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Wiegerinck, R. F., R. Schreurs e F. W. Prinzen. "Pathophysiology of dyssynchrony: of squirrels and broken bones". Netherlands Heart Journal 24, n.º 1 (10 de dezembro de 2015): 4–10. http://dx.doi.org/10.1007/s12471-015-0765-7.
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Shapkin, Yu G., P. A. Seliverstov e E. A. Skripal. "THE PHENOMENON OF «SECOND HIT» AFTER OPERATIONS OF OSTEOSYNTHESIS IN CASE OF POLY-TRAUMA". Medical Journal of the Russian Federation 23, n.º 6 (15 de dezembro de 2017): 331–36. http://dx.doi.org/10.18821/0869-2106-2017-23-6-331-336.
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In case of poly-trauma the early operations of osteosynthesis under fractures of long bones, unstable fractures of pelvis and backbone bones being an operational trauma, can provoke progression of inflammatory reaction, development of systemic complications and poly-organ inadequacy i.e. causing a «second hit» effect. The pathophysiologic mechanisms of «second hit» phenomenon are complicated and they are implementing by means of modulation of immune response. The risk of development of the given phenomenon depends on period of implementation and method of osteosynthesis, severity of injuries and condition, age, concomitant pathology of patient, presence of chest trauma and craniocerebral trauma. The study of pathophysiology of «second hit» phenomenon is perspective for development and optimization of clinical concepts of treatment of patients with poly-trauma and skeletal damages.
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Thévenin-Lemoine, C., J. Vial, J. L. Labbé, B. Lepage, B. Ilharreborde e F. Accadbled. "MRI of acute osteomyelitis in long bones of children: Pathophysiology study". Orthopaedics & Traumatology: Surgery & Research 102, n.º 7 (novembro de 2016): 831–37. http://dx.doi.org/10.1016/j.otsr.2016.06.014.
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Tasis, Nikolaos, Ioannis Tsouknidas, Argyrios Ioannidis, Konstantinos Nassiopoulos e Dimitrios Filippou. "Left Functional Pneumonectomy Caused by a Very Rare Giant Intrathoracic Cystic Lesion in a Patient with Gorham–Stout Syndrome: Case Report and Review of the Literature". Case Reports in Pulmonology 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/2406496.
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Gorham–Stout syndrome is an uncommon entity, with few cases reported in bibliography. It consists of osteolytic manifestations affecting various bones and replacing them with lymphangiomatous tissue. With pathophysiology unknown, Gorham–Stout disease affects also cardiorespiratory system usually causing lytic lesions to the bones of the thoracic cage or directly invading the thoracic duct. This is a case report of a unique respiratory manifestation of the disease and a review of its cardiorespiratory complications.
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Kuhweide, R., V. Van de Steene, S. Vlaminck e J. W. Casselman. "Ramsay Hunt syndrome: pathophysiology of cochleovestibular symptoms". Journal of Laryngology & Otology 116, n.º 10 (outubro de 2002): 844–48. http://dx.doi.org/10.1258/00222150260293691.
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Ramsay Hunt’s hypothesis that herpes zoster oticus results from reactivation of the varicella zoster virus (VZV) in the geniculate ganglion is supported by the detection of viral genome in archival temporal bones of normals and Ramsay Hunt patients by the polymerase chain reaction. Ramsay Hunt syndrome is characterized by the presence of cochleovestibular symptoms in association with facial paralysis. VZV has also been demonstrated in the spiral and/or vestibular ganglion. Two cases are reported in which cochleovestibular symptoms outweighed the facial nerve symptoms, presumably representing VZV reactivation in the spiral and/or vestibular ganglion. From these observations and the known dormancy of VZV in non-neuronal satellite cells, it is argued that the cochleovestibular symptoms in Ramsay Hunt syndrome may result from VZV transmission across the nerves inside the internal auditory canal and that prompt treatment with an antiviral-corticosteroid combination might be justified in the management of any acute non-hydropic cochleovestibular syndrome.
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Puntillo, Filomena, Mariateresa Giglio, Antonella Paladini, Gaetano Perchiazzi, Omar Viswanath, Ivan Urits, Carlo Sabbà, Giustino Varrassi e Nicola Brienza. "Pathophysiology of musculoskeletal pain: a narrative review". Therapeutic Advances in Musculoskeletal Disease 13 (janeiro de 2021): 1759720X2199506. http://dx.doi.org/10.1177/1759720x21995067.
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Musculoskeletal pain (excluding bone cancer pain) affects more than 30% of the global population and imposes an enormous burden on patients, families, and caregivers related to functional limitation, emotional distress, effects on mood, loss of independence, and reduced quality of life. The pathogenic mechanisms of musculoskeletal pain relate to the differential sensory innervation of bones, joints, and muscles as opposed to skin and involve a number of peripheral and central nervous system cells and mediators. The interplay of neurons and non-neural cells (e.g. glial, mesenchymal, and immune cells) amplifies and sensitizes pain signals in a manner that leads to cortical remodeling. Moreover, sex, age, mood, and social factors, together with beliefs, thoughts, and pain behaviors influence the way in which musculoskeletal pain manifests and is understood and assessed. The aim of this narrative review is to summarize the different pathogenic mechanisms underlying musculoskeletal pain and how these mechanisms interact to promote the transition from acute to chronic pain.
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Shams, Ramsha, Kelsey P. Drasites, Vandana Zaman, Denise Matzelle, Donald C. Shields, Dena P. Garner, Christopher J. Sole, Azizul Haque e Narendra L. Banik. "The Pathophysiology of Osteoporosis after Spinal Cord Injury". International Journal of Molecular Sciences 22, n.º 6 (17 de março de 2021): 3057. http://dx.doi.org/10.3390/ijms22063057.
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Spinal cord injury (SCI) affects approximately 300,000 people in the United States. Most individuals who sustain severe SCI also develop subsequent osteoporosis. However, beyond immobilization-related lack of long bone loading, multiple mechanisms of SCI-related bone density loss are incompletely understood. Recent findings suggest neuronal impairment and disability may lead to an upregulation of receptor activator of nuclear factor-κB ligand (RANKL), which promotes bone resorption. Disruption of Wnt signaling and dysregulation of RANKL may also contribute to the pathogenesis of SCI-related osteoporosis. Estrogenic effects may protect bones from resorption by decreasing the upregulation of RANKL. This review will discuss the current proposed physiological and cellular mechanisms explaining osteoporosis associated with SCI. In addition, we will discuss emerging pharmacological and physiological treatment strategies, including the promising effects of estrogen on cellular protection.
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Gore, Ashwini P., Soon Ho Kwon e Antine E. Stenbit. "A Roadmap to the Brittle Bones of Cystic Fibrosis". Journal of Osteoporosis 2011 (2011): 1–10. http://dx.doi.org/10.4061/2011/926045.
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Cystic fibrosis (CF) is an autosomal recessive disorder which despite advances in medical care continues to be a life-limiting and often fatal disease. With increase in life expectancy of the CF population, bone disease has emerged as a common complication. Unlike the osteoporosis seen in postmenopausal population, bone disease in CF begins at a young age and is associated with significant morbidity due to fractures, kyphosis, increased pain, and decreased lung function. The maintenance of bone health is essential for the CF population during their lives to prevent pain and fractures but also as they approach lung transplantation since severe bone disease can lead to exclusion from lung transplantation. Early recognition, prevention, and treatment are key to maintaining optimal bone health in CF patients and often require a multidisciplinary approach. This article will review the pathophysiology, current clinical practice guidelines, and potential future therapies for treating CF-related bone disease.
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Assi, Tarek, Sarah Watson, Bachar Samra, Elie Rassy, Axel Le Cesne, Antoine Italiano e Olivier Mir. "Targeting the VEGF Pathway in Osteosarcoma". Cells 10, n.º 5 (18 de maio de 2021): 1240. http://dx.doi.org/10.3390/cells10051240.
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Osteosarcoma is the most common primary tumor of the bones affecting mainly young adults. Despite the advances in the field of systemic anticancer therapy, the prognosis of relapsed of metastatic osteosarcoma patients remain dismal with very short survival. However, the better understanding of the pathophysiology of this subtype of sarcoma has led to the identification of new targeted agents with significant activity. In fact, increased angiogenesis plays a major role in the tumor growth and survival of osteosarcoma patients. Several targeted agents have demonstrated a significant anti-tumor activity including multi-kinase inhibitors. In this review, we will discuss the pathophysiology, rationale, and role of targeting angiogenesis via the VEGF pathway in patients with osteosarcoma with emphasis on the published clinical trials and future directions.
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Golovach, I. Yu. "Clinical significance of spondyloarthritis-attended enthesites: from pathophysiology to treatment (review)". PAIN, JOINTS, SPINE 11, n.º 1 (1 de abril de 2021): 17–27. http://dx.doi.org/10.22141/2224-1507.11.1.2021.226905.
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The article presents the latest views on enthesites’ anatomy and pathogenesis, clinical features, diagnostic and therapeutic options. The enthesis lesions are considered an outstanding pathologic and clinical manifestation of spondyloarthritis group; this symptom is included into the classification criteria by the Assessment of SpondyloArthritis International Society for the peripheral and axial forms. The typical spondyloarthritis-attended enthesites’ localizations are: the site of Achilles tendon and plantar aponeurosis’ attachment to the calcaneus, the lateral condyle of the humerus, the medial condyle of the femur, the upper edge of the patella, the upper edge of the iliac bones, trochanters of the femoral bones, spinous processes of the vertebrae. The structures focused in the entheses’ sites have anatomical, functional and physiological interactions and constitute a single synovial-entheseal complex. Unlike the rheumatoid arthritis with a key pathological process occurring in the synovial lining, the spondyloarthritis is mainly provoking the morphological modifications, namely enthesites, while the developing arthritis (synovitis) appears secondary to enthesites. The enthesitis is detected in 30–50 % of spondyloarthritis patients and associated with a higher activity, higher pain indices and a compromised life quality. The presence of enthesites in the psoriatic arthritis patients is associated with axial and peripheral joint lesions, a high chance of ankylosation, a high disease activity, pronounced pains, a compromised life quality and functional state, sleeping disorders. Furthermore, the enthesitis is considered a precursor of the negative disease outcome, and may forecast a lower probability of remission and a low activity. The entheseal inflammation occurs as a result of mechanical and/or infection-originating stress, resulting in the prostaglandin E2 and interleukin-23 activation with a further vasodilatation, and T-cell and Group 3 innate lymphoid cell (ILC3) activation. The innate immunity-generated inflammation is characterized by a release of tumor necrosis factor and interleukin-17, resulting in the immune cell influx, namely the polymorphonuclear neutrophils. Under the influence of interleukin-17 and interleukin-22, the mesenchymal proliferation is characterized by an activation and proliferation of resident mesenchymal stem cells in the periosteum. The enthesitis treatment strategies remain undefined; however, the ones most commonly used are the nonsteroidal anti-inflammatory drugs (NSAIDs), localized glucocorticoid injections, Apremilast, as well as targeted medications, namely the tumor necrosis factor, interleukin-17 and interleukin-23 inhibitors.
