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Pulsatile Perfusion Therapy at 0.1 Hz Protects Cerebral Blood Flow and Tissue Oxygenation in Humans During Simulated Hemorrhage
No full textBackground: Pulsatile Perfusion Therapy (PPT) is a method we have developed to induce hemodynamic oscillations at 0.1 Hz (10-s cycle), which are associated with protection of tissue oxygenation during conditions of reduced tissue perfusion. We previously demonstrated that PPT, via oscillatory lower body negative pressure (LBNP), protected cerebral tissue oxygenation (ScO₂) without affecting middle cerebral artery blood velocity (MCAv) responses during simulated hemorrhage in humans (via LBNP), leading to increased tolerance to LBNP. We have since developed a new approach to administer PPT via rapid inflatable thigh cuffs to achieve similar 0.1 Hz hemodynamic oscillations. We hypothesized that PPT induced via thigh cuffs would also protect ScO₂ without affecting cerebral blood flow during simulated hemorrhage in humans, subsequently leading to increased tolerance to this stress. Methods: 15 young and healthy participants (9M/6F; aged 25.8 ± 4.4 y) completed two experimental protocols in which they underwent −60 mmHg LBNP for up to 10-min. In the PPT condition, 0.1 Hz hemodynamic oscillations were induced by intermittently inflating and deflating bilateral thigh cuffs (0–230 mmHg) in 10-s cycles for the duration of the LBNP protocol. In the control condition (CON), thigh cuffs were in place but remained inactive throughout the entire protocol. The order of PPT and CON were randomized. Beat-to-beat arterial pressure was measured via finger photoplethysmography. Cerebral blood flow was indexed by internal carotid artery (ICA) blood flow (via duplex Doppler ultrasound) and by MCAv (via transcranial Doppler ultrasound). ScO₂ was measured via near-infrared spectroscopy. Fast Fourier transform analysis was used to assess the amplitude of 0.1 Hz oscillations in mean arterial pressure (MAP) and MCAv. Results: PPT induced greater 0.1 Hz oscillations in MAP (PPT: 69.9 ± 109.1 fold vs. CON: 3.9 ± 6.0 fold from baseline; P = 0.03) and MCAv (PPT: 21.2 ± 21.6 fold vs. CON: 3.6 ± 3.5 fold from baseline; P = 0.02) compared to CON. PPT attenuated reductions in ICA blood flow compared to CON (PPT: −17.5 ± 13.0% vs. CON: −29.8 ± 17.2% from baseline; P = 0.03), but did not affect MCAv responses (PPT: −18.3 ± 8.3% vs. CON: −18.8 ± 11.6% from baseline; P = 0.90). PPT also attenuated reductions in ScO₂ compared to CON (PPT: −5.2 ± 3.2% vs. CON: −7.3 ± 3.2% from baseline; P = 0.05), and increased tolerance to LBNP (PPT: 851.9 ± 84.0 seconds vs. CON: 788.4 ± 135.7 seconds; P = 0.04). Conclusions: PPT via thigh cuffs protected cerebral blood flow (indexed by ICA blood flow, but not MCAv) and cerebral tissue oxygenation in humans during simulated hemorrhage, and increased tolerance to this stress. These data add further evidence for the potential use of 0.1 Hz hemodynamic oscillations as a therapeutic intervention for the treatment of hemorrhage, and other conditions of cerebral hypoperfusion
Optimization of Adipogenic Differentiation Medium for Use with Obese Breast Adipose Tissue-Derived Mesenchymal Stem Cells
No full textPurpose: Due to their regenerative capacity and multipotent nature, mesenchymal stem cells (MSCs) continue to gain interest as therapeutic tools in regenerative medicine. Initially, MSCs were extracted from bone marrow, but it was later discovered they could be isolated from various sources throughout the body. Adipose-derived mesenchymal stem cells (ASCs) have gained popularity due to their abundance and ease of harvest. However, studies have revealed depot-specific differences, making it essential to characterize ASCs according to established criteria. ASCs isolated from breast adipose tissue have been shown to have impaired differentiation abilities compared to ASCs harvested from other subcutaneous sites, such as the abdomen. Regardless, confirmation of adipogenic differentiation is necessary not only to confirm ASC identity for scientific integrity and reproducibility purposes but also for translation into clinical practice. Methods: ASCs from breast adipose tissue of women living with obesity (ob-brASCs) were cultured to passages 3 for adipogenic differentiation experiments. Ob-brASCs were seeded in 12-well culture plates, and adipogenic differentiation mediums with varying concentrations of dexamethasone (0.25 µM, 0.5 µM, 0.75 µM, 1 µM, and 1.5 µM), insulin (0 µg, 100 µg, 250 µg, 500 µg, and 1 mg), or dexamethasone and insulin (0.25 µM with 100 µg, 0.5 µM with 100 µg, 0.75 µM with 250 