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Sample records for 2-induced heterotopic ossification

  1. Pseudomalignant heterotopic ossification.

    PubMed

    Kaplan, F S; Gannon, F H; Hahn, G V; Wollner, N; Prauner, R

    1998-01-01

    Pseudomalignant heterotopic ossification is a rare, self limited connective tissue disorder of unknown origin that may occur atypically during childhood and can simulate either soft tissue sarcoma or fibrodysplasia ossificans progressiva. A complex constellation of diagnostic features usually enable the differentiation of pseudomalignant heterotopic ossification from extraosseous osteosarcoma and fibrodysplasia ossificans progressiva during a time span of approximately 8 to 12 weeks. Orthopaedic surgeons who treat children with connective tissue tumors should be familiar with pseudomalignant heterotopic ossification and its differential diagnosis. The occasional mild and variable expression of fibrodysplasia ossificans progressiva rarely may make it more difficult to distinguish from pseudomalignant heterotopic ossification. It is possible that pseudomalignant heterotopic ossification is a form fruste of fibrodysplasia ossificans progressiva. PMID:9577421

  2. Neurogenic heterotopic ossification.

    PubMed

    Jensen, L L; Halar, E; Little, J W; Brooke, M M

    1987-12-01

    Neurogenic heterotopic ossification is a potential sequela of neurological disorders, especially spinal cord injury and head injury. The etiology is unknown. Clinical, radiologic, and bone scan findings are typical. Complications may threaten function. The differential diagnosis is crucial in its early stages. Treatment options include diphosphonates, non-steroidal anti-inflammatory drugs, and surgery. This article has reviewed the literature on neurogenic heterotopic ossification (HO), soft tissue ossification of neurologic disease, including pathogenesis, histology, presentation, diagnosis, natural history, complications, and current treatments. PMID:3124630

  3. Heterotopic Ossification in Neurorehabilitation.

    PubMed

    Gil, Joseph A; Waryasz, Gregory R; Klyce, Walter; Daniels, Alan H

    2015-12-01

    Neurogenic heterotopic ossification (NHO) involves deposition of bone in extraskeletal tissue in the setting of a neurological disorder, and its pathophysiology is incompletely understood. NHO can lead to significant disability and functional impairment. NHO initially manifests as pain and joint stiffness. Early diagnosis requires appropriate suspicion and imaging studies to detect the uncalcified collagen matrix that forms in the early stages of NHO. If diagnosis is made in the early phase of NHO, progression may be halted with bisphosphonates, indomethacin or radiation therapy. If NHO progresses to its final stages without intervention, it may restrict joints and render them dysfunctional. Surgical treatment of NHO may restore function, but complications may occur, and prophylaxis and aggressive rehabilitation are essential. PMID:26623453

  4. Heterotopic ossification following lumbar total disc replacement.

    PubMed

    Park, Se-Jun; Kang, Kyung-Jung; Shin, Seong-Kee; Chung, Sung-Soo; Lee, Chong-Suh

    2011-08-01

    The main goal of total disc replacement (TDR) is to preserve motion. Despite reports of good clinical outcomes, various degrees of heterotopic ossification after TDR have been reported. The purpose of this study was to investigate the prevalence and its clinical relevance of heterotopic ossification. We evaluated 65 consecutive patients (82 segments) with mean follow-up duration of 45 months (range, 12-88 months). Two kinds of prosthesis, ProDisc® for 75 segments (91.5%) and CHARITE™ for seven segments (8.5%), were used. Patients with heterotopic ossification were compared with those without heterotopic ossification with regard to segmental flexion-extension ROM, VAS and ODI. We analysed the occurrence site by nine zones. Heterotopic ossification was detected in 25 out of 82 segments (30.5%) at a mean follow-up of 17 months. According to McAfee's classification, there was Class-I heterotopic ossification in eight segments (9.8%), Class-II in 12 segments (14.6%), and Class-III in five segments (6.1%). There was no Class-IV heterotopic ossification. There were no significant differences in the segmental ROM, VAS and ODI between the patients with Class-I or Class-II heterotopic ossification and those without heterotopic ossification The segmental ROM in the patients with Class-III heterotopic ossification was significantly decreased compared with the patients without heterotopic ossification (p = 0.018). But VAS and ODI were not significantly different compared with those of patients with no heterotopic ossification. Most heterotopic ossification (82.5%) was detected in the anterior and posterior aspects. In conclusion, most of the heterotopic ossification (Classes I and II) did not affect segmental ROM and clinical outcomes such as pain or function. In Class-III heterotopic ossification segmental ROM was decreased, but it did not affect clinical outcomes. PMID:20652248

  5. Heterotopic ossification after hip arthroscopy

    PubMed Central

    Amar, Eyal; Sharfman, Zachary T.; Rath, Ehud

    2015-01-01

    Heterotopic ossification (HO) after hip arthroscopy is the abnormal formation of mature lamellar bone within extra skeletal soft tissues. HO may lead to pain, impaired range of motion and possibly revision surgery. There has been a substantial amount of recent research on the pathophysiology, prophylaxis and treatment of HO associated with open and arthroscopic hip surgery. This article reviews the literature on the aforementioned topics with a focus on their application in hip arthroscopy. PMID:27011859

  6. Heterotopic ossification after hip arthroscopy.

    PubMed

    Amar, Eyal; Sharfman, Zachary T; Rath, Ehud

    2015-12-01

    Heterotopic ossification (HO) after hip arthroscopy is the abnormal formation of mature lamellar bone within extra skeletal soft tissues. HO may lead to pain, impaired range of motion and possibly revision surgery. There has been a substantial amount of recent research on the pathophysiology, prophylaxis and treatment of HO associated with open and arthroscopic hip surgery. This article reviews the literature on the aforementioned topics with a focus on their application in hip arthroscopy. PMID:27011859

  7. Heterotopic Ossification in Orthopaedic Trauma

    PubMed Central

    Nauth, Aaron; Giles, Erica; Potter, Benjamin K.; Nesti, Leon J.; O’Brien, Frederick P.; Bosse, Michael J.; Anglen, Jeffrey O.; Mehta, Samir; Ahn, Jaimo; Miclau, Theodore; Schemitsch, Emil H.

    2012-01-01

    Heterotopic ossification (HO) can be defined as the pathological formation of bone in extra-skeletal tissues. There has been a substantial amount of recent research on the pathophysiology, prophylaxis and treatment of HO and traumatic conditions associated with the development of HO. This research has advanced our understanding of this disease and helped to clarify evidence-based approaches to both the prophylaxis and treatment of HO. This article reviews the literature on these topics with a focus on their application in orthopaedic trauma. PMID:23010648

  8. Heterotopic ossification: a systematic review.

    PubMed

    Edwards, Dafydd S; Clasper, J C

    2015-12-01

    Heterotopic ossification (HO) is the formation of mature lamellar bone in extraskeletal soft tissues. It was first described 1000 years ago in the healing of fractures, and in relation to military wounds, texts from the American Civil War and World War I refer to HO specifically. It continues to cause problems to injured service personnel; the consequences of wound and soft tissue complications in traumatic amputations pose particular problems to rehabilitation and prosthetic use. While HO is seen in rare genetic conditions, it is most prevalent after joint replacement surgery and trauma. In the civilian setting HO has been commonly described in patients after traumatic brain injuries, spinal cord injuries and burns. Militarily, as a consequence of recent operations, and the characteristic injury of blast-related amputations, a renewed interest in HO has emerged due to an increased incidence seen in casualties. The heterogeneous nature of a blast related amputation makes it difficult for a single aetiological event to be identified, although it is now accepted that blast, amputation through the zone of injury, increased injury severity and associated brain injuries are significant risk factors in HO formation. The exact cellular event leading to HO has yet to be identified, and as a consequence its prevention is restricted to the use of anti-inflammatory medication and radiation, which is often contraindicated in the acute complex military casualty. A systematic review in PubMed and the Cochrane Database identified research articles related to HO to illustrate the military problem of HO and its management, current research concepts and experimental theories regarding HO. This also served as a gap analysis providing the researchers detail of any knowledge deficit in this field, in particular to the military aspects of HO; 637 out of 7891 articles initially identified that referenced HO were relevant to this review. PMID:25015927

  9. Heterotopic ossification after central nervous system trauma

    PubMed Central

    Sullivan, M. P.; Torres, S. J.; Mehta, S.; Ahn, J.

    2013-01-01

    Neurogenic heterotopic ossification (NHO) is a disorder of aberrant bone formation affecting one in five patients sustaining a spinal cord injury or traumatic brain injury. Ectopic bone forms around joints in characteristic patterns, causing pain and limiting movement especially around the hip and elbow. Clinical sequelae of neurogenic heterotopic ossification include urinary tract infection, pressure injuries, pneumonia and poor hygiene, making early diagnosis and treatment clinically compelling. However, diagnosis remains difficult with more investigation needed. Our pathophysiological understanding stems from mechanisms of basic bone formation enhanced by evidence of systemic influences from circulating humor factors and perhaps neurological ones. This increasing understanding guides our implementation of current prophylaxis and treatment including the use of non-steroidal anti-inflammatory drugs, bisphosphonates, radiation therapy and surgery and, importantly, should direct future, more effective ones. PMID:23610702

  10. [Radiation therapy for heterotopic ossification prophylaxis].

    PubMed

    Utzon, Henrik; Skov, Ole; Johansen, Jørgen

    2014-06-01

    Heterotopic ossification (HO) is a well-known condition of bone formation in soft tissues due to trauma (e.g. surgery) or neurological injury, but the exact aetiology is unknown. In most cases, HO is asymptomatic, but it may cause pain, reduced mobility of joints, and loss of functioning. Various patient groups have a significant risk of developing HO after surgery and should be offered prophylactic treatment. Nonsteroidal anti-inflammatory drugs and radiotherapy are internationally accepted treatments. This review discusses the potential for radiotherapy as prophylaxis against HO. PMID:25352198

  11. Functional Outcomes of the Surgery and Rehabilitation in a Challenging Case of Heterotopic Ossification after Encephalitis

    PubMed Central

    Ekiz, T; Aslan, M Doğan; Demir, S Özbudak; Altay, M; Özgirgin, N

    2015-01-01

    ABSTRACT Heterotopic ossification is the formation of the lamellar bone where normally osseous tissue does not exist. Since heterotopic ossification can cause severe functional loss, it is a challenging condition for both clinicians and patients. Neurogenic heterotopic ossification is a rare condition after encephalitis. Likewise, in this paper, we have presented a challenging case of heterotopic ossification after viral encephalitis and functional outcomes after the management of heterotopic ossification. PMID:26426185

  12. Heterotopic ossification in chronic fibrosing otitis externa

    PubMed Central

    Maughan, Elizabeth F.; Bhutta, Mahmood F.; Lavy, Jeremy

    2015-01-01

    Acquired external auditory canal atresia is a rare complication of chronic inflammatory otitis, and is generally fibrous or soft tissue in nature. Here, we present the first reported case of heterotopic ossification within chronic fibrosing otitis externa in a 25-year-old male patient with a childhood history of granular myringitis and failed tympanoplasty. A calcified mass was demonstrated adjacent to the tympanic membrane on CT imaging, and surgical exploration revealed a cohesive bar of bone traversing the medial external auditory canal. Drill canaloplasty and split-thickness skin graft coverage of the lateral tympanic membrane resulted in an improvement in the pure tone average from 79 to 55 dB. As the treatment for chronic fibrosing otitis externa involves the surgical widening of the external auditory canal, we alert surgeons to the possibility of cohesive bone formation as a potential cause of navigational confusion and inadvertent over- or under-drilling of the canal stenosis. PMID:26429555

  13. Heterotopic Ossification: Basic-Science Principles and Clinical Correlates.

    PubMed

    Ranganathan, Kavitha; Loder, Shawn; Agarwal, Shailesh; Wong, Victor W; Wong, Victor C; Forsberg, Jonathan; Davis, Thomas A; Wang, Stewart; James, Aaron W; Levi, Benjamin

    2015-07-01

    Heterotopic ossification occurs most commonly after joint arthroplasty, spinal cord injury, traumatic brain injury, blast trauma, elbow and acetabular fractures, and thermal injury.➤ The conversion of progenitor cells to osteogenic precursor cells as a result of cell-mediated interactions with the local tissue environment is affected by oxygen tension, pH, availability of micronutrients, and mechanical stimuli, and leads to heterotopic ossification.➤ Radiation and certain nonsteroidal anti-inflammatory medications are important methods of prophylaxis against heterotopic ossification.➤ Well-planned surgical excision can improve patient outcomes regardless of the joint involved or the initial cause of injury.➤ Future therapeutic strategies are focused on targeted inhibition of local factors and signaling pathways that catalyze ectopic bone formation. PMID:26135077

  14. Heterotopic Ossification Causing Radiculopathy after Lumbar Total Disc Arthroplasty.

    PubMed

    Jackson, Keith L; Hire, Justin M; Jacobs, Jeremy M; Key, Charles C; DeVine, John G

    2015-06-01

    To date, no reports have presented radiculopathy secondary to heterotopic ossification following lumbar total disc arthroplasty. The authors present a previously unpublished complication of lumbar total disk arthroplasty (TDA) secondary to heterotopic ossification (HO) in the spinal canal, and they propose a modification to the McAfee classification of HO. The patient had undergone an L5/S1 lumbar TDA two years prior due to discogenic back pain. His preoperative back pain was significantly relieved, but he developed new, atraumatic onset radiculopathy. Radiographs and a computed tomography myelogram revealed an implant malposition posteriorly with heterotopic bone formation in the canal, causing an impingement of the traversing nerve root. Revision surgery was performed with implant extraction, L5/S1 anterior lumbar interbody fusion, supplemental posterior decompression, and pedicle screw fixation. The patient tolerated the procedure well, with complete resolution of the radicular leg pain. At a two-year follow up, the patient had a solid fusion without subsidence or recurrence of heterotopic bone. This case represents a novel pattern of heterotopic ossification, and it describes a previously unreported cause for implant failure in lumbar disc replacement surgery-reinforcing the importance of proper intraoperative component positioning. We propose a modification to the existing McAfee classification of HO after TDA with the addition of Class V and VI HO. PMID:26097664

  15. Heterotopic Ossification Causing Radiculopathy after Lumbar Total Disc Arthroplasty

    PubMed Central

    Jackson, Keith L.; Jacobs, Jeremy M.; Key, Charles C.; DeVine, John G.

    2015-01-01

    To date, no reports have presented radiculopathy secondary to heterotopic ossification following lumbar total disc arthroplasty. The authors present a previously unpublished complication of lumbar total disk arthroplasty (TDA) secondary to heterotopic ossification (HO) in the spinal canal, and they propose a modification to the McAfee classification of HO. The patient had undergone an L5/S1 lumbar TDA two years prior due to discogenic back pain. His preoperative back pain was significantly relieved, but he developed new, atraumatic onset radiculopathy. Radiographs and a computed tomography myelogram revealed an implant malposition posteriorly with heterotopic bone formation in the canal, causing an impingement of the traversing nerve root. Revision surgery was performed with implant extraction, L5/S1 anterior lumbar interbody fusion, supplemental posterior decompression, and pedicle screw fixation. The patient tolerated the procedure well, with complete resolution of the radicular leg pain. At a two-year follow up, the patient had a solid fusion without subsidence or recurrence of heterotopic bone. This case represents a novel pattern of heterotopic ossification, and it describes a previously unreported cause for implant failure in lumbar disc replacement surgery-reinforcing the importance of proper intraoperative component positioning. We propose a modification to the existing McAfee classification of HO after TDA with the addition of Class V and VI HO. PMID:26097664

  16. Radionuclide assessment of heterotopic ossification in spinal cord injury patients

    SciTech Connect

    Prakash, V.

    1983-01-01

    Whole body /sup 99m/T-pyrophosphate bone scans were obtained and correlated with skeletal radiographs for detection of heterotopic ossification in 135 spinal injury patients. There were 40 patients with recent injury (less than 6 months) and 95 with injury of over 6 months duration. Heterotopic new bone was detected on the bone scan in 33.7% of 95 patients with spinal cord injuries of more than 6 months duration and 30% of 40 patients with injuries of less than 6 months. The radionuclide scan was found to be useful in detection of heterotopic ossification at its early stage and in its differentiation from other complications in spinal cord injury patients.

  17. Ankylosing pelvitrochanteric heterotopic ossification in a patient with spinal cord injury

    PubMed Central

    Gurcan, Serkan; Ozyurek, Selahattin; Kose, Ozkan; Sehirlioglu, Ali

    2013-01-01

    Heterotopic ossification is a frequent complication after spinal cord injury. It usually develops around major weight bearing joints. However, ankylosing hip is a rare presentation. Various treatment methods have been reported and advocated as efficacious methods for management of heterotopic ossification. We report a case of ankylosing pelvitrochanteric heterotopic ossification treated with surgical excision before full maturation, postoperative radiation therapy and indomethacine without recurrence after 1 year. Treatment options are discussed in this particular case. PMID:23697455

  18. Slipped capital femoral epiphysis caused by neurogenic heterotopic ossification.

    PubMed

    Chang, Sam Yeol; Yoo, Won Joon; Park, Moon Seok; Chung, Chin Youb; Choi, In Ho; Cho, Tae-Joon

    2013-11-01

    Slipped capital femoral epiphysis (SCFE) is rare in nonambulatory patients, as mechanical factors play important roles in the development of the disease. We report a case of SCFE, which occurred in a 12-year-old girl with a nonambulatory status after cerebral infarction. SCFE occurred after she received passive range of motion exercise and extracorporeal shock wave treatment for neurogenic heterotopic ossification around the hip joint. The patient was successfully managed by a stepwise approach, with radiological and clinical improvements. PMID:23969564

  19. Spontaneous Knee Ankylosis through Heterotopic Ossification after Total Knee Arthroplasty

    PubMed Central

    Boulezaz, Samuel; Gibon, Emmanuel; Loriaut, Philippe; Casabianca, Laurent; Rousseau, Romain; Dallaudiere, Benjamin; Pascal-Moussellard, Hugues

    2016-01-01

    This paper reports on a case of total ankylosis of the knee after a cruciate-sacrificing cemented total knee arthroplasty (TKA). An 82-year-old female patient previously underwent primary TKA for osteoarthritis twenty years ago in our institution. She had recovered uneventfully and returned to her regular activities. There was no history of postsurgical trauma; however, she progressively lost knee range of motion. Radiographs revealed severe bridging heterotopic ossification. PMID:27119034

  20. Incidence and Clinical Significance of Heterotopic Ossification After Partial Ray Resection.

    PubMed

    Boffeli, Troy J; Thompson, Jonathan C; Waverly, Brett J; Pfannenstein, Ryan R; Mahoney, Kevin J

    2016-01-01

    Heterotopic bone growth is a common finding after partial foot amputation that can predispose to recurrent wounds, osteomyelitis, and reamputation. Heterotopic ossification is the formation of excessive mature lamellar bone in the soft tissues adjacent to bone that is exacerbated by trauma or surgical intervention. The relevance of heterotopic ossification is dependent on its anatomic location. Its occurrence as a sequela of partial foot amputation can lead to prominence on the plantar aspect of the foot that can predispose the patient to recurrent neuropathic ulceration or preclude appropriate wound healing. Reulceration puts the high-risk patient who has already undergone local amputation at greater risk of recurrent infection and further amputation. The present study aimed to assess the incidence and risk factors for heterotopic ossification to further evaluate its role in partial foot amputation. A retrospective analysis of 72 consecutive patients who had undergone partial metatarsal resection was performed, with 90% of the cohort having peripheral neuropathy and 88% diabetes mellitus. Our findings revealed a heterotopic ossification incidence of 75% diagnosed radiographically. The initial onset of heterotopic ossification was not appreciated >10 weeks postoperatively. Ten patients (18.5%) exhibited heterotopic ossification-associated ulceration. The incidence of heterotopic ossification was 30% less in patients with peripheral vascular disease. These results indicate that heterotopic ossification is a common sequela of partial ray resection in an already high-risk patient population. The perioperative use of pharmacologic or radiation prophylaxis in an attempt to minimize amputation-related morbidity should be considered. PMID:26922732

  1. Experimental model of heterotopic ossification in Wistar rats

    PubMed Central

    Zotz, T.G.G.; de Paula, J.B.; Moser, A.D.L.

    2012-01-01

    Heterotopic ossification (HO) is a metaplastic biological process in which there is newly formed bone in soft tissues adjacent to large joints, resulting in joint mobility deficit. In order to determine which treatment techniques are more appropriate for such condition, experimental models of induced heterotopic bone formation have been proposed using heterologous demineralized bone matrix implants and bone morphogenetic protein and other tissues. The objective of the present experimental study was to identify a reliable protocol to induce HO in Wistar rats, based on autologous bone marrow (BM) implantation, comparing 3 different BM volumes and based on literature evidence of this HO induction model in larger laboratory animals. Twelve male Wistar albino rats weighing 350/390 g were used. The animals were anesthetized for blood sampling before HO induction in order to quantify serum alkaline phosphatase (ALP). HO was induced by BM implantation in both quadriceps muscles of these animals, experimental group (EG). Thirty-five days after the induction, another blood sample was collected for ALP determination. The results showed a weight gain in the EG and no significant difference in ALP levels when comparing the periods before and after induction. Qualitative histological analysis confirmed the occurrence of heterotopic ossification in all 12 EG rats. In conclusion, the HO induction model was effective when 0.35 mL autologous BM was applied to the quadriceps of Wistar rats. PMID:22473322

  2. Prophylaxis of heterotopic ossification – an updated review

    PubMed Central

    Baird, Evan O; Kang, Qian K

    2009-01-01

    Heterotopic ossification (HO) is defined as the process by which trabecular bone forms outside of the skeletal structure, occupying space in soft tissue where it does not normally exist. The current popular prophylactic treatment modalities include non-steroidal anti-inflammatory drugs (NSAIDs) and radiation therapy, although the literature remains inconclusive as to which is superior. Additionally, both treatments can lead to adverse effects to the patient. Recently there have been several studies attempting to identify new aspects of the etiology of heterotopic bone formation and introduce new prophylactic modalities with increased efficacy and fewer side effects. For this review, we selectively retrieved articles from Medline published from 1958–2008 on the prophylaxis of HO with the aim of assisting readers in quickly grasping the current status of research and clinical aspects of HO prophylaxis. PMID:19379483

  3. Heterotopic Ossifications in a Mouse Model of Albright Hereditary Osteodystrophy

    PubMed Central

    Huso, David L.; Edie, Sarah; Levine, Michael A.; Schwindinger, William; Wang, Yingli; Jüppner, Harald; Germain-Lee, Emily L.

    2011-01-01

    Albright hereditary osteodystrophy (AHO) is characterized by short stature, brachydactyly, and often heterotopic ossifications that are typically subcutaneous. Subcutaneous ossifications (SCO) cause considerable morbidity in AHO with no effective treatment. AHO is caused by heterozygous inactivating mutations in those GNAS exons encoding the α-subunit of the stimulatory G protein (Gαs). When inherited maternally, these mutations are associated with obesity, cognitive impairment, and resistance to certain hormones that mediate their actions through G protein-coupled receptors, a condition termed pseudohypoparathyroidism type 1a (PHP1a). When inherited paternally, GNAS mutations cause only AHO but not hormonal resistance, termed pseudopseudohypoparathyroidism (PPHP). Mice with targeted disruption of exon 1 of Gnas (GnasE1−/+) replicate human PHP1a or PPHP phenotypically and hormonally. However, SCO have not yet been reported in GnasE1+/− mice, at least not those that had been analyzed by us up to 3 months of age. Here we now show that GnasE1−/+ animals develop SCO over time. The ossified lesions increase in number and size and are uniformly detected in adult mice by one year of age. They are located in both the dermis, often in perifollicular areas, and the subcutis. These lesions are particularly prominent in skin prone to injury or pressure. The SCO comprise mature bone with evidence of mineral deposition and bone marrow elements. Superficial localization was confirmed by radiographic and computerized tomographic imaging. In situ hybridization of SCO lesions were positive for both osteonectin and osteopontin. Notably, the ossifications were much more extensive in males than females. Because GnasE1−/+ mice develop SCO features that are similar to those observed in AHO patients, these animals provide a model system suitable for investigating pathogenic mechanisms involved in SCO formation and for developing novel therapeutics for heterotopic bone formation

  4. Radial extracorporeal shock wave therapy for heterotopic ossification.

    PubMed

    Ryu, Byung-Ju; Ha, Kang-Wook; Lee, Jin-Young; Kim, Sung-Hwan; Kwak, Ho-Jun; Seol, Pyong-Hwa

    2016-01-01

    [Purpose] To report the effects of radial extracorporeal shock wave therapy (RSWT) on heterotopic ossification (HO). [Subjects and Methods] Two cases of neurogenic HO in the upper extremity were administered RSWT using the MASTER PLUS(®) MP 2000 (Storz, Tägerwilen, Switzerland) and ultrasonographic guidance. The RSWT protocol consisted of 3,000 pulses at a frequency of 12 Hz during each treatment. The intensity level ranged from 2-5 bars, and it was administered 5 times a week for 4 weeks, a total of 20 treatments. [Results] RSWT improved pain, range of motion, and hand function in 2 patients with neurogenic HO in the upper extremity. [Conclusion] Further studies are needed to support these results and to understand the mechanism and to devise the protocol of RSWT for neurogenic HO. PMID:27064476

  5. Progression of Heterotopic Ossification around the Elbow after Trauma

    PubMed Central

    ter Meulen, Dirk P.; Nota, Sjoerd P.F.T.; Hageman, Michiel G.J.S.; Ring, David C.

    2016-01-01

    Background: This study addresses the null hypothesis that there is no expansion of heterotopic ossification (HO) in the elbow beyond what can be seen early on. Methods: The area of HO was measured on lateral radiographs of 38 consecutive patients that had operative treatment of HO between 2000 and 2013. Measurements from radiographs obtained between 3 to 7 weeks were compared to measurements from radiographs made 3 months or more after injury. Results: There was no significant difference between the average area of HO on the first (median 2.8 square centimeters, Q1: 1.5, Q3: 5.1) and later radiographs (median of 2.8 square centimeters, Q1: 1.4, Q3: 5.0) (P = 0.99). Conclusion: According to our results the area of HO does not expand beyond what can be seen early in the disease process. PMID:27517067

  6. Vessel formation is induced prior to the appearance of cartilage in BMP-2-mediated heterotopic ossification

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Heterotopic ossification (HO), or endochondral bone formation at nonskeletal sites, often results from traumatic injury and can lead to devastating consequences. Alternatively, the ability to harness this phenomenon would greatly enhance current orthopedic tools for treating segmental bone defects. ...

  7. Direct Mouse Trauma/Burn Model of Heterotopic Ossification.

    PubMed

    Peterson, Jonathan R; Agarwal, Shailesh; Brownley, R Cameron; Loder, Shawn J; Ranganathan, Kavitha; Cederna, Paul S; Mishina, Yuji; Wang, Stewart C; Levi, Benjamin

    2015-01-01

    Heterotopic ossification (HO) is the formation of bone outside of the skeleton which forms following major trauma, burn injuries, and orthopaedic surgical procedures. The majority of animal models used to study HO rely on the application of exogenous substances, such as bone morphogenetic protein (BMP), exogenous cell constructs, or genetic mutations in BMP signaling. While these models are useful they do not accurately reproduce the inflammatory states that cause the majority of cases of HO. Here we describe a burn/tenotomy model in mice that reliably produces focused HO. This protocol involves creating a 30% total body surface area partial thickness contact burn on the dorsal skin as well as division of the Achilles tendon at its midpoint. Relying solely on traumatic injury to induce HO at a predictable location allows for time-course study of endochondral heterotopic bone formation from intrinsic physiologic processes and environment only. This method could prove instrumental in understanding the inflammatory and osteogenic pathways involved in trauma-induced HO. Furthermore, because HO develops in a predictable location and time-course in this model, it allows for research to improve early imaging strategies and treatment modalities to prevent HO formation. PMID:26274052

  8. Single-dose radiation therapy for prevention of heterotopic ossification after total hip arthroplasty

    SciTech Connect

    Healy, W.L.; Lo, T.C.; Covall, D.J.; Pfeifer, B.A.; Wasilewski, S.A. )

    1990-12-01

    Single-dose radiation therapy was prospectively evaluated for its efficacy in prevention of heterotopic ossification in patients at high risk after total hip arthroplasty. Thirty-one patients (34 hips) were treated between 1981 and 1988. Risk factors for inclusion in the protocol included prior evidence of heterotopic ossification, ankylosing spondylitis, and diffuse idiopathic skeletal hyperostosis. Patients with hypertrophic osteoarthritis or traumatic arthritis with osteophytes were not included. Operations on 34 hips included 19 primary total and 11 revision total hip arthroplasties and 4 excisions of heterotopic ossification. All patients received radiotherapy to the hip after operation with a single dose of 700 centigray. Radiotherapy is recommended on the first postoperative day. After this single-dose radiation treatment, no patient had clinically significant heterotopic ossification. Recurrent disease developed in two hips (6%), as seen on radiography (grades 2 and 3). This series documents a 100% clinical success rate and a 94% radiographic success rate in preventing heterotopic ossification in patients at high risk after total hip arthroplasty. Single-dose radiotherapy is as effective as other radiation protocols in preventing heterotopic ossification after total hip arthroplasty. It is less expensive and easier to administer than multidose radiotherapy.

  9. Substance P Signaling Mediates BMP Dependent Heterotopic Ossification

    PubMed Central

    Kan, Lixin; Lounev, Vitali Y; Pignolo, Robert J; Duan, Lishu; Liu, Yijie; Stock, Stuart R; McGuire, Tammy L; Lu, Bao; Gerard, Norma P; Shore, Eileen M; Kaplan, Frederick S; Kessler, John A

    2012-01-01

    Heterotopic ossification (HO) is a disabling condition associated with neurologic injury, inflammation, and overactive BMP signaling. The inductive factors involved in lesion formation are unknown. We found that the expression of the neuro-inflammatory factor Substance P (SP) is dramatically increased in early lesional tissue in patients who have either fibrodysplasia ossificans progressiva (FOP) or acquired HO, and in three independent mouse models of HO. In Nse-BMP4, a mouse model of HO, robust HO forms in response to tissue injury; however null mutations of the preprotachykinin gene encoding SP prevent HO. Importantly, ablation of SP+ sensory neurons, treatment with an antagonist of SP receptor NK1r, deletion of NK1r gene, or genetic down-regulation of NK1r-expressing mast cells also profoundly inhibits injury-induced HO. These observations establish a potent neuro-inflammatory induction and amplification circuit for BMP-dependent HO lesion formation, and identify novel molecular targets for prevention of HO. PMID:21748788

  10. Prospective heterotopic ossification progenitors in adult human skeletal muscle.

    PubMed

    Downey, Jennifer; Lauzier, Dominique; Kloen, Peter; Klarskov, Klaus; Richter, Martin; Hamdy, Reggie; Faucheux, Nathalie; Scimè, Anthony; Balg, Frédéric; Grenier, Guillaume

    2015-02-01

    Skeletal muscle has strong regenerative capabilities. However, failed regeneration can lead to complications where aberrant tissue forms as is the case with heterotopic ossification (HO), in which chondrocytes, osteoblasts and white and brown adipocytes can arise following severe trauma. In humans, the various HO cell types likely originate from multipotent mesenchymal stromal cells (MSCs) in skeletal muscle, which have not been identified in humans until now. In the present study, adherent cells from freshly digested skeletal muscle tissue were expanded in defined culture medium and were FACS-enriched for the CD73(+)CD105(+)CD90(-) population, which displayed robust multilineage potential. Clonal differentiation assays confirmed that all three lineages originated from a single multipotent progenitor. In addition to differentiating into typical HO lineages, human muscle resident MSCs (hmrMSCs) also differentiated into brown adipocytes expressing uncoupling protein 1 (UCP1). Characterizing this novel multipotent hmrMSC population with a brown adipocyte differentiation capacity has enhanced our understanding of the contribution of non-myogenic progenitor cells to regeneration and aberrant tissue formation in human skeletal muscle. PMID:25445454

  11. Determinants of heterotopic ossification after total hip replacement surgery.

    PubMed

    Fransen, Marlene; Neal, Bruce; Cameron, Ian D; Crawford, Ross; Tregonning, Garnet; Winstanley, Julie; Norton, Robyn

    2009-01-01

    The ability of various pre- or peri-operative variables to determine the risk of developing moderate to severe heterotopic ossification (HO) six to twelve months after surgery was investigated among 407 patients undergoing elective total hip replacement (THR) surgery and allocated to placebo in a randomised controlled trial evaluating NSA IDs-based prophylaxis for HO. Overall, 11 (30%) of the 37 patients undergoing revision surgery developed moderate to severe HO compared with 58 (16%) of the 370 patients undergoing primary THR; odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1 to 4.9. Among patients undergoing primary THR , mutually adjusted analysis of collected independent risk factors demonstrated that receiving a transfusion of red cells or having general as well as epidural or spinal anaesthesia present as indicators of increased risk for developing moderate to severe HO. Patients who have undergone revision surgery have a significantly increased risk of clinically relevant ectopic bone, while among patients who have undergone primary THR surgery, those with indicators of excessive surgical bleeding are also at increased risk of clinically relevant HO. PMID:19455501

  12. A clinical perspective on common forms of acquired heterotopic ossification

    SciTech Connect

    Garland, D.E. )

    1991-02-01

    The clinical courses of heterotopic ossification (HO) as a consequence of trauma and central nervous system insults have many similarities as well as dissimilarities. Detection is commonly noted at two months. The incidence of clinically significant HO is 10%-20%. Approximately 10% of the HO is massive and causes severe restriction in joint motion or ankylosis. The most common sign and symptom are decreased range of motion and pain. The locations are the proximal limbs and joints. Sites of HO about a joint may vary according to the etiology of the HO. Roentgenographic evolution of HO occurs during a six-month period in the majority of patients. Treatment modalities include diphosphonates, indomethacin, radiation, range of motion exercises, and surgical excision. Surgical timing differs according to etiology: traumatic HO may be resected at six months; spinal cord injury HO is excised at one year; and traumatic brain injury HO is removed at 1.5 years. A small number of patients have progression of HO with medicinal treatment and recurrence after resection. The patients seem recalcitrant to present treatment methods regardless of the HO etiology. 117 refs.

  13. Extensive Abdominal Wall Incisional Heterotopic Ossification Reconstructed with Component Separation and Strattice Inlay

    PubMed Central

    Suleiman, Nergis Nina

    2016-01-01

    Summary: Symptomatic heterotopic ossification of abdominal surgical incisions is a rare occurrence. We present a 67-year-old man with severe discomfort caused by heterotopic ossification extending from the xiphoid to the umbilicus. The patient underwent an abdominal aortic aneurysm repair 3 years before our treatment. A 13 × 3.5 cm ossified lesion was excised. The resulting midline defect was closed using component separation and inlay Strattice. Tension-free midline adaptation of the recti muscles was achieved. A computed tomography scan of the abdomen 6 months after the surgery showed no recurrence or hernias. Heterotopic ossification in symptomatic patients has previously been treated with excision and primary closure. We believe that tension-free repair is important to prevent recurrence. Acellular dermal matrix may add to this effect and also compartmentalize the process. PMID:27536495

  14. Extensive Abdominal Wall Incisional Heterotopic Ossification Reconstructed with Component Separation and Strattice Inlay.

    PubMed

    Suleiman, Nergis Nina; Sandberg, Lars Johan Marcus

    2016-07-01

    Symptomatic heterotopic ossification of abdominal surgical incisions is a rare occurrence. We present a 67-year-old man with severe discomfort caused by heterotopic ossification extending from the xiphoid to the umbilicus. The patient underwent an abdominal aortic aneurysm repair 3 years before our treatment. A 13 × 3.5 cm ossified lesion was excised. The resulting midline defect was closed using component separation and inlay Strattice. Tension-free midline adaptation of the recti muscles was achieved. A computed tomography scan of the abdomen 6 months after the surgery showed no recurrence or hernias. Heterotopic ossification in symptomatic patients has previously been treated with excision and primary closure. We believe that tension-free repair is important to prevent recurrence. Acellular dermal matrix may add to this effect and also compartmentalize the process. PMID:27536495

  15. The Impact of Body Mass Index on Heterotopic Ossification

    SciTech Connect

    Mourad, Waleed Fouad; Packianathan, Satya; Shourbaji, Rania A.; Zhang Zhen; Graves, Mathew; Khan, Majid A.; Baird, Michael C.; Russell, George; Vijayakumar, Srinivasan

    2012-04-01

    Purpose: To analyze the impact of different body mass index (BMI) as a surrogate marker for heterotopic ossification (HO) in patients who underwent surgical repair (SR) for displaced acetabular fractures (DAF) followed by radiation therapy (RT). Methods and Materials: This is a single-institution retrospective study of 395 patients. All patients underwent SR for DAF followed by RT {+-} indomethacin. All patients received postoperative RT, 7 Gy, within 72 h. The patients were separated into four groups based on their BMI: <18.5, 18.5-24.9, 25-29.9, and >30. The end point of this study was to evaluate the efficacy of RT {+-} indomethacin in preventing HO in patients with different BMI. Results: Analysis of BMI showed an increasing incidence of HO with increasing BMI: <18.5, (0%) 0/6 patients; 18.5-24.9 (6%), 6 of 105 patients developed HO; 25-29.9 (19%), 22 of 117; >30 (31%), 51 of 167. Chi-square and multivariate logistic regression analysis showed that the correlation between odds of HO and BMI is significant, p < 0.0001. As the BMI increased, the risk of HO and Brooker Classes 3, 4 HO increased. The risk of developing HO is 1.0 Multiplication-Sign (10%) more likely among those with higher BMI compared with those with lower BMI. For a one-unit increase in BMI the log odds of HO increases by 1.0, 95% CI (1.06-1.14). Chi-square test shows no significant difference among all other factors and HO (e.g., indomethacin, race, gender). Conclusions: Despite similar surgical treatment and prophylactic measures (RT {+-} indomethacin), the risk of HO appears to significantly increase in patients with higher BMI after DAF. Higher single-fraction doses or multiple fractions and/or combination therapy with nonsteroidal inflammatory drugs may be of greater benefit to these patients.

  16. Heterotopic ossification in cervical disc arthroplasty: Is it clinically relevant?

    PubMed Central

    Barbagallo, Giuseppe M.; Corbino, Leonardo A.; Olindo, Giuseppe; Albanese, Vincenzo

    2010-01-01

    Study design: Retrospective cohort study. Objective: To analyze the presence and clinical relevance of heterotopic ossification (HO) at 3 years mean follow-up. Methods: Thirty patients suffering from cervical radiculopathy and/or myelopathy treated with anterior disc replacement (ADR) were studied. HO was classified using the McAfee grading system. Range of motion was measured from flexion and extension x-rays. Short-form 36 and neck disability index (NDI) assessed functional outcome. Results: Forty-five prostheses were implanted in 30 patients with cervical radiculopathy and/or myelopathy, mean age 40.9 years. Nineteen patients received 1 level and 11 patients received multilevel disc replacement. The incidence rate of HO was 42.2% (19 levels). Segmental range of motion was ≥3° in 93.8% of patients with HO. There was no significant difference in functional scores between those who did and those who did not develop HO. Males tended to develop HO more frequently than females, though this was not statistically significant. The indication for surgery (soft disc hernia or spondylosis) was not associated with the formation of HO. Conclusions: Functional improvement is maintained despite the presence of HO following cervical disc arthroplasty. Indications for arthroplasty should not be halted by the risk of HO. Methods evaluation and class of evidence (CoE) Methodological principle: Study design:  Prospective cohort  Retrospective cohort •  Case-control  Case series Methods  Patients at similar point in course of treatment •  Follow-up ≥85%  Similarity of treatment protocols for patient groups •  Patients followed for long enough for outcomes to occur •  Control for extraneous risk factors* Evidence class: III *Authors must provide a description of robust baseline characteristics, and control for those that are potential prognostic factors. The definiton of the different classes of evidence is available on page 83. PMID:23544019

  17. Heterotopic ossification: review of histologic findings and tissue distribution in a 10-year experience.

    PubMed

    Liu, Katharine; Tripp, Sheryl; Layfield, Lester J

    2007-01-01

    Heterotopic ossification (HO) within tissues involved by a pathologic process is a well-recognized phenomenon. It is most frequently observed in atherosclerotic plaques, in soft tissue around joints, and in the central nervous system. Less frequently, carcinomas and some benign neoplasms will undergo heterotopic ossification. We performed a retrospective review of our experience with HO over a 10-year period to determine the frequency and tissue site distribution of heterotopic ossification. A computerized review of surgical pathology records of approximately 126,000 reports revealed 85 cases in which heterotopic ossification, ectopic bone or metaplastic bone was specifically mentioned in the surgical pathology diagnosis. Twenty-two cases were neoplasms of non-osseous tissues, and 63 cases were non-neoplastic lesions. Immunohistochemical staining for bone morphogenic proteins (BMP) 1, 4, and 6 was performed. Fourteen cases showed staining for BMP-1, 22 cases showed staining for BMP-4, and five cases showed weak staining for BMP-6. HO is a relatively infrequent finding and is more commonly seen in degenerative and reparative conditions than in neoplasms. PMID:17728073

  18. Intra-Articular Giant Heterotopic Ossification following Total Knee Arthroplasty for Charcot Arthropathy

    PubMed Central

    Tsuge, Shintaro; Aoki, Yasuchika; Sonobe, Masato; Shibata, Yoshifumi; Sasaki, Yu; Nakagawa, Koichi

    2013-01-01

    Although the Charcot arthropathy may be associated with serious complications, total knee arthroplasty (TKA) is the preferred choice of treatment by patients. This case report presents an 80-year-old man with intra-articular giant heterotopic ossification following loosening of femoral and tibial implants and femoral condylar fracture. He had undergone TKA because of Charcot neuropathy seven years ago and had been doing well since. Immediately after a left knee sprain, he became unable to walk. Because he had developed a skin ulcer on his left calf where methicillin-resistant Staphylococcus aureus was detected, we postponed revision surgery until the ulcer was completely healed. While waiting, intra-articular bony fragments grew larger and formed giant heterotopic ossified masses. Eventually, the patient underwent revision surgery, and two major ossified masses were carefully and successfully extirpated. It should be noted that intra-articular heterotopic giant ossification is a significant complication after TKA for neuropathic arthropathy. PMID:24151574

  19. MiR-630 Inhibits Endothelial-Mesenchymal Transition by Targeting Slug in Traumatic Heterotopic Ossification

    PubMed Central

    Sun, Yangbai; Cai, Jiangyu; Yu, Shiyang; Chen, Shuai; Li, Fengfeng; Fan, Cunyi

    2016-01-01

    Heterotopic ossification (HO) is the abnormal formation of mature bone in extraskeletal soft tissues that occurs as a result of inflammation caused by traumatic injury or associated with genetic mutation. Despite extensive research to identify the source of osteogenic progenitors, the cellular origins of HO are controversial and the underlying mechanisms, which are important for the early detection of HO, remain unclear. Here, we used in vitro and in vivo models of BMP4 and TGF-β2-induced HO to identify the cellular origin and the mechanisms mediating the formation of ectopic bone in traumatic HO. Our results suggest an endothelial origin of ectopic bone in early phase of traumatic HO and indicate that the inhibition of endothelial-mesenchymal transition by miR-630 targeting Slug plays a role in the formation of ectopic bone in HO. A matched case-control study showed that miR-630 is specifically downregulated during the early stages of HO and can be used to distinguish HO from other processes leading to bone formation. Our findings suggest a potential mechanism of post-traumatic ectopic bone formation and identify miR-630 as a potential early indicator of HO. PMID:26940839

  20. Characterization of Cells Isolated from Genetic and Trauma-Induced Heterotopic Ossification

    PubMed Central

    Agarwal, Shailesh; Drake, James; Qureshi, Ammar T.; Loder, Shawn; Li, Shuli; Shigemori, Kay; Peterson, Jonathan; Cholok, David; Forsberg, Jonathan A.; Mishina, Yuji; Davis, Thomas A.; Levi, Benjamin

    2016-01-01

    Heterotopic ossification (HO) is the pathologic formation of bone separate from the normal skeleton. Although several models exist for studying HO, an understanding of the common in vitro properties of cells isolated from these models is lacking. We studied three separate animal models of HO including two models of trauma-induced HO and one model of genetic HO, and human HO specimens, to characterize the properties of cells derived from tissue containing pre-and mature ectopic bone in relation to analogous mesenchymal cell populations or osteoblasts obtained from normal muscle tissue. We found that when cultured in vitro, cells isolated from the trauma sites in two distinct models exhibited increased osteogenic differentiation when compared to cells isolated from uninjured controls. Furthermore, osteoblasts isolated from heterotopic bone in a genetic model of HO also exhibited increased osteogenic differentiation when compared with normal osteoblasts. Finally, osteoblasts derived from mature heterotopic bone obtained from human patients exhibited increased osteogenic differentiation when compared with normal bone from the same patients. These findings demonstrate that across models, cells derived from tissues forming heterotopic ossification exhibit increased osteogenic differentiation when compared with either normal tissues or osteoblasts. These cell types can be used in the future for in vitro investigations for drug screening purposes. PMID:27494521

  1. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification

    PubMed Central

    Yuasa, Masato; Mignemi, Nicholas A.; Nyman, Jeffry S.; Duvall, Craig L.; Schwartz, Herbert S.; Okawa, Atsushi; Yoshii, Toshitaka; Bhattacharjee, Gourab; Zhao, Chenguang; Bible, Jesse E.; Obremskey, William T.; Flick, Matthew J.; Degen, Jay L.; Barnett, Joey V.; Cates, Justin M.M.; Schoenecker, Jonathan G.

    2015-01-01

    Bone formation during fracture repair inevitably initiates within or around extravascular deposits of a fibrin-rich matrix. In addition to a central role in hemostasis, fibrin is thought to enhance bone repair by supporting inflammatory and mesenchymal progenitor egress into the zone of injury. However, given that a failure of efficient fibrin clearance can impede normal wound repair, the precise contribution of fibrin to bone fracture repair, whether supportive or detrimental, is unknown. Here, we employed mice with genetically and pharmacologically imposed deficits in the fibrin precursor fibrinogen and fibrin-degrading plasminogen to explore the hypothesis that fibrin is vital to the initiation of fracture repair, but impaired fibrin clearance results in derangements in bone fracture repair. In contrast to our hypothesis, fibrin was entirely dispensable for long-bone fracture repair, as healing fractures in fibrinogen-deficient mice were indistinguishable from those in control animals. However, failure to clear fibrin from the fracture site in plasminogen-deficient mice severely impaired fracture vascularization, precluded bone union, and resulted in robust heterotopic ossification. Pharmacological fibrinogen depletion in plasminogen-deficient animals restored a normal pattern of fracture repair and substantially limited heterotopic ossification. Fibrin is therefore not essential for fracture repair, but inefficient fibrinolysis decreases endochondral angiogenesis and ossification, thereby inhibiting fracture repair. PMID:26214526

  2. Intracerebral haemorrhage and hemiplegia with heterotopic ossification of the affected hip.

    PubMed

    O'Brien, M M C; Murray, T; Keeling, F; Williams, D

    2015-01-01

    We present the case of a 72-year-old woman who developed right hemiparesis following a left frontal intraparenchymal haemorrhage. Three months following initial presentation, the patient noted poorly localised right lower quadrant pain. Following extensive investigations, a diagnosis of heterotopic ossification of the hip was made. We discuss the aetiology and pathogenesis of this uncommon entity, and discuss its relationship to ipsilateral neurological injury. The link with neurological injury can result in a delayed and atypical presentation. Early recognition and treatment are important for those caring for patients with acquired neurological deficits, and permit improved patient outcomes. PMID:26243751

  3. Real time early detection imaging system of failed wounds and heterotopic ossification using unique Raman signatures

    NASA Astrophysics Data System (ADS)

    Papour, Asael; Taylor, Zach; Stafsudd, Oscar; Grundfest, Warren

    2015-03-01

    Our team has established a method to enable imaging of heterotopic ossification and bone growth locations in tissue using Stokes Raman signals with fast acquisition times. This technique relies on the unique Raman signatures of bone to capture parallel, full-field, 1 cm2 field of view, without utilizing a spectrometer. This system was built in mind as a compact complementary tool for in vivo patient monitoring that can offer a high resolution optical characterization for early detection of failed wounds. Preliminary results of bone detection in flesh are presented here and pave the way for further development of this tool in clinical setting.

  4. Heterotopic Ossification Circumferentia Articularis (HOCA) of Both Knee Joints After Guillain-Barré Syndrome

    PubMed Central

    Vaishya, Raju; Vijay, Vipul; Vaish, Abhishek

    2016-01-01

    Heterotopic ossification (HO) is the abnormal development of bone within soft tissue. It is a frequent complication after traumatic as well as atraumatic central nervous system (CNS) insult. It has rarely been found to be associated with Guillain-Barré syndrome (GBS). Only a few cases of HO associated with GBS have been reported so far in medical literature. We present a 30-year-old female patient with severe bilateral knee stiffness following axonal polyneuropathy type of GBS that developed 10 months ago in her immediate post-partum period. She was put on mechanical ventilation for two weeks. She was diagnosed as HO based on clinical and radiological studies. This is an extremely unusual presentation of HO encircling both the knees following GBS without any other well-known risk factors. We have coined a new nomenclature—Heterotopic Ossification Circumferentia Articularis (HOCA)—for this type of presentation. In our patient, various factors such as prolonged ICU stay, mechanical ventilation, hypoxia, and long-standing hypomobility could be attributed to the development of this severe form of HO. PMID:27004157

  5. The use of spect/ct in the evaluation of heterotopic ossification in para/tetraplegics

    PubMed Central

    Lima, Maurício Coelho; Passarelli, Marcus Ceregati; Dario, Virgílio; Lebani, Bruno Rodrigues; Monteiro, Paulo Henrique Silva; Ramos, Celso Darío

    2014-01-01

    Objective: To evaluate the stage of maturation and the metabolism of neurogenic heterotopic ossification by using SPECT/CT. Methods: A total of 12 medical records of patients with spinal cord injury, all of them classified according to the ASIA protocol (disability scale from the American Spinal Injury Association) in complete lesion (A) and partial lesions (B, C and D) and registered at the Laboratory of Biomechanics and Rehabilitation of the Locomotor System, were submitted to SPECT/CT evaluation. Results: Sixteen hips with heterotopic ossification observed in X-ray were studied and only two (12.5%) had high osteoblastic activity. Five hips showed medium activity, three (18.75%) low activity and six (37.5%) did not present any activity detected by SPECT/CT. Conclusion: SPECT/CT helps to determinate which patients have a greater risk of relapse after surgical resection, proving to be a useful imaging study in preoperative evaluation that can be used to determinate the postoperative prognosis of these patients. Level of Evidence III, Investigating a Diagnostic Test. PMID:24644413

  6. Heterotopic Ossification and Entrapment of the Tibial Nerve Within the Tarsal Tunnel: A Case Report.

    PubMed

    Willis, Alexander R; Samad, Adil A; Prado, Gail T; Gabisan, Glenn G

    2016-01-01

    Heterotopic ossification has been reported to occur after musculoskeletal trauma (including orthopedic procedures). This has been known to cause nerve entrapment syndromes and persistent pain, limiting joint mobility. We present a case of a 19-year old female collegiate athlete who had previously undergone ankle arthroscopy and arthrotomy to remove 2 ossicles. At approximately 1 year postoperatively, the patient developed pain when planting and pivoting her foot. Imaging revealed a radiodense lesion at the posteromedial ankle consistent with heterotopic ossification and entrapment of the tibial nerve within the tarsal tunnel. The patient underwent surgical resection and postoperative indomethacin prophylaxis. At the 1-year follow-up visit, the patient remained asymptomatic, without evidence of recurrence of the heterotopic ossification. In our review of the published data, we found no previously reported cases of heterotopic ossification causing entrapment of the tibial nerve within the tarsal tunnel. In the present case report, we describe this rare case and the postulated etiologies and pathophysiology of this disease process. In addition, we discuss the clinical signs and symptoms and recommended imaging modalities and treatment. PMID:27079305

  7. Heterotopic ossification: Pathophysiology, clinical features, and the role of radiotherapy for prophylaxis

    SciTech Connect

    Balboni, Tracy A.; Gobezie, Reuben; Mamon, Harvey J. . E-mail: hmamon@partners.org

    2006-08-01

    Heterotopic ossification (HO) is a benign condition of abnormal formation of bone in soft tissue. HO is frequently asymptomatic, though when it is more severe it typically manifests as decreased range of motion at a nearby joint. HO has been recognized to occur in three distinct contexts-trauma, neurologic injury, and genetic abnormalities. The etiology of HO is incompletely understood. A posited theory is that HO results from the presence of osteoprogenitor cells pathologically induced by an imbalance in local or systemic factors. Individuals at high risk for HO development frequently undergo prophylaxis to prevent HO formation. The two most commonly employed modalities for prophylaxis are nonsteroidal anti-inflammatory drugs and radiation therapy. This review discusses HO pathophysiology, clinical features, and the role of radiotherapy for prophylaxis.

  8. Heterotopic ossification in victims of the London 7/7 bombings.

    PubMed

    Edwards, D S; Clasper, J C; Patel, H D L

    2015-12-01

    Heterotopic ossification (HO) is the formation of bone at extraskeletal sites. Over 60% of amputees injured by improvised explosive devices in the recent conflict in Afghanistan have developed HO, resulting in functional impairment. It is hypothesised that a key aetiological factor is the blast wave; however, other environmental and medical risk factors, which the casualties have been exposed to, have also been postulated. The suicide terrorist bombings in London in 2005 resulted in many blast-related casualties, many of whom were managed by the Royal London Hospital. This cohort of severely injured patients whose injuries also included trauma-related amputations shared some, but not all, of the risk factors identified in the military population. We reviewed these patients, in particular to assess the presence or absence of military-established risk factors for the formation of HO in these casualties. PMID:25645697

  9. Role of Gender in Burn-Induced Heterotopic Ossification and Mesenchymal Cell Osteogenic Differentiation

    PubMed Central

    Ranganathan, Kavitha; Peterson, Jonathan; Agarwal, Shailesh; Oluwatobi, Eboda; Loder, Shawn; Forsberg, Jonathan A.; Davis, Thomas A.; Wang, Stewart C.; Levi, Benjamin

    2015-01-01

    BACKGROUND Heterotopic ossification (HO) most commonly occurs after burn injury, joint arthroplasty, and trauma. Male gender has been identified as a risk factor for the development of HO. It remains unclear why adult males are more predisposed to this pathology than adult females. In this study, we explore differences in heterotopic ossification between male and female mice using an in vivo burn/tenotomy model. METHODS Our Achilles tenotomy and burn model was used to evaluate the osteogenic potential of tissue-derived mesenchymal stem cells (MSCs) of male and female mice in injured and non-injured mice. Groups consisted of injured male (n=3), injured female (n=3), non-injured male (n=3), and non-injured female (n=3). The osteogenic potential of cells harvested from each group was assessed through RNA and protein levels and quantified using micro-CT scan. Histomorphometry was used to verify micro-CT findings, and immunohistochemistry was used to assess osteogenic signaling at the site of HO. RESULTS MSCs of male mice demonstrated greater osteogenic gene and protein expression than female MSCs (p<.05). Male mice in the burn group formed 35% more bone as compared to female mice in the burn group. This bone formation correlated with increased pSmad and IGF-1 signaling at the HO site in male mice. Differences were also seen between the non-injured male and female groups. CONCLUSIONS We demonstrate that male mice form quantitatively more bone as compared to female mice using our burn/tenotomy model. These findings can be explained at least in part by differences in BMP and IGF-1 signaling. PMID:26017598

  10. Pseudo-Acetabulum due to Heterotopic Ossification in a Child with Post Traumatic Neglected Posterior Hip Dislocation

    PubMed Central

    Pathak, Aditya C; Patil, Atul K; Sheth, Binoti; Bansal, Rohan

    2012-01-01

    Introduction: Traumatic neglected dislocations of hip in children are rare entity. Neglected traumatic dislocations of hip in children along with heterotopic ossification are still rare. Post traumatic neglected hip dislocations are to be diagnosed as early as possible and have to be treated with precision and aggression as the outcome of treatment for the same is not predictable. Case Report: 5 year female with post-traumatic neglected hip dislocation with heterotopic ossification forming a pseudoacetabulum postero-superiorly in which femur head was lodged. The girl was operated by open reduction using Moore’s Posterior approach and showed good results. Here is a mention of a rare case with a good 18 months follow up with no complication. Conclusions: Post-traumatic neglected posterior hip dislocation mostly requires open reduction and relocation of femoral head in original acetabulum with concentric reduction. Heterotopic ossification is a rare but known complication of traumatic dislocation of hip in children. Good results can be achieved in such cases and regular follow-up of patient is required post-operatively.

  11. Early Detection of Burn Induced Heterotopic Ossification using Transcutaneous Raman Spectroscopy

    PubMed Central

    Peterson, Jonathan R.; Okagbare, Paul I.; De La Rosa, Sara; Cilwa, Katherine E.; Perosky, Joseph E.; Eboda, Oluwatobi N.; Donneys, Alexis; Su, Grace L.; Buchman, Steven R.; Cederna, Paul S.; Wang, Stewart C.; Kozloff, Kenneth M.; Morris, Michael D; Levi, Benjamin

    2013-01-01

    Introduction Heterotopic ossification (HO), or the abnormal formation of bone in soft tissue, occurs in over 60% of major burn injuries and blast traumas. A significant need exists to improve the current diagnostic modalities for HO which are inadequate to diagnose and intervene on HO at early time-points. Raman spectroscopy has been used in previous studies to report on changes in bone composition during bone development but has not yet been applied to burn induced HO. In this study, we validate transcutaneous, in-vivo Raman spectroscopy as a methodology for early diagnosis of HO in mice following a burn injury. Methods An Achilles tenotomy model was used to study HO formation. Following tenotomy, mice were divided into burn and sham groups with exposure of 30% surface area on the dorsum to 60° water or 30° water for 18 seconds respectively. In-vivo, transcutaneous Raman spectroscopy was performed at early time points (5 days, 2 and 3 weeks) and a late time point (3 months) on both the tenotomized and non-injured leg. These same samples were then dissected down to the bone and ex-vivo Raman measurements were performed on the excised tissue. Bone formation was verified with Micro CT and histology at corresponding time-points. Results Our Raman probe allowed non-invasive, transcutaneous evaluation of heterotopic bone formation. Raman data showed significantly increased bone mineral signaling in the tenotomy compared to control leg at 5 days post injury, with the difference increasing over time whereas Micro CT did not demonstrate heterotopic bone until three weeks. Ex-vivo Raman measurements showed significant differences in the amount of HO in the burn compared to sham groups and also showed differences in the spectra of new, ectopic bone compared to pre-existing cortical bone. Conclusions Burn injury increases the likelihood of developing HO when combined with traumatic injury. In our in-vivo mouse model, Raman spectroscopy allowed for detection of HO formation

  12. Heterotopic ossification after total hip replacement and the HLA system in the Sicilian population.

    PubMed

    Sessa, G; Costarella, L; Mollica, R; Pavone, V

    2002-06-01

    Heterotopic ossification (HO) is a frequent complication following total hip arthroplasty (THA). At present, the etiology HO is unknown, however, genetic predisposition may be a cause of HO in individuals in whom no risk factors can be detected. The goal of this study was to investigate the HLA system, searching for any correlation with the presence of HO after THA. Thirty-five patients of Sicilian origin were operated on between January 1997 and January 1999 for cementless THA under regional anesthesia. The entire series was divided into three groups and all underwent histocompatibility typing. Group I was made up of 10 patients who presented with HO Brooker grades 1 and 2 after THA; group 2 comprised 7 patients affected by grades 3 and 4 HO after THA; and group 3 was made up of 18 subjects who presented with one or more preoperative risk factors for developing peri-prosthetic HO before undergoing THA. No positivity for HLA-B27 antigen was observed, but there was as an increase in HLA-B18 (with respect to that in the Sicilian population) in patients with HO following THA. The main conclusion from the study is that there is a strong correlation between the presence of the antigens HLA-A2 and HLA-B18 in patients with HO grades 3 and 4. PMID:24604489

  13. Characterization of Heterotopic Ossification Using Radiographic Imaging: Evidence for a Paradigm Shift

    PubMed Central

    Brownley, R. Cameron; Agarwal, Shailesh; Loder, Shawn; Eboda, Oluwatobi; Li, John; Peterson, Joshua; Hwang, Charles; Breuler, Christopher; Kaartinen, Vesa; Zhou, Bin; Mishina, Yuji; Levi, Benjamin

    2015-01-01

    Heterotopic ossification (HO) is the growth of extra-skeletal bone which occurs following trauma, burns, and in patients with genetic bone morphogenetic protein (BMP) receptor mutations. The clinical and laboratory evaluation of HO is dependent on radiographic imaging to identify and characterize these lesions. Here we show that despite its inadequacies, plain film radiography and single modality microCT continue to serve as a primary method of HO imaging in nearly 30% of published in vivo literature. Furthermore, we demonstrate that detailed microCT analysis is superior to plain film and single modality microCT radiography specifically in the evaluation of HO formed through three representative models due to its ability to 1) define structural relationships between growing extra-skeletal bone and normal, anatomic bone, 2) provide accurate quantification and growth rate based on volume of the space-occupying lesion, thereby facilitating assessments of therapeutic intervention, 3) identify HO at earlier times allowing for evaluation of early intervention, and 4) characterization of metrics of bone physiology including porosity, tissue mineral density, and cortical and trabecular volume. Examination of our trauma model using microCT demonstrated two separate areas of HO based on anatomic location and relationship with surrounding, normal bone structures. Additionally, microCT allows HO growth rate to be evaluated to characterize HO progression. Taken together, these data demonstrate the need for a paradigm shift in the evaluation of HO towards microCT as a standard tool for imaging. PMID:26544555

  14. Imaging symptomatic bone morphogenetic protein-2-induced heterotopic bone formation within the spinal canal: case report.

    PubMed

    Chryssikos, Timothy; Crandall, Kenneth M; Sansur, Charles A

    2016-05-01

    Heterotopic bone formation within the spinal canal is a known complication of bone morphogenetic protein-2 (BMP-2) and presents a clinical and surgical challenge. Imaging modalities are routinely used for operative planning in this setting. Here, the authors present the case of a 59-year-old woman with cauda equina syndrome following intraoperative BMP-2 administration. Plain film myelographic studies showed a region of severe stenosis that was underappreciated on CT myelography due to a heterotopic bony lesion mimicking the dorsal aspect of a circumferentially patent thecal sac. When evaluating spinal stenosis under these circumstances, it is important to carefully consider plain myelographic images in addition to postmyelography CT images as the latter may underestimate the true degree of stenosis due to the potentially similar radiographic appearances of evolving BMP-2-induced heterotopic bone and intrathecal contrast. Alternatively, comparison of sequentially acquired noncontrast CT scans with CT myelographic images may also assist in distinguishing BMP-2-induced heterotopic bony lesions from the thecal sac. Further studies are needed to elucidate the roles of the available imaging techniques in this setting and to characterize the connection between the radiographic and histological appearances of BMP-2-induced heterotopic bone. PMID:26824586

  15. Opioid signaling in mast cells regulates injury responses associated with heterotopic ossification

    PubMed Central

    Mutso, Amelia A.; McGuire, Tammy L.; Apkarian, Apkar Vania; Kessler, John A.

    2016-01-01

    Introduction Previous studies found that neuron specific enolase promoter (Nse-BMP4) transgenic mice have increased expression of the nociceptive mediator, substance P and exaggerated local injury responses associated with heterotopic ossification (HO). It is of interest great to know the pain responses in these mice and how the opioid signaling is involved in the downstream events such as mast cell (MC) activation. Materials and methods This study utilized a transgenic mouse model of HO in which BMP4 is expressed under the control of the Nse-BMP4. The tactile sensitivity and the cold sensitivity of the mice were measured in a classic inflammatory pain model (carrageenan solution injected into the plantar surface of the left hind paw). The MC activation and the expression profiles of different components in the opioid signaling were demonstrated through routine histology and immunohistochemistry and Western blotting, in the superficial and deep muscle injury models. Results We found that the pain responses in these mice were paradoxically attenuated or unchanged, and we also found increased expression of both Methionine Enkephalin (Met-Enk), and the µ-opioid receptor (MOR). Met-Enk and MOR both co-localized within activated MCs in limb tissues. Further, Nse-BMP4;MOR−/− double mutant mice showed attenuated MC activation and had a significant reduction in HO formation in response to injuries. Conclusions These observations suggest that opioid signaling may play a key role in MC activation and the downstream inflammatory responses associated with HO. In addition to providing insight into the role of MC activation and associated injury responses in HO, these findings suggest opioid signaling as a potential therapeutic target in HO and possibly others disorders involving MC activation. PMID:24327087

  16. Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

    PubMed Central

    Agarwal, Shailesh; Loder, Shawn; Brownley, Cameron; Cholok, David; Mangiavini, Laura; Li, John; Breuler, Christopher; Sung, Hsiao H.; Li, Shuli; Ranganathan, Kavitha; Peterson, Joshua; Tompkins, Ronald; Herndon, David; Xiao, Wenzhong; Jumlongras, Dolrudee; Olsen, Bjorn R.; Davis, Thomas A.; Mishina, Yuji; Schipani, Ernestina; Levi, Benjamin

    2016-01-01

    Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1αfl:fl) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone. PMID:26721400

  17. Cost of Radiotherapy Versus NSAID Administration for Prevention of Heterotopic Ossification After Total Hip Arthroplasty

    SciTech Connect

    Strauss, Jonathan B. Chen, Sea S.; Shah, Anand P.; Coon, Alan B.; Dickler, Adam

    2008-08-01

    Purpose: Heterotopic ossification (HO), or abnormal bone formation, is a common sequela of total hip arthroplasty. This abnormal bone can impair joint function and must be surgically removed to restore mobility. HO can be prevented by postoperative nonsteroidal anti-inflammatory drug (NSAID) use or radiotherapy (RT). NSAIDs are associated with multiple toxicities, including gastrointestinal bleeding. Although RT has been shown to be more efficacious than NSAIDs at preventing HO, its cost-effectiveness has been questioned. Methods and Materials: We performed an analysis of the cost of postoperative RT to the hip compared with NSAID administration, taking into account the costs of surgery for HO formation, treatment-induced morbidity, and productivity loss from missed work. The costs of RT, surgical revision, and treatment of gastrointestinal bleeding were estimated using the 2007 Medicare Fee Schedule and inpatient diagnosis-related group codes. The cost of lost wages was estimated using the 2006 median salary data from the U.S. Census Bureau. Results: The cost of administering RT was estimated at $899 vs. $20 for NSAID use. After accounting for the additional costs associated with revision total hip arthroplasty and gastrointestinal bleeding, the corresponding estimated costs were $1,208 vs. $930. Conclusion: If the costs associated with treatment failure and treatment-induced morbidity are considered, the cost of NSAIDs approaches that of RT. Other NSAID morbidities and quality-of-life differences that are difficult to quantify add to the cost of NSAIDs. These considerations have led us to recommend RT as the preferred modality for use in prophylaxis against HO after total hip arthroplasty, even when the cost is considered.

  18. Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification.

    PubMed

    Agarwal, Shailesh; Loder, Shawn; Brownley, Cameron; Cholok, David; Mangiavini, Laura; Li, John; Breuler, Christopher; Sung, Hsiao H; Li, Shuli; Ranganathan, Kavitha; Peterson, Joshua; Tompkins, Ronald; Herndon, David; Xiao, Wenzhong; Jumlongras, Dolrudee; Olsen, Bjorn R; Davis, Thomas A; Mishina, Yuji; Schipani, Ernestina; Levi, Benjamin

    2016-01-19

    Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1α(fl:fl)) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone. PMID:26721400

  19. Heterotopic ossification after hemiarthroplasty of the hip – A comparison of three common approaches

    PubMed Central

    Corrigan, Chad M.; Greenberg, Sarah E.; Sathiyakumar, Vasanth; Mitchell, Phillip M.; Francis, Arie; Omar, Adan; Thakore, Rachel V.; Obremskey, William T.; Sethi, Manish K.

    2014-01-01

    Objective Heterotopic ossification (HO) about the hip after total hip arthroplasty and internal fixation of the hip, pelvis, and acetabulum has been linked to surgical approach. However, no study has investigated surgical approach and HO in patients undergoing hemiarthroplasty. We therefore aimed to explore the influence of operative approach in patients undergoing hemiarthroplasty. Methods Through a retrospective case series at an Urban level I trauma center, we found 80 patients over the age of 60 undergoing hemiarthroplasty for femoral neck fractures from 2000 to 2009. Patient charts, operative notes, and radiographs were reviewed for demographics, operative approach (anterior: A, anterior-lateral: AL, posterior: P), and any development of HO. Fisher's exact test compared rates of HO among the three approaches. Student's t-tests compared Brooker Classification levels of HO among the approaches. Results 82 hemiarthroplasties (26 A, 32 AL, 24 P) were included for analysis. 22 patients (27%) had HO. There was no significant difference in the development of HO based upon surgical approach: A: 19% (n = 5); AL: 34% (n = 11); P: 25% (n = 6). There was a significant difference in the grade of HO based on Brooker Classification (BC) with the posterior approach resulting in significantly lower grade of HO: A (BC: 2.60); AL (BC: 2.64); P (BC: 1.50) (p = 0.012). Conclusions Our data is the first to evaluate surgical approach and HO in patients with hemiarthroplasty. Patients have a significant risk of developing higher grade HO based on surgical approach (A or AL). Orthopedists should be mindful of these risks when considering A or AL approaches. PMID:26549944

  20. Postoperative Single-Fraction Radiation for Prevention of Heterotopic Ossification of the Elbow

    SciTech Connect

    Robinson, Clifford G.; Polster, Joshua M.; Reddy, Chandana A.; Lyons, Janice A.; Evans, Peter J.; Lawton, Jeffrey N.; Graham, Thomas J.; Suh, John H.

    2010-08-01

    Purpose: Heterotopic ossification (HO) about the elbow has been described after surgery, trauma, and burns. Even limited deposits can lead to significant functional deficits. Little data exist regarding outcomes of patients treated with radiation therapy (RT) after elbow surgery. We report here the Cleveland Clinic experience with single-fraction radiation following surgery to the elbow. The primary endpoint was the rate of new HO after RT. Secondary endpoints were range of motion, functional compromise, and toxicity. Methods and Materials: From May 1993 to July 2006, 36 patients underwent elbow surgery followed by single-fraction RT. Range of motion data were collected before and during surgery and at last follow-up. Radiographs were reviewed for persistent or new HO. Patient and treatment factors were analyzed for correlation with development of HO or functional compromise. Results: Median follow-up was 8.7 months, median age was 42 years, and 75% of patients were male. Twenty-six (72%) patients had HO prior to surgery. All patients had significant limitations in flexion/extension or pronation/supination at baseline. Thirty-one (86%) patients had prior elbow trauma, and 26 (72%) patients had prior surgery. RT was administered a median of 1 day postoperatively (range, 1-4 days). Thirty-four patients received 700 cGy, and 2 patients received 600 cGy. Three (8%) patients developed new HO after RT. All patients had improvement in range of motion from baseline. No patient or treatment factors were significantly associated with the development of HO or functional compromise. Conclusions: Single-fraction RT after surgery to the elbow is associated with favorable functional and radiographic outcomes.

  1. Risk of Radiation-Induced Malignancy With Heterotopic Ossification Prophylaxis: A Case–Control Analysis

    SciTech Connect

    Sheybani, Arshin; TenNapel, Mindi J.; Lack, William D.; Clerkin, Patrick; Hyer, Daniel E.; Sun, Wenqing; Jacobson, Geraldine M.

    2014-07-01

    Purpose: To determine the risk of radiation-induced malignancy after prophylactic treatment for heterotopic ossification (HO). Methods and Materials: A matched case–control study was conducted within a population-based cohort of 3489 patients treated either for acetabular fractures with acetabular open reduction internal fixation or who underwent total hip arthroplasty from 1990 to 2009. Record-linkage techniques identified patients who were diagnosed with a malignancy from our state health registry. Patients with a prior history of malignancy were excluded from the cohort. For each documented case of cancer, 2 controls were selected by stratified random sampling from the cohort that did not develop a malignancy. Matching factors were sex, age at time of hip treatment, and duration of follow-up. Results: A total of 243 patients were diagnosed with a malignancy after hip treatment. Five patients were excluded owing to inadequate follow-up time in the corresponding control cohort. A cohort of 238 cases (control, 476 patients) was included. Mean follow-up was 10 years, 12 years in the control group. In the cancer cohort, 4% of patients had radiation therapy (RT), compared with 7% in the control group. Of the 9 patients diagnosed with cancer after RT, none occurred within the field. The mean latency period was 5.9 years in the patients who received RT and 6.6 years in the patients who did not. Median (range) age at time of cancer diagnosis in patients who received RT was 62 (43-75) years, compared with 70 (32-92) years in the non-RT patients. An ad hoc analysis was subsequently performed in all 2749 patients who were not matched and found neither an increased incidence of malignancy nor a difference in distribution of type of malignancy. Conclusion: We were unable to demonstrate an increased risk of malignancy in patients who were treated with RT for HO prophylaxis compared with those who were not.

  2. Influence of transcutaneous electrical stimulation on heterotopic ossification: an experimental study in Wistar rats.

    PubMed

    Zotz, T G G; Paula, J B de

    2015-11-01

    Heterotopic ossification (HO) is a metaplastic biological process in which there is newly formed bone in soft tissues, resulting in joint mobility deficit and pain. Different treatment modalities have been tried to prevent HO development, but there is no consensus on a therapeutic approach. Since electrical stimulation is a widely used resource in physiotherapy practice to stimulate joint mobility, with analgesic and anti-inflammatory effects, its usefulness for HO treatment was investigated. We aimed to identify the influence of electrical stimulation on induced HO in Wistar rats. Thirty-six male rats (350-390 g) were used, and all animals were anesthetized for blood sampling before HO induction, to quantify the serum alkaline phosphatase. HO induction was performed by bone marrow implantation in both quadriceps of the animals, which were then divided into 3 groups: control (CG), transcutaneous electrical nerve stimulation (TENS) group (TG), and functional electrical stimulation (FES) group (FG) with 12 rats each. All animals were anesthetized and electrically stimulated twice per week, for 35 days from induction day. After this period, another blood sample was collected and quadriceps muscles were bilaterally removed for histological and calcium analysis and the rats were killed. Calcium levels in muscles showed significantly lower results when comparing TG and FG (P<0.001) and between TG and CG (P<0.001). Qualitative histological analyses confirmed 100% HO in FG and CG, while in TG the HO was detected in 54.5% of the animals. The effects of the muscle contractions caused by FES increased HO, while anti-inflammatory effects of TENS reduced HO. PMID:26292223

  3. Morphological and clinical aspects of heterotopic ossification in sports. A case study.

    PubMed

    Bosse, A; Wanner, K F; Weber, A; Müller, K M

    1994-08-01

    Heterotopic ossification (HO) caused through sport injuries is a rare, clearly defined lesion. In a considerable number of cases, however, no adequate trauma can be remembered or otherwise established in the "sporting history". Differential diagnosis of this non-traumatic HO variant often presents many problems which may lead to the wrong diagnosis of sarcoma. We looked at 28 cases, in which in more than 50% a sarcoma was discussed as primary diagnosis. These difficulties arise mainly in cases where clinical features suggest a tumor, radiological changes are unspecific, and the diagnosis is based on a small biopsy sample. We demonstrate and discuss the problems involved in differential diagnosis using the history of a matchgrade sportsman as a sample. Unlike in sarcoma, patients with HO usually suffer severe pain, and well over 50% of all patients develop the disease during the 2nd or 3rd decade. Over 90% of all patients with soft tissue sarcoma, however, are over the age of 30. From the morphological point of view, the different histological pattern of HO has to be taken into account, since early stages may mimick a sarcomatous lesion. If the clinical findings suggest the presence of HO, surgical intervention including the taking of biopsy sample should be postponed, so that instead of early highly mitotic active phases more mature bone structures, which are easier to classify, will be available for evaluation. Only a profound knowledge of the different phases of HO, together with clinical and radiological features, will clarify the differential diagnostic problems of the non-traumatic variant of this lesion in sportsmen. PMID:7822071

  4. Prophylactic radiotherapy against heterotopic ossification following internal fixation of acetabular fractures: a comparative estimate of risk

    PubMed Central

    Nasr, P; Yip, G; Scaife, J E; House, T; Thomas, S J; Harris, F; Owen, P J; Hull, P

    2014-01-01

    Objective: Radiotherapy (RT) is effective in preventing heterotopic ossification (HO) around acetabular fractures requiring surgical reconstruction. We audited outcomes and estimated risks from RT prophylaxis, and alternatives of indometacin or no prophylaxis. Methods: 34 patients underwent reconstruction of acetabular fractures through a posterior approach, followed by a 8-Gy single fraction. The mean age was 44 years. The mean time from surgery to RT was 1.1 days. The major RT risk is radiation-induced fatal cancer. The International Commission on Radiological Protection (ICRP) method was used to estimate risk, and compared with a method (Trott and Kemprad) specifically for estimating RT risk for benign disease. These were compared with risks associated with indometacin and no prophylaxis. Results: 28 patients (82%) developed no HO; 6 developed Brooker Class I; and none developed Class II–IV HO. The ICRP method suggests a risk of fatal cancer in the range of 1 in 1000 to 1 in 10,000; the Trott and Kemprad method suggests 1 in 3000. For younger patients, this may rise to 1 in 2000; and for elderly patients, it may fall to 1 in 6000. The risk of death from gastric bleeding or perforation from indometacin is 1 in 180 to 1 in 900 in older patients. Without prophylaxis risk of death from reoperation to remove HO is 1 in 4000 to 1 in 30,000. Conclusion: These results are encouraging, consistent with much larger series and endorse our multidisciplinary management. Risk estimates can be used in discussion with patients. Advances in knowledge: The risk from RT prophylaxis is small, it is safer than indometacin and substantially overlaps with the range for no prophylaxis. PMID:25089852

  5. Use of calcitonin in recalcitrant phantom limb pain complicated by heterotopic ossification

    PubMed Central

    Viana, Ricardo; Payne, Michael WC

    2015-01-01

    BACKGROUND: Phantom limb pain (PLP) is a common complication after amputation, affecting up to 80% of the amputee population. However, only 5% to 10% of amputees have severe PLP impacting daily function. The present report details the management of severe, treatment-resistant PLP in a 72-year-old man with a traumatic left transradial amputation and a comorbid complication of heterotopic ossification (HO). OBJECTIVE: To describe a case of PLP with HO and the possible role of calcitonin in the treatment of both conditions. METHODS: A systematic review of the literature regarding the management of PLP. RESULTS: Seventeen articles that directly addressed PLP were identified; 11 were randomized controlled trials. All involved small samples and follow-up ranged from 6 h to one year, with the majority limited to six weeks. DISCUSSION: In the present case, medication management was limited by side effects, lack of response and the patient’s desire to avoid long-term medication. Investigations revealed HO, which was suspected to envelop the median nerve in the proximal forearm. After several unsuccessful medication trials, the literature was reviewed in search of common variables between HO formation and persistent PLP. Ultimately, the biochemical effects associated with nerve injury were identified to be a possible factor in both HO and PLP development. Calcitonin’s proposed mechanisms of action may help to manage HO and PLP at multiple stages of disease development and maintenance. In the present case, a four-week trial of intranasal calcitonin was successful, with pain control lasting at least 18 months. CONCLUSION: The present case report provided a review of the current literature in PLP pharmacological management and the current understanding of the etiology of PLP and HO, as well as how the two may coexist. It also provided an opportunity to discuss the proposed mechanisms of action of calcitonin in the management of PLP and HO. PMID:26291126

  6. Influence of transcutaneous electrical stimulation on heterotopic ossification: an experimental study in Wistar rats

    PubMed Central

    Zotz, T.G.G.; de Paula, J.B.

