1997 research outputs found
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Neuromedin-U (NMU) negatively regulates bone remodeling
No full textOsteoporosis, a disease of low bone density that occurs when bone resorption ex-ceeds bone formation, places individuals at a higher risk for fracture and disability. We previously reported that deletion of the Bmpr2 gene in embryonic skeletal progenitor cells causes substantially elevated bone density in young adulthood and reduced age-related decline in bone density associated with elevated bone formation rate. Notably, bone-specific expression of the neuropeptide Neuromedin-U (Nmu) is inversely correlated with serum levels of the bone formation marker PINP in Bmpr2-cKO mice and a prior study reported global knockout of Nmu causes high bone mass. Together, these findings suggest that NMU, which is processed into two isoforms (NMU-8 and NMU-25) and signals via two GPCRs (NMU Receptor 1 (NMUR1) and NMU Receptor 2 (NMUR2)), is a negative regulator of osteoblast differentiation and/or activity. The molecular mechanism(s) by which these effects occur are unknown. Here, we provide secondary confirmation of a high bone mass phenotype in the absence of NMU func-tion, with tibiae BV/TV elevated 32% in 12-week-old female Nmu knockout mice (p-value=0.046). We additionally examine the bone-specific cell communication events that are associated with NMU-deficiency using high-throughput phospho-profiling anti-body arrays, which allow detection of ~300 targets using very small quantities of protein. This revealed decreased activation of the mTOR pathway in tibiae of Nmu knock-out mice compared to controls, with reduced activity-associated phosphorylation of mTOR and the mTOR target ribosomal protein S6. To begin establishing the skeletal NMU pathway, we determined that both Nmur1 and Nmur2 are expressed in bone and osteogenic cells. Cell-based in vitro assays indicate that NMU-25 reduces osteoblastic differentiation of W-20-17 murine bone marrow stromal cells (BMSCs) whereas NMU-8 has no effect on osteoblastic differentiation. In contrast, NMU-8 treatment of differenti-ated W-20-17 cells leads to increased proliferation whereas NMU-25 does not. Consistent with this, NMU-8 treatment of the osteoblast-like cell line MC3T3-E1 leads to increased proliferation and expression of alkaline phosphatase. Phospho-profiling ar-rays are currently underway to examine the mechanism(s) allowing for differential effects between NMU-8 and NMU-25 and the response of undifferentiated BMSCs versus osteoblastic cells. Collectively, our work highlights a novel factor associated with bone remodeling and may identify a new opportunity for treating low bone density in humans
The cytotoxic role of the inhibition of different steps in the PI-3-kinase pathway and acto-myosin cross bridge formation in human metastatic breast cancer cells
No full textIntroduction: Externally added survival/growth factors are essential for the survival of healthy cells, however cancer cells are believed to be self-sufficient in supporting their auto-proliferation without the need of exogenously added growth factors. The Phospha-tidyl-Inositol-3-kinase (PI-3-kinase) pathway is crucial in cell survival. Also, cancer cells exhibit enhanced potential to metastasize via increased acto-myosin cross bridges formation which requires increased Ca2+ influx via cell surface voltage-gated Ca2+ channels leading to activation of myosin light chain kinase (MLCK). The MLCK then phosphorylates myosin and forms acto-myosin cross-bridges. The role of MLCK, PI-3-kinase, and calcium channel in cancer cell growth has not been extensively tested. In this study, we tested the individual effects of blocking cell survival pathway (PI-3 kinase), voltage-gated Ca2+ channels, and MLCK on human metastatic breast cancer cell line (MCF-7) survival. Hypothesis: We hypothesized that all three drugs would inhibit cell proliferation. Aims: Our aim was to firstly test if these drugs had any effect at all on cancer cell growth. Secondly, it was to test each drug at different concentrations and see which concentration had the most effect on cell death. Methods: PI-3-kianse inhibitor (Wortmannin); MLCK inhibitor (ML-7), and lastly, a calcium channel inhibitor (nifedipine) were used. 1% Bitter melon extract (BME) was also tested as this was found to inhibit MCF-cell growth in our lab by earlier investigators. Cells were thawed, mixed with a medium that contained all essential nutrients for cell growth (DMEM + fetal bovine serum), and then were added onto 96-well plates and allowed to grow for 48 hours. We incorporated control plates (no drug), plates with drugs at different concentrations, a plate with the compound the drug was originally dissolved in (DMSO or ethanol), and a plate with 1% BME (bitter melon extract). The plates were analyzed under a microscope and cell viability was measured using MTT assays. Results and Discussion: All three drugs inhibited cell growth in a dose-dependent manner. The observable differences between the different drugs were the concentrations at which they were effective. Images of each plate were taken and correlated with the MTT assay graphs. Acknowledgement: The research was partially supported by the Research and Honors and Awards Committees at MU-CO
