Decline In Function Research Articles

Higher socioeconomic deprivation in areas predicts cognitive decline in New Zealanders without cognitive impairment.

Previous studies identified individual-level socioeconomic factors as key determinants of cognitive health. This study investigated the effect of area-based socioeconomic deprivation on cognitive outcomes in midlife to early late-life New Zealanders without cognitive impairment at baseline. Data stemmed from a subsample of the New Zealand Health, Work and Retirement Study, a cohort study on ageing, who completed face-to-face interviews and were reassessed two years later. Cognitive functioning was measured using Addenbrooke's Cognitive Examination-Revised, adapted for culturally acceptable use in Aotearoa New Zealand. Area-based socioeconomic deprivation was assessed using the New Zealand Deprivation Index (NZDep2006). Linear mixed-effects models analysed the association between area-based socioeconomic deprivation and cognitive outcomes. The analysis included 783 participants without cognitive impairment at baseline (54.7% female, mean age 62.7 years, 25.0% Māori, the Indigenous people of Aotearoa New Zealand). There was an association between higher area-based socioeconomic deprivation and lower cognitive functioning (B = -0.08, 95%CI: -0.15;-0.01; p = .050) and cognitive decline (B = -0.12, 95%CI: -0.20;-0.04, p = .013) over two years, while controlling for covariates. The findings emphasise the importance of considering neighbourhood characteristics and broader socioeconomic factors in strategies aimed at mitigating cognitive health disparities and reducing the impact of dementia in disadvantaged communities.

Effect of JM-20 on Age-Related Cognitive Impairment in Mice.

The decline in cognitive function associated with aging significantly impacts the well-being of elderly individuals and their families. This decline is a major recognized risk factor for neurodegenerative diseases, notably Alzheimer's disease. Animal models of aging provide a platform for evaluating drugs concerning aspects like memory and oxidative stress. JM-20 has demonstrated protective effects on short-term memory acquisition and consolidation, along with antioxidant properties and modulation of Acetylcholinesterase activity. This study assesses the potential protective JM-20 against cognitive decline and age-related memory loss. For the study, aged mice exhibiting aging-associated damage were initially selected. Experimental groups were then formed, and the effect of 8mg/kg of JM-20 was evaluated for 40 days on aging-related behavior, such as spatial memory, novelty recognition memory, ambulatory activity, and anxiety. Subsequently, animals were sacrificed, and the hippocampal region was extracted for redox studies and to assess acetylcholinesterase activity. Results indicated that JM-20 at 8mg/kg reversed damage to spatial working and reference memory, exhibiting performance comparable to untreated young adult animals. Furthermore, JM-20 preserved the enzymatic activity of superoxide dismutase, catalase, and total sulfhydryl levels in age-related cognitive impairment in mice, indicating a potent protective effect against oxidative events at the brain level. However, only young, healthy animals showed decreased acetylcholinesterase enzyme activity. These findings provide preclinical pharmacological evidence supporting the neuroprotective activity of JM-20, positioning it as a promising therapeutic candidate for treating memory disorders associated with aging.

Tiliroside protects against diabetic nephropathy in streptozotocin-induced diabetes rats by attenuating oxidative stress and inflammation

BACKGROUND Diabetic nephropathy (DN), affecting half of diabetic patients and contributing significantly to end-stage kidney disease, poses a substantial medical challenge requiring dialysis or transplantation. The nuanced onset and clinical progression of kidney disease in diabetes involve consistent renal function decline and persistent albuminuria. AIM To investigate Tiliroside's (Til) protective effect against diabetic nephropathy (DN) in rats under diabetic conditions. METHODS Five groups of six rats each were included in this study: Rats treated with DMSO by intraperitoneal injection as controls, those treated with STZ by intraperitoneal injection, those treated with STZ + Til (25 mg/kg body weight [bwt]) or Til (50 mg/kg bwt), and those treated with anti-diabetic medication glibenclamide (600 μg/kg bwt). Biochemical markers, fasting blood glucose, food intake, kidney weight, antioxidant enzymes, inflammatory and fibrotic markers, and renal injury were monitored in different groups. Molecular docking analysis was performed to identify the interactions between Til and its targeted biomarkers. RESULTS Til significantly reduced biochemical markers, fasting blood glucose, food intake, and kidney weight and elevated antioxidant enzymes in diabetic rats. It also mitigated inflammatory and fibrotic markers, lessened renal injury, and displayed inhibitory potential against crucial markers associated with DN as demonstrated by molecular docking analysis. CONCLUSION These findings suggest Til's potential as a therapeutic agent for DN treatment, highlighting its promise for future drug development.