µg, and 1.0 µM with 500 µg, respectively) were prepared. At 80% confluence, ob-brASCs were treated with one of the prepared mediums which was replaced every 3 to 4 days for 21 days. Cells were then washed with PBS, fixed with 4% PFA, and stained with Oil Red O before being rinsed with deionized water until no more stain lifted off. Plates were imaged and allowed to dry overnight. Isopropanol was used to de-stain the cells and the absorbances were quantified at 584 nm. The absorbances of the differentiated cells were then analyzed relative to the undifferentiated control. Results: The adipogenic differentiation ability of ob-brASCs increased with greater concentrations of dexamethasone, peaking at 0.75 µM, and drastically decreased at 1.5 µM. When treated with 0.75 µM of dexamethasone, there was a 31-fold increase and a 5.8-fold increase in differentiation compared to the original and new in-house media. While cells could still differentiate without insulin supplementation, better results were observed with increasing concentrations of insulin up to 250 µg; using 500 µg of insulin resulted in the same amount of differentiation as seen using 100 µg of insulin. When optimal concentrations of dexamethasone and insulin were used together, differentiation decreased. Conclusion: Increasing the dexamethasone concentration alone increases ob-brASCs adipogenic capacity the most. Supplementation with insulin increased the differentiation capacity of ob-brASCs, but there was no significant difference among the varying concentrations. Although individually, 0.75 µM of dexamethasone and 250 µg of insulin enhance differentiation capacity the most, there appears to be an antagonistic interaction between the two when increased together. Additional studies using more cell lines are necessary to confirm these findings
Long Covid is Associated with Excess Healthcare Expenditures among Adults in the United States
No full textPoster Highlight: HSC College of Pharmacy, RAD 2025 Award Winning Posters & Oral PresentationsLong Covid is Associated with Excess Healthcare Expenditures among Adults in the US Hailie Fellers, Rolake Neba, Sraddha Pedaprolu, Usha Sambamoorthi Background: Long COVID is defined as a chronic health condition that has persisted three months after the initial COVID-19 diagnosis. Long COVID has various implications across the entire body and symptoms can include weakness, fatigue, brain fog, dyspnea, chest pain, and other prolonged symptoms. Individuals experiencing long COVID incur significantly higher healthcare costs compared to patients without a history of COVID-19. Further research is required for a comprehensive understanding of the economic burden associated with Long COVID. Objective: This study estimated the excess expenditures—total, payer with Long COVID among adults in the US. Methods: A cross-sectional analysis was conducted on adults aged over 18 years with long COVID (N =17,119 , representing approximately 254 million adults) using data from 2021 of the Medical Expenditure Panel Survey. Economic burden was assessed by examining total and payer healthcare expenditures. Unadjusted group differences in expenditures were evaluated using t-statistics, and Generalized Linear Models with gamma distribution and log link were utilized to estimate excess expenditures associated with long COVID use after adjusting for age, sex, race and ethnicity, social determinants of health: education, employment, health, insurance, prescription drug coverage, poverty status, and region coverage, and number of chronic conditions: obesity, physical activity, and smoking. Results: Overall, 7.0% of the population reported Long COVID. Adults with long COVID exhibited higher total costs (10,078 vs 6,291.78 and $4,939.40 for total and payer expenditures, respectively. Conclusion: Adults with long COVID had significantly higher total healthcare costs compared to those without COVID. For payers, the results highlight the need to invest in early intervention programs, and integrated care models, to potentially reduce long-term costs. Policymakers should consider expanding insurance coverage for chronic conditions associated with long COVID, as these high expenditures could exacerbate financial strain and limit access to necessary care
C/EBP Homologous Protein Expression in Retinal Ganglion Cells Induces Neurodegeneration in Mice