    2015-01-01

    Heterotopic ossification (HO) is a metaplastic biological process in which there is newly formed bone in soft tissues, resulting in joint mobility deficit and pain. Different treatment modalities have been tried to prevent HO development, but there is no consensus on a therapeutic approach. Since electrical stimulation is a widely used resource in physiotherapy practice to stimulate joint mobility, with analgesic and anti-inflammatory effects, its usefulness for HO treatment was investigated. We aimed to identify the influence of electrical stimulation on induced HO in Wistar rats. Thirty-six male rats (350-390 g) were used, and all animals were anesthetized for blood sampling before HO induction, to quantify the serum alkaline phosphatase. HO induction was performed by bone marrow implantation in both quadriceps of the animals, which were then divided into 3 groups: control (CG), transcutaneous electrical nerve stimulation (TENS) group (TG), and functional electrical stimulation (FES) group (FG) with 12 rats each. All animals were anesthetized and electrically stimulated twice per week, for 35 days from induction day. After this period, another blood sample was collected and quadriceps muscles were bilaterally removed for histological and calcium analysis and the rats were killed. Calcium levels in muscles showed significantly lower results when comparing TG and FG (P<0.001) and between TG and CG (P<0.001). Qualitative histological analyses confirmed 100% HO in FG and CG, while in TG the HO was detected in 54.5% of the animals. The effects of the muscle contractions caused by FES increased HO, while anti-inflammatory effects of TENS reduced HO. PMID:26292223

  7. Anaplerotic Accumulation of Tricarboxylic Acid Cycle Intermediates as Well as Changes in Other Key Metabolites During Heterotopic Ossification

    PubMed Central

    Davis, Eleanor L.; Salisbury, Elizabeth A.; Olmsted‐Davis, Elizabeth

    2015-01-01

    ABSTRACT Heterotopic ossification (HO) is the de novo formation of bone that occurs in soft tissue, through recruitment, expansion, and differentiation of multiple cells types including transient brown adipocytes, osteoblasts, chondrocytes, mast cells, and platelets to name a few. Much evidence is accumulating that suggests changes in metabolism may be required to accomplish this bone formation. Recent work using a mouse model of heterotopic bone formation reliant on delivery of adenovirus‐transduced cells expressing low levels of BMP2 showed the immediate expansion of a unique brown adipocyte‐like cell. These cells are undergoing robust uncoupled oxidative phosphorylation to a level such that oxygen in the microenvironment is dramatically lowered creating areas of hypoxia. It is unclear how these oxygen changes ultimately affect metabolism and bone formation. To identify the processes and changes occurring over the course of bone formation, HO was established in the mice, and tissues isolated at early and late times were subjected to a global metabolomic screen. Results show that there are significant changes in both glucose levels, as well as TCA cycle intermediates. Additionally, metabolites necessary for oxidation of stored lipids were also found to be significantly elevated. The complete results of this screen are presented here, and provide a unique picture of the metabolic changes occurring during heterotopic bone formation. J. Cell. Biochem. 117: 1044–1053, 2016. © 2015 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc. PMID:26627193

  8. Cancer risk estimates from radiation therapy for heterotopic ossification prophylaxis after total hip arthroplasty

    SciTech Connect

    Mazonakis, Michalis; Berris, Theoharris; Damilakis, John; Lyraraki, Efrossyni

    2013-10-15

    Purpose: Heterotopic ossification (HO) is a frequent complication following total hip arthroplasty. This study was conducted to calculate the radiation dose to organs-at-risk and estimate the probability of cancer induction from radiotherapy for HO prophylaxis.Methods: Hip irradiation for HO with a 6 MV photon beam was simulated with the aid of a Monte Carlo model. A realistic humanoid phantom representing an average adult patient was implemented in Monte Carlo environment for dosimetric calculations. The average out-of-field radiation dose to stomach, liver, lung, prostate, bladder, thyroid, breast, uterus, and ovary was calculated. The organ-equivalent-dose to colon, that was partly included within the treatment field, was also determined. Organ dose calculations were carried out using three different field sizes. The dependence of organ doses upon the block insertion into primary beam for shielding colon and prosthesis was investigated. The lifetime attributable risk for cancer development was estimated using organ, age, and gender-specific risk coefficients.Results: For a typical target dose of 7 Gy, organ doses varied from 1.0 to 741.1 mGy by the field dimensions and organ location relative to the field edge. Blocked field irradiations resulted in a dose range of 1.4–146.3 mGy. The most probable detriment from open field treatment of male patients was colon cancer with a high risk of 564.3 × 10{sup −5} to 837.4 × 10{sup −5} depending upon the organ dose magnitude and the patient's age. The corresponding colon cancer risk for female patients was (372.2–541.0) × 10{sup −5}. The probability of bladder cancer development was more than 113.7 × 10{sup −5} and 110.3 × 10{sup −5} for males and females, respectively. The cancer risk range to other individual organs was reduced to (0.003–68.5) × 10{sup −5}.Conclusions: The risk for cancer induction from radiation therapy for HO prophylaxis after total hip arthroplasty varies considerably by the

  9. Extracorporeal shock wave therapy for painful chronic neurogenic heterotopic ossification after traumatic brain injury: a case report.

    PubMed

    Choi, Yong Min; Hong, Seok Hyun; Lee, Chang Hyun; Kang, Jin Ho; Oh, Ju Sun

    2015-04-01

    Neurogenic heterotopic ossification (NHO) is a process of benign bone formation and growth in soft tissues surrounding major synovial joints and is associated with central nervous system (CNS) injuries. It is a common complication in major CNS injuries, such as traumatic brain injury, spinal cord injury, and stroke. Here, we report the case of a 72-year-old male, who experienced a traumatic brain injury and painful chronic NHO around the left hip joint. Three applications of extracorporeal shock wave therapy (ESWT) were administered to the area of NHO, which resulted in pain relief and an improvement in the loss of motion in the left hip joint. Improvements were also noted in walking performance and activities of daily living, although the size of NHO remained unchanged. Therapeutic effects of ESWT lasted for 12 weeks. PMID:25932431

  10. Double-level cervical total disc replacement for adjacent segment disease: is it a useful treatment? Description of late onset heterotopic ossification and review of the literature.

    PubMed

    Barbagallo, G M V; Certo, F; Visocchi, M; Sciacca, G; Albanese, V

    2014-01-01

    We report a rare case of double-level adjacent segment disease (ASD), occurring ten years later an anterior cervical discectomy (ACD) without fusion, treated by cervical arthroplasty, highlighting the outcome at long-term follow-up and focusing on heterotopic ossification. In 1995 a 25-year-old man satisfactorily underwent ACD at C4/C5. At that time MRI also showed signs of degenerative disc disease (DDD) at C3/C4 and C5/C6. Ten years later, a new MRI scan showed a large C3/C4 and a smaller C5/C6 soft disc hernia together with spondylotic changes at the level above and below the site of the first surgery. At C4/C5 imaging revealed a kyphotic stable "pseudoarthrosis" with anterior bridging osteophyte. The patient underwent double-level arthroplasty with ProDisc-C. Clinical and radiological outcome was satisfactory. 3 and 5 years after surgery, X-rays and CT scan documented the progressive development of heterotopic ossification, with gradual reduction of range of motion. A late onset heterotopic ossification can neutralize the theoretical advantages of cervical arthroplasty, which should be considered an effective surgical option only in selected cases. ACDF and restoration of normal lordosis can be a viable alternative in cervical revision surgery, as motion preservation can not be always mantained for a long time. PMID:24825036

  11. Chiropractic Care of a Patient With Neurogenic Heterotopic Ossification of the Anterior Longitudinal Ligament After Traumatic Brain Injury: A Case Report

    PubMed Central

    Morgan, William E.; Morgan, Clare P.

    2014-01-01

    Objective The purpose of this case report is to describe the use of chiropractic care for a patient with neurogenic heterotopic ossification of the anterior longitudinal ligament in the cervical spine and soft tissues of the right hip after a traumatic brain injury and right femur fracture. Clinical Features A 25-year-old military officer was referred to a hospital-based chiropractic clinic with complaints of pain and stiffness of the neck and back along with reduced respiratory excursions that began several months after a motor vehicle accident in which he had a traumatic brain injury. The patient had a fractured right femur from the accident, which had since been treated surgically, but had complications of heterotopic ossification in the soft tissues of the hip. His overall pain level was 3 of 10 on a verbal pain scale during use of oxycodone HCL/acetaminophen. Chest excursion was initially measured at .5 cm. Intervention and Outcome With the intent to restore respiratory chest motion and to reduce the patient's back and neck pain, the patient was placed on a program of chiropractic and myofascial manipulation, exercise therapy, and respiratory therapy. After a year of care, the patient rated overall pain at 3 of 10 verbal pain scale level but was no longer taking medications for pain and an increase in respiratory chest excursions measured at 3.5 cm. Conclusion This case demonstrated that chiropractic treatment provided benefit to a patient with heterotopic ossification concurrent with musculoskeletal pain. PMID:25435839

  12. Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis.

    PubMed

    Suzuki, Hidetsugu; Ito, Yoshiaki; Shinohara, Masahiro; Yamashita, Satoshi; Ichinose, Shizuko; Kishida, Akio; Oyaizu, Takuya; Kayama, Tomohiro; Nakamichi, Ryo; Koda, Naoki; Yagishita, Kazuyoshi; Lotz, Martin K; Okawa, Atsushi; Asahara, Hiroshi

    2016-07-12

    Cell-based or pharmacological approaches for promoting tendon repair are currently not available because the molecular mechanisms of tendon development and healing are not well understood. Although analysis of knockout mice provides many critical insights, small animals such as mice have some limitations. In particular, precise physiological examination for mechanical load and the ability to obtain a sufficient number of primary tendon cells for molecular biology studies are challenging using mice. Here, we generated Mohawk (Mkx)(-/-) rats by using CRISPR/Cas9, which showed not only systemic hypoplasia of tendons similar to Mkx(-/-) mice, but also earlier heterotopic ossification of the Achilles tendon compared with Mkx(-/-) mice. Analysis of tendon-derived cells (TDCs) revealed that Mkx deficiency accelerated chondrogenic and osteogenic differentiation, whereas Mkx overexpression suppressed chondrogenic, osteogenic, and adipogenic differentiation. Furthermore, mechanical stretch stimulation of Mkx(-/-) TDCs led to chondrogenic differentiation, whereas the same stimulation in Mkx(+/+) TDCs led to formation of tenocytes. ChIP-seq of Mkx overexpressing TDCs revealed significant peaks in tenogenic-related genes, such as collagen type (Col)1a1 and Col3a1, and chondrogenic differentiation-related genes, such as SRY-box (Sox)5, Sox6, and Sox9 Our results demonstrate that Mkx has a dual role, including accelerating tendon differentiation and preventing chondrogenic/osteogenic differentiation. This molecular network of Mkx provides a basis for tendon physiology and tissue engineering. PMID:27370800

  13. Shielding of the Hip Prosthesis During Radiation Therapy for Heterotopic Ossification is Associated with Increased Failure of Prophylaxis

    SciTech Connect

    Balboni, Tracy A.; Gaccione, Peter; Gobezie, Reuben; Mamon, Harvey J. . E-mail: hmamon@partners.org

    2007-04-01

    Purpose: Radiation therapy (RT) is frequently administered to prevent heterotopic ossification (HO) after total hip arthroplasty (THA). The purpose of this study was to determine if there is an increased risk of HO after RT prophylaxis with shielding of the THA components. Methods and Materials: This is a retrospective analysis of THA patients undergoing RT prophylaxis of HO at Brigham and Women's Hospital between June 1994 and February 2004. Univariate and multivariate logistic regressions were used to assess the relationships of all variables to failure of RT prophylaxis. Results: A total of 137 patients were identified and 84 were eligible for analysis (61%). The median RT dose was 750 cGy in one fraction, and the median follow-up was 24 months. Eight of 40 unshielded patients (20%) developed any progression of HO compared with 21 of 44 shielded patients (48%) (p = 0.009). Brooker Grade III-IV HO developed in 5% of unshielded and 18% of shielded patients (p 0.08). Multivariate analysis revealed shielding (p = 0.02) and THA for prosthesis infection (p = 0.03) to be significant predictors of RT failure, with a trend toward an increasing risk of HO progression with age (p = 0.07). There was no significant difference in the prosthesis failure rates between shielded and unshielded patients. Conclusions: A significantly increased risk of failure of RT prophylaxis for HO was noted in those receiving shielding of the hip prosthesis. Shielding did not appear to reduce the risk of prosthesis failure.

  14. A Prolonged Time Interval Between Trauma and Prophylactic Radiation Therapy Significantly Increases the Risk of Heterotopic Ossification

    SciTech Connect

    Mourad, Waleed F.; Packianathan, Satyaseelan; Shourbaji, Rania A.; Zhang Zhen; Graves, Mathew; Khan, Majid A.; Baird, Michael C.; Russell, George; Vijayakumar, Srinivasan

    2012-03-01

    Purpose: To ascertain whether the time from injury to prophylactic radiation therapy (RT) influences the rate of heterotopic ossification (HO) after operative treatment of displaced acetabular fractures. Methods and Materials: This is a single-institution, retrospective analysis of patients referred for RT for the prevention of HO. Between January 2000 and January 2009, 585 patients with displaced acetabular fractures were treated surgically followed by RT for HO prevention. We analyzed the effect of time from injury on prevention of HO by RT. In all patients, 700 cGy was prescribed in a single fraction and delivered within 72 hours postsurgery. The patients were stratified into five groups according to time interval (in days) from the date of their accident to the date of RT: Groups A {<=}3, B {<=}7, C {<=}14, D {<=}21, and E >21days. Results: Of the 585 patients with displaced acetabular fractures treated with RT, (18%) 106 patients developed HO within the irradiated field. The risk of HO after RT increased from 10% for RT delivered {<=}3 days to 92% for treatment delivered >21 days after the initial injury. Wilcoxon test showed a significant correlation between the risk of HO and the length of time from injury to RT (p < 0.0001). Chi-square test and multiple logistic regression analysis showed no significant association between all other factors and the risk of HO (race, gender, cause and type of fracture, surgical approach, or the use of indomethacin). Conclusions: Our data suggest that there is higher incidence and risk of HO if prophylactic RT is significantly delayed after a displaced acetabular fracture. Thus, RT should be administered as early as clinically possible after the trauma. Patients undergoing RT >3 weeks from their displaced acetabular fracture should be informed of the higher risk (>90%) of developing HO despite prophylaxis.

  15. Sustained delivery of rhBMP-2 via PLGA microspheres: cranial bone regeneration without heterotopic ossification or craniosynostosis

    PubMed Central

    Wink, Jason D.; Gerety, Patrick A.; Sherif, Rami D.; Lim, Youngshin; A.Clarke, Nadya; Rajapakse, Chamith S.; Nah, Hyun-Duck; Taylor, Jesse A.

    2014-01-01

    Background Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. In this study, we utilize rhBMP2 encapsulated in PLGA microspheres (PLGA-rhBMP2) placed in a rabbit cranial defect model to test whether low-dose, sustained, delivery can effectively induce bone regeneration. Methods rhBMP2 was encapsulated in 15% poly (lactic-co-glycolic acid), using a double emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10mm) were created in the calvarium of New Zealand White rabbits (5-7 mos of age, M/F) and filled with a collagen scaffold containing one of four groups: 1) no implant, 2) collagen scaffold only, 3) PLGA-rhBMP2(0.1ug/implant), or 4) free rhBMP2 (0.1ug/implant). After 6 weeks, the rabbits were sacrificed and defects were analyzed by μCT, histology, and finite element analysis. Results RhBMP2 delivered via bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by μCT and histology (p=0.025, 0.025). FEA indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p=0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation. Conclusions Sustained delivery via PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reduce the risk for recently reported rhBMP2 related adverse effects. Level of Evidence Animal Study PMID:24622573

  16. Neuromuscular electrical stimulation and testosterone did not influence heterotopic ossification size after spinal cord injury: A case series.

    PubMed

    Moore, Pamela D; Gorgey, Ashraf S; Wade, Rodney C; Khalil, Refka E; Lavis, Timothy D; Khan, Rehan; Adler, Robert A

    2016-07-16

    Neuromuscular electrical stimulation (NMES) and testosterone replacement therapy (TRT) are effective rehabilitation strategies to attenuate muscle atrophy and evoke hypertrophy in persons with spinal cord injury (SCI). However both interventions might increase heterotopic ossification (HO) size in SCI patients. We present the results of two men with chronic traumatic motor complete SCI who also had pre-existing HO and participated in a study investigating the effects of TRT or TRT plus NMES resistance training (RT) on body composition. The 49-year-old male, Subject A, has unilateral HO in his right thigh. The 31-year-old male, Subject B, has bilateral HO in both thighs. Both participants wore transdermal testosterone patches (4-6 mg/d) daily for 16 wk. Subject A also underwent progressive NMES-RT twice weekly for 16 wk. Magnetic resonance imaging scans were acquired prior to and post intervention. Cross-sectional areas (CSA) of the whole thigh and knee extensor skeletal muscles, femoral bone, and HO were measured. In Subject A (NMES-RT + TRT), the whole thigh skeletal muscle CSA increased by 10%, the knee extensor CSA increased by 17%, and the HO + femoral bone CSA did not change. In Subject B (TRT), the whole thigh skeletal muscle CSA increased by 13% in the right thigh and 6% in the left thigh. The knee extensor CSA increased by 7% in the right thigh and did not change in the left thigh. The femoral bone and HO CSAs in both thighs did not change. Both the TRT and NMES-RT + TRT protocols evoked muscle hypertrophy without stimulating the growth of pre-existing HO. PMID:27458592

  17. Determining early markers of disease using Raman spectroscopy in a rat combat-trauma model of heterotopic ossification

    NASA Astrophysics Data System (ADS)

    Cilwa, Katherine E.; Qureshi, Ammar T.; Forsberg, Jonathan A.; Davis, Thomas A.; Crane, Nicole J.

    2016-02-01

    Traumatic heterotopic ossification (HO) is the pathological formation of bone in soft tissue and is a debilitating sequela following acute trauma involving blast-related extremity musculoskeletal injuries, severe burns, spinal cord injury, and traumatic brain injury. Over 60% of combat related injuries and severe burns develop HO; often resulting in reduced mobility, chronic pain, ulceration, tissue entrapment, and reduced ambulation. Detection and prognosis is limited by current clinical imaging modalities (computed tomography, radiography, and ultrasound). This study identifies Raman spectral signatures corresponding to histological changes in a combat-trauma induced rat HO model at early time points prior to radiographic evidence of HO. HO was induced in Sprague-Dawley rats via blast over pressure injury, mid-femoral fracture, soft tissue crush injury, and limb amputation through the zone of injury. Rats were euthanized, and amputated limbs were formalin fixed and embedded in paraffin; 10 μm sections were placed on gold slides, and paraffin was chemically removed. Tissues from sham-treated animals served as controls. Tissue maps consisting of Raman spectra were generated using a Raman microprobe system with an 80-90 μm spot size and 785 nm excitation in regions exhibiting histological evidence of early HO development according to adjacent HE sections. Factors were extracted from mapping data using Band-Target Entropy Minimization algorithms. Areas of early HO were highlighted by a Raman factor indicative of the presence of collagen. Identification of collagen as an early marker of HO prior to radiographic detection in a clinically relevant animal model serves to inform future clinical work.

  18. Neuromuscular electrical stimulation and testosterone did not influence heterotopic ossification size after spinal cord injury: A case series

    PubMed Central

    Moore, Pamela D; Gorgey, Ashraf S; Wade, Rodney C; Khalil, Refka E; Lavis, Timothy D; Khan, Rehan; Adler, Robert A

    2016-01-01

    Neuromuscular electrical stimulation (NMES) and testosterone replacement therapy (TRT) are effective rehabilitation strategies to attenuate muscle atrophy and evoke hypertrophy in persons with spinal cord injury (SCI). However both interventions might increase heterotopic ossification (HO) size in SCI patients. We present the results of two men with chronic traumatic motor complete SCI who also had pre-existing HO and participated in a study investigating the effects of TRT or TRT plus NMES resistance training (RT) on body composition. The 49-year-old male, Subject A, has unilateral HO in his right thigh. The 31-year-old male, Subject B, has bilateral HO in both thighs. Both participants wore transdermal testosterone patches (4-6 mg/d) daily for 16 wk. Subject A also underwent progressive NMES-RT twice weekly for 16 wk. Magnetic resonance imaging scans were acquired prior to and post intervention. Cross-sectional areas (CSA) of the whole thigh and knee extensor skeletal muscles, femoral bone, and HO were measured. In Subject A (NMES-RT + TRT), the whole thigh skeletal muscle CSA increased by 10%, the knee extensor CSA increased by 17%, and the HO + femoral bone CSA did not change. In Subject B (TRT), the whole thigh skeletal muscle CSA increased by 13% in the right thigh and 6% in the left thigh. The knee extensor CSA increased by 7% in the right thigh and did not change in the left thigh. The femoral bone and HO CSAs in both thighs did not change. Both the TRT and NMES-RT + TRT protocols evoked muscle hypertrophy without stimulating the growth of pre-existing HO. PMID:27458592

  19. Clinical results and development of heterotopic ossification in total cervical disc replacement during a 4-year follow-up

    PubMed Central

    Suchomel, Petr; Jurák, Lubomír; Brabec, Radim; Bradáč, Ondřej; Elgawhary, Shamel

    2009-01-01

    Cervical total disc replacement (CTDR) aims to decrease the incidence of adjacent segment disease through motion preservation in the operated disc space. Ongoing data collection and increasing number of studies describing heterotopic ossification (HO) resulting in decreased mobility of implants, forced us to carefully evaluate our long-term clinical and morphological results of patients with CTDR. We present the first 54 consecutive patients treated with 65 ProdiscC™ prostheses during a 12-month period (2/2004–3/2005). All patients signed an informed consent and were included in prospective long-term study approved by hospital ethical committee. The 1- and 2-year follow-up analysis were available for all patients included and 4-year results for 50 patients (60 implants). Clinical (neck disability index-NDI, visual analog scale-VAS) and radiological follow-up was conducted at 1-, 2- and 4-years after the procedure. The Mehren/Suchomel modification of McAfee scale was used to classify the appearance of HO. Mean preoperative NDI was 34.5%, VAS for neck pain intensity 4.6 and VAS for arm pain intensity 5.0. At 1-, 2- and 4-year follow-up, the mean NDI was 30.7, 27.2, and 30.4, mean VAS for neck pain intensity 2.5, 2.1 and 2.9 and mean VAS for arm pain intensity pain 2.2, 1.9 and 2.3, respectively. Significant HO (grade III) was present in 45% of implants and segmental ankylosis (grade IV) in another 18% 4 years after intervention. This finding had no clinical consequences and 92% of patients would undergo the same surgery again. Our clinical results (NDI, VAS) are comparable with fusion techniques. Although, advanced non-fusion technology is used, a significant frequency of HO formation and spontaneous fusion in cervical disc replacement surgery must be anticipated during long-term follow-up. PMID:20035357

  20. Rational design of YAP WW1 domain-binding peptides to target TGFβ/BMP/Smad-YAP interaction in heterotopic ossification.

    PubMed

    Chen, Dong; Liu, Shenghe; Zhang, Wen; Sun, Luyuan

    2015-11-01

    The transforming growth factor-β/bone morphogenic protein/Smad signaling pathway has been raised as a new and promising therapeutic target of heterotopic ossification, which is mediated by recruitment of transcription coactivator Yes-associated protein (YAP) to Smad. Here, we described a successful integration of computational modeling and experimental assay to rationally design novel peptide aptamers to disrupt YAP-Smad interaction by targeting YAP WW1 domain. In the protocol, a computational genetic evolution strategy was used to improve a population of potential YAP WW1-binding peptides generated from the YAP-recognition site in Smad protein, from which several promising peptides were selected and their affinities toward YAP WW1 domain were determined using binding assay. In addition, a high-activity peptide was further optimized based on its complex structure with YAP WW1 domain to derive a number of derivative peptides with higher binding potency to the domain. We also found that a strong YAP WW1 binder should have a negatively charged N-terminus, a positively charged C-terminus and a nonpolar core to match the electrostatic distribution pattern in peptide-binding pocket of YAP WW1 domain, which may also form additional nonbonded interactions such as hydrogen bond, salt bridge and π-π stacking to confer stability and specificity for the domain-peptide recognition. PMID:26435515

  1. Differences between C3-4 and other subaxial levels of cervical disc arthroplasty: more heterotopic ossification at the 5-year follow-up.

    PubMed

    Chang, Peng-Yuan; Chang, Hsuan-Kan; Wu, Jau-Ching; Huang, Wen-Cheng; Fay, Li-Yu; Tu, Tsung-Hsi; Wu, Ching-Lan; Cheng, Henrich

    2016-05-01

    OBJECTIVE Several large-scale clinical trials demonstrate the efficacy of 1- and 2-level cervical disc arthroplasty (CDA) for degenerative disc disease (DDD) in the subaxial cervical spine, while other studies reveal that during physiological neck flexion, the C4-5 and C5-6 discs account for more motion than the C3-4 level, causing more DDD. This study aimed to compare the results of CDA at different levels. METHODS After a review of the medical records, 94 consecutive patients who underwent single-level CDA were divided into the C3-4 and non-C3-4 CDA groups (i.e., those including C4-5, C5-6, and C6-7). Clinical outcomes were measured using the visual analog scale for neck and arm pain and by the Japanese Orthopaedic Association scores. Postoperative range of motion (ROM) and heterotopic ossification (HO) were determined by radiography and CT, respectively. RESULTS Eighty-eight patients (93.6%; mean age 45.62 ± 10.91 years), including 41 (46.6%) female patients, underwent a mean follow-up of 4.90 ± 1.13 years. There were 11 patients in the C3-4 CDA group and 77 in the non-C3-4 CDA group. Both groups had significantly improved clinical outcomes at each time point after the surgery. The mean preoperative (7.75° vs 7.03°; p = 0.58) and postoperative (8.18° vs 8.45°; p = 0.59) ROMs were similar in both groups. The C3-4 CDA group had significantly greater prevalence (90.9% vs 58.44%; p = 0.02) and higher severity grades (2.27 ± 0.3 vs 0.97 ± 0.99; p = 0.0001) of HO. CONCLUSIONS Although CDA at C3-4 was infrequent, the improved clinical outcomes of CDA were similar at C3-4 to that in the other subaxial levels of the cervical spine at the approximately 5-year follow-ups. In this Asian population, who had a propensity to have ossification of the posterior longitudinal ligament, there was more HO formation in patients who received CDA at the C3-4 level than in other subaxial levels of the cervical spine. While the type of artificial discs could have confounded the

  2. Targeted stimulation of retinoic acid receptor-γ mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model.

    PubMed

    Pavey, Gabriel J; Qureshi, Ammar T; Tomasino, Allison M; Honnold, Cary L; Bishop, Danett K; Agarwal, Shailesh; Loder, Shawn; Levi, Benjamin; Pacifici, Maurizio; Iwamoto, Masahiro; Potter, Benjamin K; Davis, Thomas A; Forsberg, Jonathan A

    2016-09-01

    Heterotopic ossification (HO) involves formation of endochondral bone at non-skeletal sites, is prevalent in severely wounded service members, and causes significant complications and delayed rehabilitation. As common prophylactic treatments such as anti-inflammatory drugs and irradiation cannot be used after multi-system combat trauma, there is an urgent need for new remedies. Previously, we showed that the retinoic acid receptor γ agonist Palovarotene inhibited subcutaneous and intramuscular HO in mice, but those models do not mimic complex combat injury. Thus, we tested Palovarotene in our validated rat trauma-induced HO model that involves blast-related limb injury, femoral fracture, quadriceps crush injury, amputation and infection with methicillin-resistant Staphylococcus aureus from combat wound infections. Palovarotene was given orally for 14days at 1mg/kg/day starting on post-operative day (POD) 1 or POD-5, and HO amount, wound dehiscence and related processes were monitored for up to 84days post injury. Compared to vehicle-control animals, Palovarotene significantly decreased HO by 50 to 60% regardless of when the treatment started and if infection was present. Histological analyses showed that Palovarotene reduced ectopic chondrogenesis, osteogenesis and angiogenesis forming at the injury site over time, while fibrotic tissue was often present in place of ectopic bone. Custom gene array data verified that while expression of key chondrogenic and osteogenic genes was decreased within soft tissues of residual limb in Palovarotene-treated rats, expression of cartilage catabolic genes was increased, including matrix metalloproteinase-9. Importantly, Palovarotene seemed to exert moderate inhibitory effects on wound healing, raising potential safety concerns related to dosing and timing. Our data show for the first time that Palovarotene significantly inhibits HO triggered by blast injury and associated complications, strongly indicating that it may prevent

  3. Peripheral organ doses from radiotherapy for heterotopic ossification of non-hip joints: is there a risk for radiation-induced malignancies?

    PubMed

    Berris, Theocharis; Mazonakis, Michalis; Kachris, Stefanos; Damilakis, John

    2014-05-01

    Radiotherapy, used for heterotopic ossification (HO) management, may increase radiation risk to patients. This study aimed to determine the peripheral dose to radiosensitive organs and the associated cancer risks due to radiotherapy of HO in common non-hip joints. A Monte Carlo model of a medical linear accelerator combined with a mathematical phantom representing an average adult patient were employed to simulate radiotherapy for HO with standard AP and PA fields in the regions of shoulder, elbow and knee. Radiation dose to all out-of-field radiosensitive organs defined by the International Commission on Radiological Protection was calculated. Cancer induction risk was estimated using organ-specific risk coefficients. Organ dose change with increased field dimensions was also evaluated. Radiation therapy for HO with a 7 Gy target dose in the sites of shoulder, elbow and knee, resulted in the following equivalent organ dose ranges of 0.85-62 mSv, 0.28-1.6 mSv and 0.04-1.6 mSv, respectively. Respective ranges for cancer risk were 0-5.1, 0-0.6 and 0-1.3 cases per 10(4) persons. Increasing the field size caused an average increase of peripheral doses by 15-20%. Individual organ dose increase depends upon the primary treatment site and the distance between organ of interest and treatment volume. Relatively increased risks of more than 1 case per 10,000 patients were found for skin, breast and thyroid malignancies after treatment in the region of shoulder and for skin cancer following elbow irradiation. The estimated risk for inducing any other malignant disease ranges from negligible to low. PMID:24084192

  4. Effectiveness and mode of action of a combination therapy for heterotopic ossification with a retinoid agonist and an anti-inflammatory agent.

    PubMed

    Sinha, Sayantani; Uchibe, Kenta; Usami, Yu; Pacifici, Maurizio; Iwamoto, Masahiro

    2016-09-01

    Heterotopic ossification (HO) consists of ectopic cartilage and bone formation following severe trauma or invasive surgeries, and a genetic form of it characterizes patients with Fibrodysplasia Ossificans Progressiva (FOP). Recent mouse studies showed that HO was significantly inhibited by systemic treatment with a corticosteroid or the retinoic acid receptor γ agonist Palovarotene. Because these drugs act differently, the data raised intriguing questions including whether the drugs affected HO via similar means, whether a combination therapy would be more effective or whether the drugs may hamper each other's action. To tackle these questions, we used an effective HO mouse model involving subcutaneous implantation of Matrigel plus rhBMP2, and compared the effectiveness of prednisone, dexamathaosone, Palovarotene or combination of. Each corticosteroid and Palovarotene reduced bone formation at max doses, and a combination therapy elicited similar outcomes without obvious interference. While Palovarotene had effectively prevented the initial cartilaginous phase of HO, the steroids appeared to act more on the bony phase. In reporter assays, dexamethasone and Palovarotene induced transcriptional activity of their respective GRE or RARE constructs and did not interfere with each other's pathway. Interestingly, both drugs inhibited the activity of a reporter construct for the inflammatory mediator NF-κB, particularly in combination. In good agreement, immunohistochemical analyses showed that both drugs markedly reduced the number of mast cells and macrophages near and within the ectopic Matrigel mass and reduced also the number of progenitor cells. In sum, corticosteroids and Palovarotene appear to block HO via common and distinct mechanisms. Most importantly, they directly or indirectly inhibit the recruitment of immune and inflammatory cells present at the affected site, thus alleviating the effects of key HO instigators. PMID:26891836

  5. True heterotopic bone in the paralyzed patient

    SciTech Connect

    Blane, C.E.; Perkash, I.

    1981-10-01

    In past years the clinical and radiologic presentation of true heterotopic bone in the paralyzed patient has been confused with osteomyelitis, neoplasm, trauma, and thrombophlebitis. We reviewed 376 paralyzed patients' roentgenographic files and found 78 patients with soft tissue ossification unassociated with infection, neoplasm, or underlying fractures, which we called true heterotopic bone. From this population the usual spectrum of radiologic findings is described, so that the radiologist may separate roentgenographically a group of patients from other types of ectopic ossification.

  6. Heterotopic endochondrial ossification with mixed tumor formation in C3(1)/Tag transgenic mice is associated with elevated TGF-beta1 and BMP-2 expression.

    PubMed

    Maroulakou, I G; Shibata, M A; Anver, M; Jorcyk, C L; Liu, M l; Roche, N; Roberts, A B; Tsarfaty, I; Reseau, J; Ward, J; Green, J E

    1999-09-23

    Transgenic mice which express the simian virus 40 large T-antigen (Tag) under the regulatory control of the hormone responsive rat C3(1) gene develop unusual lesions of heterotopic bone growth associated with mixed tumor formation arising from eccrine sweat glands found only in the foot pads of mice, ischiocavernosus muscle adjacent to bulbourethral glands and occasionally the salivary and mammary glands. These lesions are very similar to mixed tumors arising in several types of human cancers. Based upon electron microscopic examination and immunocytochemical analyses of cellular differentiation markers, the mixed proliferative lesions in this transgenic mouse model begin with the Tag-induced proliferation of epithelial and myoepithelial cells. The proliferation of these two types of cells results in hyperplasia and adenomatous transformation of the epithelial component, whereas the proliferating myoepithelial cells undergo metaplasia to form chondrocytes which deposit extracellular matrix, including collagen fibers. Cartilage develops focally between areas of epithelial proliferation and subsequently ossifies through a process of endochondrial bone formation. The metaplasia of myoepithelial cells to chondrocytes appears to require the inductive interaction of factors produced by the closely associated proliferating epithelial cells, including members of the TGF-beta superfamily. We demonstrate that TGF-beta1 protein accumulates in the extracellular matrix of the lesions, whereas RNA in situ hybridization reveals that BMP-2, another strong inducer of heterotopic bone formation, is overexpressed by the proliferating epithelial cells during the development of ectopic bone. The formation of sarcomatous tumors within the mixed tumors appears to be androgen-dependent and more frequent in mice lacking a normal allele of p53. This process of cartilage and bone induction may mimic epithelial-mesenchymal interactions which occur during embryonic bone formation. These

  7. Heterotopic ossification following single-level anterior cervical discectomy and fusion: results from the prospective, multicenter, historically controlled trial comparing allograft to an optimized dose of rhBMP-2.

    PubMed

    Arnold, Paul M; Anderson, Karen K; Selim, Abdulhafez; Dryer, Randall F; Kenneth Burkus, J

    2016-09-01

    OBJECTIVE Heterotopic ossification (HO) has been reported following total hip, knee, cervical, and lumbar arthroplasty, as well as following posterolateral lumbar fusion using recombinant human bone morphogenetic protein-2 (rhBMP-2). Data regarding HO following anterior cervical discectomy and fusion (ACDF) with rhBMP-2 are sparse. A subanalysis was done of the prospective, multicenter, investigational device exemption trial that compared rhBMP-2 on an absorbable collagen sponge (ACS) versus allograft in ACDF for patients with symptomatic single-level cervical degenerative disc disease. METHODS To assess differences in types of HO observed in the treatment groups and effects of HO on functional and efficacy outcomes, clinical outcomes from previous disc replacement studies were compared between patients who received rhBMP-2/ACS versus allograft. Rate, location, grade, and size of ossifications were assessed preoperatively and at 24 months, and correlated with clinical outcomes. RESULTS Heterotopic ossification was primarily anterior in both groups. Preoperatively in both groups, and including osteophytes in the target regions, HO rates were high at 40.9% and 36.9% for the rhBMP-2/ACS and allograft groups, respectively (p = 0.350). At 24 months, the rate of HO in the rhBMP-2/ACS group was higher than in the allograft group (78.6% vs 59.2%, respectively; p < 0.001). At 24 months, the rate of superior-anterior adjacent-level Park Grade 3 HO was 4.2% in both groups, whereas the rate of Park Grade 2 HO was 19.0% in the rhBMP-2/ACS group compared with 9.8% in the allograft group. At 24 months, the rate of inferior-anterior adjacent-level Park Grade 2/3 HO was 11.9% in the rhBMP-2/ACS group compared with 5.9% in the allograft group. At 24 months, HO rates at the target implant level were similar (p = 0.963). At 24 months, the mean length and anteroposterior diameter of HO were significantly greater in the rhBMP-2/ACS group compared with the allograft group (p = 0.033 and

  8. Genetic disorders with heterotopic ossificans.

    PubMed

    Sankar, Ruthiramurthy; Gowrishankar, Kalpana; Viswanathan, Saraswati

    2015-01-01

    Fibrodysplasia ossificans progressiva (FOP) and progressive ossific heteroplasia (POH) are rare genetic disorders characterized by heterotopic bone formation leading to progressive loss of mobility and function. We report three cases of these rare disorders (two cases of FOP and one case of POH), which were clinically diagnosed and underwent genetic analysis. The aim of this report is to highlight the clinical features and the differences between these two conditions. We would also like to emphasize on the morbidity that can arise from unnecessary invasive investigations for diagnostic purposes. PMID:26015640

  9. Genetic disorders with heterotopic ossificans

    PubMed Central

    Sankar, Ruthiramurthy; Gowrishankar, Kalpana; Viswanathan, Saraswati

    2015-01-01

    Fibrodysplasia ossificans progressiva (FOP) and progressive ossific heteroplasia (POH) are rare genetic disorders characterized by heterotopic bone formation leading to progressive loss of mobility and function. We report three cases of these rare disorders (two cases of FOP and one case of POH), which were clinically diagnosed and underwent genetic analysis. The aim of this report is to highlight the clinical features and the differences between these two conditions. We would also like to emphasize on the morbidity that can arise from unnecessary invasive investigations for diagnostic purposes. PMID:26015640

  10. Dendriform pulmonary ossification in a patient with mucoepidermoid carcinoma.

    PubMed

    Triki, Meriam; Kallel, Rim; Hentati, Abdessalem; Hentati, Yosr; Mnif, Hela; Boudawara, Tahya

    2016-07-01

    Dendriform pulmonary ossification is a chronic process characterized by the presence of heterotopic bone within the interstitium and alveolar walls. It usually occurs in the setting of chronic inflammation. We report an unusual case of a 54-year-old man with a history of relapsing Hodgkin lymphoma who was diagnosed with concomitant mucoepidermoid pulmonary carcinoma and dendriform ossifications. The radiological features were initially misinterpreted as post-radiation pulmonary fibrosis and bronchiectasis. The diagnosis was finally established after considering both the radiological and pathological findings. Dendriform pulmonary ossification is an under-recognized disease that should be considered in the differential diagnosis of lung chronic diseases. PMID:27252231

  11. Radiation-blocking shields to localize periarticular radiation precisely for prevention of heterotopic bone formation around uncemented total hip arthroplasties

    SciTech Connect

    Jasty, M.; Schutzer, S.; Tepper, J.; Willett, C.; Stracher, M.A.; Harris, W.H. )

    1990-08-01

    Sixteen patients (18 hips) were treated with localized radiation therapy limited to periarticular regions surrounding the femoral neck by shielding the prosthesis and the adjacent regions to prevent heterotopic bone formation around the uncemented prosthesis. All hips received 1500 rads. Eight of these hips were irradiated after excising severe heterotopic bone, five because they developed extensive heterotopic ossification in the opposite hip, and five others because they were considered to be at high risk for developing heterotopic ossification. Only two of the 18 hips developed a small amount of heterotopic bone after localized periarticular radiation. All wounds healed primarily. No progressive radiolucencies developed at the bone-prosthesis interface. There was only one trochanteric nonunion of six trochanteric osteotomies. Localized periarticular radiation therapy with precision shielding of the prosthetic components and adjacent skeletal structures is an effective means to prevent heterotopic bone formation around cementless total hip arthroplasties. It also has the advantage of not adversely affecting the healing of the trochanteric osteotomy.

  12. Hypoxic adipocytes pattern early heterotopic bone formation.

    PubMed

    Olmsted-Davis, Elizabeth; Gannon, Francis H; Ozen, Mustafa; Ittmann, Michael M; Gugala, Zbigniew; Hipp, John A; Moran, Kevin M; Fouletier-Dilling, Christine M; Schumara-Martin, Shannon; Lindsey, Ronald W; Heggeness, Michael H; Brenner, Malcolm K; Davis, Alan R

    2007-02-01

    The factors contributing to heterotopic ossification, the formation of bone in abnormal soft-tissue locations, are beginning to emerge, but little is known about microenvironmental conditions promoting this often devastating disease. Using a murine model in which endochondral bone formation is triggered in muscle by bone morphogenetic protein 2 (BMP2), we studied changes near the site of injection of BMP2-expressing cells. As early as 24 hours later, brown adipocytes began accumulating in the lesional area. These cells stained positively for pimonidazole and therefore generated hypoxic stress within the target tissue, a prerequisite for the differentiation of stem cells to chondrocytes and subsequent heterotopic bone formation. We propose that aberrant expression of BMPs in soft tissue stimulates production of brown adipocytes, which drive the early steps of heterotopic endochondral ossification by lowering oxygen tension in adjacent tissue, creating the correct environment for chondrogenesis. Results in misty gray lean mutant mice not producing brown fat suggest that white adipocytes convert into fat-oxidizing cells when brown adipocytes are unavailable, providing a compensatory mechanism for generation of a hypoxic microenvironment. Manipulation of the transcriptional control of adipocyte fate in local soft-tissue environments may offer a means to prevent or treat development of bone in extraskeletal sites. PMID:17255330

  13. Severe soft tissue ossification in a southern right whale Eubalaena australis

    PubMed Central

    Sala, Luciano F. La; Pozzi, Luciana M.; McAloose, Denise; Kaplan, Frederick S.; Shore, Eileen M.; Kompanje, Erwin J. O.; Sidor, Inga F.; Musmeci, Luciana; Uhart, Marcela M.

    2013-01-01

    The carcass of a stranded southern right whale Eubalaena australis, discovered on the coast of Golfo Nuevo in Península Valdés, Argentina, exhibited extensive orthotopic and heterotopic ossification, osteochondroma-like lesions, and early degenerative joint disease. Extensive soft tissue ossification led to ankylosis of the axial skeleton in a pattern that, in many respects, appeared more similar to a disabling human genetic disorder, fibrodysplasia ossificans progressiva (FOP), than to more common skeletal system diseases in cetaceans and other species. This is the first reported case of a FOP-like condition in a marine mammal and raises important questions about conserved mechanisms of orthotopic and heterotopic ossification in this clade. PMID:23269389

  14. Soft tissue ossification and condylar cartilage degeneration following TMJ disc perforation in a rabbit pilot study

    PubMed Central

    Embree, Mildred C.; Iwaoka, George M.; Kong, Danielle; Martin, Brittany N.; Patel, Ryan K.; Lee, Andrew; Nathan, John M.; Eisig, Sidney B.; Safarov, Aram; Koslovsky, David A; Koch, Alia; Romanov, Alex; Mao, Jeremy J

    2015-01-01

    Objective There are limited clinical treatments for temporomandibular joint pathologies, including degenerative disease, disc perforation and heterotopic ossification. One barrier hindering the development of new therapies is that animal models recapitulating TMJ diseases are poorly established. The objective of this study was to develop an animal model for TMJ cartilage degeneration and disc pathology, including disc perforation and soft tissue heterotopic ossification. Methods New Zealand white rabbits (n=9 rabbits) underwent unilateral TMJ disc perforation surgery and sham surgery on the contralateral side. A 2.5 mm defect was created using a punch biopsy in rabbit TMJ disc. The TMJ condyles and discs were evaluated macroscopically and histologically after 4, 8 and 12 weeks. Condyles were blindly scored by 4 independent observers using OARSI recommendations for macroscopic and histopathological scoring of osteoarthritis in rabbit tissues. Results Histological evidence of TMJ condylar cartilage degeneration was apparent in experimental condyles following disc perforation relative to sham controls after 4 and 8 weeks, including surface fissures and loss of Safranin O staining. At 12 weeks, OARSI scores indicated experimental condylar cartilage erosion into the subchondral bone. Most strikingly, heterotopic ossification occurred within the TMJ disc upon perforation injury in 6 rabbits after 8 and 12 weeks. Conclusion We report for the first time a rabbit TMJ injury model that demonstrates condylar cartilage degeneration and disc ossification, which is indispensible for testing the efficacy of potential TMJ therapies. PMID:25573797

  15. Ossification of a rectal tumor: an uncommon finding.

    PubMed

    Smajda, Stanislas; Danse, Etienne; Mertens de Wilmars, Maud; Humblet, Yves; Kartheuser, Alex; Jouret-Mourin, Anne

    2015-12-01

    The authors report the case of a 29-year-old woman with partially calcified stage cT4N2M0 mucoid adenocarcinoma of the mid-rectum. Concomitant neoadjuvant chemoradiotherapy was administered. Preoperative CT scan and MRI demonstrated stable disease with a marked increase of its mineralized component. Histology confirmed a mucoid adenocarcinoma with ossified matrix. Osteocytes were identified in the tumor. TNM (5th edition) staging was ypT3N2M1. This case illustrates heterotopic ossification of a rectal tumor, a fairly uncommon finding. The mechanism of heterotopic bone formation within gastrointestinal adenocarcinoma has not been fully elucidated. The impact of this particular feature on patient outcome is unknown. PMID:26712056

  16. Usefulness of postoperative hip irradiation in the prevention of heterotopic bone formation in a high risk group of patients

    SciTech Connect

    MacLennan, I.; Keys, H.M.; Evarts, C.M.; Rubin, P.

    1984-01-01

    Heterotopic ossification is a complication of total hip arthroplasty in 14 to 30% of patients. Significant functional impairment will occur in up to 28% of patients with ectopic bone. The high risk group includes those with preexisting heterotopic bone in either hip, those suffering from hypertrophic osteoarthritis or ankylosing spondylitis and patients who have had multiple procedures on the hip. Fifty-eight patients (67 hips) were irradiated after surgical removal of ectopic bone (53 hips) or received radiation prophylaxis of heterotopic ossification (14 hips). Ninety-five percent of patients had either no bone visible or insignificant amounts of ectopic bone visible on postoperative hip X-rays. Only 5% of patients showed significant persistence of ectopic bone. Postoperative hip function was dramatically improved compared to preoperative function in all patients treated. The importance of early commencement of irradiation is emphasized.

  17. [Diffuse Pulmonary Ossification].

    PubMed

    Avsar, K; Behr, J; Morresi-Hauf, A

    2016-04-01

    Diffuse pulmonary ossification (DPO) represents an uncommon condition usually associated with different underlying pulmonary and extrapulmonary diseases. In this work, we discuss eleven patients of our clinic with the diagnosis of a diffuse pulmonary ossification. We focus on histological changes in the surrounding lung tissue. Clinical and radiological findings were analysed. The aim of the study is to collect data for a better understanding of this condition, especially in association with interstitial lung disease.Three patients with interstitial lung disease had histological findings of UIP. The follow-up data of these patients showed a benign course of the disease.The analysis of the clinical data yielded a very heterogenous group. Regarding these fact we assume, that DPO is not an own entity, but a pathological epiphenomenon in the context of different conditions, possibly with pathogenetic overlap. PMID:26829606

  18. Ossification of thoracic ligamenta flava

    SciTech Connect

    Kudo, S.; Minoru, O.; Russell, W.J.

    1983-07-01

    Although ligamentum flavum ossification (LFO) often occurs in normal persons, there are no reports of its detection on lateral chest radiographs made during screening examinations. Review of 1,744 consecutive lateral chest radiographs identified LFO in 6.2% of males and 4.8% of females. LFO occurred mainly at the intervertebral segments from T9-T10 through T12-L1. Most prevalent was the hook-shaped LFO, protruding inferoirly from the inferior facets into the projections of the intervertabral foramina. Though LFO can cause severe neurologic symptoms, none of the affected persons in this study reported such symptoms. LFO was first visualized radiographically when the subjects were 20-40 years old, and it may be a physiologic condition. The LFO in these cases existed independent of thoracic posterior longitudinal ligament ossification, diffuse idiopathic skeletal hyperostosis, and degenerative osteoarthritis.

  19. Heterotopic pregnancy after a single embryo transfer

    PubMed Central

    Lee, Ji Sun; Cha, Hyun-Hwa; Han, Ae Ra; Lee, Seong Goo

    2016-01-01

    Heterotopic pregnancy is a rare and life-threatening condition which is defined as coexistent intrauterine and ectopic gestation. The risk of ectopic and heterotopic pregnancy is increasing due to the increased risk of multiple pregnancies with the aid of assisted reproductive technologies. However, it hardly happens in the setting of single embryo transfer, since single embryo transfer significantly reduces the incidence of multiple pregnancies. Surprisingly, we experienced a case of heterotopic pregnancy after a single embryo transfer caused by coincidental natural pregnancy during assisted reproductive technologies. An infertile woman who underwent, during her natural cycle, transfer of a single embryo that had been cryopreserved for 3 years was found to be heterotopically pregnant. After an early and successful management with laparoscopic right salpingectomy, she finally reached at full-term vaginal delivery. PMID:27462600

  20. [Ossification of the collagen implant].

    PubMed

    Walter, M; Müller, J M; Keller, H W; Brenner, U

    1985-12-01

    Native collagen type I was studied morphologically and fluorescent-histologically after implantation in bony defects. As criteria for revitalisation we used depth and density of immigration, type of immigrated cells, revascularisation, formation of new cartilage and bone. Furthermore the deposition of fluorochromes was studied. The maximum of cellular immigration was reached after 8 weeks and remained at this level for the period of observation. The implants were impregnated only with fibroblasts and fibrocytes, developing into chondroblasts, chondrocytes, osteoblasts and osteocytes. Only in one case basophilic round-cells could be seen. The centres of the implants were after 6 weeks rarely, after 8 weeks fully revascularized. Formation of new cartilage and bone could be seen after 6 weeks, increasing in number and extension during the observation-period. Osteoneogenesis was performed both by desmal and enchondral ossification, enchondral ossification much more in evidence. The deposition of fluorochromes could be seen in each implant. After 8 weeks fluorochromes could only be seen at the bone-implant interface, after 12 and 16 weeks even the centres were well impregnated. In a single case reossification in a control-rib could be seen as well morphologically as fluorescent-histologically. PMID:2868614

  1. The classification and treatment of heterotopic ossification about the elbow and forearm.

    PubMed

    Hastings, H; Graham, T J

    1994-08-01

    Successful treatment of HO about the forearm and elbow relies on a working understanding of the risk factors, the pathophysiology and pathoanatomy, and the potential role for reconstructive procedures. These elements must be combined with a certain degree of flexibility in the approach to patients with a wide range of individual needs. Class I HO should be managed primarily with close observation, serial radiographs, and appropriate physical therapy regimens. The temporal relationship between the insult and the appearance of HO may modify the approach. When HO is noted within the first 6 weeks, use of anti-inflammatory agents is recommended; if the patient has developed limiting ectopic bone in the past, consideration should be given to a single dose of radiotherapy. In the 6-week to 3-month period, therapy is conducted to maintain full motion and an anti-inflammatory agent continued or started. We have not observed initial HO appearance after the third month. Class IIA HO can involve the anterior or posterior aspects of the elbow joint, or both. These groups are further divided into those limited by soft tissue (muscle and capsular contracture) and those blocked by bone (coronoid extension, humeroradial, humeroulnar, blocked olecranon fossa). The anterior group limited by soft tissue is addressed by capsulotomy, releases, and lengthenings. This group requires careful neurolysis and protection of vascular structures. For anterior bony bridges, resection is combined with capsulotomy. The location of the forearm "insertion" site of the new bone dictates alternative procedures such as interposition or radial head resection. The condition of the joint is usually preserved in these cases, but arthroplasty must always be considered when injury has led to joint derangement. Posteriorly, limitations in motion are caused by a contracted scarred triceps, capsular contracture, or bony impingement and synostosis. Treatment requires posterior capsular release and triceps tenolysis. Bridging bone is excised, the olecranon partially excised, and the olecranon fossa reestablished. Attempts should be made to preserve the fat pad of the olecranon fossa, which can act as an effective interposition material. Although characterized by limited pronosupination, class IIB HO can be located in any of the six distinct anatomic sites previously outlined. Simple resection, with or without interposition, is useful for a majority of the HO that is coincident with the interosseous membrane, but the areas at the proximal and distal extent of the forearm may demand special procedures to restore motion.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7962148

  2. Regulation of endochondral ossification by transcription factors.

    PubMed

    Nishimura, Riko; Hata, Kenji; Ono, Koichiro; Amano, Katsuhiko; Takigawa, Yoko; Wakabayashi, Makoto; Takashima, Rikako; Yoneda, Toshiyuki

    2012-01-01

    Endochondral ossification is very unique and complex biological event which is associated with skeletal development and tissue partnering. Genetic studies and gene-targeting approaches identified several transcription factors that play important roles in endochondral ossification. These transcription factors sequentially and harmoniously regulate each step of endochondral ossification, and consequently maintain the spatio-temporal control of the program. Importantly, these transcription factors form large protein complex to control chromatin remodeling, histone modification, transcription and splicing steps during endochondral ossification. It is also important to understand how these transcription factors regulate expression of their target genes. Biochemical and molecular cloning techniques largely contributed to identification of the components of the transcriptional complex and the target genes. Most recently, importance of endoplasmic reticulum (ER) stress in endochondral ossification has been reported. A transcription factor, BBF2H7, functions as an ER stress sensor in chondrocytes through regulation of appropriate secretion of chondrogenic matrices. We would like to discuss how the transcription factors regulate endochondral ossification. PMID:22652803

  3. Spontaneous Heterotopic Triplet Pregnancy With Tubal Rupture

    PubMed Central

    Danso, Dennis

    2014-01-01

    The recent increase in heterotopic pregnancies has been largely attributed to the increased use of assisted reproduction technologies. We report the rare case of a multiparous woman with a spontaneous conception resulting in a triplet heterotopic pregnancy: a twin intrauterine pregnancy and a single right tubal ectopic pregnancy. Heterotopic pregnancy is a rare and potentially life-threatening condition in which simultaneous gestations occur at 2 or more implantation sites. It is infrequent in natural conception cycles, occurring in 1:30 000 pregnancies. However, the prevalence is rising with the increased use of assisted reproduction techniques to that of 1:100 to 1:500 in these patient subgroups, highlighting the need to incorporate it into a clinician’s diagnostic algorithm. PMID:26425603

  4. [Heterotopic pregnancy: value of transabdominal sonography].

    PubMed

    Ousehal, A; Mamouchi, H; Ghazli, M; Kadiri, R

    2001-07-01

    The authors report a case of an heterotopic pregnancy where the transabdominal US was more useful than endovaginal US. The embryon in this case was located in upper zone of the right iliac fossa, inaccessible to endovaginal US. Both methods are complementary. PMID:11507450

  5. Ossification of the discoid meniscus: A case report

    PubMed Central

    Duran, Semra; Çavuşoğlu, Mehtap; Kocadal, Onur

    2014-01-01

    Meniscal ossification, or bone formation within the substance of the meniscus, is a rare entity. Magnetic resonance imaging allows the unequivocal diagnosis of a meniscal ossification. We aimed to present a case of discoid meniscal ossification, which is quite rare, with the emphasis on imaging findings. PMID:25983511

  6. Falx Cerebri Ossification: CT and MRI Evaluation.

    PubMed

    Tsitouridis, I; Natsis, K; Goutsaridou, F; Tsitouridis, K; Tarazi, L; Chondromatidou, S; Papapostolou, P; Papastergiou, C; Emmanouilidou, M

    2006-11-30

    During the last three years, CT and MRI brain scans of 40 patients revealed falx cerebri partial ossification as an incidental finding. The patients had been admitted for brain CT and MRI for several reasons. In most cases, there was no problem in the differential diagnosis of falx cerebri ossification during interpretation of the cases. In a few cases, the lesion should be distinguished from calcified meningioma, small hematoma in the interhemispheric fissure and in one case there was also meningeal infiltration of breast cancer. In these cases both CT and MRI scans of the brain were evaluated and a definite diagnosis was made. PMID:24351265

  7. Early Gastric Cancer Just above a Heterotopic Pancreas

    PubMed Central

    Murabayashi, Toji; Kawaguchi, Shinya; Okuda, Naoko; Oyamada, Jun; Yabana, Tadashi

    2016-01-01

    We report the first case of early gastric cancer just above a heterotopic pancreas for which the differential diagnosis was carcinoma arising from heterotopic pancreas. Routine upper gastrointestinal endoscopy in an 83-year-old man with sigmoid colon cancer revealed a gastric cancer in the lesser curvature of the antrum. Endoscopic ultrasonography (EUS) for evaluating the depth of tumor invasion revealed a hypoechoic mass in the submucosal layer. The depth of tumor invasion was diagnosed as muscularis propria. Distal gastrectomy and sigmoidectomy were performed. Histologically, the resected specimen of the stomach unexpectedly revealed a heterotopic pancreas just below the gastric cancer. They were not linked, and the heterotopic pancreas had no dysplasia. The gastric cancer had slightly invaded the submucosa. The hypoechoic mass on EUS was not the invasive tumor but the heterotopic pancreas. The preoperative staging of the gastric cancer on EUS was confounded by the presence of the heterotopic pancreas just below the gastric cancer. PMID:27482189

  8. Ossification in the human calcaneus: a model for spatial bone development and ossification

    PubMed Central

    FRITSCH, HELGA; BRENNER, ERICH; DEBBAGE, PAUL

    2001-01-01

    Perichondral bone, the circumferential grooves of Ranvier and cartilage canals are features of endochondral bone development. Cartilage canals containing connective tissue and blood vessels are found in the epiphysis of long bones and in cartilaginous anlagen of small and irregular bones. The pattern of cartilage canals seems to be integral to bone development and ossification. The canals may be concerned with the nourishment of large masses of cartilage, but neither their role in the formation of ossification centres nor their interaction with the circumferential grooves of Ranvier has been established. The relationships between cartilage canals, perichondral bone and the ossification centre were studied in the calcaneus of 9 to 38-wk-old human fetuses, by use of epoxy resin embedding, three-dimensional computer reconstructions and immunhistochemistry on paraffin sections. We found that cartilage canals are regularly arranged in shells surrounding the ossification centre. Whereas most of the shell canals might be involved in the nourishment of the cartilage, the inner shell is directly connected with the perichondral ossification groove of Ranvier and with large vessels from outside. In this way the inner shell canal imports extracellular matrix, cells and vessels into the cartilage. With the so-called communicating canals it is also connected to the endochondral ossification centre to which it delivers extracellular matrix, cells and vessels. The communicating canals can be considered as inverted ‘internal’ ossification grooves. They seem to be responsible for both build up intramembranous osteoid and for the direction of growth and thereby for orientation of the ossication centre. PMID:11760892

  9. Unusual ganglioglioma with extensive calcification and ossification.

    PubMed

    Kavishwar, Vikas Shashikant; Chadha, Kirti G; Barodawala, Shaikhali Moiz; Murthy, Anuradha Krishna

    2016-01-01

    Ganglioglioma is a slow-growing relatively low-grade mixed glioneuronal tumor with most cases corresponding to the WHO Grade I category. It frequently presents with seizures. The temporal lobe is the most common location followed by frontal, parietal, and occipital lobes. These generally behave in a benign fashion and have a favorable prognosis. We describe a case of a 24-year-old male presenting with convulsions and a calcified parieto-occipital mass. This mass removed from the parietal lobe showed neoplastic glial and dysplastic neuronal tissue amidst extensive areas of calcification and foci of ossification. On immunohistochemistry, the glial component expressed glial fibrillary acidic protein whereas the dysplastic neuronal component expressed synaptophysin and CD34. Epithelial membrane antigen was negative and Ki-67 showed a low proliferative index. After the surgery, the patient is free of neurological symptoms. Widespread calcification and ossification are very unusual in ganglioglioma, which prompted us to report this case. PMID:27510688

  10. Uncommon Cause of Trigeminal Neuralgia: Tentorial Ossification over Trigeminal Notch

    PubMed Central

    Bang, Sun Woo; Han, Kyung Ream; Kim, Seung Ho; Jeong, Won Ho; Kim, Eun Jin; Choi, Jin Wook; Kim, Chan

    2015-01-01

    Ossification of the tentorium cerebelli over the trigeminal notch is rare, but it may cause compression of the trigeminal nerve, leading to trigeminal neuralgia (TN). We were unable to find any previously reported cases with radiological evaluation, although we did find one case with surgically proven ossification of the tentorium cerebelli. Here, we present a case of TN caused by tentorial ossification over the trigeminal notch depicted on magnetic resonance imaging (MRI) and computed tomography (CT). PMID:26380124

  11. Heterotopic pregnancy: a growing diagnostic challenge

    PubMed Central

    Ibrahim, Azza G; Badawi, Faiza; Tahlak, Muna

    2009-01-01

    This report describes a 26-year-old female who presented at 5 weeks of gestation with intrauterine pregnancy after gonadotrophin stimulation and intrauterine insemination. The patient complained of abdominal pain, abdominal distension and nausea diagnosed as moderate ovarian hyper-stimulation syndrome (OHSS) with early pregnancy and was treated accordingly. The patient was readmitted at 7 and 9 weeks of gestation with persistent left lower abdominal pain. At 9 weeks’ gestation she also had a low grade fever and since the pelvic ultrasound showed a left tubo-ovarian mass she was treated for pelvic infection. The follow-up ultrasounds in the 5th, 9th and 12th weeks showed a normal intrauterine pregnancy in addition to a persistent left adnexal mass without any suspicion of a heterotopic pregnancy. The diagnosis of heterotopic pregnancy became possible only at 13 weeks of gestation during laparotomy when the right fallopian tube showed a leaking ectopic pregnancy. A right-sided salpingostomy was carried out. The intrauterine pregnancy is still ongoing without complications. PMID:21686636

  12. Liposarcoma of the thigh with mixed calcification and ossification.

    PubMed

    Child, Jeremy R; Young, Colin R; Amini, Behrang

    2016-09-01

    Liposarcoma is one of the most common soft-tissue sarcomas. Calcification and ossification can occur in liposarcoma; however, the presence of both ossification and calcification is a very rare entity. We present a case of a partially calcified and ossified dedifferentiated liposarcoma of the thigh in a 76-year-old woman, which contained heterologous elements of chondrosarcoma and rhabdomyosarcoma. PMID:27594953

  13. Heterotopic Pancreas: A Rare Cause of Ileo-Ileal Intussusception

    PubMed Central

    Monier, Ahmed; Awad, Ahmed; Szmigielski, Wojciech; Muneer, Mohamed; Alrashid, Amal; Darweesh, Adham; Hassan, Heba

    2014-01-01

    Background Heterotopic pancreas is a rare developmental anomaly defined as pancreatic tissue found on ectopic sites without contiguity with the main pancreas. An isolated heterotopic pancreas as a cause of bowel intussusception is extremely rare. Case Report A case of 47-year old male with multiple episodes of melena, constipation and abdominal pain for one year duration is presented. CT eneterography revealed a large circumferential lesion involving the terminal ileum that acted as a leading point to an ileo-ileal intussusception. The resection of the lesion and related bowel segment was carried out. The histopathological examination confirmed the excised lesion as a heterotopic pancreatic tissue. Conclusions Though a rare entity, heterotopic pancreas should be considered in the differential diagnosis of bowel intussusception. PMID:25302087

  14. Spontaneous Heterotopic Pregnancy: Dual Case Report and Review of Literature

    PubMed Central

    Chadee, Annika; Kirby, Catherine; Chadwick, Ekaterina; Gottimukkala, Sri; Hamaoui, Abraham; Stankovich, Vasiliy; Hale, Theodore; Gilak, Hamid; Momtaz, Mohammad; Sasken, Harvey; Henderson, Cassandra E.

    2016-01-01

    Introduction. Heterotopic pregnancy is a rare complication usually seen in populations at risk for ectopic pregnancy or those undergoing fertility treatments. It is a potentially dangerous condition occurring in only 1 in 30,000 spontaneous pregnancies. With the advent of Assisted Reproduction Techniques (ART) and ovulation induction, the overall incidence of heterotopic pregnancy has risen to approximately 1 in 3,900 pregnancies. Other risk factors include a history of pelvic inflammatory disease (PID), tubal damage, pelvic surgery, uterine Mullerian abnormalities, and prior tubal surgery. Heterotopic pregnancy is a potentially fatal condition, rarely occurring in natural conception cycles. Most commonly, heterotopic pregnancy is diagnosed at the time of rupture when surgical management is required. Case. This paper represents two cases of heterotopic pregnancies as well as a literature review. Conclusion. Heterotopic pregnancy should be suspected in patients with an adnexal mass, even in the absence of risk factors. Clinicians must be alert to the fact that confirming an intrauterine pregnancy clinically or by ultrasound does not exclude the coexistence of an ectopic pregnancy. A high index of suspicion in women is needed for early and timely diagnosis, and management with laparotomy or laparoscopy can result in a favorable and successful obstetrical outcome. PMID:27413561

  15. Spontaneous Heterotopic Pregnancy: Dual Case Report and Review of Literature.

    PubMed

    Chadee, Annika; Rezai, Shadi; Kirby, Catherine; Chadwick, Ekaterina; Gottimukkala, Sri; Hamaoui, Abraham; Stankovich, Vasiliy; Hale, Theodore; Gilak, Hamid; Momtaz, Mohammad; Sasken, Harvey; Henderson, Cassandra E

    2016-01-01

    Introduction. Heterotopic pregnancy is a rare complication usually seen in populations at risk for ectopic pregnancy or those undergoing fertility treatments. It is a potentially dangerous condition occurring in only 1 in 30,000 spontaneous pregnancies. With the advent of Assisted Reproduction Techniques (ART) and ovulation induction, the overall incidence of heterotopic pregnancy has risen to approximately 1 in 3,900 pregnancies. Other risk factors include a history of pelvic inflammatory disease (PID), tubal damage, pelvic surgery, uterine Mullerian abnormalities, and prior tubal surgery. Heterotopic pregnancy is a potentially fatal condition, rarely occurring in natural conception cycles. Most commonly, heterotopic pregnancy is diagnosed at the time of rupture when surgical management is required. Case. This paper represents two cases of heterotopic pregnancies as well as a literature review. Conclusion. Heterotopic pregnancy should be suspected in patients with an adnexal mass, even in the absence of risk factors. Clinicians must be alert to the fact that confirming an intrauterine pregnancy clinically or by ultrasound does not exclude the coexistence of an ectopic pregnancy. A high index of suspicion in women is needed for early and timely diagnosis, and management with laparotomy or laparoscopy can result in a favorable and successful obstetrical outcome. PMID:27413561

  16. Fungal osteomyelitis with vertebral re-ossification

    PubMed Central

    O′Guinn, Devon J.; Serletis, Demitre; Kazemi, Noojan

    2015-01-01

    Introduction We present a rare case of thoracic vertebral osteomyelitis secondary to pulmonary Blastomyces dermatitides. Presentation of case A 27-year-old male presented with three months of chest pains and non-productive cough. Examination revealed diminished breath sounds on the right. CT/MR imaging confirmed a right-sided pre-/paravertebral soft tissue mass and destructive lytic lesions from T2 to T6. CT-guided needle biopsy confirmed granulomatous pulmonary Blastomycosis. Conservative management with antifungal therapy was initiated. Neurosurgical review confirmed no clinical or profound radiographic instability, and the patient was stabilized with TLSO bracing. Serial imaging 3 months later revealed near-resolution of the thoracic soft tissue mass, with vertebral re-ossification from T2 to T6. Discussion Fungal osteomyelitis presents a rare entity in the spectrum of spinal infections. In such cases, lytic spinal lesions are classically seen in association with a large paraspinous mass. Fungal infections of the spinal column may be treated conservatively, with surgical intervention reserved for progressive cases manifesting with neurological compromise and/or spinal column instability. Here, we found unexpected evidence for vertebral re-ossification across the affected thoracic levels (T2-6) in response to IV antibiotic therapy and conservative bracing, nearly 3 months later. PMID:26692163

  17. [Heterotopic cloacogenic carcinoma of the lower lip].

    PubMed

    Vulcan, P; Dumitriu, E; Grigore, M

    1994-01-01

    Cloacogenic carcinoma is a tumour which develops from cylindric epithelial cells at the anorectal junction. Besides this usual localization, other sites have been described including the vagina, urethra, sigmoid colon, vulva and perianal skin. We observed a labial localization in a 50-year-old woman. A 15 mm tumorous formation developed rapidly after initial excision without skin or mucosal changes. The clinical diagnosis was epidermoid carcinoma but histological examination revealed an aspect comparable to cloacogenic carcinoma with nodules of basaloid tumour cells showing atypical mitosis within the nodules and the uniformly eosinophilic masses. We considered that this particular histological aspect eliminated the diagnosis of basocellular or epidermoid carcinoma and suggest that the carcinoma developed from embryon reliquats of cloacoanal transition cells in a heterotopic localization. PMID:7979028

  18. Case series of congenital heterotopic neuroglial tissue in the parapharyngeal space.

    PubMed

    Chen, Daniel; Dedhia, Kavita; Ozolek, John; Mehta, Deepak

    2016-07-01

    Cases of congenital heterotopic tissue presenting in the head and neck are frequent in the pediatric otolaryngology literature. Heterotopic glioneuronal tissue is rare and fewer than 20 cases of heterotopic glioneuronal tissue in the parapharyngeal space have been reported. We present two cases of infant children who were seen at the Children's Hospital of Pittsburgh in 2013 with glioneuronal heterotopic masses in the parapharyngeal space. PMID:27260585

  19. Mucinous cyst exhibiting severe dysplasia in gastric heterotopic pancreas associated with gastrointestinal stromal tumour.