Prevalence, associated factors, and impact of vitamin B12 deficiency in older medical inpatients.

This retrospective cohort study aims to explore the prevalence of vitamin B12 deficiency in older hospitalized adults and identify key factors associated with this deficiency, as well as its impact on frailty and functional decline. Data were collected from older adults (≥65years) sequentially admitted to the Internal Medicine Department of a tertiary university hospital. Clinical and laboratory characteristics, including age, sex, somatometric data, cause of admission, past medical history, chronic medication use, and laboratory tests, were recorded. Frailty and functional status were assessed using the Fried Frailty Scale (FFS), Clinical Frailty Scale (CFS), Barthel Index, and Katz Index. Vitamin B12 levels on admission were categorised as deficient (<200pg/ml), borderline (200-300pg/ml), normal (300-999pg/ml), and high (≥1000pg/ml). A total of 894 patients were included. The median age was 83years and 487 (54.5%) were females. The prevalence of vitamin B12 deficiency was found in 9.1%, while 17.3% of the sample had borderline levels. Multivariate analysis identified polypharmacy (≥5 drugs), low albumin levels/Geriatric Nutritional Risk Index (GNRI), and nursing home residency as independent factors associated with low B12 levels. Multivariate analyses showed that B12 deficiency was significantly associated with higher frailty rates and lower functional status. Vitamin B12 deficiency is prevalent among hospitalized older patients and is significantly associated with increased frailty and reduced functional status. These findings underscore the importance of routine screening for B12 deficiency in this vulnerable population to improve clinical outcomes and quality of life.

Adolescents and young adults with sickle cell disease exhibit accelerated aging with elevated T-cell p16INK4a expression.

People living with sickle cell disease (SCD) experience complications indicative of an accelerated aging phenotype typified by early decline in physical function and increased risk for age-related conditions. Cellular senescence, measured by expression of p16INK4a in peripheral T-lymphocytes, is recognized as one of the underlying contributors to organismal aging. To examine if cellular senescence is increased in SCD patients, we cross-sectionally measured and compared expression of p16 mRNA in peripheral blood T lymphocytes in 18 adolescents and young adults with SCD to 27 similarly aged individuals without SCD. Expression of p16 was dramatically higher in individuals with SCD vs. without SCD (10.1 vs. 8.7 log2 p16 units, respectively, p < 0.001) - a gap of 43 years in biological age - consistent with accelerated aging in the SCD population. Race was not associated with the increased p16 expression in the SCD group. These initial results suggest that individuals with SCD have a significantly higher cellular senescence burden which may contribute to premature aging, physiological decline, and excess morbidities. Additional longitudinal assessment and consideration for trials of senolytic therapies among individuals living with SCD and high p16 expression are warranted to improve their health span.

Downregulation of miR-214 promotes dilated Cardiomyopathy Progression through PDE5A-Mediated cGMP regulation.

