Peroxisome Proliferator Activated Receptor-gamma P465L Point Mutation in Diabetes and Atherosclerosis

The dominant-negative P467L mutation in peroxisome proliferator activated receptor-[gamma] (PPAR[gamma]) was identified in insulin resistant patients with hyperglycemia and lipodystrophy. However, mice carrying the corresponding Pparg-P465L mutation have normal insulin sensitivity, with mild hyperinsulinemia. I hypothesized that murine Pparg-P465L mutation leads to covert insulin resistance, masked by hyperinsulinemia, to retain normal plasma glucose. I introduced in PpargP465L/+ mice, Ins2-Akita mutation that causes islet apoptosis to lower plasma insulin. Unlike Ins2Akita/+ littermates, male PpargP465L/+Ins2Akita/+mice have drastically reduced life-span. PpargP465L/+Ins2Akita/+ females have aggravated hyperglycemia, smaller islets, reduced plasma insulin and impaired insulin sensitivity. Enhanced gluoconeogenesis, due to reduced plasma insulin, in PpargP465L/+Ins2Akita/+ females compared to Ins2Akita/+ littermates, contributes to their fasting hyperglycemia. While liver and skeletal muscles remain sensitive, adipose tissue is resistant to insulin. PpargP465L/+Ins2Akita/+ mice have smaller fat depots composed of larger adipocytes suggesting impaired lipid storage with subsequent hepatomegaly and hypertriglyceridemia. The increasing prevalence of obesity and insulin resistance and its negative impact on atherosclerotic cardiovascular disease is of major concern. In the second part of my study, I hypothesized that the L/+ mutation will worsen atherosclerosis in Apoe-/- mice. Despite a consistent increase in blood pressure, PPAR[gamma]P465L/+ mutation did not affect plaque size in Apoe-/- mice fed normal chow or high-fat-diet. Gene expression studies revealed significantly increased ABCA-1 and decreased CD-36 in PPAR[gamma]P465L/+;Apoe-/- macrophages compared to Apoe-/- littermates, suggesting reduced lipid accumulation. Cultured PPAR[gamma]P465L/+;Aoe-/- macrophages, had a significant reduction in DiI-labeled-VLDL uptake, compared to Apoe-/- macrophages. It is likely that balance between increased blood pressure with its pro-atherogenic potential and macrophage athero-protective phenotype results in an unchanged plaque. Bone marrow transfer experiments to investigate the role of PPAR[gamma]P465L/+ mutation specifically in the macrophage showed a trend towards decrease in plaque size in mice reconstituted with PPAR[gamma]P465L/+;Apoe-/- macrophages. Thus, I have established the causative link between PPAR[gamma]P465L mutation and insulin resistance phenotype, consolidating the crucial role of PPAR[gamma] in diabetes. PPAR[gamma]P465L mutation, however, does not change the atherosclerotic plaque size in Apoe-/- mice, and warrants further investigation

Health Disparities in Afro-Latinx Populations: Chronic Health Diseases, Linguistic and Cultural Competency, and Inequities and Barriers in Richmond, Virginia

Afro-Latinx individuals face health disparities that differ from those faced by white Latinx individuals. This literature review was conducted by the Collective Corazón—a VCU student organization, mentored by Dr. Indira Sultanić, that addresses Latinx health equity through service and advocacy—in order to examine the underlying causes of Afro-Latinx health disparities. Skin color is a predictor of health, life expectancy, and quality of life for many Latinx individuals. On average, Afro-Latinx individuals in particular have less access to education, fewer financial freedoms, and poorer health outcomes. The Afro-Latinx community also describes higher rates of discrimination compared to white Latinx individuals. As a result, Afro-Latinx individuals suffer from higher rates of chronic illness, stress, anxiety, and depression. Furthermore, due to a lower average socioeconomic status and decreased education access that many Afro-Latinx individuals face, the prevalence and incidence of chronic diseases, such as type 2 diabetes, are higher for such populations when compared to national averages. Additionally, COVID-19 has exacerbated inequities and unequal access to resources; chronic comorbidities that Afro-Latinx individuals have are also predictors of poor COVID-19 outcomes. In Richmond in particular, another barrier that affects the health of many Afro-Latinx populations is the lack of access to healthcare services and/or insurance. This review argues that increasing cultural competency and racial equity trainings in healthcare systems, addressing social determinants of health, and encouraging connections with community leaders are ways to reduce health disparities that Afro-Latinx individuals face.https://scholarscompass.vcu.edu/uresposters/1407/thumbnail.jp

A Rare Case of Mucinous Adenocarcinoma of the Colon Presenting as Ileoileal Intussusception in an Adult

Intussusception is the cause of around 1% of all bowel obstructions in adults. Unlike in children, where intussusception is most often idiopathic in nature, cases in adults usually have an identifiable etiology, most commonly malignancy. Symptoms are usually non-specific, but timely identification and management is crucial due to high rates of carcinoma as the lead point of intussusception. Here we present a rare case of mucinous adenocarcinoma of the colon that presented as ileoileal intussusception. Diagnostic and treatment issues are also discussed

