Browsing by Author "Mendenhall, Stephen K."

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    Cerebellopontine Angle Primary Choroid Plexus Carcinoma Present in an Adult: Case Report and Literature Review
    (Cureus, 2021-02-10) Witten, Andrew J.; Mendenhall, Stephen K.; DeWitt, Logan S.; Vortmeyer, Alexander; Cohen-Gadol, Aaron; Neurological Surgery, School of Medicine
    Choroid plexus tumors (CPTs) are rare intraventricular neoplasms that primarily occur in children and are rare in adults. Of the CPT subtypes, choroid plexus carcinomas (CPC) are highly aggressive and malignant and of World Health Organization (WHO) Grade III. Dissemination through the cerebrospinal fluid space is the inevitable natural course of the disease. In this case report, we present a 33-year-old female with a past medical history notable for schizophrenia and bipolar disease who suffered from left-sided acute vision loss and hearing loss. Magnetic resonance imaging (MRI) demonstrated multiple enhancing masses found in the left cerebellopontine angle (CPA), right internal auditory canal, the atrium of the left ventricle, and the left foramen of Monroe. After surgical decompression of the CPA tumor, the permanent final pathology was consistent with CPC. To our knowledge, this is the first reported case of a primary CPC occurring within the CPA in an adult. The unique presentation and progression of this rare adult-onset CPC provide insight for the diagnosis and treatment of other rare instances of CPTs.
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    Effects of diet, BMP-2 treatment, and femoral skeletal injury on endothelial cells derived from the ipsilateral and contralateral limbs
    (Wiley, 2022) Dadwal, Ushashi C.; Staut, Caio de Andrade; Tewari, Nikhil P.; Awosanya, Olatundun D.; Mendenhall, Stephen K.; Valuch, Conner R.; Nagaraj, Rohit U.; Blosser, Rachel J.; Li, Jiliang; Kacena, Melissa Ann; Orthopaedic Surgery, School of Medicine
    Type 2 diabetes (T2D) results in physiological and structural changes in bone, contributing to poor fracture healing. T2D compromises microvascular performance, which can negatively impact bone regeneration as angiogenesis is required for new bone formation. We examined the effects of bone morphogenetic protein-2 (BMP-2) administered locally at the time of femoral segmental bone defect (SBD) surgery, and its angiogenic impacts on endothelial cells (ECs) isolated from the ipsilateral or contralateral tibia in T2D mice. Male C57BL/6 mice were fed either a low fat diet (LFD) or high fat diet (HFD) starting at 8 weeks. After 12 weeks, the T2D phenotype in HFD mice was confirmed via glucose and insulin tolerance testing and echoMRI, and all mice underwent SBD surgery. Mice were treated with BMP-2 (5μg) or saline at the time of surgery. Three weeks post-surgery, bone marrow ECs were isolated from ipsilateral and contralateral tibias, and proliferation, angiogenic potential, and gene expression of the cells was analyzed. BMP-2 treatment increased EC proliferation by 2 fold compared to saline in LFD contralateral tibia ECs, but no changes were seen in surgical tibia EC proliferation. BMP-2 treatment enhanced vessel-like structure formation in HFD mice whereas, the opposite was observed in LFD mice. Still, in BMP-2 treated LFD mice, ipsilateral tibia ECs increased expression of CD31, FLT-1, ANGPT1, and ANGPT2. These data suggest that the modulating effects of T2D and BMP-2 on the microenvironment of bone marrow ECs may differentially influence angiogenic properties at the fractured limb versus the contralateral limb.