Dilated cardiomyopathy (DCM) is a myocardial disorder resulting in a substantial decline in cardiac function and potentially leading to heart failure. This research combines bioinformatics analysis with empirical validation to explore the roles and mechanisms of miR-214 in DCM. Using the DEseq2 R package, a total of 125 differentially expressed circulating miRNAs (DE c-miRNAs) and 784 DE genes (DEGs) were identified. Cross-analysis between target genes of DE c-miRNAs and DEGs identified 124 common genes, and protein-protein interaction analysis of common genes identified 11 hub genes. Twelve DE c-miRNAs were further verified by quantifying their levels in the serum of DCM patients and healthy individuals. miR-214 levels were significantly decreased in serum from DCM patients, positively correlated with left ventricular ejection fraction and left ventricular fractional shortening. Further analysis showed that miR-214 directly targets and negatively regulates phosphodiesterase 5A (PDE5A). Elevated PDE5A expression reduced cGMP levels; however, using sildenafil, a PDE5A inhibitor, reversed this effect, substantiating the regulatory mechanism of miR-214 on cGMP via PDE5A. These results provide new potential targets for the diagnosis and treatment of DCM.

Deranged cytokine levels are linked to cancer-related cognitive impairment in lymphoma patients receiving R-CHOP chemotherapy

Cancer-related cognitive impairment (CRCI) is a significant issue commonly observed following chemotherapy treatment. The study aimed to investigate the changes in cognitive function and their association with IL-6, IL-1β, and IL-10 levels before and after R-CHOP chemotherapy over six cycles. Seventy chemotherapy naïve, newly diagnosed lymphoma patients were enrolled. Cognitive functions and inflammatory cytokines were assessed at baseline (TP1), after 3rd cycle (TP2), and after 6th cycle (TP3). Patients, with mean age of 44.17 ± 13.67 years, showed significantly increased levels of IL-6 and IL-1β and decreased IL-10 levels over time (p < .001). On the Montreal Cognitive Assessment (MoCA), scores of domains such as executive functioning (p = .002), attention (p < .001), language (p < .001), recall (p = .005), and orientation (p < .001) significantly decreased post six cycles of R-CHOP chemotherapy. Correlation analysis at TP2 indicated a positive association between elevated IL-6 levels with a decrease in MoCA scores indicating a decline in cognitive function (ρ = 0.68, p < .001). At TP3, no association of MoCA scores with IL-6 and IL-1β was observed. Decreased IL-10 levels showed a weak association with decreased MoCA scores at TP2 and TP3 ( ρ = 0.2, p = .09; for TP3, ρ = 0.16, p = .17), but this was not significant. In summary, the findings of the present study highlight significant cognitive decline and changes in inflammatory cytokine levels following six cycles of R-CHOP. Objective cognitive assessments may be done to detect CRCI in patients treated with R-CHOP.

How do apathetic and depressive symptoms relate to functional capacity? A cross-sectional survey among community-dwelling middle-aged and older adults in Japan.

Apathetic and depressive symptoms are frequently observed among older adults, and are risk factors for functional decline and dementia progression. However, how these symptoms influence functional capacity remains unclear. This study investigated the relationship between apathetic and depressive symptoms and functional capacity, considering the interaction between apathetic and depressive symptoms. A cross-sectional questionnaire survey targeting community dwelling middle-aged or older adults was conducted. We sent a questionnaire to 984 individuals and received 320 responses. Data with missing values and participants aged under 50 were excluded, resulting in 212 participants (88 men and 124 women, mean age = 73.4 ± 9.3 years). Apathetic symptoms were evaluated using the Dimensional Apathy Scale (J-DAS), which comprises executive, emotional, and cognitive and behavioral initiation aspects of apathy. Depressive symptoms were evaluated using the Geriatric Depression Scale (GDS). Functional capacity was assessed using the Japan Science and Technology Agency Index of Competence, which comprises technology usage, information practice, life management, and social engagement. Mean score of each J-DAS factor and GDS was 5.3 ± 3.4 (executive), 12.0 ± 3.0 (emotional), 11.8 ± 5.1 (initiation), and 4.5 ± 3.3, respectively. The emotional and initiation aspects of J-DAS were significantly associated with information practice (β = -0.15, p < .05 for emotional; β = -0.27, p < .001 for initiation) and life management (β = -0.20, p < .01 for emotional; β = -0.22, p < .01 for initiation) in functional capacity. GDS was associated only with social engagement (β = -0.31, p < .001). Although the interaction between the initiation factor of J-DAS and GDS was significantly associated with life management (β = -0.16, p < .05), the R2 change was insignificant. The emotional factor of J-DAS was associated with technology usage (β = -0.13, p < .05), although less strongly than age. The executive factor of J-DAS had insignificant associations with all aspects of functional capacity. Apathetic and depressive symptoms are independently, rather than interactively, associated with different aspects of functional capacity. As older adults with apathetic or depressive symptoms might struggle to seek help from public health services, they should be targeted with active interventions from healthcare professionals.