Targeting DNA-PK and the DNA Damage Response via Small Molecule Ku Inhibitors
No full textThe DNA dependent protein kinase (DNA-PK) is a validated target for cancer therapeutics that drives the DNA damage response (DDR) and plays a critical role as a primary sensor in the non-homologous end joining (NHEJ) DNA double strand break (DSB) repair pathway. Various anti-cancer therapeutic strategies mediate their cytotoxic effects by inducing DSBs, inducing ionizing radiation (IR), and clinical outcomes are directly related to the repair of DNA damage. Modulating the pathway responsible for repairing DSBs will have a profound impact on the efficacy of DNA damaging agents in the clinic. To date, development of inhibitors for DNA-PK has focused on targeting the active site with ATP mimetics. We have taken the novel and innovative approach to inhibiting DNA-PK via blocking the Ku 70/80 heterodimer interaction with DNA, a necessary step in DNA-PK activation. Exploiting this unique mechanism of kinase activa-tion, we have identified a series of highly potent and specific DNA-PK inhibitors that impart their inhibitory activity via disruption of the binding of Ku protein to DNA ends. This novel approach affords significant advantages to current approaches in kinase inhibition. Novel derivatives of our initial hit inhibit DNA-PK catalytic activity at nanomo-lar concentrations and potentiate cellular sensitivity to DSB-inducing agents like etopo-side and bleomycin. Data demonstrate that the cellular effects observed are a function of Ku inhibition and that this novel class of DNA-PK inhibitors can be further developed as anti-cancer therapeutics that can be used as an adjuvant to, or concomitant with radiotherapy and other cancer therapies that induce DNA damage
Implementing Mindfulness Meditation Among Nurse Anesthesia Students to Decrease Stress and Anxiety and Improve Self-Awareness
Get PDFThroughout the country, Student Registered Nurse Anesthetists (SRNAs) are experiencing stress at an alarming rate. While stress is unavoidable, it tends to upset academic and clinical performance and overall health. This project was the implementation of mindfulness meditation among nurse anesthesia students to decrease stress and anxiety and improve self-awareness. The implementation of mindfulness meditation among nurse anesthesia students to decrease stress and anxiety and improve self-awareness will subsequently enhance the ability to learn. Literature supports the effects and importance of mindfulness interventions to reduce stress, anxiety, improve self-efficacy, resiliency and general health. Mindfulness interventions are not routinely incorporated into graduate nursing curricula; therefore, students are not learning these types of stress reduction techniques needed on a day-to-day basis. This study selected a convenience sample of nurse anesthesia students enrolled in the only two programs in Indiana. A pre/postsurvey via the Perceived Stress Scale-14 along with instructions to download the Mindfulness app to a mobile device and utilize it for 10 minutes a day for 14 days. Upon completion of the mindfulness meditation implementation, a reassessment of the perceived stress level of each participant was administered post-final exams of the spring semester. Findings suggest that the implementation of the Mindfulness app for meditation can be fundamentally related to decreased perceived stress and improve self-awareness among nurse anesthesia students
Kathleen Robertson
Get PDFIn this entry Jesus describes the impact his friend and neighbor, Kathleen Robertson has had upon him. Mancera describes both the eccentricity and courage Kathleen displays in working toward a more just and equitable society, starting in their their neighborhood
Experience with and perception of research among first year osteopathic medical students
No full textThere are limited data regarding the research experience and/or interest among osteopathic medical students despite a rapidly increasing enrollment and expansion of the number of osteopathic medical schools. A 2016 study of first-year osteopathic medical students at WesternU/COMP and WesternU/COMP-NW indicated that 81% of respondents had prior research experience and 75% were either currently doing research or were interested in doing research during medical school. Here, we extended that survey to Marian University College of Osteopathic Medicine to determine the research experience and interest among first-year osteopathic medical students. Based on a response rate of 55.69%, a majority of respondents reported prior research experience (91.34%), with 19.49% of those students having garnered peer-reviewed publication(s). This is consistent with a strong perception of research being valuable, with 98.81% indicating some level of importance and 47.62% indicating very or extremely important. Interestingly, fewer respondents (71.95%) are either currently participating in research or affirmed interest in performing research during medical