No full textThe progressive loss of retinal ganglion cell (RGC) axons leading to irreversible loss of vision is the pathological hallmark of glaucoma. However, the pathological mechanisms of RGC degeneration are not completely understood. Here, we investigated the role of chronic endoplasmic reticulum (ER) stress in glaucomatous neurodegeneration. To evaluate whether chronic ER stress-induced transcriptional factors, activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) are induced in RGCs; we utilized human donor tissue and the microbead occlusion model of glaucoma. Additionally, we performed the intravitreal injection of adeno-associated virus (AAV) 2 to express CHOP selectively in RGCs in C57BL/6 mice and evaluated its effect on RGC function and structure by pattern electroretinogram (PERG) and whole-mount retina staining with the RBPMS antibody. Here, we report that the ATF4-CHOP pathway is activated in the retinas of human glaucoma donor eyes and a mouse model of ocular hypertension. Further, the expression of CHOP in RGCs led to a significant loss of function, as evidenced by reduced PERG. Notably, the expression of CHOP in the retina induced a significant structural loss of RGCs within 15 weeks of injection. Altogether, our studies indicate that the expression of CHOP in RGCs leads to neurodegeneration in mice.These studies were supported by the National Institutes of Health (EY034333, EY026177, EY028616, and T32 AG020494). The authors acknowledge support from NIH grant EY034238 and an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute at the University of California, Irvine
Characterization of plasma AT(N) biomarkers among a racial and ethnically diverse community-based cohort: an HABS-HD study
Get PDFINTRODUCTION: Alzheimer's disease (AD) biomarkers of Amyloid(A), Tau(T), and Neurodegeneration(N) have been increasingly studied to fill the gap in our understanding of racial and ethnic differences. This study aimed to examine the relationship between plasma AT(N) biomarkers and (1) AT(N) neuroimaging biomarkers, (2) demographics, (3) medical comorbidities, and (4) cognitive diagnosis. METHODS: Data were analyzed from n = 764 non-Hispanic Black (NHB), n = 1230 Hispanic, and n = 1232 non-Hispanic White (NHW) participants. Plasma AT(N) biomarkers were derived using single molecule array (SIMOA) technology on an HD-X imager and included amyloid beta (Abeta)42/40, total tau, ptau181, and neurofilament light chain (NfL). Clinical reads of positron emission tomography (PET) amyloid and tau positivity were used to examine the link between AT(N) plasma and neuroimaging biomarkers. Generalized linear models were conducted to examine the relationship between plasma AT(N) biomarkers and select demographic, diagnostic, and medical comorbidities (hypertension, diabetes, dyslipidemia, chronic kidney disease). RESULTS: Differences in the AT(N) biomarkers were found across racial/ethnic groups. Plasma Abeta42/40 was found to be associated with PET amyloid positivity only among NHW participants, while plasma NfL was found to correlate with Meta-ROI among NHB and Hispanic participants. Ptau181 was associated with PET amyloid positivity among NHB and NHW participants and well as PET tau positivity among the latter group and Hispanic participants. Diabetes was related to increased plasma AT(N) biomarkers among NHB and Hispanic participants. CKD was associated with increased AT(N) biomarkers for all race/ethnic groups with the exception of Abeta42/40. While Abeta42/40, total tau, ptau181, and NfL were found to be related to a dementia diagnosis among NHW participants, only ptau181 and NfL were found to be related to this same diagnostic category among NHB and Hispanic participants. DISCUSSION: Our findings indicate differential relationships between comorbidities (demographic, medical, diagnostic) across NHB, Hispanic, and NHW participants. This work expands our knowledge regarding the associations of plasma biomarkers to AD pathology in diverse populations. HIGHLIGHTS: Differences in AT(N) plasma biomarkers were found in a diverse community cohort.While plasma Abeta42/40 was associated with PET amyloid positivity among non-Hispanic white participants, this did not apply to non-Hispanic Black or Hispanic participants.Medical comorbidity of diabetes and chronic kidney disease was related to increased plasma AT(N) biomarkers among the ethnically diverse segment of the cohort.Plasma AT(N) biomarkers were more so related to a diagnosis of dementia for non-Hispanic white as compared to Hispanic or non-Hispanic Black participants.Across racial/ethnic groups, the plasma biomarkers of neurodegeneration (NfL) and ptau181 were related to a diagnosis of dementia.National Institute on Aging; National Institutesof Health, Grant/Award Numbers:R01AG054073, R01AG058533,P41EB015922, U19AG07810
