Recent Submissions

  • The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System

    Tao, Z.-Y.; Wang, P.-X.; Traub, R.J. (Hindawi Limited, 2019)
    Chronic primary pain (CPP) is a group of diseases with long-term pain and functional disorders but without structural or specific tissue pathologies. CPP is becoming a serious health problem in clinical practice due to the unknown cause of intractable pain and high cost of health care yet has not been satisfactorily addressed. During the past decades, a significant role for the descending pain modulation and alterations due to specific diseases of CPP has been emphasized. It has been widely established that central sensitization and alterations in neuroplasticity induced by the enhancement of descending pain facilitation and/or the impairment of descending pain inhibition can explain many chronic pain states including CPP. The descending serotonergic neurons in the raphe nuclei target receptors along the descending pain circuits and exert either pro- or antinociceptive effects in different pain conditions. In this review, we summarize the possible underlying descending pain regulation mechanisms in CPP and the role of serotonin, thus providing evidence for potential application of analgesic medications based on the serotonergic system in CPP patients. Copyright 2019 Zhuo-Ying Tao et al.
  • Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice

    Moyer, A.L.; Lovering, R.; Rovira Gonzalez, Y.I. (American Society for Clinical Investigation, 2019)
    Myostatin is a negative regulator of muscle growth and metabolism and its inhibition in mice improves insulin sensitivity, increases glucose uptake into skeletal muscle, and decreases total body fat. A recently described mammalian protein called MSS51 is significantly downregulated with myostatin inhibition. In vitro disruption of Mss51 results in increased levels of ATP, ?-oxidation, glycolysis, and oxidative phosphorylation. To determine the in vivo biological function of Mss51 in mice, we disrupted the Mss51 gene by CRISPR/Cas9 and found that Mss51-KO mice have normal muscle weights and fiber-type distribution but reduced fat pads. Myofibers isolated from Mss51-KO mice showed an increased oxygen consumption rate compared with WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid ?-oxidation were enhanced in skeletal muscle of Mss51-KO mice compared with that of WT mice. We found that mice lacking Mss51 and challenged with a high-fat diet were resistant to diet-induced weight gain, had increased whole-body glucose turnover and glycolysis rate, and increased systemic insulin sensitivity and fatty acid ?-oxidation. These findings demonstrate that MSS51 modulates skeletal muscle mitochondrial respiration and regulates whole-body glucose and fatty acid metabolism, making it a potential target for obesity and diabetes.
  • Intraoperative Fragmentation and Retention of Endovascular Devices: Clinical Consequences and Preventative Strategies

    Endicott, K.M.; Drucker, C.B.; Orbay, H.; DuBose, J.J.; Nagarsheth, K.; Toursavadkohi, S.; Sarkar, R. (SAGE Publications Inc., 2020)
    Background: Expanded applications and increasing volumes of complex endovascular procedures have increased the risk of unintended intraoperative fragmentation and retention of catheters and sheaths. We describe a series of retained or fragmented endovascular devices, a quality improvement program to address this unmet need for improved detection of catheter fragmentation, and the results of this program. Methods: Cases utilizing endovascular devices that resulted in a retained catheter fragment were identified and analyzed during divisional quality improvement review. One consistent area of concern was operating room (OR) staff unfamiliarity with verifying the integrity of an endovascular device. In response, a slide-based training protocol of focused, endovascular nursing education was implemented. Following perceived lack of improvement after this approach, we developed a handheld visual reference display of the tips of common catheters and sheaths. Staff was surveyed before and after intervention to assess the educational value of the display and the impact on staff device familiarity. Results: All 4 described cases resulted in an unplanned return to the OR for retrieval of the fragmented catheter or sheath. No thromboembolic complications were observed, although associated intra-arterial thrombus was noted in 2 cases. Thirty-four OR nurses were polled to trial the visual reference display initiative, with 70% of those reporting primary surgical assignments outside of cardiovascular ORs. Introduction of the new visual reference display improved staff confidence in their ability to identify a broken device (2.4-3.7, P <.001). This improvement was most significant in OR staff with primary assignments in noncardiovascular services. Conclusion: Current OR standard operating procedures fail to address the potential for unintentionally retained catheters and wires during endovascular procedures. Our novel visual reference display of common endovascular items rather than conventional in-service training improved the ability of staff to identify device fragmentation at the time of the index procedure. Copyright The Author(s) 2019.
  • Recognizing Hemiparetic Ankle Deficits Using Wearable Pressure Sensors

