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Liver TET1 promotes metabolic dysfunction-associated steatotic liver disease
Get PDFGlobal hepatic DNA methylation change has been linked to human patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DNA demethylation is regulated by the TET family proteins, whose enzymatic activities require 2-oxoglutarate (2-OG) and iron that both are elevated in human MASLD patients. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 using two different strategies substantially alleviated MASLD progression. Knockout (KO) of TET1 slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, and CD36 were significantly decreased upon TET1 depletion. Consistently, liver specific TET1 KO led to improvement of MASLD progression. Mechanistically, TET1 promoted CD36 expression through transcriptional upregulation via DNA demethylation control. Overexpression of CD36 reversed the impacts of TET1 downregulation on fatty acid uptake in hepatocytes. More importantly, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Conclusively, liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD
Is Postoperative Steroid Use Associated With Improved Outcomes in Severe Odontogenic Infections?
No full textBACKGROUND: The use of steroids as an adjunctive therapy in odontogenic infections is common, but few studies have focused on the effect of steroids in improving outcomes in these infections. PURPOSE: The purpose of the study was to measure the association between postoperative steroid use and length of stay (LOS) and reoperation among patients with severe odontogenic infections. STUDY DESIGN, SETTING, SAMPLE: The authors conducted a prospective cohort study consisting of all adult patients treated in the operating room for an odontogenic infection from August 1, 2019, to December 31, 2022, at University Medical Center of New Orleans. Patients were excluded if an odontogenic source could not be confirmed. PREDICTOR VARIABLE: The predictor variable was the use of steroids postoperatively (after conclusion of surgery until discharge), coded as a yes or no. MAIN OUTCOME VARIABLE: The outcome variables were total LOS, postsurgical LOS, and reoperation. COVARIATES: The covariates were demographics, medical history, exam findings, diagnosis, and treatment-related variables. ANALYSES: Descriptive and bivariate analyses were performed, as well as linear regression analyses. A P value of ≤ .05 was considered significant. RESULTS: The study sample consisted of 240 patients with a mean age of 40.3 ± 14.5 years and a sex distribution of 57.5% (138) male and 42.5% (102) female. Steroids were used in 114 patients (47.5%) postoperatively. The mean total LOS and postsurgical LOS were 3.7 ± 2.4 days and 3.1 ± 2.4 days, respectively. Reoperation was performed for 12 (5.0%) patients. Postoperative steroid use group was not significantly associated with total LOS (3.7 ± 2.6 days vs 3.6 ± 2.2 days, P = .59), postsurgical LOS (3.3 ± 2.6 days vs 2.9 ± 2.1 days, P = .13), or reoperation (58.3 vs 41.7%, P = .56) for the group that received steroids versus those that did not, respectively. CONCLUSIONS AND RELEVANCE: Postoperative steroid use was not associated with reduced LOS, postsurgical LOS, or reoperation in patients with severe odontogenic infections
Exacerbated cardiac dysfunction from combined alcohol binge and synthetic cannabinoid use
No full textAlcohol remains the most frequently used intoxicant, posing a significant global health concern. Binge drinking has been linked to acute cardiovascular complications, including reduced cardiac performance, arrhythmias, and blood pressure instability. Additionally, there is a growing number of clinical reports describing severe adverse cardiac events associated with the recreational use of synthetic cannabinoids. Recent surveys reveal a troubling rise in polydrug misuse, particularly among young adults, with an increasing number of cases linked to fatal outcomes. This study aimed to characterize left ventricular performance in mice following combined acute alcohol and synthetic cannabinoid exposure using complex hemodynamic measurements via the pressure-volume (P-V) approach. Our findings revealed that alcohol ingestion or intravenous synthetic cannabinoid (CP55,940) administration led to a dose-dependent decline in systolic cardiac performance in mice. Moreover, the concurrent administration of alcohol and CP55,940 led to cardiodepression, surpassing the contractile dysfunction observed with each drug administered individually. Intravenous administration of the cannabinoid type-1 receptor (CB1R) antagonist rimonabant largely improved the combined drug administration-induced left ventricular contractile dysfunction in mice, while its intracerebroventricular administration resulted in only partial restoration of normal cardiac function, implicating a role for both central and peripheral CB1R signaling. Our results emphasize the severe cardiac consequences of simultaneous alcohol and synthetic cannabinoid misuse and offer a potential therapeutic avenue for mitigating the adverse cardiac effects of their combined use by repurposing CB1R antagonists