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Kang, Hongje. "Comprehension of Midcarpal Instability". Archives of Hand and Microsurgery 26, n.º 2 (1 de junho de 2021): 82–92. http://dx.doi.org/10.12790/ahm.21.0082.
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The midcarpal instability is the state with instability between the proximal and distal carpal rows, without dissociation between carpal bones. It can be divided into the intrinsic one that is caused by ligament hyperlaxity, and extrinsic one that is caused secondarily by the malunion of distal radius. The pathophysiology of the intrinsic one is still unknown, and the treatment is also controversial. On the other hand, the extrinsic one can be treated by corrective osteotomy of the radial malunion. This review investigated the comprehension, definition, classification, symptoms, diagnosis, and treatment of the midcarpal instability.
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Shokri, Tom, Weitao Wang, Aurora Vincent, Jason E. Cohn, Sameep Kadakia e Yadranko Ducic. "Osteoradionecrosis of the Maxilla: Conservative Management and Reconstructive Considerations". Seminars in Plastic Surgery 34, n.º 02 (maio de 2020): 106–13. http://dx.doi.org/10.1055/s-0040-1709144.
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AbstractThe implementation of radiotherapy in the multimodal treatment of advanced head and neck cancer has greatly improved survival rates. In some patients, however, this benefit comes at the potential expense of the tissue surrounding the primary site of malignancy. Osteoradionecrosis (ORN) of the facial bones, in particular the maxilla, is a debilitating complication of radiation therapy. Exposure to ionizing radiation results in devitalization of underlying bone with necrosis of adjacent soft tissue. Controversy surrounding appropriate early intervention in ORN persists and no consensus for clinical treatment has been established. In the present article, we review the pathophysiology of maxillary ORN and discuss the role of both conservative medical therapy and reconstruction.
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Ruparelia, Jigish, Rajnish Patidar, Jaskaran Singh Gosal, Mayank Garg, Suryanarayanan Bhaskar e Deepak Kumar Jha. "An Aberrant Line on CT Head: The Mendosal Suture". Journal of Neurosciences in Rural Practice 11, n.º 03 (16 de junho de 2020): 502–3. http://dx.doi.org/10.1055/s-0040-1713304.
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AbstractA knowledge of variant anatomy is important in clinical practice. The skull bones have several normal anatomical variations, especially in the occipital bone. Accessory sutures have been described in newborns and young children.In this study, we discussed radiological findings of an accessory occipital suture in a 14-year-old child who had presented with mastoiditis and brain abscess. We further describe this “mendosal suture,” and its pathophysiology and clinical implications. It is important to bear this entity in mind to avoid misdiagnosing this as a fracture. The use of CT scans and 3D CT using volume rendering technique (VRT) helps in detection and correct diagnosis.
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Sharma, Suresh, Sakshi Mathur, Puneet Joshi e Upendra Kumar Gupta. "MORPHOLOGICAL AND MORPHOMETRIC STUDY OF FORAMEN MAGNUM IN DRIED HUMAN SKULL BONES OF NORTH-WEST INDIAN REGION". International Journal of Anatomy and Research 8, n.º 4.1 (10 de novembro de 2020): 7777–81. http://dx.doi.org/10.16965/ijar.2020.217.
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Background: The Foramen Magnum is communication between vertebral canal and posterior cranial fossa and important landmark to key structures such as brain, spinal cord, vertebral arteries. Anatomical knowledge of the foramen magnum is significant for understanding the pathophysiology of various disorders of the craniovertebral junction as well as for planning surgical procedures. Materials and Methods: The study was conducted on 62 dry skulls of unknown gender obtained from the Department of Anatomy. The shape of foramen magnum was classified as oval, round, tetragonal, pentagonal, hexagonal and irregular in shape and measurements like anterio-posterior diameter and transverse diameter of foramen magnum were taken using the Digital Vernier sliding caliper. Results: In the present study most common shape was oval in 22 (35.48%) skulls, followed by Egg shape in 12 (19.35%) skulls and least common pentagonal shape in 1(1.61%) skulls. In our study the mean anteroposterior diameter was 34.17 mm. and mean transverse diameter was observed to be 28.86 mm. Conclusion: Results of our present study may help in neurosurgeons, orthopedicians, radiologist and anesthetist in North West indian population. KEY WORDS: foramen magnum, skull, transverse diameter, oval.
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Franco, Melanie, Emmanuel Collec, Philippe Connes, Emile van den Akker, Thierry Billette de Villemeur, Nadia Belmatoug, Marieke von Lindern et al. "Abnormal properties of red blood cells suggest a role in the pathophysiology of Gaucher disease". Blood 121, n.º 3 (17 de janeiro de 2013): 546–55. http://dx.doi.org/10.1182/blood-2012-07-442467.
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AbstractGaucher disease (GD) is a lysosomal storage disorder caused by glucocerebrosidase deficiency. It is notably characterized by splenomegaly, complex skeletal involvement, ischemic events of the spleen and bones, and the accumulation of Gaucher cells in several organs. We hypothesized that red blood cells (RBCs) might be involved in some features of GD and studied the adhesive and hemorheologic properties of RBCs from GD patients. Hemorheologic analyses revealed enhanced blood viscosity, increased aggregation, and disaggregation threshold of GD RBCs compared with control (CTR) RBCs. GD RBCs also exhibited frequent morphologic abnormalities and lower deformability. Under physiologic flow conditions, GD RBCs adhered more strongly to human microvascular endothelial cells and to laminin than CTR. We showed that Lu/BCAM, the unique erythroid laminin receptor, is overexpressed and highly phosphorylated in GD RBCs, and may play a major role in the adhesion process. The demonstration that GD RBCs have abnormal rheologic and adhesion properties suggests that they may trigger ischemic events in GD, and possibly phagocytosis by macrophages, leading to the appearance of pathogenic Gaucher cells.
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Arora, Vijinder, e Nilanshu Kataria. "Magnetic Resonance Imaging Diagnosis of Osteopetrosis in a Child Presenting with Blindness". Indian Journal of Musculoskeletal Radiology 1 (18 de agosto de 2019): 64–67. http://dx.doi.org/10.25259/ijmsr_17_2019.
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Osteopetrosis is a rare hereditary bone dysplasia of heterogeneous pathophysiology in which failure of osteoclastic bone resorption leads to increased bone mass, which has poor mechanical properties. Patients present in childhood with complaints of bone pains, failure to thrive and growth retardation. Other clinical findings include severe anemia, hepatosplenomegaly, lymphadenopathy and thrombocytopenia. The dense, extremely brittle bones fracture easily. Involvement of the cranium can lead to optic nerve atrophy with blindness or other cranial nerve defects. The diagnosis is primarily radiographic and may be supported by computed tomography scan. We are reporting a case of a 4-year-old boy who presented with blindness since the age of 6 months and the diagnosis of osteopetrosis was suggested on magnetic resonance imaging.
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Elwany, Samy. "Pathology of the eustachian tube in otitis media: an electron microscopic study". Journal of Laryngology & Otology 107, n.º 7 (julho de 1993): 651–55. http://dx.doi.org/10.1017/s0022215100124004.
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The ultrastructure of the mucosa of the eustachian tube was studied in four temporal bones showing tympanosclerosis, cholesteatoma, otitic meningitis and a grafted tympanic membrane (tympanoplasty). The mucosa of tube was abnormal in the four cases confirming the relationship between the state of the eustachian tube and the inflammatory process in the middle ear. The observed abnormalities included: ciliary loss, abnormal ciliary morphology and motility, oedema of the microvilli, hyperplasia of the goblet cells and the seromucinous acini, desquamation of the non-ciliated cells and appearance of mast cells in the lamina propria of the tube. Ciliary changes were the most frequent abnormalities and the morphological changes, in general, were fewest in the case of healed tympanoplasty. The pathophysiology of the morphological changes was discussed and correlated with the disease in the middle ear.
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Nadol Jr., Joseph B., E. Tessa Hedley-Whyte, Sami Samir Amr, Jennifer T. O'Malley e Takefumi Kamakura. "Histopathology of the Inner Ear in Charcot-Marie-Tooth Syndrome Caused by a Missense Variant (p.Thr65Ala) in the MPZ Gene". Audiology and Neurotology 23, n.º 6 (2018): 326–34. http://dx.doi.org/10.1159/000495176.
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Charcot-Marie-Tooth (CMT) syndrome is a clinically and genetically heterogeneous group of neuropathies affecting both peripheral motor and sensory nerves. Progressive sensorineural hearing loss, vestibular abnormalities, and dysfunction of other cranial nerves have been described. This is the second case report of otopathology in a patient with CMT syndrome. Molecular genetic testing of DNA obtained at autopsy revealed a missense variant in the MPZ gene (p.Thr65Ala), pathogenic for an autosomal-dominant form of CMT1B. The temporal bones were also prepared for light microscopy by hematoxylin and eosin and Gömöri trichome stains, and immunostaining for anti-myelin protein zero. Pathology was consistent with a myelinopathy of the auditory, vestibular, and facial nerves bilaterally. The pathophysiology of cranial nerve dysfunction in CMT is unknown. Findings in the current case suggested, at least in cranial nerves 7 and 8, that a myelinopathy may be causative.
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Hofmann, Sigrun R., Anja Schnabel, Angela Rösen-Wolff, Henner Morbach, Hermann J. Girschick e Christian M. Hedrich. "Chronic Nonbacterial Osteomyelitis: Pathophysiological Concepts and Current Treatment Strategies". Journal of Rheumatology 43, n.º 11 (1 de setembro de 2016): 1956–64. http://dx.doi.org/10.3899/jrheum.160256.
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Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder, covering a clinical spectrum with asymptomatic inflammation of single bones at the one end, and chronic recurrent multifocal osteomyelitis (CRMO) at the other end. The exact molecular pathophysiology of CNO remains largely unknown. Provided familial clusters and the association with inflammatory disorders of the skin and intestine suggest a genetic predisposition. Recently, profound dysregulation of cytokine responses was demonstrated in CRMO. Failure to produce antiinflammatory cytokines interleukin (IL)-10 and IL-19 contributes to activation of inflammasomes and subsequent IL-1β release. In IL-10–deficient and in CNO-prone chronic multifocal osteomyelitis mice, IL-1β was linked to bone inflammation. Further, alterations to the gut microbiome were suggested in contributing to IL-1β release from innate immune cells in mice, offering an interesting target in the search for molecular mechanisms in CNO. Here, we summarize clinical presentation and treatment options in CNO/CRMO, current pathophysiological concepts, available mouse models, and promising future scientific directions.
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Nadol, Joseph B. "Techniques for human temporal bone removal: Information for the scientific community". Otolaryngology–Head and Neck Surgery 115, n.º 4 (outubro de 1996): 298–305. http://dx.doi.org/10.1016/s0194-5998(96)70042-6.