Impact of arteriovenous fistula formation on trajectory of kidney function decline: a target trial emulation

Abstract Background Prior nonrandomised studies have suggested nephroprotective effects of arteriovenous fistula (AVF) formation, but these are plausibly susceptible to immortal time and selection biases. Methods We studied patients attending nephrology clinics in the West of Scotland during 2010-2022 with an eGFR ≤15mL/min/1.73m2 and no prior AVF. Using target trial emulation and a sequential trial design, we simulated a hypothetical trial that would randomise patients to either undergo AVF formation immediately or not to undergo AVF formation. The primary outcome was the difference in eGFR slope for the first six months of follow-up, estimated using a mixed-effects model. The secondary outcomes were 5-year absolute risks of dialysis and death, estimated using the Aalen-Johansen and Kaplan-Meier estimators respectively. Results 1,364 unique patients (mean age 51.1, 55.7% male) contributed 3,125 person-trials, with 561 in the AVF and 2,564 in the no AVF group. Mean eGFR was 12.6mL/min/1.73m2 and the median number of eGFR measurements per person-trial was 7 (IQR 4 – 12). Slope of eGFR decline did not differ significantly between the AVF and no AVF groups (between group difference -0.67mL/min/1.73m2/year, 95%CI -1.43, 0.10). The 5-year absolute risk of dialysis was 87% (95%CI 84, 91) in the AVF group and 75% (95%CI 73, 77) in the no AVF group and the 5-year survival probability was 77% (95%CI 70, 83) in the AVF group and 67% (95%CI 64, 69) in the no AVF group. Conclusions In this study of patients with advanced CKD, there was no evidence of a nephroprotective effect of AVF formation.

EGS SO19 - Outcome Analysis of Laparotomies in the Elderly Population in Devon: A Retrospective Cohort Study

Abstract Background Emergency laparotomy is understood to be high risk in the elderly, but there is limited long term outcome data. This study assesses long term outcomes in the elderly including: survival and functional outcomes. Method Patients, aged 80 and above, were identified from the prospective National Emergency Laparotomy Audit (NELA) database, who underwent surgery between: January 2020 and August 2023 at Torbay Hospital. Surviving patients were followed up. 132 cases were undertaken. Mean age was 85 years. Most common ASA was 3. Preoperative clinical frailty score was 6, and 89% were living at home without care. Results 50% of patients were admitted to intensive care. 17% were readmitted within 30 days of discharge. The most common reason for was fall. 20% of patients did not survive to discharge. 38% did not survive to August 2023. 46% of patients returned home independently; 5% had care at home; 26% were discharged to community hospital and 2% to care home. By January 2024 61% of survivors were living independently with no functional decline. Most commonly, patients needed support with bathing/stairs/dressing (37%). 11% of respondents were completely dependent. Conclusion Emergency laparotomy confers a significant mortality, morbidity and risk to an elderly patient’s long term functional status. We believe this information is essential for surgical decision making and the consent process.