    PubMed

    Kaufman, Antony; Storey, David; Lee, Cheok Soon; Murali, Rajmohan

    2007-11-21

    Heterotopic pancreatic tissue within the stomach is rare and dysplasia within heterotopic pancreatic tissue is very rare. We present the first report of a patient with concurrent occurrence of heterotopic pancreas in the stomach with a gastrointestinal stromal tumour. PMID:17963310

  20. Hypovolemic shock following induced abortion and spontaneous heterotopic pregnancy

    PubMed Central

    Pakniyat, Abdolghader; Yazdanbakhsh, Arash; Moshar-mowahed, Ghasem; Talebi, Fatimah

    2015-01-01

    Spontaneous heterotopic pregnancy is a rare clinical condition in which intrauterine and extrauterine pregnancies occur at the same time. It is rare, estimated to occur in 1 in 30,000 pregnancies. The case was a 38-year-old woman with spontaneously conceived heterotopic pregnancy. She was admitted to our center with hypovolemic shock. Focused assessment sonography for trauma examination in emergency department showed large amount of free fluid in peritoneal cavity. She was managed surgical laparotomy. Considering spontaneous pregnancies, physician should be aware of the possibility of heterotopic pregnancy in all reproductive age women, especially those with history of recent abortion. It can occur without any predisposing risk factors. Patients should be informed about possible side effects of nonprescription medicines, and also the health care centers must be safe peaceful environment for them without severe legal consequences. PMID:26813259

  1. Heterotopic Intestinal Cyst of the Submandibular Gland: A Case Study

    PubMed Central

    Kwon, Mi Jung; Park, Hye-Rim; Min, Soo Kee; Seo, Jinwon; Kim, Eun Soo; Kim, Si Whan; Park, Bumjung

    2013-01-01

    Heterotopic gastrointestinal cysts are rarely found in the oral cavity. Most of these cysts are lined with gastric mucosa and involve the tongue. There have been no reported heterotopic intestinal cysts of the submandibular gland that are completely lined with colonic mucosa. An 8-year-old girl presented with an enlarging swelling in the left submandibular area, and a 4-cm unilocular cyst was fully excised. The cyst was completely lined with colonic mucosa that was surrounded by smooth muscle layer, and the lining cells were positive for CDX-2, an intestinal marker, indicating a high degree of differentiation. The pathogenesis remains unclear, but it may be related to the misplacement of embryonic rests within the oral cavity during early fetal development. Although heterotopic intestinal cysts rarely occur in the submandibular gland, they should be considered in the differential diagnosis of facial swellings in the pediatric population. PMID:23837022

  2. Hypovolemic shock following induced abortion and spontaneous heterotopic pregnancy.

    PubMed

    Pakniyat, Abdolghader; Yazdanbakhsh, Arash; Moshar-Mowahed, Ghasem; Talebi, Fatimah

    2015-12-01

    Spontaneous heterotopic pregnancy is a rare clinical condition in which intrauterine and extrauterine pregnancies occur at the same time. It is rare, estimated to occur in 1 in 30,000 pregnancies. The case was a 38-year-old woman with spontaneously conceived heterotopic pregnancy. She was admitted to our center with hypovolemic shock. Focused assessment sonography for trauma examination in emergency department showed large amount of free fluid in peritoneal cavity. She was managed surgical laparotomy. Considering spontaneous pregnancies, physician should be aware of the possibility of heterotopic pregnancy in all reproductive age women, especially those with history of recent abortion. It can occur without any predisposing risk factors. Patients should be informed about possible side effects of nonprescription medicines, and also the health care centers must be safe peaceful environment for them without severe legal consequences. PMID:26813259

  3. Bone morphogenetic protein 2 stimulates endochondral ossification by regulating periosteal cell fate during bone repair

    PubMed Central

    Yu, Yan Yiu; Lieu, Shirley; Lu, Chuanyong; Colnot, Céline

    2010-01-01

    Bone repair depends on the coordinated action of numerous growth factors and cytokines to stimulate new skeletal tissue formation. Among all the growth factors involved in bone repair, Bone Morphogenetic Proteins (BMPs) are the only molecules now used therapeutically to enhance healing. Although BMPs are known as strong bone inducers, their role in initiating skeletal repair is not entirely elucidated. The aim of this study was to define the role of BMP2 during the early stages of bone regeneration and more specifically in regulating the fate of skeletal progenitors. During healing of non-stabilized fractures via endochondral ossification, exogenous BMP2 increased the deposition and resorption of cartilage and bone, which was correlated with a stimulation of osteoclastogenesis but not angiogenesis in the early phase of repair. During healing of stabilized fractures, which normally occurs via intramembranous ossification, exogenous BMP2 induced cartilage formation suggesting a role in regulating cell fate decisions. Specifically, the periosteum was found to be a target of exogenous BMP2 as shown by activation of the BMP pathway in this tissue. Using cell lineage analyses, we further show that BMP2 can direct cell differentiation towards the chondrogenic lineage within the periosteum but not the endosteum, indicating that skeletal progenitors within periosteum and endosteum respond differently to BMP signals. In conclusion, BMP2 plays an important role in the early stages of repair by recruiting local sources of skeletal progenitors within periosteum and endosteum and by determining their differentiation towards the chondrogenic and osteogenic lineages. PMID:20348041

  4. Risks of secondary malignancies with heterotopic bone radiation therapy for patients younger than 40 years.

    PubMed

    Cadieux, Catherine L; DesRosiers, Colleen; McMullen, Kevin

    2016-01-01

    Heterotopic ossification (HO) of the bone is defined as a benign condition in which abnormal bone formation occurs in soft tissue. One of the most common prophylactic treatments for HO is radiation therapy (RT). This study retrospectively reviewed 20 patients younger than the age of 40 who received radiation to prevent HO in a single fraction of 7 Gray. The purpose of this study is to assess the risk of a second malignancy in these patients by recreating their treatment fields and contouring organs at risk to estimate the radiation dose absorbed by normal tissues outside the radiation treatment field. Diagnostic computed tomography (CT) scans for each patient were used to recreate treatment fields and to calculate dose to structures of interest. The distance from the field edge to each structure and its depth was recorded. Dose measurements in a water phantom were performed for the range of depths, distances, and field sizes used in the actual treatment plans. Computer-generated doses were compared to estimates based on measurement. The structure dose recorded was the higher dose generated between the 2 methods. Scatter dose was recorded to the rectum, bladder, sigmoid colon, small bowel, ovaries and utero-cervix in female patients, and prostate and gonads in male patients. In some patients, there is considerable dose received by certain organs from scatter because of their proximity to the radiation field. The average dose to the ovarian region was 4.125Gy with a range of 1.085 to 6.228Gy. The risk estimate for these patients ranged from 0.16% to 0.93%. The average total lifetime risk estimate for the bladder in all patients is 0.22% and the average total lifetime risk estimate for the remainder organs in all patients is 1.25%. In conclusions, proper shielding created from multileaf collimators (MLCs), blocks, and shields should always be used when possible. PMID:27156238

  5. Detection of secondary ossification centers by sonography

    PubMed Central

    Karami, Mehdi; Moradi, Maryam; Khazaei, Mehdi; Modaresi, Mohamad-Reza; Asadi, Kambiz; Soleimani, Marzie

    2016-01-01

    Background: To assess the validity of ultrasonography (US) in detection of secondary ossification centers (SOC) of the hand. Radiography is the standard technique for estimating skeletal bone age with its unwanted harmful effects mostly undesirable in little children. If efficient enough, US could be an appropriate substitute. Materials and Methods: Left hand US was performed on 6-60 months children (n = 24, with 29 SOCs for each child in his/her hand and a total of 696 SOCs) referred for wrist radiography and bone age determination during a 4 months period. The presence of SOCs was investigated by US and radiography by two radiologists under blind conditions. Results: US was evaluated 696 SOCs, and 446 SOCs were detected, by US and 436 by radiography without statistically significant difference. The results of US and radiography in detection of SOCs of distal forearm (23 SOCs were detected by both US and radiography) and carpi (87 SOCs) were identical. However, in metacarpi (94 for US, 88 for radiography) and phalanges (242 for US, 238 for radiography) US appeared better. Conclusion: On the base of our data, US is at least as effective as radiography in detection of SOCs and therefore can play a role in the skeletal age estimation. PMID:26962514

  6. A potential mechanism of dural ossification in ossification of ligamentum flavum.

    PubMed

    Li, Bo; Guo, Shigong; Qiu, Guixing; Li, Wenjing; Liu, Yongsheng; Zhao, Yu

    2016-07-01

    Ossification of the ligamentum flavum (OLF) mostly occurs in the thoracic spine, leading to thoracic spinal stenosis. Surgical treatment is considered as the best option for OLF patients. When the dura mater ossifies, the difficulty of surgery and the risk of complications significantly increase. The cause of dural ossification (DO) is still unknown. Based on the existing research and clinical studies, we propose a potential mechanism of DO in OLF. Firstly, with the progression of OLF, it will compress the dura mater and even the spinal cord. Then, with flexion and extension of spine, relative movement (friction) between the ossified ligamentum flavum and compressed dura mater will lead to local inflammation, subsequently causing dural adhesion. Finally, the adhesion tissue can serve as a pathway for the transportation of osteogenic cytokines (BMP for example) from the ossified ligamentum flavum to the compressed dura mater. Dura will ossify under exposure of these osteogenic cytokines. If this hypothesis is confirmed, it will contribute to the prevention and management of DO. For progressive OLF patients, early surgical treatment before DO should be recommended. PMID:27241243

  7. Yap/Taz transcriptional activity in endothelial cells promotes intramembranous ossification via the BMP pathway

    PubMed Central

    Uemura, Mami; Nagasawa, Ayumi; Terai, Kenta

    2016-01-01

    Osteogenesis is categorized into two groups based on developmental histology, intramembranous and endochondral ossification. The role of blood vessels during endochondral ossification is well known, while their role in intramembranous ossification, especially the intertissue pathway, is poorly understood. Here, we demonstrate endothelial Yap/Taz is a novel regulator of intramembranous ossification in zebrafish. Appropriate blood flow is required for Yap/Taz transcriptional activation in endothelial cells and intramembranous ossification. Additionally, Yap/Taz transcriptional activity in endothelial cells specifically promotes intramembranous ossification. BMP expression by Yap/Taz transactivation in endothelial cells is also identified as a bridging factor between blood vessels and intramembranous ossification. Furthermore, the expression of Runx2 in pre-osteoblast cells is a downstream target of Yap/Taz transcriptional activity in endothelial cells. Our results provide novel insight into the relationship between blood flow and ossification by demonstrating intertissue regulation. PMID:27273480

  8. Progressive relapse of ligamentum flavum ossification following decompressive surgery.

    PubMed

    Ando, Kei; Imagama, Shiro; Ito, Zenya; Kobayashi, Kazuyoshi; Ukai, Junichi; Muramoto, Akio; Shinjo, Ryuichi; Matsumoto, Tomohiro; Nakashima, Hiroaki; Ishiguro, Naoki

    2014-12-01

    Thoracic ossification of the ligamentum flavum (T-OLF) is a relatively rare spinal disorder that generally requires surgical intervention, due to its progressive nature and the poor response to conservative therapy. The prevalence of OLF has been reported at 3.8%-26%, which is similar to that of cervical ossification of the posterior longitudinal ligament (OPLL). The progression of OPLL after cervical laminoplasty for the treatment of OPLL is often shown in long-term follow-up. However, there have been no reports on the progression of OLF following surgery. We report a case of thoracic myelopathy secondary to the progressive relapse of OLF following laminectomy. PMID:25558329

  9. Cholecystitis Associated with Heterotopic Pancreas, Pseudopyloric Metaplasia, and Adenomyomatous Hyperplasia: A Rare Combination

    PubMed Central

    Kaur, Navjot; Chander, Bal; Kaur, Harjit; Kaul, Rashmi

    2016-01-01

    Heterotopic pancreatic tissue in the gall bladder is an uncommon incidental finding in most cases. We hereby describe the case of a 45-year-old woman who presented with symptoms of acalculous cholecystitis. Pathological examination detected heterotopic pancreatic tissue, pseudopyloric metaplasia, and adenomyomatous hyperplasia in the gall bladder. This is a rare combination of three entities which is being reported for the first time. This case emphasizes that heterotopic pancreas might be the causative factor for cholecystitis. PMID:27365925

  10. Jagged1 is essential for osteoblast development during maxillary ossification.

    PubMed

    Hill, Cynthia R; Yuasa, Masato; Schoenecker, Jonathan; Goudy, Steven L

    2014-05-01

    Maxillary hypoplasia occurs due to insufficient maxillary intramembranous ossification, leading to poor dental occlusion, respiratory obstruction and cosmetic deformities. Conditional deletion of Jagged1 (Jag1) in cranial neural crest (CNC) cells using Wnt1-cre; Jagged1(f/f) (Jag1CKO) led to maxillary hypoplasia characterized by intrinsic differences in bone morphology and density using μCT evaluation. Jag1CKO maxillas revealed altered collagen deposition, delayed ossification, and reduced expression of early and late determinants of osteoblast development during maxillary ossification. In vitro bone cultures on Jag1CKO mouse embryonic maxillary mesenchymal (MEMM) cells demonstrated decreased mineralization that was also associated with diminished induction of osteoblast determinants. BMP receptor expression was dysregulated in the Jag1CKO MEMM cells suggesting that these cells were unable to respond to BMP-induced differentiation. JAG1-Fc rescued in vitro mineralization and osteoblast gene expression changes. These data suggest that JAG1 signaling in CNC-derived MEMM cells is required for osteoblast development and differentiation during maxillary ossification. PMID:24491691

  11. The emergence of mechanoregulated endochondral ossification in evolution.

    PubMed

    Khayyeri, Hanifeh; Prendergast, Patrick J

    2013-02-22

    The differentiation of skeletal tissue phenotypes is partly regulated by mechanical forces. This mechanoregulatory aspect of tissue differentiation has been the subject of many experimental and computational investigations. However, little is known about what factors promoted the emergence of mechanoregulated tissue differentiation in evolution, even though mechanoregulated tissue differentiation, for example during development or healing of adult bone, is crucial for vertebrate phylogeny. In this paper, we use a computational framework to test the hypothesis that the emergence of mechanosensitive genes that trigger endochondral ossification in evolution will stabilise in the population and create a variable mechanoregulated response, if the endochondral ossification process enhances fitness for survival. The model combines an evolutionary algorithm that considers genetic change with a mechanoregulated fracture healing model in which the fitness of animals in a population is determined by their ability to heal their bones. The simulations show that, with the emergence of mechanosensitive genes through evolution enabling skeletal cells to modulate their synthetic activities, novel differentiation pathways such as endochondral ossification could have emerged, which when favoured by natural selection is maintained in a population. Furthermore, the model predicts that evolutionary forces do not lead to a single optimal mechanoregulated response but that the capacity of endochondral ossification exists with variability in a population. The simulations correspond with many existing findings about the mechanosensitivity of skeletal tissues in current animal populations, therefore indicating that this kind of multi-level models could be used in future population based simulations of tissue differentiation. PMID:23261239

  12. Skeletal ossification and sequence heterochrony in xenarthran evolution.

    PubMed

    Hautier, Lionel; Weisbecker, Vera; Goswami, Anjali; Knight, Frank; Kardjilov, Nikolay; Asher, Robert J

    2011-01-01

    Previous analyses of how mammals vary in their ossification sequences have focused on monotremes, marsupials, and boreoeutherian placentals. Here, we focus on the sequence of cranial and postcranial ossification events during growth in the xenarthran skull and skeleton, including armadillos, anteaters, and sloths. We use two different methods to quantify sequence heterochrony: sequence analysis of variance (ANOVA) and event-paring/Parsimov. Our results indicate that Parsimov is conservative and does not detect clear heterochronic shifts between xenarthran and boreoeutherian placentals. Sequence-ANOVA performs better, but both methods exhibit sensitivity to the artifactual accumulation of ties. By controlling for ties and taking into account results that the methods have in common, our analysis suggests that xenarthrans significantly differ from other placentals by a late ossification of the sternum and an early ossification of the phalanges and pubis. We interpret these differences as showing that heterochrony plays a role in the skeletal development of xenarthrans, a change from previous studies that have emphasized the developmental homogeneity of the skeleton across placental mammals. PMID:23016907

  13. Monotreme ossification sequences and the riddle of mammalian skeletal development.

    PubMed

    Weisbecker, Vera

    2011-05-01

    The developmental differences between marsupials, placentals, and monotremes are thought to be reflected in differing patterns of postcranial development and diversity. However, developmental polarities remain obscured by the rarity of monotreme data. Here, I present the first postcranial ossification sequences of the monotreme echidna and platypus, and compare these with published data from other mammals and amniotes. Strikingly, monotreme stylopodia (humerus, femur) ossify after the more distal zeugopodia (radius/ulna, tibia/fibula), resembling only the European mole among all amniotes assessed. European moles also share extreme humeral adaptations to rotation digging and/or swimming with monotremes, suggesting a causal relationship between adaptation and ossification heterochrony. Late femoral ossification with respect to tibia/fibula in monotremes and moles points toward developmental integration of the serially homologous fore- and hindlimb bones. Monotreme cervical ribs and coracoids ossify later than in most amniotes but are similarly timed as homologous ossifications in therians, where they are lost as independent bones. This loss may have been facilitated by a developmental delay of coracoids and cervical ribs at the base of mammals. The monotreme sequence, although highly derived, resembles placentals more than marsupials. Thus, marsupial postcranial development, and potentially related diversity constraints, may not represent the ancestral mammalian condition. PMID:21521190

  14. Thinking Meillassoux's Factiality: A Pedagogical Movement against Ossification of Bodymind

    ERIC Educational Resources Information Center

    Oral, Sevket Benhur

    2015-01-01

    This article is about a pedagogical movement I discern in Quentin Meillassoux's ontology. The goal of the essay is to introduce his approach to reality in outline form and offer it as a possible route to conceptualize education as the practice of keeping the bodymind attentive and agile against its unsound ossification by way of providing a…

  15. Genetic analysis of Runx2 function during intramembranous ossification.

    PubMed

    Takarada, Takeshi; Nakazato, Ryota; Tsuchikane, Azusa; Fujikawa, Koichi; Iezaki, Takashi; Yoneda, Yukio; Hinoi, Eiichi

    2016-01-15

    Runt-related transcription factor 2 (Runx2) is an essential transcriptional regulator of osteoblast differentiation and its haploinsufficiency leads to cleidocranial dysplasia because of a defect in osteoblast differentiation during bone formation through intramembranous ossification. The cellular origin and essential period for Runx2 function during osteoblast differentiation in intramembranous ossification remain poorly understood. Paired related homeobox 1 (Prx1) is expressed in craniofacial mesenchyme, and Runx2 deficiency in cells of the Prx1 lineage (in mice referred to here as Runx2prx1 (-/-)) resulted in defective intramembranous ossification. Runx2 was heterogeneously expressed in Prx1-GFP(+) cells located at the intrasutural mesenchyme in the calvaria of transgenic mice expressing GFP under the control of the Prx1 promoter. Double-positive cells for Prx1-GFP and stem cell antigen-1 (Sca1) (Prx1(+)Sca1(+) cells) in the calvaria expressed Runx2 at lower levels and were more homogeneous and primitive than Prx1(+)Sca1(-) cells. Osterix (Osx) is another transcriptional determinant of osteoblast lineages expressed by osteoblast precursors; Osx is highly expressed by Prx1(-)Runx2(+) cells at the osteogenic front and on the surface of mineralized bone in the calvaria. Runx2 deficiency in cells of the Osx lineage (in mice referred to here as Runx2osx (-/-)) resulted in severe defects in intramembranous ossification. These findings indicate that the essential period of Runx2 function in intramembranous ossification begins at the Prx1(+)Sca1(+) mesenchymal stem cell stage and ends at the Osx(+)Prx1(-)Sca1(-) osteoblast precursor stage. PMID:26657773

  16. Skeletal development in the African elephant and ossification timing in placental mammals.

    PubMed

    Hautier, Lionel; Stansfield, Fiona J; Allen, W R Twink; Asher, Robert J

    2012-06-01

    We provide here unique data on elephant skeletal ontogeny. We focus on the sequence of cranial and post-cranial ossification events during growth in the African elephant (Loxodonta africana). Previous analyses on ossification sequences in mammals have focused on monotremes, marsupials, boreoeutherian and xenarthran placentals. Here, we add data on ossification sequences in an afrotherian. We use two different methods to quantify sequence heterochrony: the sequence method and event-paring/Parsimov. Compared with other placentals, elephants show late ossifications of the basicranium, manual and pedal phalanges, and early ossifications of the ischium and metacarpals. Moreover, ossification in elephants starts very early and progresses rapidly. Specifically, the elephant exhibits the same percentage of bones showing an ossification centre at the end of the first third of its gestation period as the mouse and hamster have close to birth. Elephants show a number of features of their ossification patterns that differ from those of other placental mammals. The pattern of the initiation of the ossification evident in the African elephant underscores a possible correlation between the timing of ossification onset and gestation time throughout mammals. PMID:22298853

  17. What is the best treatment of heterotopic cervical pregnancies for a successful pregnancy outcome?

    PubMed Central

    Kim, Ji Won; Park, Han Moie; Lee, Woo Sik

    2012-01-01

    Heterotopic pregnancy is rare event and the risk is increased with assisted reproductive technology procedures. Heterotopic cervical pregnancy is even more unusual. We report a rare case of heterotopic cervical pregnancy that was managed successfully. A 36-year-old women who conceived by IVF-ICSI was diagnosed with heterotopic cervical pregnancy. She visited the emergency room with vaginal bleeding at 5 weeks of gestation and underwent careful intracervical gestational sac reduction with forceps under abdominal guidance the next day. The postoperative course was uneventful and with regular check-ups, the intrauterine pregnancy (IUP) progressed unremarkably through 41 weeks with delivery of a healthy newborn. We reviewed a total of 37 cases of heterotopic pregnancy that have been reported in the English language literature. There have been many attempts to eliminate the cervical embryo while preserving the IUP, and complete cervical evacuation is important in order to avoid infection, bleeding, and premature birth. PMID:23346531

  18. Endobronchial Carcinoid Tumour with Extensive Ossification: An Unusual Case Presentation.

    PubMed

    Osmond, Allison; Filter, Emily; Joseph, Mariamma; Inculet, Richard; Kwan, Keith; McCormack, David

    2016-01-01

    Carcinoid tumour is a well-known primary endobronchial lung neoplasm. Although calcifications may be seen in up to 30% of pulmonary carcinoid tumours, near complete ossification of these tumours is an unusual finding. Such lesions can prove diagnostically challenging at the time of intraoperative frozen section as the latter technique requires thin sectioning of the lesion for microscopic assessment. We present an unusual case of endobronchial carcinoid tumour with extensive ossification in a 45-year-old male. Preliminary intraoperative diagnosis was achieved through the alternative use of cytology scrape smears. The final diagnosis was confirmed after decalcification of the tumour. The prognostic implications of heavily ossified carcinoid tumours remain elusive. Long-term clinical follow-up of these patients is recommended. PMID:27610135

  19. Endobronchial Carcinoid Tumour with Extensive Ossification: An Unusual Case Presentation

    PubMed Central

    Filter, Emily; Joseph, Mariamma; Inculet, Richard; Kwan, Keith; McCormack, David

    2016-01-01

    Carcinoid tumour is a well-known primary endobronchial lung neoplasm. Although calcifications may be seen in up to 30% of pulmonary carcinoid tumours, near complete ossification of these tumours is an unusual finding. Such lesions can prove diagnostically challenging at the time of intraoperative frozen section as the latter technique requires thin sectioning of the lesion for microscopic assessment. We present an unusual case of endobronchial carcinoid tumour with extensive ossification in a 45-year-old male. Preliminary intraoperative diagnosis was achieved through the alternative use of cytology scrape smears. The final diagnosis was confirmed after decalcification of the tumour. The prognostic implications of heavily ossified carcinoid tumours remain elusive. Long-term clinical follow-up of these patients is recommended. PMID:27610135

  20. Intracochlear Bleeding Enhances Cochlear Fibrosis and Ossification: An Animal Study

    PubMed Central

    Ryu, Kyeung A.; Lyu, Ah-Ra; Park, Heesung; Choi, Jin Woong; Hur, Gang Min; Park, Yong-Ho

    2015-01-01

    The aim of this study was to investigate the effects of intracochlear bleeding during cochleostomy on cochlear inflammatory response and residual hearing in a guinea pig animal model. Auditory brainstem response threshold shifts were greater in blood injected ears (p<0.05). Interleukin-1β, interleukin-10, tumor necrosis factor-α and nitric oxide synthase 2, cytokines that are related to early stage inflammation, were significantly increased in blood injected ears compared to normal and cochleostomy only ears at 1 day after surgery; with the increased IL-1β being sustained until 3 days after the surgery (p<0.05). Hair cells were more severely damaged in blood injected ears than in cochleostomy only ears. Histopathologic examination revealed more extensive fibrosis and ossification in blood injected ears than cochleostomy only ears. These results show that intracochlear bleeding enhanced cochlear inflammation resulting in increased fibrosis and ossification in an experimental animal model. PMID:26308864

  1. Mead acid (20:3n-9) and n-3 polyunsaturated fatty acids are not associated with risk of posterior longitudinal ligament ossification: results of a case-control study.

    PubMed

    Hamazaki, Kei; Kawaguchi, Yoshiharu; Nakano, Masato; Yasuda, Taketoshi; Seki, Shoji; Hori, Takeshi; Hamazaki, Tomohito; Kimura, Tomoatsu

    2015-05-01

    Ossification of the posterior longitudinal ligament (OPLL) involves the replacement of ligamentous tissue with ectopic bone. Although genetics and heritability appear to be involved in the development of OPLL, its pathogenesis remains to be elucidated. Given previous findings that 5,8,11-eicosatrienoic acid [20:3n-9, Mead acid (MA)] has depressive effects on osteoblastic activity and anti-angiogenic effects, and that n-3 polyunsaturated fatty acids (PUFAs) have a preventive effect on heterotopic ossification, we hypothesized that both fatty acids would be involved in OPLL development. To examine the biological significance of these and other fatty acids in OPLL, we conducted this case-control study involving 106 patients with cervical OPLL and 109 age matched controls. Fatty acid composition was determined from plasma samples by gas chromatography. Associations between fatty acid levels and incident OPLL were evaluated by logistic regression. Contrary to our expectations, we found no significant differences between patients and controls in the levels of MA or n-3 PUFAs (e.g., eicosapentaenoic acid and docosahexaenoic acid). Logistic regression analysis did not reveal any associations with OPLL risk for MA or n-3 PUFAs. In conclusion, no potential role was found for MA or n-3 PUFAs in ectopic bone formation in the spinal canal. PMID:25669698

  2. Pulsed electromagnetic field may accelerate in vitro endochondral ossification.

    PubMed

    Wang, Jue; Tang, Na; Xiao, Qiang; Zhang, Li; Li, Yu; Li, Juan; Wang, Jun; Zhao, Zhihe; Tan, Lijun

    2015-01-01

    Recapitulation of embryonic endochondral bone formation is a promising alternative approach to bone tissue engineering. However, the time-consuming process is one of the reasons the approach is unpractical. Here, we aimed at accelerating the in vitro endochondral ossification process of tissue engineering by using a pulsed electromagnetic field (PEMF). The rat bone marrow-derived stem cells were chondrogenic or hypertrophic differentiated in a three-dimensional pellet culture system, and treated with different intensities of PEMF (1, 2, and 5 mT with modulation frequency 750 Hz, carrier frequency 75 Hz and a duty ratio of 0.8, 3 h/day for 4 weeks). The effects of PEMF on hypertrophy and endochondral ossification were assessed by safranin O staining, immunohistochemistry, and quantitative real-time polymerase chain reaction. The results suggest that PEMF at 1, 2, and 5 mT may inhibit the maintenance of the cartilaginous phenotype and increase cartilage-specific extracellular matrix degradation in the late stage of chondrogenic differentiation. In addition, among the three different intensities, only PEMF at 1 mT directed the differentiation of chondrogenic-induced stem cell pellets to the hypertrophic stage and promoted osteogenic differentiation. Our findings provide the feasibility to optimize the process of in vitro endochondral ossification with PEMF stimulation. PMID:25358461

  3. Laparoscopic Management of Heterotopic Interstitial Pregnancy with Subsequent Term Delivery.

    PubMed

    Kwon, Yong-Soon; Lee, Sang-Hun; Im, Kyong Shil; Ro, Jae Hun

    2015-01-01

    A 35 year-old woman at 7-week gestational age was referred to our hospital. The patient was diagnosed with the heterotopic interstitial pregnancy by transvaginal ultrasonogra- phy after receiving in vitro fertilization (IVF) and embryo transfer. Laparoscopic excision and curettage was successfully performed at 8.4-gestational age under general anesthesia and the patient was discharged 2 days after operation without any post-operative complications. The woman had normal antenatal follow-up and deliv- ered a healthy baby at term by cesarean section. PMID:26246887

  4. Relationship between the chondrocyte maturation cycle and the endochondral ossification in the diaphyseal and epiphyseal ossification centers.

    PubMed

    Pazzaglia, Ugo E; Congiu, Terenzio; Sibilia, Valeria; Pagani, Francesca; Benetti, Anna; Zarattini, Guido

    2016-09-01

    The chondrocyte maturation cycle and endochondral ossification were studied in human, fetal cartilage Anlagen and in postnatal meta-epiphyses. The relationship between the lacunar area, the inter-territorial fibril network variations, and calcium phosphorus nucleation in primary and secondary ossification centers were assessed using light microscopy and scanning electron microscopy (SEM) morphometry. The Anlage topographic, zonal classification was derived from the anatomical nomenclature of the completely developed long bone (diaphysis, metaphyses and epiphyses). A significant increase in the chondrocyte lacunar area was documented in the Anlage of epiphyseal zones 4 and 3 to zone 2 (metaphysis) and zone 1 (diaphysis), with the highest variation from zone 2 to zone 1. An inverse reduction in the intercellular matrix area and matrix interfibrillar empty space was also documented. These findings are consistent with the osmotic passage of free cartilage water from the interfibrillar space into the swelling chondrocytes, which increased the ion concentrations to a critical threshold for mineral precipitation in the matrix. The mineralized cartilage served as a scaffold for osteoblast apposition both in primary and secondary ossification centers and in the metaphyseal growth plate cartilage, though at different periods of bone Anlage development and with distinct patterns for each zone. All developmental processes shared a common initial pathway but progressed at different rates, modes and organization in diaphysis, metaphysis and epiphysis. In the ossification phase the developing vascular supply appeared to play a key role in determining the cortical or trabecular structure of the long bones. J. Morphol. 277:1187-1198, 2016. © 2016 Wiley Periodicals, Inc. PMID:27312928

  5. Mucus retention in heterotopic pancreas of the gastric antrum. A lesion mimicking mucinous carcinoma.

    PubMed

    Nopajaroonsri, C

    1994-09-01

    This report describes mucus retention developing in heterotopic pancreas of the gastric antrum. This unusual complication of heterotopic pancreas was seen in a 54-year-old black man who presented with postprandial nausea, vomiting, and weight loss. Gastroscopy revealed a 2-cm pyloric polyp, which was seen to intermittently obstruct the pylorus. Exploratory laparotomy confirmed an intramural mass in the antrum with serosal thickening and nodules. Frozen-section examination of the serosal nodule revealed a pool of mucus containing epithelial clusters and chronic inflammatory cells with no verifiable pancreatic tissue. These findings suggested the possibility of a mucinous carcinoma involving the serosa. Following gastrectomy, however, heterotopic pancreatic tissue was identified in the outer muscular propria extending to the mucosa of the antrum with no evidence of carcinoma. This heterotopic pancreatic tissue showed ductal obstruction and mucus retention. As a result, some ducts were ruptured and transformed into small nodules of mucus lakes with clusters of residual ductal epithelium. We therefore concluded that the mucous extravasation nodules on the antral serosa represented a benign lesion resulting from mucus retention in the heterotopic pancreas. In contrast to mucinous carcinoma, these benign mucous extravasation nodules were closely associated with the heterotopic pancreas, and showed significant inflammation and fibrosis but no overt epithelial anaplasia. The significance of the mucous extravasation nodule in the heterotopic pancreas is its potential confusion with mucinous carcinoma. PMID:8067516

  6. The development of centres of ossification of bones forming elbow joints in young swine.

    PubMed Central

    Visco, D M; Hill, M A; Van Sickle, D C; Kincaid, S A

    1990-01-01

    Epiphyseal centres of ossification in the bones forming the elbow joints of pigs between one day and 15 weeks of age were examined radiographically, macroscopically, mesoscopically and microscopically. Thoracic limbs from 39 pigs were perfused with India ink or silicone rubber injection compound and the bones were dissected free of soft tissues. The humerus, ulna and radius were fixed in formalin or ethyl alcohol and then cleared by the modified Spalteholz technique. Bones were radiographed, examined grossly, and then cut into slabs for mesoscopical evaluation. Foci considered to be calcifying within cartilaginous anlage were selected for microscopical examination. It was concluded that the epiphyseal centre of ossification develops at different times in different sites in the bones forming the elbow joint. Centres of ossification are initiated when foci of chondrocytes adjacent to one side of a cartilage canal undergo hypertrophy and the inter-territorial matrix becomes calcified. Osteogenesis then proceeds in the calcified focus, presumably with osteoprogenitor cells that originate within the cartilage canals. Subsequently, each epiphyseal centre of ossification enlarges by one of two methods. Firstly, the layer of cartilage adjacent to the centre undergoes endochondral ossification, thus allowing for the circumferential growth of the epiphyseal centre of ossification. Secondly, foci of calcification develop adjacent to the ends of cartilage canals near the epiphyseal centre of ossification and eventually the focus of calcification coalesces with the developing epiphyseal centre of ossification, thus establishing a new ossification front. Endochondral ossification continues at the periphery of the mass of bone. Mesoscopical examination is more useful than radiographical evaluation for identifying small foci of calcification which precede epiphyseal centres of ossification. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:2081708

  7. The effect of prenatal indium chloride exposure on chondrogenic ossification.

    PubMed

    Ungváry, G; Tátrai, E; Szakmáry, E; Náray, M

    2001-03-01

    Daily indium chloride doses of control (0) or 400 mg/kg were administered orally to pregnant Sprague-Dawley (SD) rats by gavage, on d 20 of gestation. Indium concentration was determined in the maternal and fetal blood, livers, kidneys, skulls, and femurs by atomic absorption spectrometry. Further groups of pregnant rats were treated with control (0) or 400 mg/kg indium chloride orally, during the whole gestation period. The fetuses were examined on d 21 of gestation, using histological and histochemical methods. Four hours after the administration indium concentration was found to be significant in the blood, liver, and kidneys of the dams. Twenty-four hours later it increased in the blood but not in the liver and kidney. Fetal indium concentrations were 40-50% of the maternal levels due to a barrier of the placenta. In the skull and the femur, indium was already detectable at 4 h after the administration, and by the end of 24 h, metal concentration was several times higher than that at 4 h, indicating accumulation. Furthermore, it was found that the birefringency of collagen detectable by picrosirius red staining in polarized light around the chondrocytes disappeared and became irregular. In the matrix of the epiphyseal cartilage, the regular, birefringent network demonstrable by Rivanol reaction became irregular and hardly recognizable. In the cytoplasm of the chondrocytes, the diffuse, evenly distributed positive Ricinus communis agglutinin reaction became irregular or disappeared. Similar but much weaker changes were observed with concanavalin A and wheat germ agglutinin stainings. It was concluded that the missing femur and micromelia diagnosed by alizarin staining is the consequence of a specific toxic effect of indium that inhibits chondrogenic ossification. No similar histochemical changes were observed in the bones of the skull developing by desmogenic ossification, despite the presence of indium. Data indicate that the mechanisms of the effects of indium

  8. MEMO1 drives cranial endochondral ossification and palatogenesis.

    PubMed

    Van Otterloo, Eric; Feng, Weiguo; Jones, Kenneth L; Hynes, Nancy E; Clouthier, David E; Niswander, Lee; Williams, Trevor

    2016-07-15

    The cranial base is a component of the neurocranium and has a central role in the structural integration of the face, brain and vertebral column. Consequently, alteration in the shape of the human cranial base has been intimately linked with primate evolution and defective development is associated with numerous human facial abnormalities. Here we describe a novel recessive mutant mouse strain that presented with a domed head and fully penetrant cleft secondary palate coupled with defects in the formation of the underlying cranial base. Mapping and non-complementation studies revealed a specific mutation in Memo1 - a gene originally associated with cell migration. Expression analysis of Memo1 identified robust expression in the perichondrium and periosteum of the developing cranial base, but only modest expression in the palatal shelves. Fittingly, although the palatal shelves failed to elevate in Memo1 mutants, expression changes were modest within the shelves themselves. In contrast, the cranial base, which forms via endochondral ossification had major reductions in the expression of genes responsible for bone formation, notably matrix metalloproteinases and markers of the osteoblast lineage, mirrored by an increase in markers of cartilage and extracellular matrix development. Concomitant with these changes, mutant cranial bases showed an increased zone of hypertrophic chondrocytes accompanied by a reduction in both vascular invasion and mineralization. Finally, neural crest cell-specific deletion of Memo1 caused a failure of anterior cranial base ossification indicating a cell autonomous role for MEMO1 in the development of these neural crest cell derived structures. However, palate formation was largely normal in these conditional mutants, suggesting a non-autonomous role for MEMO1 in palatal closure. Overall, these findings assign a new function to MEMO1 in driving endochondral ossification in the cranium, and also link abnormal development of the cranial base

  9. Developmental ossification sequences of the appendicular and axial skeleton in Kuttanad duck embryos (Anas platyrhynchos domesticus).

    PubMed

    Firdous, A D; Maya, S; Massarat, K; Baba, M A

    2016-01-01

    The processes of ossification sequences are poorly investigated for birds in general, even for domestic and experimental species and when it comes to the waterfowl it is almost negligible. Such sequences constitute a rich source of data on character evolution, and may even provide phylogenetic information. A pre-hatch developmental study on ossification sequences of axial and appendicular skeletal system in Kuttanad duck embryos was undertaken using 78 viable embryos. From day 3 to day 7 of incubation no ossification densities were seen both by alizarin red staining and computerized radiography. The first indication of ossification as small ossification centers in skull bones, clavicle, scapula, humerus, radius and ulna in forelimb and ilium, pubis femur and fibula in hind limb were observed on the 9(th) day of incubation. The ossification of the body of the ribs started at the 11(th) day of incubation towards the proximal extremity. On day 13(th) the ossification process of vertebrae was started from cervical end. The variation in appearance of the ossification centers in different bones at different stages of incubation period suggests relative importance of phylogeny to the sequences. PMID:26862514

  10. Developmental ossification sequences of the appendicular and axial skeleton in Kuttanad duck embryos (Anas platyrhynchos domesticus)

    PubMed Central

    Firdous, A.D.; Maya, S.; Massarat, K.; Baba, M.A.

    2016-01-01

    The processes of ossification sequences are poorly investigated for birds in general, even for domestic and experimental species and when it comes to the waterfowl it is almost negligible. Such sequences constitute a rich source of data on character evolution, and may even provide phylogenetic information. A pre-hatch developmental study on ossification sequences of axial and appendicular skeletal system in Kuttanad duck embryos was undertaken using 78 viable embryos. From day 3 to day 7 of incubation no ossification densities were seen both by alizarin red staining and computerized radiography. The first indication of ossification as small ossification centers in skull bones, clavicle, scapula, humerus, radius and ulna in forelimb and ilium, pubis femur and fibula in hind limb were observed on the 9th day of incubation. The ossification of the body of the ribs started at the 11th day of incubation towards the proximal extremity. On day 13th the ossification process of vertebrae was started from cervical end. The variation in appearance of the ossification centers in different bones at different stages of incubation period suggests relative importance of phylogeny to the sequences. PMID:26862514

  11. [Endometrial ossification: a report of four cases and literature review].

    PubMed

    Nevarez Bernal, Roberto; Vilchis Nava, Pablo; Kably Ambe, Alberto

    2007-03-01

    Endometrial ossification is a rare endometrial pathology. Its predisposing factors include history of uterine curettage to metabolic abnormalities. It usually presents in patients with secondary infertility and history of first trimester pregnancy loss, accompanied by severe dysmenorrhea and dyspareunia. The diagnosis is suspected by OB-GYN history and USG findings, therapeutic strategies range from D&C to hysterectomy, we propose diagnosis and management by hysteroscopy in order to preserve future fertility and minimize uterine damage. A review of four cases during 1985-2004 from a large assisted reproduction center in Mexico City is presented. PMID:17547092

  12. Prenatal cranial ossification of the humpback whale (Megaptera novaeangliae).

    PubMed

    Hampe, Oliver; Franke, Helena; Hipsley, Christy A; Kardjilov, Nikolay; Müller, Johannes

    2015-05-01

    Being descendants of small terrestrial ungulate mammals, whales underwent enormous transformations during their evolutionary history, that is, extensive changes in anatomy, physiology, and behavior were evolved during secondary adaptations to life in water. However, still only little is known about whale ontogenetic development, which help to identify the timing and sequence of critical evolutionary events, such as modification of the cetacean ear. This is particularly true for baleen whales (Mysticeti), the group including the humpback whale Megaptera novaeangliae. We use high-resolution X-ray computed tomography to reinvestigate humpback whale fetuses from the Kükenthal collection at the Museum für Naturkunde, Berlin, thus, extending historic descriptions of their skeletogenesis and providing for the first time sequences of cranial ossification for this species. Principally, the ossification sequence of prenatal Megaptera follows a typical mammalian pattern with the anterior dermal bones being the first ossifying elements in the skull, starting with the dentary. In contrast to other mammals, the ectotympanic bone ossifies at an early stage. Alveolar structure can be observed in both the maxillae and dentaries in these early prenatal specimens but evidence for teeth is lacking. Although the possibility of obtaining new embryological material is unlikely due to conservation issues, our study shows that reexamination of existing specimens employing new technologies still holds promise for filling gaps in our knowledge of whale evolution and ontogeny. PMID:25728778

  13. Heterotopic Pancreas Presented as Duodenal Tumor with Obstruction.

    PubMed

    Kim, Sung Heun; Nam, So Hyun

    2015-12-01

    Heterotopic pancreas (HP) is defined as pancreatic tissue lacking anatomic and vascular continuity with the main body of the pancreas. Most are asymptomatic, but can cause ulcer, bleeding, intussusception, and mechanical obstruction. Herein, we presented one case of HP presented as duodenal tumor causing duodenal obstruction. A 7-year-old girl visited the emergency room for abdominal pain with vomiting for 24 hours. Computed tomography and upper gastrointestinal series revealed a polypoid mass with short stalk in the 2nd portion of duodenum. We attempted an endoscopic removal. However, the lumen was nearly obstructed by the mass and the stalk was too broad and hard to excise. The mass was surgically removed via duodenotomy. It was confirmed as a HP with ductal and acini components (type 2 by Heinrich classification). Postoperatively, the patient has been well without any complication and recurrence. PMID:26770904

  14. An Extraperitoneal Technique for Murine Heterotopic Cardiac Transplantation.

    PubMed

    Nowocin, A K; Brown, K; Edwards, L A; Meader, L; Hill, J I; Wong, W

    2015-09-01

    The mouse heterotopic cardiac transplantation model has been used extensively by investigators in the field of organ transplantation to study the rejection process, test new antirejection treatments, tolerance induction protocols or to understand basic immunological principles. Due to its extensive use, any small refinement of the technique would have a major impact on replacement, reduction and refinement (commonly known as the 3Rs). Here, we describe a novel approach to refine this model. The donor aorta and pulmonary artery are anastomosed peripherally to the femoral artery and vein of the recipient, respectively. The technical success rate is comparable to the conventional abdominal site, but it avoids a laparotomy and handling of the bowels making it less invasive method. As a result, recipients recover faster and require less postoperative analgesia. It is a major refinement under one of the 3Rs and would represent an advance in animal welfare in scientific research. PMID:25997384

  15. The clinical implications of heterotopic ossification in patients treated with radial head replacement for trauma: A case series and review of the literature.

    PubMed

    Bowman, Seth H; Barfield, William R; Slone, Harris S; Shealy, Gerald J; Walton, Zeke J

    2016-12-01

    Radial head arthroplasty (RHA) is an acceptable treatment for comminuted radial head fractures (RHF). Fourteen patients with no postop HO prophylaxis were treated with RHA for comminuted RHF. A 50% incidence in HO was seen following RHA with a statistically increased risk (p ≤ 0.05) of reoperation compared to those without HO. Decreased ROM was seen on the affected side (p ≤ 0.05); patients without HO showed no statistical difference (p ≥ 0.05) in ROM or grip strength. HO following RHA increases patient risk for reoperation and decreases ROM. We recommend HO prophylaxis with NSAIDs and/or radiotherapy if no direct patient contraindications are found. PMID:27408502

  16. Prognostic Value of the Radiologic Appearance of the Navicular Ossification Center in Congenital Talipes Equinovarus.

    PubMed

    Atanda, Abiola A; Oni, Julius K; Ramsden, David M; Yoon, Richard S; Ahmad, Alaa A; Otsuka, Norman Y

    2015-01-01

    Congenital talipes equinovarus (CTEV), more commonly known as clubfoot, is a deformity of the foot that is not well understood. The tarsal navicular is at the center of the disease process and exhibits abnormal development and delayed ossification. However, its role in the pathologic process is not clear. The aim of the present study was to better understand the role of the tarsal navicular in CTEV by correlating the presence of the navicular ossification center and relapse of clubfoot deformity after surgical treatment. The medical records and radiographs of 34 patients (41 feet) with surgically treated CTEV were reviewed for the presence of the navicular ossification center and the lateral talocalcaneal angles. Of the 41 feet, 17 (41.46%) did not have the tarsal navicular ossification center present before surgery, and 24 (58.54%) did have the ossification center present. The talocalcaneal angles were similar between those with and without the navicular ossification center present. No significant difference was found in the incidence of relapse between the nonossified navicular group (17.6%) and the ossified navicular group (16.7%; p = .63). The presence of the navicular ossification center before surgery does not appear to have prognostic value for the relapse of CTEV after surgical intervention. PMID:26049641

  17. Pulmonary Idiopathic Alveolar Ossification in a Raccoon (Procyon lotor)

    PubMed Central

    Hamir, Amir N; Rupprecht, Charles E

    2010-01-01

    Here we describe gross and histopathologic findings in a laboratory-confined adult male raccoon (Procyon lotor) with microscopic ossified areas in pulmonary alveoli. At the time of necropsy, gross lesions were present in the kidneys and in one thyroid gland. Noteworthy microscopic findings included multifocal foci of osseous tissue within the alveoli of the lungs, bilateral thyroid adenomas, pancreatic islet cell amyloidosis, cortical kidney infarcts, cystic adenomatous hyperplasia of urinary bladder, and mineralizations (psommama bodies) of small blood vessels of meninges and choroid plexus. Pulmonary ossification in raccoons has not been reported previously. The other histopathologic lesions have been documented to occur as incidental findings in raccoons and do not appear to have any apparent association with the formation of osseous foci in the lungs of the animal described. PMID:20858368

  18. [Updates on ossification of posterior longitudinal ligament. Effect of insulin/IGF-1 signals and leptin signals on ossification of the spinal ligament in Zucker fatty rats].

    PubMed

    Yamamoto, Kengo; Kosaka, Taiichi

    2009-10-01

    The involvement of insulin/IGF-1 signals and leptin signals in spinal ligament cells was investigated using Zucker fatty rats (fa/fa) that carry mutation of the leptin receptor gene (fa) and monosodium glutamate-treated (MSG) rats that present obesity due to destruction of the hypothalamic ventromedial nucleus. Zucker fatty rats (ZFR) , that have a with functional abnormality of leptin receptors are a spontaneous model of ossification of the posterior longitudinal ligament that develops sympathetic nerve hypoactivity. (insulin/IGF-1 signals) IRS-1-positive cells, IRS-1 protein were eminent by detected in the cartilage endplate and the enthesis region in ZFR group. On the other hand, IRS-2-positive cells were slightly less in the ZFR group than in the MSG and control groups. The results suggest that IRS-1-mediated signaling for cell proliferation was enhanced in ZFR, which may explain the ossification of the posterior longitudinal ligament. (Leptin signals) We investigated the effects of leptin on the spinal ligament in ZFR histopathologically and immunohistochemically. Since Ob-R does not play any role due to functional abnormality in ZFR, the direct involvement of leptin in ligament ossification may be slight in ZFR. beta(2)AR expression in the stage preceding ligament ossification was confirmed, suggesting that ossification of the spinal ligament may be inhibited by sympathetic nerve stimulation in ZFR. PMID:19794255

  19. Ossification score is a better indicator of maturity related changes in eating quality than animal age.

    PubMed

    Bonny, S P F; Pethick, D W; Legrand, I; Wierzbicki, J; Allen, P; Farmer, L J; Polkinghorne, R J; Hocquette, J-F; Gardner, G E

    2016-04-01

    Ossification score and animal age are both used as proxies for maturity-related collagen crosslinking and consequently decreases in beef tenderness. Ossification score is strongly influenced by the hormonal status of the animal and may therefore better reflect physiological maturity and consequently eating quality. As part of a broader cross-European study, local consumers scored 18 different muscle types cooked in three ways from 482 carcasses with ages ranging from 590 to 6135 days and ossification scores ranging from 110 to 590. The data were studied across three different maturity ranges; the complete range of maturities, a lesser range and a more mature range. The lesser maturity group consisted of carcasses having either an ossification score of 200 or less or an age of 987 days or less with the remainder in the greater maturity group. The three different maturity ranges were analysed separately with a linear mixed effects model. Across all the data, and for the greater maturity group, animal age had a greater magnitude of effect on eating quality than ossification score. This is likely due to a loss of sensitivity in mature carcasses where ossification approached and even reached the maximum value. In contrast, age had no relationship with eating quality for the lesser maturity group, leaving ossification score as the more appropriate measure. Therefore ossification score is more appropriate for most commercial beef carcasses, however it is inadequate for carcasses with greater maturity such as cull cows. Both measures may therefore be required in models to predict eating quality over populations with a wide range in maturity. PMID:26687476

  20. [Heterotopic pregnancy in intrauterine insemination. Presentation of a case].

    PubMed

    Kably Ambe, A; Garza Rios, P; Serviere Zaragoza, C; Delgado Urdapilleta, J

    1992-04-01

    The heterotopic (ectopic and orthotopic simultaneous) pregnancy shows a frequency of 1 to 15,000 to 1 to 30,000 gestations. The clinical diagnosis is difficult due to the lack of precise indicators, as to diagnose an intrauterine pregnancy eliminates the possibility of ectopic pregnancy. The methods of Assisted Reproduction seem to be factors that have influenced on the increment of this type of gestations. A case of a 32 year patient with primary sterility by pelvic adhesions process, that was surgically treated, as there was no pregnancy after surgery, she was given intrauterine insemination with her husband's semen (IU) pregnancy was obtained, determined at 15 days of menstrual lack by presence of subunit B of HCG in serum and vaginal ultrasound that confirmed gestational sac. One month after she presented at Urgencies with an acute abdominal condition; laparotomy was done and salpingectomy was carried out for ruptured tubal pregnancy confirmed by histopathology. The evolution on intrauterine pregnancy was normal culminating with cesarean section at week 35 by inminence of eclampsia/Mother and child in good conditions. PMID:1601314

  1. Thyroid Sporadic Goiter with Adult Heterotopic Bone Formation

    PubMed Central

    Handra-Luca, Adriana; Dumuis-Gimenez, Marie-Laure; Bendib, Mouna; Anagnostis, Panagiotis

    2015-01-01

    Thyroid heterotopic bone formation (HBF) in goiter is a rare finding. Five thyroid resection specimens were analyzed for HBF. The results were correlated with clinicomorphological features. All patients were women (33–82 years). The preoperative diagnosis was thyroid goiter or nodule. Treatment consisted in thyroidectomy and lobectomy (3 and 2, resp.). Microscopy showed sporadic nodular goiter. Malformative blood vessels and vascular calcifications were seen in intra- and extrathyroid location (5 and 3, resp.). The number and size of HBFs (total: 28) ranged between 1 and 23/thyroid gland (one bilateral) and 1 and 10 mm, respectively. Twelve HBFs were in contact with the thyroid capsule. Most were extranodular (21, versus 6 intranodular). The medical history was positive for dyslipidemia, hyperglycemia, renal dysfunction, and hyperuricemia (2, 3, and 3 cases and 1 case, resp.) without any parathyroid abnormality. In conclusion, thyroid HBF may be characterized by subcapsular or extranodular location, various size (usually ≥2 mm), and vascular calcifications and malformations. Features of metabolic syndrome and renal dysfunction may be present, but their exact role in the pathogenesis of HBFs remains to be elucidated. PMID:26697239

  2. Heterotopic pregnancy after GIFT managed with expectancy: a case report.

    PubMed

    Wang, Y L; Yang, T S; Chang, S P; Ng, H T

    1996-09-01

    A 29-year-old female patient visited our out-patient department (OPD) due to primary infertility in March 1993. Hysterosalpingography revealed cervical canal stricture. Gamete intra-Fallopian transfer (GIFT) was performed on Apr. 10, 1993 after ovulation induction. Three oocytes were placed into each Fallopian tube, then the patient was afflicted with lower abdominal discomfort and fullness 2 weeks later. Ovarian hyperstimulation syndrome (OHSS) was diagnosed. Ultrasonography showed intrauterine twin pregnancy and bilateral tubal pregnancy. During admission, supportive care for OHSS and expectant management only for ectopic pregnancies were given. OHSS resolved gradually. After a series of sonographic follow-up, disappearance of fetal heart beat (FHB) in the left ectopic gestational sac, resolution of bilateral ectopic gestational sacs and normal growth of intrauterine pregnancies were noted. On Dec. 16, 1993, the patient received cesarean section (C/S) due to twin pregnancy with vertex and breech presentation at the 37th gestational week. Twin A was female. Birth weight was 2590 gm. Apgar scores at 1 and 5 min. were 7 and 9. Twin B was also female. Birth weight was 2930 gm. Apgar scores at 1 and 5 main. were 8 and 9. Urinary bladder was injured accidentally at C/S. Repairment was done. The patient and her twins were discharged one week later in stable condition. Literature on heterotopic pregnancy after assisted reproductive technique (ART) was reviewed and discussed in this article. PMID:8940796

  3. Different ossification patterns of intermuscular bones in fish with different swimming modes

    PubMed Central

    Yao, Wenjie; Lv, Yaoping; Gong, Xiaoling; Wu, Jiaming; Bao, Baolong

    2015-01-01

    ABSTRACT Intermuscular bones are found in the myosepta in teleosts. However, there is very little information on the development and ossification of these intermuscular bones. In this study, we performed an in-depth investigation of the ossification process during development in zebrafish (Danio rerio) and Japanese eel (Anguilla japonica). In Japanese eel, a typical anguilliform swimmer, the intermuscular bones ossified predominantly from the anterior to the posterior. By contrast, in the zebrafish, a sub-carangiform or carangiform swimmer, the intermuscular bones ossified predominantly from the posterior to the anterior regions of the fish. Furthermore, tail amputation affected the ossification of the intermuscular bones. The length of the intermuscular bones in the posterior area became significantly shorter in tail-amputated zebrafish and Japanese eels, and both had less active and lower swimming speeds; this indicates that swimming might induce the ossification of the intermuscular bones. Moreover, when a greater length of tail was amputated in the zebrafish, the intermuscular bones became even shorter. Tail amputation affected the length and ossification of intermuscular bones in the anterior part of the fish, close to the head, differently between the two fish: they became significantly shorter in the zebrafish, but did not in the Japanese eel. This might be because tail amputation did not significantly affect the undulations in the anterior of the Japanese eel, especially near the head. This study shows that the ossification of intermuscular bones might be induced through mechanical force loadings that are produced by swimming. PMID:26603470

  4. Extensive arachnoid ossification with associated syringomyelia presenting as thoracic myelopathy. Case report and review of the literature.

    PubMed

    Slavin, K V; Nixon, R R; Nesbit, G M; Burchiel, K J

    1999-10-01

    The authors present the case of progressive thoracic myelopathy caused by the extensive ossification of the arachnoid membrane and associated intramedullary syrinx. Based on their findings and results of the literature search, they describe a pathological basis for this rare condition, discuss its incidence and symptomatology, and suggest a simple classification for various types of the arachnoid ossification. They also discuss the magnetic resonance imaging features of arachnoid ossification and associated spinal cord changes. The particular value of plain computerized tomography, which is highly sensitive in revealing intraspinal calcifications and ossifications, in the diagnostic evaluation of patients with a clinical picture of progressive myelopathy is emphasized. PMID:10505510

  5. PIXE study of the kinetics of biomaterials ossification

    NASA Astrophysics Data System (ADS)

    Weber, G.; Robaye, G.; Braye, F.; Oudadesse, H.; Irigaray, J. L.

    1994-05-01

    Biomaterials are frequently implanted in bones. This implantation is followed by a phenomenon of ossification. The purpose of this work was to study the time evolution of the gradient of characteristic atomic element's concentrations in the bone, the implant and the bone-implant interface. We have studied two types of neutral biomaterials: pure synthetic hydroxyapatite and porite's asteroid coral. The animal implantations have been made on sheep of the same age and sex having received the same basic diet. The implantations have been made in the cortical femur. On both sides of the implant, at the same distance, two screws were placed to allow further determination of the position of the implant. The PIXE method is particularly suitable here because of the possibility to analyze directly the samples without any preparation and to choose easily the dimensions of beam used for the gradient study. The X-rays have been detected with an ultra LEGe instead of the usual Si(Li) device to avoid the Si escape peak associated with the K α X-ray of calcium, the major constituent of bone. This peak is particularly disturbing here because its energy corresponds to the K α line of phosphorus, an important constituent of bone. The results of these determinations are presented and discussed.

  6. Evolution and functional significance of derived sternal ossification patterns in ornithothoracine birds.

    PubMed

    O'Connor, J K; Zheng, X-T; Sullivan, C; Chuong, C-M; Wang, X-L; Li, A; Wang, Y; Zhang, X-M; Zhou, Z-H

    2015-08-01

    The midline pattern of sternal ossification characteristic of the Cretaceous enantiornithine birds is unique among the Ornithodira, the group containing birds, nonavian dinosaurs and pterosaurs. This has been suggested to indicate that Enantiornithes is not the sister group of Ornithuromorpha, the clade that includes living birds and their close relatives, which would imply rampant convergence in many nonsternal features between enantiornithines and ornithuromorphs. However, detailed comparisons reveal greater similarity between neornithine (i.e. crown group bird) and enantiornithine modes of sternal ossification than previously recognized. Furthermore, a new subadult enantiornithine specimen demonstrates that sternal ossification followed a more typically ornithodiran pattern in basal members of the clade. This new specimen, referable to the Pengornithidae, indicates that the unique ossification pattern observed in other juvenile enantiornithines is derived within Enantiornithes. A similar but clearly distinct pattern appears to have evolved in parallel in the ornithuromorph lineage. The atypical mode of sternal ossification in some derived enantiornithines should be regarded as an autapomorphic condition rather than an indication that enantiornithines are not close relatives of ornithuromorphs. Based on what is known about molecular mechanisms for morphogenesis and the possible selective advantages, the parallel shifts to midline ossification that took place in derived enantiornithines and living neognathous birds appear to have been related to the development of a large ventral keel, which is only present in ornithuromorphs and enantiornithines. Midline ossification can serve to medially reinforce the sternum at a relatively early ontogenetic stage, which would have been especially beneficial during the protracted development of the superprecocial Cretaceous enantiornithines. PMID:26079847

  7. A Modified Method for Heterotopic Mouse Heart Transplantion

    PubMed Central

    Wang, Chuanmin; Wang, Zane; Allen, Richard; Bishop, G. Alex; Sharland, Alexandra F.

    2014-01-01

    Mice are often used as heart transplant donors and recipients in studies of transplant immunology due to the wide range of transgenic mice and reagents available. A difficulty is presented due to the small size of the animal and the considerable technical challenges of the microsurgery involved in heart transplantation. In particular, a high rate of technical failure early after transplantation may result from recipient death and post-operative complications such as hind limb paralysis or a non-beating heart. Here, the complete technique for heterotopic mouse heart transplantation is demonstrated, involving harvesting the donor heart and its subsequent implantation into a recipient mouse. The donor heart is harvested immediately following in situ perfusion with cold heparinized saline and transection of the ascending aorta and pulmonary artery. The recipient operation involves preparation of the abdominal aorta and inferior vena cava (IVC), followed by end-to-side anastomosis of the donor aorta with the recipient aorta using a single running 10-0 microsuture and a similar anastomosis of the donor pulmonary artery with the recipient IVC. Following the operation the animal is injected with 0.6 ml normal saline subcutaneously and allowed to recover on a 37 °C heating pad. The results from 227 mouse heart transplants are summarized with a success rate at 48 hr of 86.8%. Of the 13.2% failures within 48 hr, 5 (2.2%) experienced hind limb paralysis, 10 (4.4%) had a non-beating heart due to graft ischemic injury and/or thrombosis, while 15 (6.6%) died within 48 hr. PMID:24998365

  8. Variation in timing of ossification affects inferred heterochrony of cranial bones in Lissamphibia.

    PubMed

    Sheil, Christopher A; Jorgensen, Michael; Tulenko, Frank; Harrington, Sean

    2014-09-01

    The evolutionary origin of Lissamphibia likely involved heterochrony, as demonstrated by the biphasic lifestyles of most extant orders, differences between Anura (with tadpole-to-froglet metamorphosis) and Urodela (which lack strongly defined metamorphosis), and the appearance of direct development among separate lineages of frogs. Patterns in the timing of appearance of skeletal elements (i.e., ossification sequence data) represent a possible source of information for understanding the origin of Lissamphibia, and with the advent of analytical methods to directly optimize these data onto known phylogenies, there has been a renewed interest in assessing the role of changes in these developmental events. However, little attention has been given to the potential impact of variation in ossification sequence data--this is particularly surprising given that different criteria for collecting these data have been employed. Herein, new and previously published ossification data are compiled and all pairs of data for same-species comparisons are selected. Analyses are run to assess the impact of using data that were collected by different methodologies: (1) wild- versus lab-raised animals; (2) different criteria for recognizing timing of ossification; and (3) randomly selecting ossification sequences for species from which multiple studies have been published, but for which the data were collected by different criteria. Parsimov-based genetic inference is utilized to map ossification sequence data onto an existing phylogeny to reconstruct ancestral sequences of ossification and infer instances of heterochrony. All analyses succeeded in optimizing sequence data on internal nodes and instances of heterochrony were identified. However, among all analyses little congruence was found in reconstructed ancestral sequences or among inferred instances of heterochrony. These results indicate a high degree of variation in timing of ossification, and suggest a cautionary note about use

  9. Modified technique for heterotopic implantation of a right ventricular outflow tract conduit.

    PubMed

    Dave, Hitendu; Dodge-Khatami, Ali; Kadner, Alexander; Prêtre, René

    2006-06-01

    This article describes a modified technique of side-to-side proximal connection of a conduit during heterotopic implantation in the right ventricular outflow tract. It results in a better geometry of the right ventricular outflow and avoids distortion of the valve annulus, especially when the newer generation of straight xenografts are used. PMID:16731190

  10. Identity Formation and Affective Spaces in Conflict-Ridden Societies: Inventing Heterotopic Possibilities

    ERIC Educational Resources Information Center

    Zembylas, Michalinos; Ferreira, Ana

    2009-01-01

    In this article, we present vignettes from two projects--one in Cyprus and the other in South Africa--to show how some classrooms enact "heterotopic" affective spaces that oppose normal/ized identities, that is, identities grounded in polarized trauma narratives. The notion of heterotopia is a spatial concept developed by Foucault to emphasize the…

  11. Pathological Calcification and Ossification in Relation to Leriche and Policard's Theory

    PubMed Central

    Jones, Watson; Roberts, R. E.

    1933-01-01

    (1) Pathology of calcification and ossification.—The Leriche-Policard theories. Hyperæmia of bone causes decalcification. Reduced blood supply causes sclerosis. Diminution of vascularity of fibrous tissue causes calcification. Excess of calcium, adequate blood supply and fibroblasts give rise to bone anywhere. Subperiosteal ossification. “Myositis ossificans.” (2) Radiological significance of density of bone shadows.—Decalcification of disuse, of infections, of neoplasms. Traumatic and infective scquestra. Evidence that a fragment of bone is avascular. (3) Hyperæmic decalcification of bone.—Delayed and non-union of fractures. Kummel's disease. Spontaneous hyperæmic dislocation of the atlas. Hyperæmic decalcification and nephrolithiasis. (4) Anæmic sclerosis of bone.—Syphilitic bone disease. Malignant bone disease. Fragility of sclerosed bone—Paget's, Kienboch's, Kohler's and Panner's, Albers-Schönberg's diseases. (5) Pathological calcification.—Calcification of supraspinatus tendon. Calcification of tumours—angioma, hæmatoma, and thrombosed vessels, lipoma, cysts, etc. Calcification of semilunar cartilages and intervertebral discs. (6) Pathological ossification.—Ossification of tendons. Ossification of semilunar cartilages. PMID:19989304

  12. The Transcription Factor Hand1 Is Involved In Runx2-Ihh-Regulated Endochondral Ossification

    PubMed Central

    Laurie, Lindsay E.; Kokubo, Hiroki; Nakamura, Masataka; Saga, Yumiko; Funato, Noriko

    2016-01-01

    The developing long bone is a model of endochondral ossification that displays the morphological layers of chondrocytes toward the ossification center of the diaphysis. Indian hedgehog (Ihh), a member of the hedgehog family of secreted molecules, regulates chondrocyte proliferation and differentiation, as well as osteoblast differentiation, through the process of endochondral ossification. Here, we report that the basic helix-loop-helix transcription factor Hand1, which is expressed in the cartilage primordia, is involved in proper osteogenesis of the bone collar via its control of Ihh production. Genetic overexpression of Hand1 in the osteochondral progenitors resulted in prenatal hypoplastic or aplastic ossification in the diaphyses, mimicking an Ihh loss-of-function phenotype. Ihh expression was downregulated in femur epiphyses of Hand1-overexpressing mice. We also confirmed that Hand1 downregulated Ihh gene expression in vitro by inhibiting Runx2 transactivation of the Ihh proximal promoter. These results demonstrate that Hand1 in chondrocytes regulates endochondral ossification, at least in part through the Runx2-Ihh axis. PMID:26918743

  13. Chondrocyte-specific ablation of Osterix leads to impaired endochondral ossification

    SciTech Connect

    Oh, Jung-Hoon; Park, Seung-Yoon; Crombrugghe, Benoit de; Kim, Jung-Eun

    2012-02-24

    Highlights: Black-Right-Pointing-Pointer Conditional ablation of Osterix (Osx) in chondrocytes leads to skeletal defects. Black-Right-Pointing-Pointer Osx regulates chondrocyte differentiation and bone growth in growth plate chondrocytes. Black-Right-Pointing-Pointer Osx has an autonomous function in chondrocytes during endochondral ossification. -- Abstract: Osterix (Osx) is an essential transcription factor required for osteoblast differentiation during both intramembranous and endochondral ossification. Endochondral ossification, a process in which bone formation initiates from a cartilage intermediate, is crucial for skeletal development and growth. Osx is expressed in differentiating chondrocytes as well as osteoblasts during mouse development, but its role in chondrocytes has not been well studied. Here, the in vivo function of Osx in chondrocytes was examined in a chondrocyte-specific Osx conditional knockout model using Col2a1-Cre. Chondrocyte-specific Osx deficiency resulted in a weak and bent skeleton which was evident in newborn by radiographic analysis and skeletal preparation. To further understand the skeletal deformity of the chondrocyte-specific Osx conditional knockout, histological analysis was performed on developing long bones during embryogenesis. Hypertrophic chondrocytes were expanded, the formation of bone trabeculae and marrow cavities was remarkably delayed, and subsequent skeletal growth was reduced. The expression of several chondrocyte differentiation markers was reduced, indicating the impairment of chondrocyte differentiation and endochondral ossification in the chondrocyte-specific Osx conditional knockout. Taken together, Osx regulates chondrocyte differentiation and bone growth in growth plate chondrocytes, suggesting an autonomous function of Osx in chondrocytes during endochondral ossification.

  14. Gray, White Matter Concentration Changes and Their Correlation with Heterotopic Neurons in Temporal Lobe Epilepsy

    PubMed Central

    Tae, Woo Suk; Joo, Eun Yun; Kim, Sung Tae

    2010-01-01

    Objective To identify changes in gray and white matter concentrations (GMC, WMC), and their relation to heterotopic neuron numbers in mesial temporal lobe epilepsy (mTLE). Materials and Methods The gray matter or white matter concentrations of 16 left and 15 right mTLE patients who achieved an excellent surgical outcome were compared with those of 24 healthy volunteers for the left group and with 23 healthy volunteers for the right group, by optimized voxel-based morphometry using unmodulated and modulated images. A histologic count of heterotopic neurons was obtained in the white matter of the anterior temporal lobe originating from the patients' surgical specimens. In addition, the number of heterotopic neurons were tested to determine if there was a correlation with the GMC or WMC. Results The GMCs of the left and right mTLE groups were reduced in the ipsilateral hippocampi, bilateral thalami, precentral gyri, and in the cerebellum. The WMCs were reduced in the ipsilateral white matter of the anterior temporal lobe, bilateral parahippocampal gyri, and internal capsules, but increased in the pons and bilateral precentral gyri. The heterotopic neuron counts in the left mTLE group showed a positive correlation (r = 0.819, p < 0.0001) with GMCs and a negative correlation (r = -0.839, p < 0.0001) with WMCs in the white matter of the anterior temporal lobe. Conclusion The present study shows the abnormalities of the cortico-thalamo-hippocampal network including a gray matter volume reduction in the anterior frontal lobes and an abnormality of brain tissue concentration in the pontine area. Furthermore, heterotopic neuron numbers were significantly correlated with GMC or WMC in the left white matter of anterior temporal lobe. PMID:20046492

  15. [Contribution to the formal origin of multiple branched ossifications in the lung].

    PubMed

    Weigel, B; Hammer, H J; Ziegan, J

    1979-09-01

    The observation of multiple ossifications in the lungs as secondary findings of the post-mortem examination of a 62-year-old male with chronic cardiac stasis and emphysema of the lung is reported. Apart from bone nodules larger branched mature bone clasps with marrow caves as well as a in most cases fibromatosis with a small focus which represents the matrix of ossification is represented. Apart from this histologically a hyperaemia with an oedema rich in protein, focal precipitation of protein with formation of a granulation tissue and later fibrosation are to be proved as presteps of nodular fibromatosis which according to the kind of the desmal ossification changes into bones. The chronic haemostasis in the pulmonary circulation is thus apparently of importance in our observation. The case is compared with literature. Up to now about 65 of such observations are reported which nearly exclusively concern old men. The etiology remains unclear. PMID:120086

  16. Voriconazole-associated soft tissue ossification: an undescribed cause of glenohumeral joint capsulitis.

    PubMed

    Raghavan, Meera; Hayes, Alex

    2014-09-01

    Voriconazole-related periostitis has been increasingly described in the literature over the last several years as a recognizable disease entity, especially in lung transplant patients. This relationship should be considered when approaching immunosuppressed patients presenting with diffuse bone pain and imaging findings of periostitis. We present a case of voriconazole-associated periostitis, capsular and enthesial ossification and glenuhumeral capsulitis in a patient with a hematologic malignancy. To the authors' knowledge, soft tissue ossification associated with voriconazole has not been described in the radiology literature. PMID:24699891

  17. A Case of Intradermal Melanocytic Nevus with Ossification (Nevus of Nanta)

    PubMed Central

    Lee, Young Bok; Lee, Kyung Ho

    2008-01-01

    A 49-year-old woman presented with a 30-year history of asymptomatic plaque on her right temple. The histological examination revealed nests of nevus cells throughout the entire dermis. Bony spicules were seen just beneath the nevus cell nests in the lower dermis. Cutaneous ossification is an unusual event. Herein, we present a case of intradermal melanocytic nevus with unusual ossification (nevus of Nanta). To the best of our knowledge, this is the first such case report in the Korean literature. PMID:27303191

  18. Age estimation based on pelvic ossification using regression models from conventional radiography.

    PubMed

    Zhang, Kui; Dong, Xiao-Ai; Fan, Fei; Deng, Zhen-Hua

    2016-07-01

    To establish regression models for age estimation from the combination of the ossification of iliac crest and ischial tuberosity. One thousand three hundred and seventy-nine conventional pelvic radiographs at the West China Hospital of Sichuan University between January 2010 and June 2012 were evaluated retrospectively. The receiver operating characteristic analysis was performed to measure the value of estimation of 18 years of age with the classification scheme for the iliac crest and ischial tuberosity. Regression analysis was performed, and formulas for calculating approximate chronological age according to the combination developmental status of the ossification for the iliac crest and ischial tuberosity were developed. The areas under the receiver operating characteristic (ROC) curves were above 0.9 (p < 0.001), indicating a good prediction of the grading systems, and the cubic regression model was found to have the highest R-square value (R (2) = 0.744 for female and R (2) = 0.753 for male). The present classification scheme for apophyseal iliac crest ossification and the ischial tuberosity may be used for age estimation. And the present established cubic regression model according to the combination developmental status of the ossification for the iliac crest and ischial tuberosity can be used for age estimation. PMID:27169673

  19. Inhibition of cyclooxygenase-2 impacts chondrocyte hypertrophic differentiation during endochondral ossification.

    PubMed

    Welting, T J M; Caron, M M J; Emans, P J; Janssen, M P F; Sanen, K; Coolsen, M M E; Voss, L; Surtel, D A M; Cremers, A; Voncken, J W; van Rhijn, L W

    2011-01-01

    Skeletogenesis and bone fracture healing involve endochondral ossification, a process during which cartilaginous primordia are gradually replaced by bone tissue. In line with a role for cyclooxygenase-2 (COX-2) in the endochondral ossification process, non-steroidal anti-inflammatory drugs (NSAIDs) were reported to negatively affect bone fracture healing due to impaired osteogenesis. However, a role for COX-2 activity in the chondrogenic phase of endochondral ossification has not been addressed before. We show that COX-2 activity fulfils an important regulatory function in chondrocyte hypertrophic differentiation. Our data reveal essential cross-talk between COX-2 and bone morphogenic protein-2 (BMP-2) during chondrocyte hypertrophic differentiation. BMP-2 mediated chondrocyte hypertrophy is associated with increased COX-2 expression and pharmacological inhibition of COX-2 activity by NSAIDs (e.g., Celecoxib) decreases hypertrophic differentiation in various chondrogenic models in vitro and in vivo, while leaving early chondrogenic development unaltered. Our findings demonstrate that COX-2 activity is a novel factor partaking in chondrocyte hypertrophy in the context of endochondral ossification and these observations provide a novel etiological perspective on the adverse effects of NSAIDs on bone fracture healing and have important implications for the use of NSAIDs during endochondral skeletal development. PMID:22183916

  20. Timing of Ossification in Duck, Quail, and Zebra Finch: Intraspecific Variation, Heterochronies, and Life History Evolution

    PubMed Central

    Mitgutsch, Christian; Wimmer, Corinne; Sánchez-Villagra, Marcelo R.; Hahnloser, Richard; Schneider, Richard A.

    2011-01-01

    Skeletogenic heterochronies have gained much attention in comparative developmental biology. The temporal appearance of mineralized individual bones in a species – the species ossification sequence – is an excellent marker in this kind of study. Several publications describe interspecific variation, but only very few detail intraspecific variation. In this study, we describe and analyze the temporal order of ossification of skeletal elements in the zebra finch, Taeniopygia guttata, the Japanese quail, Coturnix coturnix japonica, and the White Pekin duck, a domestic race of the mallard Anas platyrhynchos, and explore patterns of intraspecific variation in these events. The overall sequences were found to be conserved. In the duck, variability is present in the relative timing of ossification in the occipital, the basisphenoid and the otic regions of the skull and the phalanges in the postcranium. This variation appears generally in close temporal proximity. Comparison with previously published data shows differences in ossification sequence in the skull, the feet, and the pelvis in the duck, and especially the pelvis in the quail. This clearly documents variability among different breeds. PMID:21728797

  1. Endochondral Ossification for Enhancing Bone Regeneration: Converging Native Extracellular Matrix Biomaterials and Developmental Engineering In Vivo

    PubMed Central

    Dennis, S. Connor; Berkland, Cory J.; Bonewald, Lynda F.

    2015-01-01

    Autologous bone grafting (ABG) remains entrenched as the gold standard of treatment in bone regenerative surgery. Consequently, many marginally successful bone tissue engineering strategies have focused on mimicking portions of ABG's “ideal” osteoconductive, osteoinductive, and osteogenic composition resembling the late reparative stage extracellular matrix (ECM) in bone fracture repair, also known as the “hard” or “bony” callus. An alternative, less common approach that has emerged in the last decade harnesses endochondral (EC) ossification through developmental engineering principles, which acknowledges that the molecular and cellular mechanisms involved in developmental skeletogenesis, specifically EC ossification, are closely paralleled during native bone healing. EC ossification naturally occurs during the majority of bone fractures and, thus, can potentially be utilized to enhance bone regeneration for nearly any orthopedic indication, especially in avascular critical-sized defects where hypoxic conditions favor initial chondrogenesis instead of direct intramembranous ossification. The body's native EC ossification response, however, is not capable of regenerating critical-sized defects without intervention. We propose that an underexplored potential exists to regenerate bone through the native EC ossification response by utilizing strategies which mimic the initial inflammatory or fibrocartilaginous ECM (i.e., “pro-” or “soft” callus) observed in the early reparative stage of bone fracture repair. To date, the majority of strategies utilizing this approach rely on clinically burdensome in vitro cell expansion protocols. This review will focus on the confluence of two evolving areas, (1) native ECM biomaterials and (2) developmental engineering, which will attempt to overcome the technical, business, and regulatory challenges that persist in the area of bone regeneration. Significant attention will be given to native “raw” materials

  2. Heterotopic new bone formation causes resorption of the inductive bone matrix

    SciTech Connect

    Nilsson, O.S.; Persson, P.E.; Ekelund, A. )

    1990-08-01

    The bone matrix of growing rats was labeled by multiple injections of 3H-proline, and demineralized bone matrix (DBM) was prepared. The DBM was allotransplanted heterotopically into growing rats. New bone formation was induced in and around the implants. The new bone formation was accompanied by a decrease in the content of 3H; 20 and 30 days after implantation, 72% and 46%, respectively, of the activity remained in the implants. Daily injections of indomethacin (2 mg/kg) inhibited calcium uptake by about 20% at 20 and 30 days and inhibited the release of 3H from the DBM to a similar degree. Heterotopic bone induction by DBM is accompanied by matrix resorption, and inhibition of the new bone formation decreases the resorption of DBM.

  3. Decreased heterotopic osteogenesis in vitamin-D-deficient, but normocalcemic guinea pigs

    NASA Technical Reports Server (NTRS)

    Dziedzic-Goclawska, A.; Toverud, S. U.; Kaminski, A.; Boass, A.; Yamauchi, M.

    1992-01-01

    The effect of vitamin D deficiency unhampered by hypocalcemia on de novo bone formation was studied in guinea pigs. Heterotopic induction of osteogenesis was evaluated 4 weeks after intramuscular transplantation of allogenic urinary bladder transitional epithelium from vitamin-D-repleted (+D) donors into +D and -D recipients. In -D recipients the frequency of osteogenesis and the amount of induced bone were significantly diminished; induced bone was less mature, scantly cellular woven bone poorly repopulated with bone marrow. No effect of vitamin D deficiency on orthotopic bone growth and on mineralization of orthotopic and heterotopically induced bone was observed. It is proposed that in addition to inducing factors (BMPs, growth factors) which may be responsible for transformation of mesenchymal cells to osteoprogenitor cells, normal concentrations of 1,25-(OH)2D3 may be required for proliferation and further differentiation of these cells into osteoblasts and for expression of genes engaged in extracellular matrix formation and maturation.

  4. Mirror Image Artifact Mimicking Heterotopic Pregnancy on Transvaginal Ultrasound: Case Series

    PubMed Central

    Malhotra, Radhika; Bramante, Robert M.; Radomski, Marek; Nelson, Mathew

    2014-01-01

    Vaginal bleeding in early pregnancy is a common emergency department complaint. Point-of-care ultrasound is a useful tool to evaluate for intrauterine ectopic pregnancy. Emergency physicians performing these studies need to be cognizant of artifacts produced by ultrasound technology, as they can lead to misdiagnosis. We present two cases where mirror-image artifacts initially led to a concern for heterotopic pregnancies but were excluded on further imaging. PMID:25247050

  5. A rare case of heterotopic pregnancy with ruptured left rudimentary horn pregnancy.

    PubMed

    Rathod, Setu; Samal, Sunil Kumar

    2015-03-01

    Heterotopic pregnancy(HP) occurs when intrauterine and ectopic pregnancies coexist. We report a case of HP at 14 wk of gestation presenting as ruptured left rudimentary horn ectopic pregnancy with live intrauterine gestation and was managed with emergency laparotomy followed by resection of left rudimentary non communicating horn of uterus. The intrauterine pregnancy continued uneventfully. A female baby was delivered vaginally at 41 wk following induction of labour. PMID:25954670

  6. A Rare Case of Heterotopic Pregnancy with Ruptured Left Rudimentary Horn Pregnancy

    PubMed Central

    Rathod, Setu

    2015-01-01

    Heterotopic pregnancy(HP) occurs when intrauterine and ectopic pregnancies coexist. We report a case of HP at 14 wk of gestation presenting as ruptured left rudimentary horn ectopic pregnancy with live intrauterine gestation and was managed with emergency laparotomy followed by resection of left rudimentary non communicating horn of uterus. The intrauterine pregnancy continued uneventfully. A female baby was delivered vaginally at 41 wk following induction of labour. PMID:25954670

  7. Effect of alendronate on endochondral ossification in mandibular condyles of growing rats

    PubMed Central

    Bradaschia-Correa, V.; Barrence, F.A.C.; Ferreira, L.B.; Massa, L.F.; Arana-Chavez, V.E.

    2012-01-01

    The replacement of the calcified cartilage by bone tissue during the endochondral ossification of the mandibular condyle is dependent of the resorbing activity of osteoclats. After partial resorption, calcified cartilage septa are covered by a primary bone matrix secreted by osteoblasts. Osteoadherin (OSAD) is a small proteoglycan present in bone matrix but absent in cartilage during the endochondral ossification. The aim of this study was to analyze the effect of alendronate, a drug known to inhibit bone resorption by osteoclasts, on the endochondral ossification of the mandibular condyle of young rats, by evaluating the distribution of osteoclasts and the presence of OSAD in the bone matrix deposited. Wistar newborn rats (n=45) received daily injections of alendronate (n=27) or sterile saline solution as control (n=18) from the day of birth until the ages of 4, 14 and 30 days. At the days mentioned, the mandibular condyles were collected and processed for transmission electron microscopy analysis. Specimens were also submitted to tartrate resistant acid phosphatase (TRAP) histochemistry and ultrastructural immunodetection of OSAD. Alendronate treatment did not impede the recruitment and fusion of osteoclasts at the ossification zone during condyle growth, but they presented inactivated phenotype. The trabeculae at the ossification area consisted of cartilage matrix covered by a layer of primary bone matrix that was immunopositive to OSAD at all time points studied. Apparently, alendronate impeded the removal of calcified cartilage and maturation of bone trabeculae in the mandibular ramus, while in controls they occurred normally. These findings highlight for giving attention to the potential side-effects of bisphosphonates administered to young patients once it may represent a risk of disturbing maxillofacial development. PMID:22688305

  8. Nuclear magnetic resonance and proton relaxation times in experimental heterotopic heart transplantation

    SciTech Connect

    Eugene, M.; Lechat, P.; Hadjiisky, P.; Teillac, A.; Grosgogeat, Y.; Cabrol, C.

