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Adaptive Immunity: From Autoimmune Diseases to Neuroinflammation
Get PDFInflammation is essential for the clearance of pathogens and to facilitate healing of damaged tissue. However, this process must be controlled to limit immunopathology. Cell-intrinsic effects of inhibitory and signaling molecules are known to maintain quiescence and prevent effector differentiation and inflammation. Moreover, specific populations of immune cells exert cell-extrinsic effects for immunosuppression. Therefore, studies on the immunosuppressive functions of these cell populations will provide a better understanding of how inflammation is regulated and how its dysregulation causes human disease. Additional insights in this area may uncover novel targets to be manipulated for therapeutic benefit in autoimmune and inflammatory disorders, such as neurodegenerative diseases.
Foxp3-expressing regulatory T (Treg) cells are specialized immunosuppressive cells that establish immune tolerance to prevent the development of autoimmune and other inflammatory diseases, with effector-Treg (eTreg) cells playing a pivotal role. Recently, cellular metabolism has emerged as a mediator to enforce Treg-cell function and heterogeneity. In Chapter 3, we used genetic and pharmacological tools to demonstrate that isoprenoid-dependent posttranslational lipid modifications dictate eTreg-cell accumulation and function by intersecting with T cell receptor (TCR)-induced intracellular signaling. We showed that isoprenoids are essential for activated Treg-cell suppressive activity, and Treg cell-specific deletion of the enzymes that mediate farnesylation and geranylgeranylation (encoded by Fntb and Pggt1b, respectively) leads to a reduction of eTreg cells and the development of fatal autoimmunity. In Chapter 4, we further explored the mechanistic role of protein prenylation in the regulation of eTreg cells by performing a comprehensive analysis of protein prenylation-dependent molecular signaling in eTreg-cells. Specifically, we found that Fntb drives eTreg-cell maintenance by promoting mTORC1 activity-dependent proliferation and ICOS-mediated cellular fitness. In contrast, Pggt1b orchestrated transcriptional programming by TCR stimulation and Rac signaling to establish eTreg-cell differentiation and immune tolerance. Therefore, our results reveal a bidirectional interplay between immune signals, metabolism-mediated posttranslational modifications, and intracellular signaling for the differentiation and maintenance of eTreg cells.
Neuroinflammation is also a feature of neurogenerative diseases, but the underlying cellular mechanisms that limit inflammation in neurodegenerative diseases are largely unknown. In Chapter 5, using single cell RNA-sequencing (scRNA-seq) of immune cells in a mouse model of neurodegeneration (specifically, Alzheimer’s disease AD), we found that CD8 T cells accumulated in the brain parenchyma. These CD8 T cells had tissue resident memory-associated features and appeared to retain functionality. Importantly, T cell ablation was found to exacerbate disease-associated deposition of Beta- amyloid (A-Beta) and cognitive decline in a mouse model of AD. Moreover, in the absence of T cells, microglia acquired proinflammatory features and clustered in regions near A-Beta plaques, features associated with more severe disease. Collectively, these results suggest that T cells are critical to restrain microglia activation and limit neurodegeneration-associated pathologies in a murine model of AD
Embracing the value of a CME/Library partnership: growing from a common ground
Get PDFObjective The objective of this poster is to validate the significance of the partnership between library services and continuing medical education (CME). We will show the value of our collaboration through planned and implemented multi-faceted educational activities.
Methods A diversity team was created to determine the types of education we would offer, the speakers who could meet the needs of our objectives, and planning of the activities. With Covid-19 and social unrest, we decided to focus on diversity, equity and inclusion (DEI) and how we could impact our health system. We worked with public relations to market events internally and externally using social media. Survey monkey and Zoom were used for advanced registration and post evaluation.
Results We hosted six DEI continuing medical education speakers, three virtual book clubs, 13 COVID-19 perspectives, a documentary screening, and a panel discussion. Activities were designed for participants to learn strategies they could implement, engage in open conversations, and share their thoughts/feelings surrounding social issues. We developed partnerships within the community and institution. Due to the virtual option, we had over 1000 registered participants from hospitals, academic institutions, and community organizations. Survey results concluded participants made a change in their policies, protocols, or procedures.