    Ramadan, A.; Roy, A.; Smela, E. (Institute of Electrical and Electronics Engineers Inc., 2019)
    Objective: To provide proof-of-concept for a novel method to recognize impaired push-off and foot-drop deficits in hemiparetic gait using analog pressure sensors. These data may enhance feedback from a modular ankle exoskeleton (such as Anklebot) for stroke rehabilitation, which now employs on/off foot switches under the foot. Methods: A pressure sensor was positioned on the posterior side of the calcaneus. Experiments were conducted on two healthy subjects with normal walking and with hip circumduction and foot drop, the latter to mimic hemiparetic gait post-stroke. Results: Unlike the foot switches, the pressure sensor yielded data during swing. The initial swing and terminal stance readings followed local foot-shoe dynamics and were thus able to detect foot drop swing deficits while also providing push-off information during stance. Discussion: The analog pressure sensors provided more information than foot switches, even during stance. This system may provide clinicians with a tool to monitor foot drop and push-off.
  • Stem cells in the periodontal ligament differentiated into osteogenic, fibrogenic and cementogenic lineages for the regeneration of the periodontal complex

    Liu, J.; Zhao, Z.; Weir, M.D.; Ma, T.; Ren, K.; Schneider, A.; Oates, T.W.; Xu, H.H.K. (Elsevier Ltd, 2020)
    Objective Human periodontal ligament stem cells (hPDLSCs) are promising for periodontal regeneration. However, to date, there has been no report of hPDLSC differentiation into the fibrogenic lineage. There has been no report demonstrating hPDLSC differentiation into all three (osteogenic, fibrogenic and cementogenic fibrogenic) lineages in the same report. The objectives of this study were to harvest hPDLSCs from the periodontal ligaments (PDL) of the extracted human teeth, and use the same vial of hPDLSCs to differentiate into all three (osteogenic, fibrogenic and cementogenic) lineages for the first time. Methods hPDLSCs were harvested from PDL tissues of the extracted premolars. The ability of hPDLSCs to form bone, cementum and collagen fibers was tested in culture mediums. Gene expressions were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Immunofluorescence, alizarin red (ARS), Xylenol orange, picro sirius red staining (PSRS), alcian blue staining (ABS) and alkaline phosphatase (ALP) staining were evaluated. Results In osteogenic medium, hPDLSCs had high expressions of osteogenic genes (RUNX2, ALP, OPN and COL1) at 14 and 21 days (15–20 folds of that of control), and produced mineral nodules and ALP activity (5 and 10 folds those of the control). hPDLSCs in fibrogenic medium expressed high levels of PDL fibrogenic genes (COL1, COL3, FSP-1, PLAP-1 and Elastin) at 28 days (20–70 folds of control). They were stained strongly with F-actin and fibronection, and secreted PDL collagen fibers (5 folds of control). hPDLSCs in cementogenic medium showed high expressions of cementum genes (CAP, CEMP1 and BSP) at 21 days (10–15 folds of control) and synthesized mineralized cementum (50 folds via ABS, and 40 folds via ALP staining, compared to those of control). Conclusions hPDLSCs differentiated into bone-, fiber- and cementum-forming cells, with potential for regeneration of periodontium to form the bone-PDL-cementum complex.
  • Two-staged time-dependent materials for the prevention of implant-related infections