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    The Effects of High Fat Diet, Bone Healing, and BMP-2 Treatment on Endothelial Cell Growth and Function
    (Elsevier, 2021-05) Bhatti, Fazal Ur Rehman; Dadwal, Ushashi C.; Valuch, Conner R.; Tewari, Nikhil P.; Awosanya, Olatundun D.; Staut, Caio de Andrade; Sun, Seungyup; Mendenhall, Stephen K.; Perugini, Anthony J., III; Nagaraj, Rohit U.; Battini, Hanisha L.; Nazzal, Murad K.; Blosser, Rachel J.; Maupin, Kevin A.; Childress, Paul J.; Li, Jiliang; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Angiogenesis is a vital process during the regeneration of bone tissue. The aim of this study was to investigate angiogenesis at the fracture site as well as at distal locations from obesity-induced type 2 diabetic mice that were treated with bone morphogenetic protein-2 (BMP-2, local administration at the time of surgery) to heal a femoral critical sized defect (CSD) or saline as a control. Mice were fed a high fat diet (HFD) to induce a type 2 diabetic-like phenotype while low fat diet (LFD) animals served as controls. Endothelial cells (ECs) were isolated from the lungs (LECs) and bone marrow (BMECs) 3 weeks post-surgery, and the fractured femurs were also examined. Our studies demonstrate that local administration of BMP-2 at the fracture site in a CSD model results in complete bone healing within 3 weeks for all HFD mice and 66.7% of LFD mice, whereas those treated with saline remain unhealed. At the fracture site, vessel parameters and adipocyte numbers were significantly increased in BMP-2 treated femurs, irrespective of diet. At distal sites, LEC and BMEC proliferation was not altered by diet or BMP-2 treatment. HFD increased the tube formation ability of both LECs and BMECs. Interestingly, BMP-2 treatment at the time of surgery reduced tube formation in LECs and humeri BMECs. However, migration of BMECs from HFD mice treated with BMP-2 was increased compared to BMECs from HFD mice treated with saline. BMP-2 treatment significantly increased the expression of CD31, FLT-1, and ANGPT2 in LECs and BMECs in LFD mice, but reduced the expression of these same genes in HFD mice. To date, this is the first study that depicts the systemic influence of fracture surgery and local BMP-2 treatment on the proliferation and angiogenic potential of ECs derived from the bone marrow and lungs.
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    Gene-metabolite networks associated with impediment of bone fracture repair in spaceflight
    (Elsevier, 2021-06-08) Chakraborty, Nabarun; Zamarioli, Ariane; Gautam, Aarti; Campbell, Ross; Mendenhall, Stephen K.; Childress, Paul J.; Dimitrov, George; Sowe, Bintu; Tucker, Aamir; Zhao, Liming; Hammamieh, Rasha; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Adverse effects of spaceflight on musculoskeletal health increase the risk of bone injury and impairment of fracture healing. Its yet elusive molecular comprehension warrants immediate attention, since space travel is becoming more frequent. Here we examined the effects of spaceflight on bone fracture healing using a 2 mm femoral segmental bone defect (SBD) model. Forty, 9-week-old, male C57BL/6J mice were randomized into 4 groups: 1) Sham surgery on Ground (G-Sham); 2) Sham surgery housed in Spaceflight (FLT-Sham); 3) SBD surgery on Ground (G-Surgery); and 4) SBD surgery housed in Spaceflight (FLT-Surgery). Surgery procedures occurred 4 days prior to launch; post-launch, the spaceflight mice were house in the rodent habitats on the International Space Station (ISS) for approximately 4 weeks before euthanasia. Mice remaining on the Earth were subjected to identical housing and experimental conditions. The right femur from half of the spaceflight and ground groups was investigated by micro-computed tomography (µCT). In the remaining mice, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomic and metabolomic assays. µCT confirmed escalated bone loss in FLT-Sham compared to G-Sham mice. Comparing to their respective on-ground counterparts, the morbidity gene-network signal was inhibited in sham spaceflight mice but activated in the spaceflight callus. µCT analyses of spaceflight callus revealed increased trabecular spacing and decreased trabecular connectivity. Activated apoptotic signals in spaceflight callus were synchronized with inhibited cell migration signals that potentially hindered the wound site to recruit growth factors. A major pro-apoptotic and anti-migration gene network, namely the RANK-NFκB axis, emerged as the central node in spaceflight callus. Concluding, spaceflight suppressed a unique biomolecular mechanism in callus tissue to facilitate a failed regeneration, which merits a customized intervention strategy.