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Human temporal bones provide an irreplaceable resource for study of the pathology and pathophysiology of disorders of hearing, balance, taste, and facial nerve function. Additional specimens are needed to study disorders for which there are few human specimens; to increase the number of specimens for a given disorder to understand the natural variability and expression of the disease entity; to evaluate the accuracy of otologic diagnoses and the efficacy of otologic treatment modalities; to apply newly available scientific methods, including immunohistochemistry and molecular biologic or molecular genetic techniques; and to teach the anatomy of the human ear and modern otologic surgical techniques. This article provides information for the scientific community concerning techniques for temporal bone and auditory brain stem removal, including intracranial and extracranial approaches and methods to minimize postmortem autolysis and cosmetic defects. Close collaboration between physicians and funeral directors will maximize the yield and utility of these valuable specimens for scientific inquiry and training. (Otolaryngol Head Neck Surg 1996;115:298-305.)
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Briolay, A., S. Delplace, F. Duboeuf, O. Peyruchaud, D. Magne, L. Brizuela e C. Bougault. "POS0404 VOLUNTARY WHEEL RUNNING MODEL IN MICE TO MECHANICALLY STIMULATE THE ENTHESIS OF THE ACHILLES TENDON". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de maio de 2021): 431.3–431. http://dx.doi.org/10.1136/annrheumdis-2021-eular.833.
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Background:Excessive bone formation in the entheses is one of the features of peripheral spondyloarthritis. Biomechanical stress is proposed to occupy a central place in spondyloarthritis pathophysiology, but the precise molecular and cellular mechanisms underlying the pathological response of the enthesis are still largely unknown [1]. Besides, physical therapy and exercise are recommended as non-pharmacologic therapies for patients. We focused on the effect of exercising on enthesis ossification.Objectives:We aimed to develop and characterize an in vivo model in mice to study the impact of mechanical stimulation on the enthesis of the Achilles tendon.Methods:DBA/1 mice were subjected to voluntary running exercise by the use of activity wheels for two weeks, and compared to mice housed in standard conditions (n=17 per group). The running performances were recorded. mRNAs were extracted from the long bones (flushed tibia and femur) and the ankles’ entheses for real-time PCR analysis. µCT was performed on the femurs. Alkaline phosphatase activity was detected by histology on the anchorage of the Achilles tendon to the calcaneum, and by enzymatic assay in serum samples. Luminex analysis was also conducted on serum samples for Il-6 and Il-8/Kc detection.Results:Free access to the activity wheel resulted in a running exercise of 5.5±0.8 km/day (approximately 80 km in total) at 14.5±0.5 m/min. No effect was detected on the femur architecture by µCT. Sclerostin (Sost) gene expression was monitored as a mechanosensitive marker. Its expression was expectedly reduced by half in entheseal tissues, but no modulation was observed in long bones (Figure 1). Similarly, exercise-induced regulation of Osterix and Runx2 expressions was observed only in enthesis samples. This tissue-specific pattern was also verified for key genes of the sphingosine-1 phosphate metabolic pathway, which we recently implicated in spondyloarthritis pathophysiology [2]. The in situ staining of alkaline phosphatase activity suggested the presence of more positive cells in the anchorage of Achilles tendon of running mice, compared to control ones. However, alkaline phosphatase activity in serum samples and its gene expression in rough tissue extracts were unchanged. No inflammatory response was detected as Il-8/Kc serum levels were similar in the control and the exercising group (59±14 vs 57±14 pg/mL). In addition, Il-6 was not detected in the serum and its expression was very faint and constant in the tissue extracts.Conclusion:This work is still in progress for a more complete characterization of the model. We believe that this experimental design will be useful to study the role of mechanical stimulation specifically in the enthesis and that it can help to better understand the spondyloarthritis pathophysiology.References:[1]Cambré, et al. Nat Commun, 2018; [2] El Jamal, et al. J Bone Miner Res, 2019Figure 1.Expression level of the mechanosensitive gene Sclerostin (Sost). It dropped in response to exercise in entheseal tissues, but not in long bones, revealing a tissue-specific response to mechanical stimulation.Acknowledgements:Société Arthritis R&D (2020)Disclosure of Interests:None declared
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Lintz, Francois, Alessio Bernasconi, Céline Fernando e Cesar de Cesar Netto. "Assessing Hallux Valgus using Automatically Segmented Weight Bearing CT Datasets: A Case-Control Study". Foot & Ankle Orthopaedics 5, n.º 4 (1 de outubro de 2020): 2473011420S0005. http://dx.doi.org/10.1177/2473011420s00056.
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Category: Bunion; Midfoot/Forefoot Introduction/Purpose: Hallux Valgus (HV) is a complex 3D deformity. Coronal rotation of the first column has been advocated as a key component of its pathophysiology. Cone Beam Weightbearing CT (CB-WBCT) provides 3D images of the foot and ankle bones under physiological load and may provide any absolute or relative measurements. However, the fact that numerous bones and joints are concerned makes analysis time-consuming and results difficult to render and interpret. Artificial Intelligence based Automatic Segmentation (AIAS) is a new tool which allows for volumetric identification and localization of bones. The objective of this study was to use this tool to obtain exhaustive measurements of the whole first column relative to the second and third columns in HV and compare them to the normal population. Methods: Retrospective comparative, level III study including 16 HV cases and 16 controls matched for age, sex and BMI. Bilateral CB-WBCT images performed as standard care were available for each patient. Inclusion criteria were clinically identified HV cases with first intermetatarsal angle (IMA) >10° and HV angles (HVA) >15° as measured on digitally reconstructed radiographs. Patients under 18 years of age, history of trauma or surgery resulting in a potential modification of the forefoot were excluded. Datasets were analyzed using AIAS software which provided: 3D coordinates for spatial position and orientation and angles of the first, second and third metatarsals and cuneiforms, sesamoids, first phalanx of the first ray, navicular, talus, calcaneus. Normality was assessed using a Shapiro-Wilk test and differences between means were calculated using Welch’s unequal variances t-test. Results:: Mean age and BMI were respectively 57.25 +- 9.65 years and 22.23 +- 2.85 kg.m2; 93.75% (31/32) feet came from women. The mean IMA was 12.9° +- 3° in HV and 8.7° +- 1.4° in controls. In the axial plane, the following measurements were found to be significantly different: IMA (p<0.001), first tarsometatarsal angle (p<0.001) and first-fifth metatarsal angle (p=0.001). In the coronal plane, sesamoid angle (p<0.001), sesamoid shift (p<0.001) and sesamoid rotation (p<0.001) were found significantly different, while first metatarsal torsion was similar in the two groups (p=0.347). Conclusion:: The main finding of this study is that AIAS provided an exhaustive series of measurements in the 3 planes of space which were efficient in discriminating between HV and controls with highly significant figures, even when small numerical differences were observed. The introduction of CB-WBCT, which provides images taken during physiological standing stance, followed by the elaboration of data through AIAS (in order to determine absolute or relative positions of bones in space) may help increase efficiency in clinical daily practice.
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Razmara, Ehsan, Amirreza Bitaraf, Hassan Yousefi, Tina H. Nguyen, Masoud Garshasbi, William Chi-shing Cho e Sadegh Babashah. "Non-Coding RNAs in Cartilage Development: An Updated Review". International Journal of Molecular Sciences 20, n.º 18 (11 de setembro de 2019): 4475. http://dx.doi.org/10.3390/ijms20184475.
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In the development of the skeleton, the long bones are arising from the process of endochondral ossification (EO) in which cartilage is replaced by bone. This complex process is regulated by various factors including genetic, epigenetic, and environmental elements. It is recognized that DNA methylation, higher-order chromatin structure, and post-translational modifications of histones regulate the EO. With emerging understanding, non-coding RNAs (ncRNAs) have been identified as another mode of EO regulation, which is consist of microRNAs (miRNAs or miRs) and long non-coding RNAs (lncRNAs). There is expanding experimental evidence to unlock the role of ncRNAs in the differentiation of cartilage cells, as well as the pathogenesis of several skeletal disorders including osteoarthritis. Cutting-edge technologies such as epigenome-wide association studies have been employed to reveal disease-specific patterns regarding ncRNAs. This opens a new avenue of our understanding of skeletal cell biology, and may also identify potential epigenetic-based biomarkers. In this review, we provide an updated overview of recent advances in the role of ncRNAs especially focus on miRNA and lncRNA in the development of bone from cartilage, as well as their roles in skeletal pathophysiology.
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Chinoy, Amish, Mohamed Zulf Mughal e Raja Padidela. "Metabolic bone disease of prematurity: causes, recognition, prevention, treatment and long-term consequences". Archives of Disease in Childhood - Fetal and Neonatal Edition 104, n.º 5 (11 de maio de 2019): F560—F566. http://dx.doi.org/10.1136/archdischild-2018-316330.
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Metabolic bone disease of prematurity (MBDP) is characterised by skeletal demineralisation, and in severe cases it can result in fragility fractures of long bones and ribs during routine handling. MBDP arises from prenatal and postnatal factors. Infants who are born preterm are deprived of fetal mineral accumulation, 80% of which occurs in the third trimester. Postnatally, it is difficult to maintain a comparable intake of minerals, and medications, such as corticosteroids and diuretic therapy, lead to bone resorption. With improvements in neonatal care and nutrition, the incidence of MBDP in preterm infants appears to have decreased, although the recent practice of administering phosphate supplements alone will result in secondary hyperparathyroidism and associated bone loss, worsening MBDP. Postnatal immobilisation and loss of placental supply of oestrogen also contribute to skeletal demineralisation. There is no single diagnostic or screening test for MBDP, with pitfalls existing for most radiological and biochemical investigations. By reviewing the pathophysiology of calcium and phosphate homeostasis, one can establish that plasma parathyroid hormone is important in determining the aetiology of MBDP – primarily calcipaenia or phosphopaenia. This will then direct treatment with the appropriate supplements while considering optimal physiological calcium to phosphate ratios.
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Walallawita, Umani S., Frances M. Wolber, Ayelet Ziv-Gal, Marlena C. Kruger e Julian A. Heyes. "Potential Role of Lycopene in the Prevention of Postmenopausal Bone Loss: Evidence from Molecular to Clinical Studies". International Journal of Molecular Sciences 21, n.º 19 (27 de setembro de 2020): 7119. http://dx.doi.org/10.3390/ijms21197119.
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Osteoporosis is a metabolic bone disease characterized by reduced bone mineral density, which affects the quality of life of the aging population. Furthermore, disruption of bone microarchitecture and the alteration of non-collagenous protein in bones lead to higher fracture risk. This is most common in postmenopausal women. Certain medications are being used for the treatment of osteoporosis; however, these may be accompanied by undesirable side effects. Phytochemicals from fruits and vegetables are a source of micronutrients for the maintenance of bone health. Among them, lycopene has recently been shown to have a potential protective effect against bone loss. Lycopene is a lipid-soluble carotenoid that exists in both all-trans and cis-configurations in nature. Tomato and tomato products are rich sources of lycopene. Several human epidemiological studies, supplemented by in vivo and in vitro studies, have shown decreased bone loss following the consumption of lycopene/tomato. However, there are still limited studies that have evaluated the effect of lycopene on the prevention of bone loss in postmenopausal women. Therefore, the aim of this review is to summarize the relevant literature on the potential impact of lycopene on postmenopausal bone loss with molecular and clinical evidence, including an overview of bone biology and the pathophysiology of osteoporosis.