Chronic binge alcohol dysregulates omental adipose tissue extracellular matrix in simian immunodeficiency virus-infected macaques
No full textBackground: Increased survival, prolonged antiretroviral treatment (ART), and lifestyle choices, including alcohol misuse, increase the risk for comorbid conditions, including cardiometabolic comorbidities among people with HIV (PWH). Published studies indicate that dysregulated adipose tissue phenotype, particularly of the visceral adipose depot, contributes to metabolic dysregulation. Using a nonhuman primate model of simian immunodeficiency virus (SIV) infection, we previously demonstrated that chronic binge alcohol (CBA) administration to ART-treated rhesus macaques decreases whole-body glucose-insulin dynamics, increases omental adipose tissue (OmAT) collagen content, decreases OmAT adipocyte size, and alters pancreatic endocrine function. The objective of this study was to delineate the depot-specific effects of CBA on visceral (VAT) and subcutaneous adipose tissue (SAT) extracellular matrix (ECM) phenotype, the potential mechanisms involved in AT ECM remodeling, and the implications of increased tissue stiffness on AT metabolic alterations in female SIV-infected macaques. Methods: Omental and subcutaneous adipose samples were obtained from female SIV-infected, ART-treated macaques that received intragastric administration of CBA (1215 g/kg/week, CBA/SIV) or water (VEH/SIV) for 14.5 months. Results: CBA preferentially altered the ECM phenotype in OmAT, a VAT depot. The CBA-associated changes included increased ECM accumulation, increased collagen I III ratio, a profibrotic milieu, and decreased matrix metalloproteinase 13 activity. These changes were associated with smaller adipocyte size, decreased triglyceride content, decreased gene expression of perilipins, and a potential dysregulation of peroxisome proliferator-activated receptor gamma signaling. Conclusions: Collectively, these findings suggest that CBA-mediated ECM remodeling adipocytes within a stiff environment that we propose disrupts adipocyte metabolic programming and may increase the risk for metabolic comorbidities
The obstetric experience among vascular surgery trainees
Get PDFBACKGROUND: Vascular surgery training poses unique risks to pregnancy, including long hours, physically demanding work, and radiation exposure. Our objectives were to (1) understand pregnancy and parenthood experiences among vascular surgery trainees, (2) assess the rate of obstetric complications among vascular trainees, and (3) evaluate factors associated with trainee-parent wellness. METHODS: A survey was administered after the 2021 Vascular Surgery In-Training Examination. Residents and fellows who (or whose partners) experienced pregnancies during their clinical years of training were asked about their perceptions of the learning environment (work hours and mistreatment, including discrimination, bullying, and harassment), obstetric complications (miscarriage, pre-eclampsia, placental abruption, intrauterine growth restriction, cesarean section, and postpartum depression), and burnout. Multivariable logistic regression models identified factors associated with burnout. RESULTS: Among 510 trainees from 123 vascular surgery training programs (response rate 85.9%), 128 (25.1%) reported pregnancy during clinical training (12.7% female and 35.4% male; P \u3c .001). Compared with male trainees, female trainees more frequently reported delaying having children owing to training (53.1% vs 30.0%; P \u3c .001) and being advised against having children during residency (7.9% vs 0.4%; P \u3c .001). Both female trainees and the partners of male trainees had high rates of obstetric complications (female 47.1% vs partners of male trainees 34.0%; P = .3). Compared with male trainees who had female partners, female trainees more frequently reported pregnancy/parenthood-related mistreatment (female 60.0% vs male 15.6%; P = .002) and duty-hour violations (female 47.4% vs male 12.0%; P \u3c .001). Female gender was associated with increased risk for burnout (odds ratio, 4.8; 95% confidence interval,1.14-20.15); however, this difference was no longer significant after adjusting for mistreatment and duty-hour violations. CONCLUSIONS: Vascular trainees experience high rates of obstetric complications. Senior-level trainees were more likely to experience obstetric complications, potentially owing to older age, longer and more complex surgical cases, and increased frequency of overnight calls. Women experienced more stigma related to pregnancy and childbearing, which may be associated with higher rates of burnout. Increased support for childbearing during training may help to maintain the wellness of a diverse workforce and better maternal-fetal health