    Weir, M.D.; Oates, T.W.; Xu, H.H.K. (Elsevier, 2020)
    Infection is a main cause of implant failure. Early implant-related infections often occur in the first 4 weeks post-operation. Inhibiting bacterial adhesion and biofilm formation at the early stage and promoting subsequent implant osseointegration are important for implant success. Our previous studies demonstrated that dimethylaminododecyl methacrylate (DMADDM) provided dental materials with antibacterial effects. In the present study, DMADDM and hydroxyapatite (HA) are loaded on to the titanium (Ti) surface via poly dopamine (PDA) self-polymerization. This local DMADDM-delivery Ti is referred as Ti-PHD. Here we report the two-staged capability of Ti-PHD: (1) in the first stage, releasing DMADDM during the high-infection-risk initial period post-implantation for 4 weeks; (2) then in the second stage, enhancing osteogenesis and promoting osseointegration. Ti-PHD has a porous surface with higher average roughness and greater hydrophilicity than pure Ti. Its biocompatibility is verified in vitro and in vivo. During the first 4 weeks of release, both DMADDM remaining on Ti surface and DMADDM released into the soaking medium greatly reduced the adherence and growth of pathogens. This is further confirmed by the prevention of bone destruction in a rat osteomyelitis model. After releasing DMADDM for 4 weeks, Ti-PHD promotes osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) and new bone formation around the implants in vivo. This article represents the first report on the two-staged, time-dependent antibacterial and osteogenesis effects of Ti-PHD, demonstrating its potential for clinical applications to inhibit implant-associated infections. Statement of Significance: The present study develops a two-staged time-dependent system for local dimethylaminododecyl methacrylate (DMADDM) delivery via Ti implant (referred to as Ti-PHD). DMADDM and hydroxyapatite (HA) are loaded on to the Ti surface with poly dopamine (PDA). Ti-PHD can release DMADDM during the high-risk period of infection in the first stage, and then promote osseointegration and new bone formation in the second stage. This bioactive and therapeutic Ti is promising to inhibit infections and enhance implant success.
  • Classical Schizophrenia: Liddle and the Core of Schizophrenia

    Carpenter, W.T. (SAGE Publications Inc., 2019)
  • High-affinity binding of plasminogen-activator inhibitor 1 complexes to LDL receptor-related protein 1 requires lysines 80, 88, and 207

    Migliorini, M.; Li, S.-H.; Zhou, A. (American Society for Biochemistry and Molecular Biology, 2020)
    It is well-established that complexes of plasminogen-activator inhibitor 1 (PAI-1) with its target enzymes bind tightly to low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), but the molecular details of this interaction are not well-defined. Furthermore, considerable controversy exists in the literature regarding the nature of the interaction of free PAI-1 with LRP1. In this study, we examined the binding of free PAI-1 and complexes of PAI-1 with low-molecular-weight urokinase-type plasminogen activator to LRP1. Our results confirmed that uPA:PAI-1 complexes bind LRP1 with ?100-fold increased affinity over PAI-1 alone. Chemical modification of PAI-1 confirmed an essential requirement of lysine residues in PAI-1 for the interactions of both PAI-1 and uPA:PAI-1 complexes with LRP1. Results of surface plasmon resonance measurements supported a bivalent binding model in which multiple sites on PAI-1 and uPA:PAI-1 complexes interact with complementary sites on LRP1. An ionic-strength dependence of binding suggested the critical involvement of two charged residues for the interaction of PAI-1 with LRP1 and three charged residues for the interaction of uPA:PAI-1 complexes with LRP1. An enhanced affinity resulting from the interaction of three regions of the uPA:PAI-1 complex with LDLa repeats on LRP1 provided an explanation for the increased affinity of uPA:PAI-1 complexes for LRP1. Mutational analysis revealed an overlap between LRP1 binding and binding of a small-molecule inhibitor of PAI-1, CDE-096, confirming an important role for Lys-207 in the interaction of PAI-1 with LRP1 and of the orientations of Lys-207, -88, and -80 for the interaction of uPA:PAI-1 complexes with LRP1. Copyright 2020 Migliorini et al.
  • Breaking the selectivity-uptake trade-off of photoimmunoconjugates with nanoliposomal irinotecan for synergistic multi-tier cancer targeting