school, with the highest level of interest in clinical research (28.13%) followed by basic science (20.7%). Regarding incentives that might encourage participation in research, respondents prefer monetary compensation (46.25%) and/or extra credit in courses (29.38%). Reported barriers to performing research include possible negative impact on coursework (62.18%) and preference for other extracurricular activities (16.81%). Although a majority of the students (85.71%) reported awareness that research opportunities are available, fewer (56.09%) were aware of whether opportunities exist in their specific field of interest. Our findings indicate a strong positive perception of research among MU-COM students and highlight opportunities for improved communication and enhancement of the research environment through incentivization and/or removal of perceived barrier
Community Paramedicine/Mobile Integrated Healthcare in The United States
No full textMobile Integrated Healthcare (MIH), also called Community Paramedicine (CP) or EMS 3.0, is a novel approach to prehospital care. With the use of specially trained paramedics, MIH-CP seeks to fill the current healthcare gaps in communities by facilitating an interconnected healthcare system. This project investigates current United States MIH-CP legislation in effort to provide Indiana Department of Homeland Security with updated regulations to aid in formulating future MIH-CP policy recommendations. Information was collected by primary literature review of state legislation. Data collected was based off 3 criteria: whether the state mentioned MIH-CP in their regulations, were educational standards outlined and the details of their requirements, and was it possible to bill for MIH-CP services. Numerical data that was collected was analyzed by comparing the mean and median of the applicable states. There are currently 24 states that mention MIH-CP in their state legislation but far more states have the practice occurring without regulations. Of those 24 states, 9 of them have outlined requirements for what a para-medic must accomplish in order to earn the title of Community Paramedic. Within these states there is great variance in the minimum standards of educational requirements ranging from 10 hours up to 300 hours. There was a mean requirement of 68.4 hours and a median requirement of 100 hours. Although 24 states have regulations for MIH-CP, only 8 states have laws that allow some kind of reimbursement for a community paramedic’s service. MIH-CP’s role in the EMS system is just beginning to be realized but current legislation is lagging behind. Without clear guidelines and regulations, EMS agencies must overcome obstacles that are slowing progress and hindering care. It is up to state legislators to capitalize on the potential of MIH-CP by enacting clear regulations that allow for a patient centered and interconnected healthcare system to emerge
A 3D Visualization of Depression and Anxiety
No full textThe goal of this project is to build a teaching tool geared towards patients, students, and clinicians to further educate themselves about the anatomical and biochemical implications of various syndromes involving depression and anxiety. Secondarily, we also want to inform patients, students, and clinicians about the most common treatment methods used to treat these syndromes. We achieved this by mapping the mesolimbic system and other relevant neuroanatomical structures using a high-resolution cryosec-tion dataset made available by the Big Brain project at McGill University using cutting-edge 3D analysis software tools. The results of this project were compiled into a series of three videos serving each of the goals. The first video described the neuroanatomical structures involved in syndromes of depression and anxiety along with their functions. The second video describes various forms of clinical depression and treatment options, including the mechanism of action and how it applies to the underlying disease process. The third video did the same but described anxiety rather than depression. This tool we developed is important because it explains neuroanatomical and biochemical aspects of these syndromes in a straight-forward and easy-to-understand visual manner. It also describes the context of the best pharmacological interventions for each syndrome, which is a substantial step to help engage patients in their personalized mental health treatment plan
Fracture Healing and Pain Tolerance in Aging Populations