    1986-01-01

    It should be possible to detect heart transplant rejection by nuclear magnetic resonance (NMR) imaging if it induces myocardial T1 and T2 proton relaxation time alterations or both. We studied 20 Lewis rats after a heterotopic heart transplantation. In vitro measurement of T1 and T2 was performed on a Minispec PC20 (Bruker) 3 to 9 days after transplantation. Histologic analysis allowed the quantification of rejection process based on cellular infiltration and myocardiolysis. Water content, a major determinant of relaxation time, was also studied. T1 and T2 were significantly prolonged in heterotopic vs orthotopic hearts (638 +/- 41 msec vs 606 +/- 22 msec for T1, p less than 0.01 and 58.2 +/- 8.4 msec vs 47.4 +/- 1.9 msec for T2, p less than 0.001). Water content was also increased in heterotopic hearts (76.4 +/- 2.3 vs 73.8 +/- 1.0, p less than 0.01). Most importantly, we found close correlations between T1 and especially T2 vs water content, cellular infiltration, and myocardiolysis. We conclude that rejection reaction should be noninvasively detected by NMR imaging, particularly with pulse sequences emphasizing T2.

  9. Celastrol inhibits prostaglandin E2-induced proliferation and osteogenic differentiation of fibroblasts isolated from ankylosing spondylitis hip tissues in vitro

    PubMed Central

    Zou, Yu-Cong; Yang, Xian-Wen; Yuan, Shi-Guo; Zhang, Pei; Li, Yi-Kai

    2016-01-01

    Background Heterotopic ossification on the enthesis, which develops after subsequent inflammation, is one of the most distinctive features in ankylosing spondylitis (AS). Prostaglandin E2 (PGE-2) serves as a key mediator of inflammation and bone remodeling in AS. Celastrol, a well-known Chinese medicinal herb isolated from Tripterygium wilfordii, is widely used in treating inflammatory diseases, including AS. It has been proven that it can inhibit lipopolysac-charide-induced expression of various inflammation mediators, such as PGE-2. However, the mechanism by which celastrol inhibits inflammation-induced bone forming in AS is unclear. Objective To investigate whether celastrol could inhibit isolated AS fibroblast osteogenesis induced by PGE-2. Methods Hip synovial tissues were obtained from six AS patients undergoing total hip replacement in our hospital. Fibroblasts were isolated, primarily cultured, and then treated with PGE-2 for osteogenic induction. Different doses of celastrol and indometacin were added to observe their effects on osteogenic differentiation. Cell proliferation, osteogenic markers, alizarin red staining as well as the activity of alkaline phosphatase were examined in our study. Results Celastrol significantly inhibits cell proliferation of isolated AS fibroblasts and in vitro osteogenic differentiation compared with control groups in a time- and dose-dependent manner. Conclusion Our results demonstrated that celastrol could inhibit isolated AS fibroblast proliferation and in vitro osteogenic differentiation. The interaction of PI3K/AKT signaling and Wnt protein may be involved in the process. Further studies should be performed in vivo and animal models to identify the potential effect of celastrol on the bone metabolism of AS patients. PMID:27022241

  10. Engineering Small-Scale and Scaffold-Based Bone Organs via Endochondral Ossification Using Adult Progenitor Cells.

    PubMed

    Scotti, Celeste; Tonnarelli, Beatrice; Papadimitropoulos, Adam; Piccinini, Elia; Todorov, Atanas; Centola, Matteo; Barbero, Andrea; Martin, Ivan

    2016-01-01

    Bone development, growth, and repair predominantly occur through the process of endochondral ossification, characterized by remodelling of cartilaginous templates. The same route efficiently supports engineering of bone marrow as a niche for hematopoietic stem cells (HSC). Here we describe a combined in vitro/in vivo system based on bone marrow-derived Mesenchymal Stem/Stromal Cells (MSC) that duplicates the hallmark cellular and molecular events of endochondral ossification during development. The model requires MSC culture with instructive molecules to generate hypertrophic cartilage tissues. The resulting constructs complete the endochondral route upon in vivo implantation, in the timeframe of up to 12 weeks. The described protocol is clearly distinct from the direct ossification approach typically used to drive MSC towards osteogenesis. Recapitulation of endochondral ossification allows modelling of stromal-HSC interactions in physiology and pathology and allows engineering processes underlying bone regeneration. PMID:27236686

  11. Stimulation of experimental endochondral ossification by low-energy pulsing electromagnetic fields

    SciTech Connect

    Aaron, R.K.; Ciombor, D.M.; Jolly, G.

    1989-04-01

    Pulsed electromagnetic fields (PEMFs) of certain configuration have been shown to be effective clinically in promoting the healing of fracture nonunions and are believed to enhance calcification of extracellular matrix. In vitro studies have suggested that PEMFs may also have the effect of modifying the extracellular matrix by promoting the synthesis of matrix molecules. This study examines the effect of one PEMF upon the extracellular matrix and calcification of endochondral ossification in vivo. The synthesis of cartilage molecules is enhanced by PEMF, and subsequent endochondral calcification is stimulated. Histomorphometric studies indicate that the maturation of bone trabeculae is also promoted by PEMF stimulation. These results indicate that a specific PEMF can change the composition of cartilage extracellular matrix in vivo and raises the possibility that the effects on other processes of endochondral ossification (e.g., fracture healing and growth plates) may occur through a similar mechanism.

  12. Inactivation of Fam20B in Joint Cartilage Leads to Chondrosarcoma and Postnatal Ossification Defects.

    PubMed

    Ma, Pan; Yan, Wenjuan; Tian, Ye; Wang, Jingya; Feng, Jian Q; Qin, Chunlin; Cheng, Yi-Shing Lisa; Wang, Xiaofang

    2016-01-01

    During endochondral ossification, chondrocytes embed themselves in a proteoglycan-rich matrix during the proliferation-maturation transition. Accumulating evidence shows that proteoglycans are essential components for chondrocyte proliferation and differentiation. When we conditionally inactivated FAM20B (Family with sequence similarity 20 member-B), which is a newly identified xylose kinase essential for glycosaminoglycan (GAG) formation on the protein core of proteoglycans, from the dental mesenchyme using Osr2-Cre, which is also strongly expressed in joint cartilage, we found chondrosarcoma in the knee joint and remarkable defects of postnatal ossification in the long bones. Mechanistic analysis revealed that the defects were associated with gain of function in multiple signaling pathways in the epiphyseal chondrocytes, such as those derived by WNT, BMP, and PTHrP/IHH molecules, suggesting that the FAM20B-catalyzed proteoglycans are critical mediators for a signaling balance in the regulatory network controlling chondrocyte differentiation and proliferation. In particular, we demonstrated that the WNT inhibitor was able to rescue part of the bone defects in Osr2-Cre;Fam20B(fl/fl) mice, indicating that FAM20B-catalyzed proteoglycans regulate postnatal endochondral ossification partially through the mediation of WNT signaling. PMID:27405802

  13. Inactivation of Fam20B in Joint Cartilage Leads to Chondrosarcoma and Postnatal Ossification Defects

    PubMed Central

    Ma, Pan; Yan, Wenjuan; Tian, Ye; Wang, Jingya; Feng, Jian Q.; Qin, Chunlin; Cheng, Yi-Shing Lisa; Wang, Xiaofang

    2016-01-01

    During endochondral ossification, chondrocytes embed themselves in a proteoglycan-rich matrix during the proliferation-maturation transition. Accumulating evidence shows that proteoglycans are essential components for chondrocyte proliferation and differentiation. When we conditionally inactivated FAM20B (Family with sequence similarity 20 member-B), which is a newly identified xylose kinase essential for glycosaminoglycan (GAG) formation on the protein core of proteoglycans, from the dental mesenchyme using Osr2-Cre, which is also strongly expressed in joint cartilage, we found chondrosarcoma in the knee joint and remarkable defects of postnatal ossification in the long bones. Mechanistic analysis revealed that the defects were associated with gain of function in multiple signaling pathways in the epiphyseal chondrocytes, such as those derived by WNT, BMP, and PTHrP/IHH molecules, suggesting that the FAM20B-catalyzed proteoglycans are critical mediators for a signaling balance in the regulatory network controlling chondrocyte differentiation and proliferation. In particular, we demonstrated that the WNT inhibitor was able to rescue part of the bone defects in Osr2-Cre;Fam20Bfl/fl mice, indicating that FAM20B-catalyzed proteoglycans regulate postnatal endochondral ossification partially through the mediation of WNT signaling. PMID:27405802

  14. Variation in mammalian proximal femoral development: comparative analysis of two distinct ossification patterns

    PubMed Central

    Serrat, Maria A; Reno, Philip L; McCollum, Melanie A; Meindl, Richard S; Lovejoy, C Owen

    2007-01-01

    The developmental anatomy of the proximal femur is complex. In some mammals, including humans, the femoral head and greater trochanter emerge as separate ossification centres within a common chondroepiphysis and remain separate throughout ontogeny. In other species, these secondary centres coalesce within the chondroepiphysis to form a single osseous epiphysis much like the proximal humerus. These differences in femoral ontogeny have not been previously addressed, yet are critical to an understanding of femoral mineralization and architecture across a wide range of mammals and may have key implications for understanding and treating hip abnormalities in humans. We evaluated femora from 70 mammalian species and categorized each according to the presence of a ‘separate’ or ‘coalesced’ proximal epiphysis based on visual assessment. We found that ossification type varies widely among mammals: taxa in the ‘coalesced’ group include marsupials, artiodactyls, perissodactyls, bats, carnivores and several primates, while the ‘separate’ group includes hominoids, many rodents, tree shrews and several marine species. There was no clear relationship to body size, phylogeny or locomotion, but qualitative and quantitative differences between the groups suggest that ossification type may be primarily an artefact of femoral shape and neck length. As some osseous abnormalities of the human hip appear to mimic the normal morphology of species with coalesced epiphyses, these results may provide insight into the aetiology and treatment of human hip disorders such as femoroacetabular impingement and early-onset osteoarthritis. PMID:17331175

  15. Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

    PubMed Central

    Guo, Mian; Shen, Jia; Kwak, Jin Hee; Choi, Bogyu; Lee, Min; Hu, Shen; Zhang, Xinli; Ting, Kang; Soo, Chia B.

    2015-01-01

    Recent studies showed that cyclophilin A (CypA) promotes NF-κB/p65 nuclear translocation, resulting in enhanced NF-κB activity and altered expression of its target genes, such as the Sox9 transcriptional factor, which plays a critical role in chondrogenic differentiation and endochondral ossification. In this report, we unveil the role of CypA in signal-induced chondrogenic differentiation and endochondral ossification. Expression levels of the chondrogenic differentiation markers and transcriptional regulators Sox9 and Runx2 were all significantly lower in CypA knockdown chondrogenic cells than in wild-type cells, indicating that CypA plays a functional role in chondrogenic differentiation. In vitro differentiation studies using micromass cultures of mouse limb bud cells further supported the conclusion that CypA is needed for chondrogenic differentiation. Newborn CypA-deficient pups double stained with alcian blue and alizarin red exhibited generalized, pronounced skeletal defects, while high-resolution micro-computed tomography (microCT) analyses of the femurs and lumbar vertebrae revealed delayed or incomplete endochondral ossification. Comparative histology and immunohistochemistry (IHC) analyses further verified the effects of CypA deficiency on chondrogenic differentiation. Our results provide evidence for the important contribution of CypA as a pertinent component acting through NF-κB–Sox9 in regulation of chondrogenesis signaling. These findings are important to better understand signal-induced chondrogenesis of chondrogenic progenitors in physiological and pathophysiological contexts. PMID:25870110

  16. Osteogenic capillaries orchestrate growth plate-independent ossification of the malleus

    PubMed Central

    Matsuo, Koichi; Kuroda, Yukiko; Nango, Nobuhito; Shimoda, Kouji; Kubota, Yoshiaki; Ema, Masatsugu; Bakiri, Latifa; Wagner, Erwin F.; Takeda, Yoshihiro; Yashiro, Wataru; Momose, Atsushi

    2015-01-01

    Endochondral ossification is a developmental process by which cartilage is replaced by bone. Terminally differentiated hypertrophic chondrocytes are calcified, vascularized, and removed by chondroclasts before bone matrix is laid down by osteoblasts. In mammals, the malleus is one of three auditory ossicles that transmit vibrations of the tympanic membrane to the inner ear. The malleus is formed from a cartilaginous precursor without growth plate involvement, but little is known about how bones of this type undergo endochondral ossification. Here, we demonstrate that in the processus brevis of the malleus, clusters of osteoblasts surrounding the capillary loop produce bone matrix, causing the volume of the capillary lumen to decrease rapidly in post-weaning mice. Synchrotron X-ray tomographic microscopy revealed a concentric, cylindrical arrangement of osteocyte lacunae along capillaries, indicative of pericapillary bone formation. Moreover, we report that overexpression of Fosl1, which encodes a component of the AP-1 transcription factor complex, in osteoblasts significantly blocked malleal capillary narrowing. These data suggest that osteoblast/endothelial cell interactions control growth plate-free endochondral ossification through ‘osteogenic capillaries’ in a Fosl1-regulated manner. PMID:26428006

  17. Osteogenic capillaries orchestrate growth plate-independent ossification of the malleus.

    PubMed

    Matsuo, Koichi; Kuroda, Yukiko; Nango, Nobuhito; Shimoda, Kouji; Kubota, Yoshiaki; Ema, Masatsugu; Bakiri, Latifa; Wagner, Erwin F; Takeda, Yoshihiro; Yashiro, Wataru; Momose, Atsushi

    2015-11-15

    Endochondral ossification is a developmental process by which cartilage is replaced by bone. Terminally differentiated hypertrophic chondrocytes are calcified, vascularized, and removed by chondroclasts before bone matrix is laid down by osteoblasts. In mammals, the malleus is one of three auditory ossicles that transmit vibrations of the tympanic membrane to the inner ear. The malleus is formed from a cartilaginous precursor without growth plate involvement, but little is known about how bones of this type undergo endochondral ossification. Here, we demonstrate that in the processus brevis of the malleus, clusters of osteoblasts surrounding the capillary loop produce bone matrix, causing the volume of the capillary lumen to decrease rapidly in post-weaning mice. Synchrotron X-ray tomographic microscopy revealed a concentric, cylindrical arrangement of osteocyte lacunae along capillaries, indicative of pericapillary bone formation. Moreover, we report that overexpression of Fosl1, which encodes a component of the AP-1 transcription factor complex, in osteoblasts significantly blocked malleal capillary narrowing. These data suggest that osteoblast/endothelial cell interactions control growth plate-free endochondral ossification through 'osteogenic capillaries' in a Fosl1-regulated manner. PMID:26428006

  18. Novel role for cyclophilin A in regulation of chondrogenic commitment and endochondral ossification.

    PubMed

    Guo, Mian; Shen, Jia; Kwak, Jin Hee; Choi, Bogyu; Lee, Min; Hu, Shen; Zhang, Xinli; Ting, Kang; Soo, Chia B; Chiu, Robert H

    2015-06-01

    Recent studies showed that cyclophilin A (CypA) promotes NF-κB/p65 nuclear translocation, resulting in enhanced NF-κB activity and altered expression of its target genes, such as the Sox9 transcriptional factor, which plays a critical role in chondrogenic differentiation and endochondral ossification. In this report, we unveil the role of CypA in signal-induced chondrogenic differentiation and endochondral ossification. Expression levels of the chondrogenic differentiation markers and transcriptional regulators Sox9 and Runx2 were all significantly lower in CypA knockdown chondrogenic cells than in wild-type cells, indicating that CypA plays a functional role in chondrogenic differentiation. In vitro differentiation studies using micromass cultures of mouse limb bud cells further supported the conclusion that CypA is needed for chondrogenic differentiation. Newborn CypA-deficient pups double stained with alcian blue and alizarin red exhibited generalized, pronounced skeletal defects, while high-resolution micro-computed tomography (microCT) analyses of the femurs and lumbar vertebrae revealed delayed or incomplete endochondral ossification. Comparative histology and immunohistochemistry (IHC) analyses further verified the effects of CypA deficiency on chondrogenic differentiation. Our results provide evidence for the important contribution of CypA as a pertinent component acting through NF-κB-Sox9 in regulation of chondrogenesis signaling. These findings are important to better understand signal-induced chondrogenesis of chondrogenic progenitors in physiological and pathophysiological contexts. PMID:25870110

  19. Tranilast stimulates endochondral ossification by upregulating SOX9 and RUNX2 promoters.

    PubMed

    Hasegawa, Sachi; Kitoh, Hiroshi; Ohkawara, Bisei; Mishima, Kenichi; Matsushita, Masaki; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

    2016-02-01

    Endochondral ossification is an essential process for reparative phase of fracture healing, which starts with the differentiation of mesenchymal cells into chondrocytes followed by substitution of bone tissue. It is strictly controlled by the expression of crucial transcriptional factors: SOX9 in the early phase and RUNX2 in the late phase. Screening of FDA-approved compounds revealed that an anti-allergic drug, tranilast, that has been used for more than 30 years in clinical practice, enhanced the SOX9 promoter in chondrogenic cells and the RUNX2 promoter in osteoblastic cells. We observed that tranilast increased mRNA expression of both Sox9 and Runx2 in differentiating ATDC5 chondrogenic progenitor cells. Tranilast upregulated mRNA expression of chondrogenic marker genes (Col2a1, Acan, Col10a1, and Mmp13) in differentiating ATDC5 cells. Moreover, tranilast upregulated mRNA expression of essential signaling molecules involved in endochondral ossification (Pthrp, Ihh, and Axin2). In the later phase of differentiation of ATDC5 cells, tranilast increased synthesis of matrix proteoglycans, induced the alkaline phosphatase activity, and tended to accelerate mineralization. Tranilast is a potential agent that accelerates fracture repair by promoting the regulatory steps of endochondral ossification. PMID:26777999

  20. The Role of Matrix Gla Protein in Ossification and Recovery of the Avian Growth Plate

    PubMed Central

    Dan, Harel; Simsa-Maziel, Stav; Reich, Adi; Sela-Donenfeld, Dalit; Monsonego-Ornan, Efrat

    2012-01-01

    Extracellular matrix mineralization is an essential physiologic process in bone, teeth, and hypertrophic cartilage. Matrix Gla protein (MGP), an inhibitor of mineralization, is expressed by chondrocytes and vascular smooth muscle cells to inhibit calcification of those soft tissues. Tibial dyschondroplasia (TD), a skeletal abnormality apparent as a plug of non-vascularized, non-mineralized, white opaque cartilage in the tibial growth plate of avian species can serve as a good model for studying process and genes involved in matrix mineralization and calcification. In this work, we studied the involvement of MGP in the development of TD, as well as in the processes of spontaneous and induced recovery from this syndrome. First, we found that during normal bone development, MGP is expressed in specific time and locations, starting from wide-spread expression in the yet un-ossified diaphysis during embryonic development, to specific expression in hypertrophic chondrocytes adjacent to the chondro-osseous junction and the secondary ossification center just prior to calcification. In addition, we show that MGP is not expressed in the impaired TD lesion, however when the lesion begins to heal, it strongly express MGP prior to its calcification. Moreover, we show that when calcification is inhibited, a gap is formed between the expression zones of MGP and BMP2 and that this gap is closed during the healing process. To conclude, we suggest that MGP, directly or through interaction with BMP2, plays a role as ossification regulator that acts prior to ossification, rather then simple inhibitor. PMID:22787455

  1. ADAM17 Controls Endochondral Ossification by Regulating Terminal Differentiation of Chondrocytes

    PubMed Central

    Hall, Katherine C.; Hill, Daniel; Otero, Miguel; Plumb, Darren A.; Froemel, Dara; Dragomir, Cecilia L.; Maretzky, Thorsten; Boskey, Adele; Crawford, Howard C.; Selleri, Licia; Goldring, Mary B.

    2013-01-01

    Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17ΔCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis. PMID:23732913

  2. Heterotopic cardiac transplantation decreases the capacity for rat myocardial protein synthesis

    SciTech Connect

    Klein, I.; Samarel, A.M.; Welikson, R.; Hong, C. )

    1991-04-01

    Heterotopic cardiac isografts are vascularly perfused hearts that maintain structural and functional integrity for prolonged periods of time. When placed in an infrarenal location, the heart is hemodynamically unloaded and undergoes negative growth, leading to cardiac atrophy. At 7 and 14 days after transplantation, the transplanted heart was decreased in size compared with the in situ heart (p less than 0.001). To assess the possible mechanism(s) to account for this reduction in size we studied in vivo rates of total left ventricular (LV) protein synthesis, total LV RNA content, and 18S ribosomal RNA content by nucleic acid hybridization. The LV protein synthetic rate was 4.7 and 5.3 mg/day in the in situ heart and was significantly decreased to 2.9 and 2.7 mg/day in the transplanted hearts at 7 and 14 days, respectively. LV RNA content of the transplant declined to 53% and 48% of the in situ value at 7 and 14 days, respectively. Hybridization studies revealed that LV 18S ribosomal subunit content was reduced proportionately to total RNA in the heterotopic hearts. As a result of these changes, there was no significant difference in the efficiency of total LV protein synthesis between the in situ and transplanted hearts. The present studies demonstrate that the hemodynamic unloading and cardiac atrophy that is characteristic of heterotopic cardiac transplantation is accompanied by a decrease in LV total RNA content and 18S RNA, resulting in a decreased capacity for myocardial protein synthesis.

  3. Welfare Assessment following Heterotopic or Orthotopic Inoculation of Bladder Cancer in C57BL/6 Mice.

    PubMed

    Miller, Amy; Burson, Hannah; Söling, Ariane; Roughan, Johnny

    2016-01-01

    Few studies have assessed whether mice used as cancer models experience pain. Despite this possibility, the usual practice is to withhold analgesics as these are generally viewed as confounding. However, pain also alters cancer progression, so preventing it might not only be beneficial to welfare but also to study validity. Establishing the extent to which different cancer models result in pain is an important first step towards their refinement. We used conditioned place preference (CPP) testing and body-weight and behaviour analyses to evaluate the assumption that heterotopically implanted tumours result in less pain and fewer welfare concerns than those implanted orthotopically. C57Bl/6 mice received MB49Luc luciferase expressing bladder cancer cells or saline implanted subcutaneously or into the bladder. These tumour-bearing or control groups underwent 2 daily 45 minute conditioning trials to saline or morphine (2mg/kg) and then a 15 minute drug-free preference test on day 3 of a 3 day cycle, continuing until the study ended. Tumours were imaged and behaviour data obtained following preference tests. Development of preference for the morphine-paired chamber (morphine-seeking) was determined over time. Heterotopic tumour development had no effect on morphine-seeking, and although the restraint used for heterotopic inoculation caused greater initial weight losses than anaesthesia, these mice steadily gained weight and behaved comparatively normally throughout the study. Orthotopic tumour inoculation caused no initial weight losses, but over the final 7 days these mice became less active and lost more body weight than cancer-free controls. This indicated orthotopic implantation probably caused a more negative impact on welfare or conceivably pain; but only according to the current test methods. Pain could not be confirmed because morphine-seeking in the tumour-bearing groups was similar to that seen in controls. Imaging was not found to be an effective method of

  4. Welfare Assessment following Heterotopic or Orthotopic Inoculation of Bladder Cancer in C57BL/6 Mice

    PubMed Central

    Miller, Amy; Burson, Hannah; Söling, Ariane

    2016-01-01

    Few studies have assessed whether mice used as cancer models experience pain. Despite this possibility, the usual practice is to withhold analgesics as these are generally viewed as confounding. However, pain also alters cancer progression, so preventing it might not only be beneficial to welfare but also to study validity. Establishing the extent to which different cancer models result in pain is an important first step towards their refinement. We used conditioned place preference (CPP) testing and body-weight and behaviour analyses to evaluate the assumption that heterotopically implanted tumours result in less pain and fewer welfare concerns than those implanted orthotopically. C57Bl/6 mice received MB49Luc luciferase expressing bladder cancer cells or saline implanted subcutaneously or into the bladder. These tumour-bearing or control groups underwent 2 daily 45 minute conditioning trials to saline or morphine (2mg/kg) and then a 15 minute drug-free preference test on day 3 of a 3 day cycle, continuing until the study ended. Tumours were imaged and behaviour data obtained following preference tests. Development of preference for the morphine-paired chamber (morphine-seeking) was determined over time. Heterotopic tumour development had no effect on morphine-seeking, and although the restraint used for heterotopic inoculation caused greater initial weight losses than anaesthesia, these mice steadily gained weight and behaved comparatively normally throughout the study. Orthotopic tumour inoculation caused no initial weight losses, but over the final 7 days these mice became less active and lost more body weight than cancer-free controls. This indicated orthotopic implantation probably caused a more negative impact on welfare or conceivably pain; but only according to the current test methods. Pain could not be confirmed because morphine-seeking in the tumour-bearing groups was similar to that seen in controls. Imaging was not found to be an effective method of

  5. Special pattern of endochondral ossification in human laryngeal cartilages: X-ray and light-microscopic studies on thyroid cartilage.

    PubMed

    Claassen, Horst; Schicht, Martin; Sel, Saadettin; Paulsen, Friedrich

    2014-04-01

    Endochondral ossification is a process that also occurs in the skeleton of the larynx. Differences in the ossification mechanism in comparison to growth plates are not understood until now. To get deeper insights into this process, human thyroid cartilage was investigated by the use of X-rays and a series of light-microscopic stainings. A statistical analysis of mineralization was done by scanning areas of mineralized cartilage and of ossification. We detected a special mode of endochondral ossification which differs from the processes in growth plates. Thyroid cartilage ossifies very slowly and in a gender-specific manner. Compared with age-matched women, bone formation in thyroid cartilage of men is significantly higher in the age group 41-60 years. Endochondral ossification is prepared by internal changes of extracellular matrix leading to areas of asbestoid fibers with ingrowing cartilage canals. In contrast to growth plates, bone is deposited on large areas of mineralized cartilage, which appear at the rims of cartilage canals. Furthermore, primary parallel fibered bone was observed which was deposited on woven bone. The predominant bone type is cancellous bone with trabeculae, whereas compact bone with Haversian systems was seldom found. Trabeculae contain a great number of reversal and arresting lines meaning that the former were often reconstructed and that bone formation was arrested and resumed again with advancing age. It is hypothesized that throughout life trabeculae of ossified thyroid cartilage undergo adaptation to different loads due to the use of voice. PMID:24496984

  6. Effect of posterior decompression extent on biomechanical parameters of the spinal cord in cervical ossification of the posterior longitudinal ligament.

    PubMed

    Khuyagbaatar, Batbayar; Kim, Kyungsoo; Park, Won Man; Kim, Yoon Hyuk

    2016-06-01

    Ossification of the posterior longitudinal ligament is a common cause of the cervical myelopathy due to compression of the spinal cord. Patients with ossification of the posterior longitudinal ligament usually require the decompression surgery, and there is a need to better understand the optimal surgical extent with which sufficient decompression without excessive posterior shifting can be achieved. However, few quantitative studies have clarified this optimal extent for decompression of cervical ossification of the posterior longitudinal ligament. We used finite element modeling of the cervical spine and spinal cord to investigate the effect of posterior decompression extent for continuous-type cervical ossification of the posterior longitudinal ligament on changes in stress, strain, and posterior shifting that occur with three different surgical methods (laminectomy, laminoplasty, and hemilaminectomy). As posterior decompression extended, stress and strain in the spinal cord decreased and posterior shifting of the cord increased. The location of the decompression extent also influenced shifting. Laminectomy and laminoplasty were very similar in terms of decompression results, and both were superior to hemilaminectomy in all parameters tested. Decompression to the extents of C3-C6 and C3-C7 of laminectomy and laminoplasty could be considered sufficient with respect to decompression itself. Our findings provide fundamental information regarding the treatment of cervical ossification of the posterior longitudinal ligament and can be applied to patient-specific surgical planning. PMID:26951839

  7. Epiphyseal chondrocyte secondary ossification centers require thyroid hormone activation of Indian hedgehog and osterix signaling.

    PubMed

    Xing, Weirong; Cheng, Shaohong; Wergedal, Jon; Mohan, Subburaman

    2014-10-01

    Thyroid hormones (THs) are known to regulate endochondral ossification during skeletal development via acting directly in chondrocytes and osteoblasts. In this study, we focused on TH effects on the secondary ossification center (SOC) because the time of appearance of SOCs in several species coincides with the time when peak levels of TH are attained. Accordingly, micro-computed tomography (µCT) evaluation of femurs and tibias at day 21 in TH-deficient and control mice revealed that endochondral ossification of SOCs is severely compromised owing to TH deficiency and that TH treatment for 10 days completely rescued this phenotype. Staining of cartilage and bone in the epiphysis revealed that whereas all of the cartilage is converted into bone in the prepubertal control mice, this conversion failed to occur in the TH-deficient mice. Immunohistochemistry studies revealed that TH treatment of thyroid stimulating hormone receptor mutant (Tshr(-/-) ) mice induced expression of Indian hedgehog (Ihh) and Osx in type 2 collagen (Col2)-expressing chondrocytes in the SOC at day 7, which subsequently differentiate into type 10 collagen (Col10)/osteocalcin-expressing chondro/osteoblasts at day 10. Consistent with these data, treatment of tibia cultures from 3-day-old mice with 10 ng/mL TH increased expression of Osx, Col10, alkaline phosphatase (ALP), and osteocalcin in the epiphysis by sixfold to 60-fold. Furthermore, knockdown of the TH-induced increase in Osx expression using lentiviral small hairpin RNA (shRNA) significantly blocked TH-induced ALP and osteocalcin expression in chondrocytes. Treatment of chondrogenic cells with an Ihh inhibitor abolished chondro/osteoblast differentiation and SOC formation. Our findings indicate that TH regulates the SOC initiation and progression via differentiating chondrocytes into bone matrix-producing osteoblasts by stimulating Ihh and Osx expression in chondrocytes. PMID:24753031

  8. Epiphyseal chondrocyte secondary ossification centers require thyroid hormone activation of Indian hedgehog and osterix signaling

    PubMed Central

    Xing, Weirong; Cheng, Shaohong; Wergedal, Jon; Mohan, Subburaman

    2015-01-01

    Thyroid hormones (TH) are known to regulate endochondral ossification during skeletal development via acting directly in chondrocytes and osteoblasts. In this study, we focused on TH effects on the secondary ossification center (SOC), since the time of appearance of SOCs in several species coincides with the time when peak levels of TH are attained. Accordingly, μCT evaluation of femurs and tibias at day 21 in TH-deficient and control mice revealed that endochondral ossification of SOCs is severely compromised due to TH deficiency and that TH treatment for 10 days completely rescued this phenotype. Staining of cartilage and bone in the epiphysis revealed that while all of the cartilage is converted into bone in the prepubertal control mice, this conversion failed to occur in the TH-deficient mice. Immunohistochemistry studies revealed that TH treatment of Tshr−/− mice induced expression of Ihh and Osx in Col2 expressing chondrocytes in the SOC at day 7 which subsequently differentiate into Col10/osteocalcin expressing chondro-osteoblasts at day 10. Consistent with these data, treatment of tibia cultures from 3-day old mice with10 ng/ml TH increased expression of Osx, Col10, ALP and osteocalcin in the epiphysis by 6–60 fold. Furthermore, knockdown of the TH-induced increase in Osx expression using lentiviral shRNA significantly blocked TH-induced ALP and osteocalcin expression in chondrocytes. Treatment of chondrogenic cells with an Ihh inhibitor abolished chondro-osteoblast differentiation and SOC formation. Our findings indicate that TH regulates the SOC initiation and progression via differentiating chondrocytes into bone matrix producing osteoblasts by stimulating Ihh and Osx expression in chondrocytes. PMID:24753031

  9. Delayed hypertrophic differentiation of epiphyseal chondrocytes contributes to failed secondary ossification in mucopolysaccharidosis VII dogs.

    PubMed

    Peck, Sun H; O'Donnell, Philip J M; Kang, Jennifer L; Malhotra, Neil R; Dodge, George R; Pacifici, Maurizio; Shore, Eileen M; Haskins, Mark E; Smith, Lachlan J

    2015-11-01

    Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient β-glucuronidase activity, which leads to the accumulation of incompletely degraded glycosaminoglycans (GAGs). MPS VII patients present with severe skeletal abnormalities, which are particularly prevalent in the spine. Incomplete cartilage-to-bone conversion in MPS VII vertebrae during postnatal development is associated with progressive spinal deformity and spinal cord compression. The objectives of this study were to determine the earliest postnatal developmental stage at which vertebral bone disease manifests in MPS VII and to identify the underlying cellular basis of impaired cartilage-to-bone conversion, using the naturally-occurring canine model. Control and MPS VII dogs were euthanized at 9 and 14 days-of-age, and vertebral secondary ossification centers analyzed using micro-computed tomography, histology, qPCR, and protein immunoblotting. Imaging studies and mRNA analysis of bone formation markers established that secondary ossification commences between 9 and 14 days in control animals, but not in MPS VII animals. mRNA analysis of differentiation markers revealed that MPS VII epiphyseal chondrocytes are unable to successfully transition from proliferation to hypertrophy during this critical developmental window. Immunoblotting demonstrated abnormal persistence of Sox9 protein in MPS VII cells between 9 and 14 days-of-age, and biochemical assays revealed abnormally high intra and extracellular GAG content in MPS VII epiphyseal cartilage at as early as 9 days-of-age. In contrast, assessment of vertebral growth plates and primary ossification centers revealed no significant abnormalities at either age. The results of this study establish that failed vertebral bone formation in MPS VII can be traced to the failure of epiphyseal chondrocytes to undergo hypertrophic differentiation at the appropriate developmental stage, and suggest that aberrant processing of Sox9 protein

  10. Genomic study of ossification of the posterior longitudinal ligament of the spine

    PubMed Central

    IKEGAWA, Shiro

    2014-01-01

    Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common disease after the middle age. OPLL frequently causes serious neurological problems due to compression of the spinal cord and/or nerve roots. OPLL occurs in patients with monogenic metabolic diseases including rickets/osteomalacia and hypoparathyroidism; however most of OPLL is idiopathic and is considered as a multi-factorial (polygenic) disease influenced by genetic and environmental factors. Genomic studies for the genetic factors of OPLL have been conducted, mainly in Japan, including linkage and association studies. This paper reviews the recent progress in the genomic study of OPLL and comments on its future direction. PMID:25504229

  11. Endothelial Rictor is crucial for midgestational development and sustained and extensive FGF2-induced neovascularization in the adult

    PubMed Central

    Aimi, Fabio; Georgiopoulou, Stavroula; Kalus, Ina; Lehner, Fabienne; Hegglin, Alica; Limani, Përparim; Gomes de Lima, Vinicius; A. Rüegg, Markus; Hall, Michael N.; Lindenblatt, Nicole; Haas, Elvira; Battegay, Edouard J.; Humar, Rok

    2015-01-01

    To explore the general requirement of endothelial mTORC2 during embryonic and adolescent development, we knocked out the essential mTORC2 component Rictor in the mouse endothelium in the embryo, during adolescence and in endothelial cells in vitro. During embryonic development, Rictor knockout resulted in growth retardation and lethality around embryonic day 12. We detected reduced peripheral vascularization and delayed ossification of developing fingers, toes and vertebrae during this confined midgestational period. Rictor knockout did not affect viability, weight gain, and vascular development during further adolescence. However during this period, Rictor knockout prevented skin capillaries to gain larger and heterogeneously sized diameters and remodeling into tortuous vessels in response to FGF2. Rictor knockout strongly reduced extensive FGF2-induced neovascularization and prevented hemorrhage in FGF2-loaded matrigel plugs. Rictor knockout also disabled the formation of capillary-like networks by FGF2-stimulated mouse aortic endothelial cells in vitro. Low RICTOR expression was detected in quiescent, confluent mouse aortic endothelial cells, whereas high doses of FGF2 induced high RICTOR expression that was associated with strong mTORC2-specific protein kinase Cα and AKT phosphorylation. We demonstrate that the endothelial FGF-RICTOR axis is not required during endothelial quiescence, but crucial for midgestational development and sustained and extensive neovascularization in the adult. PMID:26635098

  12. Endothelial Rictor is crucial for midgestational development and sustained and extensive FGF2-induced neovascularization in the adult.

    PubMed

    Aimi, Fabio; Georgiopoulou, Stavroula; Kalus, Ina; Lehner, Fabienne; Hegglin, Alica; Limani, Përparim; Gomes de Lima, Vinicius; Rüegg, Markus A; Hall, Michael N; Lindenblatt, Nicole; Haas, Elvira; Battegay, Edouard J; Humar, Rok

    2015-01-01

    To explore the general requirement of endothelial mTORC2 during embryonic and adolescent development, we knocked out the essential mTORC2 component Rictor in the mouse endothelium in the embryo, during adolescence and in endothelial cells in vitro. During embryonic development, Rictor knockout resulted in growth retardation and lethality around embryonic day 12. We detected reduced peripheral vascularization and delayed ossification of developing fingers, toes and vertebrae during this confined midgestational period. Rictor knockout did not affect viability, weight gain, and vascular development during further adolescence. However during this period, Rictor knockout prevented skin capillaries to gain larger and heterogeneously sized diameters and remodeling into tortuous vessels in response to FGF2. Rictor knockout strongly reduced extensive FGF2-induced neovascularization and prevented hemorrhage in FGF2-loaded matrigel plugs. Rictor knockout also disabled the formation of capillary-like networks by FGF2-stimulated mouse aortic endothelial cells in vitro. Low RICTOR expression was detected in quiescent, confluent mouse aortic endothelial cells, whereas high doses of FGF2 induced high RICTOR expression that was associated with strong mTORC2-specific protein kinase Cα and AKT phosphorylation. We demonstrate that the endothelial FGF-RICTOR axis is not required during endothelial quiescence, but crucial for midgestational development and sustained and extensive neovascularization in the adult. PMID:26635098

  13. Heterotopic Triplet Pregnancy after In Vitro Fertilization with Favorable Outcome of the Intrauterine Twin Pregnancy Subsequent to Surgical Treatment of the Tubal Pregnancy

    PubMed Central

    Akrivis, Christodoulos; Tsirkas, Panagiotis; Korkontzelos, Ioannis

    2014-01-01

    Heterotopic triplet pregnancy is an exceptionally rare medical condition. The broad use of assisted reproductive technologies has contributed to the increase of ectopic and subsequently heterotopic pregnancy rate, masking a life-threatening condition for the gravid and the intrauterine pregnancy. We describe a case of a woman with heterotopic triplets at 9+4 gestational week following transfer of three embryos obtained by in vitro fertilization techniques. The ectopic tubal pregnancy was ruptured and salpingectomy was performed by laparotomy. The intrauterine pregnancy progressed to the delivery by cesarean section of two healthy twins at 36+2 gestational age. Heterotopic triplets with tubal ectopic are a special diagnostic and therapeutic challenge for the obstetrician. High index of suspicion and timely treatment by laparotomy or laparoscopy can preserve the intrauterine gestation with a successful outcome of the pregnancy. PMID:24527252

  14. Complex Evolutionary and Genetic Patterns Characterize the Loss of Scleral Ossification in the Blind Cavefish Astyanax mexicanus

    PubMed Central

    O’Quin, Kelly E.; Doshi, Pooja; Lyon, Anastasia; Hoenemeyer, Emma; Yoshizawa, Masato; Jeffery, William R.

    2015-01-01

    The sclera is the tough outer covering of the eye that provides structural support and helps maintain intraocular pressure. In some fishes, reptiles, and birds, the sclera is reinforced with an additional ring of hyaline cartilage or bone that forms from scleral ossicles. Currently, the evolutionary and genetic basis of scleral ossification is poorly understood, especially in teleost fishes. We assessed scleral ossification among several groups of the Mexican tetra (Astyanax mexicanus), which exhibit both an eyed and eyeless morph. Although eyed Astyanax surface fish have bony sclera similar to other teleosts, the ossicles of blind Astyanax cavefish generally do not form. We first sampled cavefish from multiple independent populations and used ancestral character state reconstructions to determine how many times scleral ossification has been lost. We then confirmed these results by assessing complementation of scleral ossification among the F1 hybrid progeny of two cavefish populations. Finally, we quantified the number of scleral ossicles present among the F2 hybrid progeny of a cross between surface fish and cavefish, and used this information to identify quantitative trait loci (QTL) responsible for this trait. Our results indicate that the loss of scleral ossification is common–but not ubiquitous–among Astyanax cavefish, and that this trait has been convergently lost at least three times. The presence of wild-type, ossified sclera among the F1 hybrid progeny of a cross between different cavefish populations confirms the convergent evolution of this trait. However, a strongly skewed distribution of scleral ossicles found among surface fish x cavefish F2 hybrids suggests that scleral ossification is a threshold trait with a complex genetic basis. Quantitative genetic mapping identified a single QTL for scleral ossification on Astyanax linkage group 1. We estimate that the threshold for this trait is likely determined by at least three genetic factors which

  15. Complex Evolutionary and Genetic Patterns Characterize the Loss of Scleral Ossification in the Blind Cavefish Astyanax mexicanus.

    PubMed

    O'Quin, Kelly E; Doshi, Pooja; Lyon, Anastasia; Hoenemeyer, Emma; Yoshizawa, Masato; Jeffery, William R

    2015-01-01

    The sclera is the tough outer covering of the eye that provides structural support and helps maintain intraocular pressure. In some fishes, reptiles, and birds, the sclera is reinforced with an additional ring of hyaline cartilage or bone that forms from scleral ossicles. Currently, the evolutionary and genetic basis of scleral ossification is poorly understood, especially in teleost fishes. We assessed scleral ossification among several groups of the Mexican tetra (Astyanax mexicanus), which exhibit both an eyed and eyeless morph. Although eyed Astyanax surface fish have bony sclera similar to other teleosts, the ossicles of blind Astyanax cavefish generally do not form. We first sampled cavefish from multiple independent populations and used ancestral character state reconstructions to determine how many times scleral ossification has been lost. We then confirmed these results by assessing complementation of scleral ossification among the F1 hybrid progeny of two cavefish populations. Finally, we quantified the number of scleral ossicles present among the F2 hybrid progeny of a cross between surface fish and cavefish, and used this information to identify quantitative trait loci (QTL) responsible for this trait. Our results indicate that the loss of scleral ossification is common-but not ubiquitous-among Astyanax cavefish, and that this trait has been convergently lost at least three times. The presence of wild-type, ossified sclera among the F1 hybrid progeny of a cross between different cavefish populations confirms the convergent evolution of this trait. However, a strongly skewed distribution of scleral ossicles found among surface fish x cavefish F2 hybrids suggests that scleral ossification is a threshold trait with a complex genetic basis. Quantitative genetic mapping identified a single QTL for scleral ossification on Astyanax linkage group 1. We estimate that the threshold for this trait is likely determined by at least three genetic factors which may

  16. Ossification of the Medial Clavicular Epiphysis on Chest Radiographs: Utility and Diagnostic Accuracy in Identifying Korean Adolescents and Young Adults under the Age of Majority.

    PubMed

    Yoon, Soon Ho; Yoo, Hye Jin; Yoo, Roh Eul; Lim, Hyun Ju; Yoon, Jeong Hwa; Park, Chang Min; Lee, Sang Seob; Yoo, Seong Ho

    2016-10-01

    The aim of our study was to evaluate the utility and diagnostic accuracy of the ossification grade of medial clavicular epiphysis on chest radiographs for identifying Korean adolescents and young adults under the age of majority. Overall, 1,151 patients (age, 16-30) without any systemic disease and who underwent chest radiography were included for ossification grading. Two radiologists independently classified the ossification of the medial clavicular epiphysis from chest radiographs into five grades. The age distribution and inter-observer agreement on the ossification grade were assessed. The diagnostic accuracy of the averaged ossification grades for determining whether the patient is under the age of majority was analyzed by using receiver operating characteristic (ROC) curves. Two separate inexperienced radiologists assessed the ossification grade in a subgroup of the patients after reviewing the detailed descriptions and image atlases developed for ossification grading. The median value of the ossification grades increased with increasing age (from 16 to 30 years), and the trend was best fitted by a quadratic function (R-square, 0.978). The inter-observer agreements on the ossification grade were 0.420 (right) and 0.404 (left). The area under the ROC curve (AUC) was 0.922 (95% CI, 0.902-0.942). The averaged ossification scores of 2.62 and 4.37 provided 95% specificity for a person < 19 years of age and a person ≥ 19 years of age, respectively. A preliminary assessment by inexperienced radiologists resulted in an AUC of 0.860 (95% CI, 0.740-0.981). The age of majority in Korean adolescents and young adults can be estimated using chest radiographs. PMID:27550480

  17. Role of Matrix Metalloproteinase 13 in Both Endochondral and Intramembranous Ossification during Skeletal Regeneration

    PubMed Central

    Behonick, Danielle J.; Xing, Zhiqing; Lieu, Shirley; Buckley, Jenni M.; Lotz, Jeffrey C.; Marcucio, Ralph S.; Werb, Zena; Miclau, Theodore; Colnot, Céline

    2007-01-01

    Extracellular matrix (ECM) remodeling is important during bone development and repair. Because matrix metalloproteinase 13 (MMP13, collagenase-3) plays a role in long bone development, we have examined its role during adult skeletal repair. In this study we find that MMP13 is expressed by hypertrophic chondrocytes and osteoblasts in the fracture callus. We demonstrate that MMP13 is required for proper resorption of hypertrophic cartilage and for normal bone remodeling during non-stabilized fracture healing, which occurs via endochondral ossification. However, no difference in callus strength was detected in the absence of MMP13. Transplant of wild-type bone marrow, which reconstitutes cells only of the hematopoietic lineage, did not rescue the endochondral repair defect, indicating that impaired healing in Mmp13−/− mice is intrinsic to cartilage and bone. Mmp13−/− mice also exhibited altered bone remodeling during healing of stabilized fractures and cortical defects via intramembranous ossification. This indicates that the bone phenotype occurs independently from the cartilage phenotype. Taken together, our findings demonstrate that MMP13 is involved in normal remodeling of bone and cartilage during adult skeletal repair, and that MMP13 may act directly in the initial stages of ECM degradation in these tissues prior to invasion of blood vessels and osteoclasts. PMID:17987127

  18. [The non-damaging method for the insertion of a standard electrode for cochlear ossification].

    PubMed

    Diab, Kh M; Daikhes, N A; Pashchinina, O A; Siraeva, A R; Kuznetsov, A O

    2016-01-01

    The objective of the present study was to develop the non-damaging method for the insertion of a standard electrode for cochlear ossification with a view to improving the results of hearing and speech rehabilitation of the patients presenting with grade IV sensorineural impairment of hearing. Twenty preparations of the cadaveric temporal bone were used to investigate topographic and anatomical relationships in the main structures of the middle and internal ears, viz. the second cochlear coil, vestibulum and its windows, processus cochleaformis, spiral lamina, and modiolus. The optimal method for the insertion of a standard electrode into the spiral canal of the cochlea after the removal of the ossified structures is proposed. The optimal site for constructing the second colostomy is determined that allows the spiral plate and modiolus to be maximally preserved. The proposed method was employed to treat 11 patients with grade IV sensorineural impairment of hearing and more than 5 mm ossification of the basal cochlear coil. With this method, it proved possible to insert the maximum number of electrodes into the cochlear spiral canal and thereby to obtain excellent results of hearing and speech rehabilitation in the patients with the ossified cochlea. PMID:27367352

  19. Surgical treatment for ossification of the posterior longitudinal ligament in the cervical spine.

    PubMed

    An, Howard S; Al-Shihabi, Laith; Kurd, Mark

    2014-07-01

    Although classically associated with patients of East Asian origin, ossification of the posterior longitudinal ligament (OPLL) may cause myelopathy in patients of any ethnic origin. Degeneration of the PLL is followed by endochondral ossification, resulting in spinal cord compression. Specific genetic polymorphisms and medical comorbidities have been implicated in the development of OPLL. Patients should be evaluated with a full history and neurologic examination, along with cervical radiographs. Advanced imaging with CT and MRI allows three-dimensional evaluation of OPLL. Minimally symptomatic patients can be treated nonsurgically, but patients with myelopathy or severe stenosis are best treated with surgical decompression. OPLL can be treated via an anterior (ie, corpectomy and fusion) or posterior (ie, laminectomy and fusion or laminoplasty) approach, or both. The optimal approach is dictated by the classification and extent of OPLL, cervical spine sagittal alignment, severity of stenosis, and history of previous surgery. Anterior surgery is associated with superior outcomes when OPLL occupies >50% to 60% of the canal, despite increased technical difficulty and higher complication rates. Posterior surgery is technically easier and allows decompression of the entire cervical spine, but patients may experience late deterioration because of disease progression. PMID:24966248

  20. Ossification of the Posterior Petroclinoid Dural Fold: A Cadaveric Study with Neurosurgical Significance.

    PubMed

    Kimball, David; Kimball, Heather; Matusz, Petru; Tubbs, R Shane; Loukas, Marios; Cohen-Gadol, A Aaron

    2015-08-01

    Objectives The roof of the porus trigeminus, composed of the posterior petroclinoid dural fold, is an important landmark to the skull base surgeon. Ossification of the posterior petroclinoid dural fold is an anatomical variation rarely mentioned in the literature. Such ossification results in the trigeminal nerve traversing a bony foramen as it enters Meckel cave. The authors performed this study to better elucidate this anatomical variation. Design Fifteen adult cadaveric head halves were subjected to dissection of the middle cranial fossa. Microdissection techniques were used to examine the posterior petroclinoid dural folds. Skull base osteology was also studied in 71 dry human skulls with attention paid to the attachment point of the posterior petroclinoid dural folds at the trigeminal protuberances. Setting Cadaver laboratory Main Outcome Measures Measurements were made using a microcaliper. Digital images were made of the dissections. Results Completely ossified posterior petroclinoid folds were present in 20% of the specimens. Of the 142 dry skull sides examined, 9% had large trigeminal protuberances. Conclusions Based on this study, the posterior petroclinoid dural fold may completely ossify in adults that may lead to narrowing of the porus trigeminus and potential compression of the trigeminal nerve at the entrance to Meckel cave. PMID:26225315

  1. Heterotopic nephrogenic rests in the colon and multiple congenital anomalies: possibly related association.

    PubMed

    Jain, Dhanpat; Martel, Maritza; Reyes-Múgica, Miguel; Parkash, Vinita

    2002-01-01

    Heterotopic renal tissue (HRT) in the wall of the colon is a very rare occurrence, with only five cases published. Our patient is only the second patient reported to have this abnormality in the absence of sirenomelia. We describe colonic HRT in a child, associated with multiple congenital anomalies. The congenital abnormalities were of the VACTERL type, accompanied by valvular cardiac anomalies that were clinically diagnosed as Shone syndrome. The HRT was not apparent clinically or grossly. Microscopically, multifocal islands of renal tissue consisting of glomeruli, cystically dilated tubules, and blastema were seen in all layers of the bowel, and simulated "cystic partially differentiated nephroblastoma." Our case provides further support to the belief that VACTERL association and sirenomelia represent related entities. PMID:12375130

  2. New technique to protect ovarian function before pelvic irradiation. Heterotopic ovarian autotransplantation

    SciTech Connect

    Leporrier, M.; von Theobald, P.; Roffe, J.L.; Muller, G.

    1987-11-01

    The authors describe a new technique for the subcutaneous heterotopic transplantation of the ovary before pelvic irradiation to treat Hodgkin's disease. Creation of a cavity to receive the transplant and the use of two surgical teams and the surgical microscope during the operation ensured its successful outcome. The transplanted ovary was followed up clinically and by ultrasound monitoring: ovarian cycles remained regular despite radiotherapy, and follicle growth occurred normally. In comparison to other types of oophoropexy described in the literature, the advantages of this technique included total protection of the ovary from irradiation, and conservation of ovarian function and fertility. One year after the procedure, puncture of the ovarian compartment produced a mature oocyte specimen.

  3. Trauma-induced heterotopic bone formation and the role of the immune system: A review.

    PubMed

    Kraft, Casey T; Agarwal, Shailesh; Ranganathan, Kavitha; Wong, Victor W; Loder, Shawn; Li, John; Delano, Matthew J; Levi, Benjamin

    2016-01-01

    Extremity trauma, spinal cord injuries, head injuries, and burn injuries place patients at high risk of pathologic extraskeletal bone formation. This heterotopic bone causes severe pain, deformities, and joint contractures. The immune system has been increasingly implicated in this debilitating condition. This review summarizes the various roles immune cells and inflammation play in the formation of ectopic bone and highlights potential areas of future investigation and treatment. Cell types in both the innate and adaptive immune system such as neutrophils, macrophages, mast cells, B cells, and T cells have all been implicated as having a role in ectopic bone formation through various mechanisms. Many of these cell types are promising areas of therapeutic investigation for potential treatment. The immune system has also been known to also influence osteoclastogenesis, which is heavily involved in ectopic bone formation. Chronic inflammation is also known to have an inhibitory role in the formation of ectopic bone, whereas acute inflammation is necessary for ectopic bone formation. PMID:26491794

  4. [Heterotopic pancreas as a cause of intussusception: first case reported in Peru].

    PubMed

    Bazán Zender, Carlos; Reyes Coloma, Luis; León Cueto, José Luis; Revoredo Palacios, Giancarlo; Arias Stella Castillo, Javier; Pezo, Alonso

    2015-01-01

    The heterotopic pancreas (HP) is a rare condition in the pediatric population. HP cases involving an ileal intussusception are rare in children and very rarely reported, usually presenting with symptoms of intestinal obstruction. We report the case of a one year old male patient with a chronic history of anorexia, irritability, abdominal pain, accompanied by intermittent episodes of "currant jelly" stools that evolved to rectal bleeding. The patient presented a concomitant diagnosis of allergic colitis, which prolonged the effective surgical treatment at an external health center. In the abdominal CT scan, the classic "target" sign was found. In the exploratory laparotomy an ileoileal intussusception was confirmed, a mass was found that the histopathology laboratory confirmed as HP. To our knowledge, it is the first case of pediatric intussusception by HP reported in Peru. PMID:26580946

  5. Excess BMP Signaling in Heterotopic Cartilage Forming in Prg4-null TMJ Discs.

    PubMed

    Bechtold, T E; Saunders, C; Mundy, C; Um, H; Decker, R S; Salhab, I; Kurio, N; Billings, P C; Pacifici, M; Nah, H D; Koyama, E

    2016-03-01

    Heterotopic cartilage develops in certain pathologic conditions, including those affecting the human temporomandibular joint (TMJ), but the underlying molecular mechanisms remain obscure. This is in part due to the fact that a reliable animal model of such TMJ diseases is not available. Here, we show that aberrant chondrocyte differentiation and ectopic cartilage formation occur spontaneously in proteoglycan 4 (Prg4) mutant TMJ discs without further invasive procedure. By 2 mo of age, mutant disc cells displayed chondrocyte transdifferentiation, accompanied by strong expression of cartilage master gene Sox9 and matrix genes aggrecan and type II collagen. By 6 mo, heterotopic cartilage had formed in the discs and expressed cartilage hypertrophic markers Runx2 and ColX. The ectopic tissue grew in size over time and exhibited regional mineralization by 12 mo. Bone morphogenetic protein (BMP) signaling was activated with the ectopic chondrogenic cells and chondrocytes, as indicated by phosphorylated Smad 1/5/8 nuclear staining and by elevated expression of Bmp2, Bmpr1b, Bmpr2, and BMP signaling target genes. Likewise, we found that upon treatment with recombinant human BMP 2 in high-density micromass culture, mutant disc cells differentiated into chondrocytes and synthesized cartilage matrix more robustly than control cells. Importantly, a specific kinase inhibitor of BMP receptors drastically attenuated chondrogenesis in recombinant human BMP 2-treated mutant disc cultures. Unexpectedly, we found that Prg4 was expressed at joint-associated sites, including disc/muscle insertion and muscle/bone interface, and all these structures were abnormal in Prg4 mutants. Our data indicate that Prg4 is needed for TMJ disc integrity and function and that its absence leads to ectopic chondrogenesis and cartilage formation in conjunction with abnormal BMP signaling. Our findings imply that the BMP signaling pathway could be a potential therapeutic target for prevention or inhibition

  6. Treating pain with pain: supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation.

    PubMed

    Sprenger, Christian; Bingel, Ulrike; Büchel, Christian

    2011-02-01

    While being exposed to an intensive tonic pain stimulus at one area of the body, another phasic pain stimulus applied to a remote site is perceived as less painful. The neurophysiological basis for this "pain inhibits pain" phenomenon has been presumed to be an activation of the spino-bulbo-spinal mechanism termed "diffuse noxious inhibitory controls." However, several additional mechanisms such as an activation of the descending pain control system may contribute to this observation. Here we investigated the underlying supraspinal mechanisms of "heterotopic noxious conditioning stimulations" (HNCS), representing this specific experimental constellation. We used functional magnetic resonance imaging and behavioral recordings in combination with a modified cold-pressor task and phasic painful stimuli, and investigated the contribution of endogenous opioids to this mechanism using the opioid antagonist naloxone in a double-blind crossover design. HNCS led to marked endogenous analgesia and this effect correlated positively with the perceived intensity of the tonic painful stimulus. Furthermore, HNCS was paralleled by reduced blood oxygen level dependent (BOLD) responses in classical pain-responsive regions. Conversely, HNCS led to tonic BOLD increases in subregions of the anterior cingulate cortex. The strength of functional coupling between the subgenual anterior cingulate cortex and key structures of the descending pain control system was enhanced during HNCS, which correlated positively with the individual endogenous analgesia during HNCS. These effects were in part reversed by naloxone, speaking for the contribution of endogenous opioid neurotransmission to this mechanism. Taken together, these results demonstrate a substantial contribution of higher-order brain regions to the phenomenon of hypoalgesia during HNCS. Functional magnetic resonance imaging shows how the human brain is involved in heterotopic noxious conditioning and reveals active supraspinal pain

  7. New patterns of the growing L3 vertebra and its 3 ossification centers in human fetuses – a CT, digital, and statistical study

    PubMed Central

    Szpinda, Michał; Baumgart, Mariusz; Szpinda, Anna; WoŸniak, Alina; Mila-Kierzenkowska, Celestyna

    2013-01-01

    Background This study describes reference data for L3 vertebra and its 3 ossification centers at varying gestational ages. Material/Methods Using CT, digital-image analysis and statistics, the growth of L3 vertebra and its 3 ossification centers in 55 spontaneously aborted human fetuses aged 17–30 weeks was examined. Results Neither sex nor right-left significant differences were found. The height and transverse and sagittal diameters of the L3 vertebral body increased logarithmically. Its cross-sectional area followed linearly, whereas its volume increased parabolically. The transverse and sagittal diameters of the ossification center of the L3 vertebral body varied logarithmically, but its cross-sectional area and volume grew linearly. The ossification center-to-vertebral body volume ratio gradually declined with age. The neural ossification centers increased logarithmically in length and width, and proportionately in cross-sectional area and volume. Conclusions With no sex differences, the growth dynamics of the L3 vertebral body follow logarithmically in height, sagittal and transverse diameters, linearly (in cross-sectional area), and parabolically (in volume). The growth dynamics of the 3 ossification centers of the L3 vertebra follow logarithmically in transverse and sagittal diameters, and linearly (in cross-sectional area and volume). The age-specific reference intervals of the L3 vertebra and its 3 ossification centers present the normative values of clinical importance in the diagnosis of congenital spinal defects. PMID:23778313

  8. Meniscal ossification.

    PubMed

    Mine, Takatomo; Taguchi, Tosihiko; Ihara, Koichiro; Tanaka, Hiroshi; Moriwaki, Tohru; Kawai, Shinya

    2003-02-01

    Meniscal ossicles are rare in the human knee. We present one case. A 57-year-old taxi driver complained of right knee pain and swelling with radiographic findings of a meniscal ossicle. Arthroscopic inspection showed a degenerative and horizontal tear and calcium deposit at the middle and posterior thirds of lateral discoid meniscus. His lateral discoid meniscus, containing the ossicle, was removed. He was asymptomatic at a 3-year follow-up. PMID:12579140

  9. Twenty-Year Outcome After Right Ventricular Outflow Tract Repair Using Heterotopic Pulmonary Conduits in Infants and Children.

    PubMed

    Hoxha, Stiljan; Torre, Salvatore; Rungatscher, Alessio; Sandrini, Camilla; Rossetti, Lucia; Barozzi, Luca; Faggian, Giuseppe; Luciani, Giovanni Battista

    2016-01-01

    Durability of pulmonary conduits (PCs) used for reconstruction of the right ventricular outflow tract (RVOT) may be affected by a variety of factors. Among these, the technique used for PC implantation, whether in orthotopic or heterotopic position, strictly dependent upon the underlying anatomy, has been suggested to influence long-term outcome after RVOT repair. To determine the outcome of heterotopic implantation in infants and children treated at our institution, late results of heterotopic PC in non-Ross patients were analyzed and compared with data of orthotopic PC in age-matched pediatric Ross patients operated during the same time period. Between November 1991 and January 2015, 58 infants and children, 32 male and 26 female, with a median age of 9.4 years (range 1 day-18 years) underwent implantation of heterotopic PC (31 homografts [HG] and 27 xenografts [XG]) for reconstruction of RVOT. Median age in the XG group was significantly lower than in the HG group (0.9 vs. 13.4 years, P = 0.01), while male/female ratio was similar. Fifty (86%) patients had undergone one or more prior cardiac operations, while 32 (55%) required associated procedures during PC implantation. Comparison with data in 305 children and with a median age of 9.4 years, receiving orthotopic PC between 1990 and 2012 (Italian Pediatric Ross Registry), was undertaken. Descriptive, univariate, and Kaplan-Meier analysis defined outcome. There were three (5.2%) early and five (9.0%) late deaths, during a median follow-up of 7.6 years (range 2 months-23 years). Patients having XG had trend toward higher hospital mortality (2/27 vs. 1/31, P = 0.2), but similar late mortality (2/24 vs. 3/30, P = 0.3). Overall survival was 88 and 62%, while freedom from PC replacement was 49 and 21%, at 10 and 20 years, respectively. The latter proved significantly worse than freedom from orthotopic PC replacement, which was 94 ± 2 and 70 ± 9% at 10 and 20 years (P = 0.02). When stratified

  10. Laparoscopic distal gastrectomy for pyloric stenosis caused by heterotopic glands in a young female: report of a case.

    PubMed

    Tanioka, Toshiro; Matsumoto, Satoru; Takahashi, Shusaku; Ueki, Shinya; Takahashi, Masahiro; Ichihara, Shin

    2015-06-01

    A 17-year-old female was referred to our hospital with worsening dietary intake and abdominal bloating. She had epigastric fullness, but no abdominal pain. Gastrointestinal endoscopy revealed food residue and pyloric stenosis. A contrast-enhanced radiograph also showed pyloric stenosis, and gastrografin was not passed well through her pylorus. Computed tomography revealed similar findings. The biopsy results indicated hyperplasia of the gastric glands. The patient was diagnosed with a benign lesion, and underwent endoscopic balloon dilation several times. However, her stenosis worsened and we decided to perform surgery. In consideration of the cosmetic outcome, we performed laparoscopic distal gastrectomy. The postoperative course was good, and the patient was discharged on postoperative day 10. The final diagnosis was pyloric stenosis caused by heterotopic glands. No malignant lesions were found. Since gastric stenosis caused by heterotopic glands has not been reported previously, we consider this to be a very rare case. PMID:24986451

  11. The first Australian experience of heterotopic grafting of cryopreserved ovarian tissue: evidence of establishment of normal ovarian function.

    PubMed

    Stern, Catharyn J; Toledo, Manuela G; Hale, Lyndon G; Gook, Debra A; Edgar, David H

    2011-06-01

    Cryostorage of reproductive potential, in the form of ovarian cortex, for young women about to undergo cytotoxic therapies has been offered clinically for some time. However, the prospects of re-establishing reproductive function using this tissue remain unclear. We now report reproducible follicular development, oocyte retrieval and embryo development following heterotopic grafting of cryopreserved ovarian cortex which had been stored for over 10 years. PMID:21631450

  12. Avulsion fracture of the anterior inferior iliac spine with abundant reactive ossification in the soft tissue.

    PubMed

    Resnick, J M; Carrasco, C H; Edeiken, J; Yasko, A W; Ro, J Y; Ayala, A G

    1996-08-01

    Patients who have sustained an avulsion fracture and present clinically during the healing phase of the injury may manifest a mass that clinically and radiographically mimics a malignant neoplasm. A 15-year-old male soccer goalkeeper presented with a large ossified mass in the soft tissues overlying the right hip 6 months after experiencing a popping sensation in his hip joint during a game. Although an osteosarcoma was suspected clinically and radiographically, a Tru-Cut needle biopsy of the lesion revealed reactive bone formation. Correlation of the clinical, radiographic, and pathologic findings indicated an avulsion fracture of the anterior inferior iliac spine with abundant reactive ossification in the soft tissues. The healing phase of an avulsion fracture may clinically and radiographically be mistaken for neoplasia. In such cases, a Tru-Cut needle biopsy may reveal the reactive nature of the process. PMID:8865496

  13. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I

    PubMed Central

    Zhou, Zhongjun; Apte, Suneel S.; Soininen, Raija; Cao, Renhai; Baaklini, George Y.; Rauser, Richard W.; Wang, Jianming; Cao, Yihai; Tryggvason, Karl

    2000-01-01

    Membrane-type matrix metalloproteinase I (MT1-MMP)-deficient mice were found to have severe defects in skeletal development and angiogenesis. The craniofacial, axial, and appendicular skeletons were severely affected, leading to a short and domed skull, marked deceleration of postnatal growth, and death by 3 wk of age. Shortening of bones is a consequence of decreased chondrocyte proliferation in the proliferative zone of the growth plates. Defective vascular invasion of cartilage leads to enlargement of hypertrophic zones of growth plates and delayed formation of secondary ossification centers in long bones. In an in vivo corneal angiogenesis assay, null mice did not have angiogenic response to implanted FGF-2, suggesting that the defect in angiogenesis is not restricted to cartilage alone. In tissues from null mice, activation of latent matrix metalloproteinase 2 was deficient, suggesting that MT1-MMP is essential for its activation in vivo. PMID:10737763

  14. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.

    PubMed

    Zhou, Z; Apte, S S; Soininen, R; Cao, R; Baaklini, G Y; Rauser, R W; Wang, J; Cao, Y; Tryggvason, K

    2000-04-11

    Membrane-type matrix metalloproteinase I (MT1-MMP)-deficient mice were found to have severe defects in skeletal development and angiogenesis. The craniofacial, axial, and appendicular skeletons were severely affected, leading to a short and domed skull, marked deceleration of postnatal growth, and death by 3 wk of age. Shortening of bones is a consequence of decreased chondrocyte proliferation in the proliferative zone of the growth plates. Defective vascular invasion of cartilage leads to enlargement of hypertrophic zones of growth plates and delayed formation of secondary ossification centers in long bones. In an in vivo corneal angiogenesis assay, null mice did not have angiogenic response to implanted FGF-2, suggesting that the defect in angiogenesis is not restricted to cartilage alone. In tissues from null mice, activation of latent matrix metalloproteinase 2 was deficient, suggesting that MT1-MMP is essential for its activation in vivo. PMID:10737763

  15. Ossification of ligamentum flavum, a rare cause of myelopathy: First case report of a Lebanese patient.

    PubMed

    El Helou, Antonios; Alaywan, Moussa; Tarabay, Antonio; Nachanakian, Antoine

    2016-01-01

    Ossification of ligamentum flavum (OLF) is a well-known pathology causing myelopathy, although it is a rare disease. The most commonly affected population is from the Far East and mainly Japanese. However, few reports and studies have shown the prevalence of the disease all over the world. We report the case of a 33-year-old man presenting with signs of progressive myelopathy. Magnetic resonance imaging (MRI) showed Th2-Th11 OLF with severe narrowing and intramedullary hypersignal at the level Th2-Th3. This is the first Lebanese case reported in the literature. A decompressive laminectomy with flavectomy was done. This case adds to the previous reported cases on the occurrence of the disease in different populations. PMID:27057241

  16. Ontogenetic and structural variation of mineralizations and ossifications in the integument within ceratophryid frogs (anura, Ceratophryidae).

    PubMed

    Quinzio, Silvia; Fabrezi, Marissa

    2012-12-01

    Ceratophryidae represent a monophyletic group of terrestrial and aquatic frogs inhabiting lowlands of South America where they are more diverse in semiarid environments of the Chaco region. Adult morphology of ceratophryids presents some features associated to terrestrial and fossorial life such as hyper-ossified skulls, spade feet for digging, among others. For anurans, different mineralized structures have been described in the integument as calcium reservoirs and related to the terrestrial life and water balance (e.g., the calcified layer and dermal ossifications). We describe the ontogeny of the integument in the three genera of ceratophryids (Chacophrys, Ceratophrys, and Lepidobatrachus) that inhabit in semiarid environments. Data obtained demonstrated the early acquisition of metamorphic transformations in the integument layers in larvae of Ceratophrys cranwelli and Lepidobatrachus spp. and a continuous increment in the thickness of them up to old postmetamorphic stages. The integument of ceratophryids develops calcium deposits as the calcified layer during postmetamorphic stages. Furthermore, dorsal shields are also present in adult stages independently of terrestrial versus aquatic lifestyles. While the calcified layer seems to be a feature of a fully developed integument, in which their layers have acquired the adult thickness, dorsal shields develop at premetamorphic stages in L. llanensis and postmetamorphic individuals of C. cranwelli. In ceratophryids, similar to other studied taxa (e.g., Brachycephalus spp.) dorsal shields develop via an intramembranous ossification in which the calcified layer does not precede its differentiation. Within anurans, the occurrence of dorsal shields in the monophyletic ceratophryids suggested a distinctive evolutionary history in the lineage. PMID:23074148

  17. Ceranib-2-induced suicidal erythrocyte death.

    PubMed

    Signoretto, Elena; Zierle, Jens; Bhuyan, Abdulla Al Mamun; Castagna, Michela; Lang, Florian

    2016-07-01

    Ceramide is known to trigger apoptosis of nucleated cells and eryptosis of erythrocytes. Eryptosis is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Besides ceramide, stimulators of eryptosis include increase of cytosolic Ca(2+) -activity ([Ca(2+) ]i ) and oxidative stress. Ceramide is degraded by acid ceramidase and inhibition of the enzyme similarly triggers apoptosis. The present study explored, whether ceramidase inhibitor Ceranib-2 induces eryptosis. Flow cytometry was employed to quantify phosphatidylserine-exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca(2+) ]i from Fluo3-fluorescence, reactive oxygen species (ROS) from DCF dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant. A 48 h exposure of human erythrocytes to Ceranib-2 significantly increased the percentage of annexin-V-binding cells (≥50 μM) and the percentage of hemolytic cells (≥10 μM) without significantly modifying forward scatter. Ceranib-2 significantly increased Fluo3-fluorescence, DCF fluorescence and ceramide abundance. The effect of Ceranib-2 on annexin-V-binding was not significantly blunted by removal of extracellular Ca(2+) . Ceranib-2 triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to increase of ceramide abundance and induction of oxidative stress, but not dependent on Ca(2+) entry. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27291470

  18. Heterotopic auxiliary rat liver transplantation with flow-regulated portal vein arterialization in acute hepatic failure.

    PubMed

    Schleimer, Karina; Kalder, Johannes; Grommes, Jochen; Jalaie, Houman; Tawadros, Samir; Greiner, Andreas; Jacobs, Michael; Kokozidou, Maria

    2014-01-01

    In acute hepatic failure auxiliary liver transplantation is an interesting alternative approach. The aim is to provide a temporary support until the failing native liver has regenerated.(1-3) The APOLT-method, the orthotopic implantation of auxiliary segments- averts most of the technical problems. However this method necessitates extensive resections of both the native liver and the graft.(4) In 1998, Erhard developed the heterotopic auxiliary liver transplantation (HALT) utilizing portal vein arterialization (PVA) (Figure 1). This technique showed promising initial clinical results.(5-6) We developed a HALT-technique with flow-regulated PVA in the rat to examine the influence of flow-regulated PVA on graft morphology and function (Figure 2). A liver graft reduced to 30 % of its original size, was heterotopically implanted in the right renal region of the recipient after explantation of the right kidney.  The infra-hepatic caval vein of the graft was anastomosed with the infrahepatic caval vein of the recipient. The arterialization of the donor's portal vein was carried out via the recipient's right renal artery with the stent technique. The blood-flow regulation of the arterialized portal vein was achieved with the use of a stent with an internal diameter of 0.3 mm. The celiac trunk of the graft was end-to-side anastomosed with the recipient's aorta and the bile duct was implanted into the duodenum. A subtotal resection of the native liver was performed to induce acute hepatic failure. (7) In this manner 112 transplantations were performed. The perioperative survival rate was 90% and the 6-week survival rate was 80%. Six weeks after operation, the native liver regenerated, showing an increase in weight from 2.3±0.8 g to 9.8±1 g. At this time, the graft's weight decreased from 3.3±0.8 g to 2.3±0.8 g. We were able to obtain promising long-term results in terms of graft morphology and function. HALT with flow-regulated PVA reliably bridges acute hepatic failure

  19. Use of postoperative irradiation for the prevention of heterotopic bone formation after total hip replacement

    SciTech Connect

    Sylvester, J.E.; Greenberg, P.; Selch, M.T.; Thomas, B.J.; Amstutz, H.

    1988-03-01

    Formation of heterotopic bone (HTB) following total hip replacement may partially or completely ankylose the joint space, causing pain and/or limiting the range of motion. Patients at high risk for formation of HTB postoperatively include those with previous HTB formation, heterotopic osteoarthritis, and active rheumatoid spondylitis. Patients in these high risk groups have a 63-69% incidence of post-operative HTB formation, usually seen radiographically by 2 months post-operation. From 1980-1986 twenty-nine hips in 28 consecutively treated patients were irradiated post-operatively at the UCLA Center for the Health Sciences. The indication for irradiation was documented HTB formation previously in 26 of the 27 hips presented below. From 1980-1982 patients received 20 Gray (Gy) in 2 Gy fractions; from 1982-1986 the dose was reduced to 10 Gy in 2 Gy fractions. Twenty-seven hips in 26 patients completed therapy and were available for evaluation, with a minimum of 2 month follow-up, and a median follow-up of 12 months. Three of 27 hips developed significant HTB (Brooker grade III or IV) post-operatively, whereas 5 of 27 hips developed minor, nonsymptomatic HTB (Brooker grade I). When irradiation was begun by postoperative day 4, 0 of 17 hips formed significant HTB. If irradiation began after post-operative day 4, 3 of 10 hips formed significant HTB (Brooker grade III or IV). These 3 hips received doses of 10 Gy in one hip and 20 Gy in the other 2 hips. There were no differences in the incidence or severity of side effects in the 10 Gy vs. the 20 Gy treatment groups. Eighteen hips received 10 Gy, 8 hips 20 Gy and, 1 hip 12 Gy. In conclusion, 10 Gy in 5 fractions appears as effective as 20 Gy in 10 fractions at preventing post-operative formation of HTB. For optimal results, treatment should begin as early as possible prior to post-operative day 4.