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Koç, Ahmet, Gazanfer Ekinci, A. Mert Bilgili, Ihsan N. Akpinar, Hamdi Yakut e Turgay Han. "Evaluation of the mastoid air cell system by high resolution computed tomography: three-dimensional multiplanar volume rendering technique". Journal of Laryngology & Otology 117, n.º 8 (agosto de 2003): 595–98. http://dx.doi.org/10.1258/002221503768199906.
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The mastoid air cell system is an important contributor to the pathophysiology of middle-ear inflammatory disease. The mastoid cavity is not only an air reservoir, but also an active space for gas exchange. Various methods of temporal bone imaging have been designed to investigate mastoid pneumatization. In this study, we examined 100 normal temporal bones for the evaluation of mastoid pneumatization. Mastoid air cell systems were measured by reconstructed axial and coronal high resolution computed tomography (HRCT) images. The reconstructions were made by a three-dimensional multiplanar volume rendering (3D MPVR) technique. The mean volume of the mastoid air cell pneumatization was 7.9 cm3 (4.0-14.0 cm3, SD = 2.3 cm3). The ears were allocated to the groups with respect to measured mastoid air cell pneumatization. Twenty-eight per cent of the ears have small pneumatization with an aircell system not exceeding 6 cm3. Fifty-two per cent had an air cell system between six and 10 cm3, and 20 per cent had an air cell system exceeding 10 cm3. With its excellent imaging quality and the ability to eliminate bone and soft tissue, HRCT is the best method for evaluating the mastoid air cell system. The 3D MPVR technique must be used tomeasure the temporal bone/mastoid pneumatization for the best results.
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Placha, Daniela, e Josef Jampilek. "Chronic Inflammatory Diseases, Anti-Inflammatory Agents and Their Delivery Nanosystems". Pharmaceutics 13, n.º 1 (6 de janeiro de 2021): 64. http://dx.doi.org/10.3390/pharmaceutics13010064.
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Inflammatory diseases, whether caused by excessive stress on certain tissues/parts of the body or arising from infections accompanying autoimmune or secondary diseases, have become a problem, especially in the Western world today. Whether these are inflammations of visceral organs, joints, bones, or the like, they are always a physiological reaction of the body, which always tries to eradicate noxious agents and restore tissue homeostasis. Unfortunately, this often results in damage, often irreversible, to the affected tissues. Nevertheless, these inflammatory reactions of the body are the results of excessive stress, strain, and the generally unhealthy environment, in which the people of Western civilization live. The pathophysiology and pathobiochemistry of inflammatory/autoimmune processes are being studied in deep detail, and pharmaceutical companies are constantly developing new drugs that modulate/suppress inflammatory responses and endogenous pro-inflammatory agents. In addition to new specifically targeted drugs for a variety of pro-inflammatory agents, a strategy can be found for the use of older drugs, which are formulated into special nanodrug delivery systems with targeted distribution and often modified release. This contribution summarizes the current state of research and development of nanoformulated anti-inflammatory agents from both conventional drug classes and experimental drugs or dietary supplements used to alleviate inflammatory reactions.
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Rothschild, Bruce. "Intertwining of paleontology and medicine: implications for structure-function relationships, behavior, and habitat in paleontology". Paleontological Society Special Publications 6 (1992): 252. http://dx.doi.org/10.1017/s2475262200008121.
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Medicine and paleontology have been intertwined from the start. Gideon Algernon Mantell, a family physician from Sussex, and his wife, while on patient care “rounds,” found the first English dinosaur. Nineteen years later in 1841, Sir Richard Owen established the neologism, dinosaur, to categorize these animals. It is not accidental that the first Dean of Kansas University School of Medicine was also the founder of the University's Museum of Natural History. Rheumatology and paleontology paths have also crossed in the form of Thinocetus arthritus, so named because the ligamentous fusion in a specimen mistaken for arthritis.Technology and understanding of disease processes have advanced sufficiently to allow hypotheses to be critically examined. The underlying assumptions are that:1. Disease manifestations are relatively stable through time.2. Tissue is preserved in a state amenable to analysis.3. Pathology can be distinguished from diagenesis (pseudopathology).4. Analysis of pathology as a skeletal phenomenon provides more insight than examination of isolated bones.5. Analysis of pathology as a population phenomenon provides more insight than examination of isolated skeletons.Exemplifying the intertwining nature of the fields is the presence of spine and sacroiliac involvement and the nature and distribution of erosive lesions in the great apes (Gorilla and Pan (chimpanzee), the lesser ape (Hylobates) and Old World monkeys (Theropithecus, Papio, Cercopithecus, Macaca, Presbytis, Colobus, and Erythrocebus). This allowed definitive diagnosis of spondyloarthropathy. Reproducibility of diseases across species lines has been established for spondyloarthropathy (gorilla, chimp, monkey), not only for gross or radiologic appearance of individual bones, but also for skeletal distribution. More recently, similar observations have been made for Smilodon and Mammuthus. Reactive arthritis, related to infectious agent diarrhea or sexually transmitted, is a consideration. Infectious agent diarrhea is common in Old World primates. This natural disease state provides a unique model system for in depth analysis of the contribution of genetic and environmental factors to disease pathophysiology.
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Tona, Risa, Ivan A. Lopez, Cristina Fenollar-Ferrer, Rabia Faridi, Claudio Anselmi, Asma A. Khan, Mohsin Shahzad et al. "Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness". Genes 11, n.º 10 (24 de setembro de 2020): 1122. http://dx.doi.org/10.3390/genes11101122.
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Human pathogenic variants of TBC1D24 are associated with clinically heterogeneous phenotypes, including recessive nonsyndromic deafness DFNB86, dominant nonsyndromic deafness DFNA65, seizure accompanied by deafness, a variety of isolated seizure phenotypes and DOORS syndrome, characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures. Thirty-five pathogenic variants of human TBC1D24 associated with deafness have been reported. However, functions of TBC1D24 in the inner ear and the pathophysiology of TBC1D24-related deafness are unknown. In this study, a novel splice-site variant of TBC1D24 c.965 + 1G > A in compound heterozygosity with c.641G > A p.(Arg214His) was found to be segregating in a Pakistani family. Affected individuals exhibited, either a deafness-seizure syndrome or nonsyndromic deafness. In human temporal bones, TBC1D24 immunolocalized in hair cells and spiral ganglion neurons, whereas in mouse cochlea, Tbc1d24 expression was detected only in spiral ganglion neurons. We engineered mouse models of DFNB86 p.(Asp70Tyr) and DFNA65 p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human TBC1D24. Unexpectedly, no auditory dysfunction was detected in Tbc1d24 mutant mice, although homozygosity for some of the variants caused seizures or lethality. We provide some insightful supporting data to explain the phenotypic differences resulting from equivalent pathogenic variants of mouse Tbc1d24 and human TBC1D24.
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Drago, Lorenzo, Gian Vincenzo Zuccotti, Carlo Luca Romanò, Karan Goswami, Jorge Hugo Villafañe, Roberto Mattina e Javad Parvizi. "Oral–Gut Microbiota and Arthritis: Is There an Evidence-Based Axis?" Journal of Clinical Medicine 8, n.º 10 (22 de outubro de 2019): 1753. http://dx.doi.org/10.3390/jcm8101753.
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The gut microbiome appears to be a significant contributor to musculoskeletal health and disease. Recently, it has been found that oral microbiota are involved in arthritis pathogenesis. Microbiome composition and its functional implications have been associated with the prevention of bone loss and/or reducing fracture risk. The link between gut–oral microbiota and joint inflammation in animal models of arthritis has been established, and it is now receiving increasing attention in human studies. Recent papers have demonstrated substantial alterations in the gut and oral microbiota in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). These alterations resemble those established in systemic inflammatory conditions (inflammatory bowel disease, spondyloarthritides, and psoriasis), which include decreased microbial diversity and a disturbance of immunoregulatory properties. An association between abundance of oral Porphyromonas gingivalis and intestinal Prevotella copri in RA patients compared to healthy controls has been clearly demonstrated. These new findings open important future horizons both for understanding disease pathophysiology and for developing novel biomarkers and treatment strategies. The changes and decreased diversity of oral and gut microbiota seem to play an important role in the etiopathogenesis of RA and OA. However, specific microbial clusters and biomarkers belonging to oral and gut microbiota need to be further investigated to highlight the mechanisms related to alterations in bones and joints inflammatory pathway.
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Sanketh, DS, N. Amrutha e Shankargouda Patil. "Metastatic Tumors of the Oral Cavity". Journal of Contemporary Dental Practice 15, n.º 2 (2014): 263–71. http://dx.doi.org/10.5005/jp-journals-10024-1526.
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ABSTRACT The pivotal reason for morbidity and mortality of any type of cancer is due to metastasis that occurs as a result of adaptation of genetically unstable cancer cells, in an ectopic conducive environment. Oral metastasis in spite of being unusual or rare represents around 25% of the first signs of metastatic spread. Literature says there are more number of cases of jaw bone metastasis reported than in the oral soft tissues. The most common primary organs metastasizing to the jaw bones and the oral soft tissues are the breast and the lungs respectively. The issue in diagnosing a metastatic tumor arises either when the patient does not reveal the history of the primary illness he or she may be suffering from or when he or she is unaware of it. Diagnosis in such situations is a challenge to the clinician or pathologist. Diagnosing any lymph node or distant metastasis from oral cancer is very important for the prognosis of the patient. In this review we have made an attempt, to explain some recent concepts of pathophysiology of the metastatic process, the clinical manifestations of metastatic tumors to the oral region and to discuss their diagnostic workup. How to cite this article Rao RS, Patil S, Sanketh DS, Amrutha N. Metastatic Tumors of the Oral Cavity. J Contemp Dent Pract 2014;15(2):263-271.
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Hosseini, Ali, Pim Van Dijk, Sofie Breuking, Bryan Vopat, Daniel Guss, A. Holly Johnson e Christopher DiGiovanni. "The Peroneus Brevis and Plantar Fascia Insertions Are Related to Proximal Fifth Metatarsal Fractures". Foot & Ankle Orthopaedics 2, n.º 3 (1 de setembro de 2017): 2473011417S0001. http://dx.doi.org/10.1177/2473011417s000198.