    Liang, B.J.; Pigula, M.; Huang, H.-C. (BioMed Central Ltd., 2020)
    Background: Photoimmunotherapy involves targeted delivery of photosensitizers via an antibody conjugate (i.e., photoimmunoconjugate, PIC) followed by light activation for selective tumor killing. The trade-off between PIC selectivity and PIC uptake is a major drawback limiting the efficacy of photoimmunotherapy. Despite ample evidence showing that photoimmunotherapy is most effective when combined with chemotherapy, the design of nanocarriers to co-deliver PICs and chemotherapy drugs remains an unmet need. To overcome these challenges, we developed a novel photoimmunoconjugate-nanoliposome (PIC-Nal) comprising of three clinically used agents: anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab (Cet), benzoporphyrin derivative (BPD) photosensitizer, and irinotecan (IRI) chemotherapy. Results: The BPD photosensitizers were first tethered to Cet at a molar ratio of 6:1 using carbodiimide chemistry to form PICs. Conjugation of PICs onto nanoliposome irinotecan (Nal–IRI) was facilitated by copper-free click chemistry, which resulted in monodispersed PIC–Nal–IRI with an average size of 158.8 ± 15.6 nm. PIC–Nal–IRI is highly selective against EGFR-overexpressing epithelial ovarian cancer cells with 2- to 6-fold less accumulation in low EGFR expressing cells. Successful coupling of PIC onto Nal–IRI enhanced PIC uptake and photoimmunotherapy efficacy by up to 30% in OVCAR-5 cells. Furthermore, PIC–Nal–IRI synergistically reduced cancer viability via a unique three-way mechanism (i.e., EGFR downregulation, mitochondrial depolarization, and DNA damage). Conclusion: It is increasingly evident that the most effective therapies for cancer will involve combination treatments that target multiple non-overlapping pathways while minimizing side effects. Nanotechnology combined with photochemistry provides a unique opportunity to simultaneously deliver and activate multiple drugs that target all major regions of a cancer cell—plasma membrane, cytoplasm, and nucleus. PIC–Nal–IRI offers a promising strategy to overcome the selectivity-uptake trade-off, improve photoimmunotherapy efficacy, and enable multi-tier cancer targeting. Controllable drug compartmentalization, easy surface modification, and high clinical relevance collectively make PIC–Nal–IRI extremely valuable and merits further investigations in living animals. Copyright 2020 The Author(s).
  • Prevention and treatment of acute lung injury with time-controlled adaptive ventilation: physiologically informed modification of airway pressure release ventilation

    Nieman, G.F.; Andrews, P.; Madden, M.; Habashi, N.M. (Springer, 2020)
    Mortality in acute respiratory distress syndrome (ARDS) remains unacceptably high at approximately 39%. One of the only treatments is supportive: mechanical ventilation. However, improperly set mechanical ventilation can further increase the risk of death in patients with ARDS. Recent studies suggest that ventilation-induced lung injury (VILI) is caused by exaggerated regional lung strain, particularly in areas of alveolar instability subject to tidal recruitment/derecruitment and stress-multiplication. Thus, it is reasonable to expect that if a ventilation strategy can maintain stable lung inflation and homogeneity, regional dynamic strain would be reduced and VILI attenuated. A time-controlled adaptive ventilation (TCAV) method was developed to minimize dynamic alveolar strain by adjusting the delivered breath according to the mechanical characteristics of the lung. The goal of this review is to describe how the TCAV method impacts pathophysiology and protects lungs with, or at high risk of, acute lung injury. We present work from our group and others that identifies novel mechanisms of VILI in the alveolar microenvironment and demonstrates that the TCAV method can reduce VILI in translational animal ARDS models and mortality in surgical/trauma patients. Our TCAV method utilizes the airway pressure release ventilation (APRV) mode and is based on opening and collapsing time constants, which reflect the viscoelastic properties of the terminal airspaces. Time-controlled adaptive ventilation uses inspiratory and expiratory time to (1) gradually "nudge" alveoli and alveolar ducts open with an extended inspiratory duration and (2) prevent alveolar collapse using a brief (sub-second) expiratory duration that does not allow time for alveolar collapse. The new paradigm in TCAV is configuring each breath guided by the previous one, which achieves real-time titration of ventilator settings and minimizes instability induced tissue damage. This novel methodology changes the current approach to mechanical ventilation, from arbitrary to personalized and adaptive. The outcome of this approach is an open and stable lung with reduced regional strain and greater lung protection. Copyright 2020, The Author(s).
  • Allogeneic hematopoietic cell transplantation improves outcome of adults with t(6;9) acute myeloid leukemia: results from an international collaborative study