No full textIntroduction: Delayed fracture healing is associated with increased morbidity and mortality, and patients with fractures suffer from injury-associated pain as well as post- operative surgical pain. Age is associated with an increased risk of fracture and delayed/impaired fracture healing. Opioids are commonly prescribed for post-orthopedic pain mitigation. Opioids, beyond eliciting cognitive impairment, are commonly associated with tolerance and addiction. This class of drugs, including buprenorphine, may also be associated with a slower resolution of pain and functional status. Objective: Here we used a mouse femoral segmental bone defect (SBD) bone repair model to examine the impact of opioids and fracture/fracture healing on pain behaviors in old and young mice. Methods: Young (3-4-month-old) and old (22-24-month-old) C57BL/6 male mice underwent a SBD surgery (8-10 mice/group). Animals were treated with either bone morphogenetic protein 2 (BMP-2) or vehicle (saline). Bone healing was examined via longitudinal x-rays and terminal micro-computed tomography (μCT). All mice were subjected to a three-day course of buprenorphine. Stimulus dependent mechanical and thermal pain thresholds as well as stimulus independent locomotion activity and exploration behavior were determined before and after SBD surgery/opioid exposure. Addition-ally, asymmetric directed pain behaviors including flinching, licking, lifting, shaking of the ipsilateral hindlimb were assayed in both treatment groups at post-injury timepoints using 20- minute-long video sessions by blinded observers. All animal procedures were approved by the Indiana University IACUC. Results: The ability of BMP-2 to enhance SBD bone union was evident by 2 weeks post-surgery (x-ray) and the return to pre-injury levels of ambulation/locomotion activity was observed by week 4. Vehicle-treated SBD mice did not meet these milestones even at 8 weeks post-surgery. The relative change in tactile allodynia was determined between baseline and 2 weeks post-surgery for young and old mice treated with saline or BMP-2. Contrary to what would be expected, all 4 groups: old, young, healed and unhealed had a reduction of their pain threshold by ~70% at 2 weeks post-surgery (p\u3e0.05). Stimulus- independent pain behavior was also evident in both vehicle and BMP-2 treated CSD animals as defined by asymmetric directed behaviors including flinching, licking, lifting, and shaking of the ipsilateral hindlimb. Conclusion: The data indicates that post-fracture pain thresholds are similar between both healed and unhealed, young and old mice. Therefore, the effect of musculoskele-tal injury and/or buprenorphine may be responsible for the pain experienced following trauma. Distinguishing between these will be critical for further understanding how to best treat acute and chronic pain associated with musculoskeletal injury, particularly for geriatric patients
School Success Clinic
No full textThe work of children is school; despite this, medical providers and educators often live completely separately in their child-family interactions from one another. Yet, medical issues impact school success and school issues are commonly brought by families to the primary care provider. Evaluation of children with school needs frequently takes place in a silo of school or the medical domain. Our team recognized the potential to bring together medical, psychosocial, and educational information to promote access to educational supports and medical care from a whole person model. The School Success Clinic focuses on children and adolescents with academic under-achievement to provide developmentally sensitive medical evaluation with emphasis on medical and psychosocial risk factors for learning differences/needs.The clinic combines medical techniques including medical history taking and physical examination together with psychological interview techniques and psychological testing interpretation. The clinic works with community schools and families to communicate the medical-educational information around the child’s school needs; with primary care providers on the medical interventions (e.g. hearing testing, vision testing); with school to discuss need based accommodation planning, initiation of psychoeducational evaluation, and to share eligibility making diagnoses. The Developmental-behavioral pediatrician uses a triage model for children and youth referred from primary care providers and subspecialty care providers during initial en-counter to determine the level of need and next steps. Engagement with the child psychologist includes diagnostic assessment, guidance through testing interpretation, and psychosocial recommendations. Teacher input allows families with additional needs to have individualized supports when working with the school, access to educational accommodation and law information, among other resources. Medical and education trainees are likewise trained within the clinic with focus on their needs for current and future practice. From a 1 year pilot of the clinic, the majority of referred children are in elementary school (\u3c11 years). The clinical needs have been broken into 3 large categories: children and youth without current educational supports needing psychoeducational evaluation, children and youth with current educational supports needing addition-alternative supports, children and youth with excellent educational supports needing family education about the child’s needs. Common diagnoses from the clinic include Intellectual Disability, Developmental Delay(s), sleep problems, and anxiety disorder/anxiousness. Community partnerships have developed with the Indiana Department of Education and local family educational advocacy group IN*Source as well as a special education educator