Conclusion In the past year, COVID helped us solidify our strong team partnership. We embraced the adversities of working through a pandemic and had to be fluid in decision making and planning of activities. Our teamwork qualities served as an advantage to planning, collaborating, and implementing DEI educational activities. Using virtual technologies enabled us to reach communities outside of our health system. Survey results concluded participants made changes in their policies, protocols, and/or procedures. Through our common ground we were able to influence the starting of crucial conversations within our health system
Increasing Confidence and Mental Health in Caregivers
Get PDFThe purpose of our critically appraised topic is to synthesize the highest-level evidence available regarding interventions for increasing confidence and mental health outcomes in caregivers taking loved ones home from inpatient rehabilitation. The final portfolio contains six research articles from peer-reviewed journals. Study designs include randomized control trials, a systematic review, and a pretest-posttest without a control group. All studies relate directly to the components of the PICO question. Four of the articles discussed both caregiver confidence and mental health while two articles discussed only mental health. There is strong evidence to support that in-person hands on training, in person discussion-based training, and/or virtual resources helped increase confidence in caregivers of patients. There is mixed evidence and only limited improvement to support mental health. The findings from this critically appraised topic will be used to draft new ideas for practice guidelines for addressing caregiver education and caregiver mental health in an inpatient rehabilitation facility
Intravenous Lidocaine for Rib Fractures: Effect on Pain Control and Outcome
Get PDFBackground
Multimodal analgesia in rib fractures (RFs) is designed to maximize pain control while minimizing narcotics. Prior research with intravenous lidocaine (IVL) efficacy produced conflicting results. We hypothesized IVL infusion reduces opioid utilization and pain scores. Methods
A retrospective review of RF patients at an ACS-verified Level I trauma center from April 2018 to 2/2020 was conducted. Patients (pts) stratified as receiving IVL vs no IVL. Initial lidocaine dose: 1 mg/kg/hr with a maximum of 3 mg/kg/hr. Duration of infusion: 48 h. Pain quantified by the Stanford Pain Score system (PS). Bivariate and multivariate analyses of variables were performed on SPSS, version 21 (IBM Corp). Results
414 pts met inclusion criteria: 254 males and 160 females. The average age for the non-IVL = 67.4 ± 15.2 years vs IVL = 58.3 ± 17.1 years (P \u3c .001). There were no statistically significant differences between groups for ISS, PS for initial 48 h, and ICU length of stay (LOS). There was a difference in morphine equivalents per hour: non-IVL = 1.25 vs IVL = 1.72 (P = .004) and LOS non-IVL = 10.2+/−7.6 vs IVL = 7.82+/−4.94. By analyzing IVL pts in a crossover comparison before and after IVL, there was reduction in opiates: 3.01 vs 1.72 (P \u3c .001) and PS: 7.0 vs 4.9 (P \u3c .001). Stanford Pain Score system reduction in the IVL = 48.3 ± 23.9%, but less effective in narcotic dependency (27 ± 22.9%, P = .035); IVL pts had hospital cost reduction: 118,202 (P \u3c .01). Discussion
In a crossover analysis, IVL is effective for reduction of PS and opiate use and reduces hospital LOS and costs. Patient age may confound interpretation of results. Our data support IVL use in multimodal pain regimens. Future prospective study is warranted
The Molecular Mechanisms of Estrogen Receptor α on Two Single Nucleotide Polymorphisms to Regulate WNT Signaling in Osteoblasts
Get PDFOsteoporosis is the most common bone metabolic disorder, affecting over 200 million people globally. It is characterized by bone mass depletion and microarchitectural deterioration, leading to bone fragility and susceptibility to bone fracture. Genetic factors, estrogen deficiency, and dysregulation of the WNT signaling pathway contribute to the development of this disease. Genome-wide association studies have predicted that the single nucleotide polymorphisms (SNPs) rs2887571 and rs9921222 associate with low bone mass, but the mechanism of these SNPs has remained unknown. Analysis of osteoblasts from 112 different joint replacement patients reveals that the genotype of rs2887571 correlates with WNT5B expression, and the genotype of rs9921222 correlates with AXIN1 expression. Mechanistically, SNP rs2887571 has less binding of ERα and NFATc1 to allele A than allele G, resulting in more expression of WNT5B in homozygous AA than homozygous GG. Furthermore, WNT5B exhibits distinct effects from other WNTs on osteoblastogenesis. WNT5B increases mesenchymal stem cell proliferation, promotes adipogenesis, and suppresses osteoblast differentiation via ROR1/2, then activates DVL2/3, Rac1/Cdc42, JNK, and SIN3A signaling, as well as inhibits ROCK2 and β-catenin activity. For SNP rs9921222, homozygous TT has a higher expression of AXIN1 than homozygous CC. Molecular analysis shows that GATA4 favors binding at rs9921222 allele T to promote AXIN1 expression; in contrast, ERα prefers to bind at allele C to suppress the expression, resulting in more expression of AXIN1 in homozygous TT than homozygous CC. Functionally, the level of AXIN1 negatively correlates with the level of active β-catenin, which enhances osteoblast differentiation. Taken together, the biological mechanisms of SNPs rs2887571 and rs9921222, which are associated with osteoporosis via the WNT signaling pathway, are revealed, as well as the inhibitory effect of WNT5B on osteoblastogenesis. These data will be the fundamental knowledge for the development of osteoporosis prediction and therapeutic strategies