  20. Heterotopic Auxiliary Rat Liver Transplantation With Flow-regulated Portal Vein Arterialization in Acute Hepatic Failure

    PubMed Central

    Schleimer, Karina; Kalder, Johannes; Grommes, Jochen; Jalaie, Houman; Tawadros, Samir; Greiner, Andreas; Jacobs, Michael; Kokozidou, Maria

    2014-01-01

    In acute hepatic failure auxiliary liver transplantation is an interesting alternative approach. The aim is to provide a temporary support until the failing native liver has regenerated.1-3 The APOLT-method, the orthotopic implantation of auxiliary segments- averts most of the technical problems. However this method necessitates extensive resections of both the native liver and the graft.4 In 1998, Erhard developed the heterotopic auxiliary liver transplantation (HALT) utilizing portal vein arterialization (PVA) (Figure 1). This technique showed promising initial clinical results.5-6 We developed a HALT-technique with flow-regulated PVA in the rat to examine the influence of flow-regulated PVA on graft morphology and function (Figure 2). A liver graft reduced to 30 % of its original size, was heterotopically implanted in the right renal region of the recipient after explantation of the right kidney.  The infra-hepatic caval vein of the graft was anastomosed with the infrahepatic caval vein of the recipient. The arterialization of the donor’s portal vein was carried out via the recipient’s right renal artery with the stent technique. The blood-flow regulation of the arterialized portal vein was achieved with the use of a stent with an internal diameter of 0.3 mm. The celiac trunk of the graft was end-to-side anastomosed with the recipient’s aorta and the bile duct was implanted into the duodenum. A subtotal resection of the native liver was performed to induce acute hepatic failure. 7 In this manner 112 transplantations were performed. The perioperative survival rate was 90% and the 6-week survival rate was 80%. Six weeks after operation, the native liver regenerated, showing an increase in weight from 2.3±0.8 g to 9.8±1 g. At this time, the graft’s weight decreased from 3.3±0.8 g to 2.3±0.8 g. We were able to obtain promising long-term results in terms of graft morphology and function. HALT with flow-regulated PVA reliably bridges acute hepatic failure

  1. Acupuncture at heterotopic acupoints enhances jejunal motility in constipated and diarrheic rats

    PubMed Central

    Qin, Qing-Guang; Gao, Xin-Yan; Liu, Kun; Yu, Xiao-Chun; Li, Liang; Wang, Hai-Ping; Zhu, Bing

    2014-01-01

    AIM: To investigate the effect and mechanism of acupuncture at heterotopic acupoints on jejunal motility, particularly in pathological conditions. METHODS: Jejunal motility was assessed using a manometric balloon placed in the jejunum approximately 18-20 cm downstream from the pylorus and filled with approximately 0.1 mL warm water in anesthetized normal rats or rats with diarrhea or constipation. The heterotopic acupoints including LI11 (Quchi), ST37 (Shangjuxu), BL25 (Dachangshu), and the homotopic acupoint ST25 (Tianshu), and were stimulated for 60 s by rotating acupuncture needles right and left at a frequency of 2 Hz. To determine the type of afferent fibers mediating the regulation of jejunal motility by manual acupuncture, the ipsilateral sciatic A or C fibers of ST37 were inactivated by local application of the A-fiber selective demyelination agent cobra venom or the C fiber blocker capsaicin. Methoctramine, a selective M2 receptor antagonist, was injected intravenously to identify a specific role for M2 receptors in mediating the effect of acupuncture on jejunal motility. RESULTS: Acupuncture at heterotopic acupoints, such as LI11 and ST37, increased jejunal motility not only in normal rats, but also in rats with constipation or diarrhea. In normal rats, manual acupuncture at LI11 or ST37 enhanced jejunal pressure from 7.34 ± 0.19 cmH2O to 7.93 ± 0.20 cmH2O, an increase of 9.05% ± 0.82% (P < 0.05), and from 6.95 ± 0.14 cmH2O to 8.97 ± 0.22 cmH2O, a significant increase of 27.44% ± 1.96% (P < 0.01), respectively. In constipated rats, manual acupuncture at LI11 or ST37 increased intrajejunal pressure from 8.17 ± 0.31 cmH2O to 9.86 ± 0.36 cmH2O, an increase of 20.69% ± 2.10% (P < 0.05), and from 8.82 ± 0.28 cmH2O to 10.83 ± 0.28 cmH2O, an increase of 22.81% ± 1.46% (P < 0.05), respectively. In rats with diarrhea, MA at LI11 or ST37 increased intrajejunal pressure from 11.95 ± 0.35 cmH2O to 13.96 ± 0.39 cmH2O, an increase of 16.82% ± 2.35% (P

  2. Lhermitte-Duclos disease with neurofibrillary tangles in heterotopic cerebral grey matter.

    PubMed

    Rusiecki, D; Lach, B

    2016-01-01

    Lhermitte-Duclos disease (LDD), a disorder first described by French physicians Lhermitte and Duclos in 1920 [25], is a benign, slow growing dysplastic gangliocytoma of the cerebellum, characterized by replacement of the granule cell layer by abnormal granule and Purkinje like cells. The most frequent presenting signs and symptoms are megalocephaly, increased intracranial pressure, nausea, hydrocephalus, ataxia, gait abnormalities, and intermittent headaches, all of which are attributed to the mass effect [6,11,25]. Many cases are associated with a mutation in the phosphatase and tensin homolog or PTEN gene which is also involved in numerous otherwise unrelated central nervous system abnormalities, namely Cowden syndrome [1,6,11], autism spectrum disorder [18], cerebral cortical dysplasia [11,30] and Bannayan-Riley-Ruvalcaba syndrome [30]. The presence of cortical heterotopia has been reported in a small number of LDD cases [3,5,17,32]. We describe a unique case of LDD with cerebral cortical heterotopic grey matter containing neurofibrillary tangles. PMID:27543776

  3. Risk Factors and Early Predictors for Heterotopic Pregnancy after In Vitro Fertilization.

    PubMed

    Liu, Meiju; Zhang, Xiuqing; Geng, Ling; Xia, Mingdi; Zhai, Junyu; Zhang, Wei; Zhang, Yuchao; Sun, Yinhua; Zhang, Jiangtao; Zhu, Dongyi; Zhao, Han; Chen, Zi-Jiang

    2015-01-01

    This study investigated the risk factors and early predictors for heterotopic pregnancy (HP) after in vitro fertilization and embryo transfer (IVF-ET). From January 2008 to January 2013, 41 cases of HP and 72 cases of intrauterine twin pregnancy after IVF-ET were recruited and retrospectively analyzed. Compared with intrauterine twin pregnancy group, the HP group had a lower basal luteinizing hormone (LH) level (P = 0.005) and more cases had a history of hydrosalpinx (P = 0.008). After 14 days of IVF-ET, the serum β-HCG (β-human chorionic gonadotropin), E2 (Estradiol) and P (Progesterone) levels were lower in HP group (P<0.001, respectively). Moreover, vaginal bleeding and abdominal pain were the significant features of HP before diagnosis (P<0.001, respectively). Further by logistic regression, serum β-hCG, P levels on the 14th day after ET, and vaginal bleeding were identified as the independent factors of HP. These results indicate that when two or more embryos transferred in IVF procedure, β-hCG, P levels on the 14th day after ET, and vaginal bleeding could be taken as predictors for HP. PMID:26510008

  4. Risk Factors and Early Predictors for Heterotopic Pregnancy after In Vitro Fertilization

    PubMed Central

    Geng, Ling; Xia, Mingdi; Zhai, Junyu; Zhang, Wei; Zhang, Yuchao; Sun, Yinhua; Zhang, Jiangtao; Zhu, Dongyi; Zhao, Han; Chen, Zi-Jiang

    2015-01-01

    This study investigated the risk factors and early predictors for heterotopic pregnancy (HP) after in vitro fertilization and embryo transfer (IVF-ET). From January 2008 to January 2013, 41 cases of HP and 72 cases of intrauterine twin pregnancy after IVF-ET were recruited and retrospectively analyzed. Compared with intrauterine twin pregnancy group, the HP group had a lower basal luteinizing hormone (LH) level (P = 0.005) and more cases had a history of hydrosalpinx (P = 0.008). After 14 days of IVF-ET, the serum β-HCG (β-human chorionic gonadotropin), E2 (Estradiol) and P (Progesterone) levels were lower in HP group (P<0.001, respectively). Moreover, vaginal bleeding and abdominal pain were the significant features of HP before diagnosis (P<0.001, respectively). Further by logistic regression, serum β-hCG, P levels on the 14th day after ET, and vaginal bleeding were identified as the independent factors of HP. These results indicate that when two or more embryos transferred in IVF procedure, β-hCG, P levels on the 14th day after ET, and vaginal bleeding could be taken as predictors for HP. PMID:26510008

  5. Technique, complications, and clinical value of endomyocardial biopsy in patients with heterotopic heart transplants.

    PubMed Central

    Cooper, D K; Fraser, R C; Rose, A G; Ayzenberg, O; Oldfield, G S; Hassoulas, J; Novitzky, D; Uys, C J; Barnard, C N

    1982-01-01

    A review of 157 consecutive biopsies of donor endomyocardium in patients with heterotopic heart transplants is reported. The technique of percutaneous transvenous endomyocardial biopsy after this operation is described; manipulation of the catheter and bioptome into the junction of the donor superior vena cava and right atrium can be difficult when this anastomotic junction is small, as a result either of operative surgical technique or of subsequent contraction. The complication rate was 4%, but one patient may have died from infection resulting from biopsy when the bioptome had to be introduced at the groin. The histopathological changes seen in the biopsy specimens have been graded according to a scoring system to give the clinician a guide to the severity of rejection. Histopathological assessment was of clinical value in 96% of cases, but was inaccurate on two occasions, once because an opinion was given on what was in retrospect an inadequate sample. In patients undergoing persistent low-grade acute or chronic rejection there was difficulty in detecting or appreciating the true extent of myocardial fibrosis; this led to inadequate immunosuppressive treatment in two patients. Attention is drawn to the fact that ischaemic fibrosis resulting from the vascular changes of chronic rejection may spare the endomyocardium, which is kept viable by intracavitary blood, and that this may lead to a misleading histopathological report. Images PMID:6760446

  6. Postoperative paralysis following posterior decompression with instrumented fusion for thoracic myelopathy caused by ossification of the posterior longitudinal ligament.

    PubMed

    Yamazaki, Masashi; Okawa, Akihiko; Mannoji, Chikato; Fujiyoshi, Takayuki; Furuya, Takeo; Koda, Masao

    2011-02-01

    A 60-year-old man presented with thoracic myelopathy due to ossification of the posterior longitudinal ligament (OPLL). His spinal cord was severely impinged anteriorly by a beak-type OPLL and posteriorly by ossification of the ligamentum flavum at T4/5. He underwent surgical posterior decompression with instrumented fusion (PDF). Immediately after surgery, he developed a Brown-Séquard-type paralysis, which spontaneously resolved without requiring the addition of OPLL extirpation. This example highlights that the risk of postoperative neurological deterioration cannot be eliminated even when PDF is selected as the surgical procedure for thoracic OPLL, especially in instances in which the spinal cord is severely compressed. PMID:21030260

  7. Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs

    PubMed Central

    Tamura, Naohisa; Doolittle, Lynda K.; Hammer, Robert E.; Shelton, John M.; Richardson, James A.; Garbers, David L.

    2004-01-01

    Guanylyl cyclase B is the receptor for a small peptide (C-type natriuretic peptide) produced locally in many different tissues. To unravel the functions of the receptor, we generated mice lacking guanylyl cyclase B through gene targeting. Expression of the receptor mRNA in tissues such as bone and female reproductive organs was evident, and significant phenotypes associated with each of these tissues were apparent in null mice. A dramatic impairment of endochondral ossification and an attenuation of longitudinal vertebra or limb-bone growth were seen in null animals. C-type natriuretic peptide-dependent increases of guanylyl cyclase B activity, but not basal enzyme activity, appeared to be required for the progression of endochondral ossification. Female mice were infertile, but male mice were not. This result was due to the failure of the female reproductive tract to develop. Thus, the guanylyl cyclase B receptor is critical for the development of both bone and female reproductive organs. PMID:15572448

  8. Osteolytic bone metastasis is hampered by impinging on the interplay among autophagy, anoikis and ossification.

    PubMed

    Maroni, P; Bendinelli, P; Matteucci, E; Locatelli, A; Nakamura, T; Scita, G; Desiderio, M A

    2014-01-01

    Here we show that the fate of osteolytic bone metastasis depends on the balance among autophagy, anoikis resistance and ossification, and that the hepatocyte growth factor (HGF) signaling pathway seems to have an important role in orchestrating bone colonization. These findings are consistent with the pathophysiology of bone metastasis that is influenced by the cross-talk of supportive and neoplastic cells through molecular signaling networks. We adopted the strategy to target metastasis and stroma with the use of adenovirally expressed NK4 (AdNK4) and Dasatinib to block HGF/Met axis and Src activity. In human bone metastatic 1833 cells, HGF conferred anoikis resistance via Akt and Src activities and HIF-1α induction, leading to Bim isoforms degradation. When Src and Met activities were inhibited with Dasatinib, the Bim isoforms accumulated conferring anoikis sensitivity. The proviability effect of HGF, under low-nutrient stress condition, was related to a faster autophagy deactivation with respect to HGF plus Dasatinib. In the 1833 xenograft model, AdNK4 switched metastasis vasculature to blood lacunae, increasing HIF-1α in metastasis. The combination of AdNK4 plus Dasatinib gave the most relevant results for mice survival, and the following molecular and cellular changes were found to be responsible. In bone metastasis, we observed a hypoxic condition - marked by HIF-1α - and an autophagy failure - marked by p62 without Beclin-1. Then, osteolytic bone metastases were largely prevented, because of autophagy failure in metastasis and ossification in bone marrow, with osteocalcin deposition. The abnormal repair process was triggered by the dysfunctional autophagy/anoikis interplay. In conclusion, the concomitant blockade of HGF/Met axis and Src activity seemed to induce HIF-1α in metastasis, whereas the bone marrow hypoxic response was reduced. As a consequence, anoikis resistance might be hampered favoring, instead, autophagy failure and neoformation of woven

  9. Protective effect of naringin against ankylosing spondylitis via ossification, inflammation and oxidative stress in mice

    PubMed Central

    Liu, Kang; Wu, Lianguo; Shi, Xiaolin; Wu, Fengqing

    2016-01-01

    Naringin is an abundant flavanone in pomelo, grapefruit as well as lime and its variants, has been shown to exhibit certain antioxidative, anti-inflammatory, anti-cancer and hypoglycemic effects. The aim of the current study was to evaluate the protective effects of naringin against ankylosing spondylitis (AS) and to elucidate the potential underlying mechanism. Firstly, a mouse model of ankylosing spondylitis (AS) was established. Next, osteocalcin (OC), alkaline phosphatase (ALP) and triglyceride (TG) activity values, inflammatory factor and oxidative stress were evaluated in the AS mice. Then, the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) protein expression levels in the AS mice were investigated using western blot analysis. The results showed that naringin increased OC, ALP and TG activity values in the AS mouse model. Furthermore, inflammatory factor and oxidative stress levels in the AS mice were restrained by treatment with naringin. Furthermore, JAK2 and STAT3 protein expression levels were reduced by treatment with naringin. In conclusion, the present results indicated that the protective effects of naringin against AS are exerted via the induction of ossification, suppression of inflammation and oxidative stress and the downregulation of JAK2/STAT3 in mice. PMID:27446336

  10. Investigation of aluminum and iron deposition on metaplastic bones in three patients with diffuse pulmonary ossification.

    PubMed

    Ohtsuki, Yuji; Mori, Kousuke; Ohnishi, Hirozo; Enzan, Hideaki; Iguchi, Mitsuko; Lee, Gang-Hong; Furihata, Mutsuo

    2015-12-01

    Diffuse pulmonary ossification (DPO) is a rare pulmonary lesion. DPO is typically detected at autopsy rather than premortem. Recently, however, several cases were diagnosed antemortem using computed tomography, high-resolution computed tomography, or video-assisted thoracic surgery. In the present study, we evaluated DPO at autopsy from two patients with post-myocardial infarction (cases 1 and 3) and one patient with duodenal cancer (case 2). Multiple metaplastic bones (nodular in case 1 and 3 or dendriform in case 2) were detected in these three cases. In an attempt to detect aluminum and iron deposition in these metaplastic bones, histochemical investigations were performed. The two nodular types of one and three cases were positive for aluminum and iron, but the dendriform type of case 2 was positive only for aluminum. The depositions occurred in a linear pattern along the calcifying front. It is of great interest that these deposition patterns were similar to those of bones from three previously reported DPO cases and from the bones of hemodialysis patients. It is suggested that these abnormal metal depositions in the calcifying front might disturb the normal mineralization processes of the metaplastic bones, although no morphological abnormality was detected, except for dense black color of calcifying front lines. Further investigations are needed in more patients with DPO to obtain more information on this topic. PMID:25631789

  11. Hypomorphic mutation in mouse Nppc gene causes retarded bone growth due to impaired endochondral ossification

    SciTech Connect

    Tsuji, Takehito Kondo, Eri; Yasoda, Akihiro; Inamoto, Masataka; Kiyosu, Chiyo; Nakao, Kazuwa; Kunieda, Tetsuo

    2008-11-07

    Long bone abnormality (lbab/lbab) is a spontaneous mutant mouse characterized by dwarfism with shorter long bones. A missense mutation was reported in the Nppc gene, which encodes C-type natriuretic peptide (CNP), but it has not been confirmed whether this mutation is responsible for the dwarf phenotype. To verify that the mutation causes the dwarfism of lbab/lbab mice, we first investigated the effect of CNP in lbab/lbab mice. By transgenic rescue with chondrocyte-specific expression of CNP, the dwarf phenotype in lbab/lbab mice was completely compensated. Next, we revealed that CNP derived from the lbab allele retained only slight activity to induce cGMP production through its receptor. Histological analysis showed that both proliferative and hypertrophic zones of chondrocytes in the growth plate of lbab/lbab mice were markedly reduced. Our results demonstrate that lbab/lbab mice have a hypomorphic mutation in the Nppc gene that is responsible for dwarfism caused by impaired endochondral ossification.

  12. Posterior decompression with instrumented fusion for thoracic myelopathy caused by ossification of the posterior longitudinal ligament.

    PubMed

    Yamazaki, Masashi; Okawa, Akihiko; Fujiyoshi, Takayuki; Furuya, Takeo; Koda, Masao

    2010-05-01

    We evaluated the clinical results of posterior decompression with instrumented fusion (PDF) for thoracic myelopathy due to ossification of the posterior longitudinal ligament (OPLL). A total of 24 patients underwent PDF, and their surgical outcomes were evaluated by the Japanese Orthopaedic Association (JOA) scores (0-11 points) and by recovery rates calculated at 3, 6, 9 and 12 months after surgery and at a mean final follow-up of 4 years and 5 months. The mean JOA score before surgery was 3.7 points. Although transient paralysis occurred immediately after surgery in one patient (3.8%), all patients showed neurological recovery at the final follow-up with a mean JOA score of 8.0 points and a mean recovery rate of 58.1%. The mean recovery rate at 3, 6, 9 and 12 months after surgery was 36.7, 48.8, 54.0 and 56.8%, respectively. The median time point that the JOA score reached its peak value was 9 months after surgery. No patient chose additional anterior decompression surgery via thoracotomy. The present findings demonstrate that despite persistent anterior impingement of the spinal cord by residual OPLL, PDF can result in considerable neurological recovery with a low risk of postoperative paralysis. Since neurological recovery progresses slowly after PDF, we suggest that additional anterior decompression surgery is not desirable during the early stage of recovery. PMID:20049486

  13. Ossification of the Posterior Longitudinal Ligament: Etiology, Diagnosis, and Outcomes of Nonoperative and Operative Management

    PubMed Central

    Abiola, Rasheed; Rubery, Paul; Mesfin, Addisu

    2015-01-01

    Study Design Narrative review. Objective To provide an overview on the diagnosis, natural history, and nonoperative and operative management of ossification of the posterior longitudinal ligament (OPLL). OPLL is a multifactorial condition caused by ectopic hyperostosis and calcification of the posterior longitudinal ligament. Familial inheritance and genetic factors have been implicated in the etiology of OPLL. The cervical spine is most commonly affected followed by the thoracic spine. The clinical manifestations range from asymptomatic to myelopathy or myeloradiculopathy. Methods Using PubMed, studies published prior to October 2014 with the keywords “OPLL, etiology”; “OPLL, genetics”; “OPLL, spinal cord injury”; “OPLL, natural history”; “OPLL, non-surgical management”; OPLL, surgical management”; “OPLL, surgical complications” were evaluated. Results The review addresses the etiology, epidemiology, classification, clinical presentation, imaging findings, and nonoperative and operative management of OPLL. Complications associated with surgical management of OPLL are also discussed. Conclusions OPLL commonly presents with myelopathy and radiculopathy. Spine providers should consider OPLL in their differential diagnosis and when reviewing images. If surgical intervention is pursued, imaging-based measurements and findings can help in choosing an anterior versus posterior surgical approach. PMID:26933622

  14. Ossification of the Posterior Longitudinal Ligament: Etiology, Diagnosis, and Outcomes of Nonoperative and Operative Management.

    PubMed

    Abiola, Rasheed; Rubery, Paul; Mesfin, Addisu

    2016-03-01

    Study Design Narrative review. Objective To provide an overview on the diagnosis, natural history, and nonoperative and operative management of ossification of the posterior longitudinal ligament (OPLL). OPLL is a multifactorial condition caused by ectopic hyperostosis and calcification of the posterior longitudinal ligament. Familial inheritance and genetic factors have been implicated in the etiology of OPLL. The cervical spine is most commonly affected followed by the thoracic spine. The clinical manifestations range from asymptomatic to myelopathy or myeloradiculopathy. Methods Using PubMed, studies published prior to October 2014 with the keywords "OPLL, etiology"; "OPLL, genetics"; "OPLL, spinal cord injury"; "OPLL, natural history"; "OPLL, non-surgical management"; OPLL, surgical management"; "OPLL, surgical complications" were evaluated. Results The review addresses the etiology, epidemiology, classification, clinical presentation, imaging findings, and nonoperative and operative management of OPLL. Complications associated with surgical management of OPLL are also discussed. Conclusions OPLL commonly presents with myelopathy and radiculopathy. Spine providers should consider OPLL in their differential diagnosis and when reviewing images. If surgical intervention is pursued, imaging-based measurements and findings can help in choosing an anterior versus posterior surgical approach. PMID:26933622

  15. Anterior corpectomy and fusion for severe ossification of posterior longitudinal ligament in the cervical spine.

    PubMed

    Chen, Yu; Chen, Deyu; Wang, Xinwei; Lu, Xuhai; Guo, Yongfei; He, Zhimin; Tian, Haijun

    2009-04-01

    Between May 2002 and October 2006, 19 patients (17 men and 2 women; average age 57.2; range 47-71 years) received anterior corpectomy and fusion for severe ossification of the posterior longitudinal ligament (OPLL) in our department. Preoperative radiological evaluation showed the narrowing by the OPLL exceeded 50% in all cases, and OPLL extended from one to three vertebrae. We followed-up all patients for 12-36 months (mean 18 months). The Japanese Orthopaedic Association (JOA) score before surgery was 9.3 +/- 1.8 (range 5-12) which significantly increased to 14.2 +/- 1.3 (range 11-16) points at the last follow-up (P < 0.01). The improvement rate (IR) of neurological function ranged from 22.2-87.5%, with a mean of 63.2% +/- 15.2%. The operation also provided a significant increase in the cervical lordosis and the cord flatting rate (P < 0.01). No severe neurological complication developed. We therefore concluded that anterior decompression and fusion was effective and safe in the treatment of the selected patients, although OPLL exceeded 50% diameter of the spinal canal. PMID:18408927

  16. The Risk Factors and Pregnancy Outcomes of 48 Cases of Heterotopic Pregnancy from a Single Center

    PubMed Central

    2016-01-01

    The purpose of this study was to investigate risk factors that are associated with heterotopic pregnancy (HP) following in vitro fertilization (IVF)-embryo transfer (ET) and to demonstrate the outcomes of HP after the surgical treatment of ectopic pregnancies. Forty-eight patients from a single center, who were diagnosed with HP between 1998 and 2012 were included. All of the patients had received infertility treatments, such as Clomid with timed coitus (n = 1, 2.1%), superovulation with intrauterine insemination (n = 7, 14.6%), fresh non-donor IVF-ET (n = 33, 68.8%), and frozen-thawed cycles (n = 7, 14.6%). Eighty-four additional patients were randomly selected as controls from the IVF registry database. HP was diagnosed at 7.5 ± 1.2 weeks (range 5.4-10.3) gestational age. In six cases (12.5%), the diagnosis was made three weeks after the patients underwent treatment for abortion. There were significant differences in the history of ectopic pregnancy (22.5% vs. 3.6%, P = 0.002). There were no significant differences in either group between the rates of first trimester intrauterine fetal loss (15.0% vs. 13.1%) or live birth (80.0% vs. 84.1%) after the surgical treatment for ectopic pregnancy. The risk factors for HP include a history of ectopic pregnancy (OR 7.191 [1.591-32.513], P = 0.010), abortion (OR 3.948 [1.574-9.902], P = 0.003), and ovarian hyperstimulation syndrome (OHSS) (OR 10.773 [2.415-48.060], P = 0.002). In patients undergoing IVF-ET, history of ectopic pregnancy, abortion, and OHSS may be risk factors for HP as compared to the control group of other IVF patients. The surgical treatment of HP does not appear to affect the rates of first trimester fetal loss or live birth. PMID:27366008

  17. Experimentally induced muscle pain induces hypoalgesia in heterotopic deep tissues, but not in homotopic deep tissues.

    PubMed

    Graven-Nielsen, T; Babenko, V; Svensson, P; Arendt-Nielsen, L

    1998-03-23

    The ability of muscle pain to generate somatosensory sensibility changes is controversial. Thus, in the present study, tonic infusion of hypertonic saline (5%, 7.1 ml administered over 15 min) into the tibialis anterior (TA) muscle was used as an experimental model to induce local and referred pain. The sensibility to high-intensity pressure stimuli applied to the local pain area, referred pain area and an arm was assessed in 14 healthy volunteers. Infusion of isotonic (0.9%) saline into the other leg served as control. The subject continuously scored the pain intensity on an electronic visual analogue scale (VAS). Pressure pain threshold (PPT) was determined on the TA muscle (2 cm and 10 cm from the infusion site), at the frontal aspect of the ankle (area of referred pain) and on the arm. To minimise the skin component of the PPT, the skin covering the assessment sites was anaesthetised with an anaesthetic creme. The PPTs were obtained before and after cutaneous analgesia, 1 min and 10 min after infusion start and 10 min after the pain had disappeared. Infusion of hypertonic saline caused significantly (P<0. 05) higher VAS scores than infusion of isotonic saline. A significant (P<0.04) increase of the PPT (i.e., decreased sensibility) was found at the ankle and on the arm during muscle pain compared to the control condition. No significant differences in PPTs on the TA muscle were found during saline-induced muscle pain compared to the infusion of isotonic saline. The decrease in deep sensibility at the heterotopic sites (referred pain area and arm), but not at homotopic sites (TA muscle), probably reflected the phenomenon of diffuse noxious inhibitory control (DNIC). The inhibitory mechanism during muscle pain was shown to be effective for the deep tissue sensibility in healthy subjects. Thus, a pathologically disturbed inhibitory mechanism may result in widespread deep hyperalgesia in muscle pain patients. PMID:9518613

  18. Improved donor liver position selection and revascularization for heterotopic auxiliary liver transplantation with portal vein arterialization

    PubMed Central

    Li, Jun; Zhang, Yujun; Ren, Jianjun; Zhang, Junjing; Qiao, Jianliang; Meng, Xingkai

    2015-01-01

    Purpose: To establish an animal model of improved donor liver position selection and revascularization for heterotopic auxiliary liver transplantation with portal vein arterialization (HALT-PVA). Methods: Sprague-Dawley rats were utilized to establish models. Improved HALT-PVA was conducted for the experimental rat: hepatic common artery of donor liver was end-to-side anastomosed to portal vein which was end-to-side anastomosed to the left common iliac artery of host rat, while the segments of inferior vena cava superior and inferior to the donor liver were end-to-side anastomosed to the inferior vena cava of host rat, respectively. For the control rats, liver transplantations were conducted through end-to-end anastomosis between portal vein of donor liver and stand tube placed in right renal artery of host rat, and end-to-side anastomosis between the inferior vena cava inferior to the donor liver with the inferior vena cava of host rat, while the inferior vena cava superior to the donor liver was stitched up. Besides, hepaticoenterostomy were performed to all rats and survival status were monitored. ALT, AST, TBil and CHE were tested continuously after operation, and pathological examination of liver tissues were performed. Results: The survival rate was 93.3% (14/15). ALT, AST, TBil and CHE for experimental group showed a rapider recovery of liver functions than controls. Pathological examinations of liver tissues from the experimental-group rats showed better presentation than the control-group rats. Conclusions: The improved HALT-PVA better accords with the normal anatomy, with little detriment to implanted liver, and therefore is a good model for HALT-PVA related research. PMID:26770477

  19. The Risk Factors and Pregnancy Outcomes of 48 Cases of Heterotopic Pregnancy from a Single Center.

    PubMed

    Jeon, Ji Hyun; Hwang, Yu Im; Shin, Im Hee; Park, Chan Woo; Yang, Kwang Moon; Kim, Hye Ok

    2016-07-01

    The purpose of this study was to investigate risk factors that are associated with heterotopic pregnancy (HP) following in vitro fertilization (IVF)-embryo transfer (ET) and to demonstrate the outcomes of HP after the surgical treatment of ectopic pregnancies. Forty-eight patients from a single center, who were diagnosed with HP between 1998 and 2012 were included. All of the patients had received infertility treatments, such as Clomid with timed coitus (n = 1, 2.1%), superovulation with intrauterine insemination (n = 7, 14.6%), fresh non-donor IVF-ET (n = 33, 68.8%), and frozen-thawed cycles (n = 7, 14.6%). Eighty-four additional patients were randomly selected as controls from the IVF registry database. HP was diagnosed at 7.5 ± 1.2 weeks (range 5.4-10.3) gestational age. In six cases (12.5%), the diagnosis was made three weeks after the patients underwent treatment for abortion. There were significant differences in the history of ectopic pregnancy (22.5% vs. 3.6%, P = 0.002). There were no significant differences in either group between the rates of first trimester intrauterine fetal loss (15.0% vs. 13.1%) or live birth (80.0% vs. 84.1%) after the surgical treatment for ectopic pregnancy. The risk factors for HP include a history of ectopic pregnancy (OR 7.191 [1.591-32.513], P = 0.010), abortion (OR 3.948 [1.574-9.902], P = 0.003), and ovarian hyperstimulation syndrome (OHSS) (OR 10.773 [2.415-48.060], P = 0.002). In patients undergoing IVF-ET, history of ectopic pregnancy, abortion, and OHSS may be risk factors for HP as compared to the control group of other IVF patients. The surgical treatment of HP does not appear to affect the rates of first trimester fetal loss or live birth. PMID:27366008

  20. Uterus transplantation model in sheep with heterotopic whole graft and aorta and cava anastomoses.

    PubMed

    Gonzalez-Pinto, I M; Tryphonopoulos, P; Avison, D L; Nishida, S; Tekin, A; Santiago, S; Tzakis, A G

    2013-06-01

    Uterine transplantation in the sheep model has been described as a partial or whole orthotopic graft from a living donor with vascular anastomoses. As an alternative to surrogate pregnancy or adoption uterus transplantation might be indicated for cases of infertility of uterine origin. The main complications might be rejection and thrombosis. The objective of this work was to develop a model of whole uterus transplantation that was applicable to the human setting, using grafts obtained from brain-dead donors, and suitable for immunologic and viability follow-up with a reduced risk of thrombosis. Two donors and 1 recipient were operated. The first graft was used for an anatomic study; the second was used for transplantation. The donor operation consisted of an en bloc harvest of the uterus, adnexa, and proximal vagina with the distal aorta and cava. After harvest the donor sheep was humanely killed. In the recipient ewe, heterotopic implantation was performed in the lower abdomen. An End-to-side anastomoses of aorta and cava were performed below the recipient's renal vessels. A cutaneous vaginal stoma was performed in the right lower quadrant. The recipient ewe was humanely killed for an autopsy study. The anatomy of uterine veins of the ewe differs from the human. The uterine and ovarian veins join, forming the utero-ovarian vein, which drains at the confluence of the common iliac to the cava. En bloc harvesting allows for rapid graft preparation, with vascular cuffs easily anastomosed with a low risk of thrombosis. The vaginal stoma seems appropriate to facilitate follow-up and graft biopsy. This approach can be a suitable experimental model applicable to humans using grafts from brain-dead donors. PMID:23769047

  1. Effect of Different rhBMP-2 and TG-VEGF Ratios on the Formation of Heterotopic Bone and Neovessels

    PubMed Central

    Cai, Wei Xin; Li, Chun Lei; Ehrbar, Martin; Weber, Franz E.; Zwahlen, Roger A.

    2014-01-01

    Bioengineered bone substitutes might represent alternatives to autologous bone grafts in medically compromised patients due to reduced operation time and comorbidity. Due to the lack of an inherent vascular system their dimension is limited to the size of critical bone size defect. To overcome this shortcoming, the experiment tried to create heterotopic bone around vessels. In vivo, a two-component fibrin and thrombin gel containing recombinant bone morphogenic protein (rhBMP-2) and transglutamate vascular endothelial growth factor (TG-VEGF) in different ratios, respectively, was injected into a dimensionally stable membrane tube, wrapped around the femoral vessel bundle in twelve New Zealand white rabbits. Sacrifice occurred eight weeks postoperatively. Microcomputed tomography of the specimens showed significantly increased bone volume in the rhBMP-2 to TG-VEGF ratio of 10 to 1 group. Histology showed new bone formation in close proximity to the vessel bundle. Immunohistochemistry detected increased angiogenesis within the newly formed bone in the rhBMP-2 to TG-VEGF ratios of 3 to 1 and 5 to 1. Heterotopic bone was engineered in vivo around vessels using different rhBMP-2 and TG-VEGF ratios in a fibrin matrix injected into a dimensionally stable membrane tube which prevented direct contact with skeletal muscles. PMID:24783213

  2. Auricular ossification: A newly recognized feature of osteoprotegerin-deficiency juvenile Paget disease.

    PubMed

    Gottesman, Gary S; Madson, Katherine L; McAlister, William H; Nenninger, Angela; Wenkert, Deborah; Mumm, Steven; Whyte, Michael P

    2016-04-01

    We report auricular ossification (AO) affecting the elastic cartilage of the ear as a newly recognized feature of osteoprotegerin (OPG)-deficiency juvenile Paget disease (JPD). AO and auricular calcification refer interchangeably to rigid pinnae, sparing the ear lobe, from various etiologies. JPD is a rare Mendelian disorder characterized by elevated serum alkaline phosphatase activity accompanied by skeletal pain and deformity from rapid bone turnover. Autosomal recessive transmission of loss-of-function mutations within TNFRSF11B encoding OPG accounts for most JPD (JPD1). JPD2 results from heterozygous constitutive activation of TNFRSF11A encoding RANK. Other causes of JPD remain unknown. In 2007, we reported a 60-year-old man with JPD1 who described hardening of his external ears at age 45 years, after 4 years of treatment with bisphosphonates (BPs). Subsequently, we noted rigid pinnae in a 17-year-old boy and 14-year-old girl, yet pliable pinnae in a 12-year-old boy, each with JPD1 and several years of BP treatment. Cranial imaging indicated cortical bone within the pinnae of both teenagers. Radiologic studies of our three JPD patients without mutations in TNFRSF11B showed normal auricles. Review of the JPD literature revealed possible AO in several reports. Two of our JPD1 patients had experienced difficult tracheal intubation, raising concern for mineralization of laryngeal elastic cartilage. Thus, AO is a newly recognized feature of JPD1, possibly exacerbated by BP treatment. Elastic cartilage at other sites in JPD1 might also ossify, and warrants investigation. PMID:26762549

  3. Clinical outcomes after decompressive laminectomy for symptomatic ossification of ligamentum flavum at the thoracic spine.

    PubMed

    Zhong, Zhao-Ming; Wu, Qian; Meng, Ting-Ting; Zhu, Yong-Jian; Qu, Dong-Bin; Wang, Ji-Xing; Jiang, Jian-Ming; Lu, Kai-Wu; Zheng, Shuai; Zhu, Si-Yuan; Chen, Jian-Ting

    2016-06-01

    Ossification of the ligamentum flavum (OLF) is a rare disease that causes acquired thoracic spinal canal stenosis and thoracic myelopathy. The aim of this study was to investigate clinical outcomes of symptomatic thoracic OLF treated using posterior decompressive laminectomy. We retrospectively analyzed the medical records of 22 patients who underwent posterior decompressive laminectomy for symptomatic thoracic OLF. The surgical results were evaluated using the modified Japanese Orthopaedic Association (JOA) scoring system and Hirabayashi recovery rate. The intensity of pain was evaluated using a visual analog scale (VAS). The mean duration of follow-up was 35.6months. The mean JOA score was significantly improved at final follow-up (9.18±standard deviation of 1.53 points [range, 6-11 points]) compared with before surgery (5.64±2.04 points [range, 3-9 points]) (P<0.001). The mean Hirabayashi recovery rate was 65.49% (range, 20-100%). Recovery outcomes were excellent in nine patients, good in eight patients, fair in four patients and unchanged in one patient. No patient was classified as deteriorated. The VAS scores were 2.82±3.08 before surgery and 0.59±1.05 at final follow-up (P=0.001). Surgical complications, which resolved after appropriate and prompt treatment, included dural tear in five patients, cerebrospinal fluid leakage in one patient, immediate postoperative neurologic deterioration in one patient, epidural hematoma in one patient, and wound infection in one patient. Our findings suggest that posterior decompressive laminectomy is an effective treatment for symptomatic thoracic OLF and provides satisfactory clinical improvement, but surgery for thoracic OLF is associated with a relatively high incidence of complications. PMID:26898582

  4. Evaluation of age estimation in forensic medicine by examination of medial clavicular ossification from thin-slice computed tomography images.

    PubMed

    Gurses, Murat Serdar; Inanir, Nursel Turkmen; Gokalp, Gokhan; Fedakar, Recep; Tobcu, Eren; Ocakoglu, Gokhan

    2016-09-01

    Forensic age estimation, a recent topic of research in forensic medicine, is of primary importance to criminal and civil law. Previous studies indicate that the observation of medial clavicular ossification allows for age discrimination along the completed 18th and 21st years of life. Experts recommend that the Schmeling and Kellinghaus methods be used together. In this study, we used these staging methods to retrospectively analyze 725 case studies (385 males, 340 females) of thin-slice computed tomography (CT) images, ranging from 0.6 to 1 mm in thickness, from individuals aged 10 to 35 years. Stage 1 was found at 18 years of age maximum for males, whereas it was found at 17 years of age for females. Stage 2a was found at 18 years of age maximum for both genders. Stage 3c was initially observed at 18 years for both genders. Stage 4 was initially found at 21 years for males and 20 years for females. Stage 5 was initially observed at 25 years for both genders. Of note, stage 3c was found close to 19 years of age for both genders (18.92 years for male, 18.99 years for female), and it may be employed to differentiate along the age majority cutoff. The data obtained from our study were consistent with previous studies. We believe that such a comprehensive database will greatly contribute to future studies focusing on medial clavicular ossification based on thin-slice CT. Moreover, we also recommend that if medial clavicular ossification based on CT is to be examined for forensic age estimation, both methods should be employed together. PMID:27352083

  5. Dysregulation of ossification-related miRNAs in circulating osteogenic progenitor cells obtained from patients with aortic stenosis

    PubMed Central

    Takahashi, Kan; Takahashi, Yuji; Osaki, Takuya; Nasu, Takahito; Tamada, Makiko; Okabayashi, Hitoshi; Nakamura, Motoyuki; Morino, Yoshihiro

    2016-01-01

    CAVD (calcific aortic valve disease) is the defining feature of AS (aortic stenosis). The present study aimed to determine whether expression of ossification-related miRNAs is related to differentiation intro COPCs (circulating osteogenic progenitor cells) in patients with CAVD. The present study included 46 patients with AS and 46 controls. Twenty-nine patients underwent surgical AVR (aortic valve replacement) and 17 underwent TAVI (transcatheter aortic valve implantation). The number of COPCs was higher in the AS group than in the controls (P<0.01). Levels of miR-30c were higher in the AS group than in the controls (P<0.01), whereas levels of miR-106a, miR-148a, miR-204, miR-211, miR-31 and miR-424 were lower in the AS group than in the controls (P<0.01). The number of COPCs and levels of osteocalcin protein in COPCs were positively correlated with levels of miR-30a and negatively correlated with levels of the remaining miRNAs (all P<0.05). The degree of aortic valve calcification was weakly positively correlated with the number of COPCs and miR-30c levels. The number of COPCs and miR-30c levels were decreased after surgery, whereas levels of the remaining miRNAs were increased (all P<0.05). Changes in these levels were greater after AVR than after TAVI (all P<0.05). In vitro study using cultured peripheral blood mononuclear cells transfected with each ossification-related miRNA showed that these miRNAs controlled levels of osteocalcin protein. In conclusion, dysregulation of ossification-related miRNAs may be related to the differentiation into COPCs and may play a significant role in the pathogenesis of CAVD. PMID:27129184

  6. Dysregulation of ossification-related miRNAs in circulating osteogenic progenitor cells obtained from patients with aortic stenosis.

    PubMed

    Takahashi, Kan; Satoh, Mamoru; Takahashi, Yuji; Osaki, Takuya; Nasu, Takahito; Tamada, Makiko; Okabayashi, Hitoshi; Nakamura, Motoyuki; Morino, Yoshihiro

    2016-07-01

    CAVD (calcific aortic valve disease) is the defining feature of AS (aortic stenosis). The present study aimed to determine whether expression of ossification-related miRNAs is related to differentiation intro COPCs (circulating osteogenic progenitor cells) in patients with CAVD. The present study included 46 patients with AS and 46 controls. Twenty-nine patients underwent surgical AVR (aortic valve replacement) and 17 underwent TAVI (transcatheter aortic valve implantation). The number of COPCs was higher in the AS group than in the controls (P<0.01). Levels of miR-30c were higher in the AS group than in the controls (P<0.01), whereas levels of miR-106a, miR-148a, miR-204, miR-211, miR-31 and miR-424 were lower in the AS group than in the controls (P<0.01). The number of COPCs and levels of osteocalcin protein in COPCs were positively correlated with levels of miR-30a and negatively correlated with levels of the remaining miRNAs (all P<0.05). The degree of aortic valve calcification was weakly positively correlated with the number of COPCs and miR-30c levels. The number of COPCs and miR-30c levels were decreased after surgery, whereas levels of the remaining miRNAs were increased (all P<0.05). Changes in these levels were greater after AVR than after TAVI (all P<0.05). In vitro study using cultured peripheral blood mononuclear cells transfected with each ossification-related miRNA showed that these miRNAs controlled levels of osteocalcin protein. In conclusion, dysregulation of ossification-related miRNAs may be related to the differentiation into COPCs and may play a significant role in the pathogenesis of CAVD. PMID:27129184

  7. Mid- to long-term outcomes of posterior decompression with instrumented fusion for thoracic ossification of the posterior longitudinal ligament.

    PubMed

    Koda, Masao; Furuya, Takeo; Okawa, Akihiko; Inada, Taigo; Kamiya, Koshiro; Ota, Mitsutoshi; Maki, Satoshi; Takahashi, Kazuhisa; Yamazaki, Masashi; Aramomi, Masaaki; Ikeda, Osamu; Mannoji, Chikato

    2016-05-01

    Posterior decompression with instrumented fusion (PDF) surgery has been previously reported as a relatively safe surgical procedure for any type of thoracic ossification of the longitudinal ligament (OPLL). However, mid- to long-term outcomes are still unclear. The aim of the present study was to elucidate the mid- to long-term clinical outcome of PDF surgery for thoracic OPLL patients. The present study included 20 patients who had undergone PDF for thoracic OPLL and were followed for at least 5years. Increment change and recovery rate of the Japanese Orthopaedic Association (JOA) score were assessed. Revision surgery during the follow-up period was also recorded. Average JOA scores were 3.5 preoperatively and 7.1 at final follow-up. The average improvement in JOA score was 3.8 points and the average recovery rate was 47.0%. The JOA score showed gradual increase after surgery, and took 9months to reach peak recovery. As for neurological complications, two patients suffered postoperative paralysis, but both recovered without intervention. Six revision surgeries in four patients were related to OPLL. Additional anterior thoracic decompression for remaining ossification at the same level of PDF surgery was performed in one patient. Decompression surgery for deterioration of symptoms of pre-existing cervical OPLL was performed in three patients. One patient had undergone lumbar and cervical PDF surgery for de novo ossification foci of the lumbar and cervical spine. PDF surgery for thoracic OPLL is thus considered a relatively safe and stable surgical procedure considering the mid- to long-term outcomes. PMID:26794690

  8. A new rat model of auxiliary partial heterotopic liver transplantation with liver dual arterial blood supply

    PubMed Central

    QIAO, JIANLIANG; HAN, CHUNLEI; ZHANG, JUNJING; WANG, ZHIYONG; MENG, XINGKAI

    2015-01-01

    Auxiliary partial heterotopic liver transplantation (APHLT) with portal vein arterialization is a valuable procedure to be considered in the treatment of patients with acute liver failure and metabolic liver diseases. The aim of this study was to develop a new rat model of APHLT with liver dual arterial blood supply (LDABS). A total of 20 rats were used. The donor liver was resected, and the celiac trunk was reserved. Left and medial hepatic lobes accounting for 70% of the liver mass were removed en bloc and the suprahepatic caval vein was ligated simultaneously. Thus, 30% of the donor liver was obtained as the graft. Sleeve anastomosis of the graft portal vein and splenic artery were performed after narrowing the portal vein lumen through suturing. The right kidney of the recipient was removed, and sleeve anastomosis was performed between the celiac trunk of the graft and the right renal artery of the recipient. In addition, end-to-end anastomosis was performed between the infrahepatic caval vein of the graft and the right renal vein of the recipient. Following the reperfusion of the graft, the blood flow of the arterialized portal vein was controlled within the physiological range through suturing and narrowing under monitoring with an ultrasonic flowmeter. The bile duct of the graft was implanted into the duodenum of the recipient through an internal stent catheter. A 70% section of the native liver (left and medial hepatic lobes) was resected using bloodless hepatectomy. The mean operative duration was 154.5±16.4 min, and the warm and cold ischemia times of the graft were 8.1±1.1 min and 64.5±6.6 min, respectively. The blood flow of the arterialized portal vein to the graft was 1.8±0.3 ml/min/g liver weight. The success rate of model establishment (waking with post-surgical survival of >24 h) was 70% (7/10). Following successful model establishment, all rats survived 7 days post-surgery (100%; 7/7). The graft was found to be soft in texture and bright red

  9. Protective effect of bone marrow mesenchymal stem cells in intestinal barrier permeability after heterotopic intestinal transplantation

    PubMed Central

    Zhang, Wen; Shen, Zhong-Yang; Song, Hong-Li; Yang, Yang; Wu, Ben-Juan; Fu, Nan-Nan; Liu, Tao

    2014-01-01

    AIM: To explore the protective effect of bone marrow mesenchymal stem cells (BM MSCs) in the small intestinal mucosal barrier following heterotopic intestinal transplantation (HIT) in a rat model. METHODS: BM MSCs were isolated from male Lewis rats by density gradient centrifugation, cultured, and analyzed by flow cytometry. The HIT models were divided into a non-rejection group, saline-treated rejection group (via penile vein), and BM MSC–treated group (via penile vein). Intestinal mucosal barrier injury was estimated by diamine oxidase (DAO) and D-lactic acid (D-LA) expression levels. Tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) were detected by enzyme-linked immunosorbent assay. Ultrastructural change of tight junctions (TJs) was observed under transmission electron microscope. Expression levels of the TJ proteins occludin and zona occludens (ZO)-1, affected by the inflammatory factors, were measured using real-time polymerase chain reaction and Western blotting. RESULTS: The pathological score at each time point after surgery indicated significantly less serious injury in the BM MSCs-treated group than in the rejection group (P < 0.05). In the former, graft levels of DAO and D-LA were reduced, and TNF-α and INF-γ production was inhibited (at day 7: 10.6473 ± 0.0710 vs 17.2128 ± 0.4991, P < 0.05; 545.1506 ± 31.9416 vs 810.2637 ± 25.1175, P < 0.05). IL-10 and TGF-β production was increased greatly (at day 7: 125.7773 ± 4.7719 vs 80.3756 ± 2.5866, P < 0.05; 234.5273 ± 9.3980 vs 545.1506 ± 31.9416, P < 0.05). There was increased expression of occludin and ZO-1 protein (at day 7: 0.2674 ± 0.0128 vs 0.1352 ± 0.0142, P < 0.05; at day 5: 0.7189 ± 0.0289 vs 0.4556 ± 0.0242, P < 0.05) and mRNA (at day 7: 0.3860 ± 0.0254 vs 0.1673 ± 0.0369, P < 0.05; at day 5: 0.5727 ± 0.0419 vs 0.3598 ± 0.0242, P < 0.05). CONCLUSION: BM MSCs can improve intestinal barrier permeability

  10. Mono- and dimeric complexes of an asymmetric heterotopic P,CNHC,pyr ligand.

    PubMed

    Bouché, Mathilde; Mordan, Michael; Kariuki, Benson M; Coles, Simon J; Christensen, Jeppe; Newman, Paul D

    2016-09-14

    An asymmetric heterotopic ligand (S-N(Me)CP) containing a central bicyclic, expanded-ring NHC with one pyridyl and one phosphine exo-substituent has been synthesised and its coordination chemistry with selected late transition metals investigated. The amidinium precursor [S-N(Me)CHP]PF6 shows variable coordination modes with Ag(i), Cu(i) and Au(i) depending on the L : M ratio. The reaction of two mols of [S-N(Me)CHP]PF6 with [Cu(MeCN)4]BF4, AgBF4 or Au(THT)Cl gives the bis-ligand complexes [Cu(κ-P-N(Me)CHP)2(CH3CN)2]BF4·(PF6)2, 1, and [M(κ-P-N(Me)CHP)2]X·(PF6)2 (3: M = Ag, X = BF4; 6: M = Au, X = Cl) respectively. The 1 : 1 reaction of [S-N(Me)CHP]PF6 with AgOTf gave the head-to-tail dimer H,T-[Ag2(μ-N,P-N(Me)CHP)2(μ-OTf)2](PF6)2, 2, whereas the analogous reaction with Au(THT)Cl gave monomeric [Au(κ-P-N(Me)CHP)Cl]PF6, 5. Complex 2 was converted to H,T-[Ag2(μ-C,P-N(Me)CP)2](PF6)2, 4, upon addition of base, while 6 gave [Au(κ-C-N(Me)CP)2]Cl, 8, when treated likewise. Reaction of [S-N(Me)CHP]PF6 with Ni(1,5-COD)2 gave the oxidative addition/insertion product [Ni(κ(3)-N,C,P-N(Me)CP)(η(3)-C8H13)]PF6, 9, which converted to [Ni(κ(3)-N,C,P-N(Me)CP)Cl]PF6, 10, upon exposure of a CHCl3 solution to air. Complex 10 showed conformational isomerism that was also present in [Rh(κ(3)-N,C,P-N(Me)CP)(CO)]PF6, 14, prepared from the precursor complex [Rh(κ-P-N(Me)CHP)(acac)(CO)]PF6, 13, upon heating in C6H5Cl. [Pt(κ(3)-N,C,P-N(Me)CP)(Cl)]PF6, 12, derived from trans-[Pt(κ-P-N(Me)CHP)2(Cl)2](PF6)2, 11, was isolated as a single conformer. PMID:27461718

  11. Postoperative irradiation for the prevention of heterotopic bone: Analysis of different dose schedules and shielding considerations

    SciTech Connect

    Blount, L.H.; Thomas, B.J.; Tran, L.; Selch, M.T.; Sylvester, J.E.; Parker, R.G. )

    1990-09-01

    Ninety-seven high risk hips were irradiated postoperatively for prevention of heterotopic bone (HTB) in the UCLA Department of Radiation Oncology from 1980 to 1988. Ninety-two hips in 82 patients were eligible for analysis with a minimum follow-up of 2 months and a median follow-up of 10 months. Forty-nine of the hips had porous coated ingrowth prostheses. From 1980 to 1986, 2 Gy fractions were used to deliver 20 Gy (8 hips), 12 Gy (1 hip), and 10 Gy (27 hips). Since December of 1986, 38 hips received 8 Gy in two increments and 18 hips received a single 7 Gy fraction. All porous ingrowth components were shielded with custom blocks. Six out of 92 hips developed clinically significant. There was one clinically significant failure in 78 hips (1.3%) when irradiation was initiated before post-operative day (POD) No.6 and shielding was properly placed. One clinical failure occurred in 38 hips which received 8 Gy in two increments. One clinical failure occurred out of the 18 hips treated with 7 Gy in one fraction. This failure could be related to block malposition. There were four clinical failures in the 36 hips treated with 2 Gy fractions to total doses of 10 Gy, 12 Gy, or 20 Gy. Three of these failures were associated with initiation of treatment after POD No.5, and the fourth was related to block malposition. Unshielded trochanteric osteotomies resulted in five migrations and seven fibrous unions for a total non-osseous union rate of 12/36 (33%). Shielding of the remaining 28 trochanteric osteotomies resulted in a non-osseous union rate of 7%. There were no failures of union of components, and the only side effects noted in the series were the five trochanteric migrations. In conclusion, the use of 8 Gy in two increments or 7 Gy in one fraction was found to be as efficacious as conventional 2 Gy fractionation schemes with no increase in side effects.

  12. Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway.

    PubMed Central

    Pinsky, D J; Oz, M C; Koga, S; Taha, Z; Broekman, M J; Marcus, A J; Liao, H; Naka, Y; Brett, J; Cannon, P J

    1994-01-01

    Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1 +/- 0.4 microM for freshly explanted hearts to 0.7 +/- 0.2 and 0.2 +/- 0.08 microM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5' monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist NG-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO

  13. [Ossification of the Posterior Longitudinal Ligament Found in a Case of Sudden Head-tilt Difficulty following Induction of General Anesthesia].

    PubMed

    Komasawa, Nobuyasu; Nishihara, Isao; Minami, Toshiaki

    2015-05-01

    We report a case of sudden head-tilt difficulty after induction of general anesthesia which was postoperatively diagnosed as ossification of the posterior longitudinal ligament. A 42-year-old man weighing 115 kg was scheduled for emergent laparoscopic appendectomy for acute appendicitis. Prior to induction of anesthesia, the patient could tilt his head, but was unable to do so afterwards. Following mask ventilation with jaw-thrust maneuver, we successfully performed tracheal intubation using the Pentax-AWS Airwayscope. After surgery, he was diagnosed with ossification of the posterior longitudinal ligament by an orthopedist. PMID:26422964

  14. The relationship of calcaneal apophyseal ossification and Sanders hand scores to the timing of peak height velocity in adolescents.

    PubMed

    Nicholson, A D; Sanders, J O; Liu, R W; Cooperman, D R

    2015-12-01

    The accurate assessment of skeletal maturity is essential in the management of orthopaedic conditions in the growing child. In order to identify the time of peak height velocity (PHV) in adolescents, two systems for assessing skeletal maturity have been described recently; the calcaneal apophyseal ossification method and the Sanders hand scores. The purpose of this study was to compare these methods in assessing skeletal maturity relative to PHV. We studied the radiographs of a historical group of 94 healthy children (49 females and 45 males), who had been followed longitudinally between the ages of three and 18 years with serial radiographs and physical examination. Radiographs of the foot and hand were undertaken in these children at least annually between the ages of ten and 15 years. We reviewed 738 radiographs of the foot and 694 radiographs of the hand. PHV was calculated from measurements of height taken at the time of the radiographs. Prior to PHV we observed four of six stages of calcaneal apophyseal ossification and two of eight Sanders stages. Calcaneal stage 3 and Sanders stage 2 was seen to occur about 0.9 years before PHV, while calcaneal stage 4 and Sanders stage 3 occurred approximately 0.5 years after PHV. The stages of the calcaneal and Sanders systems can be used in combination, offering better assessment of skeletal maturity with respect to PHV than either system alone. PMID:26637689

  15. Cervical Myeloradiculopathy due to Ossification of the Posterior Longitudinal Ligament with versus without Diffuse Idiopathic Spinal Hyperostosis.

    PubMed

    Tauchi, Ryoji; Lee, Sang-Hun; Peters, Colleen; Imagama, Shiro; Ishiguro, Naoki; Riew, K Daniel

    2016-06-01

    Study Design Retrospective study. Objectives Assess demographics, ossification characteristics, surgical outcomes, and complications in patients with both diffuse idiopathic spinal hyperostosis (DISH) and ossification of the posterior longitudinal ligament (OPLL) compared with patients who only have OPLL. Methods Clinical charts and radiographs of all patients treated surgically from February 2004 to July 2012 for cervical myeloradiculopathy due to DISH with OPLL or OPLL alone were reviewed retrospectively. All patients were observed for a minimum of 1 year. Pre- and postoperative Nurick grades were assessed for all patients. Results Forty-nine patients underwent surgical treatment for cervical myeloradiculopathy due to OPLL, and 8 also had DISH (average 58.9 years, range 37 to 70). The DISH with OPLL group had a significantly higher proportion of subjects with diabetes mellitus (50 versus 9.8% in the OPLL-only group). Everyone in the DISH with OPLL group had continuous or mixed-type OPLL, whereas 78% of patients in the OPLL-only group had primarily segmental type. Operative treatments for patients in the DISH with OPLL group included laminoplasty, anterior decompression and fusion, and posterior laminectomy with fusion. By Nurick grade, 5 patients improved and 3 showed no change. Conclusion Patients with both DISH and OPLL had a higher prevalence of diabetes mellitus and either continuous or mixed-type OPLL classifications. Surgical outcomes were mostly satisfactory; there was no aggravation of symptoms after surgery during the follow up period. PMID:27190737

  16. Neural crest-specific loss of Prkar1a causes perinatal lethality resulting from defects in intramembranous ossification.

    PubMed

    Jones, Georgette N; Pringle, Daphne R; Yin, Zhirong; Carlton, Michelle M; Powell, Kimerly A; Weinstein, Michael B; Toribio, Ramiro E; La Perle, Krista M D; Kirschner, Lawrence S

    2010-08-01

    The cranial neural crest (CNC) undergoes complex molecular and morphological changes during embryogenesis in order to form the vertebrate skull, and nearly three quarters of all birth defects result from defects in craniofacial development. The molecular events leading to CNC differentiation have been extensively studied; however, the role of the cAMP-dependent protein kinase [protein kinase A (PKA)] during craniofacial development has only been described in palate formation. Here, we provide evidence that strict PKA regulation in postmigratory CNC cells is essential during craniofacial bone development. Selective inactivation of Prkar1a, a regulatory subunit of the PKA holoenzyme, in the CNC results in perinatal lethality caused by dysmorphic craniofacial development and subsequent asphyxiation. Additionally, aberrant differentiation of CNC mesenchymal cells results in anomalous intramembranous ossification characterized by formation of cartilaginous islands in some areas and osteolysis of bony trabeculae with fibrous connective tissue stabilization in others. Genetic interaction studies revealed that genetic reduction of the PKA catalytic subunit C(alpha) was able to rescue the phenotype, whereas reduction in Cbeta had no effect. Overall, these observations provide evidence of the essential role of proper regulation of PKA during the ossification of the bones of the skull. This knowledge may have implications for the understanding and treatment of craniofacial birth defects. PMID:20534695

  17. Ossification of the Interosseous Membrane of the Leg in a Football Player: Case Report and Review of the Literature.

    PubMed

    Postacchini, Roberto; Carbone, Stefano; Mastantuono, Marco; Della Rocca, Carlo; Postacchini, Franco

    2016-01-01

    Introduction. We report a case of ossification of the interosseous membrane (OIM) of the leg in a football player who had no history of severe local traumas. A review of the literature of the OIM of the leg in athletes was also carried out. Case Report. A 38-year-old Caucasian male patient complained of pain on lateral aspect of the leg when playing football. Pain progressively worsened until he had to stop the sporting activity. Radiographs, and then CT and MRI, showed OIM in the middle third of the left leg. MRI showed inflammation of tibia periosteum and bone adjacent to the ossification, which was then excised. Two months after surgery the patient returned to play football. Conclusion. A thorough analysis of the literature revealed three types of OIM of the leg in athletes. Type I usually occurs after a syndesmosis ankle sprain, Type II appears to result from a tibia fracture, and Type III, of which only one fully recorded case has been published, is probably caused, as in our patient, by repetitive minor traumas to the leg. Awareness of the existence of Type III OIM can avoid erroneous diagnoses leading to useless investigations and treatments. PMID:26881161

  18. Ossification of the Interosseous Membrane of the Leg in a Football Player: Case Report and Review of the Literature

    PubMed Central

    Postacchini, Roberto; Carbone, Stefano; Mastantuono, Marco; Della Rocca, Carlo; Postacchini, Franco

    2016-01-01

    Introduction. We report a case of ossification of the interosseous membrane (OIM) of the leg in a football player who had no history of severe local traumas. A review of the literature of the OIM of the leg in athletes was also carried out. Case Report. A 38-year-old Caucasian male patient complained of pain on lateral aspect of the leg when playing football. Pain progressively worsened until he had to stop the sporting activity. Radiographs, and then CT and MRI, showed OIM in the middle third of the left leg. MRI showed inflammation of tibia periosteum and bone adjacent to the ossification, which was then excised. Two months after surgery the patient returned to play football. Conclusion. A thorough analysis of the literature revealed three types of OIM of the leg in athletes. Type I usually occurs after a syndesmosis ankle sprain, Type II appears to result from a tibia fracture, and Type III, of which only one fully recorded case has been published, is probably caused, as in our patient, by repetitive minor traumas to the leg. Awareness of the existence of Type III OIM can avoid erroneous diagnoses leading to useless investigations and treatments. PMID:26881161

  19. Multipurpose contrast enhancement on epiphyseal plates and ossification centers for bone age assessment

    PubMed Central

    2013-01-01

    Background The high variations of background luminance, low contrast and excessively enhanced contrast of hand bone radiograph often impede the bone age assessment rating system in evaluating the degree of epiphyseal plates and ossification centers development. The Global Histogram equalization (GHE) has been the most frequently adopted image contrast enhancement technique but the performance is not satisfying. A brightness and detail preserving histogram equalization method with good contrast enhancement effect has been a goal of much recent research in histogram equalization. Nevertheless, producing a well-balanced histogram equalized radiograph in terms of its brightness preservation, detail preservation and contrast enhancement is deemed to be a daunting task. Method In this paper, we propose a novel framework of histogram equalization with the aim of taking several desirable properties into account, namely the Multipurpose Beta Optimized Bi-Histogram Equalization (MBOBHE). This method performs the histogram optimization separately in both sub-histograms after the segmentation of histogram using an optimized separating point determined based on the regularization function constituted by three components. The result is then assessed by the qualitative and quantitative analysis to evaluate the essential aspects of histogram equalized image using a total of 160 hand radiographs that are implemented in testing and analyses which are acquired from hand bone online database. Result From the qualitative analysis, we found that basic bi-histogram equalizations are not capable of displaying the small features in image due to incorrect selection of separating point by focusing on only certain metric without considering the contrast enhancement and detail preservation. From the quantitative analysis, we found that MBOBHE correlates well with human visual perception, and this improvement shortens the evaluation time taken by inspector in assessing the bone age. Conclusions

  20. Noxious mechanical heterotopic stimulation induces inhibition of the spinal dorsal horn neuronal network: analysis of spinal somatosensory-evoked potentials.

    PubMed

    Meléndez-Gallardo, J; Eblen-Zajjur, A

    2016-09-01

    Most of the endogenous pain modulation (EPM) involves the spinal dorsal horn (SDH). EPM including diffuse noxious inhibitory controls have been extensively described in oligoneuronal electrophysiological recordings but less attention had been paid to responses of the SDH neuronal population to heterotopic noxious stimulation (HNS). Spinal somatosensory-evoked potentials (SEP) offer the possibility to evaluate the neuronal network behavior, reflecting the incoming afferent volleys along the entry root, SDH interneuron activities and the primary afferent depolarization. SEP from de lumbar cord dorsum were evaluated during mechanical heterotopic noxious stimuli. Sprague-Dawley rats (n = 12) were Laminectomized (T10-L3). The sural nerve of the left hind paw was electrically stimulated (5 mA, 0.5 ms, 0.05 Hz) to induce lumbar SEP. The HNS (mechanic clamp) was applied sequentially to the tail, right hind paw, right forepaw, muzzle and left forepaw during sural stimulation. N wave amplitude decreases (-16.6 %) compared to control conditions when HNS was applied to all areas of stimulation. This effect was more intense for muzzle stimulation (-23.5 %). N wave duration also decreased by -23.6 %. HNS did not change neither the amplitude nor the duration of the P wave but dramatically increases the dispersion of these two parameters. The results of the present study strongly suggest that a HNS applied to different parts of the body is able to reduce the integrated electrical response of the SDH, suggesting that not only wide dynamic range neurons but many others in the SDH are modulated by the EPM. PMID:27207681

  1. Erythroblast transformation-specific 2 correlates with vascular smooth muscle cell apoptosis in rat heterotopic heart transplantation model

    PubMed Central

    Liu, Xiaojuan; Yan, Daliang; Li, Yangcheng; Sha, Xilin; Wu, Kunpeng; Zhao, Jianhua; Yang, Chen; Zhang, Chao

    2016-01-01

    Background Cardiac allograft vasculopathy (CAV) decreases the long-term survival of heart transplantation recipients. Vascular smooth muscle cell (VSMC) apoptosis is an important pathological feature of CAV. Erythroblast transformation-specific 2 (Ets-2), as a transcription factor, participates in cell apoptosis and plays an important role in organ transplantation. Methods Hearts from Wistar-Furth (WF:RT1u) rats were heterotopically transplanted into Lewis (Lew:RT1l) rats without immunosuppression. Additional syngeneic heterotopic cardiac transplantations were performed in Lewis rats. HE staining was used to identify CAV. Ets-2 expression was examined by western blot. Ets-2 tissue location was examined by immunohistochemical assay and double immunostaining. Cleaved caspase 3 expression was detected by western blot. Co-localization of Ets-2 and cleaved caspase 3 was detected by double immunostaining. Ets-2, p53, cleaved caspase 3 and Bcl-xl expression in rat VSMC line A7R5 was examined after Ets-2 siRNA transfection. TUNEL assay was applied to detect A7R5 apoptosis with or without ETS-2 siRNA transfection. Immunoprecipitation was performed to explore the interaction between Ets-2 and p53. Results Ets-2 expression decreased in the allograft group but had no obvious change in the isograft group. Meanwhile, the phenomenon of CAV was observed in the allograft group and there is neointima formation in the isograft group which is not obvious compared with allograft group. Additionally, Ets-2 expression was opposite to VSMC apoptosis in the allograft group. In vitro, Ets-2 siRNA transfection in A7R5cells resulted in enhanced cell apoptosis. Finally, Ets-2 interacted with p53. Conclusions Ets-2 might inhibit VSMC apoptosis via p53 pathway. The results further elucidate the molecular mechanism of VSMC apoptosis after heart transplantation during CAV and provide theoretical basis for seeking new specific drug targets for CAV prevention and treatment. PMID:27621856

  2. Molecular mechanism of interleukin-2-induced mucosal homeostasis.

    PubMed

    Mishra, Jayshree; Waters, Christopher M; Kumar, Narendra

    2012-03-01

    Sustained damage to the mucosal lining in patients with inflammatory bowel disease (IBD) facilitates translocation of intestinal microbes to submucosal immune cells leading to chronic inflammation. Previously, we demonstrated the role of Jak3 in IL-2-induced intestinal epithelial cell (IEC) migration, one of the early events during intestinal wound repair. In this study, we demonstrate that IL-2 also plays a role in IEC homeostasis through concentration-dependent regulation of IEC proliferation and cell death. At lower concentrations (≤50 U/ml), IL-2 promoted proliferation, while at higher concentrations (100 U/ml), it promoted apoptosis. Activation by IL-2 led to tyrosine phosphorylation-dependent interactions between Jak3 and p52ShcA only at lower concentrations. Phosphatase SHP1 dephosphorylated IL-2-induced phosphorylated p52ShcA. Higher concentrations of IL-2 decreased the phosphorylation of Jak3 and p52ShcA, disrupted their interactions, redistributed Jak3 to the nucleus, and induced apoptosis in IEC. IL-2 also induced dose-dependent upregulation of p52shcA and downregulation of jak3-mRNA. Constitutive overexpression and mir-shRNA-mediated knockdown studies showed that expression of both Jak3 and p52ShcA were necessary for IL-2-induced proliferation of IEC. Doxycycline-regulated sh-RNA expression demonstrated that IL-2-induced downregulation of jak3-mRNA was responsible for higher IL-2-induced apoptosis in IEC. Collectively, these data demonstrate a novel mechanism of IL-2-induced mucosal homeostasis through posttranslational and transcriptional regulation of Jak3 and p52ShcA. PMID:22116305

  3. Prevention of heterotopic bone formation with early post operative irradiation in high risk patients undergoing total hip arthroplasty: comparison of 10. 00 Gy vs 20. 00 Gy schedules

    SciTech Connect

    Anthony, P.; Keys, H.; Evarts, C.M.; Rubin, P.; Lush, C.

    1987-03-01

    Prior studies have demonstrated the effectiveness of postoperative radiation therapy (RT) to the hip area following total hip replacement (THR) surgery in preventing the development of heterotopic bone formation in patients considered to be at high risk for development of this complication. Previously, patients received 20.00 Gy in 10 fractions (fx) over 2 weeks, beginning as soon postop as medically feasible (usually post-op day 2). In an effort to reduce hospital stay and risk of secondary malignancy, a prospective treatment program was initiated April 1982 using a reduced dose of 10.00 Gy in 5 fx over 5-7 days. As of February 1984, 46 consecutive hips determined to be at high risk were treated with this reduced dose. Prior studies have demonstrated that heterotopic bone is always radiographically evident by 8 weeks. Of the 46 hips, 41 had been evaluated with the minimum required 8 week follow-up X ray. Twenty-five of these hips, 61%, had a mean long term follow-up of 12 months. It historical control group, consisting of 54 consecutive high risk post-THR's, was shown to have a 68.5% incidence of heterotopic bone. The 20.00 Gy group, when RT was started by post-op day 5, demonstrated a 3.2% incidence, compared to 4.9% in the 10.00 Gy group. Complication rates were also comparable in the two RT groups, 19.4% and 7.3% respectively; 10.00 Gy is apparently as effective as 20.00 Gy in preventing heterotopic bone formation in high risk post-THR patients.

  4. Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis

    PubMed Central

    Feng, Jian Q.; Guo, Feng-Jin; Jiang, Bai-Chun; Zhang, Yan; Frenkel, Sally; Wang, Da-Wei; Tang, Wei; Xie, Yixia; Liu, Chuan-Ju

    2010-01-01

    Granulin epithelin precursor (GEP) has been implicated in development, tissue regeneration, tumorigenesis, and inflammation. Herein we report that GEP stimulates chondrocyte differentiation from mesenchymal stem cells in vitro and endochondral ossification ex vivo, and GEP-knockdown mice display skeleton defects. Similar to bone morphogenic protein (BMP) 2, application of the recombinant GEP accelerates rabbit cartilage repair in vivo. GEP is a key downstream molecule of BMP2, and it is required for BMP2-mediated chondrocyte differentiation. We also show that GEP activates chondrocyte differentiation through Erk1/2 signaling and that JunB transcription factor is one of key downstream molecules of GEP in chondrocyte differentiation. Collectively, these findings reveal a novel critical role of GEP growth factor in chondrocyte differentiation and the molecular events both in vivo and in vitro.—Feng, J. Q., Guo, F.-J., Jiang, B.-C., Zhang, Y., Frenkel, S., Wang, D.-W., Tang, W., Xie, Y., Liu, C.-J. Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis. PMID:20124436

  5. The use of postoperative irradiation for the prevention of heterotopic bone after total hip replacement with biologic fixation (porous coated) prosthesis: An animal model

    SciTech Connect

    Konski, A.; Weiss, C.; Rosier, R.; Poulter, C.; Pelligrini, V.; Anthony, P.; Evarts, C.M.; Richardson, M.; Henzler, M.; Rubin, P. )

    1990-04-01

    Radiation has been shown to be effective in the prevention of heterotopic bone. The exact etiology of heterotopic bone is unknown. Total hip prosthetic devices that do not depend upon bone cement for fixation have become increasingly popular. The mechanism by which the bone forms around the prosthesis is similar to the process by which fractures heal which has been shown to be sensitive to irradiation. Using a rabbit model we have undertaken a study to investigate the effect of irradiation on the bony ingrowth on porous coated implants. Forty-five rabbits had porous coated implants surgically placed in the tibiae bilaterally. Each rabbit had one tibia randomly irradiated with 1,000 cGy in 5 fractions starting on the first post-operative day. Animals were sacrificed weekly starting 2 weeks post-operatively and the tibae were sent for pullout studies. The amount of force necessary to pullout the treated tibae was statistically less than the amount of force necessary to remove the untreated tibae at 2 weeks. From 3 weeks on there was no difference in the force necessary to remove the prosthesis from the untreated or treated tibae. Histologically, the untreated tibae showed bone formation while the treated tibae did not. Because of these results, it is suggested that the treatment of patients at risk for development of heterotopic bone be modified to only include the area between the femur and pelvis avoiding treatment of the prosthetic device.

  6. Beneficial effects of growth hormone therapy for ossification defects after bone distraction in X linked hypophosphataemic rickets

    PubMed Central

    Cañete, Ramón; Caballero-Villarraso, Javier; Aguilar-Quintero, María; Vázquez-Rueda, Fernando

    2014-01-01

    A report on two homozygous twin girls affected by X linked hypophosphataemic rickets. They were examined due to short stature and genu varum of both tibias. They were treated with calcitriol and Joulie's solution, whereon it was observed that serum parathyroid hormone and phosphaturia decreased while phosphataemia increased. They underwent a tibial osteotomy (by means of the insertion of Kirchner needles) at 7.7 years of age for correction of genu varum and a normal consolidation was reached 1 month later. Nonetheless, height was percentile <1 after menarche, so both sisters asked for bone lengthening. Because of this, at 15 years of age femoral distraction was performed, but no bone callus was observed 14 months later. Consequently, they were treated with subcutaneous growth hormone, showing bone callus at 6 months. Finally, the external fixators were removed due to ossification in the lengthened segments. PMID:25115781

  7. Posterior Trans-Dural Repair of Iatrogenic Spinal Cord Herniation after Resection of Ossification of Posterior Longitudinal Ligament

    PubMed Central

    Kim, Hong-Ki; Kim, Ki-Jeong; Jahng, Tae-Ahn; Kim, Hyun-Jib

    2016-01-01

    Iatrogenic spinal cord herniation is a rare complication following spinal surgery. We introduce a posterior trans-dural repair technique used in a case of thoracic spinal cord herniation through a ventral dural defect following resection of ossification of the posterior longitudinal ligament (OPLL) in the cervicothoracic spine. A 51-year-old female was suffering from paraplegia after laminectomy alone for cervicothoracic OPLL. Magnetic resonance imaging revealed a severely compressed spinal cord with pseudomeningocele identified postoperatively. Cerebrospinal fluid leak and iatrogenic spinal cord herniation persisted despite several operations with duroplasty and sealing agent. Finally, the problems were treated by repair of the ventral dural defect with posterior trans-dural duroplasty. Several months after surgery, the patient could walk independently. This surgical technique can be applied to treat ventral dural defect and spinal cord herniation. PMID:27114779

  8. What you need to know about ossification of the posterior longitudinal ligament to optimize cervical spine surgery: A review

    PubMed Central

    Epstein, Nancy E.

    2014-01-01

    What are the risks, benefits, alternatives, and pitfalls for operating on cervical ossification of the posterior longitudinal ligament (OPLL)? To successfully diagnose OPLL, it is important to obtain Magnetic Resonance Images (MR). These studies, particularly the T2 weighted images, provide the best soft-tissue documentation of cord/root compression and intrinsic cord abnormalities (e.g. edema vs. myelomalacia) on sagittal, axial, and coronal views. Obtaining Computed Tomographic (CT) scans is also critical as they best demonstrate early OPLL, or hypertrophied posterior longitudinal ligament (HPLL: hypo-isodense with punctate ossification) or classic (frankly ossified) OPLL (hyperdense). Furthermore, CT scans reveal the “single layer” and “double layer” signs indicative of OPLL penetrating the dura. Documenting the full extent of OPLL with both MR and CT dictates whether anterior, posterior, or circumferential surgery is warranted. An adequate cervical lordosis allows for posterior cervical approaches (e.g. lamionplasty, laminectomy/fusion), which may facilitate addressing multiple levels while avoiding the risks of anterior procedures. However, without lordosis and with significant kyphosis, anterior surgery may be indicated. Rarely, this requires single/multilevel anterior cervical diskectomy/fusion (ACDF), as this approach typically fails to address retrovertebral OPLL; single or multilevel corpectomies are usually warranted. In short, successful OPLL surgery relies on careful patient selection (e.g. assess comorbidities), accurate MR/CT documentation of OPLL, and limiting the pros, cons, and complications of these complex procedures by choosing the optimal surgical approach. Performing OPLL surgery requires stringent anesthetic (awake intubation/positioning) and also the following intraoperative monitoring protocols: Somatosensory evoked potentials (SSEP), motor evoked potentials (MEP), and electromyography (EMG). PMID:24843819

  9. [CHARACTERISTICS OF OSTEOCYTE CELL LINES FROM BONES FORMED AS A RESULT OF MEMBRANOUS (SKULL BONES) AND CHONDRAL (LONG BONES) OSSIFICATION].

    PubMed

    Avrunin, A S; Doktorov, A A

    2016-01-01

    The aim of this work was to analyze the literature data and the results of authors' own research, to answer the question--if the osteocytes of bone tissues resulting from membranous and chondral ossification, belong to one or to different cell lines. The differences between the cells of osteocyte lines derived from bones resulting from membranous and chondral ossification were established in: 1) the magnitude of the mechanical signal, initiating the development of the process of mechanotransduction; 2) the nature of the relationship between the magnitude of the mechanical signal that initiates the reorganization of the architecture of bone structures and the resource of their strength; in membranous bones significantly lower mechanical signal caused a substantially greater increment of bone strength resource; 3) the biological activity of bone structures, bone fragments formed from membranous tissue were more optimal for transplantation; 4) the characteristics of expression of functional markers of bone cells at different stages of their differentiation; 5) the nature of the reaction of bone cells to mechanical stress; 6) the sensitivity of bone cells to one of the factors controlling the process of mechanotransduction (PGI2); 7) the functioning of osteocytes during lactation. These differences reflect the functional requirements to the bones of the skeleton--the supporting function in the bones of the limbs and the shaping and protection in the bones of the cranial vault. These data suggest that the results of research conducted on the bones of the skull, should not be transferred to the entire skeleton as a whole. PMID:27487656

  10. A review of prognostic factors for surgical outcome of ossification of the posterior longitudinal ligament of cervical spine

    PubMed Central

    Li, Hai; Jiang, Lei-Sheng

    2008-01-01

    For patients with ossification of the posterior longitudinal ligament (OPLL) who have neurological-symptoms, surgery is necessary but not always effective. Various clinical factors influence the surgical outcome. The studies identifying these factors have been inconclusive and conflicting. It is essential for surgeons to understand the significance of the factors and choose the optimal therapeutic strategy for OPLL. The objective of this review is to determine the clinical factors predictive of the surgical outcome of cervical OPLL. The authors conducted a review of literature published in the English language. They examined studies in which the correlation between clinical factors and outcome were statistically evaluated. The results showed that the traverse area of the spinal cord, the spinal cord-evoked potentials (SCEPs), the increase of the range of motion in the cervical spine (ROM), diabetes, history of trauma, the onset of ossification of the ligament flavum (OLF) in the thoracic spine, snake-eye appearance (SEA) and incomplete decompression may be predictive factors. Age at surgery seems to be closely related to the outcome of posterior surgical procedure. Whether the neurological score, OPLL type, pre-operative duration of symptoms, focal intra-medullar high signal intensity in T2-weighted (IMHSI) and progression of OPLL or kyphosis and expansion of the spinal canal predict the surgical outcome remains unclear. The use of uniform neurological score and proper statistic analysis should facilitate comparison of data from different studies. It is important to analyze the effect of each factor on groups with different surgical procedures as well as patients with different compressive pathology. Research on the etiology and pathology of cervical myelopathy due to OPLL should be helpful in precisely understanding these clinical factors and predicting surgical outcome. PMID:18704517

  11. What you need to know about ossification of the posterior longitudinal ligament to optimize cervical spine surgery: A review.