Resistance signatures to oncolytic vesiculoviruses in pancreatic ductal adenocarcinoma
Get PDFPancreatic ductal adenocarcinoma (PDAC) shows limited response to conventional therapies and immunotherapy due to dense stromal barriers and poor immunogenicity. Oncolytic vesiculoviruses hold therapeutic potential for PDAC by lysis of PDAC cells to release tumor-associated antigens, increasing tumor immunogenicity. We previously reported the efficacy of a chimeric vesicular stomatitis virus (VSV) expressing Morreton virus (MorV) glycoprotein in sarcoma. Here, we evaluated the oncolytic potency of MorV and chimeric virus, VMG, in PDAC models. VMG exhibited heterogeneous oncolysis across human PDAC cell lines and PDX cells, similar to parental viruses VSV and MorV. To evaluate potential signatures correlated with resistance to oncolytic vesiculoviruses, we compared transcriptomes of cell lines characterized as sensitive or resistant to oncolysis in vitro. We identified epithelial development and biological adhesion gene sets were significantly associated with vesiculovirus resistance. Additionally, escaped PDAC cells surviving two cycles of infection with VSV showed significant upregulation of stress keratins and downregulation of genes involved in retinoic acid metabolism and cell cycle. An overlapping 39 genes were higher in resistant cell lines at baseline as well as upregulated in escaped PDAC cells. Several resistance-associated genes are targets of anti-cancer therapies in development, offering potential combination approaches with oncolytic vesiculoviruses
Effects of exercise on inflammation, circulating tumor cells, and circulating tumor DNA in colorectal cancer
Get PDFBACKGROUND: The biological mechanisms by which postdiagnosis physical activity improves disease-free survival in colorectal cancer survivors remain incompletely understood. This trial tested the hypothesis that 12 wk of moderate-intensity aerobic exercise, when compared with a control group, would change inflammation, CTCs, and ctDNA in a manner consistent with an improved cancer prognosis. METHODS: This trial randomized Stages I-III colorectal cancer survivors to 12 wk of home-based moderate-intensity aerobic exercise or a waitlist control group. The co-primary endpoints were high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6), secondary endpoints were soluble tumor necrosis factor-α receptor 2 (sTNFαR2) and circulating tumor cells (CTCs), and the exploratory endpoint was tumor fraction quantified from circulating tumor DNA. RESULTS: Sixty subjects were randomized (age = 60.6 ± 10.8 years, mean ± SD; 39 (65%) females; 46 (77%) colonic primary tumor), and 59 (98%) subjects completed the study. Over 12 wk, exercise adherence was 92% (95% confidence interval (95%CI): 86‒99). Exercise improved submaximal fitness capacity (0.36 metabolic equivalents; 95%CI: 0.05‒0.67; p = 0.025) and objectively measured moderate-to-vigorous-intensity physical activity (34.8%, 95%CI: 11.3‒63.1; p = 0.002) compared to control. Exercise did not change hs-CRP (20.9%, 95%CI: -17.1 to 76.2; p = 0.32), IL-6 (11.4%, 95%CI: -7.5 to 34.0; p = 0.25), or sTNFαR2 (-3.6%, 95%CI: -13.7 to 7.7; p = 0.52) compared to control. In the subgroup of subjects with elevated baseline hs-CRP (n = 35, 58.3%), aerobic exercise reduced hs-CRP (-35.5%, 95%CI: -55.3 to -3.8; p = 0.031). Exercise did not change CTCs (0.59 cells/mL, 95%CI: -0.33 to 1.51; p = 0.21) or tumor fraction (0.0005, 95%CI: -0.0024 to 0.0034; p = 0.73). In exploratory analyses, higher aerobic exercise adherence correlated with a reduction in CTCs (ρ = -0.37, 95%CI: -0.66 to -0.08; p = 0.013). CONCLUSION: Colorectal cancer survivors achieved high adherence to a home-based moderate-intensity aerobic exercise prescription that improved fitness capacity and physical activity but did not reduce inflammation or change tumor endpoints from a liquid biopsy
A Sex Comparison of Fall and Fracture Occurrence in the Elderly Diabetic Population: A Quantitative Study