Using posterior probability informed thresholds to develop best practice recommendations for MorphoPASSE using the innominate, cranial, and combined traits
No full textMorphoPASSE is a free program that estimates sex based on morphological traits of the innominate, cranium, or a combined set of traits; however, MorphoPASSE does not provide recommendations on which set of traits performs best or recommend a posterior probability (PP) threshold for sex classification in modern forensic casework. The goals of this study were to compare accuracy rates when using different sets of traits and when imposing posterior probability informed thresholds (PPITs). Innominate and cranial trait score data were collected from four modern US documented skeletal collections (n = 285). Accuracy rates for five mutually exclusive PP intervals were calculated, and PP intervals that were significantly different from chance were condensed into PPITs. Using a PPIT of 0.85-1.00 produced high accuracy rates of 97.3% for the innominate traits and 90.2% for the cranial traits. Using the combined set of innominate and cranial traits resulted in significantly higher accuracy (99.6%) with a lower PPIT of 0.75-1.00. Additionally, the combined trait model corrected all previous misclassifications by either producing a correct sex classification or leaving the individual unclassified for failing to reach the required PPIT. Therefore, when both elements are available, the combined set of traits is recommended with a 0.75-1.00 PPIT. Individuals with a PP falling between 0.75 and 1.00 should be reported as consistent with the male or female reference samples, while those falling below should be reported as could not be estimated." Use of these recommendations will help standardize the use of MorphoPASSE and reporting sex estimation results."This research was funded by the National Science FoundationGrant No. 2214747 (co-funded by the National Institute of JusticeDOJ- NIJ-22-RO- 0007)
Biomarkers and Mechanisms of Cardiovascular Susceptibility and Resilience to Post-Traumatic Stress Disorder
No full textPost-traumatic stress disorder (PTSD), which develops in susceptible individuals after life-threatening or traumatizing events, manifests as a heightened anxiety and startle reflex, disordered sleep, nightmares, flashbacks, and avoidance of triggers. Moreover, PTSD is a predictor and independent risk factor of numerous cardiovascular comorbidities, including stroke, myocardial infarction, coronary atherosclerosis, and atrial fibrillation. Compounding the direct detrimental effects of PTSD on the cardiovascular system, this condition provokes classical cardiovascular risk factors, including high cholesterol and triglycerides, platelet hyperaggregation, endothelial dysfunction, hypertension, and sympathetic hyperactivation. Although most people who have experienced traumatic events do not develop PTSD and are considered PTSD resilient, a substantial minority experience persistent cardiovascular comorbidities. Experimental and clinical studies have revealed a myriad of biomarkers and/or mediators of PTSD susceptibility and resilience, including pro- and anti-inflammatory cytokines, oxidized proteins and lipids, antioxidants, troponin, catecholamines and their metabolites, glucocorticoids, and pro-coagulation factors. The use of biomarkers to predict cardiovascular susceptibility or resilience to PTSD may stratify the risk of a patient developing cardiovascular complications following severe stress. Indeed, since many PTSD biomarkers either inflict or attenuate cardiovascular damage, these biomarkers can be applied to monitor the efficacy of exercise, dietary modifications, and other interventions to enhance cardiovascular resilience and, thereby, restrict the detrimental effects of PTSD on the cardiovascular system. Biomarker-informed therapy is a promising strategy to minimize the risk and impact of cardiovascular diseases in individuals with PTSD.State Assignment of the Institute of General Pathology and Pathophysiology # FGFU U-2025-0007; State Assignment of the Avtsyn Research Institute of Human Morphology # 124021600054-9; Russian Scientific Foundation, Chelyabinsk 914 Region (#23-15-20040)
Neandertal Cold Adaptation: Technological, Anatomical, and Physiological Responses to Cold Stress in One of Our Closest Fossil Relatives