    PubMed

    Epstein, Nancy E

    2014-01-01

    What are the risks, benefits, alternatives, and pitfalls for operating on cervical ossification of the posterior longitudinal ligament (OPLL)? To successfully diagnose OPLL, it is important to obtain Magnetic Resonance Images (MR). These studies, particularly the T2 weighted images, provide the best soft-tissue documentation of cord/root compression and intrinsic cord abnormalities (e.g. edema vs. myelomalacia) on sagittal, axial, and coronal views. Obtaining Computed Tomographic (CT) scans is also critical as they best demonstrate early OPLL, or hypertrophied posterior longitudinal ligament (HPLL: hypo-isodense with punctate ossification) or classic (frankly ossified) OPLL (hyperdense). Furthermore, CT scans reveal the "single layer" and "double layer" signs indicative of OPLL penetrating the dura. Documenting the full extent of OPLL with both MR and CT dictates whether anterior, posterior, or circumferential surgery is warranted. An adequate cervical lordosis allows for posterior cervical approaches (e.g. lamionplasty, laminectomy/fusion), which may facilitate addressing multiple levels while avoiding the risks of anterior procedures. However, without lordosis and with significant kyphosis, anterior surgery may be indicated. Rarely, this requires single/multilevel anterior cervical diskectomy/fusion (ACDF), as this approach typically fails to address retrovertebral OPLL; single or multilevel corpectomies are usually warranted. In short, successful OPLL surgery relies on careful patient selection (e.g. assess comorbidities), accurate MR/CT documentation of OPLL, and limiting the pros, cons, and complications of these complex procedures by choosing the optimal surgical approach. Performing OPLL surgery requires stringent anesthetic (awake intubation/positioning) and also the following intraoperative monitoring protocols: Somatosensory evoked potentials (SSEP), motor evoked potentials (MEP), and electromyography (EMG). PMID:24843819

  12. Lentiviral-Mediated RNAi Knockdown of Cbfa1 Gene Inhibits Endochondral Ossification of Antler Stem Cells in Micromass Culture

    PubMed Central

    Sun, Hongmei; Yang, Fuhe; Chu, Wenhui; Zhao, Haiping; McMahon, Chris; Li, Chunyi

    2012-01-01

    Articular cartilage (AC) lacks ability to repair defects due to its avascular nature as healing process relies on cells being brought in by blood vessels. Multiple approaches have been taken to facilitate cartilage repair in clinics, to date there is no effective treatment available that can restores the AC lesion to a normally functioning level over extended periods. In this regard, antler cartilage is unique in being richly vascularised and hence can effectively repair and regenerate. Interestingly, antler stem cells, from which the vascularised cartilage is derived, can form avascular cartilage when taken away from their original niche, suggesting that the vascular or avascular state of antler cartilage is controlled by extrinsic factors. Understanding the mechanisms underlying this phenotype switch may help us to devise a way to trigger the effective intrinsic repair of AC. However, adoption of antler cartilage model for AC repair requires the demonstration that the cartilage specific signalling pathways also prevail in antler chondrogenesis. To achieve this, in the present study we silenced expression of Cbfa1, a key factor regulatingendochondral ossification, using RNAi, and showed that expression of the downstream genes type I collagen and osteocalcin were suppressed which, in turn, inhibited endochondral ossification process taking place in the antler stem cell-formed nodules. Therefore, we provided further evidence at molecular level that antler could be developed as novel model for the study of AC repair. The eventual identification of the extrinsic factors dictating the phenotype switch between the vascular and avascular state of antler cartilage will open up a new avenue for the cure of osteoarthritis. PMID:23056636

  13. Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with later diabetes onset and heterotopic gastric mucosa.

    PubMed

    Skopkova, Martina; Ciljakova, Miriam; Havlicekova, Zuzana; Vojtkova, Jarmila; Valentinova, Lucia; Danis, Daniel; Murgas, Dalibor; Szepeova, Renata; Stanik, Juraj; Banovcin, Peter; Klimes, Iwar; Gasperikova, Daniela

    2016-09-01

    Mitchell-Riley syndrome, an autosomal recessive disorder caused by mutations in the RFX6 gene, is defined as a combination of neonatal diabetes mellitus and serious congenital gastrointestinal defects. We describe Mitchell-Riley syndrome in two sisters with two novel compound heterozygous variants in the RFX6 gene: c.1154G > A, p.(Arg385Gln), and c.1316_1319delTCTA, p.(Ile439Thrfs*13). Both sisters present milder forms of the syndrome, likely due to possible residual activity of the p.Arg385Gln variant, which is localized in a dimerization domain of the RFX6 transcription factor. We propose that the prognosis is dependent on patient RFX6 genotype and possible residual activity of RFX6 transcription factor. Both sisters had atypical later onset of diabetes, at 2 years and 10 months and 2 years and 7 months, respectively. This supports the need of extending the definition of diabetes in Mitchell-Riley syndrome from neonatal to childhood onset and regular glyceamia check in patients with gastrointestinal tract malformations typical for Mitchell-Riley syndrome. The clinical course in both sisters improved significantly after surgical removal of parts of the small intestine with heterotopic gastric mucosa. We suggest that gastric mucosa heterotopy is an important actionable part of Mitchell-Riley syndrome and could have been responsible for the malabsorption, failure to thrive and severe anemia present in previously reported patients with Mitchell-Riley syndrome. PMID:27523286

  14. Heterotopic implantation of autologous bone marrow in rock pigeons (Columba livia): possible applications in avian bone grafting.

    PubMed

    Sanaei, M Reza; Abu, Jalila; Nazari, Mojgan; Faiz, Nik Mohd; Bakar, Mohd Zuki Abu; Allaudin, Zeenathul N

    2011-12-01

    Autologous bone marrow, alone or as a composite marrow graft, has received much attention in various species. To assess the potential osteogenicity of autologous, extramedullary bone marrow implants in an avian model, 24 adult pigeons (Columba livia) were given intramuscular implantations of autologous marrow aspirated from the medial tibiotarsus. Birds were euthanatized at 1, 4, 6, 8, 10, and 12 weeks after surgery to evaluate whether ectopic bone had formed at the implant sites. Primary evaluations by in situ radiography and postmortem histologic examinations showed no evidence of bone formation. Further evaluation with histologic scores and histomorphometry revealed a significantly increased rate of angiogenesis at the implant sites by the sixth and tenth week postimplantation (P < .05). No significant differences between the treatment and control sites were present at any other endpoints. Results of this study show that, although autologous bone marrow lacks heterotopic osteogenic potentials in this avian model, it could still function as a useful adjunct to routine bone grafting techniques because of its unique capabilities to promote early angiogenesis. PMID:22458179

  15. The Need to Handicap the Recipient's Native Liver in the Rat Model of Heterotopic Auxiliary Liver Transplantation

    PubMed Central

    Praet, Marleen; De Hemptinne, Bernard

    1999-01-01

    In the rat model of heterotopic auxiliary liver transplantation (HALTx), the opinion varies on whether and how the recipient's native liver should be handicapped. To avoid atrophy of the transplanted organ, in this study, two different handicaps were evaluated and their effects on post-operative animal survival and liver biology are described. With a sole portacaval shunt (group 1) all rats survived longer than 3 months. An additional handicap of the liver with either a 68% partial hepatectomy (68% PH) (group 2), or both a 68% PH and a common bile duct ligation (CBDL) (group 3) led to a 100% mortality within 2 days after surgery. When an auxiliary liver was transplanted to the rats handicapped with a 68% PH (group 4), serum Bilirubin and ALAT values were significantly lower than those handicapped with both a 68% PH and a CBDL (group 5). Autopsy and histology of the long-term survivors revealed the atrophy of the engrafted livers and the regeneration of the native livers in group 4, whereas it showed the opposite in group 5. Thus the various manipulations of the native liver do influence differently the post-transplant animal survival, serum liver biochemistry and the outcome of the engrafted liver in this rat model of HALTx. PMID:10468113

  16. Responses of pink salmon to CO2-induced aquatic acidification

    NASA Astrophysics Data System (ADS)

    Ou, Michelle; Hamilton, Trevor J.; Eom, Junho; Lyall, Emily M.; Gallup, Joshua; Jiang, Amy; Lee, Jason; Close, David A.; Yun, Sang-Seon; Brauner, Colin J.

    2015-10-01

    Ocean acidification negatively affects many marine species and is predicted to cause widespread changes to marine ecosystems. Similarly, freshwater ecosystems may potentially be affected by climate-change-related acidification; however, this has received far less attention. Freshwater fish represent 40% of all fishes, and salmon, which rear and spawn in freshwater, are of immense ecosystem, economical and cultural importance. In this study, we investigate the impacts of CO2-induced acidification during the development of pink salmon, in freshwater and following early seawater entry. At this critical and sensitive life stage, we show dose-dependent reductions in growth, yolk-to-tissue conversion and maximal O2 uptake capacity; as well as significant alterations in olfactory responses, anti-predator behaviour and anxiety under projected future increases in CO2 levels. These data indicate that future populations of pink salmon may be at risk without mitigation and highlight the need for further studies on the impact of CO2-induced acidification on freshwater systems.

  17. Controlled Dual Growth Factor Delivery From Microparticles Incorporated Within Human Bone Marrow-Derived Mesenchymal Stem Cell Aggregates for Enhanced Bone Tissue Engineering via Endochondral Ossification

    PubMed Central

    Dang, Phuong N.; Dwivedi, Neha; Phillips, Lauren M.; Yu, Xiaohua; Herberg, Samuel; Bowerman, Caitlin; Solorio, Loran D.; Murphy, William L.

    2016-01-01

    Bone tissue engineering via endochondral ossification has been explored by chondrogenically priming cells using soluble mediators for at least 3 weeks to produce a hypertrophic cartilage template. Although recapitulation of endochondral ossification has been achieved, long-term in vitro culture is required for priming cells through repeated supplementation of inductive factors in the media. To address this challenge, a microparticle-based growth factor delivery system was engineered to drive endochondral ossification within human bone marrow-derived mesenchymal stem cell (hMSC) aggregates. Sequential exogenous presentation of soluble transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) at various defined time courses resulted in varying degrees of chondrogenesis and osteogenesis as demonstrated by glycosaminoglycan and calcium content. The time course that best induced endochondral ossification was used to guide the development of the microparticle-based controlled delivery system for TGF-β1 and BMP-2. Gelatin microparticles capable of relatively rapid release of TGF-β1 and mineral-coated hydroxyapatite microparticles permitting more sustained release of BMP-2 were then incorporated within hMSC aggregates and cultured for 5 weeks following the predetermined time course for sequential presentation of bioactive signals. Compared with cell-only aggregates treated with exogenous growth factors, aggregates with incorporated TGF-β1- and BMP-2-loaded microparticles exhibited enhanced chondrogenesis and alkaline phosphatase activity at week 2 and a greater degree of mineralization by week 5. Staining for types I and II collagen, osteopontin, and osteocalcin revealed the presence of cartilage and bone. This microparticle-incorporated system has potential as a readily implantable therapy for healing bone defects without the need for long-term in vitro chondrogenic priming. Significance This study demonstrates the regulation of chondrogenesis

  18. In vivo analysis of Arg-Gly-Asp sequence/integrin α5β1-mediated signal involvement in embryonic enchondral ossification by exo utero development system.

    PubMed

    Inoue, Takayuki; Hashimoto, Ryuju; Matsumoto, Akihiro; Jahan, Esrat; Rafiq, Ashiq Mahmood; Udagawa, Jun; Hatta, Toshihisa; Otani, Hiroki

    2014-07-01

    Enchondral ossification is a fundamental mechanism for longitudinal bone growth during vertebrate development. In vitro studies suggested that functional blockade with RGD peptides or with an antibody that interferes with integrin α5β1-ligand interactions inhibited pre-hypertrophic chondrocyte differentiation. The purpose of this study is to elucidate in vivo the roles of the integrin α5β1-mediated signal through the Arg-Gly-Asp (RGD) sequence in the cell-extracellular matrix (ECM) interaction in embryonic enchondral ossification by an exo utero development system. We injected Arg-Gly-Asp-Ser (RGDS) peptides and anti-integrin α5β1 antibody (α5β1 ab) in the upper limbs of mouse embryos at embryonic day (E) 15.5 (RGDS-injected limbs, α5β1 ab-injected limbs), and compared the effects on enchondral ossification with those found in the control limbs (Arg-Gly-Glu-Ser peptide-, mouse IgG-, or vehicle-injected, and no surgery) at E16.5. In the RGDS-injected limbs, the humeri were shorter and there were fewer BrdU-positive cells than in the control limbs. The ratios of cartilage length and area to those of the humerus were higher in the RGDS-injected limbs. The ratios of type X collagen to type 2 collagen mRNA and protein (Coll X/Coll 2) were significantly lower in the RGDS-injected limbs. In those limbs, TUNEL-positive cells were hardly observed, and the ratios of fractin to the Coll X/Coll 2 ratio were lower than in the control limbs. Furthermore, the α5β1 ab-injected limbs showed results similar to those of RGDS-injected limbs. The present in vivo study by exo utero development system showed that RGDS and α5β1 ab injection decreased chondrocyte proliferation, differentiation, and apoptosis in enchondral ossification, and suggested that the integrin α5β1-mediated ECM signal through the RGD sequence is involved in embryonic enchondral ossification. PMID:24375788

  19. Controlled Dual Growth Factor Delivery From Microparticles Incorporated Within Human Bone Marrow-Derived Mesenchymal Stem Cell Aggregates for Enhanced Bone Tissue Engineering via Endochondral Ossification.

    PubMed

    Dang, Phuong N; Dwivedi, Neha; Phillips, Lauren M; Yu, Xiaohua; Herberg, Samuel; Bowerman, Caitlin; Solorio, Loran D; Murphy, William L; Alsberg, Eben

    2016-02-01

    Bone tissue engineering via endochondral ossification has been explored by chondrogenically priming cells using soluble mediators for at least 3 weeks to produce a hypertrophic cartilage template. Although recapitulation of endochondral ossification has been achieved, long-term in vitro culture is required for priming cells through repeated supplementation of inductive factors in the media. To address this challenge, a microparticle-based growth factor delivery system was engineered to drive endochondral ossification within human bone marrow-derived mesenchymal stem cell (hMSC) aggregates. Sequential exogenous presentation of soluble transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) at various defined time courses resulted in varying degrees of chondrogenesis and osteogenesis as demonstrated by glycosaminoglycan and calcium content. The time course that best induced endochondral ossification was used to guide the development of the microparticle-based controlled delivery system for TGF-β1 and BMP-2. Gelatin microparticles capable of relatively rapid release of TGF-β1 and mineral-coated hydroxyapatite microparticles permitting more sustained release of BMP-2 were then incorporated within hMSC aggregates and cultured for 5 weeks following the predetermined time course for sequential presentation of bioactive signals. Compared with cell-only aggregates treated with exogenous growth factors, aggregates with incorporated TGF-β1- and BMP-2-loaded microparticles exhibited enhanced chondrogenesis and alkaline phosphatase activity at week 2 and a greater degree of mineralization by week 5. Staining for types I and II collagen, osteopontin, and osteocalcin revealed the presence of cartilage and bone. This microparticle-incorporated system has potential as a readily implantable therapy for healing bone defects without the need for long-term in vitro chondrogenic priming. Significance: This study demonstrates the regulation of chondrogenesis

  20. An intramembranous ossification model for the in silico analysis of bone tissue formation in tooth extraction sites.

    PubMed

    Corredor-Gómez, Jennifer Paola; Rueda-Ramírez, Andrés Mauricio; Gamboa-Márquez, Miguel Alejandro; Torres-Rodríguez, Carolina; Cortés-Rodríguez, Carlos Julio

    2016-07-21

    The accurate modeling of biological processes allows us to predict the spatiotemporal behavior of living tissues by computer-aided (in silico) testing, a useful tool for the development of medical strategies, avoiding the expenses and potential ethical implications of in vivo experimentation. A model for bone healing in mouth would be useful for selecting proper surgical techniques in dental procedures. In this paper, the formulation and implementation of a model for Intramembranous Ossification is presented aiming to describe the complex process of bone tissue formation in tooth extraction sites. The model consists in a mathematical description of the mechanisms in which different types of cells interact, synthesize and degrade extracellular matrices under the influence of biochemical factors. Special attention is given to angiogenesis, oxygen-dependent effects and growth factor-induced apoptosis of fibroblasts. Furthermore, considering the depth-dependent vascularization of mandibular bone and its influence on bone healing, a functional description of the cell distribution on the severed periodontal ligament (PDL) is proposed. The developed model was implemented using the finite element method (FEM) and successfully validated by simulating an animal in vivo experiment on dogs reported in the literature. A good fit between model outcome and experimental data was obtained with a mean absolute error of 3.04%. The mathematical framework presented here may represent an important tool for the design of future in vitro and in vivo tests, as well as a precedent for future in silico studies on osseointegration and mechanobiology. PMID:27113783

  1. Hatching, growth, ion accumulation, and skeletal ossification of brook trout (Salvelinus fontinalis) alevins in acidic soft waters

    USGS Publications Warehouse

    Steingraeber, M.T.; Gingerich, W.H.

    1991-01-01

    Brook trout eyed eggs and subsequent alevins were exposed to pH 5.0, 6.5, and 7.0 in soft reconstituted water and to pH 8.2 in hard well water for up to 72 d. Hatching was delayed and hatching success reduced (p K+ > Cl- during yolk absorption and early exogenous feeding. Whole-body monovalent ion concentrations were reduced for short periods during yolk absorption in alevins exposed to pH 6.5 and throughout most of the experiment for those exposed to pH 5.0. Whole-body Mg2+ concentrations were not affected by treatment pH and remained near their median hatch level throughout the exposure. The whole-body concentration of Ca2+ was reduced in fish exposed to pH 5.0, particularly near the end of the experiment. Calcium accumulation in fish was influenced by the interaction of pH and time at pH 5.0 but not at the other pH levels. Alevins exposed to pH 5.0 experienced delayed ossification of skeletal structures associated with feeding, respiration, and locomotion that usually persisted for up to 10 d. The detection of skeletal abnormalities early in life might aid in identifying fish populations at risk in acidified waters.

  2. Angiogenesis in the distal femoral chondroepiphysis of the rabbit during development of the secondary centre of ossification

    PubMed Central

    Doschak, MR; Cooper, DML; Huculak, CN; Matyas, JR; Hart, DA; Hallgrimsson, B; Zernicke, RF; Bray, RC

    2003-01-01

    In the developing chondroepiphyses of long bones, the avascular cartilaginous anlage is invaded by numerous blood vessels, through the process of angiogenesis. The objective of this study was to investigate the chronology of this vascular invasion with the spontaneous calcification of the cartilaginous epiphysis during development of the secondary ossification centre in the rabbit distal femur. The time-course of chondroepiphyseal vascular invasion was determined histologically and standardized for eight gestational and four postnatal intervals by plotting kit body mass against crown–rump length. Similarly, microcomputed tomography (µ-CT) helped to visualize calcification at those same gestational and postnatal intervals. To confirm the angiogenic nature of the avascular chondroepiphysis, such samples were assayed on the chick chorio-allantoic membrane (CAM). Neovascular outgrowths from the CAM were apparent 48 h following introduction of an 18-day (gestational) chondroepiphyseal sample. Chondroepiphyseal samples were assayed for the potent developmental angiogenic factors bFGF and VEGF, with the mRNA expression for both these mediators being confirmed using RT-PCR. As angiogenesis and calcification during chondroepiphyseal development occur in a defined tissue environment initially devoid of blood vessels and mineral, those processes provided a unique opportunity to study their progression without complication of injury-related inflammation or extant vasculature and mineral. Furthermore, the discovery of angiogenic, angiostatic or mineral-regulating mediators specific to developing connective tissue may prove useful for analysing the regulation of vascular and mineral pathogenesis in articular tissues. PMID:12924822

  3. Predictors of surgical outcome in thoracic ossification of the ligamentum flavum: focusing on the quantitative signal intensity

    PubMed Central

    Zhang, JingTao; Wang, LinFeng; Li, Jie; Yang, Peng; Shen, Yong

    2016-01-01

    The association between intramedullary increased signal intensity (ISI) on T2-weighted magnetic resonance imaging (MRI) and surgical outcome in thoracic ossification of the ligamentum flavum (OLF) remains controversial. We aimed to determine the impact of signal change ratio (SCR) on thoracic OLF surgical outcomes. We retrospectively reviewed 96 cases of thoracic OLF surgery and investigated myelopathy severity, symptom duration, MRI and computed tomographic findings, surgical technique and postoperative recoveries. Surgical outcomes were evaluated according to the modified Japanese Orthopaedic Association (JOA) score and recovery rate. JOA recovery rate <50% was defined as a poor surgical outcome. By multivariate logistic regression analysis, we identified risk factors associated with surgical outcomes. Forty patients (41.7%) had a recovery rate of <50%. In receiver operating characteristic (ROC) curves, the optimal preoperative SCR cutoff value as a predictor of poor surgical outcome was 1.54. Multivariate logistic regression analysis revealed that a preoperative SCR ≥1.54 and symptom duration >12 months were significant risk factors for a poor surgical outcome. These findings suggest that preoperative SCR and duration of symptoms were significant risk factors of surgical outcome for patients with thoracic OLF. Patients with preoperative SCR ≥1.54 can experience poor postoperative recovery. PMID:26960572

  4. Probabilistic age classification with Bayesian networks: A study on the ossification status of the medial clavicular epiphysis.

    PubMed

    Sironi, Emanuele; Pinchi, Vilma; Taroni, Franco

    2016-01-01

    In the past few decades, the rise of criminal, civil and asylum cases involving young people lacking valid identification documents has generated an increase in the demand of age estimation. The chronological age or the probability that an individual is older or younger than a given age threshold are generally estimated by means of some statistical methods based on observations performed on specific physical attributes. Among these statistical methods, those developed in the Bayesian framework allow users to provide coherent and transparent assignments which fulfill forensic and medico-legal purposes. The application of the Bayesian approach is facilitated by using probabilistic graphical tools, such as Bayesian networks. The aim of this work is to test the performances of the Bayesian network for age estimation recently presented in scientific literature in classifying individuals as older or younger than 18 years of age. For these exploratory analyses, a sample related to the ossification status of the medial clavicular epiphysis available in scientific literature was used. Results obtained in the classification are promising: in the criminal context, the Bayesian network achieved, on the average, a rate of correct classifications of approximatively 97%, whilst in the civil context, the rate is, on the average, close to the 88%. These results encourage the continuation of the development and the testing of the method in order to support its practical application in casework. PMID:26699731

  5. Outcome of posterior decompression with instrumented fusion surgery for K-line (-) cervical ossification of the longitudinal ligament.

    PubMed

    Saito, Junya; Maki, Satoshi; Kamiya, Koshiro; Furuya, Takeo; Inada, Taigo; Ota, Mitsutoshi; Iijima, Yasushi; Takahashi, Kazuhisa; Yamazaki, Masashi; Aramomi, Masaaki; Mannoji, Chikato; Koda, Masao

    2016-10-01

    We investigated the outcome of posterior decompression and instrumented fusion (PDF) surgery for patients with K-line (-) ossification of the posterior longitudinal ligament (OPLL) of the cervical spine, who may have a poor surgical prognosis. We retrospectively analyzed the outcome of a series of 27 patients who underwent PDF without correction of cervical alignment for K-line (-) OPLL and were followed-up for at least 1 year after surgery. We had performed double-door laminoplasty followed by posterior instrumented fusion without excessive correction of cervical spine alignment. The preoperative Japanese Orthopedic Association (JOA) score for cervical myelopathy was 8.0 points and postoperative JOA score was 11.9 points on average. The mean JOA score recovery rate was 43.6%. The average C2-C7 angle was 2.2° preoperatively and 3.1° postoperatively. The average maximum occupation ratio of OPLL was 56.7%. In conclusion, PDF without correcting cervical alignment for patients with K-line (-) OPLL showed moderate neurological recovery, which was acceptable considering K-line (-) predicts poor surgical outcomes. Thus, PDF is a surgical option for such patients with OPLL. PMID:27591553

  6. Endochondral ossification in fracture callus during long bone repair: the localisation of 'cavity-lining cells' within the cartilage.

    PubMed

    Ford, Joanna L; Robinson, Derek E; Scammell, Brigitte E

    2004-03-01

    Successful fracture healing typically involves the production of a cartilaginous callus, which is eventually remodelled into new bone. The blood vessels in the advancing front of endochondral ossification are likely to play an important role in the replacement of cartilage with bone within the callus. This was investigated by histology and immunohistochemistry techniques carried out on rabbit tibial osteotomy tissue. Cavities within the cartilage were identified by histology and in many cases, there appeared to be vascular structures within them, identified by the immunolocalisation of the transmembrane proteins CD31 and CD34. Osteocalcin localisation and Alizarin red histology was carried out to identify 'osteoblastic' cells and mineral localisation within the cartilaginous callus respectively. However, it was the identification of a population of cells lining the cavities within the cartilage that became the main focus of this study. These cells were 'osteoblastic' in nature, (positive localisation of osteocalcin), and were also positive for the adhesion proteins CD31 and CD34. It is thought that these cells play a role in the conversion of cartilage to bone during the fracture healing process. PMID:15013098

  7. Inhibitory effects of heterotopic noxious counter-stimulation on perception and brain activity related to Aβ-fibre activation.

    PubMed

    Rustamov, Nabi; Tessier, Jessica; Provencher, Benjamin; Lehmann, Alexandre; Piché, Mathieu

    2016-07-01

    Heterotopic noxious counter-stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non-nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter-balanced sessions, including non-nociceptive (selective Aβ-fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20-min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0-100 scale, where 0 is no pain and 100 the worst pain imaginable). Non-nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII-reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non-nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak-to-peak amplitude at Cz was significantly decreased by HNCS for non-nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aβ-fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide-dynamic-range neurons by diffuse noxious inhibitory controls, supraspinal processes or both. PMID:27086672

  8. A new simplified volume-loaded heterotopic rabbit heart transplant model with improved techniques and a standard operating procedure

    PubMed Central

    Lu, Wei; Zheng, Jun; Pan, Xu-Dong; Li, Bing; Zhang, Jin-Wei; Wang, Long-Fei

    2015-01-01

    Background The classic non-working (NW) heterotopic heart transplant (HTX) model in rodents had been widely used for researches related to immunology, graft rejection, evaluation of immunosuppressive therapies and organ preservation. But unloaded models are considered not suitable for some researches. Accordingly, We have constructed a volume-loaded (VL) model by a new and simple technique. Methods Thirty male New Zealand White rabbits were randomly divided into two groups, group NW with 14 rabbits and group VL with 16 rabbits, which served as donors and recipients. We created a large and nonrestrictive shunt to provide left heart a sufficient preload. The donor superior vena cave and ascending aorta (AO) were anastomosed to the recipient abdominal aorta (AAO) and inferior vena cava (IVC), respectively. Results No animals suffered from paralysis, pneumonia and lethal bleeding. Recipients’ mortality and morbidity were 6.7% (1/15) and 13.3% (2/15), respectively. The cold ischemia time in group VL is slight longer than that in group NW. The maximal aortic velocity (MAV) of donor heart was approximately equivalent to half that of native heart in group VL. Moreover, the similar result was achieved in the parameter of late diastolic mitral inflow velocity between donor heart and native heart in group VL. The echocardiography (ECHO) showed a bidirectional flow in donor SVC of VL model, inflow during diastole and outflow during systole. PET-CT imaging showed the standard uptake value (SUV) of allograft was equal to that of native heart in both groups on the postoperative day 3. Conclusions We have developed a new VL model in rabbits, which imitates a native heart hemodynamically while only requiring a minor additional procedure. Surgical technique is simple compared with currently used HTX models. We also developed a standard operating procedure that significantly improved graft and recipient survival rate. This study may be useful for investigations in transplantation

  9. Fast-track surgery and exclusive enteral nutrition applied to a rat model of heterotopic intestinal transplantation

    PubMed Central

    XU, XINGWEI; FENG, TAO; GAO, XIN; ZHAO, XIN; LIAO, YANNIAN; JI, WU

    2016-01-01

    The present study applied fast-track surgery (FTS) concepts and exclusive enteral nutrition (EEN) to a rat model of heterotopic intestinal transplantation (HIT). A total of 96 pairs of Sprague-Dawley rats were randomly distributed into three groups, as follows: i) The conventional group (group 1); ii) the FTS group (group 2); and iii) the FTS with EEN group (EEN group). FTS alterations to the HIT protocol were as follows: i) The use of sevoflurane as an anesthetic; ii) alterations to the order of the procedure and iii) a modified suturing technique. In addition, the EEN group rats underwent an early EEN gavage. The operation time, success rate, recovery state and morphological characteristics of the grafts were compared among the groups. The average operative time was significantly decreased in the group 2 and EEN group rats (137.44±16.03 and 139.67±15.25 min, respectively), as compared with the group 1 rats (169.36±13.72 min; P<0.05). In addition, the percentage of rats surviving >14 days was significantly increased in the group 2 (87.5%) and EEN group (90.6%) rats, as compared with the group 1 rats (68.7%; P<0.05). Furthermore, the villi of graft in EEN group appeared longer, and exhibited narrower interspaces. The ischemia-reperfusion injury and mononuclear cell infiltration were attenuated at postoperative day 7. The results of the present study suggested that the application of FTS concepts and EEN gavage to HIT may accelerate recovery and ameliorate graft damage following surgery. PMID:26998015

  10. The Role of Lysophosphatidic Acid on Airway Epithelial Cell Denudation in a Murine Heterotopic Tracheal Transplant Model

    PubMed Central

    Tando, Yukiko; Ota, Chiharu; Yamada, Mitsuhiro; Kamata, Satoshi; Yamaya, Mutsuo; Kano, Kuniyuki; Okudaira, Shinichi; Aoki, Junken; Kubo, Hiroshi

    2015-01-01

    Background Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Obliterative bronchiolitis (OB), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. However, there is currently no treatment for the disease. We hypothesized that lysophosphatidic acid (LPA) participates in the progression of OB. The aim of this study was to reveal the involvement of LPA on the lesion of OB. Methods Ki16198, an antagonist specifically for LPA1 and LPA3, was daily administered into the heterotopic tracheal transplant model mice at the day of transplantation. At days 10 and 28, the allografts were isolated and evaluated histologically. The messenger RNA levels of LPAR in microdissected mouse airway regions were assessed to reveal localization of lysophosphatidic acid receptors. The human airway epithelial cell was used to evaluate the mechanism of LPA-induced suppression of cell adhesion to the extracellular matrix (ECM). Results The administration of Ki16198 attenuated airway epithelial cell loss in the allograft at day 10. Messenger RNAs of LPA1 and LPA3 were detected in the airway epithelial cells of the mice. Lysophosphatidic acid inhibited the attachment of human airway epithelial cells to the ECM and induced cell detachment from the ECM, which was mediated by LPA1 and Rho-kinase pathway. However, Ki16198 did not prevent obliteration of allograft at day 28. Conclusions The LPA signaling is involved in the status of epithelial cells by distinct contribution in 2 different phases of the OB lesion. This finding suggests a role of LPA in the pathogenesis of OB. PMID:27500235

  11. The effect of heterotopic noxious conditioning stimulation on Aδ-, C- and Aβ-fibre brain responses in humans.

    PubMed

    Torta, Diana M; Churyukanov, Maxim V; Plaghki, Leon; Mouraux, André

    2015-11-01

    Human studies have shown that heterotopic nociceptive conditioning stimulation (HNCS) applied to a given body location reduces the percept and brain responses elicited by noxious test stimuli delivered at a remote body location. It remains unclear to what extent this effect of HNCS relies on the spinal-bulbar-spinal loop mediating the effect of diffuse noxious inhibitory controls (DNICs) described in animals, and/or on top-down cortical mechanisms modulating nociception. Importantly, some studies have examined the effects of HNCS on the brain responses to nociceptive input conveyed by Aδ-fibres. In contrast, no studies have explored the effects of HNCS on the responses to selective nociceptive C-fibre input and non-nociceptive Aβ-fibre input. In this study, we measured the intensity of perception and event-related potentials (ERPs) to stimuli activating Aδ-, C- and Aβ-fibres, before, during and after HNCS, obtained by immersing one foot in painful cold water. We observed that (i) the perceived intensity of nociceptive Aδ- and C-stimuli was reduced during HNCS, and (ii) the ERPs elicited by Aδ- and Aβ- and C-stimuli were also reduced during HNCS. Importantly, because Aβ-ERPs are related to primary afferents that ascend directly through the dorsal columns without being relayed at spinal level, the modulation of these responses may not be explained by an influence of descending projections modulating the transmission of nociceptive input at spinal level. Therefore, our results indicate that, in humans, HNCS should be used with caution as a direct measure of DNIC-related mechanisms. PMID:26369522

  12. A Comparison between splenic fossa and subhepatic fossa auxiliary partial heterotopic liver transplantation in a porcine model.

    PubMed

    Ai, Lemin; Liang, Xiao; Wang, Zhifei; Shen, Jie; Yu, Feiyan; Xie, Limei; Pan, Yongming; Lin, Hui

    2016-06-01

    To test the alternative possible locations for the placement of a liver graft and the relevant surgical technique issues, we developed a porcine model of auxiliary partial heterotopic liver transplantation (APHLT) and evaluated the difference between 2 styles of liver transplantation, either subhepatic fossa or splenic fossa APHLT, by comparing survival and biochemical indexes. Thirty-eight miniature pigs were randomly divided into 2 groups. A left hemihepatic graft without the middle hepatic vein (HV) was procured from the living donor. In group A (n = 9), an 8 mm diameter polytetrafluoroethylene (PTFE) graft approximately 2.5 cm long was connected to the left HV while another PTFE graft of the same size was connected to the left portal vein (PV). The liver graft was implanted in the right subhepatic fossa following splenectomy and right nephrectomy. In group B (n = 10), a PTFE graft of the same size was connected to the left HV while the liver graft was implanted in the splenic fossa following splenectomy and left nephrectomy. Survival rate and complications were observed at 2 weeks after transplantation. Data were collected from 5 animals in group A and 6 animals in group B that survived longer than 2 weeks. The liver function and renal function of the recipients returned to normal at 1 week after surgery in both groups. Eighty-eight percent (14/16) of the PTFE grafts remained patent at 2 weeks after surgery, but 44% of the PTFE grafts (7/16) developed mural thrombus. No significant differences in the survival rate and biochemistry were found between the 2 groups. In conclusion, the splenic fossa APHLT can achieve beneficial outcomes similar to the subhepatic fossa APHLT in miniature pigs, although it also has a high morbidity rate due to hepatic artery thrombosis, PV thrombosis, and PTEF graft mural thrombus formation. Liver Transplantation 22 812-821 2016 AASLD. PMID:26785299

  13. Heterotopic pancreas: a clinicopathological study of 184 cases from a single high-volume medical center in China.

    PubMed

    Zhang, Yifen; Sun, Xitai; Gold, Jason S; Sun, Qi; Lv, Ying; Li, Qiang; Huang, Qin

    2016-09-01

    Heterotopic pancreas (HP) is often an incidental finding during operative or endoscopic procedures and described in case reports and small series in the literature. Large clinicopathological studies with a systematic analysis remain lacking. Herein, we identified 184 (0.18%; 184/99 544) consecutive histology-proven HP cases of 89 770 surgical resections and 9774 upper endoscopic biopsies carried out at a single medical center in China. Each case was diagnosed by unequivocal identification of pancreatic acini at a location outside the pancreas. The patients' median age was 49 years (range, 14-82) with a slight female predominance (male/female ratio, 0.94). Clinical presentation at diagnosis was nonspecific. Preoperatively, most (54.9%; 101/184) HP lesions were misdiagnosed. Only 26 HP lesions (14.1%) were correctly diagnosed, all in the stomach except for 1 in the duodenum; 57 (31%) were detected during operative procedures for other conditions. The most frequent location of HP was, in descending order, the stomach (97; 52.7%), small intestine (48; 26%), lesser and greater curvature omentum (18; 10%), spleen and hilar region (5; 2.7%), porta hepatis (2; 1%), gallbladder (1; 0.5%), peridistal esophageal tissue (4; 2.2%), and mesentery (7; 3.8%). The size of HP varied from smaller than 0.5 cm (35.3%), 0.6 to 1 cm (34.8%), to larger than 1.1 cm (29.9%). Because of difficulty in preoperative diagnosis, careful workup for upper gastrointestinal diseases with HP as a differential diagnosis may increase the chance of accurate diagnosis and appropriate patient management. PMID:27195908

  14. Fibrodysplasia Ossificans Progressiva (FOP): Watch the great toes!

    PubMed Central

    Kartal, Mutlu; Shore, Eileen M.; Xu, Meiqi; Schwering, Ludwig; Uhl, Markus; Korinthenberg, Rudolf; Niemeyer, Charlotte; Kaplan, Frederick S.; Lauten, Melchior

    2016-01-01

    Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder and the most disabling condition of heterotopic (extraskeletal) ossification in humans. Extraskeletal bone formation associated with inflammation preceding the osseous conversion usually begins in the first decade, predominantly in the head, neck and shoulders. All patients have malformed great toes. Most patients have a spontaneous mutation of the ACVR1 gene. We report a 17-year-old girl with malformed great toes who had her first episode of heterotopic ossification and impaired mobility of the left hip at the age of 13 years. No inflammatory fibroproliferative masses preceded the onset of heterotopic ossification. Radiographic studies demonstrated myositis ossificans, but failure to associate the great toe malformation with heterotopic ossification led to a failure to diagnose FOP. She underwent repeated and unnecessary operative procedures to remove a recurrent lesion. FOP was finally suspected when the great toe malformation was correlated with the trauma-induced heterotopic ossification. Genetic analysis confirmed the presence of the classic FOP mutation (ACVR1 c.617G>A; R206H). Conclusion This case highlights the importance of examining the great toes in anyone with heterotopic ossification. The association of malformations of the great toe with heterotopic ossification in all cases of classic FOP will lead to prompt clinical diagnosis and the prevention of iatrogenic harm. PMID:20577760

  15. Prototheca zopfii Genotype 2-induced Nasal Dermatitis in a Cat.

    PubMed

    Huth, N; Wenkel, R F; Roschanski, N; Rösler, U; Plagge, L; Schöniger, S

    2015-05-01

    Few published cases of feline protothecosis exist; all of these were restricted to the skin and speciation of the causative organism revealed an infection with Prototheca wickerhamii in each case. This report describes Prototheca zopfii genotype 2-induced inflammation of the nasal skin and cutaneous mucosa of the right nostril in a 14-year-old neutered female domestic shorthair cat. Microscopical examination revealed marked pyogranulomatous inflammation with numerous intralesional algae. These had a round to ovoid shape, were 8-21 μm in diameter, formed endospores and displayed a positive immunoreaction for Prototheca zopfii antigen. By 18S rRNA gene amplification and sequencing the intralesional algae were confirmed as Prototheca zopfii and further characterized as Prototheca zopfii genotype 2. This case report reveals Prototheca zopfii as an additional Prototheca species associated with feline protothecosis. PMID:25814431

  16. Moist Greenhouse states with solar and CO2-induced forcing

    NASA Astrophysics Data System (ADS)

    Popp, Max; Schmidt, Hauke; Marotzke, Jochem

    2016-04-01

    Water-rich planets such as Earth are expected to become eventually uninhabitable, because liquid water does not remain stable at the surface as surface temperatures increase with the solar luminosity over time. It is conceivable that a large increase in atmospheric greenhouse-gas concentrations could also destroy the habitability of water-rich planets, but previous studies could not clearly establish this. Here we use for the first time a state-of-the-art atmospheric general circulation model, namely a modified version of ECHAM6, to compare the potential of both solar and CO2-induced forcing to render a water-rich planet uninhabitable. We find that CO2-induced forcing as readily destabilizes a present-day Earth-like climate as does solar forcing. This climate instability is caused by a positive cloud feedback, which is in turn caused by the weakening large-scale circulation with increasing surface temperature. The climate does not run away, but instead attains a new steady state with global-mean sea-surface temperatures above 330 K. The upper atmosphere is considerably moister in this warm steady state than in the reference climate. The upper-atmospheric mixing ratio of water exceeds the so-called Moist-Greenhouse limit, which implies that the planet would be subject to substantial loss of water to space. For either a certain range of elevated CO2 concentrations or solar irradiation, we find both cold and warm equilibrium states. Therefore the transition to the warm state may not simply be reversed by removing the additional forcing.

  17. Tunica albuginea allograft: a new model of LaPeyronie's disease with penile curvature and subtunical ossification

    PubMed Central

    Ferretti, Ludovic; Fandel, Thomas M; Qiu, Xuefeng; Zhang, Haiyang; Orabi, Hazem; Wu, Alex K; Banie, Lia; Wang, Guifang; Lin, Guiting; Lin, Ching-Shwun; Lue, Tom F

    2014-01-01

    The pathophysiology of LaPeyronie's disease (PD) is considered to be multifactorial, involving genetic predisposition, trauma, inflammation and altered wound healing. However, these factors have not yet been validated using animal models. In this study, we have presented a new model obtained by tunica albuginea allograft. A total of 40, 16-week-old male rats were used. Of these, 8 rats served as controls and underwent a 10 × 2-mm-wide tunical excision with subsequent autografting, whereas the remaining 32 underwent the same excision with grafting of the defect with another rat's tunica. Morphological and functional testing was performed at 1, 3, 7 and 12 weeks after grafting. Intracavernous pressure, the degree of penile curvature and elastic fiber length were evaluated for comparison between the allograft and control groups. The tissues were obtained for histological examination. The penile curvature was significantly greater in the allografted rats as compared with the control rats. The erectile function was maintained in all rats, except in those assessed at 12 weeks. The elastin fiber length was decreased in the allografted tunica as compared to control. SMAD2 expression was detected in the inner part of the allograft, and both collagen-II- and osteocalcin-positive cells were also noted. Tunica albuginea (TA) allograft in rats is an excellent model of PD. The persistence of curvature beyond 12 weeks and the presence of ossification in the inner layer of the TA were similar to those observed in men with PD. Validation studies using this animal model would aid understanding of the PD pathophysiology for effective therapeutic interventions. PMID:24759578

  18. Three-dimensional polycaprolactone scaffold-conjugated bone morphogenetic protein-2 promotes cartilage regeneration from primary chondrocytes in vitro and in vivo without accelerated endochondral ossification.

    PubMed

    Jeong, Claire G; Zhang, Huina; Hollister, Scott J

    2012-08-01

    As articular cartilage is avascular, and mature chondrocytes do not proliferate, cartilage lesions have a limited capacity for regeneration after severe damage. The treatment of such damage has been challenging due to the limited availability of autologous healthy cartilage and lengthy and expensive cell isolation and expansion procedures. Hence, the use of bone morphogenetic protein-2 (BMP-2), a potent regulator of chondrogenic expression, has received considerable attention in cartilage and osteochondral tissue engineering. However, the exact role of BMP-2 in cartilage repair has been postulated to promote both cartilage formation and subsequent cartilage degradation through hypertrophy and endochondral ossification. Furthermore, it is likely that the manner in which BMP-2 is presented to chondrocytes will influence the physiologic pathway (repair vs. degeneration). This study investigates the relative influence of BMP-2 on cartilage matrix and potential subsequent bone matrix production using primary chondrocytes seeded on designed 3D polycaprolactone (PCL) scaffolds with chemically conjugated BMP-2. The results show that chemically conjugated BMP-2 PCL scaffolds can promote significantly greater cartilage regeneration from seeded chondrocytes both in vitro and in vivo compared with untreated scaffolds. Furthermore, our results demonstrate that the conjugated BMP-2 does not particularly accelerate endochondral ossification even in a readily permissible and highly vascular in vivo environment compared with untreated PCL scaffolds. This study not only reveals the potential use of the BMP-2 conjugation delivery method for enhanced cartilage tissue formation but also gives new insights for the effects of conjugated BMP-2 on cartilage regeneration and osteochondral ossification. PMID:22615065

  19. Chromomycin A2 induces autophagy in melanoma cells.

    PubMed

    Guimarães, Larissa Alves; Jimenez, Paula Christine; Sousa, Thiciana da Silva; Freitas, Hozana Patrícia S; Rocha, Danilo Damasceno; Wilke, Diego Veras; Martín, Jesús; Reyes, Fernando; Deusdênia Loiola Pessoa, Otília; Costa-Lotufo, Letícia Veras

    2014-12-01

    The present study highlights the biological effects of chromomycin A2 toward metastatic melanoma cells in culture. Besides chromomycin A2, chromomycin A3 and demethylchromomycin A2 were also identified from the extract derived from Streptomyces sp., recovered from Paracuru Beach, located in the northeast region of Brazil. The cytotoxic activity of chromomycin A2 was evaluated across a panel of human tumor cell lines, which found IC50 values in the nM-range for exposures of 48 and 72 h. MALME-3M, a metastatic melanoma cell line, showed the highest sensitivity to chromomycin A2 after 48h incubation, and was chosen as a model to investigate this potent cytotoxic effect. Treatment with chromomycin A2 at 30 nM reduced cell proliferation, but had no significant effect upon cell viability. Additionally, chromomycin A2 induced accumulation of cells in G0/G1 phase of the cell cycle, with consequent reduction of S and G2/M and unbalanced expression of cyclins. Chromomycin A2 treated cells depicted several cellular fragments resembling autophagosomes and increased expression of proteins LC3-A and LC3-B. Moreover, exposure to chromomycin A2 also induced the appearance of acidic vacuolar organelles in treated cells. These features combined are suggestive of the induction of autophagy promoted by chromomycin A2, a feature not previously described for chromomycins. PMID:25486109

  20. CO/sub 2/-induced climate change and forest resources

    SciTech Connect

    Graham, R.L.; Turner, M.G.; Dale, V.H.

    1988-01-01

    The objective of this paper is to examine potential forest responses to increases in atmospheric CO/sub 2/ and to CO/sub 2/-induced climate change. Forests both affect and respond to changes in atmospheric CO/sub 2/ and climate. Forests directly affect climate at the global scale by altering the earth's albedo, hydrological regimes, and atmospheric CO/sub 2/. At a local scale they can alter air temperature, humidity, and solar radiation. In turn, forests are affected by CO/sub 2/ and climate at many spatial and temporal scales. Forest responses to CO/sub 2/ and climate may be examined by using five biotic paradigms. Each paradigm has its own spatial and temporal scale and its own set of unique phenomena responsive to CO/sub 2/ and climate changes. We will first use these paradigms to review forest responses to CO/sub 2/ and climate. We will then describe the linkages between these paradigms and the implications of these linkages for future research on the impact of elevated atmospheric CO/sub 2/ and climate change on forest resources. 51 refs., 1 fig.

  1. Nodular pulmonary amyloidosis and obvious ossification due to primary pulmonary MALT lymphoma with extensive plasmacytic differentiation: Report of a rare case and review of the literature

    PubMed Central

    Xiang, Hua; Wu, Zuqun; Wang, Zhaoming; Yao, Hongtian

    2015-01-01

    Localized (primary) pulmonary amyloidosis associated with pulmonary low-grade B cell lymphoma is rarely occurred. Here we report an unusual case of nodular pulmonary amyloidosis and obvious ossification due to primary pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma with extensive plasmacytic differentiation in a 59-year-old man; moreover, two bronchial lymph nodes were involved histologically. The patient underwent a left lower lobectomy along with mediastinal lymphadenectomy. He received no adjuvant therapy and the postoperative course was uneventful within the 14 months follow-up period after his initial diagnosis. PMID:26261657

  2. Forensic age estimation via 3-T magnetic resonance imaging of ossification of the proximal tibial and distal femoral epiphyses: Use of a T2-weighted fast spin-echo technique.

    PubMed

    Ekizoglu, Oguzhan; Hocaoglu, Elif; Inci, Ercan; Can, Ismail Ozgur; Aksoy, Sema; Kazimoglu, Cemal

    2016-03-01

    Radiation exposure during forensic age estimation is associated with ethical implications. It is important to prevent repetitive radiation exposure when conducting advanced ultrasonography (USG) and magnetic resonance imaging (MRI). The purpose of this study was to investigate the utility of 3.0-T MRI in determining the degree of ossification of the distal femoral and proximal tibial epiphyses in a group of Turkish population. We retrospectively evaluated coronal T2-weighted and turbo spin-echo sequences taken upon MRI of 503 patients (305 males, 198 females; age 10-30 years) using a five-stage method. Intra- and interobserver variations were very low. (Intraobserver reliability was κ=0.919 for the distal femoral epiphysis and κ=0.961 for the proximal tibial epiphysis, and interobserver reliability was κ=0.836 for the distal femoral epiphysis and κ=0.885 for the proximal tibial epiphysis.) Spearman's rank correlation analysis indicated a significant positive relationship between age and the extent of ossification of the distal femoral and proximal tibial epiphyses (p<0.001). Comparison of male and female data revealed significant between-gender differences in the ages at first attainment of stages 2, 3, and 4 ossifications of the distal femoral epiphysis and stage 1 and 4 ossifications of the proximal tibial epiphysis (p<0.05). The earliest ages at which ossification of stages 3, 4, and 5 was evident in the distal femoral epiphysis were 14, 17, and 22 years in males and 13, 16, and 21 years in females, respectively. Proximal tibial epiphysis of stages 3, 4, and 5 ossification was first noted at ages 14, 17, and 18 years in males and 13, 15, and 16 years in females, respectively. MRI of the distal femoral and proximal tibial epiphyses is an alternative, noninvasive, and reliable technique to estimate age. PMID:26797254

  3. Ossification Pattern of Estuarine Dolphin (Sotalia guianensis) Forelimbs, from the Coast of the State of Espírito Santo, Brazil

    PubMed Central

    Botta, Silvina; de Queiroz, Fábio Ferreira; Campos, Adélia Sepúlveda

    2015-01-01

    The estuarine dolphin, Sotalia guianensis, is one of the most abundant cetacean species in Brazil. Determination of age and of aspects associated with the development of this species is significant new studies. Counts of growth layer groups in dentin are used to estimate age of these animals, though other ways to evaluate development are also adopted, like the measurement of total length (TL). This study presents a procedure to evaluate the development of the estuarine dolphin based on the ossification pattern of forelimbs. Thirty-seven estuarine dolphins found in the state of Espírito Santo, Brazil, were examined. Age was estimated, TL was measured and ossification of epiphyses was examined by radiography. We analyzed results using the Spearman correlation. Inspection of radiographs allowed evaluation of the significance of the correlation between age and development of the proximal (r = 0.9109) and distal (r = 0.9092) radial epiphyses, and of the distal ulnar epiphyses (r = 0.9055). Radiographic analysis of forelimbs proved to be an appropriate method to evaluate physical maturity, and may be a helpful tool to estimate age of these animals in ecological and population studies. PMID:26017269

  4. Ossification Pattern of Estuarine Dolphin (Sotalia guianensis) Forelimbs, from the Coast of the State of Espírito Santo, Brazil.

    PubMed

    de Carvalho, Anna Paula Martins; Lima, Juliana Ywasaki; Azevedo, Carolina Torres; Botta, Silvina; de Queiroz, Fábio Ferreira; Campos, Adélia Sepúlveda; Barbosa, Lupércio de Araújo; da Silveira, Leonardo Serafim

    2015-01-01

    The estuarine dolphin, Sotalia guianensis, is one of the most abundant cetacean species in Brazil. Determination of age and of aspects associated with the development of this species is significant new studies. Counts of growth layer groups in dentin are used to estimate age of these animals, though other ways to evaluate development are also adopted, like the measurement of total length (TL). This study presents a procedure to evaluate the development of the estuarine dolphin based on the ossification pattern of forelimbs. Thirty-seven estuarine dolphins found in the state of Espírito Santo, Brazil, were examined. Age was estimated, TL was measured and ossification of epiphyses was examined by radiography. We analyzed results using the Spearman correlation. Inspection of radiographs allowed evaluation of the significance of the correlation between age and development of the proximal (r = 0.9109) and distal (r = 0.9092) radial epiphyses, and of the distal ulnar epiphyses (r = 0.9055). Radiographic analysis of forelimbs proved to be an appropriate method to evaluate physical maturity, and may be a helpful tool to estimate age of these animals in ecological and population studies. PMID:26017269

  5. CO2-induced changes in mineral stoichiometry of wheat grains

    NASA Astrophysics Data System (ADS)

    Broberg, Malin; Pleijel, Håkan; Högy, Petra

    2016-04-01

    A comprehensive review of experiments with elevated CO2 (eCO2) presenting data on grain mineral concentration in wheat grain was made. Data were collected both from FACE (Free-Air CO2 Enrichment) and OTC (Open-Top Chamber) experiments. Analysis was made i) by deriving response functions for the relative effect on yield and mineral concentration in relation to CO2 concentration, ii) meta-analysis to test the magnitude and significance of observed effects and iii) comparison of the CO2 effect on the accumulation of different minerals in relation to accumulation of biomass and accumulation of N. Data were obtained for the following minerals: N, Zn, Mn, K, Ca, Mg, P, Fe, S, Cr, Cu, Cd and Na. In addition, data for starch, the dominating carbohydrate of wheat grain, were extracted. The responses ranged from near zero effects to strong negative effects of eCO2 on mineral concentration. The order of effect size was the following (from largest to smallest effect) for the different elements: Fe, Ca, S, Zn, Cd, N, Mg, Mn, P, Cu, Cr, K and Na. Particularly strong negative impacts of eCO2 were found in the essential mineral elements Fe, S, Ca, Zn and Mg. Especially Fe, Zn and Mg are nutrients for which deficiency in humans is a problem in todaýs world. The rather large differences in response of different elements indicated that the CO2-induced responses cannot be explained by a simple growth dilution model. Rather, uptake and transport mechanisms may have to be considered in greater detail, as well as the link of different elements with the uptake of nitrogen, the quantitatively dominating mineral nutrient, to explain the observed pattern. No effect of eCO2 on starch concentration could be demonstrated. This substantiates the rejection of a simple dilution model, since one would expect starch concentrations to be elevated in order to explain reduced mineral concentrations by carbohydrate dilution. The concentrations of toxic Cd was negatively affected, in principle a

  6. Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors

    PubMed Central

    Qian, Guofeng; Karnati, Srikanth; Baumgart-Vogt, Eveline

    2015-01-01

    Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11β gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARɑ/ß/ɣ in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARß than for PPARɑ and PPARɣ. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARß agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat), whereas the PPARß antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and related gene expression

  7. Suppressed osteoclast differentiation at the chondro-osseous junction mediates endochondral ossification retardation in long bones of Wistar fetal rats with prenatal ethanol exposure.

    PubMed

    Pan, Zhengqi; Zhang, Xianrong; Shangguan, Yangfan; Hu, Hang; Chen, Liaobin; Wang, Hui

    2016-08-15

    Prenatal ethanol exposure (PEE) inhibits longitudinal growth of fetal bones, but the underlying mechanisms remain unknown. In this study, we aimed to investigate how PEE induces the retardation of long bone development in fetal rats. Pregnant Wistar rats were treated with ethanol or distilled water (control group) by gavage from gestational day (GD) 9 to 20. Fetuses were delivered by cesarean section on GD20. Fetal sera were collected for assessing corticosterone (CORT) level. Fetal long bones were harvested for histochemical, immunohistochemical and gene expression analysis. Primary chondrocytes were treated with ethanol or CORT for analyzing genes expression. PEE fetuses showed a significant reduction in birth weight and body length. The serum CORT concentration in PEE group was significantly increased, while the body weight, body length and femur length all were significantly decreased in the PEE group. The length of the epiphyseal hypertrophy zone was enlarged, whereas the length of the primary ossification center was significantly reduced in PEE fetuses. TUNEL assay showed reduced apoptosis in the PEE group. Further, the gene expression of osteoprotegerin (OPG) was markedly up-regulated. In vitro experiments showed that CORT (but not ethanol) treatment significantly activated the expression of OPG, while the application of glucocorticoid receptor inhibitor, mifepristone, attenuated these change induced by CORT. These results indicated that PEE-induced glucocorticoid over-exposure enhanced the expression of OPG in fetal epiphyseal cartilage and further lead to the suppressed osteoclast differentiation in the chondro-osseous junction and consequently inhibited the endochondral ossification in long bones of fetal rats. PMID:27338645

  8. Ossified Posterior Longitudinal Ligament With Massive Ossification of the Anterior Longitudinal Ligament Causing Dysphagia in a Diffuse Idiopathic Skeletal Hyperostosis Patient.

    PubMed

    Murayama, Kazuhiro; Inoue, Shinichi; Tachibana, Toshiya; Maruo, Keishi; Arizumi, Fumihiro; Tsuji, Shotaro; Yoshiya, Shinichi

    2015-08-01

    Descriptive case report.To report a case of a diffuse idiopathic skeletal hyperostosis (DISH) patient with both massive ossification of the anterior longitudinal ligament (OALL) leading to severe dysphagia as well as ossification of the posterior longitudinal ligament (OPLL) causing mild cervical myelopathy, warranting not only an anterior approach but also a posterior one.Although DISH can cause massive OALL in the cervical spine, severe dysphagia resulting from DISH is a rare occurrence. OALLs are frequently associated with OPLL. Treatment for a DISH patient with OPLL in setting of OALL-caused dysphagia is largely unknown.A 70-year-old man presented with severe dysphagia with mild cervical myelopathy. Neurological examination showed mild spastic paralysis and hyper reflex in his lower extremities. Plane radiographs and computed tomography of the cervical spine revealed a discontinuous massive OALL at C4-5 and continuous type OPLL at C2-6. Magnetic resonance imaging revealed pronounced spinal cord compression due to OPLL at C4-5. Esophagram demonstrated extrinsic compression secondary to OALL at C4-5.We performed posterior decompressive laminectomy with posterior lateral mass screw fixation, as well as both resection of OALL and interbody fusion at C4-5 by the anterior approach. We performed posterior decompressive laminectomy with posterior lateral mass screw fixation, as well as both resection of OALL and interbody fusion at C4-5 by the anterior approach. Severe dysphagia markedly improved without any complications.We considered that this patient not only required osteophytectomy and fusion by the anterior approach but also required decompression and spinal fusion by the posterior approach to prevent both deterioration of cervical myelopathy and recurrence of OALL after surgery. PMID:26266365

  9. Cartilage-specific β-CATENIN signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development

    PubMed Central

    Dao, Debbie Y.; Jonason, Jennifer H.; Zhang, Yongchun; Hsu, Wei; Chen, Di; Hilton, Matthew J.; O’Keefe, Regis J.

    2012-01-01

    The WNT/β-CATENIN signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. While the importance of β-CATENIN signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate β-CATENIN in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for β-CATENIN in committed growth plate chondrocytes has been less robust. To identify the specific role of cartilage-derived β-CATENIN in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2CreERT2 transgene in combination with β-cateninfx(exon3)/wt or β-cateninfx/fx floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific β-CATENIN signaling promotes chondrocyte maturation, possibly involving a BMP2 mediated mechanism. Second, cartilage-specific β–CATENIN facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced MMP expression at sites of cartilage degradation, and potentially by enhancing IHH signaling activity to recruit vascular tissues. Finally, cartilage-specific β-CATENIN signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived β-CATENIN signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation. PMID:22508079

  10. Thyroid hormone receptor-β1 signaling is critically involved in regulating secondary ossification via promoting transcription of the Ihh gene in the epiphysis.

    PubMed

    Xing, Weirong; Aghajanian, Patrick; Goodluck, Helen; Kesavan, Chandrasekhar; Cheng, Shaohong; Pourteymoor, Sheila; Watt, Heather; Alarcon, Catrina; Mohan, Subburaman

    2016-05-15

    Thyroid hormone (TH) action is mediated through two nuclear TH receptors, THRα and THRβ. Although the role of THRα is well established in bone, less is known about the relevance of THRβ-mediated signaling in bone development. On ther basis of our recent finding that TH signaling is essential for initiation and formation of secondary ossification center, we evaluated the role of THRs in mediating TH effects on epiphysial bone formation. Two-day treatment of TH-deficient Tshr(-/-) mice with TH increased THRβ1 mRNA level 3.4-fold at day 7 but had no effect on THRα1 mRNA level at the proximal tibia epiphysis. Treatment of serum-free cultures of tibias from 3-day-old mice with T3 increased THRβ1 expression 2.1- and 13-fold, respectively, at 24 and 72 h. Ten-day treatment of Tshr(-/-) newborns (days 5-14) with THRβ1 agonist GC1 at 0.2 or 2.0 μg/day increased BV/TV at day 21 by 225 and 263%, respectively, compared with vehicle treatment. Two-day treatment with GC1 (0.2 μg/day) increased expression levels of Indian hedgehog (Ihh) 100-fold, osterix 15-fold, and osteocalcin 59-fold compared with vehicle at day 7 in the proximal tibia epiphysis. Gel mobility shift assay demonstrated that a putative TH response element in the distal promoter of mouse Ihh gene interacted with THRβ1. GC1 treatment (1 nM) increased Ihh distal promoter activity 20-fold after 48 h in chondroctyes. Our data suggest a novel role for THRβ1 in secondary ossification at the epiphysis that involves transcriptional upregulation of Ihh gene. PMID:27026086

  11. Morphometric Study of Anterior Clinoid Process and Optic Strut and the Ossification of Carotico-Clinoid Ligament with their Clinical Importance

    PubMed Central

    Souza, Anne D; Ankolekar, Vrinda Hari; Nayak, Nivedita; Souza, Antony Sylvan D

    2016-01-01

    Introduction Knowledge about the ossification of the Carotico-Clinoid Foramen (CCF), as it forms a potential site for compression of the internal carotid artery may be beneficial for neurosurgeons and radiologists. Aim To obtain a detailed knowledge of morphometry of Anterior Clinoid Process (ACP) and Optic Strot (OS) and the type of ossification of CCF which would be necessary to increase the success of surgeries related to the cavernous sinus and internal carotid artery. Materials and Methods Parameters such as the length of ACP from its base to the tip, the width at its base and the distance between the tip of ACP to optic strut were measured in mm using digital calipers. SPSS version 17 was used for the statistical analysis. Paired t-test was applied to compare between right and left sides. Presence of carotico-clinoid foramen was observed and was classified as incomplete, contact form or complete. Results The average length of ACP ranged from 12 to 15mm on right side and 11 to 16mm on the left side. Paired t-test was applied to compare the means between the right and left sides. The width of ACP varied between right and left sides and this difference was statistically significant (p<0.05). Out of 12 CCF observed, the commonest type was incomplete (N=7) followed by complete (N=3) and contact form (N=2). Conclusion Considering the immense anatomical surgical and radiological importance of morphology of ACP, OS and CCF, this study highlighted the detailed morphometry of these structures. The study also has explained the sexual dimorphism in their morphology. PMID:27190784

  12. Prevalence and Distribution of Ossified Lesions in the Whole Spine of Patients with Cervical Ossification of the Posterior Longitudinal Ligament A Multicenter Study (JOSL CT study).

    PubMed

    Hirai, Takashi; Yoshii, Toshitaka; Iwanami, Akio; Takeuchi, Kazuhiro; Mori, Kanji; Yamada, Tsuyoshi; Wada, Kanichiro; Koda, Masao; Matsuyama, Yukihiro; Takeshita, Katsushi; Abematsu, Masahiko; Haro, Hirotaka; Watanabe, Masahiko; Watanabe, Kei; Ozawa, Hiroshi; Kanno, Haruo; Imagama, Shiro; Fujibayashi, Shunsuke; Yamazaki, Masashi; Matsumoto, Morio; Nakamura, Masaya; Okawa, Atsushi; Kawaguchi, Yoshiharu

    2016-01-01

    Ossification of the posterior longitudinal ligament (OPLL) can cause severe and irreversible paralysis in not only the cervical spine but also the thoracolumbar spine. To date, however, the prevalence and distribution of OPLL in the whole spine has not been precisely evaluated in patients with cervical OPLL. Therefore, we conducted a multi-center study to comprehensively evaluate the prevalence and distribution of OPLL using multi-detector computed tomography (CT) images in the whole spine and to analyze what factors predict the presence of ossified lesions in the thoracolumbar spine in patients who were diagnosed with cervical OPLL by plain X-ray. Three hundred and twenty-two patients with a diagnosis of cervical OPLL underwent CT imaging of the whole spine. The sum of the levels in which OPLL was present in the whole spine was defined as the OP-index and used to evaluate the extent of ossification. The distribution of OPLL in the whole spine was compared between male and female subjects. In addition, a multiple regression model was used to ascertain related factors that affected the OP-index. Among patients with cervical OPLL, women tended to have more ossified lesions in the thoracolumbar spine than did men. A multiple regression model revealed that the OP-index was significantly correlated with the cervical OP-index, sex (female), and body mass index. Furthermore, the prevalence of thoracolumbar OPLL in patients with a cervical OP-index ≥ 10 was 7.8 times greater than that in patients with a cervical OP-index ≤ 5. The results of this study reveal that the extent of OPLL in the whole spine is significantly associated with the extent of cervical OPLL, female sex, and obesity. PMID:27548354

  13. Prevalence and Distribution of Ossified Lesions in the Whole Spine of Patients with Cervical Ossification of the Posterior Longitudinal Ligament A Multicenter Study (JOSL CT study)

    PubMed Central

    Hirai, Takashi; Yoshii, Toshitaka; Iwanami, Akio; Takeuchi, Kazuhiro; Mori, Kanji; Yamada, Tsuyoshi; Wada, Kanichiro; Koda, Masao; Matsuyama, Yukihiro; Takeshita, Katsushi; Abematsu, Masahiko; Haro, Hirotaka; Watanabe, Masahiko; Watanabe, Kei; Ozawa, Hiroshi; Kanno, Haruo; Imagama, Shiro; Fujibayashi, Shunsuke; Yamazaki, Masashi; Matsumoto, Morio; Nakamura, Masaya; Okawa, Atsushi; Kawaguchi, Yoshiharu

    2016-01-01

    Ossification of the posterior longitudinal ligament (OPLL) can cause severe and irreversible paralysis in not only the cervical spine but also the thoracolumbar spine. To date, however, the prevalence and distribution of OPLL in the whole spine has not been precisely evaluated in patients with cervical OPLL. Therefore, we conducted a multi-center study to comprehensively evaluate the prevalence and distribution of OPLL using multi-detector computed tomography (CT) images in the whole spine and to analyze what factors predict the presence of ossified lesions in the thoracolumbar spine in patients who were diagnosed with cervical OPLL by plain X-ray. Three hundred and twenty-two patients with a diagnosis of cervical OPLL underwent CT imaging of the whole spine. The sum of the levels in which OPLL was present in the whole spine was defined as the OP-index and used to evaluate the extent of ossification. The distribution of OPLL in the whole spine was compared between male and female subjects. In addition, a multiple regression model was used to ascertain related factors that affected the OP-index. Among patients with cervical OPLL, women tended to have more ossified lesions in the thoracolumbar spine than did men. A multiple regression model revealed that the OP-index was significantly correlated with the cervical OP-index, sex (female), and body mass index. Furthermore, the prevalence of thoracolumbar OPLL in patients with a cervical OP-index ≥ 10 was 7.8 times greater than that in patients with a cervical OP-index ≤ 5. The results of this study reveal that the extent of OPLL in the whole spine is significantly associated with the extent of cervical OPLL, female sex, and obesity. PMID:27548354

  14. 5-HT2A receptor activation is necessary for CO2-induced arousal.

    PubMed

    Buchanan, Gordon F; Smith, Haleigh R; MacAskill, Amanda; Richerson, George B

    2015-07-01

    Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild-type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT(2A) receptors dose-dependently blocked CO2-induced arousal. The 5-HT(2C) receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8-OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1b(f/f/p)) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT(2A), but not 5-HT(2C), receptors, dose-dependently restored CO2-induced arousal in these mice. These data identify the 5-HT(2A) receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5-HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system. PMID:25925320

  15. 5-HT2A receptor activation is necessary for CO2-induced arousal

    PubMed Central

    Smith, Haleigh R.; MacAskill, Amanda; Richerson, George B.

    2015-01-01

    Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild-type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT2A receptors dose-dependently blocked CO2-induced arousal. The 5-HT2C receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8-OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1bf/f/p) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT2A, but not 5-HT2C, receptors, dose-dependently restored CO2-induced arousal in these mice. These data identify the 5-HT2A receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5-HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system. PMID:25925320

  16. Angiopoietin 2 induces pericyte apoptosis via α3β1 integrin signaling in diabetic retinopathy.

    PubMed

    Park, Sung Wook; Yun, Jang-Hyuk; Kim, Jin Hyoung; Kim, Kyu-Won; Cho, Chung-Hyun; Kim, Jeong Hun

    2014-09-01

    Pericyte loss is an early characteristic change in diabetic retinopathy (DR). Despite accumulating evidence that hyperglycemia-induced angiopoietin 2 (Ang2) has a central role in pericyte loss, the precise molecular mechanism has not been elucidated. This study investigated the role of Ang2 in pericyte loss in DR. We demonstrated that pericyte loss occurred with Ang2 increase in the diabetic mouse retina and that the source of Ang2 could be the endothelial cell. Ang2 induced pericyte apoptosis via the p53 pathway under high glucose, whereas Ang2 alone did not induce apoptosis. Integrin, not Tie-2 receptor, was involved for Ang2-induced pericyte apoptosis under high glucose as an Ang2 receptor. High glucose changed the integrin expression pattern, which increased integrin α3 and β1 in the pericyte. Furthermore, Ang2-induced pericyte apoptosis in vitro was effectively attenuated via p53 suppression by blocking integrin α3 and β1. Although intravitreal injection of Ang2 induced pericyte loss in C57BL/6J mice retina in vivo, intravitreal injection of anti-integrin α3 and β1 antibodies attenuated Ang2-induced pericyte loss. Taken together, Ang2 induced pericyte apoptosis under high glucose via α3β1 integrin. Glycemic control or blocking Ang2/integrin signaling could be a potential therapeutic target to prevent pericyte loss in early DR. PMID:24722242

  17. Development of a new auxiliary heterotopic partial liver transplantation technique using a liver cirrhosis model in minipigs: Preliminary report of eight transplants

    PubMed Central

    ZHANG, JUN-JING; NIU, JIAN-XIANG; YUE, GEN-QUAN; ZHONG, HAI-YAN; MENG, XING-KAI

    2012-01-01

    This study aimed to develop a new auxiliary heterotopic partial liver transplantation (AHPLT) technique in minipigs using a model of liver cirrhosis. Based on our previous study, 14 minipigs were induced to cirrhosis by administration of carbon tetrachloride (CCl4) through intraperitoneal injection. All of the cirrhotic animals were utilized as recipients. The donor’s liver was placed on the recipient’s splenic bed, and the anastomosis was performed as follows: end-to-end anastomosis between the donor’s portal vein and the recipient’s splenic vein, end-to-side anastomosis between the donor’s suprahepatic vena cava and the recipient’s suprahepatic vena cava, and end-to-end anastomosis between the donor’s hepatic artery and the recipient’s splenic artery. The common bile duct of the donor was intubated and bile was collected with an extracorporeal bag. Vital signs, portal vein pressure (PVP), hepatic venous pressure (HVP) and portal vein pressure gradient (PVPG) were monitored throughout the transplantation. All 8 minipigs that developed liver cirrhosis were utilized to establish the new AHPLT; 7 cases survived. Following the surgical intervention, the PVP and PVPG of the recipients were lower than those prior to the operation (P<0.05), whereas the PVP and PVPG of the donors increased significantly compared to those of the normal animals (P<0.05). A new operative technique for AHPLT has been successfully described herein using a model of liver cirrhosis. PMID:22969983

  18. Melatonin promotes the cumulus-oocyte complexes quality of vitrified-thawed murine ovaries; with increased mean number of follicles survival and ovary size following heterotopic transplantation.

    PubMed

    Hemadi, Masoud; Abolhassani, Farid; Akbari, Mohammad; Sobhani, Aligholi; Pasbakhsh, Parichehr; Ahrlund-Richter, Lars; Modaresi, Mohammad H; Salehnia, Mojdeh

    2009-09-15

    We have tested the protective effect of melatonin on neonate murine ovarian tissue after vitrification, thawing and heterotopic transplantation into ovariectomized recipient mice. Vitrified ovaries from neonate (CBA x C57Bl/6) F1 hybrid mice were thawed under standard condition with or without the addition of 100 microM melatonin. Following transplantation, melatonin (20 mg/kg/day) or saline solution (physiological saline) was injected i.p. to the treated and non-treated groups for 48 h respectively. Follicle survival and development, together with ovary size followed. Also, vaginal cytology was carried out for monitoring restored puberty. Histological and immunohistochemical studies showed that melatonin could promote the quality of the cumulus-oocyte complexes with uniform distribution of granulosa and stromal cells in the ovarian grafts. Furthermore, the mean follicles survival was improved and the ovary size increased (P< or = 0.001). The overall mean number of follicles entering the next maturation stage dramatically increased. However, the revascularization and restoration of puberty of ovarian grafts were similar between melatonin-treated and control groups. In conclusion, melatonin as a protection from ischemic injury and a reduce oxidative stress, was shown beneficial during the early days of transplantation. PMID:19622351

  19. The effects of different schedules of total-body irradiation in heterotopic vascularized bone transplantation. An experimental study in the Lewis rat

    SciTech Connect

    Gonzalez del Pino, J.; Benito, M.; Randolph, M.A.; Weiland, A.J. )

    1990-12-01

    To evaluate the effects of irradiation on heterotopically placed vascularized knee isografts, a single dose of 10 Gy of total-body irradiation was given to Lewis donor rats. Irradiation was delivered either 2 or 6 days prior to harvesting or subsequent transplantation, and evaluated at 1, 2, and 4 weeks after grafting. Irradiation caused endothelial depopulation of the graft artery, although vascular pedicle patency was maintained throughout the study. Bone graft viability and mineralization were normal. Dramatic changes in the bone marrow were seen that included an increase of its fat content (P less than 0.001), and a concomitant decrease in bone marrow-derived immunocompetent cells. These changes were more prominent in recipients of grafts from day -6 irradiated donor rats. Total-body irradiation did not prejudice the use of vascularized bone grafts, and exhibited an associated immunosuppresant effect over the vascular endothelium and bone marrow. This may be a further rational conditioning procedure to avoid recipient manipulation in vascularized bone allotransplantation.

  20. Effects of acoustic and EHF impulses on multipotent stromal cells during formation of bone marrow containing heterotopic organs in tissue engineered constructions.

    PubMed

    Chaikhalyan, R K; Yusupov, V I; Gorskaya, Yu F; Kuralesova, A I; Gerasimov, Yu V; Sviridov, A P; Tambiev, A Kh; Vorob'eva, N N; Shishkova, A G Grosheva V V; Moskvina, I L; Bagratashvili, V N

    2015-03-01

    We studied the effects of physical factors (acoustic impulses of laser-induced hydrodynamics, AILIH, and EHF-radiation) on the formation of heterotopic bone marrow organs. Suspension of precipitated mouse bone marrow cells was exposed to AILIH and EHF or their combinations (AILIH+EHF, EHF+AILIH). The developed tissue engineering constructions (gelatin sponges containing 107 nucleated bone marrow cells exposed to physical factors) were transplanted under the renal capsule of syngeneic mice. Analysis of newly formed hemopoietic organs was performed after 3 and 5 months. The total amount of hemopoietic cells, number of multipotent stromal cells, efficiency of colony formation from these cells, and weight of bone capsule of the transplants were measured. Microscopic study showed that 5-month transplants were significantly larger than 3-month transplants and contained 3-fold more hemopoietic cells (20-fold in the AILIH+EHF group). The number of multipotent stromal cells was maximum in EHF+AILIH group (by 2.2 times higher than in the control) and minimum in AILIH+EHF group. Exposure to EHF+AILIH had most pronounced effect on the formation of the bone marrow transplants. The weight of bone capsules more rapidly increased in gelatin sponges of 3-month transplants of EHF+AILIH and AILIH groups. These data suggest that the studied physical factors can be used for acceleration of rehabilitation process. PMID:25778661

  1. Core binding factor beta (CBFB) haploinsufficiency due to an interstitial deletion at 16q21q22 resulting in delayed cranial ossification, cleft palate, congenital heart anomalies, and feeding difficulties but favorable outcome.

    PubMed

    Khan, Aneal; Hyde, R Katherine; Dutra, Amalia; Mohide, Patrick; Liu, Paul

    2006-11-01

    The core binding factor beta gene (CBFB), essential to bone morphogenesis, is located at 16q22.1. Homozygous deficiency of CBFB leads to ossification defects in mice. CBFB forms a heterodimer with RUNX2 (CBFA1) during embryonic bone development. RUNX2 mutations lead to cleidocranial dysplasia in humans. We describe an infant boy with an interstitial deletion of 16q21q22, delayed skull ossification, cleft palate, and heart anomalies who had a difficult course in infancy but eventually improved and is healthy. He was found to have CBFB haploinsufficiency, but did not have mutations in RUNX2. We suggest that 16q21q22 deletion be considered when there are antenatal or postnatal findings of enlarged cranial sutures with or without cleft palate. The finding of CBFB haploinsufficiency in our case and the similarity of cranial ossification defects with a mouse model of CBFB deletion suggest a role for CBFB in cranial bone development in humans. PMID:17022082

  2. Comparison of clinical outcomes in decompression and fusion versus decompression only in patients with ossification of the posterior longitudinal ligament: a meta-analysis.