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Category: Midfoot/Forefoot Introduction/Purpose: Proximal fifth metatarsal fractures (PFMF) are among the most common fractures in the foot and can be categorized into three fracture zones [1]. To investigate the fracture mechanism of PFMF in different zones, a better understanding of the anatomy of the bone and its surrounding soft tissues is required. Both the plantar fascia (PF) and the peroneus brevis (PB) tendon insertions are at the base of the fifth metatarsal, and may contribute to the pathophysiology of PFMF. However, the role of the PB and PF insertions in the pathogenesis of PFMF remains unclear. The purpose of this study was to accurately define the footprint of the PB and PF insertions of the base of the 5th metatarsal in relation to the different zones of PFMF. Methods: 21 cadaveric fifth metatarsal bones were harvested from cadaveric feet. All bones were freed of any remaining soft tissue adherence, except for the PB and the PF insertions. Three reference screws with a diameter of 1 mm were placed and secured on each bone with 2 screws distally and 1 screw proximally for registration. All bones were CT scanned to create a 3D bone reconstruction. Next, the insertions of the PB and PF and the reference screws of each bone were digitized and then mapped to its corresponding 3D bone model. In order to describe the three different fracture zones of the 5th metatarsal, an established coordinate system was made for each bone to simulate separate fracture zones (Figure a) based on Lawrence guideline [1]. The shape, location and surface areas of both insertions and their relation to the different fractures zones were determined (Figure b). Results: The insertion of the PB was oval shaped and located on the dorsal side of the base, with a mean surface area of 88.1 ± 46.4 mm2. The PF was oval shaped and situated around the tip of tuberosity, with a mean surface area of 150.7±53.5 mm2. The PB insertion was present in zone 1 fractures in 100% (21/21) of the 5th metatarsal models and 29% (6/21) of the models for zone 2 fractures. The PF insertion was involved in 100% (21/21) of the 5th metatarsal models for zone 1 fractures and 43% (9/21) of the models for zone 2 fractures. Conclusion: Results of this study demonstrate that the insertion of both the PB and PF are involved in all zone 1 PFMF and a significant percentage of zone 2 PFMF. The location of tendon insertions affect the forces exerted on the bone, which may indicate a relation of the insertions of both the PB and the PF with the fracture mechanism of many zone 1 and 2 PFMF. Moreover, in the treatment of these fractures, care should be taken to maintain or restore the anatomy of these insertions to maximize functional outcomes.
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Bjelica, Artur, Viktorija Vucaj-Cirilovic, Snezana Tomasevic-Todorovic e Karmela Filipovic. "Postmenopausal osteoporosis". Medical review 71, n.º 5-6 (2018): 201–5. http://dx.doi.org/10.2298/mpns1806201b.
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Introduction. Postmenopausal women are at a great risk for osteoporosis and bone fractures. Pathophysiology of osteoporosis. The two main factors causing osteoporosis are aging and loss of the gonadal function. Postmenopausal osteoporosis is primarily the consequence of estrogen deficiency, whereas senile osteoporosis is related to the natural aging process. Risk factors for the onset of osteoporosis. Risk factors include: age of 50 years and over. female gender. Caucasian race, genetic predisposition, short stature, under?nourishment, physical inactivity, amenorrhea, late menarche, early menopause, estrogen and androgen deficiency, alcohol consumption, cigarette smoking, calcium deficiency in the diet, use of some drugs. Osteoporosis complications. Osteoporosis is the main cause of bone fractures in older population. Biochemical indicators of bone metabolism. A great number of bone formation and resorption markers are listed. Diagnostics. Dual-energy X-ray absorptiometry measurements of the hip and spine are a worldwide standard in diagnosing osteoporosis. Dual X-ray laser heel measurement is an alternative to dual-energy X-ray absorptiometry. Quantitative computed tomography measures thin layers by cross-sectional scans. Quantitative ultrasonography is a good method, but the measurements are not as precise as by other imaging techniques. Drug treatment of osteoporosis. Modern treatment of osteoporosis includes application of bisphosphonates, selective estrogen-receptor modulators, calcium preparations, vitamin D, monoclonal antibodies, hormonal therapy, estrogens, and phytoestrogens. Prevention. Lifestyle changes and non-pharmacological measures are most important for healthy bones. Physical activity, nutrition rich in calcium and vitamin D, avoidance of smoking and alcohol consumption are of crucial importance for people of all ages. especially for the older ones.
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Chen, Ye, Rodrigo O. Jacamo, Nicole A. Hofmann, Yue-xi Shi, Rui-yu Wang, Sergej Konoplev, Dirk Strunk, Marina Konopleva e Michael Andreeff. "Human Extramedullary Bone and Bone Marrow in Mice: First In Vivo Model of a Genetically Controlled Hematopoietic Environment". Blood 118, n.º 21 (18 de novembro de 2011): 1323. http://dx.doi.org/10.1182/blood.v118.21.1323.1323.
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Abstract Abstract 1323 The importance of the tumor microenvironment for cancer development, progression and resistance to treatment has recently been recognized. Our group was first to report the contribution of bone marrow (BM) derived mesenchymal stromal cells (MSCs) for tumor development and metastasis. BM is also the dynamic microenvironment (niche) for normal and malignant hematopoietic stem cells (HSC) with high local concentrations of growth factors, chemokines and cytokines. The maintenance of HSCs quiescence and normal hematopoiesis require complex bidirectional interactions between the BM niches and HSCs. Accumulating evidence has shown that the BM microenvironment also plays a pivotal role in the pathophysiology and propagation of leukemia. Leukemia cells undergo spontaneous apoptosis once they are removed from the in vivo microenvironment and placed in suspension cultures without supportive stroma. The understanding of the interactions between leukemic cells and their BM niche is also critically important for leukemia therapy. We here describe a novel artificial bone and bone marrow model mimicking the human hematopoietic microenvironment by using human BM derived MSCs and endothelial colony-forming cells (ECFCs). MSCs and ECFCs were isolated from heparinized human bone marrow or peripheral blood through an initial adhesion step, grown in specific media and then subcutaneously injected into the flanks of the NOD/SCID/IL-2r-gammanull mice, where they developed into bone-like tissues with high osteoblast activity after 10 weeks (Figure 1). Histochemical stains confirmed the bone structures and also showed that these artificial bones contained typical bone marrow cavities constituting a robust hematopoietic environment. In vivo imaging with Osteosense confirmed the presence of hydroxylapatite, and luciferase imaging of firefly luciferase labeled human leukemic cells demonstrated the engraftment of MOLM13/Luc/GFP leukemic cells in the extramedullary BM sites. The extramedullary BM was markedly hypoxic, as shown by Pimonidazole staining, another critical feature of the BM microenvironment. Factors critical for MSC to support the normal and leukemic hematopoiesis are largely unknown and cannot be studied since human MSC do not engraft reliably in xenograft models. We therefore investigated the possibility of genetically modifying MSC in this system and found a significant reduction (50 ± 6%, p<0.001) in MOLM13 cell engraftment in extramedullary BM generated with HIF1-alpha knockdown MSCs (1449 ± 194 cells/mm2), compared to vector controls (3037 ± 496 cells/mm2). This finding indicates that the HIF1-alpha expression in stromal cells is a critical component for the engraftment of leukemic cells in the physiologically hypoxic BM microenvironment. These results, for the first time, establish an in vivo bone and bone marrow model with a genetically controlled human microenvironment.Figure 1Establishment a human bone marrow microenvironment in NOD/SCID/IL-2r-gammanullmice. Representative hematoxylin and eosin (H&E) staining (shown at low magnification) shows an overview of the extramedullary bones with the typical bone structures. Scale bar: 1 mm.Figure 1. Establishment a human bone marrow microenvironment in NOD/SCID/IL-2r-gammanull mice. Representative hematoxylin and eosin (H&E) staining (shown at low magnification) shows an overview of the extramedullary bones with the typical bone structures. Scale bar: 1 mm. Disclosures: No relevant conflicts of interest to declare.
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Mukkamalla, Shiva Kumar Reddy, e Dhatri Malipeddi. "Myeloma Bone Disease: A Comprehensive Review". International Journal of Molecular Sciences 22, n.º 12 (8 de junho de 2021): 6208. http://dx.doi.org/10.3390/ijms22126208.
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Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in the bone marrow microenvironment, characterized by overproduction of heavy- and light-chain monoclonal proteins (M-protein). These proteins are mainly found in the serum and/or urine. Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk of infection. The primary site of origin is the bone marrow for nearly all patients affected by MM with disseminated marrow involvement in most cases. MM is known to involve bones and result in myeloma bone disease. Osteolytic lesions are seen in 80% of patients with MM which are complicated frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain, pathological fractures, vertebral collapse, and spinal cord compression. These deteriorate the patient’s quality of life and affect the overall survival of the patient. The underlying pathogenesis of myeloma bone disease involves uncoupling of the bone remodeling processes. Interaction of myeloma cells with the bone marrow microenvironment promotes the release of many biochemical markers including osteoclast activating factors and osteoblast inhibitory factors. Elevated levels of osteoclast activating factors such as RANK/RANKL/OPG, MIP-1-α., TNF-α, IL-3, IL-6, and IL-11 increase bone resorption by osteoclast stimulation, differentiation, and maturation, whereas osteoblast inhibitory factors such as the Wnt/DKK1 pathway, secreted frizzle related protein–2, and runt-related transcription factor 2 inhibit osteoblast differentiation and formation leading to decreased bone formation. These biochemical factors also help in development and utilization of appropriate anti-myeloma treatments in myeloma patients. This review article summarizes the pathophysiology and the recent developments of abnormal bone remodeling in MM, while reviewing various approved and potential treatments for myeloma bone disease.
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Gomes, Alicia, Peter Weiser, Maria Descartes e Jariya Upadia. "A Familial Case of Multicentric Carpotarsal Osteolysis Syndrome and Treatment Outcome". Journal of Pediatric Genetics 07, n.º 04 (16 de junho de 2018): 174–79. http://dx.doi.org/10.1055/s-0038-1657760.
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AbstractMulticentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder caused by heterozygous mutations in the MAFB gene (v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B). This is an autosomal dominant condition with a high frequency of sporadic cases. MCTO is characterized by osteolysis of the carpal, metacarpal, and tarsal bones beginning in early childhood with musculoskeletal rheumatologic symptoms such as pain and disability. Renal involvement can be seen in more than half of the patients; from ages 16 months to 42 years and manifests from proteinuria to end-stage renal failure requiring renal transplantation. The association of MAFB gene mutations with this genetic condition has aided in understanding the pathophysiology of the disease. We report here a 7-year-old Caucasian boy and his 33-year-old mother diagnosed with MCTO, with the boy having concomitant juvenile idiopathic arthritis. He was initially diagnosed with arthritis at age 5 years based on bilateral wrist synovial swelling, morning stiffness, and weakness with family history of his mother being diagnosed with erosive psoriatic arthritis leading to limb deformities. Initial therapy for the boy included methotrexate and infliximab with moderate response. Later, during the course of his disease, he underwent a genetic evaluation at age 7 years for history of learning disabilities and dysmorphic features. Maternal evaluation and radiographic examination led to a clinical diagnosis of MCTO in the mother, and subsequent testing for MAFB gene in the son revealed a mutation at c.206C > T (p.Ser69Leu), the most commonly reported genetic change in MCTO. Nevertheless, further imaging still confirmed ongoing arthritis, and therapy was adjusted based on its progression including abatacept, tocilizumab, and pamidronate. Our report highlights the possibility of concomitant inflammatory arthropathy in MCTO.