Get PDFAIMS: To assess differences in falls and fractures in men and women with type 2 diabetes mellitus (T2DM) within a diverse population in Southeast Louisiana. METHODS: A list of 1200 patients was generated through an electronic health record system using keywords: diabetic diagnosis, falls, and fractures to conduct this retrospective cohort study. This chart review included adults with T2DM who experienced at least one fall and/or fracture between January 2018 and May 2023 at East Jefferson General Hospital located in Metairie, Louisiana. Only falls and fractures that resulted in a hospital visit were included. Results were compared between males and females. RESULTS: Patient data were collected from 100 randomly selected patients: 50 females and 50 males (mean age 67 years, 97% of patients were non-Hispanic, and 72% Black). Statistical analysis was conducted using the Student\u27s t test, Fisher\u27s exact, and Pearson correlation. An average of 3-4 falls occurred per patient, with no significant sex difference observed (p = 0.97). Thirty-eight percent of patients experienced a fracture with a significant sex difference (50% of female vs. 26% of male patients [p = 0.02]). Positive correlations between comorbid conditions and falls and fractures were seen, particularly in women: a moderate correlation for falls (r = 0.48, p \u3c 0.01) and a strong correlation for fractures (r = 0.52, p \u3c 0.01). Patients not on insulin treatment experienced a greater occurrence of fractures than insulin-dependent patients (46% vs. 22%, p = 0.03). CONCLUSIONS: Our findings suggest that in a diverse population, women with T2DM are at an increased risk of experiencing fractures, and specialized care should be given to this population to reduce the risk of fracture occurrence. Additional comorbidities increase the risk of falls and fractures
Clinical Reasoning: A Toddler With Acute-Onset Hypotonia, Areflexia, and Ataxia
No full textThis is a case report of an established genetic etiology with a unique clinical presentation and novel imaging findings that add to the clinical spectrum of this known condition. A 2-year-old male toddler presented with acute-onset weakness and ataxia after a respiratory viral illness. A previous admission was marked by similar weakness with areflexia, ataxia, and metabolic acidosis. Initial examination revealed weakness with areflexia, loss of tone, and ataxia, followed by intermittent encephalopathy. These physical findings localized to both central and peripheral etiologies. Differential diagnoses included atypical Guillain-Barre syndrome, acute disseminated encephalomyelitis, acute cerebellar ataxia, an inborn error of metabolism, or an underlying genetic etiology. Laboratory evaluation revealed a metabolic lactic acidosis with a normal lactate/pyruvate ratio but an unrevealing additional metabolic evaluation. CSF studies were significant for an albuminocytologic dissociation. MRI brain revealed symmetric diffusion restriction in the bilateral middle cerebellar peduncles extending into the central white matter of the cerebellum, with diffusion restriction also present in the central pons, which was considered to be a novel imaging finding of this condition. The definitive diagnosis was found with genetic testing with whole-exome sequencing. This case report reiterates the importance of genetic testing for conditions that may otherwise be difficult to identify based solely on the clinical findings
Association Between Use of Services To Address Adverse Social Determinants of Health and Documented Suicide Attempt Among Patients in the Veterans Health Administration
Get PDFSuicide prevention is a top priority for the US Department of Veterans Affairs (VA), and suicide is often associated with adverse social factors (e.g., financial, legal, and housing problems). The VA provides social services integrated with healthcare services, which may increase the opportunities to detect and document suicide attempt in EHR records. Using VA administrative data, we examined three cohorts of all patients from 2014 to 2018 who had housing instability (n = 659,987), justice involvement (n = 200,487), and unemployment (n = 346,556). Administrative records were used to determine ordinal indicators of receipt of VA social services (no services, low, or high). The outcome was suicide attempt noted in the healthcare record (i.e., documented suicide attempt) in the 1–6 months following the incident adverse social factor. We conducted logistic regressions utilizing a discrete-time survival framework with person-month as the unit of analysis, which facilitated accounting for covariates while isolating the independent association of social service utilization. After adjusting for covariates, high receipt of housing services (vs. no services) was significantly associated with documented suicide attempt during the 6-month observation period (aOR = 1.14, 95%CI = 1.06–1.22). A similar association was observed for high vs. no use of justice programs (aOR 1.24; 95% CI:1.12–1.37). There was no significant association between employment services utilization and documented suicide attempt during the 6-month observation period. Our finding that utilization of social services as positively associated with documented suicide attempt likely reflects increased suicide attempt surveillance and documentation with social service involvement. Future research should explore operationalizing patient-level distress in administrative data