EGS SO35 - Emergency laparotomies in the elderly: A patient perspective

Abstract Background Emergency laparotomy is known to convey worse morbidity and mortality for elderly patients. Despite a growing elderly population, there is a limited understanding of the patient experience in emergency laparotomy. This study aims to assess patient satisfaction following emergency laparotomy. Method Patients were identified from the National Emergency Laparotomy Audit (NELA) database, who were aged 80 and above, and underwent surgery between: January 2020 and August 2023 at Torbay Hospital. Of the patients who survived to discharge, a telephone-based interview was undertaken in January 2024. Exclusion criteria included: confusion, severe illness and relook laparotomy. Data was collected on functional status and satisfaction with the procedure. Patients were also asked what they wished they known prior to the operation. Post-operative outcomes were assessed in a separate study. Results 132 cases were undertaken in this period. 72 cases met inclusion criteria. We achieved a 54% response rate. 59% of respondents were living independently post operatively and had no functional decline. 92% of respondents were happy to have had the operation and if given the opportunity again would still have had the procedure. Patients were overall very happy with the information offered prior to the procedure, 8% felt they had no alternative option. One patient was not satisfied with the follow up received. Conclusion Although emergency laparotomy in the elderly is high risk, our data demonstrate excellent patient satisfaction. This study provides a better understanding of what is important to patients; this should be considered in the consent process and communication.

The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.

Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

Study on the Impact of Hormone Therapy for Prostate Cancer on the Quality of Life and the Psycho-Relational Sphere of Patients: ProQoL.

Prostate cancer and its treatment, particularly androgen deprivation therapy (ADT), can profoundly impact patients' quality of life. The aim of the prospective observational study reported here was to evaluate the effects of ADT on various aspects of quality of life in men with prostate cancer at a community-based hospital in Southern Italy. Eligible men initiating hormonal therapy were recruited between December 2021 and December 2023. Data were collected at baseline (T0) and after 3months (T1) and 6months (T2) of ADT using standardized questionnaires (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30, EORTC QLQ-PR25) and semi-structured interviews. Of the 52 participants, 43 completed all three assessments. The EORTC QLQ-C30 showed a statistically significant worsening in physical functioning (mean score decrease from 83.8 at T0 to 76.7 at T2; p < 0.001), increased fatigue (from 23.7 to 35.2; p < 0.001), and insomnia (from 23.7 to 31.8; p = 0.048) following ADT initiation. The QLQ-PR25 revealed a significant decline in sexual functioning (from 59 to 26.9; p < 0.001) and sexual activity (from 27.3 to 12; p = 0.001). Interviews revealed a significant rise in the number of patients reporting depressed mood. Interviews also highlighted a worsening in body image perception and sexuality, increased feelings of dependence, and challenges in the social and relational spheres. ADT significantly impacts various aspects of quality of life in men with prostate cancer, particularly physical functioning, fatigue, sexual function, body image, and emotional well-being. These results underscore the critical importance of a comprehensive, patient-centered approach that addresses both the physical and psychosocial aspects of care.

Abstract 4126628: Worse Cardiac Structure and Function is Associated with Decline in Multiple Domains of Cognitive Function: the Atherosclerosis Risk in Communities (ARIC) Study

Background: Cognitive impairment is cross-sectionally associated with worse cardiac structure/function. However, limited data exist regarding cardiac structure/function and longitudinal changes in cognitive function. Objective: Determine the association of cardiac structure and function with longitudinal changes in cognitive performance in late life. Methods: Among HF- and dementia-free participants in the community-based ARIC study who attended the 5th study visit (V5; 2011-2013), underwent protocol echocardiography, and completed a neurocognitive test battery at both V5 and study Visit 6 (V6; 2015-17), we assessed associations of cardiac structure and function measures with changes in both domain-specific and global cognitive scores between V5 and V6 using multivariable linear regression. Models were initially adjusted for demographics and education level, with additional models further adjusting for cardiovascular risk factors and disease at both V5 and V6. The neuropsychological test battery consisted of 10 neuropsychological tests that covered 3 domains of cognitive function: memory, executive functioning, and language. Factor scores were constructed for each cognitive domain, and their average represented a global composite score. Results: Among 2,988 included participants, mean age was 74±5 years, 60% were female, 20% reported Black race, and mean LVEF was 66±6%. Over a mean of 4.9±0.6 years (the V5 to V6 interval), raw scores declined for all neuropsychological tests. In fully adjusted models, worse diastolic function (larger LAVi) and LV remodeling (greater LV mass index) were associated with decline in executive function. Lower LVEF was associated with decline in language function, while worse LV longitudinal strain – a more sensitive measure of systolic dysfunction – was associated with decline in executive function, language function, and global cognition performance (all p&lt;0.05; Table). Conclusion: Subclinical LV remodeling and dysfunction is associated with greater declines in cognitive function over 5 years in late life. Differential associations were observed by cognitive domains, with executive function decline most uniformly associated with impairments in cardiac structure/function.