    PubMed

    Mehdi, Syed K; Alentado, Vincent J; Lee, Bryan S; Mroz, Thomas E; Benzel, Edward C; Steinmetz, Michael P

    2016-06-01

    OBJECTIVE Ossification of the posterior longitudinal ligament (OPLL) is a pathological calcification or ossification of the PLL, predominantly occurring in the cervical spine. Although surgery is often necessary for patients with symptomatic neurological deterioration, there remains controversy with regard to the optimal surgical treatment. In this systematic review and meta-analysis, the authors identified differences in complications and outcomes after anterior or posterior decompression and fusion versus after decompression alone for the treatment of cervical myelopathy due to OPLL. METHODS A MEDLINE, SCOPUS, and Web of Science search was performed for studies reporting complications and outcomes after decompression and fusion or after decompression alone for patients with OPLL. A meta-analysis was performed to calculate effect summary mean values, 95% CIs, Q statistics, and I(2) values. Forest plots were constructed for each analysis group. RESULTS Of the 2630 retrieved articles, 32 met the inclusion criteria. There was no statistically significant difference in the incidence of excellent and good outcomes and of fair and poor outcomes between the decompression and fusion and the decompression-only cohorts. However, the decompression and fusion cohort had a statistically significantly higher recovery rate (63.2% vs 53.9%; p < 0.0001), a higher final Japanese Orthopaedic Association score (14.0 vs 13.5; p < 0.0001), and a lower incidence of OPLL progression (< 1% vs 6.3%; p < 0.0001) compared with the decompression-only cohort. There was no statistically significant difference in the incidence of complications between the 2 cohorts. CONCLUSIONS This study represents the only comprehensive review of outcomes and complications after decompression and fusion or after decompression alone for OPLL across a heterogeneous group of surgeons and patients. Based on these results, decompression and fusion is a superior surgical technique compared with posterior

  3. Ba2+ induces contraction in swine carotid artery by mobilizing intracellular Ca2+.

    PubMed

    Hai, C M; Murphy, R A

    1987-04-01

    Recent data suggest that Ba2+ activates the smooth muscle contractile apparatus. However, in vitro studies indicate that Ba2+ activates Ca2+ calmodulin-dependent enzymes only at very high concentrations. These observations might suggest that Ba2+ activates the contractile apparatus by a mechanism independent of myosin phosphorylation. We tested this hypothesis using intact and Triton X-100 skinned swine carotid medial strips. In intact tissues, Ba2+ stimulated dose-dependent contractions in the absence of extracellular Ca2+. However, in skinned tissues, Ba2+ induced much lower stress development at concentrations more than three orders of magnitude greater than needed for Ca2+-induced contraction. Ba2+ also failed to maintain stress in skinned tissues previously contracted with 4 microM Ca2+. The Ba2+-induced contraction in intact strips was associated with gradual increases in myosin phosphorylation from a basal level of approximately 5% to a sustained level of 30.0 +/- 0.8%. Partial intracellular calcium depletion with 100 microM histamine, 25 mM caffeine, and 5 mM ethyleneglycol-bis(beta-aminoethyl-ether)-N,N'-tetraacetic acid (EGTA) failed to abolish Ba2+-induced contractions. However, repeated contractions with Ba2+ in the absence of extracellular Ca2+ led to decreases in stress development. These observations suggest that Ba2+ induces stress development by mobilizing intracellular Ca2+ that was not released by histamine and caffeine. PMID:3565557

  4. Salidroside Stimulates Mitochondrial Biogenesis and Protects against H2O2-Induced Endothelial Dysfunction

    PubMed Central

    Xing, Shasha; Yang, Xiaoyan; Li, Wenjing; Bian, Fang; Wu, Dan; Chi, Jiangyang; Xu, Gao; Zhang, Yonghui; Jin, Si

    2014-01-01

    Salidroside (SAL) is an active component of Rhodiola rosea with documented antioxidative properties. The purpose of this study is to explore the mechanism of the protective effect of SAL on hydrogen peroxide- (H2O2-) induced endothelial dysfunction. Pretreatment of the human umbilical vein endothelial cells (HUVECs) with SAL significantly reduced the cytotoxicity brought by H2O2. Functional studies on the rat aortas found that SAL rescued the endothelium-dependent relaxation and reduced superoxide anion (O2∙−) production induced by H2O2. Meanwhile, SAL pretreatment inhibited H2O2-induced nitric oxide (NO) production. The underlying mechanisms involve the inhibition of H2O2-induced activation of endothelial nitric oxide synthase (eNOS), adenosine monophosphate-activated protein kinase (AMPK), and Akt, as well as the redox sensitive transcription factor, NF-kappa B (NF-κB). SAL also increased mitochondrial mass and upregulated the mitochondrial biogenesis factors, peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1α), and mitochondrial transcription factor A (TFAM) in the endothelial cells. H2O2-induced mitochondrial dysfunction, as demonstrated by reduced mitochondrial membrane potential (Δψm) and ATP production, was rescued by SAL pretreatment. Taken together, these findings implicate that SAL could protect endothelium against H2O2-induced injury via promoting mitochondrial biogenesis and function, thus preventing the overactivation of oxidative stress-related downstream signaling pathways. PMID:24868319

  5. Guard cell hydrogen peroxide and nitric oxide mediate elevated CO2 -induced stomatal movement in tomato.

    PubMed

    Shi, Kai; Li, Xin; Zhang, Huan; Zhang, Guanqun; Liu, Yaru; Zhou, Yanhong; Xia, Xiaojian; Chen, Zhixiang; Yu, Jingquan

    2015-10-01

    Climate change as a consequence of increasing atmospheric CO2 influences plant photosynthesis and transpiration. Although the involvement of stomata in plant responses to elevated CO2 has been well established, the underlying mechanism of elevated CO2 -induced stomatal movement remains largely unknown. We used diverse techniques, including laser scanning confocal microscopy, transmission electron microscopy, biochemical methodologies and gene silencing to investigate the signaling pathway for elevated CO2 -induced stomatal movement in tomato (Solanum lycopersicum). Elevated CO2 -induced stomatal closure was dependent on the production of RESPIRATORY BURST OXIDASE 1 (RBOH1)-mediated hydrogen peroxide (H2 O2 ) and NITRATE REDUCTASE (NR)-mediated nitric oxide (NO) in guard cells in an abscisic acid (ABA)-independent manner. Silencing of OPEN STOMATA 1 (OST1) compromised the elevated CO2 -induced accumulation of H2 O2 and NO, upregulation of SLOW ANION CHANNEL ASSOCIATED 1 (SLAC1) gene expression and reduction of stomatal aperture, whereas silencing of RBOH1 or NR had no effects on the expression of OST1. Our results demonstrate that as critical signaling molecules, RBOH1-dependent H2 O2 and NR-dependent NO act downstream of OST1 that regulate SLAC1 expression and elevated CO2 -induced stomatal movement. This information is crucial to deepen the understanding of CO2 signaling pathway in guard cells. PMID:26308648

  6. TGF-{beta}2 inhibits AKT activation and FGF-2-induced corneal endothelial cell proliferation

    SciTech Connect

    Lu Jiawei; Lu Zhenyu; Reinach, Peter

    2006-11-01

    The corneal endothelial cells form a boundary layer between anterior chamber and cornea. This single cell layer is important to maintain cornea transparency by eliciting net fluid transport into the anterior chamber. Injuries of the corneal endothelial layer in humans lead to corneal swelling and translucence. This hindrance is thought to be due to limited proliferative capacity of the endothelial layer. Fibroblast growth factor 2 (FGF-2) and transforming growth factor-beta 2 (TGF-{beta}2) are both found in aqueous humor, and these two cytokines promote and inhibit cell growth, respectively. The intracellular signaling mechanisms by which TGF-{beta}2 suppresses the mitogenic response to FGF-2, however, remain unclear. We have addressed this question by investigating potential crosstalk between FGF-2-induced and TGF-{beta}2-regulated intracellular signaling events in cultured bovine corneal endothelial (BCE) cells. We found that TGF-{beta}2 and FGF-2 oppositely affect BCE cell proliferation and TGF-{beta}2 can override the stimulating effects of FGF-2 by increasing COX-2 expression in these cells. Consistent with these findings, overexpression of COX-2 significantly reduced FGF-2-induced cell proliferation whereas a COX-2 specific inhibitor NS398 reversed the effect of TGF-{beta}2 on FGF-2-induced cell proliferation. The COX-2 product prostaglandin E2 (PGE-2) blocks FGF-2-induced cell proliferation. Whereas FGF-2 stimulates cell proliferation by activating the AKT pathway, TGF-{beta}2 and PGE-2 both inhibit this pathway. In accordance with the effect of PGE-2, cAMP also inhibits FGF-2-induced AKT activation. These findings suggest that the mitogenic response to FGF-2 in vivo in the corneal endothelial layer may be inhibited by TGF-{beta}2-induced suppression of the PI3-kinase/AKT signaling pathway.

  7. The Effects of Targeted Deliveries of Lovastatin and Tocotrienol on Ossification-Related Gene Expressions in Fracture Healing in an Osteoporosis Rat Model.

    PubMed

    Ibrahim, Nurul 'Izzah; Mohamed, Norazlina; Soelaiman, Ima Nirwana; Shuid, Ahmad Nazrun

    2015-10-01

    Osteoporotic drugs are used to prevent fragility fractures, but their role in fracture healing still remains unknown. Thus, alternative agents with suitable mode of delivery are needed to promote fracture healing. This study was performed to investigate the effects of direct deliveries of lovastatin and tocotrienol to fracture sites on ossification-related gene expression in fracture healing in a postmenopausal osteoporosis model. Forty-eight Sprague Dawley female rats were divided into six groups. Group I comprised the sham-operated rats, while Groups II-VI were ovariectomized rats. After 8 weeks, the right tibiae of all rats were fractured and stabilized. Group I and Group II were given two single injections of lovastatin and tocotrienol carriers. Group III was given an estrogen preparation at 64.5 µg/kg daily via oral gavages. Group IV was injected with lovastatin particles (750 µg/kg), while Group V was injected with tocotrienol particles (60 mg/kg). Group VI received two single injections of 750 µg/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks, the gene expressions were measured. Group VI showed significantly higher gene expressions of osteocalcin, BMP-2, VEGF-α, and RUNX-2 compared to Group II. In conclusion, combined treatment of lovastatin and tocotrienol upregulated the expression of genes related to fracture healing. PMID:26501302

  8. R-spondin 2 facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification.

    PubMed

    Takegami, Yasuhiko; Ohkawara, Bisei; Ito, Mikako; Masuda, Akio; Nakashima, Hiroaki; Ishiguro, Naoki; Ohno, Kinji

    2016-04-22

    Endochondral ossification is a crucial process for longitudinal growth of bones. Differentiating chondrocytes in growth cartilage form four sequential zones of proliferation, alignment into column, hypertrophy, and substitution of chondrocytes with osteoblasts. Wnt/β-catenin signaling is essential for differentiation of proliferating chondrocytes into hypertrophic chondrocytes in growth cartilage. R-spondin 2 (Rspo2), a member of R-spondin family, is an agonist for Wnt signaling, but its role in chondrocyte differentiation remains unknown. Here we report that growth cartilage of Rspo2-knockout mice shows a decreased amount of β-catenin and increased amounts collagen type II (CII) and Sox9 in the abnormally extended proliferating zone. In contrast, expression of collagen type X (CX) in the hypertrophic zone remains unchanged. Differentiating chondrogenic ATDC5 cells, mimicking proliferating chondrocytes, upregulate Rspo2 and its putative receptor, Lgr5, in parallel. Addition of recombinant human Rspo2 to differentiating ATDC5 cells decreases expressions of Col2a1, Sox9, and Acan, as well as production of proteoglycans. In contrast, lentivirus-mediated knockdown of Rspo2 has the opposite effect. The effect of Rspo2 on chondrogenic differentiation is mediated by Wnt/β-catenin signaling, and not by Wnt/PCP or Wnt/Ca(2+) signaling. We propose that Rspo2 activates Wnt/β-catenin signaling to reduce Col2a1 and Sox9 and to facilitate differentiation of proliferating chondrocytes into hypertrophic chondrocytes in growth cartilage. PMID:27012200

  9. Ossification of the cervical ligamentum flavum and osseous brown tumor: late manifestations of primary hyperparathyroidism misdiagnosed in a case of parathyroid carcinoma.

    PubMed

    Sampanis, Nikolaos; Gavriilaki, Eleni; Paschou, Eleni; Kalaitzoglou, Asterios; Vasileiou, Sotirios

    2016-01-01

    Parathyroid carcinoma represents an extremely rare neoplasm with diverse clinical manifestations. Herein we aimed at presenting an unique case of a young patient with late manifestations of parathyroid cancer and reviewing the relevant literature. A 45-year-old male patient presented in the Outpatient Clinic with an episode of nephrolithiasis. His personal medical history includes: recurrent episodes of nephrolithiasis, laminectomy in the cervical spine due to ossification of the cervical ligamentum flavum and surgical resection of a giant cell tumor of the brain. Laboratory testing revealed findings of primary hyperparathyroidism (serum calcium 16,0 mmol/l phosphorus 1,46 mg/dl and parathyroid hormone/PTH 8560 pg/ml). Neck ultrasound and technetium-99 m sestamibi scan were performed showing a parathyroid tumor. Due to the persistently high serum calcium and PTH levels, the high alkaline phosphatase levels (440 IU/L) and the late manifestations of HPT, surgical excision of the tumor was performed. The tumor was identified as parathyroid carcinoma. Immediately after surgery serum calcium and phosphorus levels were normalized. The patient is on a regular follow-up program with no signs of recurrence or metastasis one year after the excision. We describe the coexistence of rare late manifestations of HPT, which had not been adequately investigated at their onset in this young patient. Therefore, increased awareness is needed in order to recognize and further investigate signs or symptoms of HPT. PMID:27252748

  10. Postoperative cerebrospinal-fluid fistula associated with erosion of the dura. Findings after anterior resection of ossification of the posterior longitudinal ligament in the cervical spine.

    PubMed

    Smith, M D; Bolesta, M J; Leventhal, M; Bohlman, H H

    1992-02-01

    Of twenty-two patients who had had anterior decompression of the spinal canal for ossification of the posterior longitudinal ligament and cervical myelopathy, seven had absence of the dura adjacent to the ossified part of the ligament. The spinal cord and nerve-roots were visible through this defect. Although the arachnoid membrane appeared to be intact and watertight in most patients, a cerebrospinal-fluid fistula developed postoperatively in five, and three had a second operation to repair the defect in the dura. On the basis of this experience, we recommend use of autogenous muscle or fascial dural patches, immediate lumbar subarachnoid shunting, and modification of the usual postoperative regimen, such as limitation of mechanical pulmonary ventilation to the shortest time that is safely possible and use of anti-emetic and antitussive medications to protect the remaining coverings of the spinal cord when the dura is found to be absent adjacent to an ossified portion of the posterior longitudinal ligament in the cervical spine. PMID:1541620

  11. The Effects of Targeted Deliveries of Lovastatin and Tocotrienol on Ossification-Related Gene Expressions in Fracture Healing in an Osteoporosis Rat Model

    PubMed Central

    Ibrahim, Nurul ‘Izzah; Mohamed, Norazlina; Soelaiman, Ima Nirwana; Shuid, Ahmad Nazrun

    2015-01-01

    Osteoporotic drugs are used to prevent fragility fractures, but their role in fracture healing still remains unknown. Thus, alternative agents with suitable mode of delivery are needed to promote fracture healing. This study was performed to investigate the effects of direct deliveries of lovastatin and tocotrienol to fracture sites on ossification-related gene expression in fracture healing in a postmenopausal osteoporosis model. Forty-eight Sprague Dawley female rats were divided into six groups. Group I comprised the sham-operated rats, while Groups II–VI were ovariectomized rats. After 8 weeks, the right tibiae of all rats were fractured and stabilized. Group I and Group II were given two single injections of lovastatin and tocotrienol carriers. Group III was given an estrogen preparation at 64.5 µg/kg daily via oral gavages. Group IV was injected with lovastatin particles (750 µg/kg), while Group V was injected with tocotrienol particles (60 mg/kg). Group VI received two single injections of 750 µg/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks, the gene expressions were measured. Group VI showed significantly higher gene expressions of osteocalcin, BMP-2, VEGF-α, and RUNX-2 compared to Group II. In conclusion, combined treatment of lovastatin and tocotrienol upregulated the expression of genes related to fracture healing. PMID:26501302

  12. Ossification du ligament de Hoffa: évolution finale de la maladie de Hoffa (à propos d'un cas avec revue de la littérature)

    PubMed Central

    Boukhris, Jalal; Boussouga, Mostapha; Benchakroune, Mohammed; Jaafar, Abdelouahab; Chagar, Belkacem

    2014-01-01

    La responsabilité de la bourse graisseuse sous rotulienne dans certains dérangements internes du genou est connue depuis les observations originales rapportées par Hoffa en 1904. En peropératoire, Hoffa retrouvait une frange graisseuse qui occupait l'interligne articulaire, dont l'ablation faisait disparaître les symptômes. Depuis cette date, peu de publications ont été consacrées à la maladie de Hoffa, et à notre connaissance, aucune grande série n'a été publiée récemment dans la littérature. Ce travail comprend une revue bibliographiqe associée à l’étude des différents aspects sémiologiques, étiopathogéniques et thérapeutiques de ce type d'affection, en rapportant un cas d'ossification du ligament de Hoffa qui ne serait en fait que l’évolution finale de la maladie. PMID:25852801

  13. Ossification of the cervical ligamentum flavum and osseous brown tumor: late manifestations of primary hyperparathyroidism misdiagnosed in a case of parathyroid carcinoma

    PubMed Central

    Sampanis, Nikolaos; Gavriilaki, Eleni; Paschou, Eleni; Kalaitzoglou, Asterios; Vasileiou, Sotirios

    2016-01-01

    Summary Parathyroid carcinoma represents an extremely rare neoplasm with diverse clinical manifestations. Herein we aimed at presenting an unique case of a young patient with late manifestations of parathyroid cancer and reviewing the relevant literature. A 45-year-old male patient presented in the Outpatient Clinic with an episode of nephrolithiasis. His personal medical history includes: recurrent episodes of nephrolithiasis, laminectomy in the cervical spine due to ossification of the cervical ligamentum flavum and surgical resection of a giant cell tumor of the brain. Laboratory testing revealed findings of primary hyperparathyroidism (serum calcium 16,0 mmol/l phosphorus 1,46 mg/dl and parathyroid hormone/PTH 8560 pg/ml). Neck ultrasound and technetium-99 m sestamibi scan were performed showing a parathyroid tumor. Due to the persistently high serum calcium and PTH levels, the high alkaline phosphatase levels (440 IU/L) and the late manifestations of HPT, surgical excision of the tumor was performed. The tumor was identified as parathyroid carcinoma. Immediately after surgery serum calcium and phosphorus levels were normalized. The patient is on a regular follow-up program with no signs of recurrence or metastasis one year after the excision. We describe the coexistence of rare late manifestations of HPT, which had not been adequately investigated at their onset in this young patient. Therefore, increased awareness is needed in order to recognize and further investigate signs or symptoms of HPT. PMID:27252748

  14. Functional bone histology of zebrafish reveals two types of endochondral ossification, different types of osteoblast clusters and a new bone type.

    PubMed

    Weigele, Jochen; Franz-Odendaal, Tamara A

    2016-07-01

    The zebrafish is as an important vertebrate animal model system for studying developmental processes, gene functions and signalling pathways. It is also used as a model system for the understanding of human developmental diseases including those related to the skeleton. However, surprisingly little is known about normal zebrafish skeletogenesis and osteogenesis. As in most vertebrates, it is commonly known that the bones of adult zebrafish are cellular unlike that of some other teleosts. After careful histological analyses of each zebrafish adult bone, we identified several acellular bones, with no entrapped osteocytes in addition to several cellular bones. We show that both cellular and acellular bones can even occur within the same skeletal element and transitions between these two cell types can be found. Furthermore, we describe two types of osteoblast clusters during skeletogenesis and two different types of endochondral ossification. The epiphyseal plate, for example, lacks a zone of calcification and a degradation zone with osteoblasts. A new bone type that we term tubular bone was also identified. This bone is completely filled with adipose tissue, unlike spongy bones. This study provides important insight on how osteogenesis takes place in zebrafish, and especially on the transition from cellular to acellular bones. Overall, this study leads to a deeper understanding of the functional histological composition of adult zebrafish bones. PMID:27278890

  15. Tissue reactions to particles of bone-substitute materials in intraosseous and heterotopic sites in rats: discrimination of osteoinduction, osteocompatibility, and inflammation.

    PubMed

    Eid, K; Zelicof, S; Perona, B P; Sledge, C B; Glowacki, J

    2001-09-01

    Two rat models were used to characterize tissue-specific reactions to particles of bone-substitute materials: one for osteocompatibility in a healing tibial wound and the other in a heterotopic, subcutaneous site. Small, unicortical tibial wounds in rats healed spontaneously, beginning with the rapid proliferation of intramedullary woven bone. That temporary bone was resorbed by osteoclasts and finally, the cortical wound was healed with lamellar bone and the medullary space was repopulated with marrow. When various particulate materials were implanted into fresh wounds, three types of reactions were observed. (1) Demineralized bone powder (DBP) and non-resorbable calcium phosphate (nrCP) were incorporated into the reactive medullary and cortical bone. (2) Polymethylmetlhacrylate (PMMA) particles were surrounded with a fibrous layer, but did not impair bone healing. (3) Polyethylene (PE) shards and resorbable calcium phosphates (rCPs) were inflammatory and inhibited osseous repair. Subcutaneous sites showed osteoinductive, fibrotic, or inflammatory responses to these materials. Only DBP induced endochondral osteogenesis subcutaneously. The nrCP evoked a fibrous reaction. In contrast, rCPs, PMMA, and PE shards generated inflammatory reactions with each particle being surrounded by fibrous tissue and large multinucleated giant cells. In conclusion, only DBP showed osteoinductive as well as osteocompatible properties. The nrCP was osteocompatible. The rCPs stimulated various degrees of inflammatory responses. PMMA was osteocompatible and did not interfere with the bone healing process. PE was not osteocompatible and generated foreign body reactions in both sites. Use of the two sites distinguishes osteoinductive, osteocompatible, and inflammatory properties of particles of bone-substitute materials. PMID:11562148

  16. A New Animal Model for Investigation of Mechanical Unloading in Hypertrophic and Failing Hearts: Combination of Transverse Aortic Constriction and Heterotopic Heart Transplantation

    PubMed Central

    Stenzig, Justus; Biermann, Daniel; Jelinek, Marisa; Reichenspurner, Hermann; Eschenhagen, Thomas; Ehmke, Heimo; Schwoerer, Alexander P.

    2016-01-01

    Objectives Previous small animal models for simulation of mechanical unloading are solely performed in healthy or infarcted hearts, not representing the pathophysiology of hypertrophic and dilated hearts emerging in heart failure patients. In this article, we present a new and economic small animal model to investigate mechanical unloading in hypertrophic and failing hearts: the combination of transverse aortic constriction (TAC) and heterotopic heart transplantation (hHTx) in rats. Methods To induce cardiac hypertrophy and failure in rat hearts, three-week old rats underwent TAC procedure. Three and six weeks after TAC, hHTx with hypertrophic and failing hearts in Lewis rats was performed to induce mechanical unloading. After 14 days of mechanical unloading animals were euthanatized and grafts were explanted for further investigations. Results 50 TAC procedures were performed with a survival of 92% (46/50). When compared to healthy rats left ventricular surface decreased to 5.8±1.0 mm² (vs. 9.6± 2.4 mm²) (p = 0.001) after three weeks with a fractional shortening (FS) of 23.7± 4.3% vs. 28.2± 1.5% (p = 0.01). Six weeks later, systolic function decreased to 17.1± 3.2% vs. 28.2± 1.5% (p = 0.0001) and left ventricular inner surface increased to 19.9±1.1 mm² (p = 0.0001). Intraoperative graft survival during hHTx was 80% with 46 performed procedures (37/46). All transplanted organs survived two weeks of mechanical unloading. Discussion Combination of TAC and hHTx in rats offers an economic and reproducible small animal model enabling serial examination of mechanical unloading in a truly hypertrophic and failing heart, representing the typical pressure overloaded and dilated LV, occurring in patients with moderate to severe heart failure. PMID:26841021

  17. ZN2+ INDUCES COX-2 EXPRESSION THROUGH DOWNREGULATION OF LIPID PHOSPHATASE PTEN

    EPA Science Inventory

    Zn2+ Induces COX-2 Expression through Downregulation of Lipid Phosphatase PTEN
    Weidong Wu*, James M. Samet, Philip A. Bromberg*?, Young E. Whang?, and Lee M. Graves* ?
    *CEMALB, ?Department of Medicine, and ?Department of Pharmacology, UNC-Chapel Hill, NC27599; Human Studie...

  18. STS-2 Induced Environment Contamination Monitor (IECM): Quick-Look Report

    NASA Technical Reports Server (NTRS)

    Miller, E. R. (Editor)

    1982-01-01

    The STS-2/induced environment contamination monitor (IECM) mission is described. The IECM system performance is discussed, and IECM mission time events are briefly described. Quick look analyses are presented for each of the 10 instruments comprising the IECM on the flight of STS-2. A short summary is presented.

  19. Ginsenoside Rh2 induces ligand-independent Fas activation via lipid raft disruption

    SciTech Connect

    Yi, Jae-Sung; Choo, Hyo-Jung; Cho, Bong-Rae; Kim, Hwan-Myung; Kim, Yong-Nyun; Ham, Young-Mi; Ko, Young-Gyu

    2009-07-24

    Lipid rafts are plasma membrane platforms mediating signal transduction pathways for cellular proliferation, differentiation and apoptosis. Here, we show that membrane fluidity was increased in HeLa cells following treatment with ginsenoside Rh2 (Rh2), as determined by cell staining with carboxy-laurdan (C-laurdan), a two-photon dye designed for measuring membrane hydrophobicity. In the presence of Rh2, caveolin-1 appeared in non-raft fractions after sucrose gradient ultracentrifugation. In addition, caveolin-1 and GM1, lipid raft landmarkers, were internalized within cells after exposure to Rh2, indicating that Rh2 might disrupt lipid rafts. Since cholesterol overloading, which fortifies lipid rafts, prevented an increase in Rh2-induced membrane fluidity, caveolin-1 internalization and apoptosis, lipid rafts appear to be essential for Rh2-induced apoptosis. Moreover, Rh2-induced Fas oligomerization was abolished following cholesterol overloading, and Rh2-induced apoptosis was inhibited following treatment with siRNA for Fas. This result suggests that Rh2 is a novel lipid raft disruptor leading to Fas oligomerization and apoptosis.

  20. BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1

    PubMed Central

    Shen, Jia; James, Aaron W.; Zara, Janette N.; Asatrian, Greg; Khadarian, Kevork; Zhang, James B.; Ho, Stephanie; Kim, Hyun Ju

    2013-01-01

    Bone-morphogenetic protein 2 (BMP2) is currently the only Food and Drug Administration-approved osteoinductive growth factor used in clinical settings for bone regeneration and repair. However, the use of BMP2 is encumbered by numerous clinical complications, including postoperative inflammation and life-threatening cervical swelling. Thus, methods to prevent BMP2-induced inflammation would have far-reaching clinical implications toward improving current BMP2-based methods for bone regeneration. For the first time, we investigate the potential role of the growth factor Nel-like molecule-1 (NELL-1) in inhibiting BMP2-induced inflammation. Adult rats underwent a femoral bone onlay procedure, treated with either BMP2 protein (4 mg/mL), NELL-1 protein (4 mg/mL), or both proteins combined. Animals were evaluated at 3, 7, and 14 days postoperatively by histology, histomorphometry, immunohistochemistry, and real-time PCR for markers of inflammation (TNFα, IL6). The relative levels of TNFα and IL6 in serum were also detected by ELISA. The mechanism for NELL-1's anti-inflammatory effect was further assessed through examining inflammatory markers and generation of reactive oxygen species (ROS) in the mouse embryonic fibroblast NIH3T3 cells. BMP2 significantly induced local inflammation, including an early and pronounced polymorphonuclear cell infiltration accompanied by increased expression of TNFα and IL6. Treatment with NELL-1 alone elicited no significant inflammatory response. However, NELL-1 significantly attenuated BMP2-induced inflammation by all markers and at all timepoints. These local findings were also confirmed using systemic serum inflammatory biomarkers (TNFα, IL6). In each case, NELL-1 fully reversed BMP2-induced systemic inflammation. Lastly, our findings were recapitulated in vitro, where NELL-1 suppressed BMP2 induced expression of inflammatory markers, as well as NF-κB transcriptional activity and generation of ROS. BMP2-induced inflammation is a

  1. Role of GLUT4 on angiotensin 2-induced systemic and renal hemodynamics

    PubMed Central

    Igbe, Ighodaro; Omogbai, Eric Kelly; Oyekan, Adebayo O

    2013-01-01

    Cross-talk between insulin and the renin angiotensin system signaling system shows that angiotensin 2 (A2) negatively modulates insulin signaling by stimulating multiple serine phosphorylation events in the early stages of the insulin-signaling cascade; however, the biological actions of A2 on insulin sensitivity remain controversial. Preservation of glucose transporter 4 (GLUT4) expression during hypertension has been shown to prevent the increased vascular reactivity associated with hypertension. This study tested the hypothesis that GLUT4 contributes to the renal actions of A2. In the euvolemic anesthetized rat, acute infusion of the GLUT4 antagonist, indinavir (1 mg/kg/minute), enhanced an A2-induced increase in mean arterial blood pressure (MABP) (P < 0.01), but attenuated an A2-induced increase in medullary blood flow (MBF) and glomerular filtration rate (P < 0.01). Insulin, a GLUT4 activator (20 mU/kg/minute and 40 mU/kg/minute), decreased basal MABP and urine volume (P < 0.05), but it increased MBF, and these effects were reversed and blunted by indinavir. Subchronic indinavir treatment (80 mg/kg/day orally for 15 days) did not affect A2-induced changes in MABP, cortical blood flow, and MBF, but significantly decreased basal MBF (P < 0.01) and global kidney perfusion (P < 0.05). We concluded that acute but not subchronic inhibition of GLUT4 alters A2-induced changes in systemic and renal hemodynamics by attenuating A2-induced increase in MBF and glomerular filtration rate.

  2. Phospholipase A2 induced airway hyperreactivity to cooling and acetylcholine in rat trachea: pharmacological modulation.

    PubMed Central

    Chand, N.; Diamantis, W.; Mahoney, T. P.; Sofia, R. D.

    1988-01-01

    1. Rat isolated tracheal smooth muscle preparations respond to phospholipase A2 (PLA2) and phospholipase C (PLC) with contractile responses of highly variable magnitudes. Rat tracheae exposed to PLA2 or PLC for a period of 10-30 min, exhibit airway hyperreactivity (AH) to cooling (10 degrees C), i.e., respond with strong contractile responses. Phospholipase D neither contracted rat tracheae nor induced AH to cooling. 2. PLA2-induced AH to cooling was dependent on the presence of extracellular Ca2+ in the physiological solution. 3. Verapamil, azelastine, diltiazem and TMB-8 (each 10 microM) significantly attenuated PLA2-induced AH. This effect was not shared by nifedipine (10 microM). 4. Bepridil (10 microM), a Ca2+ and calmodulin antagonist, also significantly attenuated AH induced by PLA2. 5. Indomethacin (a cyclo-oxygenase inhibitor), AA-861 (a selective 5-lipoxygenase inhibitor), FPL 55712 (a leukotriene receptor antagonist), methysergide (a 5-hydroxytryptamine D-receptor antagonist) and pyrilamine (a histamine H1-receptor antagonist) exerted little or no effect on PLA2-induced AH to cooling. 6. Atropine significantly attenuated PLA2-induced AH suggesting the participation of acetylcholine. 7. Nordihydroguaiaretic acid (an antioxidant; 5-lipoxygenase inhibitor) and BW 755C (an antioxidant; a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase) significantly attenuated PLA2-induced AH to cooling. 8. In conclusion, these data show that PLA2 (an enzyme involved in the synthesis of Paf-acether, prostaglandins, thromboxanes, leukotrienes, diacylglycerol, superoxide free radicals and lipid peroxides, etc.) induces AH to cooling and acetylcholine in rat trachea. The induction of AH to cooling is dependent on the presence of extracellular Ca2+ and is significantly attenuated by verapamil, diltiazem, bepridil, atropine and azelastine (an antiallergic/antiasthmatic drug). PMID:3207972

  3. Use of an Ultrasonic Osteotome for Direct Removal of Beak-Type Ossification of Posterior Longitudinal Ligament in the Thoracic Spine

    PubMed Central

    Kim, Chi Heon; Renaldo, Nicholas; Lee, Heui Seung

    2015-01-01

    Direct removal of beak-type ossification of posterior longitudinal ligament at thoracic spine (T-OPLL) is a challenging surgical technique due to the potential risk of neural injury. Slipping off the cutting surface of a high-speed drill may result in entrapment in neural structures, leading to serious complications. Removal of T-OPLL with an ultrasonic osteotome, utilizing back and forth micro-motion of a blade rather than rotatory-motion of drill, may reduce such complications. We have applied the ultrasonic osteotome for posterior circumferential decompression of T-OPLL for three consecutive patients with beak-type OPLL and have described the surgical techniques and patient outcomes. The preoperative chief complaint was gait disturbance in all patients. Japanese orthopedic association scores (JOA) was used for functional assessment. Scores measured 2/11, 5/11, 2/11, and 4/11 for each patient. The ventral T-OPLL mass was exposed after posterior midline approach, laminotomy and transeversectomy. The T-OPLL mass was directly removed with an ultrasonic osteotome and instrumented segmental fixation was performed. The surgeries were uneventful. Detailed surgical techniques were presented. Gait disturbance was improved in all patients. Dural tear occurred in one patient without squeal. Postoperative JOA was 6/11, 10/11, 8/11, and 8/11 (recovery rate; 44%, 83%, 67%, and 43%) respectively at 18, 18, 10, and 1 months postoperative. T-OPLL was completely removed in all patients as confirmed with computed tomography scan. We hope that surgical difficulties in direct removal of T-OPLL might be reduced by utilizing ultrasonic osteotome. PMID:26819697

  4. CO2-induced micelle to vesicle transition in zwitterionic-anionic surfactant systems.

    PubMed

    Li, Wei; Yang, Yanjuan; Luo, Tian; Zhang, Jianling; Han, Buxing

    2014-02-28

    Study of micelle to vesicle transition (MVT) is of great importance from both theoretical and practical points of view. In this work, we studied the effect of compressed CO2 on the aggregation behavior of zwitterionic-anionic (DSB (dodecyl sulfonatebetaine)-AOT(sodium bis(2-ethylhexyl) sulfosuccinate)) mixed surfactants in aqueous solution by means of direct observation, turbidity, steady-state fluorescence, fluorescence quantum yield, and entrapment quantity of vesicles. Interestingly, all the methods show that compressed CO2 can induce MVT in this zwitterionic-anionic surfactant system. The CO2-induced MVT is reversible and the degree of MVT can be easily tuned by controlling the operation pressure. Further studies show that the pH decrease and dissolution of gas molecules in the surfactant film co-contribute to the MVT, and a possible mechanism for the CO2-induced MVT was proposed based on the experimental results. PMID:24413812

  5. Elevated CO2-Induced Responses in Stomata Require ABA and ABA Signaling.

    PubMed

    Chater, Caspar; Peng, Kai; Movahedi, Mahsa; Dunn, Jessica A; Walker, Heather J; Liang, Yun-Kuan; McLachlan, Deirdre H; Casson, Stuart; Isner, Jean Charles; Wilson, Ian; Neill, Steven J; Hedrich, Rainer; Gray, Julie E; Hetherington, Alistair M

    2015-10-19

    An integral part of global environment change is an increase in the atmospheric concentration of CO2 ([CO2]) [1]. Increased [CO2] reduces leaf stomatal apertures and density of stomata that plays out as reductions in evapotranspiration [2-4]. Surprisingly, given the importance of transpiration to the control of terrestrial water fluxes [5] and plant nutrient acquisition [6], we know comparatively little about the molecular components involved in the intracellular signaling pathways by which [CO2] controls stomatal development and function [7]. Here, we report that elevated [CO2]-induced closure and reductions in stomatal density require the generation of reactive oxygen species (ROS), thereby adding a new common element to these signaling pathways. We also show that the PYR/RCAR family of ABA receptors [8, 9] and ABA itself are required in both responses. Using genetic approaches, we show that ABA in guard cells or their precursors is sufficient to mediate the [CO2]-induced stomatal density response. Taken together, our results suggest that stomatal responses to increased [CO2] operate through the intermediacy of ABA. In the case of [CO2]-induced reductions in stomatal aperture, this occurs by accessing the guard cell ABA signaling pathway. In both [CO2]-mediated responses, our data are consistent with a mechanism in which ABA increases the sensitivity of the system to [CO2] but could also be explained by requirement for a CO2-induced increase in ABA biosynthesis specifically in the guard cell lineage. Furthermore, the dependency of stomatal [CO2] signaling on ABA suggests that the ABA pathway is, in evolutionary terms, likely to be ancestral. PMID:26455301

  6. Smurf1 plays a role in EGF inhibition of BMP2-induced osteogenic differentiation

    SciTech Connect

    Lee, Hye-Lim; Park, Hyun-Jung; Kwon, Arang; Baek, Kyunghwa; Woo, Kyung Mi; Ryoo, Hyun-Mo; Kim, Gwan-Shik; Baek, Jeong-Hwa

    2014-05-01

    It has been demonstrated that epidermal growth factor (EGF) plays a role in supporting the proliferation of bone marrow stromal cells in bone but inhibits their osteogenic differentiation. However, the mechanism underlying EGF inhibition of osteoblast differentiation remains unclear. Smurf1 is an E3 ubiquitin ligase that targets Smad1/5 and Runx2, which are critical transcription factors for bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation. In this study, we investigated the effect of EGF on the expression of Smurf1, and the role of Smurf1 in EGF inhibition of osteogenic differentiation using C2C12 cells, a murine myoblast cell line. EGF increased Smurf1 expression, which was blocked by inhibiting the activity of either JNK or ERK. Chromatin immunoprecipitation and Smurf1 promoter assays demonstrated that c-Jun and Runx2 play roles in the EGF induction of Smurf1 transcription. EGF suppressed BMP2-induced expression of osteogenic marker genes, which were rescued by Smurf1 knockdown. EGF downregulated the protein levels of Runx2 and Smad1 in a proteasome-dependent manner. EGF decreased the transcriptional activity of Runx2 and Smurf1, which was partially rescued by Smurf1 silencing. Taken together, these results suggest that EGF increases Smurf1 expression via the activation of JNK and ERK and the subsequent binding of c-Jun and Runx2 to the Smurf1 promoter and that Smurf1 mediates the inhibitory effect of EGF on BMP2-induced osteoblast differentiation. - Highlights: • EGF increases the expression level of Smurf1 in mesenchymal precursor cells. • EGF reduces the protein levels and transcriptional activity of Runx2 and Smad1. • EGF suppresses BMP2-induced osteogenic differentiation, which is rescued by Smurf1 knockdown.

  7. Selenoprotein X Gene Knockdown Aggravated H2O2-Induced Apoptosis in Liver LO2 Cells.

    PubMed

    Tang, Jiayong; Cao, Lei; Li, Qiang; Wang, Longqiong; Jia, Gang; Liu, Guangmang; Chen, Xiaoling; Cai, Jingyi; Shang, Haiying; Zhao, Hua

    2016-09-01

    To determine the roles of selenoprotein X gene (Selx) in protecting liver cells against oxidative damage, the influences of Selx knockdown on H2O2-induced apoptosis in human normal hepatocyte (LO2) cells were studied. pSilencer 3.1 was used to develop knockdown vector targeting the 3'-UTR of human Selx. The Selx knockdown and control cells were further exposed to H2O2, and cell viability, cell apoptosis rate, and the expression levels of mRNA and protein of apoptosis-related genes were detected. The results showed that vector targeting the 3'-UTR of Selx successfully silenced mRNA or protein expression of SelX in LO2 cells. Selx knockdown resulted in decreased cell viability, increased percentage of early apoptotic cells, decreased Bcl2A1 and Bcl-2 expression, and increased phosphorylation of P38 in LO2 cells. When Selx knockdown LO2 cells were exposed to H2O2, characteristics of H2O2-induced cell dysfunctions were further exacerbated. Taken together, our findings suggested that SelX played important roles in protecting LO2 cells against oxidative damage and reducing H2O2-induced apoptosis in liver cells. PMID:26899321

  8. A Receptor Tyrosine Kinase Inhibitor, Dovitinib (TKI-258), Enhances BMP-2-Induced Osteoblast Differentiation In Vitro.

    PubMed

    Lee, Yura; Bae, Kyoung Jun; Chon, Hae Jung; Kim, Seong Hwan; Kim, Soon Ae; Kim, Jiyeon

    2016-05-31

    Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders. PMID:27025387

  9. BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation.

    PubMed

    Kim, Bo Ram; Oh, Sang Cheul; Lee, Dae-Hee; Kim, Jung Lim; Lee, Suk Young; Kang, Myoung Hee; Lee, Sun Il; Kang, Sanghee; Joung, Sung Yup; Min, Byung Wook

    2015-12-01

    Bone morphogenetic proteins (BMPs) have been involved in metastatic progression and tumorigenesis of many cancer types. However, it remains unclear how BMP-2 contributes to the initiation and development of these cancers. Here, we investigated the role of BMP-2 in colon cancer stem cell (CSC) development from colon cancer cells. We also determined the effects of BMP-2 on CSC development and epithelial-mesenchymal transition (EMT) in human colon cancer cell lines HCT-116 and SW620. We found that BMP-2 enhanced sphere formation of colon cancer cells without serum. Also, BMP-2-induced spheres displayed up-regulation of stemness markers (CD133+ and EpCAM+) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activators p-Smad1/5 and Snail and N-cadherin was increased in the spheres' cells, indicating that BMP-2 signaling might result in CSC self-renewal and EMT. Furthermore, siRNA-mediated knockdown of signal transducer and activator of transcription 3 (STAT3) in HCT-116 cells reversed BMP-2-induced EMT and stem cell formation. Taken together, our results suggest that the BMP-2 induced STAT3-mediated induction of colon cancer cell metastasis requires an EMT and/or changes in CSC markers. PMID:26124007

  10. Wogonin inhibits H2O2-induced vascular permeability through suppressing the phosphorylation of caveolin-1.

    PubMed

    Wang, Fei; Song, Xiuming; Zhou, Mi; Wei, Libin; Dai, Qinsheng; Li, Zhiyu; Lu, Na; Guo, Qinglong

    2013-03-01

    Wogonin, a naturally occurring monoflavonoid extracted from the root of Scutellaria baicalensis Georgi, has been reported for its anti-oxidant activity. However, it is still unclear whether wogonin can inhibit oxidant-induced vascular permeability. In this study, we evaluated the effects of wogonin on H2O2-induced vascular permeability in human umbilical vein endothelial cells (HUVECs). We found that wogonin can suppress the H2O2-stimulated actin remodeling and albumin uptake of HUVECs, as well as transendothelial cell migration of the human breast carcinoma cell MDA-MB-231. The mechanism revealed that wogonin inhibited H2O2-induced phosphorylation of caveolin-1 (cav-1) associating with the suppression of stabilization of VE-cadherin and β-catenin. Moreover, wogonin repressed anisomycin-induced phosphorylation of p38, cav-1 and vascular permeability. These results suggested that wogonin could inhibit H2O2-induced vascular permeability by downregulating the phosphorylation of cav-1, and that it might have a therapeutic potential for the diseases associated with the development of both oxidant and vascular permeability. PMID:23246481

  11. Involvement of intracellular Na^+ accumulation in Hg^{+2} or Cd^{+2} induced cytotoxicity

    NASA Astrophysics Data System (ADS)

    Pourahmad, J.; O'Brien, P. J.

    2003-05-01

    Previously we showed that hepatocyte lysis induced by Hg^{+2} or Cd^{+2} could be partly attributed to mitochondrial toxicity [1, 2]. Similar changes in Na^+ homeostasis induced when Cd^{+2} or Hg^{+2} was incubated with hepatocytes. Cd^{+2} or Hg^{+2} induced cytotoxicity were prevented by Na^+ omission from the media or by the addition of the Na^+/H^+ exchange inhibitor 5-(N, N-dimethyl)-amiloride. Furthermore the omission of CI^- from the media or 2 addition of glycine, a CI^- channel blocker also prevented Cd^{+2} or Hg^{+2} induced hepatocyte toxicity. A hypotonic media also increased Cd^{+2} or Hg^{+2} induced hepatocyte cytotoxicity. This suggests that Cd^{+2} or Hg^{+2} cytotoxicity could be partly attributed to disruption of cell volume regulation mechanisms. The increased osmotic load caused by the uncontrolled accumulation of intracellular Na^+ in Cd^{+2} or Hg^{+2} treated hepatocytes likely resulted from the activation of Na^+/H^+ exchanger and the Na^+/HCO3^- cotransporter by the acidosis and ATP depletion caused by mitochondrial toxicity.

  12. A Receptor Tyrosine Kinase Inhibitor, Dovitinib (TKI-258), Enhances BMP-2-Induced Osteoblast Differentiation In Vitro

    PubMed Central

    Lee, Yura; Bae, Kyoung Jun; Chon, Hae Jung; Kim, Seong Hwan; Kim, Soon Ae; Kim, Jiyeon

    2016-01-01

    Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders. PMID:27025387

  13. Comparison of anterior corpectomy and fusion versus laminoplasty for the treatment of cervical ossification of posterior longitudinal ligament: a meta-analysis.

    PubMed

    Chen, Zihao; Liu, Bin; Dong, Jianwen; Feng, Feng; Chen, Ruiqiang; Xie, Peigen; Zhang, Liangming; Rong, Limin

    2016-06-01

    OBJECTIVE The purpose of this study was to compare the effectiveness and safety of anterior corpectomy and fusion (ACF) with laminoplasty for the treatment of patients diagnosed with cervical ossification of the posterior longitudinal ligament (OPLL). METHODS The authors searched electronic databases for relevant studies that compared the use of ACF with laminoplasty for the treatment of patients with OPLL. Data extraction and quality assessment were conducted, and statistical software was used for data analysis. The random effects model was used if there was heterogeneity between studies; otherwise, the fixed effects model was used. RESULTS A total of 10 nonrandomized controlled studies involving 819 patients were included. Postoperative Japanese Orthopaedic Association (JOA) score (p = 0.02, 95% CI 0.30-2.81) was better in the ACF group than in the laminoplasty group. The recovery rate was superior in the ACF group for patients with an occupying ratio of OPLL of ≥ 60% (p < 0.00001, 95% CI 21.27-34.44) and for patients with kyphotic alignment (p < 0.00001, 95% CI 16.49-27.17). Data analysis also showed that the ACF group was associated with a higher incidence of complications (p = 0.02, 95% CI 1.08-2.59) and reoperations (p = 0.002, 95% CI 1.83-14.79), longer operation time (p = 0.01, 95% CI 17.72 -160.75), and more blood loss (p = 0.0004, 95% CI 42.22-148.45). CONCLUSIONS For patients with an occupying ratio ≥ 60% or with kyphotic cervical alignment, ACF appears to be the preferable treatment method. Nevertheless, laminoplasty seems to be effective and safe enough for patients with an occupying ratio < 60% or with adequate cervical lordosis. However, it must be emphasized that a surgical strategy should be made based on the individual patient. Further randomized controlled trials comparing the use of ACF with laminoplasty for the treatment of OPLL should be performed to make a more convincing conclusion. PMID:27246491

  14. Risk of spinal cord injury in patients with cervical spondylotic myelopathy and ossification of posterior longitudinal ligament: a national cohort study.

    PubMed

    Chen, Li-Fu; Tu, Tsung-Hsi; Chen, Yu-Chun; Wu, Jau-Ching; Chang, Peng-Yuan; Liu, Laura; Huang, Wen-Cheng; Lo, Su-Shun; Cheng, Henrich

    2016-06-01

    OBJECTIVE This study aimed to estimate the risk of spinal cord injury (SCI) in patients with cervical spondylotic myelopathy (CSM) with and without ossification of posterior longitudinal ligament (OPLL). Also, the study compared the incidence rates of SCI in patients who were managed surgically and conservatively. METHODS This retrospective cohort study covering 15 years analyzed the incidence of SCI in patients with CSM. All patients, identified from the National Health Insurance Research Database, were hospitalized with the diagnosis of CSM and followed up during the study period. These patients with CSM were categorized into 4 groups according to whether they had OPLL or not and whether they received surgery or not: 1) surgically managed CSM without OPLL; 2) conservatively managed CSM without OPLL; 3) surgically managed CSM with OPLL; and 4) conservatively managed CSM with OPLL. The incidence rates of subsequent SCI in each group during follow-up were then compared. Kaplan-Meier and Cox regression analyses were performed to compare the risk of SCI between the groups. RESULTS Between January 1, 1999, and December 31, 2013, there were 17,258 patients with CSM who were followed up for 89,003.78 person-years. The overall incidence of SCI in these patients with CSM was 2.022 per 1000 person-years. Patients who had CSM with OPLL and were conservatively managed had the highest incidence of SCI, at 4.11 per 1000 person-years. Patients who had CSM with OPLL and were surgically managed had a lower incidence of SCI, at 3.69 per 1000 person-years. Patients who had CSM without OPLL and were conservatively managed had an even lower incidence of SCI, at 2.41 per 1000 person-years. Patients who had CSM without OPLL and were surgically managed had the lowest incidence of SCI, at 1.31 per 1000 person-years. The Cox regression model demonstrated that SCIs are significantly more likely to happen in male patients and in those with OPLL (HR 2.00 and 2.24, p < 0.001 and p = 0

  15. IGF-I Signaling in Osterix-Expressing Cells Regulates Secondary Ossification Center Formation, Growth Plate Maturation, and Metaphyseal Formation During Postnatal Bone Development.

    PubMed

    Wang, Yongmei; Menendez, Alicia; Fong, Chak; ElAlieh, Hashem Z; Kubota, Takuo; Long, Roger; Bikle, Daniel D

    2015-12-01

    To investigate the role of IGF-I signaling in osterix (OSX)-expressing cells in the skeleton, we generated IGF-I receptor (IGF-IR) knockout mice ((OSX)IGF-IRKO) (floxed-IGF-IR mice × OSX promoter-driven GFP-labeled cre-recombinase [(OSX)GFPcre]), and monitored postnatal bone development. At day 2 after birth (P2), (OSX)GFP-cre was highly expressed in the osteoblasts in the bone surface of the metaphysis and in the prehypertrophic chondrocytes (PHCs) and inner layer of perichondral cells (IPCs). From P7, (OSX)GFP-cre was highly expressed in PHCs, IPCs, cartilage canals (CCs), and osteoblasts (OBs) in the epiphyseal secondary ossification center (SOC), but was only slightly expressed in the OBs in the metaphysis. Compared with the control mice, the IPC proliferation was decreased in the (OSX)IGF-IRKOs. In these mice, fewer IPCs invaded into the cartilage, resulting in delayed formation of the CC and SOC. Immunohistochemistry indicated a reduction of vessel number and lower expression of VEGF and ephrin B2 in the IPCs and SOC of (OSX)IGF-IRKOs. Quantitative real-time PCR revealed that the mRNA levels of the matrix degradation markers, MMP-9, 13 and 14, were decreased in the (OSX)IGF-IRKOs compared with the controls. The (OSX)IGF-IRKO also showed irregular morphology of the growth plate and less trabecular bone in the tibia and femur from P7 to 7 weeks, accompanied by decreased chondrocyte proliferation, altered chondrocyte differentiation, and decreased osteoblast differentiation. Our data indicate that during postnatal bone development, IGF-I signaling in OSX-expressing IPCs promotes IPC proliferation and cartilage matrix degradation and increases ephrin B2 production to stimulate vascular endothelial growth factor (VEGF) expression and vascularization. These processes are required for normal CC formation in the establishment of the SOC. Moreover, IGF-I signaling in the OSX-expressing PHC is required for growth plate maturation and osteoblast differentiation in

  16. FOXL2-induced follistatin attenuates activin A-stimulated cell proliferation in human granulosa cell tumors

    SciTech Connect

    Cheng, Jung-Chien; Chang, Hsun-Ming; Qiu, Xin; Fang, Lanlan; Leung, Peter C.K.

    2014-01-10

    Highlights: •Activin A stimulates cell proliferation in KGN human granulosa cell tumor-derived cell line. •Cyclin D2 mediates activin A-induced KGN cell proliferation. •FOXL2 induces follistatin expression in KGN cells. •FOXL2-induced follistatin attenuates activin A-stimulated KGN cell proliferation. -- Abstract: Human granulosa cell tumors (GCTs) are rare, and their etiology remains largely unknown. Recently, the FOXL2 402C > G (C134W) mutation was found to be specifically expressed in human adult-type GCTs; however, its function in the development of human GCTs is not fully understood. Activins are members of the transforming growth factor-beta superfamily, which has been shown to stimulate normal granulosa cell proliferation; however, little is known regarding the function of activins in human GCTs. In this study, we examined the effect of activin A on cell proliferation in the human GCT-derived cell line KGN. We show that activin A treatment stimulates KGN cell proliferation. Treatment with the activin type I receptor inhibitor SB431542 blocks activin A-stimulated cell proliferation. In addition, our results show that cyclin D2 is induced by treatment with activin A and is involved in activin A-stimulated cell proliferation. Moreover, the activation of Smad signaling is required for activin A-induced cyclin D2 expression. Finally, we show that the overexpression of the wild-type FOXL2 but not the C134W mutant FOXL2 induced follistatin production. Treatment with exogenous follistatin blocks activin A-stimulated cell proliferation, and the overexpression of wild-type FOXL2 attenuates activin A-stimulated cell proliferation. These results suggest that FOXL2 may act as a tumor suppressor in human adult-type GCTs by inducing follistatin expression, which subsequently inhibits activin-stimulated cell proliferation.

  17. Prostaglandin D2 induces the production of human beta-defensin-3 in human keratinocytes.

    PubMed

    Kanda, Naoko; Ishikawa, Takeko; Watanabe, Shinichi

    2010-04-01

    The antimicrobial peptide human beta-defensin-3 (hBD-3) is produced by epidermal keratinocytes and protects the skin from infections. This peptide induces the release of a lipid mediator, prostaglandin D(2) from dermal mast cells. Prostaglandin D(2) binds to cell-surface G protein-coupled receptors, D prostanoid receptor, and chemoattractant receptor-homologous molecule expressed on T helper cell type 2 (CRTH2). Both receptors are detected on epidermal keratinocytes. It is reported that prostaglandin D(2) is involved in cutaneous allergy, however, its role in antimicrobial defense is unknown. We examined the in vitro effects of prostaglandin D(2) on hBD-3 production in normal human keratinocytes. Prostaglandin D(2) enhanced hBD-3 secretion and mRNA expression in human keratinocytes. Prostaglandin D(2)-induced hBD-3 production was suppressed by the CRTH2 antagonist ramatroban and by antisense oligonucleotides against c-Jun and c-Fos, components of a transcription factor, activator protein-1 (AP-1). Prostaglandin D(2) enhanced the transcriptional activity and DNA binding of AP-1, expression, phosphorylation, and DNA binding of c-Fos proteins in keratinocytes. Prostaglandin D(2)-induced hBD-3 production, AP-1 activity, and c-Fos expression and phosphorylation were suppressed by U0126, PP2, and pertussis toxin, which are inhibitors of mitogen-activated protein kinase kinase (MEK), src, and G(i) proteins, respectively. The phosphorylation of extracellular signal-regulated kinase (ERK), downstream kinase of MEK, was induced by prostaglandin D(2), and suppressed by ramatroban, pertussis toxin, PP2, and U0126. These results suggest that prostaglandin D(2) induces hBD-3 production in human keratinocytes by activating AP-1 through the expression and phosphorylation of c-Fos via the CRTH2/G(i)/src/MEK/ERK pathway. Prostaglandin D(2) may promote cutaneous antimicrobial activity via hBD-3. PMID:19925780

  18. PGE{sub 2}-induced colon cancer growth is mediated by mTORC1

    SciTech Connect

    Dufour, Marc Faes, Seraina Dormond-Meuwly, Anne Demartines, Nicolas Dormond, Olivier

    2014-09-05

    Highlights: • PGE{sub 2} activates mTORC1 in colon cancer cells. • Inhibition of mTORC1 blocks PGE{sub 2} induced colon cancer cell growth. • mTORC1 is a signaling intermediary in PGE{sub 2} induced colon cancer cell responses. - Abstract: The inflammatory prostaglandin E{sub 2} (PGE{sub 2}) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE{sub 2} directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE{sub 2}-induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE{sub 2} increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE{sub 2} EP{sub 4} receptor was responsible for transducing the signal to mTORC1. Moreover, PGE{sub 2} increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE{sub 2}-induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE{sub 2} increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE{sub 2} mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth.

  19. Effect of Intracerebroventricularly Administered Octopamines and Synephrines on Angiotensin 2-Induced Water Intake in Rats

    NASA Technical Reports Server (NTRS)

    Fregly, Melvin J.; Rowland, Neil E.; Williams, Clyde M.; Greenleaf, John E.

    1984-01-01

    Recent studies from this laboratory showed that l-m-synephrine (phenylephrine), a metabolite of l-m-octapamine, inhibited the drinking response of rats to peripherally administered angiotensin 2. The objective of this investigation was to determine whether the isomers ofboth octapamine and synephrine could inhibit angiotensin 2-induced dipsogenesis in the rat. Of the isomers tested, only d,l-m-octopamine and l-m-synephrine blocked the dipsogenic response to administration of angiotensin 2 (200 micrograms/kg, SC). The antidipsogenic effect of both d,l-m-octopamine and l-m-synephrine could be blocked by concurrent administration of yohimbine (300 micrograms/kg, IP), an alpha(sub 2)-adrenoceptor antagonist. The results indicate that m-octopamine and m-synephrine exert their antidipsogenic effect via alpha(sub 2)-adrenoceptors. These studies add to a growing body of data suggesting that activation of alpha(sub 2)-adrenoceptors inhibits, while blockade of these receptors enhances, angiotensin 2-induced drinking.

  20. Latexin is involved in bone morphogenetic protein-2-induced chondrocyte differentiation

    SciTech Connect

    Kadouchi, Ichiro; Sakamoto, Kei; Tangjiao, Liu; Murakami, Takashi; Kobayashi, Eiji; Hoshino, Yuichi; Yamaguchi, Akira

    2009-01-16

    Latexin is the only known carboxypeptidase A inhibitor in mammals. We previously demonstrated that BMP-2 significantly induced latexin expression in Runx2-deficient mesenchymal cells (RD-C6 cells), during chondrocyte and osteoblast differentiation. In this study, we investigated latexin expression in the skeleton and its role in chondrocyte differentiation. Immunohistochemical studies revealed that proliferating and prehypertrophic chondrocytes expressed latexin during skeletogenesis and bone fracture repair. In the early phase of bone fracture, latexin mRNA expression was dramatically upregulated. BMP-2 upregulated the expression of the mRNAs of latexin, Col2a1, and the gene encoding aggrecan (Agc1) in a micromass culture of C3H10T1/2 cells. Overexpression of latexin additively stimulated the BMP-2-induced expression of the mRNAs of Col2a, Agc1, and Col10a1. BMP-2 treatment upregulated Sox9 expression, and Sox9 stimulated the promoter activity of latexin. These results indicate that latexin is involved in BMP-2-induced chondrocyte differentiation and plays an important role in skeletogenesis and skeletal regeneration.

  1. Low-Dose IL-2 Induces Regulatory T Cell-Mediated Control of Experimental Food Allergy.

    PubMed

    Bonnet, Benjamin; Vigneron, James; Levacher, Béatrice; Vazquez, Thomas; Pitoiset, Fabien; Brimaud, Faustine; Churlaud, Guillaume; Klatzmann, David; Bellier, Bertrand

    2016-07-01

    Regulatory T cells (Tregs) are pivotal for maintenance of immune self-tolerance and also regulate immune responses to exogenous Ags, including allergens. Both decreased Treg number and function have been reported in allergic patients, offering new therapeutic perspectives. We previously demonstrated that Tregs can be selectively expanded and activated by low doses of IL-2 (ld-IL-2) inducing immunoregulation without immunosuppression and established its protective effect in autoimmune diseases. In this study, we evaluated the ability of ld-IL-2 to control allergy in an experimental model of food allergy. Ld-IL-2 induced Treg expansion and activation that elicited protection against clinical manifestations of food allergy in two mouse models with OVA and peanut. This clinical effect was lost in Treg-depleted mice, demonstrating the major contribution of Tregs in ld-IL-2 efficacy. Mechanistic studies further indicated that protection from allergy could be explained by a Treg-dependent local modification of the Th1/Th2 balance and an inhibition of mast cell recruitment and activation. Preventive and therapeutic effects of ld-IL-2 were observed over a 7-mo-period, highlighting its long-term efficacy. This study demonstrated that ld-IL-2 is efficient to prevent and to treat allergic immune responses, and thus represents a promising therapeutic strategy for managing allergic diseases. PMID:27259854

  2. Polydatin Attenuates H2O2-Induced Oxidative Stress via PKC Pathway

    PubMed Central

    2016-01-01

    Oxidative stress plays an important role in the pathogenesis of endothelial dysfunction, which is found to precede the development of diverse cardiovascular diseases (CVDs). The aim of this study was to observe the protective effects of PD against H2O2-induced oxidative stress injury (OSI) in human umbilical vein endothelial cells (HUVECs) and the possible mechanism of PD in OSI treatment. HUVECs were subjected to H2O2 in the absence or presence of PD. It turned out that PD improved cell viability and adhesive and migratory abilities, inhibited the release of lactate dehydrogenase (LDH) and reactive oxygen species (ROS), and elevated the content of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). TUNEL, fluorometric assays, and Western blotting showed that OSI upregulated the apoptosis ratio, the activity of caspase-3 and the level of proapoptotic protein Bax and decreased the level of antiapoptotic protein Bcl-2. However, PD treatment partially reversed these damage effects and Protein Kinase C (PKC) activation by thymeleatoxin (THX) in turn eliminated the antiapoptotic effect of PD. Furthermore, PD attenuated the H2O2-induced phosphorylation of PKCs α and δ and increased the phosphorylation of PKC ε. Our results indicated that PD might exert protective effects against OSI through various interactions with PKC pathway. PMID:26881030

  3. Oxidative stress underlies the mechanism for Ca(2+)-induced permeability transition of mitochondria.

    PubMed

    Kanno, Tomoko; Sato, Eisuke E; Muranaka, Shikibu; Fujita, Hirofumi; Fujiwara, Takuzo; Utsumi, Toshihiko; Inoue, Masayasu; Utsumi, Kozo

    2004-01-01

    Recent studies demonstrated that the generation of intracellular reactive oxygen species (ROS) was enhanced prior to the onset of mitochondrial membrane permeability transition (MPT), a critical step for the induction of DNA fragmentation and apoptosis. Although Ca2+ induces typical MPT that involves depolarization and swelling of mitochondria and finally releases cytochrome c into cytosol, the mechanism by which ROS induce MPT remains unclear. In the presence of inorganic phosphate, Ca2+ increased the oxygen consumption and ROS production by isolated mitochondria as determined by a chemiluminescence (CHL) method using L-012. Ca2+ increased the generation of H2O2 by some mechanism that was inhibited by cyclosporin A but not by superoxide dismutase (SOD) and trifluoperazine. Ca2+ decreased the content of free thiols in adenine nucleotide translocase (ANT) in mitochondrial membranes with concomitant increase in ROS generation. The presence of cyclosporin A, trifluoperazine, or SOD inhibited the Ca(2+)-induced increase of L-012 CHL and decrease in the free thiols of ANT. These results indicate that Ca2+ increases the generation of ROS which oxidize the free thiol groups in mitochondrial ANT, thereby inducing MPT to release cytochrome c. PMID:15061651

  4. Enforced expression of E47 has differential effects on Lmo2-induced T-cell leukemias.

    PubMed

    Goodings, Charnise; Tripathi, Rati; Cleveland, Susan M; Elliott, Natalina; Guo, Yan; Shyr, Yu; Davé, Utpal P

    2015-01-01

    LIM domain only-2 (LMO2) overexpression in T cells induces leukemia but the molecular mechanism remains to be elucidated. In hematopoietic stem and progenitor cells, Lmo2 is part of a protein complex comprised of class II basic helix loop helix proteins, Tal1and Lyl1. The latter transcription factors heterodimerize with E2A proteins like E47 and Heb to bind E boxes. LMO2 and TAL1 or LYL1 cooperate to induce T-ALL in mouse models, and are concordantly expressed in human T-ALL. Furthermore, LMO2 cooperates with the loss of E2A suggesting that LMO2 functions by creating a deficiency of E2A. In this study, we tested this hypothesis in Lmo2-induced T-ALL cell lines. We transduced these lines with an E47/estrogen receptor fusion construct that could be forced to homodimerize with 4-hydroxytamoxifen. We discovered that forced homodimerization induced growth arrest in 2 of the 4 lines tested. The lines sensitive to E47 homodimerization accumulated in G1 and had reduced S phase entry. We analyzed the transcriptome of a resistant and a sensitive line to discern the E47 targets responsible for the cellular effects. Our results suggest that E47 has diverse effects in T-ALL but that functional deficiency of E47 is not a universal feature of Lmo2-induced T-ALL. PMID:25499232

  5. Effect of sophoridine on Ca(2+) induced Ca(2+) release during heart failure.

    PubMed

    Hu, S-T; Shen, Y-F; Gong, J-M; Yang, Y-J

    2016-03-14

    Sophoridine is a type of alkaloid extract derived from the Chinese herb Sophora flavescens Ait (kushen) and possess a variety of pharmacological effects including anti-inflammation, anti-anaphylaxis, anti-cancer, anti-arrhythmic and so on. However, the effect of sophoridine on heart failure has not been known yet. In this study, the effect of sophoridine on heart failure was investigated using Sprague-Dawley (SD) rat model of chronic heart failure. Morphological results showed that in medium and high dose group, myofilaments were arranged orderly and closely, intermyofibrillar lysis disappeared and mitochondria contained tightly packed cristae compared with heart failure group. We investigated the Ca(2+) induced Ca(2+) transients and assessed the expression of ryanodine receptor (RyR2) and L-type Ca(2+) channel (dihydropyridine receptor, DHPR). We found that the cytosolic Ca(2+) transients were markedly increased in amplitude in medium (deltaF/F(0)=43.33+/-1.92) and high dose groups (deltaF/F(0)=47.21+/-1.25) compared with heart failure group (deltaF/F(0)=16.7+/-1.29, P<0.01), Moreover, we demonstrated that the expression of cardiac DHPR was significantly increased in medium- and high dose-group compared with heart failure rats. Our results suggest that sophoridine could improve heart failure by ameliorating cardiac Ca(2+) induced Ca(2+) transients, and that this amelioration is associated with upregulation of DHPR. PMID:26596316

  6. PbCl2-induced hyperpolarization of rat thymocytes: involvement of charybdotoxin-sensitive K+ channels.

    PubMed

    Nishizaki, Yasutaka; Oyama, Yasuo; Sakai, Yoshiro; Hirama, Seigo; Tomita, Kazuyoshi; Nakao, Hiromi; Umebayashi, Chisato; Ishida, Shiro; Okano, Yoshiro; Carpenter, David O

    2003-10-01

    The effect of PbCl2 on membrane potential and intracellular divalent metal cation concentrations of rat thymocytes was examined by flow cytometry. PbCl2 at concentrations of 0.3 microM or higher (up to 10 microM) produced persistent, dose-dependent hyperpolarization (decrease in the intensity of di-BA-C4 fluorescence). Removal of external Ca2+ did not significantly affect the PbCl2-induced hyperpolarization. Charybdotoxin, a specific antagonist of Ca(2+)-dependent K+ conductance, greatly attenuated the PbCl2-induced hyperpolarization. PbCl2 increased the intensity of fluo-3 fluorescence under both normal Ca2+ and nominally Ca(2+)-free conditions. These results suggest that Pb2+ enters thymocytes, causing an increase in fluo-3 fluorescence, and activates Ca(2+)-dependent K+ channels, resulting in hyperpolarization. The persistent activation of K+ channels by Pb2+, leading to persistent hyperpolarization, may be one mechanism whereby Pb2+ alters immune function, as membrane potential changes influence physiological functions of lymphocytes. PMID:14502585

  7. Mitochondrial Ca2+-induced Ca2+ Release Mediated by the Ca2+ Uniporter

    PubMed Central

    Montero, Mayte; Alonso, Maria Teresa; Albillos, Almudena; García-Sancho, Javier; Alvarez, Javier

    2001-01-01

    We have reported that a population of chromaffin cell mitochondria takes up large amounts of Ca2+ during cell stimulation. The present study focuses on the pathways for mitochondrial Ca2+ efflux. Treatment with protonophores before cell stimulation abolished mitochondrial Ca2+ uptake and increased the cytosolic [Ca2+] ([Ca2+]c) peak induced by the stimulus. Instead, when protonophores were added after cell stimulation, they did not modify [Ca2+]c kinetics and inhibited Ca2+ release from Ca2+-loaded mitochondria. This effect was due to inhibition of mitochondrial Na+/Ca2+ exchange, because blocking this system with CGP37157 produced no further effect. Increasing extramitochondrial [Ca2+]c triggered fast Ca2+ release from these depolarized Ca2+-loaded mitochondria, both in intact or permeabilized cells. These effects of protonophores were mimicked by valinomycin, but not by nigericin. The observed mitochondrial Ca2+-induced Ca2+ release response was insensitive to cyclosporin A and CGP37157 but fully blocked by ruthenium red, suggesting that it may be mediated by reversal of the Ca2+ uniporter. This novel kind of mitochondrial Ca2+-induced Ca2+ release might contribute to Ca2+ clearance from mitochondria that become depolarized during Ca2+ overload. PMID:11160823

  8. A Role for Presynaptic alpha(sub 2)-Adrenoceptors in Angiotensin 2-Induced Drinking in Rats

    NASA Technical Reports Server (NTRS)

    Fregly, Melvin J.; Rowland, Neil E.; Greenleaf, John E.

    1984-01-01

    Studies from this laboratory have shown that either central or peripheral administration of clonidine, the alpha(sub 2)-adrenoceptor agonist, can attenuate a variety of dipsogenic stimuli in rats. Further, yohimbine and tolazoline, alpha(sub 2)-adrenoceptor antagonists, augment the drinking response to both peripherally administered isoproterenol and angiotensin 2. Studies reported here establish a dose-inhibition relationship between the dose of clonidine administered (2 to 32 micrograms/kg) intracerebroventricularly (IVT) and inhibition of the drinking response to peripherally administered angiotensin 2 (200 micrograms/kg, SC). DI(sub 50) was approximately 4 micrograms/kg. Yohimbine (300 micrograms/kg, SC) reversed the antidipsogenic effect of centrally administered clonidine (32 micrograms/kg, IVT) on angiotensin 2-induced (200 micrograms/kg, SC) water intake. Phenylephrine, an alpha(sub 2)-adrenoceptor agonist, administered IVT (40 and 80 micrograms/kg) also inhibited angiotensin 2-induced drinking in a dose-related fashion. The antidipsogenic effect of phenylephfine (80 micrograms/kg) was blocked by administration of yohimbine (100 micrograms/kg, SC). Thus, this effect of phenylephrine most likely occurs by way of alpha(sub 2)- adrenoceptors. These results support a role for the pre-synaptic alpha(sub 2)-adrenoceptor in the mediation of drinking in rats. Activation of alpha(sub 2)-adrenoceptors is accompanied by reduced water intake while inhibition of these receptors enhances water intake.

  9. Harem Education and Heterotopic Imagination

    ERIC Educational Resources Information Center

    Aksit, Elif Ekin

    2011-01-01

    Education can cease to be a showcase for political projects and start serving women's lives only when the agency of women in their own education is acknowledged. In this paper I have addressed issues concerning harem education to emphasise that possible solutions to issues of girls' education require an awareness concerning the history of girls'…

  10. Murine heterotopic heart transplant technique.

    PubMed

    Plenter, Robert J; Grazia, Todd J

    2014-01-01

    It is now over forty years since this technique was first reported by Corry, Wynn and Russell. Although it took some years for other labs to become proficient in and utilize this technique, it is now widely used by many laboratories around the world. A significant refinement to the original technique was developed and reported in 2001 by Niimi. Described here are the techniques that have evolved over more than a decade in the hands of three surgeons (Plenter, Grazia, Pietra) in our center. These techniques are now being passed on to a younger generation of surgeons and researchers. Based largely on the Niimi experience, the procedures used have evolved in the fine details - details which we will endeavor to relate here in such a way that others may be able to use this very useful model. Like Niimi, we have found that a video aid to learning is a priceless resource for the beginner. PMID:25046118

  11. Starch Biosynthesis in Guard Cells But Not in Mesophyll Cells Is Involved in CO2-Induced Stomatal Closing.

    PubMed

    Azoulay-Shemer, Tamar; Bagheri, Andisheh; Wang, Cun; Palomares, Axxell; Stephan, Aaron B; Kunz, Hans-Henning; Schroeder, Julian I

    2016-06-01

    Starch metabolism is involved in stomatal movement regulation. However, it remains unknown whether starch-deficient mutants affect CO2-induced stomatal closing and whether starch biosynthesis in guard cells and/or mesophyll cells is rate limiting for high CO2-induced stomatal closing. Stomatal responses to [CO2] shifts and CO2 assimilation rates were compared in Arabidopsis (Arabidopsis thaliana) mutants that were either starch deficient in all plant tissues (ADP-Glc-pyrophosphorylase [ADGase]) or retain starch accumulation in guard cells but are starch deficient in mesophyll cells (plastidial phosphoglucose isomerase [pPGI]). ADGase mutants exhibited impaired CO2-induced stomatal closure, but pPGI mutants did not, showing that starch biosynthesis in guard cells but not mesophyll functions in CO2-induced stomatal closing. Nevertheless, starch-deficient ADGase mutant alleles exhibited partial CO2 responses, pointing toward a starch biosynthesis-independent component of the response that is likely mediated by anion channels. Furthermore, whole-leaf CO2 assimilation rates of both ADGase and pPGI mutants were lower upon shifts to high [CO2], but only ADGase mutants caused impairments in CO2-induced stomatal closing. These genetic analyses determine the roles of starch biosynthesis for high CO2-induced stomatal closing. PMID:27208296

  12. Starch Biosynthesis in Guard Cells But Not in Mesophyll Cells Is Involved in CO2-Induced Stomatal Closing1[OPEN

    PubMed Central

    Stephan, Aaron B.; Schroeder, Julian I.

    2016-01-01

    Starch metabolism is involved in stomatal movement regulation. However, it remains unknown whether starch-deficient mutants affect CO2-induced stomatal closing and whether starch biosynthesis in guard cells and/or mesophyll cells is rate limiting for high CO2-induced stomatal closing. Stomatal responses to [CO2] shifts and CO2 assimilation rates were compared in Arabidopsis (Arabidopsis thaliana) mutants that were either starch deficient in all plant tissues (ADP-Glc-pyrophosphorylase [ADGase]) or retain starch accumulation in guard cells but are starch deficient in mesophyll cells (plastidial phosphoglucose isomerase [pPGI]). ADGase mutants exhibited impaired CO2-induced stomatal closure, but pPGI mutants did not, showing that starch biosynthesis in guard cells but not mesophyll functions in CO2-induced stomatal closing. Nevertheless, starch-deficient ADGase mutant alleles exhibited partial CO2 responses, pointing toward a starch biosynthesis-independent component of the response that is likely mediated by anion channels. Furthermore, whole-leaf CO2 assimilation rates of both ADGase and pPGI mutants were lower upon shifts to high [CO2], but only ADGase mutants caused impairments in CO2-induced stomatal closing. These genetic analyses determine the roles of starch biosynthesis for high CO2-induced stomatal closing. PMID:27208296

  13. H2O2-Induced Oxidative Stress Affects SO4= Transport in Human Erythrocytes

    PubMed Central

    Morabito, Rossana; Romano, Orazio; La Spada, Giuseppa; Marino, Angela

    2016-01-01

    The aim of the present investigation was to verify the effect of H2O2-induced oxidative stress on SO4= uptake through Band 3 protein, responsible for Cl-/HCO3- as well as for cell membrane deformability, due to its cross link with cytoskeletal proteins. The role of cytoplasmic proteins binding to Band 3 protein has been also considered by assaying H2O2 effects on hemoglobin-free resealed ghosts of erythrocytes. Oxidative conditions were induced by 30 min exposure of human erythrocytes to different H2O2 concentrations (10 to 300 μM), with or without GSH (glutathione, 2 mM) or curcumin (10 μM), compounds with proved antioxidant properties. Since SO4= influx through Band 3 protein is slower and better controllable than Cl- or HCO3- exchange, the rate constant for SO4= uptake was measured to prove anion transport efficiency, while MDA (malondialdehyde) levels and –SH groups were estimated to quantify the effect of oxidative stress. H2O2 induced a significant decrease in rate constant for SO4= uptake at both 100 and 300 μM H2O2. This reduction, observed in erythrocytes but not in resealed ghosts and associated to increase in neither MDA levels nor in –SH groups, was impaired by both curcumin and GSH, whereas only curcumin effectively restored H2O2-induced changes in erythrocytes shape. Our results show that: i) 30 min exposure to 300 μM H2O2 reduced SO4= uptake in human erythrocytes; ii) oxidative damage was revealed by the reduction in rate constant for SO4= uptake, but not by MDA or –SH groups levels; iii) the damage was produced via cytoplasmic components which cross link with Band 3 protein; iv) the natural antioxidant curcumin may be useful in protecting erythrocytes from oxidative injury; v) SO4= uptake through Band 3 protein may be reasonably suggested as a tool to monitor erythrocytes function under oxidative conditions possibly deriving from alcohol consumption, use of drugs, radiographic contrast media administration, hyperglicemia or

  14. H2O2-Induced Oxidative Stress Affects SO4= Transport in Human Erythrocytes.

    PubMed

    Morabito, Rossana; Romano, Orazio; La Spada, Giuseppa; Marino, Angela

    2016-01-01

    The aim of the present investigation was to verify the effect of H2O2-induced oxidative stress on SO4= uptake through Band 3 protein, responsible for Cl-/HCO3- as well as for cell membrane deformability, due to its cross link with cytoskeletal proteins. The role of cytoplasmic proteins binding to Band 3 protein has been also considered by assaying H2O2 effects on hemoglobin-free resealed ghosts of erythrocytes. Oxidative conditions were induced by 30 min exposure of human erythrocytes to different H2O2 concentrations (10 to 300 μM), with or without GSH (glutathione, 2 mM) or curcumin (10 μM), compounds with proved antioxidant properties. Since SO4= influx through Band 3 protein is slower and better controllable than Cl- or HCO3- exchange, the rate constant for SO4= uptake was measured to prove anion transport efficiency, while MDA (malondialdehyde) levels and -SH groups were estimated to quantify the effect of oxidative stress. H2O2 induced a significant decrease in rate constant for SO4= uptake at both 100 and 300 μM H2O2. This reduction, observed in erythrocytes but not in resealed ghosts and associated to increase in neither MDA levels nor in -SH groups, was impaired by both curcumin and GSH, whereas only curcumin effectively restored H2O2-induced changes in erythrocytes shape. Our results show that: i) 30 min exposure to 300 μM H2O2 reduced SO4= uptake in human erythrocytes; ii) oxidative damage was revealed by the reduction in rate constant for SO4= uptake, but not by MDA or -SH groups levels; iii) the damage was produced via cytoplasmic components which cross link with Band 3 protein; iv) the natural antioxidant curcumin may be useful in protecting erythrocytes from oxidative injury; v) SO4= uptake through Band 3 protein may be reasonably suggested as a tool to monitor erythrocytes function under oxidative conditions possibly deriving from alcohol consumption, use of drugs, radiographic contrast media administration, hyperglicemia or neurodegenerative

  15. Comparison of anterior decompression and fusion versus laminoplasty in the treatment of multilevel cervical ossification of the posterior longitudinal ligament: a systematic review and meta-analysis

    PubMed Central

    Liu, Weijun; Hu, Ling; Chou, Po-Hsin; Liu, Ming; Kan, Wusheng; Wang, Junwen

    2016-01-01

    Purpose A meta-analysis was conducted to evaluate the clinical outcomes, complications, reoperation rates, and late neurological deterioration between anterior decompression and fusion (ADF) and laminoplasty (LAMP) in the treatment of multilevel cervical ossification of the posterior longitudinal ligament (OPLL). Methods All related studies published up to August 2015 were acquired by searching PubMed and EMBASE. Exclusion criteria were case reports, revision surgeries, combined anterior and posterior surgeries, the other posterior approaches including laminectomy or laminectomy and instrumented fusion, non-English studies, and studies with quality assessment scores of <7. The main end points including Japanese Orthopedic Association (JOA) score, recovery rate of JOA, cervical lordosis, complication rate, reoperation rate, and late neurological deterioration were analyzed. All available data was analyzed using RevMan 5.2.0 and Stata 12.0. Results A total of seven studies were included in the meta-analysis. The mean surgical level of ADF was 3.1, and the mean preoperative occupation ratios of ADF and LAMP group were 55.9% and 51.9%, respectively. No statistical difference was observed with regard to preoperative occupation ratio and preoperative JOA score. Although LAMP group had a higher preoperative cervical lordosis than ADF group (P<0.05, weighted mean difference [WMD] =−5.73, 95% confidence interval [CI] =−9.67–−1.80), significantly decreased cervical lordosis was observed in LAMP group after operation. ADF group had higher postoperative JOA score (P<0.05, WMD =2.18, 95% CI =0.98–3.38) and neurological recovery rate (P<0.05, WMD =27.22, 95% CI =15.20–39.23). Furthermore, ADF group had a lower late neurological deterioration rate than the LAMP group (P<0.05, risk difference =0.16, 95% CI =0.04–0.73). The complication rates of both groups had no statistical difference. However, LAMP group had a significantly lower reoperation rate than ADF group

  16. Do intramedullary spinal cord changes in signal intensity on MRI affect surgical opportunity and approach for cervical myelopathy due to ossification of the posterior longitudinal ligament?