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    The Natural History of Coiled Cerebral Aneurysms Stratified by Modified Raymond-Roy Occlusion Classification
    (Elsevier, 2019) Mendenhall, Stephen K.; Sahlein, Daniel H.; Wilson, Christopher D.; Filley, Anna C.; Ordaz, Josue; Ahluwalia, Rahul K.; Bakare, Wale A.; Huh, Andrew; Dancour, Elie; Zaazoue, Mohamed A.; Shapiro, Scott A.; Cohen-Gadol, Aaron A.; Neurological Surgery, School of Medicine
    Objective The natural history and long-term durability of Guglielmi detachable coil (GDC) embolization is still unknown. We hypothesize a stepwise decrease in durability of embolized cerebral aneurysms as stratified by the Modified Raymond-Roy Classification (MRRC). Methods First-time GDC-embolized cerebral aneurysms were retrospectively reviewed from 2004 to 2015. Loss of durability (LOD) was defined by change in aneurysm size or patency seen on serial radiographic follow-up. Kaplan-Meier survival analysis was performed to evaluate embolization durability. Multivariate Cox regression modeling was used to assess baseline aneurysm and patient characteristics for their effect on LOD. Results A total of 427 patients with 443 aneurysms met the inclusion criteria. Overall, 89 (21%) aneurysms met LOD criteria. Grade 1 aneurysms had statistically significantly greater durability than did all other MRRC grades. Grade 3b aneurysms had significantly worse durability than did all other aneurysm grades. There was no difference in durability between grade 2 and 3a aneurysms. Of aneurysms with LOD, 26 (29%) experienced worsening of MRRC grade. Thirty-five (24%) initial MRRC grade 2, 72 (45%) initial MRRC grade 3a, and 6 (22%) initial MRRC grade 3b aneurysms progressed to MRRC grade 1 without retreatment. In our multivariate analysis, only initial MRRC grade was statistically significantly associated with treatment durability (P < 0.001). Conclusions MRRC grade is independently associated with first-time GDC-embolized cerebral aneurysm durability. Achieving MRRC grade 1 occlusion outcome is significantly associated with greater long-term GDC durability. Although few aneurysms experience further growth and/or recanalization, most incompletely obliterated aneurysms tend to remain stable over time or even progress to occlusion. Grading scales such as the MRRC are useful for characterizing aneurysm occlusion but may lack sensitivity and specificity for characterizing changes in aneurysm morphology over time.
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    The Effects of Bone Morphogenetic Protein 2 and Thrombopoietin Treatment on Angiogenic Properties of Endothelial Cells Derived from the Lung and Bone Marrow of Young and Aged, Male and Female Mice
    (Wiley, 2021) Dadwal, Ushashi C.; Bhatti, Fazal Ur Rehman; Awosanya, Olatundun D.; Nagaraj, Rohit U.; Perugini, Anthony J., III.; Sun, Seungyup; Valuch, Conner R.; Staut, Caio de Andrade; Mendenhall, Stephen K.; Tewari, Nikhil P.; Mostardo, Sarah L.; Nazzal, Murad K.; Battina, Hanisha L.; Zhou, Donghui; Kanagasabapathy, Deepa; Blosser, Rachel J.; Mulcrone, Patrick L.; Li, Jiliang; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    With an aging world population, there is an increased risk of fracture and impaired healing. One contributing factor may be aging-associated decreases in vascular function; thus, enhancing angiogenesis could improve fracture healing. Both bone morphogenetic protein 2 (BMP-2) and thrombopoietin (TPO) have pro-angiogenic effects. The aim of this study was to investigate the effects of treatment with BMP-2 or TPO on the in vitro angiogenic and proliferative potential of endothelial cells (ECs) isolated from lungs (LECs) or bone marrow (BMECs) of young (3-4 months) and old (22-24 months), male and female, C57BL/6J mice. Cell proliferation, vessel-like structure formation, migration, and gene expression were used to evaluate angiogenic properties. In vitro characterization of ECs generally showed impaired vessel-like structure formation and proliferation in old ECs compared to young ECs, but improved migration characteristics in old BMECs. Differential sex-based angiogenic responses were observed, especially with respect to drug treatments and gene expression. Importantly, these studies suggest that NTN1, ROBO2, and SLIT3, along with angiogenic markers (CD31, FLT-1, ANGPT1, and ANGP2) differentially regulate EC proliferation and functional outcomes based on treatment, sex, and age. Furthermore, treatment of old ECs with TPO typically improved vessel-like structure parameters, but impaired migration. Thus, TPO may serve as an alternative treatment to BMP-2 for fracture healing in aging owing to improved angiogenesis and fracture healing, and the lack of side effects associated with BMP-2.