    Kayser, S.; Hills, R.K.; Baer, M.R. (Ferrata Storti Foundation, 2020)
    Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of AML cases. A substantial proportion of these patients have a concomitant FLT3-ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation (allo-HCT) may improve survival if performed early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 years (range: 16-76), AML was de novo in 88%, FLT3-ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow up of 5.43 years, estimated overall survival at five years was 38% (95%CI: 31-47%). Allo-HCT was performed in 117 (66%) patients, including 89 in first complete remission. Allo-HCT in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy: 45% (95%CI: 35-59%) and 53% (95%CI: 42-66%) versus 7% (95%CI: 3-19%) and 23% (95%CI: 13-38%), respectively. For patients undergoing allo-HCT, there was no difference in overall survival rates at five years according to whether it was performed in first [53% (95%CI: 42-66%)], or second [58% (95%CI: 31-100%); n=10] complete remission or with active disease/relapse [54% (95%CI: 34-84%); n=18] (P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) AML are poor with chemotherapy, and can be substantially improved with allo-HCT. Copyrigh 2020 Ferrata Storti Foundation.
  • Successes and challenges in simulating the folding of large proteins

    Gershenson, A.; Gosavi, S.; Wintrode, P.L. (American Society for Biochemistry and Molecular Biology, 2020)
    Computational simulations of protein folding can be used to interpret experimental folding results, to design new folding experiments, and to test the effects of mutations and small molecules on folding. However, whereas major experimental and computational progress has been made in understanding how small proteins fold, research on larger, multidomain proteins, which comprise the majority of proteins, is less advanced. Specifically, large proteins often fold via long-lived partially folded intermediates, whose structures, potentially toxic oligomerization, and interactions with cellular chaperones remain poorly understood. Molecular dynamics based folding simulations that rely on knowledge of the native structure can provide critical, detailed information on folding free energy landscapes, intermediates, and pathways. Further, increases in computational power and methodological advances have made folding simulations of large proteins practical and valuable. Here, using serpins that inhibit proteases as an example, we review native-centric methods for simulating the folding of large proteins. These synergistic approaches range from Gō and related structure-based models that can predict the effects of the native structure on folding to all-atom-based methods that include side-chain chemistry and can predict how disease-associated mutations may impact folding. The application of these computational approaches to serpins and other large proteins highlights the successes and limitations of current computational methods and underscores how computational results can be used to inform experiments. These powerful simulation approaches in combination with experiments can provide unique insights into how large proteins fold and misfold, expanding our ability to predict and manipulate protein folding. Copyright 2020 Gershenson et al.
  • Emergency and critical care providers' perception about the use of bedside ultrasound for confirmation of above-diaphragm central venous catheter placement

    Tran, Q.K.; Foster, M.; Andersen, K.; Matta, A.; Haase, D.J. (Elsevier Ltd, 2020)
    Introduction: Chest radiography (CXR) is commonly used to confirm the proper placement of above-diaphragm central venous catheters (CVCs) and to detect associated complications. Recent studies have shown that point-of-care ultrasound (POCUS) has better sensitivity and is faster than CXR for these purposes. We were interested in documenting how often emergency medicine and critical care practitioners perform POCUS to confirm proper CVC positioning as well as their confidence in performing it. Methods: We surveyed members of our state's chapters of the College of Emergency Physicians and the Society of Critical Care Medicine between April and December 2018. Our primary outcome was the percentage of providers who would agree to perform only POCUS, forgoing CXR, for confirmation of CVC position. We performed multivariable logistic regressions to measure associations between demographic, clinical information, and outcomes. Results: One hundred thirty-six providers participated (a 25% participation rate). Their specialties were as follows: emergency medicine, 75%; critical care, 13%; and emergency medicine/critical care, 11%. Thirty-one percent would use POCUS only for CVC confirmation, while 42% were confident in performing POCUS for this purpose. Multivariable logistic regressions showed that performing more non-procedural ultrasound examinations was associated with a higher likelihood of agreeing to perform POCUS only (OR, 2.9; 95% CI: 1.3-6.3). Forty-six percent of relevant comments suggested more training to increase the use of POCUS. Conclusion: Participants in this study did not frequently use POCUS for CVC confirmation. Designers of training curricula should consider including more instruction in the use of POCUS to confirm proper CVC placement and to detect complications.
  • Clerkships in Emergency Medicine