Abstract 4147633: Structural and Electrophysiological Cardiac Changes in Children with Osteogenesis Imperfecta (OI)

Introduction: Osteogenesis imperfecta (OI) is an inherited type 1 collagen disorder leading to bone fragility and increased fractures. Cardiovascular disease is the leading cause of death of adults with OI, but studies on cardiac changes from this collagen defect in children are sparse. We aim to fill this gap by assessing changes in EKG and echocardiogram (ECHO) variables in children with OI. Hypothesis: Children with OI will exhibit arrhythmogenic EKG changes and/or ECHO abnormalities which will precede changes that are documented in adults. Methods: 53 children with OI receiving care at Children’s Mercy-Kansas City were identified via ICD-10 codes. 64 with Duchenne Muscular Dystrophy (DMD, expected cardiac abnormalities) and 55 with non-accidental trauma (NAT, no expected cardiac abnormalities) served as controls. We specifically compared the most recent EKG and ECHO metrics extracted from medical charts by Kruskal-Wallis testing. Results: EKG: Children with OI differed from both NAT and DMD. OI had shorter median PR intervals (p&lt;0.001) plus longer median QRS (p&lt;0.001) and QTc intervals (p=0.002) than NAT. DMD had the shortest PR and longest QRS and QTc (see Table). Echo: The three groups showed no difference in systolic/diastolic BP or LV thickness. However, OI differed from NAT and/or DMD in other metrics. OI had higher end diastolic volume (p&lt;0.001), end systolic volume (p&lt;0.001) and stroke volume (p&lt;0.05) than NAT, but lower values than the DMD group. Similarly, OI children had higher LV mass and LV internal diastolic and systolic diameters than NAT, but lower than DMD (p&lt;0.001). OI LVOT diameter and Aortic root diameter were lower than NAT, but not as low as DMD (p&lt;0.05 and p&lt;0.001, respectively). Conclusion: Children with OI exhibit EKG and ECHO abnormalities that are similar to but less severe than for DMD, a group in which cardiovascular abnormalities are well documented. These abnormalities may be predictive of arrythmia/sudden cardiac death and/or functional decline in heart function. Our data suggest that OI children could benefit from ongoing routine cardiology studies along with orthopedic/metabolic management. Future studies would assess effects of age and OI treatments on cardiac abnormalities.

Exploring the Critical Role of Tight Junction Proteins in Kidney Disease Pathogenesis.

Kidney disease poses a significant global health challenge, marked by a rapid decline in renal function due to a variety of causative factors. A crucial element in the pathophysiology of kidney disease is the dysregulation of epithelial cells, which are vital components of renal tissue architecture. The integrity and functionality of these cells are largely dependent on tight junctions (TJ) proteins, complex molecular structures that link adjacent epithelial cells. These TJ not only confer cellular polarity and maintain essential barrier functions but also regulate epithelial permeability. TJ proteins are pivotal in their traditional role at cell junctions and in their non-junctional capacities. Recent research has shifted the perception of these proteins from mere structural elements to dynamic mediators of kidney disease, playing significant roles in various renal pathologies. This review explores the multifaceted roles of TJ proteins, focusing on their functions both within and external to the renal epithelial junctions. It highlights how these proteins contribute to mechanisms underlying kidney disease, emphasizing their impact on disease progression and outcomes. TJ proteins have emerged as significant players in the field of nephrology, not only for their structural role but also for their regulatory functions in disease pathology. Their dual roles in maintaining epithelial integrity and mediating pathological processes make them promising therapeutic targets for kidney disease. Understanding the intricate contributions of TJ proteins in kidney pathology offers potential for novel therapeutic strategies, aiming to modulate these proteins to halt or reverse the progression of kidney disease.