Evaluation and Feasibility of a Head Positioning Intervention in Patients with Intraparenchymal Hemorrhage
Get PDFStroke caused by intraparenchymal hemorrhage (IPH) is most commonly the result of hypertension-induced blood vessel rupture in the brain and is associated with devastating disability and high rates of death. To date, no intervention has improved outcomes in IPH stroke patients; however, head elevation may be one of the most important first steps to promote clinical stability in the hyperacute stage of IPH stroke because of the risk of increased intracranial pressure (ICP) in these patients. Nursing research completed in the late 1970s and early 1980s in patients with increased ICP due to traumatic brain injury showed that elevating the head of bed (HOB) increased gravity drainage of venous blood and cerebrospinal fluid, lowering ICP, However, no study has yet been completed in a generalizable sample of hyperacute IPH stroke patients to examine serial changes in clinical stability in relation to HOB positioning.
Recently, the Head Position in Stroke Trial (HeadPoST), which enrolled a highly heterogeneous sample of subacute stroke patients, found that head position does not affect 3-month outcome; however, the study was heavily criticized by international stroke experts due to significant internal validity concerns. HeadPoST findings have created significant confusion within the acute stroke practice community about whether there is a role for head positioning in hyperacute IPH stroke management.
The focus of our research was to build knowledge of key clinical methods that will support future definitive HOB research in hyperacute IPH stroke patients. We established 1) the clinical knowledge and skill set supporting nurses’ ability to localize stroke disability within vascular territories in the brain and 2) use of the National Institutes of Health Stroke Scale as a valid assessment tool for serial monitoring of clinical change in hyperacute IPH patients. We also 3) examined the degree of acceptance of HeadPoST findings internationally among nurse and physician clinicians caring for IPH stroke patients and 4) evaluated elements tied to the feasibility of conducting hyperacute IPH HOB research at a large, comprehensive stroke center in the Midsouth. Collectively, the chapters in this dissertation create a foundation for future IPH head-positioning research, providing direction for our next steps in understanding the contribution of HOB positioning to hyperacute IPH patient management.
Patients with hypertensive IPH stroke suffer significantly higher rates of disability and death compared to other forms of stroke, yet despite a great deal of inquiry into interventions to improve outcomes, none have been successful. Positioning the patient’s HOB at 30-degrees may be one of the most important early interventions that nurses can employ to impart stability in hypertensive IPH patients. Our research and conclusions position nurse scientists to further their examination of the effect of this simple HOB-positioning intervention in this highly vulnerable patient population
Environmental and Genetic Factors Affecting Bone Diseases and Phenotypes in Mouse Models
Get PDFBone diseases and phenotypes are affected in multiple ways. We focused on studying the effects of genetic and environmental factors, especially their impact on bone properties. Firstly, we investigated the effects of β-caryophyllene (BCP), a naturally occurring dietary cannabinoid, on protecting bone from vitamin D deficiency in mice fed on a diet lacking or supplemented with vitamin D (VD). We found that the VD-deficient diet enhanced the length of femur and tibia bones (P\u3c0.05), and increased bone volume (BV; P\u3c0.01) and the trabecular bone volume fraction (BV/TV; P \u3c0.01) compared to the D+ diet. When given BCP-containing diet, mice exhibited higher BV and bone mineral density (BMD; P\u3c0.05) than the control group. The trabecular and cortical bone were also affected by VD and BCP. In addition, the inclusion of dietary BCP improved the serum concentrations of klotho (P \u3c 0.05). In summary, these data indicate that BCP enhances the level of klotho in the serum, leading to improved bone properties and mineralization in an experimental mouse model. Under conditions lacking UV light, the D-deficient diet could affect multiple properties of bone, including trabecular and cortical bone, in mice. The D-deficient diet can also result in weight loss in mice.