    Garmel, G.M.; Pettis, H.M.; Winters, M.; Vallee, P. (Elsevier USA, 2020)
    Planning for clerkships in emergency medicine (EM) can be stressful, prolonged, and challenging. Therefore, medical students should start planning for them early. In this article, we offer guidance regarding several issues pertinent to the EM clerkship, such as the best time to schedule one (or more) during medical school, the most appropriate institution or program to schedule it, the process of selecting and applying for the clerkship, and the number of EM clerkships to consider. We will explain why an EM clerkship should be scheduled between June and October and the reason that 2 EM clerkships at different sites are sufficient for the majority of students. Additionally, we emphasize that clerkships in emergency departments associated with EM residency programs or with reputations for outstanding student teaching tend to be most beneficial. Above all, students interested in EM should attempt to leave a great impression after completing their clerkships by providing stellar patient care, demonstrating enthusiasm at all times, and maintaining professionalism. In turn, they will gain knowledge and clinical experiences that should prove valuable in their future.
  • The state of Oral Medicine and Oral Pathology in the Arab Middle East

    Khoury, Z.H.; Sultan, A.S. (Elsevier B.V., 2020)
    The Arab World consists of 22 countries with more than half located in the Arab Middle East. Whereas the current state of Oral Medicine and Oral Pathology in the Western World is well known, available information on the current state of Oral Medicine and Oral Pathology across the Arab Middle East is lacking. This concise communication sheds light on the current state of these two specialties with specific reference to specialty training programs, board certification, and future directions. This piece provides valuable information to the general public and other disciplines to raise awareness and guide clinicians in making appropriate referrals. Additionally, it is of importance to newly graduated dentists interested in pursuing a career in either of these two disciplines.
  • Interleukin 1 receptor antagonist (IL1RN) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease.

    Attur, Mukundan; Yau, Michelle; Mitchell, Braxton D. (BMJ, 2019-12-18)
    In these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA). This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license.
  • Molecular Neuropathology in Practice: Clinical Profiling and Integrative Analysis of Molecular Alterations in Glioblastoma

    Nasrallah, M.P.; Binder, Z.A.; Sukhadia, S. (SAGE Publications Ltd, 2019)
    Molecular profiling of glioblastoma has revealed complex cytogenetic, epigenetic, and molecular abnormalities that are necessary for diagnosis, prognosis, and treatment. Our neuro-oncology group has developed a data-driven, institutional consensus guideline for efficient and optimal workup of glioblastomas based on our routine performance of molecular testing. We describe our institution�s testing algorithm, assay development, and genetic findings in glioblastoma, to illustrate current practices and challenges in neuropathology related to molecular and genetic testing. We have found that coordination of test requisition, tissue handling, and incorporation of results into the final pathologic diagnosis by the neuropathologist improve patient care. Here, we present analysis of O6-methylguanine-DNA-methyltransferase promoter methylation and next-generation sequencing results of 189 patients, obtained utilizing our internal processes led by the neuropathology team. Our institutional pathway for neuropathologist-driven molecular testing has streamlined the management of glioblastoma samples for efficient return of results for incorporation of genomic data into the pathological diagnosis and optimal patient care. Copyright The Author(s) 2019.
  • Measurement of Retinal Microvascular Blood Velocity Using Erythrocyte Mediated Velocimetry