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Ahamed, Irshad, e Niyati Jauhar. "Hypercalcemia Due to Immobilization". Journal of the Endocrine Society 5, Supplement_1 (1 de maio de 2021): A196. http://dx.doi.org/10.1210/jendso/bvab048.398.
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Abstract Background: Hypercalcemia associated with immobilization is an infrequent diagnosis. It is usually associated with prolonged immobility due to traumatic brain injury or spinal cord injuries. It results from rapid bone turnover. Diagnosis requires workup to rule out other causes of hypercalcemia. Keywords: Hypercalcemia; immobilizationCASE REPORT: We report a case of a 49 year old woman with severe traumatic brain injury and paraplegia following an electric-scooter accident. She had an extended stay in hospital and was noted to be hypercalcemic after six months’ in-patient. Laboratory investigations showed increased calcium level at 3.34 mmol/l (ref. 2.15–2.50 mmol/l) with diminished parathyroid hormone (PTH) level of 0.2 pmol/l (ref. 1.6–6.9 pmol/l), low 25-hydroxyvitamin D at 26.7 ug/l (toxicity >100 ug/l) and low 1,25-dihydroxyvitamin D at 13 pg/l (ref. 18–78 pg/l) with increased 24-H urinary calcium at 11.74 mmol/day (ref. 2.50 – 7.50 mmol/day). There was no clinical or biochemical evidence of other endocrinopathies such as hyperthyroidism or adrenal insufficiency. There was also no underlying malignancy to explain the hypercalcemia. In the context of recent prolonged immobility, a diagnosis of immobilisation hypercalcemia (IH) was made. The pathophysiology of IH is unclear. It is said that muscle activity transmits signal for bone formation through osteocytes and with immobility, mechanical stimulation is reduced, causing unopposed resorption. Another cause may be increased acidic environment due to low blood flow which impairs bone mineralization. There is also increased osteoclastic resorption, leading to loss of calcium from bones and hypercalciuria. Hypercalcemia occurs when calcium efflux from bone exceeds renal calcium excretion. For our patient, hydration therapy was initiated with no improvement in calcium. SC calcitonin was added and IV pamidronate given. Two weeks after treatment serum calcium improved to 2.38 mmol/L and remained normal on subsequent monitoring. Conclusion: IH is a known but uncommonly recognized complication in immobile patients. If not treated properly patients may develop typical complications of hypercalcemia including dehydration, confusion and renal impairment. Mobilization by using weight bearing exercises where possible is a cornerstone of long term management. In conclusion, our case serves as an important reminder of this differential and illustrates the management of IH.
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Arudkumaran, Dharscika, Albert Chang, Deviani Umadat e Deirdre Cocks Eschler. "Acute Sensorineural Hearing Loss - an Unusual Presentation of Uncontrolled DM". Journal of the Endocrine Society 5, Supplement_1 (1 de maio de 2021): A363—A364. http://dx.doi.org/10.1210/jendso/bvab048.740.
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Abstract Background: Diabetes mellitus (DM) is a systemic metabolic disorder that possesses macro- and microangiopathic consequences. Studies have demonstrated that a relationship exists between sensorineural hearing loss (SNHL) and DM, particularly in patients of older age, longer disease duration, and uncontrolled DM. The pathophysiology of DM related hearing loss is poorly understood, however proposed mechanisms include ischemia, fibrosis, demyelination, and atrophy of the eighth cranial nerve. We however, present a case of acute, transient sensorineural hearing loss in the setting of diabetic ketoacidosis that resolved with blood glucose control. Clinical Case: A 34-year-old male with type 2 diabetes mellitus (A1c 6.5% -diagnosed 6 months prior), hypertension, hyperlipidemia, and morbid obesity presented with shortness of breath and acute hearing loss without tinnitus, after being treated for pneumonia and otitis media with a course of levofloxacin for 7 days. On presentation, patient was tachypneic and tachycardic. Physical examination was significant for mild erythema of the right tympanic membrane without bulging, fluid level, mastoid tenderness, or discharge. Laboratory values were significant for hyperglycemia with blood glucose of 628 mg/dL(n 70–99 mg/dL), A1c 15.9% (n 4.8–5.6%), bicarbonate 8 mmol/L (21–31 mmol/L), anion gap 37 mmol/L (9–16 mmol/L), beta-hydroxybutyrate 11.7 mmol/L (0.02–0.27 mmol/L). Venous gas was suggestive of metabolic acidosis, urinalysis was positive for moderate ketones and glucose >500 mg/dL. The patient was diagnosed with diabetic ketoacidosis and was started on an insulin drip. An audiogram revealed profound bilateral sensorineural hearing loss. A Computerized tomography (CT) scan of the bilateral temporal bones was negative for abnormalities, and a magnetic resonance imaging (MRI) of the brain was negative for morphologic abnormalities of 7th and 8th cranial nerves. Infectious and rheumatologic etiologies were excluded with normal syphilis FTA-ABs, Lyme PCR, Rheumatoid factor, ANCA, and ANA. The patient received one dose of empiric prednisone. His hearing improved after 2 days with normalization of blood glucose to a range of 100–200 mg/dL. A repeat audiogram and auditory brainstem response showed significant improvement with normal bilateral hearing. Discussion: SNHL in DM typically presents in a gradual progression with bilateral involvement, affecting higher frequencies. In patients with DM, studies show that chronicity (greater than 10 years) is strongly associated with SNHL. Other variables include older age and HbA1c greater than 8%. This is the first case to demonstrate acute bilateral SNHL, associated with uncontrolled type 2 diabetes mellitus, which resolved after blood glucose control. In the appropriate context, clinicians should consider significant hyperglycemia as a possible etiology of acute hearing loss.
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Wootton, Elizabeth, Matthew Balcerek, Syndia Lazarus e Emma L. Duncan. "Post-Traumatic Heterotopic Ossification With Incidental Hyperparathyroidism". Journal of the Endocrine Society 5, Supplement_1 (1 de maio de 2021): A212. http://dx.doi.org/10.1210/jendso/bvab048.431.
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Abstract Background: Heterotopic ossification (HO) is a rare disease characterised by abnormal bone growth in non-osseous tissues, causing pain, immobility and impaired quality of life. Although still being elucidated, the underlying pathophysiology may relate to local macrophage-driven inflammation in response to trauma1. Case: A 35-year-old man involved in a motor vehicle accident (MVA) fractured over twenty bones (multiple vertebrae, ribs and complex open book pelvic fracture with shattered left acetabulum) with extensive soft tissue injuries requiring multiple surgeries. Past medical history included a renal calculus three years earlier. His serum corrected calcium on admission was elevated at 2.87mmol/L (2.10-2.60mmol/L). Peri-operative fluid over-resuscitation necessitated boluses of intravenous furosemide, and serum calcium transiently normalised before rapidly incrementing and peaking at 3.04 mmol/L. Serum parathyroid hormone post-operatively was inappropriately high at 9.4pmol/L (1.0–7.0pmol/L) and 25-hydroxyvitamin D low at 24nmol/L (50-150nmol/L). Oral vitamin D replacement was commenced and he received intravenous pamidronate (3x60mg infusions) which briefly restored normocalcaemia. Neck ultrasound and sestamibi scintigraphy demonstrated a left parathyroid adenoma, and he underwent parathyroidectomy. Histology revealed a single parathyroid adenoma. He has been normocalcaemic since surgery. Despite excellent overall recovery, mobility at the left hip remained restricted in all planes of movement. He could not perform simple activities such as putting on his shoe. Plain radiographs showed HO lateral to the left acetabulum, femoral head and neck, with bony bridging to the left ilium on computed tomography. Bone turnover markers (BTMs) measured eleven months post-MVA (and pamidronate) were elevated, with CTX of 750ng/L (100-600ng/L) and P1NP of 207ug/L (15-80ug/L). BTMs gradually reduced over time, plateauing two years post-MVA (CTX 480ng/L and P1NP 103ug/L). Surgery with pre-operative radiotherapy to remove the left hip HO is now planned. Discussion: This man had multiple recognised risk factors for HO, including male sex, trauma followed by immobilisation and pelvic fracture. His hyperparathyroidism may have predisposed HO development through excess calcium-phosphate product promoting soft tissue calcification. Bisphosphonates may also increase the risk2. Elevated BTMs have been demonstrated in the early phase of HO; further research may elucidate whether BTMs can guide timing of surgical intervention relative to the pathophysiological processes driving HO. References: 1 Meyers C et al. Heterotopic Ossification: A Comprehensive Review. JBMR Plus 2019, 3: e10172 2 Genêt F et al. Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle 2015. J Pathol. 236(2):229–40
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Mironov, S. P., N. A. Es’kin, A. I. Krupatkin, G. A. Kesyan, R. Z. Urazgil’deev e I. G. Arsen’ev. "Pathophysiologic Aspects of Soft Tissue Microcirculation in the Zone of Long Bones Pseudarthrosis". N.N. Priorov Journal of Traumatology and Orthopedics 19, n.º 4 (15 de dezembro de 2012): 22–26. http://dx.doi.org/10.17816/vto20120422-26.
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Thirty four patients with delayed consolidating fractures and long bones pseudarthrosis and 30 healthy individuals (control group) were examined using laser Doppler flowmetry and computed thermography. It was shown that during the osteogenesis process no isolated changes in bone circulation took place but the potentialities of blood flow in the extremity segment as a whole were mobilized. Important role of bone surrounding soft tissue circulation for provision of adequate osteogenesis was confirmed. In case of pseudarthrosis formation microcirculation system, especially its nutrient part, responded «keenly» to the changes in regional metabolism and bone regeneration. That stipulated diagnostic and prognostic importance of soft tissue microhemocirculation study in the zone of pseudarthrosis. Preoperative functional examination of soft tissue circulation enabled to determine risk group for nonconsolidation ordelayed consolidation of fractures. For better result special treatment tactics can be used (osteogenesis stimulators, free vascularized autografts, etc.).
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Kawata, Yuki, Hisashi Hirano, Ren Takahashi, Yukari Miyano, Ayuko Kimura, Natsumi Sato, Yukio Morita, Hirokazu Kimura e Kiyotaka Fujita. "Detailed Structure and Pathophysiological Roles of the IgA-Albumin Complex in Multiple Myeloma". International Journal of Molecular Sciences 22, n.º 4 (10 de fevereiro de 2021): 1766. http://dx.doi.org/10.3390/ijms22041766.
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Immunoglobulin A (IgA)-albumin complexes may be associated with pathophysiology of multiple myeloma, although the etiology is not clear. Detailed structural analyses of these protein–protein complexes may contribute to our understanding of the pathophysiology of this disease. We analyzed the structure of the IgA-albumin complex using various electrophoresis, mass spectrometry, and in silico techniques. The data based on the electrophoresis and mass spectrometry showed that IgA in the sera of patients was dimeric, linked via the J chain. Only dimeric IgA can bind to albumin molecules leading to IgA-albumin complexes, although both monomeric and dimeric forms of IgA were present in the sera. Molecular interaction analyses in silico implied that dimeric IgA and albumin interacted not only via disulfide bond formation, but also via noncovalent bonds. Disulfide bonds were predicted between Cys34 of albumin and Cys311 of IgA, resulting in an oxidized form of albumin. Furthermore, complex formation prolongs the half-life of IgA molecules in the IgA-albumin complex, leading to excessive glycation of IgA molecules and affects the accumulation of IgA in serum. These findings may demonstrate why complications such as hyperviscosity syndrome occur more often in patients with IgA dimer producing multiple myeloma.