My second project is to evaluate the bone properties in a mouse model with Il-1rn mutation. When knockout for IL-1rn, mice of Balb/c genomic background exhibited susceptibility to spontaneous arthritis disease (SAD), while those of a DBA/1 background were resistant to developing SAD. Our progress on the study of SAD suggested that some of the bone phenotypes, BMD, BV, tibia length, and cortical thickness, were different between wildtype and IL-1rn knockout mice both in Balb/c and DBA/1 strains. The two congenic mouse strains were also evaluated for bone properties. The results revealed that IL-1rn affected BMD differently between Balb/c and DBA/1 mouse strains. The absence of IL-1rn decreased BMD in Balb/c mice and increased BMD in DBA/1 -/- mice compared with wildtype animals. QTL in DBA.B -/- which affect arthritis in congenic strains also regulated BMD, with interferon activated gene 202b (Ifi202b) being the most favored candidate gene for BMD. Our data suggest some of the bone phenotypes are affected by the regulation of gene expression in the context of IL-1ra loss. To our knowledge, this is the first study to investigate the relationship of gene interaction in bone phenotypes with the loss of IL-1ra in an animal model.
In my third study, we studied the different effects between endogenously produced and diet-supplied vitamin C on spontaneous arthritis disease susceptibility. In this study, we sought to investigate whether the source of vitamin C (endogenously produced or exogenously supplied) influences the development of inflammatory arthritis using a mouse model of SAD. SAD-susceptible Balb/c IL-1rn-/- mice were bred with vitamin C-deficient Sfx mice to produce a double mutant (SAD-susceptible, vitamin C-deficient) mouse strain. The three strains were raised, with the double mutant and Sfx mice supplied with vitamin C in drinking water, and mice’s arthritis severity scores were measured biweekly. Incidence and average severity for each strain were calculated. At four months of age, the mice were sacrificed, and body measurements and leg samples were collected. X-ray microcomputed tomography was used to scan the legs to characterize the bone profile. Femur length, tibia length, and bone volume were found to be significantly lower in double mutant mice than in Balb/c IL-1rn-/- mice. There was no significant difference in bone mineral density and femur thickness between the two arthritis-susceptible strains. The double mutant mice had an earlier onset of arthritis as well as a more severe disease than that of the Balb/c knockout (KO) strain. Our findings suggest that the source of vitamin C could affect both the susceptibility of mice to SAD and the severity of disease.
In addition, we examined the sex differences in several mouse models of inflammatory arthritis. To understand the basis for these differences we conducted analysis of several mouse models of inflammatory arthritis. The study of whether there are gender and symmetry differences in experimental arthritis expression in the mouse models may be of significance to the study of human rheumatoid arthritis. Our observations and statistical analyses on the incidence of arthritis in four different animal models incorporated relatively large numbers of mice allowing for robust conclusions. Our research showed that there is a sexual dimorphism for arthritis incidence and severity of arthritis in mice harboring specific genetic modifications. For F2 population the incidence of arthritis was 57.1% in female mice and 75.6% in male mice. There was a difference in severity related to sex in two populations: B6.DR1/ B6.DR4 (P \u3c 0.001) and F2 (P = 0.023). Among these populations, scores for the right hindlimbs were significantly higher than those for the left hindlimbs in males (P\u3c0.05). When examining disease manifestation using the collagen induced arthritis model with DBA/1 mice, sex-dimorphism did not reach statistical significance. However, left hindlimbs showed a tendency toward greater disease expression over the right. Our results suggest that sex difference of arthritis exists in animal models not only in terms of gender, but also of left and right limbs. Using animal models, this work has laid the foundation for future research on gender differences in rheumatoid arthritis.
In conclusion, our studies on genetic and environmental factors regulating bone phenotypes and diseases have significant implications. Not only have they raised the concept of sexual dimorphism in disease, but they have highlighted the influence of genetic background on bone disease. The link between different sources of vitamins and immune-mediated disease is intriguing and warrants further research, as is the bone protective effect of BCP
The Future of Conferences: Adapting to a New Way of Life
Get PDFObjectives This paper examines the changes to conferences over the past year and a half and recommends a path forward. The authors will discuss the challenges and opportunities of these changes and what that can mean for future conferences.
Methods The authors used their own experiences of attending and planning conferences and a review of current literature to develop recommendations for future conference programming.