    Tracey, B.M.; Le, C.T.; Chen, V.Y.; Renner, C.Y.; Li, J.; Kalarn, S.P.; Mohammed, T.K.; Mohammed, I.S.K.; Thompson, G.M.; Im, L.T.; et al. (Nature Research, 2019)
    Changes in retinal blood flow may be involved in the pathogenesis of glaucoma and other ocular diseases. Erythrocyte mediated velocimetry (EMV) is a novel technique where indocyanine green (ICG) dye is sequestered in erythrocyte ghosts and autologously re-injected to allow direct visualization of erythrocytes for in vivo measurement of speed. The purpose of this study is to determine the mean erythrocyte speed in the retinal microvasculature, as well as the intravisit and intervisit variability of EMV. Data from 23 EMV sessions from control, glaucoma suspect, and glaucoma patients were included in this study. In arteries with an average diameter of 43.11 µm ± 6.62 µm, the mean speed was 7.17 mm/s ± 2.35 mm/s. In veins with an average diameter of 45.87 µm ± 12.04 µm, the mean speed was 6.05 mm/s ± 1.96 mm/s. Intravisit variability, as measured by the mean coefficient of variation, was 3.57% (range 0.44–9.68%). Intervisit variability was 4.85% (range 0.15–8.43%). EMV may represent reliable method for determination of retinal blood speed, potentially allowing insights into the effects of pharmacologic agents or pathogenesis of ocular diseases. Copyright 2019, The Author(s).
  • Maintenance of Deep Lung Architecture and Automated Airway Segmentation for 3D Mass Spectrometry Imaging

    Scott, A.J.; Chandler, C.E.; Ernst, R.K. (Nature Research, 2019)
    Mass spectrometry imaging (MSI) is a technique for mapping the spatial distributions of molecules in sectioned tissue. Histology-preserving tissue preparation methods are central to successful MSI studies. Common fixation methods, used to preserve tissue morphology, can result in artifacts in the resulting MSI experiment including delocalization of analytes, altered adduct profiles, and loss of key analytes due to irreversible cross-linking and diffusion. This is especially troublesome in lung and airway samples, in which histology and morphology is best interpreted from 3D reconstruction, requiring the large and small airways to remain inflated during analysis. Here, we developed an MSI-compatible inflation containing as few exogenous components as possible, forgoing perfusion, fixation, and addition of salt solutions upon inflation that resulted in an ungapped 3D molecular reconstruction through more than 300 microns. We characterized a series of polyunsaturated phospholipids (PUFA-PLs), specifically phosphatidylinositol (-PI) lipids linked to lethal inflammation in bacterial infection and mapped them in serial sections of inflated mouse lung. PUFA-PIs were identified using spatial lipidomics and determined to be determinant markers of major airway features using unsupervised hierarchical clustering. Deep lung architecture was preserved using this inflation approach and the resulting sections are compatible with multiple MSI modalities, automated interpretation software, and serial 3D reconstruction. Copyright 2019, The Author(s).
  • Nonsurgical endodontic management of dens invaginatus: a report of two cases

    Abu, Hasna, A.; Ungaro, D.M.T.; Martinho, F.C. (F1000Research, 2019)
    Dens invaginatus is a malformation affecting mainly the superior lateral incisors. It is defined as an infolding of the crown hard tissues, including the enamel and dentin, and can extend up to the root apex. Root canal treatment of this abnormality is considered difficult due to the complex anatomy presented by these teeth. This case series presents nonsurgical endodontic treatment in two cases of dens invaginatus (type II and III) in maxillary lateral incisors. This nonsurgical or conventional endodontic treatment results in healing of the periapical lesions associated with both cases, with no need for extra intervention e.g. surgical or invasive management. The manual instrumentation associated with sodium hypochlorite and calcium hydroxide were able to completely heal the lesions. Radiographic exams were carried out to control and asses the healing. Nonsurgical treatment was successful in both cases with adequate repair after a 6-year follow-up with radiographic and tomographic assessments. Copyright: 2019 Abu Hasna A et al.

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