No full textNeandertals occupied western Eurasia for over 100 000 years, repeatedly enduring climates that ranged from seasonally cold to glacial. This paper reexamines the question of Neandertal cold adaptation using updated fossil, physiological, and archaeological evidence. While some populations lived outside glacial extremes, all faced periodic cold stress, and their survival depended on a diverse set of strategies. Technological buffers, including fire use, hide processing tools, and possible clothing and footwear, likely played a primary role in reducing cold exposure. Anatomically, Neandertals exhibit high body mass, broad trunks, and abbreviated limbs, consistent with thermoregulatory principles. The Neandertal nasal region, long considered paradoxical, now appears well suited to cold-dry air-conditioning; computational fluid dynamics and new endoscopic data support a functionally integrated nasal cavity with substantial internal surface area. Physiological adaptations remain inferential but plausible, including elevated basal metabolism, energy-dense diets, and potential use of brown adipose tissue. These factors likely contributed to high total energy expenditures, enabling thermoregulation in demanding environments. Rather than a single trait or signature" adaptation, Neandertals present an integrated response to cold stress shaped by geography, development, culture, and genetics. This holistic view reframes Neandertal biology as deeply thermally engaged and sets the stage for targeted tests of function and mechanism in future research."The authors received no specific funding for this work
Recruitment Strategies To Enhance Diversity In Cancer Clinical Research In The Dallas Fort Worth Metropolitan Area
Get PDFPotential Therapeutic Effects of Chitin Analog AVR-48 on Cytokines and CD163-Positive Macrophages in Human Cord Blood Mononuclear Cells Implicated in Bronchopulmonary Dysplasia (BPD)
No full textPurpose: Bronchopulmonary dysplasia (BPD) is a neonatal condition that affects the proper development of the lungs of preterm infants born at <28 weeks of gestation or with a birth weight <1000g. It remains one of the most prevalent causes of morbidity and mortality in prematurely born infants. BPD is characterized by abnormal alveolarization and microvascular organization of the lungs as a result of exogenous oxygen exposure, leading to a cascade of inflammation mediated by cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin(IL)-1β. Current treatments for BPD remain elusive. AVR-48, a novel chitin analog, has exhibited immunomodulatory effects through its actions on toll-like receptor (TLR) 4 in hyperoxia- and lipopolysaccharide (LPS)-induced injury in adult and neonatal mouse models. We investigated the efficacy of AVR-48 in reducing soluble CD163 (sCD163), a hemoglobin-haptoglobin scavenger receptor and pro-inflammatory biomarker highly expressed in M2 macrophages of human cord blood mononuclear cells (CBMC). Methods: For the human soluble CD163 sandwich ELISA assay, a 96-well microplate was plated with 61 samples containing CBMC supernatants, treated with various combinations of AVR-48 (100 µM) and other molecules such as LPS (50 ng/ml), TLR4 antagonist TAK-242, and CD163 antibody RM3/1. CBMCs were chosen as they provide the most accurate representation of the neonatal immune system condition, making them an ideal model for studying neonatal inflammatory processes. Each condition was performed in triplicate to ensure accuracy and reproducibility. The microplate was incubated for a period of 72 hours before subsequent washing and addition of CD163 biotinylated antibody, HRP-conjugated streptavidin, and TMB substrate. Stop solution was added to the microplate after the TMB incubation for 30 minutes, allowing for a gross color change in the wells from blue to yellow. Absorbance was measured at 450 nm to determine mean values. The same ELISA protocol was repeated for TNF-α and IL-1β. Readings were averaged across triplicates and analyzed using a one-way ANOVA. Results: AVR-48 and LPS+AVR-48 treatment significantly decreased TNF-α and IL-1β (pg/ml) in CBMC samples. sCD163 shedding (pg/ml) was reduced in the samples containing LPS+AVR-48 compared to LPS-treated cells, a similar reduction observed in LPS+RM3/1-treated cells. Cells treated with TAK-242 showed a reduction in sCD163 as well. A further reduction in sCD163 levels was noted in cells treated with AVR-48+TAK-242, which warrants further investigation. Conclusion: Our study demonstrates the therapeutic potential and immunomodulatory capacity of AVR-48 in counteracting the storm of inflammatory cytokines that predominate in BPD. AVR-48 also reduced the shedding of soluble CD163 scavenger receptors by specific macrophage populations. This suggests that AVR-48 could have beneficial effects on the downstream inflammatory cascades induced by lung injury and oxidative stress from excessive hemoglobin release. Thus, AVR-48 emerges as a promising candidate for BPD management