Anxiety, memory, and social impairments in the YAC128 mouse model of Huntington’s disease

Background Huntington’s disease (HD) is an autosomal dominant hereditary disorder, caused by an expansion of polyglutamine in the huntingtin protein. HD is characterized by a progressive decline in motor functions. This decline includes involuntary movements (chorea) and the worsening of controlled motions caused mainly by neuronal dysfunction in the striatum. In addition to the deterioration of motor symptoms, HD patients also suffer from cognitive changes, mood swings, apathy, depression, outbursts of anger, psychosis, and social withdrawal. Objective A comprehensive examination of cognitive, affective, and social changes in the HD mouse model is required for the development of combined therapy for both motor and non-motor deficits in HD. Methods The behavioral tests for anxiety, memory, and social traits were used in this study. Results YAC128 HD transgenic mice exhibited anxiolytic behavior in the novel brightly illuminated environment of the open field and light-dark place preference tests. Moreover, YAC128 HD mice also suffered from a decline in their recognition memory during the novel object recognition test. YAC128 HD mice demonstrated reduced exploration interest during the open field with a non-social target as well as during the first day of the three-chamber social test. Social interaction was also impaired in YAC128 HD mice as it was shown in the social interaction with resident intruder test. Conclusions YAC128 HD mouse model may be used as a model system to test the possible treatments for both motor and non-motor symptoms including memory loss, agitation and social withdrawal.

Polyploidy-mediated resilience in hepatic aging: molecular mechanisms and functional implication

Abstract Background Polyploidization, a process where cells acquire additional chromosome sets, is a unique characteristic of hepatocytes. This process has been increasingly recognized as an adaptive mechanism for maintaining liver function during aging, a period characterized by cellular senescence, DNA damage, and metabolic dysregulation. Purpose This review explores the molecular mechanisms underlying hepatocyte polyploidization and its potential role in promoting resilience against the aging-related decline in liver function. We assess how polyploid hepatocytes contribute to genomic stability, stress resistance, and metabolic adaptation, highlighting their relevance to liver aging. Main body Hepatocyte polyploidization occurs through mechanisms such as cytokinesis failure and endoreplication, leading to binuclear or mononuclear polyploid cells. Polyploid hepatocytes exhibit enhanced DNA repair capacity, which helps mitigate the accumulation of age-related genomic damage. The increased gene dosage in polyploid cells facilitates better stress responses, particularly against oxidative stress and genotoxic insults. Metabolic adaptations, including enhanced xenobiotic metabolism and lipid regulation, further support the liver’s ability to maintain homeostasis during aging. Additionally, polyploid cells demonstrate altered epigenetic landscapes and proteostasis mechanisms, contributing to improved cellular function and reduced susceptibility to senescence. These adaptations collectively enhance liver resilience against age-related metabolic and structural challenges. Conclusion Hepatocyte polyploidization represents a critical protective mechanism in liver aging, promoting cellular adaptations that safeguard against genomic instability, metabolic dysfunction, and oxidative stress. Understanding the molecular pathways driving polyploidization could pave the way for novel therapeutic strategies to combat age-related liver disorders and enhance health span. Graphical Abstract

Abstract 4134417: Cardiotoxicity Conundrum: Distinguishing Immune Checkpoint Inhibitor Myocarditis from Fluorouracil Cardiotoxicity in Concurrent Therapy