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Pozzi, Samantha, Raffaella Marcheselli, Alessia Bari, Eliana Valentina Liardo, Paola Bresciani, Maria Teresa Donini, Santo Neri et al. "Evaluation of Atypical Low Energy Fractures in Patients Affected by Multiple Myeloma Treated with Bispohosphonates". Blood 118, n.º 21 (18 de novembro de 2011): 5134. http://dx.doi.org/10.1182/blood.v118.21.5134.5134.
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Abstract Abstract 5134 BACKGROUND: Bisphosphonates (BP) are standard supportive care in patients affected by symptomatic multiple myeloma (MM) with skeletal lesions. Despite the long term use of BP in the clinic, many of the effects of this category of drugs and their optimal schedule of administration are still matter of debate. In the recent past the identification of osteonecrosis of the jaw induced clinicians and researchers to reevaluate the schedule of administration of BP in myeloma, questioning about their effects on other cells than osteoclasts. Therefore a better definition of risks and benefits of anti-catabolic agents may help addressing future studies in this field. Recently a growing number of publications alerted orthopedics and endocrinologists about a rare but serious event called “atypical low energy fractures” (LEF) in patients affected by osteoporosis treated with long term BP (1–3). LEF refer to stress fractures, mainly localized in the subtrochanteric region, spontaneous or secondary to minor trauma, often preceded by local pain, with specific radiologic patterns and sometimes delayed healing. Localizations in bones different than femur have been reported. Still debated is the association with BP and the pathophysiology of this condition. So far three cases of fractures with the characteristics of LEF have been described in MM patients. METHODS: in order to evaluate the possible existence of other cases of LEF in patients with MM we started a retrospective survey in hematological centers, collecting the cases of MM followed by each center between January 2005 and December 2010, and any case of atypical fracture not related to MM or major trauma. Inclusion criteria for LEF were so defined: diagnosis of MM; treatment with BP; fractures induced by minor trauma or spontaneous, not associated with MM localization; radiological aspect of stress fracture; +/− prodromic pain. Central revision of patients history and radiology will be conducted with the support of an orthopedic in the patients with atypical fractures, followed by bone histomorphometry on bone marrow biopsy. RESULTS: The study is ongoing. At present seven centers reported a total of 1065 patients affected by MM followed between 2005 and 2010 and five cases of suspect LEF. The first patient is a woman diagnosed with anaplastic myeloma in 2002, apparently in complete remission after 4 lines of treatment. In June 2008 the patient was diagnosed with an atraumatic left fracture of the fifth metatarsal bone, followed by a right metatarsal fracture one month later and second right metatarsal stress fracture in 2011. The fractures were not related to myeloma localization. Other four cases of fractures are under investigation in other two center. CONCLUSIONS: MM patients are exposed to high rate of bone fractures related to the hematological disease and at the best of our knowledge the frequency of stress fractures in this population is unknown. With the present study, over a population of more than one thousand patients, we observed five cases of possible LEF that will undergo detailed analysis through central revision of patients history, radiology and bone histomorphometry with the aim to identify individual risk factors. Despite LEF is a rare and still controversial condition, the identification of individual risks to develop fractures not secondary to MM, may help clinicians tailoring the treatment for bone disease, much needed in an era of new drug discoveries for bone treatment. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria.
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Shimizu, Yu, Kiminori Nakamura, Aki Yoshii, Yuki Yokoi, Mani Kikuchi, Ryuga Shinozaki, Shunta Nakamura, Shuya Ohira, Rina Sugimoto e Tokiyoshi Ayabe. "Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice". Life Science Alliance 3, n.º 6 (28 de abril de 2020): e201900592. http://dx.doi.org/10.26508/lsa.201900592.
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Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.
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Wakahashi, Kanako, Kentaro Minagawa, Noboru Asada, Yuko Kawano, Mari Sato, Hiroki Kawano, Akiko Sada et al. "αSMA+ Macrophages Skewed From Hematopoietic Stem Cells By Vitamin D3 Initiate Myelofibrosis and Subsequent Osteosclerosis". Blood 122, n.º 21 (15 de novembro de 2013): 340. http://dx.doi.org/10.1182/blood.v122.21.340.340.
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Abstract Myelofibrosis (MF) is characterized as the proliferation of fibroblasts resulting in the replacement of marrow space by collagenous connective tissue fibers and is also known to be frequently complicated with osteosclerosis. However, the pathogenesis of this phenomenon is largely unknown. Allogeneic stem cell transplantation is the therapeutic choice in clinic with complete resolution of the disorder despite the recognition as microenvironment problem by the hematologists. Here, we establish a novel inducible murine MF model and propose a new paradigm in the pathophysiology of MF. Vitamin D receptor-deficient (VDR-/-) mice display rickets type II, which can be restored by high calcium diet, resulting in their usefulness as transplant recipients. We transplanted wild-type (WT) bone marrow (BM) cells into lethally irradiated VDR-/- mice and found that the vast majority died due to BM failure (n=25, median survival 66 days), though for the time being hematopoiesis was reconstituted during the first month after transplantation. The homing of long-term repopulating hematopoietic stem cells (HSCs) into marrow space was normal at 3 hrs, but the HSCs selectively disappeared at 3 weeks after transplantation as assessed by competitive reconstitution. Since VDR-/- mice showed normal hematopoiesis in steady-state, we transplanted VDR-/- BM into lethally irradiated VDR-/- recipients, which resulted in survival with no BM failure. Thus, engraftment failure of the WT HSCs in VDR-/- recipients did not originate from radiation-induced irreversible niche destruction, but it was likely intrinsic to donor HSC behavior. Histological analysis of femurs at 1-2 months after transplantation of WT BM into VDR-/- recipients revealed that the BM cavity was occupied by spindle-shaped cells and silver fibers. There was also prominently increased trabecular bones only in the metaphysis; whereas, normal hematopoietic appearance was observed in the diaphysis. This was initiated by hematopoietic cells since CD45+lin-c-kit+ cells isolated from WT CAG-EGFP transgenic mice as donor source induced the same MF and osteosclerosis in VDR-/- recipients. Metaphysial BM was replaced by monotonous fibroblastic cells in this particular setting; however, these cells were composed of two distinct populations with mutual distribution, 1) GFP+F4/80+ donor-derived macrophages and 2) GFP-osterix+ (or runx2+) host-derived preosteoblasts. These two distinct cells were tangled around each other equally in the fibrotic tissue area, and preosteoblasts were dominant in the osteoscrelotic area. Both populations were positive for αSMA. Since VDR-/- donor cells did not induce MF and it was reported that the level of 1,25(OH)2D3 (vitamin D3) is extremely high in VDR-/- mice, we hypothesized that WT HSCs exposed to high vitamin D3 might differentiate into αSMA+ macrophages and proliferate in vivo. Furthermore, since it is widely known that macrophages are strong supporter of osteoblasts, these cells might drive osteoblast-lineage cells. In the culture of hematopoietic stem/progenitor cell line FDCP-mix, vitamin D3 induced strong F4/80 upregulation together with partial αSMA induction, and MCP1 secretion in the culture supernatant was highly induced depending on vitamin D3 concentration. Strikingly, a diet low in vitamin D3 prevented the development of MF with osteosclerosis in VDR-/- recipients transplanted with WT BM. Thus, in our novel MF model, the true pathogenesis is likely that αSMA+ macrophages as MF-initiating cells perhaps directly differentiated from HSCs through vitamin D3 stimulation, drive the activity of preosteoblasts as a major producer of collagen fibers, and initiate osteosclerosis. We next examined whether this new paradigm could be applied for JAK2 V617F transgenic mice, which display MF with osteosclerosis, and human MF patients (n=3 including two cases with JAK2 V617F mutation). As we expected, marrow fibroblastic cells of both mouse genetic model and human patients were similarly composed of αSMA+CD169+ (or CD163+) macrophages and αSMA+ osteoblastic lineage cells with osterix or runx2 expression. Our study may explain why BMT is useful in clinic because MF is likely initiated by hematopoietic cells. We propose the modulation of vitamin D3 signaling or macrophage-targeted strategies as novel therapeutic choices for MF. Disclosures: No relevant conflicts of interest to declare.
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Chae, Young Kwang, Hagop M. Kantarjian, Muhamed Baljevic, Alfonso Quintás-Cardama, Gautam Borthakur, Tapan M. Kadia, Susan O'Brien et al. "Adverse Prognosis Of Extramedullary Disease In Patients With Chronic Myeloid Leukemia (CML) In The Tyrosine Kinase Inhibitor (TKI) Era: a Cohort Study Of 283 Blastic Phase CML Patients". Blood 122, n.º 21 (15 de novembro de 2013): 2724. http://dx.doi.org/10.1182/blood.v122.21.2724.2724.
