can be performed by any potential user. Our study results suggest that the MVP test was acceptable to users and that results were accurate regardless of user qualifications. Thus, this test has the potential to improve the immediate clinical outcome by supporting accurate, same day treatment for causes of vaginitis
Bioactive Supramolecular Polymers for Skin Regeneration Following Burn Injury
No full textSevere deep dermal burns present a significant challenge for the clinician, often resulting in complications including infection, scarring, and potentially multisystem organ failure. The current standard of care, which involves debridement and skin coverage, has improved survival rates but remains insufficient for optimal tissue regeneration and functional recovery. Additionally, there can be limited donor skin availability with severe burns, leading to the use of skin substitutes to be applied with varying degrees of success reported. Biomaterial scaffolds, designed to reduce the reliance on skin grafting, could promote improved healing and patient outcomes. Recent research has focused on promoting the proliferative phase of wound healing through the use of extracellular matrix (ECM) mimetic scaffolds; however, these constructs continue to exhibit critical limitations, including mechanical fragility, heightened infection susceptibility, limited morphological conformity to host tissue architecture, and the necessity for secondary surgical intervention for scaffold retrieval. This study presents a bioactive supramolecular polymer capable of rapid self-assembly into nanofibers, which act as a scaffold to promote tissue regeneration following burn injury. The scaffold is biocompatible, biodegradable, and capable of presenting a bioactive peptide designed to reduce acute inflammation and promote keratinocyte migration in the scaffold. The supramolecular polymers significantly accelerated early wound healing in a clinically relevant deep dermal murine burn injury model. This work provides a promising approach to the development of biomaterials that combine both therapeutic strategies, with scaffolding to promote skin regeneration following severe burn injury
Trauma Team Activation Criteria Effectiveness for the Management of Geriatric Patient Fall Injuries
No full textFalls are a leading cause of morbidity and mortality among the elderly, yet standardized trauma activation guidelines for this population remain lacking. This study analyzed trauma activation criteria for geriatric patients (\u3e65 years) at a level 1 trauma center, focusing on overtriage and undertriage rates. A retrospective review of 500 patients assessed activation levels, discharge outcomes, and ICU admissions. Overtriage, defined as discharge home post-activation, occurred in 18.5% of lower-level activations, compared to 3.7% in non-activations and 10.7% in higher activations. Undertriage, defined as ICU admission or mortality despite low or no activation, was observed in 29% of non-activated patients and 45.6% of lower-level activations. These findings highlight significant gaps in current triage practices, emphasizing the need for improved, standardized activation criteria to optimize resource allocation and outcomes for the growing geriatric trauma population
Case Report: Disseminated herpes simplex virus complicated by hemophagocytic lymphohistiocytosis in a neonate
Get PDFNeonatal herpes simplex virus (HSV) infection carries a high mortality rate due to its potential to cause disseminated disease involving multiple organ systems, which can rapidly progress to shock and death if not promptly treated. In rare cases, neonates may mount an uncontrolled inflammatory response leading to hemophagocytic lymphohistiocytosis (HLH), a severe hyperinflammatory syndrome. We present a case of neonatal HSV infection complicated by HLH, highlighting the challenges of managing both conditions concurrently. Our therapeutic approach demonstrated a reduction in systemic inflammation and viral load; however, despite these efforts, the patient developed multiorgan failure and ultimately died from the initial disease process. This case underscores the severity of neonatal HSV infection and emphasizes the critical role pediatricians play in early identification of transmission risk factors and prevention strategies
Genome sequence of Lacticaseibacillus paracasei G277-1.1, a clinical strain that forms enhanced biofilms with Streptococcus mutans
No full textLacticaseibacillus paracasei G277-1.1 was isolated from dental plaque of a patient with severe early childhood caries. It forms synergistic biofilms with Streptococcus mutans in vitro. Here, we report its high-quality genome sequence, revealing insights on its inter-species interaction with S. mutans