Results We identified several benefits and challenges of online meetings. The benefits include offering similar content at a lower cost, more flexible and dynamic content, and a broader range of speakers and attendees. The challenges include little to no opportunities to network, fewer collaborative opportunities, and employer willingness to pay for virtual meetings or allow total commitment to attend each session.
Conclusions Conference chairs and planners can use the knowledge and experiences gained from recent experiences to create more engaging and inclusive conferences that can reach a broader audience. They can accomplish this goal by offering hybrid conferences with synchronous and asynchronous events
We’re Virtually There: Providing Health Sciences Education and Wellness through Virtual Reality Experiences
Get PDFFaculty librarians at the Greenblatt Library implemented two innovative approaches for incorporating virtual reality (VR) experiences in health sciences education. The first project involves using VR to develop an escape room that introduces players to research data management principles and best practices. The second project incorporates curriculum-based VR experiences developed for the university’s undergraduate medical students and makes them available through a public space in the health sciences library. The library is centrally located on campus and is open extended hours, allowing for increased access to the VR experiences. Additionally, because burnout and stress are common in the health sciences, relaxation experiences are also available for use
The Effect of Cancer Cachexia Progression on the Feeding Regulation of Skeletal Muscle Protein Turnover
Get PDFCancer cachexia is defined as the unintentional loss of skeletal muscle mass with or without fat loss that cannot be reversed by conventional nutritional support. Cachexia occurs in ~20% of cancer patients. More specifically, 50% of lung cancer patients, the most common cancer worldwide, develop cachexia. Cachexia occurs most often in lung and gastrointestinal cancers, whereas breast and prostate have the lowest rate of cachexia. Cancer-induced cachexia disrupts skeletal muscle protein turnover (decreasing protein synthesis and increasing protein degradation). Skeletal muscle’s capacity for protein synthesis is highly sensitive to local and systemic stimuli that are controlled by mTORC1 and AMPK signaling. During cachexia, altered protein turnover is thought to occur through suppressed anabolic signaling via mTORC1, coinciding with the chronic activation of AMPK. While progress has been made in understanding some of the mechanisms underlying the suppressed anabolic signaling in cachectic muscle, gaps still remain in our understanding of muscle’s ability to respond to anabolic stimulus prior to cachexia development. The purpose of this study was to determine if cachexia progression disrupts the feeding regulation of AMPK signaling and if gp130 signaling and muscle contraction could regulate this process.
Specific aim 1 examined the feeding regulation of skeletal muscle protein synthesis in pre-cachectic tumor bearing mice. Feeding increased muscle protein synthesis, while lowering AMPK signaling in pre-cachectic tumor bearing mice. Importantly, pre-cachectic tumor bearing mice have overall suppressed muscle protein synthesis independent of the fast or fed condition. Muscle specific AMPK loss was sufficient to improve the fasting suppression of muscle mTORC1 and protein synthesis in pre-cachectic tumor bearing mice. Specific aim 2 examined if muscle gp130 signaling regulates the feeding regulation of AMPK during cancer cachexia progression. Muscle gp130 loss lowered the fasting induction of AMPK in pre-cachectic tumor bearing mice without improving protein synthesis. Muscle gp130 loss did not alter the feeding regulation of muscle Akt/mTORC1 signaling and protein synthesis. Specific Aim 3 examined if an acute bout of muscle contractions could improve the muscle protein synthesis response to feeding during the progression of cachexia. Pre-cachectic tumor bearing mice exhibit suppressed protein synthesis in response low frequency electrical stimulation, and the inability to synergistically induce protein synthesis in response to feeding and contraction.
In summary, pre-cachectic tumor bearing mice have lowered Akt/mTORC1 signaling and protein synthesis. Feeding can induce Akt/mTORC1 and protein synthesis and AMPK regulates the fasting suppression of protein synthesis in pre-cachectic tumor bearing mice. While gp130 loss reduces AMPK it is not sufficient to improve protein synthesis in pre-cachectic tumor bearing mice. The added protein synthesis response to feeding and contraction is blunted in pre-cachectic tumor bearing mice. These findings provide novel insight into the regulation of Akt/mTORC1 signaling and protein synthesis in response to feeding. Additionally, these studies highlight gp130’s regulation of AMPK prior to cachexia development, and the blunted anabolic muscle response to feeding and contraction in pre-cachectic tumor bearing mice. By understanding these intracellular signaling processes and perturbations prior to cachexia development, we will be able to elucidate potential therapeutic targets and treatment options to manipulate and prevent cancer cachexia