Utilization Patterns of IV Iron and Erythropoiesis Stimulating Agents in Anemic Chronic Kidney Disease Patients: A Multihospital Study

Intravenous (IV) iron and Erythropoiesis Stimulating Agents (ESAs) are recommended for anemia management in chronic kidney disease (CKD). This retrospective cohort study analyzed utilization patterns of IV iron and ESA in patients over 18 years of age admitted to University Health System Hospitals with a primary or secondary diagnosis of CKD between January 1, 2006 to December 31, 2008. A clustered binomial logistic regression using the GEE methodology was used to identify predictors of IV iron utilization. Only 8% (n = 6678) of CKD patients on ESA therapy received IV iron supplementation in university hospitals. Those receiving iron used significantly less amounts of ESAs. Patient demographics (age, race, primary payer), patient clinical conditions (admission status, severity of illness, dialysis status), and physician specialty were identified as predictors of IV iron use in CKD patients. Use of IV iron with ESAs was low despite recommendations from consensus guidelines. The low treatment rate of IV iron represents a gap in treatment practices and signals an opportunity for healthcare improvement in CKD anemic patients

Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent

Effects of Exercise on Immune Responses to Vaccination in Chronically Stressed Mice

Introduction: Previous studies have shown that exercise has been related with strengthened vaccine-induced immune responses and chronic stress decreases immune function. This study aims to determine whether exercise can alleviate chronic stress-induced attenuation of vaccination responses in mice. Methods: C57BL/6 mice, aged 7 weeks old, were randomly assigned: control (CTRL, n=9), sedentary (SED, n=7), eccentric exercise (ECC, n=9), or voluntary wheel running (VWR, n=10) group. SED, ECC, and VWR mice received restraint stress for 6 hours/day, 5 days/week for 3 weeks. CTRL mice did not receive restraint stress. ECC mice exercised running downhill at -20% grade at 17m/min for 45 min. VWR mice voluntarily ran on a telemetered wheel. All groups received an OVA vaccination in two phases: first a sensitization phase with an intramuscular vaccination post 1-week of stress in the gastrocnemius muscle, a second intradermal vaccination in the ear post 3-weeks of stress. Swelling in the ear was measured to determine the proportional delayed-type hypersensitivity (DTH) reaction as part of the cell-mediated immune response (recruitment of memory T cells and effector cells) to the vaccine. Blood from the retro-orbital vein was collected pre-vaccination, 1wk, 2wk and 4wk post-vaccination for antibody responses. Results: In this study, there was a trend in increased humoral immunity, in regards to IgM and IgG antibody titers in the exercised groups. This study did not show any significant differences in cell-mediated immunity (indicated with delayed-type hypersensitivity (DTH)), with respect to the effect of exercise on chronic stress. Conclusion: Both acute eccentric exercise and voluntary wheel exercise training had a tendency to attenuate stress-induced reductions in antibody responses, but not cell-mediated responses. Further experiments are required to determine the precise significance of exercise’s effects, as well as the determination of the underlying mechanisms.Ope

Robotic Guided Minimally Invasive Spine Surgery

Minimally invasive spine surgery (MISS) continues to evolve, and the advent of robotic spine technology may play a role in further facilitating MISS techniques, increasing safety, and improving patient outcomes. In this chapter we review early limitations of spinal robotic systems and go over currently available spinal robotic systems. We then summarize the evidence-based advantages of robotic spine surgery, with an emphasis on pedicle screw placement. Additionally, we review some common and expanded clinical applications of robotic spine technology to facilitate MISS. The chapter concludes with a discussion regarding the current limitations and future directions of this relatively novel technology as it applies to MISS

Comparative safety and benefit-risk profile of biologics and oral treatment for moderate-to-severe plaque psoriasis: A network meta-analysis of clinical trial data

Background The comparative safety and benefit-risk profiles of moderate-to-severe psoriasis treatment have not been well studied. Objective To compare the short-term (12-16 weeks) and long-term (48-56 weeks) safety and benefit-risk profiles of moderate-to-severe psoriasis treatments. Methods A systematic literature review of phase II-IV randomized controlled trials of moderate-to-severe psoriasis treatments was conducted (cutoff: July 1, 2020). Any adverse events (AEs), any serious AEs, and AEs leading to treatment discontinuation were compared using Bayesian network meta-analyses (NMAs). Results Fifty-two and 7, respectively, randomized controlled trials were included in the short- and long-term NMAs, respectively. In the short-term NMA, the rates of any AEs were the lowest for tildrakizumab (posterior median: 46.0%), certolizumab (46.2%), and etanercept (49.1%). The rates of any serious AE were the lowest for certolizumab (0.8%), risankizumab (1.2%), and etanercept (1.6%). The rates of AEs leading to treatment discontinuation were the lowest for risankizumab (0.5%), tildrakizumab (1.0%), and guselkumab (1.5%). In the long-term NMA, risankizumab had the lowest rates of all 3 outcomes (67.5%, 4.4%, and 1.0%, respectively) and the most favorable benefit-risk profile. Limitations The results may not be generalizable to real-world populations. Conclusions Anti–interleukin 23 agents were associated with low rates of safety events. Risankizumab had the most favorable benefit-risk profile in the long term