Case Description: The patient is a 37-year-old male with metastatic gastroesophageal junction adenocarcinoma presenting with chest pain and dyspnea two days after initiation of leucovorin, fluorouracil, oxaliplatin (FOLFOX), and nivolumab therapy. He was tachycardic and hypotensive with elevated cardiac biomarkers and globally reduced left ventricular systolic function. Suspecting immune checkpoint inhibitor (ICI) myocarditis versus fluorouracil (5-FU) cardiotoxicity, he was treated simultaneously for both. After starting high-dose steroids and before uridine triacetate, he had improved symptoms, cardiac function, biomarkers, and invasive hemodynamics. Though his endomyocardial biopsy did not show inflammatory cell infiltrates, his CMR demonstrated increased T1 and T2 relaxation times consistent with myocarditis. Testing revealed normal dihydropyrimidine dehydrogenase (DPD) activity. He completed uridine triacetate and was discharged on a steroid taper. At follow-up, he remained clinically stable, tolerating oxaliplatin and docetaxel (FLOT) initiation and nivolumab rechallenge without 5-FU. Discussion: This case is challenging as the presentation does not conclusively identify a causative agent. The patient’s symptom severity suggests ICI myocarditis, while the early onset points to 5-FU cardiotoxicity. His quick recovery of cardiac function after medication cessation suggests 5-FU-associated Takotsubo cardiomyopathy. His improvement after steroids raises concern for an adverse immunologic response as in ICI myocarditis or idiosyncratic reactions to oxaliplatin with 5-FU. This patient received ICI therapy and chemotherapy, increasing his risk for cardiac immune-related adverse events. His protracted 5-FU infusion increased his risk for 5-FU cardiotoxicity, but his normal DPD activity mitigates this risk. Although his biopsy was negative, it cannot exclude ICI myocarditis. By the IC-OS 2021 consensus, he meets the criteria for ICI myocarditis presenting 48 hours after nivolumab exposure with cardiogenic shock, elevated cardiac biomarkers, decline in cardiac function, and CMR with elevated T1 and T2 relaxation times. Yet, his biomarkers remained normal with nivolumab rechallenge, arguing against ICI myocarditis and suggesting 5-FU as the culprit. Early recognition and differentiation of the culprit in concurrent therapies impact management and future treatment options. Rechallenge carries risk and requires interdisciplinary collaboration to ensure patient safety.

Abstract 4140122: Bioengineered Self-Adhering Electrospun Nanoscaffolds to Deliver Mitochondrial Antioxidant, JP4-039

Introduction: Treatment of pathologic remodeling and subsequent decline in cardiac function post-myocardial infarction (MI) remains limited. Our lab has previously demonstrated that the targeted mitochondrial antioxidant, JP4-039 (JP4), can abrogate post-MI remodeling and decline in cardiac function, and that JP4 released from electrospun nanoscaffolds improved proliferation and migration of coronary vascular endothelial cells in vitro . The aims of this study were to develop a suture-free, bioadhesive electrospun nanoscaffold that will adhere post-MI cardiac tissue and reliably release JP4 in a localized manner. Hypothesis: Plasma treatment of JP4-loaded biocompatible electrospun nanoscaffold will adhere to cardiac tissue and deliver active moiety of JP4. Methods: A 2% poly(l-lactide-co-glycolide) (PGLA) was electrospun with and without 1% JP4. Nanoscaffolds then underwent plasma treatment for one minute followed by a force adhesion assay. SEM imaging and electron paramagnetic resonance ( EPR ) assays before and after plasma treatment of both control and JP4-loaded patches were performed to examine patch consistency and ensure the release of the unaltered, active structure of JP4. Results: JP4 loading and plasma treatment did not affect fiber dimeter of the scaffolds (p &gt; 0.5 for all; Fig. 1B). JP4-loaded patches demonstrated similar release pattern of the antioxidant’s nitroxide moiety by displaying a characteristic triple peak both before and after plasma treatment as determined by EPR (Fig. 1C). Plasma-treated patches demonstrated significant increase in force adhesion compared to non-treated patches in both the control and JP4-loaded scaffolds (p &lt; 0.0001) (Fig. 1A.). No significant difference in force adhesion was observed between the plasma treated control and JP4 loaded patch (p &gt; 0.05) as determined by ANOVA (Fig. 1A). There was no significant difference in force adhesion between one minute and two minutes of plasma treatment (p &gt; 0.05; Fig. 1A lower panel). Conclusion: The findings demonstrate that plasma-treated biocompatible JP4-loaded patches may reliably adhere to cardiac tissue and release the bioactive component of the mitochondrial antioxidant, JP4.