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Abstract Background With the advent of tyrosine kinase inhibitors (TKIs), significant improvement has been made in the survival outcome of chronic myeloid leukemia (CML) patients. However, blastic phase (BP) CML remains a therapeutic challenge. Extramedullary disease (EMD) is a diagnostic criterion for BP, and patients with this presentation represent a unique subgroup of BP CML. The characteristics of EMD in BP CML patients have not been well described, especially in the era of TKIs. Methods We have analyzed CML patients with extramedullary BP either at the time of diagnosis or progressing from CP/AP from 2000 to 2011 and treated with different TKIs such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib at a single institution. All demographic, clinicopathologic variables and medication data including TKIs were collected at the time of the diagnosis of BP. Primary outcomes, overall survival (OS) were defined as time from diagnosis of BP to death. Results Among a total of 284 BP CML patients, median age was 52.6 (range: 15-81) years. Males were 65.0%. 72.2% were in myeloid BP versus 27.7% in lymphoid BP. Median follow up was 1.5 (range: 0.01-12) years. Median time from diagnosis of CML to BP was 2.3 (range: 0.01-28) years. 128 (45%) patients have died. Cytogenetic analysis at diagnosis demonstrated that 34% had only Philadelphia chromosome (Ph) present while 66% had other chromosomal abnormalities besides Ph. Trisomy 8 was the most common additional chromosomal abnormality (18%). 280 (99%) were treated with TKIs. Among them, 176 (623%) were treated with TKI monotherapy, and the rest with a combination of TKI and conventional chemotherapy. Among the patients treated with TKI, 134 (48%) used imatinib; 85 (30%), dasatinib; 48 (17%), nilotinib; 7 (3%), bosutinib; and 6 (2%), ponatinib. EMD was diagnosed in 78 patients (28%) of all BP CML patients. Patients with EMD had a median age of 52.8 (range: 19-80) while BP patients without EMD had a median age of 52.2 (range: 15-81). There were no statistically significant differences in age, gender, ethnicity, or time from diagnosis of CML to BP between EMD and non-EMD patients. Among patients with EMD 76% were myeloid, and 23% lymphoid compared with 70% myeloid and 30% lymphoid in patients without EMD (p=0.3). Patient with EMD had more Ph-only disease compared with patients without EMD (41% vs. 28%, p=0.03). Among 28 patients with deletion 7 chromosomal abnormality, only 1 patient had EMD (EMD vs. non-EMD chi-square p=0.002). There was no association between the presence of EMD and other chromosomal abnormalities such as double Ph, isochromsome 17, trisomy 8, deletion Y and variant Ph. Among patients with EMD, 39 (50%) had EMD in CNS; 22 (28%) in soft tissue, skin, or lymph nodes; 9 (12%) in bones; 8 (10%) in lung or pleura; and 4 (5%) in GI tract and liver. Among patient with BP CML, there were no statistically significant differences between the EMD and non-EMD groups in both complete hematologic response (CHR) rate and complete cytogenetic response (CCyR) rate at 3 months after the initiation of therapy (CHR: EMD 18% vs. non-EMD 22%, p=0.4; CCyR: EMD 8% vs. non-EMD 15%, p=0.1). However, the presence of EMD was associated with worse survival outcome (Hazard Ratio [HR]=1.62, Confidence Interval [CI]= 1.13-2.32, p=0.008). Median overall survival in patients with EMD was 0.8 versus 2.5 years in patients without EMD (log-rank test p=0.008, Figure 1). EMD in CNS was not associated with survival (HR=0.87, CI=0.50-1.51, p=0.6). In multivariate analysis controlling for age, gender, ethnicity, white cell counts, cytogenetics (presence of additional chromosomal abnormality), and pathology (myeloid versus lymphoid), EMD was still linked with adverse survival (adjusted HR=1.53, CI=1.04-2.26, p=0.03). Conclusion BP CML patients presenting with EMD are likely to have less additional chromosomal abnormality and have inferior overall survival compared with those without EMD. EMD may represent more aggressive pathophysiology in BP CML and may require more intensive treatment. Disclosures: No relevant conflicts of interest to declare.
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Essex, DW, K. Chen e M. Swiatkowska. "Localization of protein disulfide isomerase to the external surface of the platelet plasma membrane". Blood 86, n.º 6 (15 de setembro de 1995): 2168–73. http://dx.doi.org/10.1182/blood.v86.6.2168.bloodjournal8662168.
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Protein disulfide isomerase (PDI) is an enzyme that catalyzes the formation as well as the isomerization of disulfide bonds. In this study, antibodies against PDI were used to show PDI antigen on the platelet surface by indirect immunofluorescence microscopy and by flow cytometry. The platelets were not activated, as evidenced by the absence of staining by an antibody against P-selectin. Permeabilized platelets showed little cytosolic PDI by indirect immunofluorescence microscopy, suggesting that the majority of platelet PDI is localized to the platelet surface. PDI activity against “scrambled” RNase was shown with intact platelets. The activity was inhibited by inhibitors of PDI and by an antibody against PDI. Other blood cells showed little PDI. Platelet surface PDI may play a role in the various physiological and pathophysiologic processes in which platelets are involved.
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Parakh, Sonam, Damian M. Spencer, Mark A. Halloran, Kai Y. Soo e Julie D. Atkin. "Redox Regulation in Amyotrophic Lateral Sclerosis". Oxidative Medicine and Cellular Longevity 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/408681.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS.
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Dubin, A., J. Potempa e J. Travis. "Structural and functional characterization of elastases from horse neutrophils". Biochemical Journal 300, n.º 2 (1 de junho de 1994): 401–6. http://dx.doi.org/10.1042/bj3000401.
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In order better to understand the pathophysiology of the equine form of emphysema, two elastinolytic enzymes from horse neutrophils, referred to as proteinases 2A and 2B, have been extensively characterized and compared with the human neutrophil proteinases, proteinase-3 and elastase. Specificity studies using both the oxidized insulin B-chain and synthetic peptides revealed that cleavage of peptide bonds with P1 alanine or valine residues was preferred. Further characterization of the two horse elastases by N-terminal sequence and reactive-site analyses indicated that proteinases 2A and 2B have considerable sequence similarity to each other, to proteinase-3 from human neutrophils (proteinase 2A), to human neutrophil elastase (proteinase 2B) and to a lesser extent to pig pancreatic elastase. Horse and human elastases differed somewhat in their interaction with some natural protein proteinase inhibitors. For example, in contrast with its action on human neutrophil elastase, aprotinin did not inhibit either of the horse proteinases. However, the Val15, alpha-aminobutyric acid-15 (Abu15), alpha-aminovaleric acid-15 (Nva15) and Ala15 reactive-site variants of aprotinin were good inhibitors of proteinase 2B (Ki < 10(-9) M) but only weak inhibitors of proteinase 2A (Ki > 10(-7) M). In summary, despite these differences, the horse neutrophil elastases were found to resemble closely their human counterparts, thus implicating them in the pathological degradation of connective tissue in chronic lung diseases in the equine species.
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Angelopoulou, Maria K., Pantelis Tsirkinidis, Georgios Boutsikas, Theodoros P. Vassilakopoulos e Panayiotis Tsirigotis. "New Insights in the Mobilization of Hematopoietic Stem Cells in Lymphoma and Multiple Myeloma Patients". BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/835138.
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Following chemotherapy and/or the administration of growth factors, such as granulocyte-colony stimulated factor (G-CSF), hematopoietic stem cells (HSC) mobilize from bone marrow to peripheral blood. This review aims to systematically present the structure of the HSC “niche” and elucidate the mechanisms of their mobilization. However, this field is constantly evolving and new pathways and molecules have been shown to contribute to the mobilization process. Understanding the importance and the possible primary pathophysiologic role of each pathway is rather difficult, since they share various overlapping components. The primary initiating event for the mobilization of HSC is chemotherapy-induced endogenous G-CSF production or exogenous G-CSF administration. G-CSF induces proliferation and expansion of the myelomonocytic series, which leads to proteolytic enzyme activation. These enzymes result in disruption of various receptor-ligand bonds, which leads to the disanchorage of HSC from the bone marrow stroma. In everyday clinical practice, CXC chemokine receptor-4 (CXCR4) antagonists are now being used as mobilization agents in order to improve HSC collection. Furthermore, based on the proposed mechanisms of HSC mobilization, novel mobilizing agents have been developed and are currently evaluated in preclinical and clinical studies.
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Reichelt, K. L. "Can the pathophysiology of autism be explained by the nature of the discovered urine peptides and dietary antigens?" European Psychiatry 33, S1 (março de 2016): S25. http://dx.doi.org/10.1016/j.eurpsy.2016.01.840.
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PurposeA: 1. To develop the urine analysis for exorphins for routine use in blood and cerebrospinal fluid (CSF).2. Disorders where patient related validation must be carried out: schizophrenia, depression (uni- and bipolar) and autism.MethodA: HPLC-MS/MS (fragmentation mass spectrometry) technology.With both a specific HPLC retention time and MS/MS (fragmentation) this method is close to an absolute technique for peptide recognition.B: ELISA against specific proteins (gliadin, gluten and casein and transglutaminase 6) (Table 1 og 2).BackgroundA: schizophrenia: increased opioid peptide levels have been found in Schizophrenia using HPLC, immune assay and behavioral tests. [1–6] as part of a general peptide increase in urine. Since peptides are signaling compounds inhibition of peptidases during transport and work up of samples is critical to prevent break down, which is as expected fast at room temperature.Strongly supporting is view is the data on postpartum psychoses (a very symptom rich psychosis) where also amino acid sequence of human casomorphin found increased, has been done [7–8]. The opioids can explain most of the symptoms of the psychotic schizophrenic state [6]. It is of paramount importance then to measure these peptides in carefully diagnosed patients on and without medication, in urine, blood and spinal fluid.As can be seen in Table 1, it is important to measure IgA and IgG antibodies against the precursor proteins for the exorphins, which are found increased by several groups, and also have direct effects on the nervous system [9].B. In depression increase levels of peptides has been found [18,28,29] and also opioid levels measured as opium receptor binding peptides [28]. In schizoaffective psychosis MS/MS exact detection of exorphins have been published [6]. Also in this syndrome it is critical to be able to measure the exorphins in blood and CSF, especially since the peptidases involved in break down of exorphins are decreased in depressions [30,31]. Inflammatory interleukins are also increased in depressions both uni- and bipolar [32] indicative of inflammatory processes probably in the gut. Inflammatory interleukins increase the permeability of epithelial membranes [33].C. Autism. Considerable work has been done using HPLC with UV detection and co-chromatography [12,34–40]. However, with HPLC–MS/MS we can ensure that we are measuring only the exorphins and not chromatographically similar peaks that hide inside the main peak [41–43]. We therefore need to validate the new method in autism for both urine, blood and CSF (CSF collected only when spinal tap has to be done in any case).Inhibition of break down in urine, blood and cerebrospinal fluid (CSF)After extensive testing we have been left with three inhibitors. Citric acid 0.2 M; acetic acid 0.2 M and aprotenine [44,45].These body fluids will be provided by Prof Dr E. Severance and Prof Dr R. Yolken (Johns Hopkins Univ.) and Prof Dr. Cunningham (Uppsala Univ. Sweden). Lab 1 provides monovettes with citric acid as peptidase inhibitor for urine collection. Blood will be collected in EDTA – aprotenin vacuum test tubes (Vacutainer) as will be CSF.HPLC and MS/MS detection.The amount of urine analyzed on the HPLC after work up = 250 nanomles creatinine. To pick out generally active peptides in any one disorder, five and five autistic children or schizophrenic derived and depressive derived urines are mixed, creatinine re-determined and rerun. Peaks that are common to all patients increase or remain the same, while individual peaks of material on the HPLC runs are diluted out.The complete procedure is published in detail [48]. If we use reporter ions we do not have to match all the peaks as shown in attached figures. On Fig. 1, synthetic bovine β-casomorphine 1-4 (Y-P-F-P) is compared to biologically isolated compound from a batch of five autistic children. On Fig. 2, the faster routine analysis using reporter ions is shown for bovine β-casomorhne 1-4. Top trace is synthetic casomorphin 1-4 and bottom trace is biologically isolated compound. The complete analysis for a series of opioids is published [48].Program is then in sequence:– A: further validation of method for urine in the different disorders;– B: validation of method for blood in the same disorders;– C: validation of method for CSF (spinal fluid) in schizophrenics and depressive patients.NB.To avoid overlooking new compounds a complete HPLC run with UV 215 nm (peptide bonds); 280 nm (aromatic groups) and 325 nm (Indolyl-acryloid) shall be run for urines. If sufficient serum is available and spinal fluid these will also be run on HPLC in addition to MS/MS detection.Antibody assays will be done at Johns Hopkins using ELISA, Transglutaminase 6 antibodies at Lab 1 also using ELISA assay.Figures and references not available in the abstract.Disclosure of interestThe authors have not supplied their declaration of competing interest.