    PubMed

    Sun, Qizhi; Hu, Hongwei; Zhang, Ying; Li, Yang; Chen, Linwei; Chen, Huajiang; Yuan, Wen

    2011-09-01

    Some controversy still exists over the optimal treatment time and the surgical approach for cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL). The aim of the current study was first to analyze the effect of intramedullary spinal cord changes in signal intensity (hyperintensity on T2-weighted imaging and hypointensity on T1-weighted imaging) on magnetic resonance imaging (MRI) on surgical opportunity and approach for cervical myelopathy due to OPLL. This was a prospective randomized controlled study. Fifty-six patients with cervical myelopathy due to OPLL were enrolled and assigned to either group A (receiving anterior decompression and fusion, n = 27) or group P (receiving posterior laminectomy, n = 29). All the patients were followed up for an average 20.3 months (12-34 months). The clinical outcomes were assessed by the average operative time, blood loss, Japanese Orthopedic Association (JOA) score, improvement rate (IR) and complication. To determine the relevant statistics, we made two factorial designs and regrouped the data of all patients to group H (with hyperintensity on MRI, n = 31), group L (with hypointensity on MRI, n = 19) and group N (no signal on MRI, n = 25), and then to further six subgroups as well: AH (with hyperintensity on MRI from group A, n = 15), PH (with hyperintensity on MRI from group P, n = 16), AL (with hypointensity on MRI from group A, n = 10), PL (with hypointensity on MRI from group P, n = 9), AN (no signal intensity on MRI from group A, n = 12) and PN (no signal intensity on MRI from group P, n = 13). Both hyperintensity on T2-weighted imaging and hypointensity on T1-weighted imaging had a close relationship with the JOA score and IR. The pre- and postoperative JOA score and postoperative IR of either group H or group L was significantly lower than that of group N (P < 0.05), regardless of whether the patients had received anterior or posterior surgery. On the other hand, both the JOA score and

  17. Potential mechanisms underlying the Runx2 induced osteogenesis of bone marrow mesenchymal stem cells

    PubMed Central

    Xu, Jiahai; Li, Zhanghua; Hou, Yudong; Fang, Weijun

    2015-01-01

    Bone marrow derived mesenchymal stem cells (BM-MSCs) belong a type of pluripotent stem cells and can be induced to differentiate into osteoblasts (OB). Runt-related transcription factor 2 (Runx2) is an osteogenesis specific transcription factor and plays an important role in osteogenesis of BM-MSCs. It can promote the expression of osteogenesis related genes, regulate cell cycle progression, improve bone microenvironment and affect functions of chondrocytes and osteoclasts, which have involvement of a large amount of signal molecules including TGF-β, BMP, Notch, Wnt, Hedgehog, FGF and microRNA. In this paper, we summarize the mechanisms underlying the Runx2 induced osteogenesis of BM-MSCs. PMID:26885254

  18. [CdCl2-induced morphogenetic variation of Triticum aestivum cultivars].

    PubMed

    Chunetova, Zh Zh; Omirbekova, N Zh; Shulembaeva, K K

    2008-11-01

    The effect cadmium chloride on released local cultivars of soft spring wheat (Triticum aestivum) has been studied under laboratory and field conditions in order to widen the variation spectrum of this plant. It has been found that treatment of grains with a 0.01% aqueous solution of CdCl2 induces the appearance of tall, strong plants with productive bushiness in the M1 generation that are characterized by various morphological changes: elongated ears, scales, and grains; increased number of grains per ear and mass of 1000 grains; anthocyan pigmentation of the stem and leaf axil; etc. Study of meiosis showed chromosome aggregation, displacement of the mitotic spindle of the metaphase plate, and empty (sterile) cells in anaphases (AI and AII). The altered characters of M1 plants are preserved in the M2-M4 generations. PMID:19137733

  19. Cdc42 and PI(4,5)P2-induced actin assembly in Xenopus egg extracts.

    PubMed

    Lebensohn, Andres M; Ma, Le; Ho, Hsin-Yi Henry; Kirschner, Marc W

    2006-01-01

    Xenopus egg cytoplasmic extracts have been used to study a variety of complex cellular processes. Given their amenability to biochemical manipulation and physiological balance of regulatory proteins, these extracts are an ideal system to dissect signal transduction pathways leading to actin assembly. We have developed methods to study Cdc42 and PI(4,5)P2-induced actin assembly in Xenopus egg extracts. In this chapter, we describe detailed procedures to prepare Xenopus egg extracts, Cdc42, and PI(4,5)P2 for use in actin assembly experiments. We also describe a fluorometric pyrene actin assay for quantitative kinetic analysis of actin polymerization and a microscopic rhodamine actin assay for quick measurement of actin rearrangements in extracts. Finally we provide a protocol for immunodepletion of proteins and discuss the use of immunodepletion and rescue experiments for functional analysis of components in the extracts. PMID:16472657

  20. CO2 induced climatic change and spectral variations in the outgoing terrestrial infrared radiation

    NASA Technical Reports Server (NTRS)

    Charlock, T. P.

    1984-01-01

    The published temperature changes produced in general circulation model simulations of CO2 induced climate modification are used to compute the top of the atmosphere, clear sky outgoing infrared radiance changes expected for doubled CO2. A significant wavenumber shift is produced, with less radiance emerging in the 500-800 per cm (20.0-12.5 micron) CO2 band and with more emerging in the 800-1200 per cm (12.5-8.3 micron) window. The effect varies greatly with latitude. The radiance shift in the 2300 per cm (4.3 micron) region is of the order of 10-30 percent for doubled CO2. It is suggested that the 2300 per cm region be carefully monitored as an aid in detecting the climatic effects of increasing CO2. The change in the wavenumber-integrated radiant exitance is at most a few percent.

  1. Cd2+-Induced Alteration of the Global Proteome of Human Skin Fibroblast Cells

    PubMed Central

    2015-01-01

    Cadmium (Cd2+) is a toxic heavy metal and a well-known human carcinogen. The toxic effects of Cd2+ on biological systems are diverse and thought to be exerted through a complex array of mechanisms. Despite the large number of studies aimed to elucidate the toxic mechanisms of action of Cd2+, few have been targeted toward investigating the ability of Cd2+ to disrupt multiple cellular pathways simultaneously and the overall cellular responses toward Cd2+ exposure. In this study, we employed a quantitative proteomic method, relying on stable isotope labeling by amino acids in cell culture (SILAC) and LC–MS/MS, to assess the Cd2+-induced simultaneous alterations of multiple cellular pathways in cultured human skin fibroblast cells. By using this approach, we were able to quantify 2931 proteins, and 400 of them displayed significantly changed expression following Cd2+ exposure. Our results unveiled that Cd2+ treatment led to the marked upregulation of several antioxidant enzymes (e.g., metallothionein-1G, superoxide dismutase, pyridoxal kinase, etc.), enzymes associated with glutathione biosynthesis and homeostasis (e.g., glutathione S-transferases, glutathione synthetase, glutathione peroxidase, etc.), and proteins involved in cellular energy metabolism (e.g., glycolysis, pentose phosphate pathway, and the citric acid cycle). Additionally, we found that Cd2+ treatment resulted in the elevated expression of two isoforms of dimethylarginine dimethylaminohydrolase (DDAH I and II), enzymes known to play a key role in regulating nitric oxide biosynthesis. Consistent with these findings, we observed elevated formation of nitric oxide in human skin (GM00637) and lung (IMR-90) fibroblast cells following Cd2+ exposure. The upregulation of DDAH I and II suggests a role of nitric oxide synthesis in Cd2+-induced toxicity in human cells. PMID:24527689

  2. Evidence for opioid modulation and generation of prostaglandins in sulphur dioxide (SO)2-induced bronchoconstriction.

    PubMed Central

    Field, P. I.; Simmul, R.; Bell, S. C.; Allen, D. H.; Berend, N.

    1996-01-01

    BACKGROUND: Inhalation of sulphur dioxide (SO2) provokes bronchoconstriction in asthmatic subjects. Cholinergic mechanisms contribute, but other mechanisms remain undefined. The effect of morphine, an opioid agonist, on the cholinergic component of SO2-induced bronchoconstriction was investigated, and the effect of indomethacin, a cyclooxygenase inhibitor, on SO2-induced bronchoconstriction and tachyphylaxis was studied. METHODS: In the first study 16 asthmatic subjects inhaled either ipratropium bromide or placebo 60 minutes before an SO2 challenge on days 1 and 2. On day 3 an SO2 challenge was performed immediately after intravenous morphine. In the second study 15 asthmatic subjects took either placebo or indomethacin for three days before each study day when two SO2 challenges were performed 30 minutes apart. The response was measured as the cumulative dose causing a 35% fall in specific airways conductance (sGaw; PDsGaw35). RESULTS: Ipratropium bromide significantly inhibited SO2 responsiveness, reducing PDsGaw35 by 0.89 (95% CI 0.46 to 1.31) doubling doses. This effect persisted after correction for bronchodilatation induced by ipratropium bromide. The effect of ipratropium bromide and morphine on SO2 responsiveness also correlated (r2 = 0.71). In the second study SO2 tachyphylaxis developed with PDsGaw35 on repeated testing, being reduced by 0.62 (95% CI 0.17 to 1.07) doubling doses. Indomethacin attenuated baseline SO2 responsiveness, increasing PDsGaw35 by 0.5 (95% CI 0.06 to 0.93) doubling doses. CONCLUSIONS: These results suggest that opioids modulate the cholinergic component of SO2 responsiveness and that cyclooxygenase products contribute to the immediate response to SO2. PMID:8711648

  3. The mineralogical responses of marine calcifiers to CO2-induced ocean acidification

    NASA Astrophysics Data System (ADS)

    Ries, J. B.; Cohen, A. L.; McCorkle, D. C.

    2008-12-01

    We have conducted 6-month laboratory experiments to investigate the effect of pCO2-induced reductions in seawater CaCO3 saturation state on biocalcification by 18 aragonitic and calcitic (low-high Mg) taxa representing eight of the major marine calcifying groups: Chlorophyta; Rhodophyta; Crustacea; Bivalvia; Gastropoda; Annelida; Cnidaria; and Echinodermata. The CaCO3 saturation states of the experimental seawaters, constrained by intercalibrated determinations of pH, alkalinity, and DIC, were attained with bubbled air-CO2 mixtures of 400 (ambient), 600, 900, and 2850 ppm pCO2, yielding Ωarag of 2.5 (ambient), 2.0, 1.5, 0.7, respectively. We previously showed that while rates of net calcification obtained from buoyant weighing declined with increasing pCO2 for nearly half of the species investigated, a nearly equal number exhibited constant or, in some cases, increased calcification under moderately (600 ppm) or extremely (900 or 2850 ppm) elevated pCO2. The organisms' investigated in this study secrete various forms of CaCO3, which differ in crystallographic structure and therefore solubility: aragonite and high-Mg are generally more soluble than low-Mg calcite. We have employed powder x-ray diffraction, Raman spectroscopy, inductively-coupled-plasma mass-spectrometry, and scanning electron microscopy to quantify changes in the organisms' skeletal mineralogy (aragonite:calcite ratio) and Mg-content (MgCO3:CaCO3 ratio) that occurred in response to the prescribed reductions in seawater CaCO3 saturation state. We will compare calcification and mineralogical response patterns amongst the organisms to elucidate the role of mineral lability in driving species-specific responses to CO2-induced ocean acidification.

  4. Loss of Prostaglandin E2-induced Extra Cortical Bone After its Withdrawal in Rats

    NASA Technical Reports Server (NTRS)

    Jee, Webster S. S.; Ke, Hua Zhu; Li, Xiao Jian

    1992-01-01

    The object of this study was to determine the fate of PGE2-(Prostaglandin E2) induced new cortical bone mass after withdrawal of PGE2 administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3 and 6 mg PGE2/kg/day for 60 days and then withdrawn for 60 and 120 days (on/off treatment). Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). In a previous report we showed that after 60, 120 and 180 days of daily PGE2 (on)treatment, a new steady state was achieved marked by increased total bone area (+16%, +25% and +34% with 1, 3 and 6 mg PGE2/kg/day) when compared to age-matched controls. The continuous PGE2 treatment stimulated periosteal and endocortical lamellar bone formation, activated endocortical woven trabecular bone formation and intracortical bone resorption. These responses increased cortical bone mass since the bone formation exceeded bone resorption. The current study showed that after withdrawal of PGE2 for 60 and 120 days, the extra endocortical bone, which was induced by the first 60-days treatment, was resorbed, but the new subperiosteal bone persisted resulting in a tibial shaft with larger cross sectional and marrow areas. Despite that, there was still the same amount of bone mass in these shafts as in age-related controls. A new steady state was achieved after 60 days of withdrawal, in which the bone mass and bone formation activity approximated that of age-related controls. It was concluded that maintaining the extra PGE2-induced cortical bone mass depends on continuous daily administration of PGE2.

  5. Loss of Prostaglandin E2-induced Extra Cortical Bone after its Withdrawal in Rats

    NASA Technical Reports Server (NTRS)

    Jee, Webster S. S.; Ke, Hua Zhu; Li, Xiao Jian

    1992-01-01

    The object of this study was to determine the fate of PGE2-induced new cortical bone mass after withdrawal of PGE2 administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3 and 6 mg PGE2/kg/day for 60 days and then withdrawn for 60 and 120 days (on/off treatment). Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). In a previous report we showed that after 60, 120 and 180 days of daily PGE2 (on)treatment, a new steady state was achieved marked by increased total bone area (+ 16%, +25% and + 34% with 1, 3 and 6 mg PGE2/kg/day) when compared to age-matched controls. The continuous PGE2 treatment stimulated periosteal and endocortical lamellar bone formation, activated endocortical woven trabecular bone formation and intracortical bone resorption. These responses increased cortical bone mass since the bone formation exceeded bone resorption. The current study showed that after withdrawal of PGE2 for 60 and 120 days, the extra endocortical bone, which was induced by the first 60-days treatment, was resorbed, but the new subperiosteal bone persisted resulting in a tibial shaft with larger cross sectional and marrow areas. Despite that, there was still the same amount of bone mass in these shafts as in age-related controls. A new steady state was achieved after 60 days of withdrawal, in which the bone mass and bone formation activity approximated that of age-related controls. It was concluded that maintaining the extra PGE2-induced cortical bone mass depends on continuous daily administration of PGE2.

  6. Osteogenic potential of alpha smooth muscle actin expressing muscle resident progenitor cells.

    PubMed

    Matthews, Brya G; Torreggiani, Elena; Roeder, Emilie; Matic, Igor; Grcevic, Danka; Kalajzic, Ivo

    2016-03-01

    Heterotopic ossification (HO) is a pathological process where bone forms in connective tissues such as skeletal muscle. Previous studies have suggested that muscle-resident non-myogenic mesenchymal progenitors are the likely source of osteoblasts and chondrocytes in HO. However, the previously identified markers of muscle-resident osteoprogenitors label up to half the osteoblasts within heterotopic lesions, suggesting other cell populations are involved. We have identified alpha smooth muscle actin (αSMA) as a marker of osteoprogenitor cells in bone and periodontium, and of osteo-chondro progenitors in the periosteum during fracture healing. We therefore utilized a lineage tracing approach to evaluate whether αSMACreERT2 identifies osteoprogenitors in the muscle. We show that in the muscle, αSMACreERT2 labels both perivascular cells, and satellite cells. αSMACre-labeled cells undergo osteogenic differentiation in vitro and form osteoblasts and chondrocytes in BMP2-induced HO in vivo. In contrast, Pax7CreERT2-labeled muscle satellite cells were restricted to myogenic differentiation in vitro, and rarely contributed to HO in vivo. Our data indicate that αSMACreERT2 labels a large proportion of osteoprogenitors in skeletal muscle, and therefore represents another marker of muscle-resident cells with osteogenic potential under HO-inducing stimulus. In contrast, muscle satellite cells make minimal contribution to bone formation in vivo. PMID:26721734

  7. Genetic mapping of Eutr1, a locus controlling E2-induced pyometritis in the Brown Norway rat, to RNO5.

    PubMed

    Gould, Karen A; Pandey, Jyotsna; Lachel, Cynthia M; Murrin, Clare R; Flood, Lisa A; Pennington, Karen L; Schaffer, Beverly S; Tochacek, Martin; McComb, Rodney D; Meza, Jane L; Wendell, Douglas L; Shull, James D

    2005-11-01

    In certain rat strains, chronic estrogen administration can lead to pyometritis, an inflammation of the uterus accompanied by infection and the accumulation of intraluminal pus. In this article, we report that the Brown Norway (BN) rat is highly susceptible to pyometritis induced by 17beta-estradiol (E2). The susceptibility of the BN rat to E2-induced pyometritis appears to segregate as a recessive trait in crosses to the resistant August x Copenhagen Irish (ACI) strain. In a (BN x ACI)F(2) population, we find strong evidence for a major genetic determinant of susceptibility to E2-induced pyometritis on rat chromosome 5 (RNO5). Our data are most consistent with a model in which the BN allele of this locus, designated Eutr1 (Estrogen-induced uterine response 1), acts in an incompletely dominant manner to control E2-induced pyometritis. Furthermore, we have confirmed the contribution of Eutr1 to E2-induced uterine pyometritis using an RNO5 congenic rat strain. In addition to Eutr1, we obtained evidence suggestive of linkage for five additional loci on RNO2, 4, 11, 17, and X that control susceptibility to E2-induced pyometritis in the (BN x ACI)F(2) population. PMID:16284801

  8. Atmospheric impacts of changing sea ice cover in CO2 induced global warming

    NASA Astrophysics Data System (ADS)

    Cvijanovic, I.; Caldeira, K.

    2013-12-01

    Changes in sea ice cover have important consequences for both Earth's energy budget and atmospheric dynamics. Sea ice amplifies the effects of applied radiative forcing, insulates ocean from atmosphere and induces changes in the meridional temperature gradients thus affecting atmospheric motion in several ways. In this study, we partition and evaluate the effect of changing sea ice cover in global warming using sets of simulations with active and suppressed sea ice response. In particular, we investigate the effect of CO2 induced sea ice changes on global circulation response and extratropical precipitation extremes. Importantly, our setup employs the Atmospheric General Circulation Model coupled to a mixed layer ocean, thus enabling the atmosphere-surface ocean interactions and global atmospheric teleconnections from remote areas. Mid-latitude circulation patterns are found to be most strongly affected by the sea ice changes. In the standard, 'active' ice setup, westerly winds weaken in response to CO2-induced warming. In contrast, in the absence of sea ice response, westerly winds strengthen with global warming. These contrasting wind responses further affect the atmospheric weather patterns and extreme precipitation event development. We identify two opposing roles of sea ice decline on extreme events: (i) a dominant warming effect leads to an increase in the number and strength of extreme events; (ii) a decrease in the pole to equator gradient (a consequence of sea ice loss) acts to temper the development of precipitation extremes due to a decreased midlatitude dry static energy transport.This leads to the conclusion that for the same global temperature increase, the magnitude and frequency of mid-latitude precipitation extremes is smaller when sea ice loss is enabled than when it is suppressed. In general, in the absence of sea ice feedbacks, we find up to 35% less global warming (depending on the simulation type). This is not only due to the smaller high

  9. Numerical Interpretation of Laboratory and Field Data Showing CO2-induced Groundwater Changes

    NASA Astrophysics Data System (ADS)

    Zheng, L.; Tinnacher, R. M.; Varadharajan, C.; Spycher, N.; Bianchi, M.; Nico, P. S.; Birkholzer, J. T.; Trautz, R. C.; Pugh, J. D.

    2012-12-01

    One of the issues related to the risk assessment of CO2 geological sequestration is the potential impact of leaking CO2 on shallow groundwater quality. Numerous studies have been conducted using laboratory tests, natural analogues and numerical models to evaluate the changes in ion concentrations in groundwater induced by elevated CO2 concentrations. In this study, a controlled-release field experiment, integrated with laboratory tests and numerical modeling, has been conducted to simulate the release of CO2 from a geologic storage site. This allowed us to study the transport as well as the chemical mechanisms leading to the CO2-induced mobilization of trace elements. The field test involved a dipole system in which the groundwater was pumped from one well, saturated with CO2 at the pressure corresponding to the hydraulic pressure of the aquifer, and then re-injected into the same aquifer using a second well. Groundwater quality data were collected in four monitoring wells. At the same time, a series of lab-scale sequential leaching experiments were carried out with synthetic groundwater solutions at different pH conditions and CO2 concentrations. Although concentration changes of some ions are generally comparable for laboratory and field tests, the release of some trace elements was observed in the laboratory but not in the field test. This might be attributed to differences in test setup and scale. In this presentation, we will discuss numerical model interpretations of both laboratory and field tests, aiming to reconcile the differences in the datasets with consistent geochemical models. This will further allow us to gain new insights on the geochemical mechanisms potentially involved in the CO2-induced mobilization of trace elements. Modeling results show that aquifer sediments possess weak pH buffering capacity provided by surface protonation reactions and possibly the dissolution of carbonate minerals. The dissolution of calcite and subsequent calcium

  10. Counteracting MDM2-induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells.

    PubMed

    Nardinocchi, Lavinia; Puca, Rosa; Givol, David; D'Orazi, Gabriella

    2010-10-01

    Homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating serine 46 (Ser46) in response to DNA damage. In tumors with wild-type p53, its tumor suppressor function is often impaired by MDM2 overexpression that targets p53 for proteasomal degradation. Likewise, MDM2 targets HIPK2 for protein degradation impairing p53-apoptotic function. Here we report that zinc antagonised MDM2-induced HIPK2 degradation as well as p53 ubiquitination. The zinc inhibitory effect on MDM2 activity leads to HIPK2-induced p53Ser46 phosphorylation and p53 pro-apoptotic transcriptional activity. These results suggest that zinc derivatives are potential molecules to target the MDM2-induced HIPK2/p53 inhibition. PMID:20849851

  11. Pregnancy in fibrodysplasia ossificans progressiva

    PubMed Central

    Muglu, Javaid A; Garg, Aditya; Pandiarajan, T; Shore, Eileen M; Kaplan, Frederick S; Uchil, Dhiraj; Dickson, Malcolm J

    2011-01-01

    Fibrodysplasia ossificans progressiva (FOP) is a rare disabling genetic disorder characterized by progressive postnatal heterotopic ossification leading to cumulative disability. Heterotopic bone formation in FOP usually begins in early childhood following a series of painful, post-traumatic, inflammatory soft-tissue swellings known as flare-ups, which later undergo ossification resulting in the progressive immobilization of the chest wall, limbs and jaw by early adulthood. Pregnancy in FOP has occurred infrequently and reproductive decisions are a dilemma for an individual or couple with FOP. We present the clinical course, medical management and potential concerns of four cases of pregnancy in FOP.

  12. Pentoxifylline inhibits interleukin-2-induced toxicity in C57BL/6 mice but preserves antitumor efficacy.

    PubMed Central

    Edwards, M J; Heniford, B T; Klar, E A; Doak, K W; Miller, F N

    1992-01-01

    Interleukin 2 (IL-2) mediates the regression of metastatic cancer but clinical use has been limited due to associated toxicities. Tumor necrosis factor (TNF) is an important mediator of IL-2 toxicity and may have a limited role in IL-2 antitumor efficacy. Because pentoxifylline (PTXF) inhibits TNF production, we hypothesized that PTXF would ameliorate IL-2 toxicity without compromising antitumor efficacy. Four groups of female C57BL/6 mice with pulmonary metastases from a 3-methylcholanthrene-induced fibrosarcoma (MCA-105) and four groups of nontumored mice were treated every 6 h for 4 d by intraperitoneal injections of either IL-2 alone, IL-2 and PTXF, PTXF alone, or equal volumes of saline. Upon completion of therapy, we found that PTXF suppressed many of the IL-2-induced effects including TNF production, lymphocytic infiltration of multiple organs, multiple organ edema, hepatic dysfunction, leukopenia, and thrombocytopenia. Tumor response was determined 21 d after cessation of therapy by quantitating the number and surface area of pulmonary metastases. PTXF preserved antitumor efficacy while reducing the morbidity and mortality caused by IL-2 treatment. These data strongly support the use of PTXF in extending the therapeutic index of IL-2 in the treatment of cancer. Images PMID:1644928

  13. Hyperoside protects human primary melanocytes against H2O2-induced oxidative damage

    PubMed Central

    YANG, BIN; YANG, QIN; YANG, XIN; YAN, HONG-BO; LU, QI-PING

    2016-01-01

    Cuscutae semen has been shown to have beneficial effects in the treatment of vitiligo, recorded in the Chinese Pharmacopoeia, whereas the effects of its constituent compounds remains to be elucidated. Using a tetrazolium bromide assay, the present study found that hyperoside (0.5–200 µg/ml) significantly increased the viability of human melanocytes in a time- and dose-dependent manner. The present study used a cell model of hydrogen peroxide (H2O2)-induced oxidative damage to examine the effect of hyperoside on human primary melanocytes. The results demonstrated that hyperoside pretreatment for 2 h decreased cell apoptosis from 54.03±9.11 to 17.46±3.10% in the H2O2-injured melanocytes. The levels of oxidative stress in the mitochondrial membrane potential of the melanocytes increased following hyperoside pretreatment. The mRNA and protein levels of B-cell lymphoma-2/Bcl-2-associated X protein and caspase 3 were regulated by hyperoside, and phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase signaling were also mediated by hyperoside. In conclusion, the results of the present study demonstrated that hyperoside protected the human primary melanocytes against oxidative damage. PMID:27082158

  14. FGF2-induced effects on transcriptome associated with regeneration competence in adult human fibroblasts

    PubMed Central

    2013-01-01

    Background Adult human fibroblasts grown in low oxygen and with FGF2 supplementation have the capacity to tip the healing outcome of skeletal muscle injury – by favoring regeneration response in vivo over scar formation. Here, we compare the transcriptomes of control adult human dermal fibroblasts and induced regeneration-competent (iRC) fibroblasts to identify transcriptional changes that may be related to their regeneration competence. Results We identified a unique gene-expression profile that characterizes FGF2-induced iRC fibroblast phenotype. Significantly differentially expressed genes due to FGF2 treatment were identified and analyzed to determine overrepresented Gene Ontology terms. Genes belonging to extracellular matrix components, adhesion molecules, matrix remodelling, cytoskeleton, and cytokines were determined to be affected by FGF2 treatment. Conclusions Transcriptome analysis comparing control adult human fibroblasts with FGF2-treated fibroblasts identified functional groups of genes that reflect transcriptional changes potentially contributing to their regeneration competence. This comparative transcriptome analysis should contribute new insights into genes that characterize cells with greater regenerative potential. PMID:24066673

  15. Cyclin D2 induces proliferation of cardiac myocytes and represses hypertrophy

    SciTech Connect

    Busk, Peter K. . E-mail: pkbu@novonordisk.com; Hinrichsen, Rebecca; Bartkova, Jirina; Hansen, Ane H.; Christoffersen, Tue E.H.; Bartek, Jiri; Haunso, Stig

    2005-03-10

    The myocytes of the adult mammalian heart are considered unable to divide. Instead, mitogens induce cardiomyocyte hypertrophy. We have investigated the effect of adenoviral overexpression of cyclin D2 on myocyte proliferation and morphology. Cardiomyocytes in culture were identified by established markers. Cyclin D2 induced DNA synthesis and proliferation of cardiomyocytes and impaired hypertrophy induced by angiotensin II and serum. At the molecular level, cyclin D2 activated CDK4/6 and lead to pRB phosphorylation and downregulation of the cell cycle inhibitors p21{sup Waf1/Cip1} and p27{sup Kip1}. Expression of the CDK4/6 inhibitor p16 inhibited proliferation and cyclin D2 overexpressing myocytes became hypertrophic under such conditions. Inhibition of hypertrophy by cyclin D2 correlated with downregulation of p27{sup Kip1}. These data show that hypertrophy and proliferation are highly related processes and suggest that cardiomyocyte hypertrophy is due to low amounts of cell cycle activators unable to overcome the block imposed by cell cycle inhibitors. Cell cycle entry upon hypertrophy may be converted to cell division by increased expression of activators such as cyclin D2.

  16. SRT1720, a SIRT1 specific activator, protected H2O2-induced senescent endothelium

    PubMed Central

    Li, Rui-Lin; Lu, Zhao-Yang; Huang, Jing-Juan; Qi, Jia; Hu, An; Su, Zhi-Xiao; Zhang, Lan; Li, Yue; Shi, Yi-Qin; Hao, Chang-Ning; Duan, Jun-Li

    2016-01-01

    Silent information regulator 1 (SIRT1) plays a critical role in maintaining vascular homeostasis via modulating senescent-related signal pathway, however, the molecular mechanism remains modest clarified. The purpose of this study was to examine whether SIRT1 specific activator SRT1720 would exhibit pro-angiogenic and anti-aging properties in response to hydrogen peroxide (H2O2)-induced endothelial senescence, and determine the underlying mechanisms. We pre-treated senescent human umbilical vein endothelial cells (HUVECs) with SRT1720, senescence-associated beta-galactosidase activity, apoptosis, migration, tube formation, proliferation and angiogenic factors were quantitatively examined. The results revealed that pharmacologic activation of SIRT1 by SRT1720 rescued apoptotic HUVECs and upregulated angiogenic response through reinforcing the protein expressions of angiogenic and survival factors in vitro. Furthermore, we confirmed that the expressions of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and phosphoryl-Akt were augmented in SRT1720-treated senescent HUVECs. In conclusion, our data indicated that SRT1720 could protect against endothelial senescence and maintain cell function via Akt/eNOS/VEGF axis. PMID:27508009

  17. SRT1720, a SIRT1 specific activator, protected H2O2-induced senescent endothelium.

    PubMed

    Li, Rui-Lin; Lu, Zhao-Yang; Huang, Jing-Juan; Qi, Jia; Hu, An; Su, Zhi-Xiao; Zhang, Lan; Li, Yue; Shi, Yi-Qin; Hao, Chang-Ning; Duan, Jun-Li

    2016-01-01

    Silent information regulator 1 (SIRT1) plays a critical role in maintaining vascular homeostasis via modulating senescent-related signal pathway, however, the molecular mechanism remains modest clarified. The purpose of this study was to examine whether SIRT1 specific activator SRT1720 would exhibit pro-angiogenic and anti-aging properties in response to hydrogen peroxide (H2O2)-induced endothelial senescence, and determine the underlying mechanisms. We pre-treated senescent human umbilical vein endothelial cells (HUVECs) with SRT1720, senescence-associated beta-galactosidase activity, apoptosis, migration, tube formation, proliferation and angiogenic factors were quantitatively examined. The results revealed that pharmacologic activation of SIRT1 by SRT1720 rescued apoptotic HUVECs and upregulated angiogenic response through reinforcing the protein expressions of angiogenic and survival factors in vitro. Furthermore, we confirmed that the expressions of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and phosphoryl-Akt were augmented in SRT1720-treated senescent HUVECs. In conclusion, our data indicated that SRT1720 could protect against endothelial senescence and maintain cell function via Akt/eNOS/VEGF axis. PMID:27508009

  18. Elevation of IGFBP2 contributes to mycotoxin T-2-induced chondrocyte injury and metabolism.

    PubMed

    Wang, Xiaoqing; Zhang, Yan; Chang, Yanhai; Duan, Dapeng; Sun, Zhengming; Guo, Xiong

    2016-09-01

    Kashin-Beck disease (KBD) is an endemic degenerative osteoarthropathy. The mycotoxin of T-2 toxin is extensively accepted as a major etiological contributor to KBD. However, its function and mechanism in KBD remains unclearly elucidated. Here, T-2 toxin treatment induced chondrocyte injury in a time- and dose-dependent manner by repressing cell viability and promoting cell necrosis and apoptosis. Importantly, T-2 suppressed the transcription of type II collagen and aggrecan, as well as the release of sulphated glycosaminoglycan (sGAG). Furthermore, exposure to T-2 enhanced the transcription of matrix metalloproteinases (MMPs), including MMP-1, -2, -3 and -9. In contrast to control groups, higher expression of insulin-like growth factor binding protein 2 (IGFBP2) was observed in chondrocytes from KBD patients. Interestingly, T-2 toxin caused a dramatical elevation of IGFBP2 expression in chondrocytes. Mechanism analysis corroborated that cessation of IGFBP2 expression alleviated T-2-induced damage to chondrocytes. Simultaneously, transfection with IGFBP2 siRNA also attenuated matrix synthesis and catabolism-related gene expressions of MMPs. Together, this study validated that T-2 toxin exposure might promote the progression of KBD by inducing chondrocyte injury, suppressing matrix synthesis and accelerating cellular catabolism through IGFBP2. Therefore, this research will elucidate a new insight about how T-2 toxin participate in the pathogenesis of KBD. PMID:27416762

  19. Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.

    PubMed

    Saddawi-Konefka, Robert; Seelige, Ruth; Gross, Emilie T E; Levy, Eric; Searles, Stephen C; Washington, Allen; Santosa, Endi K; Liu, Beichen; O'Sullivan, Timothy E; Harismendy, Olivier; Bui, Jack D

    2016-08-30

    Cells undergoing xenobiotic or oxidative stress activate the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2), which initiates an intrinsic "stress surveillance" pathway. We recently found that the cytokine IL-17D effects a form of extrinsic stress surveillance by inducing antitumor immunity, but how IL-17D is regulated remains unknown. Here, we show that Nrf2 induced IL-17D in cancer cell lines. Moreover, both Nrf2 and IL-17D were induced in primary tumors as well as during viral infection in vivo. Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d(-/-) mice experienced a higher incidence of tumors and exacerbated viral infections compared to wild-type (WT) animals. Moreover, activating Nrf2 to induce IL-17D in established tumors led to natural killer cell-dependent tumor regression. These data demonstrate that Nrf2 can initiate both intrinsic and extrinsic stress surveillance pathways and highlight the use of Nrf2 agonists as immune therapies for cancer and infection. PMID:27545889

  20. Kinetics for Cu(2+) induced Sepia pharaonis arginine kinase inactivation and aggregation.

    PubMed

    Shi, Xiao-Yu; Zhang, Li-Li; Wu, Feng; Fu, Yang-Yong; Yin, Shang-Jun; Si, Yue-Xiu; Park, Yong-Doo

    2016-10-01

    Arginine kinase plays an important role in cellular energy metabolism and is closely related to the environmental stress response in marine invertebrates. We studied the Cu(2+)-mediated inhibition and aggregation of Sepia pharaonis arginine kinase (SPAK) and found that Cu(2+) markedly inhibited the SPAK activity along with mixed-type inhibition against the arginine substrate and noncompetitive inhibition against the ATP cofactor. Spectrofluorimetry results showed that Cu(2+) induced a tertiary structure change in SPAK, resulting in exposure of the hydrophobic surface and increased aggregation. Cu(2+)-mediated SPAK aggregation followed first-order kinetics consistent with monophasic and a biphasic processes. Addition of osmolytes, including glycine and proline, effectively blocked SPAK aggregation and restored SPAK activity. Our results demonstrated the effects of Cu(2+) on SPAK catalytic function, conformation, and aggregation, as well as the protective effects of osmolytes on SPAK folding. This study provided important insights into the role of Cu(2+) as a negative effector of the S. pharaonis metabolic enzyme AK and the possible responses of cephalopods to unfavorable environmental conditions. PMID:27318110

  1. Ca(2+)-induced tension development in the stalks of glycerinated Vorticella convallaria.

    PubMed

    Moriyama, Y; Yasuda, K; Ishiwata, S; Asai, H

    1996-01-01

    We have developed a method of measuring the isometric tension in glycerinated stalks of Vorticella convallaria. Using this method, we measured tension vs. pCa relations in glycerinated V. convallaria stalks. The maximum isometric tension was 4 x 10(-8) N on average. The Hill's parameter, n, which is the number of calcium ions bound simultaneously and cooperatively to a contractile element (a force generating element), is approximately 3.2 when the Ca2+ concentration is increased and 2.5 when it is decreased. In order to estimate the efficiency of the energy conversion of Ca2+ binding to mechanical work, we measured the Ca(2+)-induced Carnot cycle in the Vorticella stalk. The energy efficiency was tentatively estimated to be about 7%. With this method, we have also succeeded in measuring the isometric tension of isolated spasmoneme, the rubber-like contractile fibrous organelle in the stalk. The maximum tension of spasmoneme was approximately one tenth that of the glycerinated stalk. We speculate that the isolated spasmoneme was only partially functional due to damage sustained when it was pulled out of the stalk. PMID:8871814

  2. Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death

    PubMed Central

    Singh, Nitu; Senapati, Sanjib; Bose, Kakoli

    2016-01-01

    High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2-mediated apoptosis is poorly understood. Here, with an interdisciplinary approach that involves in silico, mutational, biochemical and biophysical probes, we dissected and characterized the E2-procasapse-8 binding interface. Our data demonstrate direct non-homotypic interaction of HPV18 E2 transactivation domain (TAD) with α2/α5 helices of procaspase-8 death effector domain-B (DED-B). The observed interaction mimics the homotypic DED-DED complexes, wherein the conserved hydrophobic motif of procaspase-8 DED-B (F122/L123) occupies a groove between α2/α3 helices of E2 TAD. This interaction possibly drives DED oligomerization leading to caspase-8 activation and subsequent cell death. Furthermore, our data establish a model for E2-induced apoptosis in HR-HPV types and provide important clues for designing E2 analogs that might modulate procaspase-8 activation and hence apoptosis. PMID:26906543

  3. Extracellular PKM2 induces cancer proliferation by activating the EGFR signaling pathway

    PubMed Central

    Hsu, Ming-Chuan; Hung, Wen-Chun; Yamaguchi, Hirohito; Lim, Seung-Oe; Liao, Hsin-Wei; Tsai, Chia-Hua; Hung, Mien-Chie

    2016-01-01

    Pyruvate kinase is a key enzyme in the glycolytic pathway that converts phosphoenolpyruvate to pyruvate, and the M2 isoform of pyruvate kinase (PKM2) is associated with cancer. PKM2 has been reported to function independently of its pyruvate kinase activity, which is crucial for cancer cell proliferation. Moreover, there is growing evidence indicating that dimeric PKM2 is released from tumor cells into the circulation of cancer patients. However, the role of secreted PKM2 in cancer is not well understood. Here, we found that the phosphorylation level of epidermal growth factor receptor (EGFR) significantly increased upon the exposure of cells to the recombinant PKM2 protein. In addition, secreted PKM2 induces EGFR phosphorylation and activates the EGFR downstream signaling in triple-negative breast cancer cells. In contrast, knocking down PKM2 decreased EGFR phosphorylation. Moreover, expression of R399E mutant PKM2, which has been reported to preferentially form a dimer, enhanced EGFR phosphorylation, cellular transformation, and cell proliferation more strongly than the wild-type PKM2. Thus, our study revealed a novel function of extracellular PKM2 in the promoting cancer cell proliferation through EGFR activation. PMID:27152240

  4. TLR2-induced IL-10 production impairs neutrophil recruitment to infected tissues during neonatal bacterial sepsis.

    PubMed

    Andrade, Elva B; Alves, Joana; Madureira, Pedro; Oliveira, Liliana; Ribeiro, Adília; Cordeiro-da-Silva, Anabela; Correia-Neves, Margarida; Trieu-Cuot, Patrick; Ferreira, Paula

    2013-11-01

    Sepsis is the third most common cause of neonatal death, with Group B Streptococcus (GBS) being the leading bacterial agent. The pathogenesis of neonatal septicemia is still unsolved. We described previously that host susceptibility to GBS infection is due to early IL-10 production. In this study, we investigated whether triggering TLR2 to produce IL-10 is a risk factor for neonatal bacterial sepsis. We observed that, in contrast to wild-type (WT) pups, neonatal TLR2-deficient mice were resistant to GBS-induced sepsis. Moreover, if IL-10 signaling were blocked in WT mice, they also were resistant to sepsis. This increased survival rate was due to an efficient recruitment of neutrophils to infected tissues that leads to bacterial clearance, thus preventing the development of sepsis. To confirm that IL-10 produced through TLR2 activation prevents neutrophil recruitment, WT pups were treated with the TLR2 agonist Pam3CSK4 prior to nebulization with the neutrophil chemotactic agent LTB4. Neutrophil recruitment into the neonatal lungs was inhibited in pups treated with Pam3CSK4. However, the migration was restored in Pam3CSK4-treated pups when IL-10 signaling was blocked (either by anti-IL-10R mAb treatment or by using IL-10-deficient mice). Our findings highlight that TLR2-induced IL-10 production is a key event in neonatal susceptibility to bacterial sepsis. PMID:24078699

  5. 6K2-induced vesicles can move cell to cell during turnip mosaic virus infection.

    PubMed

    Grangeon, Romain; Jiang, Jun; Wan, Juan; Agbeci, Maxime; Zheng, Huanquan; Laliberté, Jean-François

    2013-01-01

    To successfully infect plants, viruses replicate in an initially infected cell and then move to neighboring cells through plasmodesmata (PDs). However, the nature of the viral entity that crosses over the cell barrier into non-infected ones is not clear. The membrane-associated 6K2 protein of turnip mosaic virus (TuMV) induces the formation of vesicles involved in the replication and intracellular movement of viral RNA. This study shows that 6K2-induced vesicles trafficked toward the plasma membrane and were associated with plasmodesmata (PD). We demonstrated also that 6K2 moved cell-to-cell into adjoining cells when plants were infected with TuMV. 6K2 was then fused to photo-activable GFP (6K2:PAGFP) to visualize how 6K2 moved intercellularly during TuMV infection. After activation, 6K2:PAGFP-tagged vesicles moved to the cell periphery and across the cell wall into adjacent cells. These vesicles were shown to contain the viral RNA-dependent RNA polymerase and viral RNA. Symplasmic movement of TuMV may thus be achieved in the form of a membrane-associated viral RNA complex induced by 6K2. PMID:24409170

  6. Long Noncoding RNA MHRT Protects Cardiomyocytes against H2O2-Induced Apoptosis.

    PubMed

    Zhang, Jianying; Gao, Caihua; Meng, Meijuan; Tang, Hongxia

    2016-01-01

    Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. The exploration of new biomarkers with high sensitivity and specificity for early diagnosis of AMI therefore becomes one of the primary task. In the current study, we aim to detect whether there is any heart specific long noncoding RNA (lncRNA) releasing into the circulation during AMI, and explore its function in the neonatal rat cardiac myocytes injury induced by H2O2. Our results revealed that the cardiac-specific lncRNA MHRT (Myosin Heavy Chain Associated RNA Transcripts) was significantly elevated in the blood from AMI patients compared with the healthy control ((*) p<0.05). Using an in vitro neonatal rat cardiac myocytes injury model, we demonstrated that lncRNA MHRT was upregulated in the cardiac myocytes after treatment with hydrogen peroxide (H2O2) via real-time RT-PCR (qRT-PCR). Furthermore, we knockdowned the MHRT gene by siRNA to confirm its roles in the H2O2-induced cardiac cell apoptosis, and found that knockdown of MHRT led to significant more apoptotic cells than the non-target control ((**) p<0.01), indicating that the lncRNA MHRT is a protective factor for cardiomyocyte and the plasma concentration of MHRT may serve as a biomarker for myocardial infarction diagnosis in humans AMI. PMID:26759697

  7. Effects of Yohimbine and Tolazoline on Isoproterenol and Angiotensin 2-Induced Water Intake in Rats

    NASA Technical Reports Server (NTRS)

    Fregly, Melvin J.; Rowland, Neil E.; Greenleaf, John E.

    1983-01-01

    Subcutaneous administration of the alpha(sub 2)-adrenoreceptor antagonists, yohimbine and tolazoline, at doses up to 1000 micro-g/kg, had no effect on water intake of female rats. However, when these compounds were administered SC in combination with either the beta-adrenoreceptor agonist, isoproterenol (10 to 25 micro-g/kg, SC), or with angiotensin 2 (200 micro-g/kg, SC). water intake was enhanced. In contrast, intraventricular administration of either tolazoline (10 and 20 micro-g/kg) or yohimbine (300 micro-g/kg) failed to augment the dipsogenic response to angiotensin 2 (150 micro-g/kg, SC). Thus, the enhancing effect of these alpha(sub 2)-adrenoreceptor antagonists on isoproterenol- and angiotensin 2-induced water intakes appears to be manifested peripherally, rather than centrally. In view of the fact that clonidine, an alpha(sub 2)-adrenoreceptor agonist, has been shown to inhibit water intake induced by both isoproterenol and angiotensin 2, the results suggest that the alpha(sub 2)-adrenoreceptor may play a role in modulating water intake induced by these two dipsogenic agents.

  8. Insights into the mechanism of human papillomavirus E2-induced procaspase-8 activation and cell death.

    PubMed

    Singh, Nitu; Senapati, Sanjib; Bose, Kakoli

    2016-01-01

    High-risk human papillomavirus (HR-HPV) E2 protein, the master regulator of viral life cycle, induces apoptosis of host cell that is independent of its virus-associated regulatory functions. E2 protein of HR-HPV18 has been found to be involved in novel FADD-independent activation of caspase-8, however, the molecular basis of this unique non-death-fold E2-mediated apoptosis is poorly understood. Here, with an interdisciplinary approach that involves in silico, mutational, biochemical and biophysical probes, we dissected and characterized the E2-procasapse-8 binding interface. Our data demonstrate direct non-homotypic interaction of HPV18 E2 transactivation domain (TAD) with α2/α5 helices of procaspase-8 death effector domain-B (DED-B). The observed interaction mimics the homotypic DED-DED complexes, wherein the conserved hydrophobic motif of procaspase-8 DED-B (F122/L123) occupies a groove between α2/α3 helices of E2 TAD. This interaction possibly drives DED oligomerization leading to caspase-8 activation and subsequent cell death. Furthermore, our data establish a model for E2-induced apoptosis in HR-HPV types and provide important clues for designing E2 analogs that might modulate procaspase-8 activation and hence apoptosis. PMID:26906543

  9. Prostaglandin E2 induces expression of MAPK phosphatase 1 (MKP-1) in airway smooth muscle cells.

    PubMed

    Rumzhum, Nowshin N; Ammit, Alaina J

    2016-07-01

    Prostaglandin E2 (PGE2) is a prostanoid with diverse actions in health and disease. In chronic respiratory diseases driven by inflammation, PGE2 has both positive and negative effects. An enhanced understanding of the receptor-mediated cellular signalling pathways induced by PGE2 may help us separate the beneficial properties from unwanted actions of this important prostaglandin. PGE2 is known to exert anti-inflammatory and bronchoprotective actions in human airways. To date however, whether PGE2 increases production of the anti-inflammatory protein MAPK phosphatase 1 (MKP-1) was unknown. We address this herein and use primary cultures of human airway smooth muscle (ASM) cells to show that PGE2 increases MKP-1 mRNA and protein upregulation in a concentration-dependent manner. We explore the signalling pathways responsible and show that PGE2-induces CREB phosphorylation, not p38 MAPK activation, in ASM cells. Moreover, we utilize selective antagonists of EP2 (PF-04418948) and EP4 receptors (GW 627368X) to begin to identify EP-mediated functional outcomes in ASM cells in vitro. Taken together with earlier studies, our data suggest that PGE2 increases production of the anti-inflammatory protein MKP-1 via cAMP/CREB-mediated cellular signalling in ASM cells and demonstrates that EP2 may, in part, be involved. PMID:27108790

  10. Mechanisms of the Ba2+-induced contraction in smooth muscle cells of the rabbit mesenteric artery.

    PubMed

    Satoh, S; Kubota, Y; Itoh, T; Kuriyama, H

    1987-02-01

    The mechanism of the Ba2+-induced contraction was investigated using intact and saponin-treated skinned smooth muscle (skinned muscle) strips of the rabbit mesenteric artery. After depletion of Ca2+ stored in the caffeine-sensitive site, greater than 0.65 mM Ba2+ evoked contraction in muscle strips depolarized with 128 mM K+ in Ca2+-free solution in a dose-dependent fashion, and the ED50 values for Ca2+ and Ba2+ were 0.5 mM and 1.2 mM in intact muscle strips, respectively. Nisoldipine (10 nM) blocked the contraction evoked by high K+ or 10 microM norepinephrine (NE) in the presence of 2.6 mM Ba2+, but did not block the contraction evoked in the presence of 2.6 mM Ca2+. These results may indicate that Ba2+ permeates the voltage-dependent Ca2+ channel. In skinned muscle strips, the ED50 values for Ca2+ and Ba2+ were 0.34 and 90 microM, respectively, as estimated from the pCa- and pBa-tension relationships. Calmodulin enhanced and trifluoperazine inhibited the Ba2+- and Ca2+-induced contractions. After the application of Ba2+ or Ca2+ with ATP gamma S in rigor solution, myosin light chain (MLC) was irreversibly thiophosphorylated, as estimated from the Ba2+- or Ca2+-independent contraction. Furthermore, both divalent cations phosphorylated MLC, as measured using two-dimensional gel electrophoresis, to the extent expected from the amplitudes of the contraction evoked by these cations. Thus, Ba2+ is capable of activating the contractile proteins as Ca2+ does. The amount of Ca2+ or Ba2+ stored in cells was estimated from the caffeine response evoked in Ca2+-free solution in intact and skinned muscle strips. After the application of 0.3 microM Ca2+ or 0.1 mM Ba2+ for 60 s to skinned muscle strips after the depletion of Ca2+ stored in cells, caffeine produced a contraction only upon pretreatment with Ca2+ but not with Ba2+. When Ba2+ was applied successively just after the application of Ca2+, the subsequently evoked caffeine-induced contraction was much smaller than that

  11. A physicochemical framework for interpreting the biological calcification response to CO2-induced ocean acidification

    NASA Astrophysics Data System (ADS)

    Ries, J. B.

    2011-12-01

    Researchers investigating the responses of marine calcifiers to CO2-induced ocean acidification have reported surprisingly variable results. A generalized proton-pumping-based model of marine organisms' calcifying fluids, considered for present and forecasted atmospheric pCO2 scenarios (400 - 2850 μatm), is able to generate the full spectrum of calcification response patterns observed in prior ocean acidification experiments, including negative, non-linear, and positive. The removal of H+ from an organism's calcifying fluid requires energy. Two factors that influence the amount of energy required to regulate calcification site pH are the quantity of H+ removed from a given volume of the calcifying fluid and the H+-gradient across the membrane(s) that bounds the calcifying fluid. The energy required to maintain a H+-gradient across a membrane, known as the Nernst potential (E), can be defined as: E = (RT)/(nF) x ln([H+]e/[H+]i) where R is the universal gas constant, T is absolute temperature, n is the valence charge of H+, F is the Faraday constant, and [H+]e and [H+]i are H+ concentrations of the external seawater and of the organism's calcifying fluid, respectively. Because R, T, n and F are constants in the described H+-membrane system, the magnitude of the Nernst potential, or the energetic cost of maintaining a H+-gradient between external seawater and an organism's membrane-bound calcifying fluid, should be roughly proportional to [H+]e/[H+]i. The proton-pumping model is therefore parameterized by two end-member scenarios: one in which a fixed number of H+ is removed from the calcifying fluid, regardless of atmospheric pCO2, and another in which a fixed [H+]e/[H+]i is maintained. The model is empirically evaluated for the temperate scleractinian coral Astrangia poculata with in situ pH microelectrode measurements of the coral's calcifying fluid under control and acidified conditions. These measurements reveal that (1) the pH and, thus, aragonite saturation

  12. Vimentin Is Involved in Peptidylarginine Deiminase 2-Induced Apoptosis of Activated Jurkat Cells

    PubMed Central

    Hsu, Pei-Chen; Liao, Ya-Fan; Lin, Chin-Li; Lin, Wen-Hao; Liu, Guang-Yaw; Hung, Hui-Chih

    2014-01-01

    Peptidylarginine deiminase type 2 (PADI2) deiminates (or citrullinates) arginine residues in protein to citrulline residues in a Ca2+-dependent manner, and is found in lymphocytes and macrophages. Vimentin is an intermediate filament protein and a well-known substrate of PADI2. Citrullinated vimentin is found in ionomycin-induced macrophage apoptosis. Citrullinated vimentin is the target of anti-Sa antibodies, which are specific to rheumatoid arthritis, and play a critical role in the pathogenesis of the disease. To investigate the role of PADI2 in apoptosis, we generated a Jurkat cell line that overexpressed the PADI2 transgene from a tetracycline-inducible promoter, and used a combination of 12-O-tetradecanoylphorbol-13-acetate and ionomycin to activate Jurkat cells. We found that PADI2 overexpression reduced the cell viability of activated Jurkat cells in a dose- and time-dependent manner. The PADI2-overexpressed and -activated Jurkat cells presented typical manifestations of apoptosis, and exhibited greater levels of citrullinated proteins, including citrullinated vimentin. Vimentin overexpression rescued a portion of the cells from apoptosis. In conclusion, PADI2 overexpression induces apoptosis in activated Jurkat cells. Vimentin is involved in PADI2-induced apoptosis. Moreover, PADI2-overexpressed Jurkat cells secreted greater levels of vimentin after activation, and expressed more vimentin on their cell surfaces when undergoing apoptosis. Through artificially highlighting PADI2 and vimentin, we demonstrated that PADI2 and vimentin participate in the apoptotic mechanisms of activated T lymphocytes. The secretion and surface expression of vimentin are possible ways of autoantigen presentation to the immune system. PMID:24850148

  13. BMP-2 Induced Expression of PLCβ1 That is a Positive Regulator of Osteoblast Differentiation.

    PubMed

    Ramazzotti, Giulia; Bavelloni, Alberto; Blalock, William; Piazzi, Manuela; Cocco, Lucio; Faenza, Irene

    2016-03-01

    Bone morphogenetic protein 2 (BMP-2) is a critical growth factor that directs osteoblast differentiation and bone formation. Phosphoinositide-phospholipase Cβ 1 (PLCβ1) plays a crucial role in the initiation of the genetic program responsible for muscle differentiation. Differentiation of C2C12 mouse myoblasts in response to insulin stimulation is characterized by a marked increase in nuclear PLCβ1. Here, the function of PLCβ1 in the osteogenic differentiation was investigated. Briefly, in C2C12 cells treated with BMP-2 we assist to a remarkable increase in PLCβ1 protein and mRNA expression. The data regarding the influence on differentiation demonstrated that PLCβ1 promotes osteogenic differentiation by up-regulating alkaline phosphatase (ALP). Moreover, PLCβ1 is present in the nuclear compartment of these cells and overexpression of a cytosolic-PLCβ1mutant (cyt-PLCβ1), which lacks a nuclear localization sequence, prevented the differentiation of C2C12 cells into osteocytes. Recent evidence indicates that miRNAs act as important post transcriptional regulators in a large number of processes, including osteoblast differentiation. Since miR-214 is a regulator of Osterix (Osx) which is an osteoblast-specific transcription factor that is needful for osteoblast differentiation and bone formation, we further investigated whether PLCβ1 could be a potential target of miR-214 in the control of osteogenic differentiation by gain- and loss- of function experiment. The results indicated that inhibition of miR-214 in C2C12 cells significantly enhances the protein level of PLCβ1 and promotes C2C12 BMP-2-induced osteogenesis by targeting PLCβ1. PMID:26217938

  14. Prostaglandin D(2) induces contraction via thromboxane A(2) receptor in rat liver myofibroblasts.

    PubMed

    Maruyama, Tomoharu; Murata, Takahisa; Ayabe, Shinya; Hori, Masatoshi; Ozaki, Hiroshi

    2008-09-01

    Increased intrahepatic resistance is one of the major characteristics of cirrhotic liver, in which extravascular cells including liver myofibroblasts (MFs) abnormally contract. Although several studies provided evidence that various prostaglandins (PG) are involved in liver cirrhosis, the role of PGD(2) remains unknown. In this study, we investigated the effect of PGD(2) on the contractile properties of liver MFs. Cultured rat liver MFs were used at passages 4-7. A collagen gel contraction assay was used for the evaluation of the MFs contraction. mRNA expression was assessed by semi-quantitative RT-PCR. Intracellular Ca(2+) concentrations ([Ca(2+)](i)) were measured by monitoring the fluorescence intensity of fura-2. PGD(2) (1-10 microM) induced liver MF contraction in a dose-dependent manner with [Ca(2+)](i) elevation. Pretreatment with 300 nM LaCl(3), a nonselective Ca(2+) channel blocker abolished the 10 microM PGD(2)-induced MFs contraction. RT-PCR revealed that three distinct PGD(2) responsive receptors, prostanoid DP receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and thromboxane A(2) receptor (prostanoid TP receptor), were expressed in liver MFs. While prostanoid DP receptor agonist and CRTH2 agonist didn't induce contraction, 0.01-1 microM U46619 (11alpha, 9alpha-epoxymethano-PGH(2), prostanoid TP receptor agonist) caused robust contraction with [Ca(2+)](i) elevation. Furthermore, pretreatment with prostanoid TP receptor antagonists ramatroban (1 microM) or SQ29548 ([1S-[1alpha, 2alpha(Z), 3alpha, 4alpha

  15. Protein composition of 6K2-induced membrane structures formed during Potato virus A infection.

    PubMed

    Lõhmus, Andres; Varjosalo, Markku; Mäkinen, Kristiina

    2016-08-01

    The definition of the precise molecular composition of membranous replication compartments is a key to understanding the mechanisms of virus multiplication. Here, we set out to investigate the protein composition of the potyviral replication complexes. We purified the potyviral 6K2 protein-induced membranous structures from Potato virus A (PVA)-infected Nicotiana benthamiana plants. For this purpose, the 6K2 protein, which is the main inducer of potyviral membrane rearrangements, was expressed in fusion with an N-terminal Twin-Strep-tag and Cerulean fluorescent protein (SC6K) from the infectious PVA cDNA. A non-tagged Cerulean-6K2 (C6K) virus and the SC6K protein alone in the absence of infection were used as controls. A purification scheme exploiting discontinuous sucrose gradient centrifugation followed by Strep-tag-based affinity chromatography was developed. Both (+)- and (-)-strand PVA RNA and viral protein VPg were co-purified specifically with the affinity tagged PVA-SC6K. The purified samples, which contained individual vesicles and membrane clusters, were subjected to mass spectrometry analysis. Data analysis revealed that many of the detected viral and host proteins were either significantly enriched or fully specifically present in PVA-SC6K samples when compared with the controls. Eight of eleven potyviral proteins were identified with high confidence from the purified membrane structures formed during PVA infection. Ribosomal proteins were identified from the 6K2-induced membranes only in the presence of a replicating virus, reinforcing the tight coupling between replication and translation. A substantial number of proteins associating with chloroplasts and several host proteins previously linked with potyvirus replication complexes were co-purified with PVA-derived SC6K, supporting the conclusion that the host proteins identified in this study may have relevance in PVA replication. PMID:26574906

  16. Physiological and genetic analysis of CO2-induced breakdown of self-incompatibility in Brassica rapa.

    PubMed

    Lao, Xintian; Suwabe, Keita; Niikura, Satoshi; Kakita, Mitsuru; Iwano, Megumi; Takayama, Seiji

    2014-03-01

    Self-incompatibility (SI) of the Brassicaceae family can be overcome by CO2 gas treatment. This method has been used for decades as an effective means to obtain a large amount of inbred seeds which can then be used for F1 hybrid seed production; however, the molecular mechanism by which CO2 alters the SI pathway has not been elucidated. In this study, to obtain new insights into the mechanism of CO2-induced SI breakdown, the focus was on two inbred lines of Brassica rapa (syn. campestris) with different CO2 sensitivity. Physiological examination using X-ray microanalysis suggested that SI breakdown in the CO2-sensitive line was accompanied by a significant accumulation of calcium at the pollen-stigma interface. Pre-treatment of pollen or pistil with CO2 gas before pollination showed no effect on the SI reaction, suggesting that some physiological process after pollination is necessary for SI to be overcome. Genetic analyses using F1 progeny of a CO2-sensitive × CO2-insensitive cross suggested that CO2 sensitivity is a semi-dominant trait in these lines. Analysis of F2 progeny suggested that CO2 sensitivity could be a quantitative trait, which is controlled by more than one gene. Quantitative trait locus (QTL) analyses identified two major loci, BrSIO1 and BrSIO2, which work additively in overcoming SI during CO2 treatment. No QTL was detected at the loci previously shown to affect SI stability, suggesting that CO2 sensitivity is determined by novel genes. The QTL data presented here should be useful for determining the responsible genes, and for the marker-assisted selection of desirable parental lines with stable but CO2-sensitive SI in F1 hybrid breeding. PMID:24376255

  17. Nitrogen mediates CO2-induced changes in rhizosphere priming effects in an aggrading forest (Invited)

    NASA Astrophysics Data System (ADS)

    Phillips, R.; Bernhardt, E. S.; Finzi, A.

    2009-12-01

    Root-induced changes in soil organic matter (SOM) decomposition are likely to provide an important feedback to carbon storage in terrestrial ecosystems but to date, there have been few measurements of such “priming effects” in forest soils. Our goal was to estimate the potential magnitude of SOM priming in a 28 year-old loblolly pine stand exposed to elevated atmospheric CO2 (ambient + 200 ppm) and nitrogen fertilization (11 g m-2 yr-1) at the Duke Forest FACE site, NC. We hypothesized that CO2- and nitrogen-induced changes in carbon supply to soil via root exudation would mediate the magnitude and timing of priming effects. Over a two-year period, trees exposed to CO2 enrichment increased dissolved carbon supply to soil by ~50% in nutrient-poor soils, resulting in a doubling of microbial biomass in the rhizosphere in the upper 10 cm of mineral soil (p < 0.05). Fumigated trees that also received nitrogen fertilizer did not exhibit significant increases in root exudation or microbial biomass. Coincident with these changes, elevated CO2 induced significant increases in lignolytic and proteolytic extracellular enzymes involved in SOM depolymerization, with the greatest changes occurring in non-fertilized soils. We interpret the enhanced microbial and enzyme activities in the rhizosphere as evidence of root-induced priming effects. Collectively, our results suggest that although increased carbon flux from to roots to soil may provide a mechanism for trees to accelerate soil nitrogen cycling under elevated CO2, such inputs may also accelerate SOM decomposition and thus reduce storage in the longest lived, most stable pools of carbon in aggrading forests.

  18. Mitochondrial Uncoupling Protein 2 Induces Cell Cycle Arrest and Necrotic Cell Death

    PubMed Central

    Palanisamy, Arun P.; Cheng, Gang; Sutter, Alton G.; Evans, Zachary P.; Polito, Carmen C.; Jin, Lan; Liu, John; Schmidt, Michael G.

    2014-01-01

    Abstract Uncoupling protein 2 (UCP2) is a mitochondrial membrane protein that regulates energy metabolism and reactive oxygen species (ROS) production. We generated mouse carboxy- and amino-terminal green fluorescent protein (GFP)-tagged UCP2 constructs to investigate the effect of UCP2 expression on cell proliferation and viability. UCP2-transfected Hepa 1–6 cells did not show reduced cellular adenosine triphosphate (ATP) but showed increased levels of glutathione. Flow cytometry analysis indicated that transfected cells were less proliferative than nontransfected controls, with most cells blocked at the G1 phase. The effect of UCP2 on cell cycle arrest could not be reversed by providing exogenous ATP or oxidant supply, and was not affected by the chemical uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP). However, this effect of UCP2 was augmented by treatment with genistein, a tyrosine kinase inhibitor, which by itself did not affect cell proliferation on control hepatocytes. Western blotting analysis revealed decreased expression levels of CDK6 but not CDK2 and D-type cyclins. Examination of cell viability in UCP2-transfected cells with Trypan Blue and Annexin-V staining revealed that UCP2 transfection led to significantly increased cell death. However, characteristics of apoptosis were absent in UCP2-transfected Hepa 1–6 cells, including lack of oligonucleosomal fragmentation (laddering) of chromosomal DNA, release of cytochrome c from mitochondria, and cleavage of caspase-3. In conclusion, our results indicate that UCP2 induces cell cycle arrest at G1 phase and causes nonapoptotic cell death, suggesting that UCP2 may act as a powerful influence on hepatic regeneration and cell death in the steatotic liver. PMID:24320727

  19. IL-2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

    PubMed Central

    Carson, Craig C.; Moschos, Stergios J.; Edmiston, Sharon N.; Darr, David B.; Nikolaishvili-Feinberg, Nana; Groben, Pamela A.; Zhou, Xin; Kuan, Pei Fen; Pandey, Shaily; Chan, Keefe T.; Jordan, Jamie L.; Hao, Honglin; Frank, Jill S.; Hopkinson, Dennis A.; Gibbs, David C.; Alldredge, Virginia D.; Parrish, Eloise; Hanna, Sara C.; Berkowitz, Paula; Rubenstein, David S.; Miller, C. Ryan; Bear, James E.; Ollila, David W.; Sharpless, Norman E.; Conway, Kathleen; Thomas, Nancy E.

    2015-01-01

    Purpose Interleukin-2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared to nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. Experimental Design An ITK specific monoclonal antibody was used to probe sections from de-identified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by immunohistochemistry. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. Results ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacological inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0/G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten null/Braf V600E) melanomas. Conclusions We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small molecule ITK inhibitor in the Tyr-Cre/Ptennull/BrafV600E mouse melanoma model supports this possibility. PMID:25934889

  20. Atmospheric impacts of sea ice decline in CO2 induced global warming

    NASA Astrophysics Data System (ADS)

    Cvijanovic, Ivana; Caldeira, Ken

    2015-03-01

    Changes in sea ice cover have important consequences for both Earth's energy budget and atmospheric dynamics. Sea ice acts as a positive feedback in the climate system, amplifying effects of radiative forcing while also affecting the meridional and interhemispheric temperature gradients that can impact mid- and low latitude atmospheric circulation. In this study, we partition and evaluate the effects of changing sea ice cover on global warming using a set of simulations with active and suppressed sea ice response. Two aspects of CO2-induced sea ice changes are investigated: (1) the effect of changing sea ice cover on global and local temperature changes; and (2) the impact of sea ice loss on atmospheric circulation and extreme weather events. We find that in the absence of sea ice decline, global temperature response decreases by 21-37 %, depending on the sea ice treatment and the CO2 forcing applied. Weakened global warming in the absence of changes in sea ice cover is not only due to a decreased high latitude warming but is also a consequence of a weaker tropical warming. In the northern midlatitudes, sea ice decline affects the magnitude and sign of zonal wind response to global warming in the winter and autumn seasons. Presence or absence of sea ice cover impacts the intensity and frequency of winter extreme precipitation and temperature events (temperature minima, number of heavy precipitation days and number of ice days). For some of the analyzed extreme weather indices, the difference between the responses with and without sea ice decline is eliminated when taking into account the amplifying effect of sea ice loss on hemispheric warming. However, in other cases, we find the influence of higher order factors, exerting weaker but opposing effects than those expected from the global temperature increase.

  1. IL-4 acts as a homeostatic regulator of IL-2-induced TNF and IFN-gamma.

    PubMed Central

    Bello-Fernandez, C; Oblakowski, P; Meager, A; Duncombe, A S; Rill, D M; Hoffbrand, A V; Brenner, M K

    1991-01-01

    Interleukin-4 (IL-4) is a cytokine secreted by interleukin-2 (IL-2)-activated lymphocytes. IL-2-stimulated lymphocytes also secrete two cytokines, tumour necrosis factor (TNF) and gamma-interferon (IFN-gamma), which contribute to effector function and which may themselves recruit fresh, cytokine-secreting effector cells. We have now investigated whether the IL-4 induced is able to homeostatically regulate secretion of the TNF and IFN-gamma. Peripheral blood mononuclear cells or lymphocytes from normal donors and from patients with neoplastic disease were cultured in the presence of IL-2 alone, IL-4 alone or with both cytokines. IL-2 induced high levels of TNF and IFN-gamma secretion in both groups. The addition of recombinant IL-4 to these IL-2-stimulated cultures lead to significant inhibition of IFN-gamma and TNF production. IFN-gamma secretion was reduced by 50-99% in normal donors and by between 11% and 99% in patients (P less than 0.001). TNF levels induced by IL-2 were similarly reduced by IL-4 both in normal donors (P less than 0.003) and in patients (P less than 0.01). These inhibitory effects were produced by IL-4 at doses of IL-2 attainable in vivo. Inhibition appears to represent a homeostatic regulatory mechanism which may limit recruitment of fresh activated killer (AK) cells. When endogenous IL-4 activity in IL-2-activated lymphocytes was blocked by anti-IL-4 antibody, significantly higher levels of IFN-gamma and TNF were secreted (P less than 0.05). Since both TNF and IFN-gamma may contribute to the anti-neoplastic action of IL-2, manipulating the level of IL-4 activity in vivo could augment the benefits of IL-2 immunotherapy. PMID:1901829

  2. Ocean Warming and CO2-Induced Acidification Impact the Lipid Content of a Marine Predatory Gastropod

    PubMed Central

    Valles-Regino, Roselyn; Tate, Rick; Kelaher, Brendan; Savins, Dale; Dowell, Ashley; Benkendorff, Kirsten

    2015-01-01

    Ocean warming and acidification are current global environmental challenges impacting aquatic organisms. A shift in conditions outside the optimal environmental range for marine species is likely to generate stress that could impact metabolic activity, with consequences for the biosynthesis of marine lipids. The aim of this study was to investigate differences in the lipid content of Dicathais orbita exposed to current and predicted future climate change scenarios. The whelks were exposed to a combination of temperature and CO2-induced acidification treatments in controlled flowthrough seawater mesocosms for 35 days. Under current conditions, D. orbita foot tissue has an average of 6 mg lipid/g tissue, but at predicted future ocean temperatures, the total lipid content dropped significantly, to almost half. The fatty acid composition is dominated by polyunsaturated fatty acids (PUFA 52%) with an n-3:6 fatty acid ratio of almost 2, which remains unchanged under future ocean conditions. However, we detected an interactive effect of temperature and pCO2 on the % PUFAs and n-3 and n-6 fatty acids were significantly reduced by elevated water temperature, while both the saturated and monounsaturated fatty acids were significantly reduced under increased pCO2 acidifying conditions. The present study indicates the potential for relatively small predicted changes in ocean conditions to reduce lipid reserves and alter the fatty acid composition of a predatory marine mollusc. This has potential implications for the growth and survivorship of whelks under future conditions, but only minimal implications for human consumption of D. orbita as nutritional seafood are predicted. PMID:26404318

  3. Endogenous PGE(2) induces MCP-1 expression via EP4/p38 MAPK signaling in melanoma.

    PubMed

    Tang, Mingrui; Wang, Yuxin; Han, Sihuan; Guo, Shu; Xu, Nan; Guo, Jiayan

    2013-02-01

    It has been demonstrated that cyclooxygenase-2 (COX-2) is expressed in melanoma tissues and prostaglandin E(2) (PGE(2)) is produced by melanoma cells in vitro. However, the roles of COX-2/PGE(2) in melanoma are largely unknown. In the present study, we set out to analyze the correlation of endogenous PGE(2) with the expression of macrophage chemoattractant protein-1 (MCP-1) and to identify the signaling pathway involved. It was found that MCP-1 mRNA was heterogeneously expressed in 18 melanoma tissue specimens, and the levels of MCP-1 mRNA were positively correlated with those of COX-2 mRNA. Inhibition of endogenous PGE(2) production by a COX-2 inhibitor, COX-2 siRNA or an NFκB inhibitor suppressed MCP-1 expression, whereas treatment with TNF-α (to stimulate endogenous PGE(2) production) or exogenous PGE(2) enhanced MCP-1 expression in melanoma cells. Both the EP4 antagonist and the p38 MAPK inhibitor reduced MCP-1 production in melanoma cells, and abrogated the increased MCP-1 secretion induced by TNF-α or exogenous PGE(2). Conditioned medium from melanoma cells promoted macrophage migration, which was blocked by inhibitors of the PGE(2)/EP4/p38 MAPK signaling pathway. These results indicate that endogenous PGE(2) induces MCP-1 expression via EP4/p38 MAPK signaling in an autocrinal manner in melanoma, and melanoma cell-derived PGE(2) may be involved in macrophage recruitment in the melanoma microenvironment. PMID:23420676

  4. Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction*

    PubMed Central

    Luth, Eric S.; Stavrovskaya, Irina G.; Bartels, Tim; Kristal, Bruce S.; Selkoe, Dennis J.

    2014-01-01

    α-Synuclein (αSyn) aggregation and mitochondrial dysfunction both contribute to the pathogenesis of Parkinson disease (PD). Although recent studies have suggested that mitochondrial association of αSyn may disrupt mitochondrial function, it is unclear what aggregation state of αSyn is most damaging to mitochondria and what conditions promote or inhibit the effect of toxic αSyn species. Because the neuronal populations most vulnerable in PD are characterized by large cytosolic Ca2+ oscillations that burden mitochondria, we examined mitochondrial Ca2+ stress in an in vitro system comprising isolated mitochondria and purified recombinant human αSyn in various aggregation states. Using fluorimetry to simultaneously measure four mitochondrial parameters, we observed that soluble, prefibrillar αSyn oligomers, but not monomeric or fibrillar αSyn, decreased the retention time of exogenously added Ca2+, promoted Ca2+-induced mitochondrial swelling and depolarization, and accelerated cytochrome c release. Inhibition of the permeability transition pore rescued these αSyn-induced changes in mitochondrial parameters. Interestingly, the mitotoxic effects of αSyn were specifically dependent upon both electron flow through complex I and mitochondrial uptake of exogenous Ca2+. Our results suggest that soluble prefibrillar αSyn oligomers recapitulate several mitochondrial phenotypes previously observed in animal and cell models of PD: complex I dysfunction, altered membrane potential, disrupted Ca2+ homeostasis, and enhanced cytochrome c release. These data reveal how the association of oligomeric αSyn with mitochondria can be detrimental to the function of cells with high Ca2+-handling requirements. PMID:24942732

  5. Prostaglandin E2-induced diarrhea in mice: importance of colonic secretion.

    PubMed

    Rivière, P J; Farmer, S C; Burks, T F; Porreca, F

    1991-02-01

    The present study has investigated the basis for induction of diarrhea by prostaglandin (PG)E2 in mice. When given i.p., PGE2 induced a dose- and time-dependent diarrhea; the shortest post-treatment time for diarrhea onset was approximately 7 min, at a PGE2 dose of 200 micrograms/kg. At this dose, PGE2 also produced accumulation of fluid in the small intestine and in the colon (enteropooling). The enteropooling reached its maximum by 9 min and did not decrease until approximately 11 min (i.e., 2 to 4 min after the mean time for diarrhea onset). PGE2 treatment altered neither gastric emptying nor gastrointestinal propulsion, but strongly enhanced the expulsion of a glass bead from the colon (i.e., decreased the time to bead expulsion). The shortest time to expulsion of the glass bead was observed at 200 micrograms/kg i.p. The induction of diarrhea by PGE2 was unaffected by cecectomy, or sham-cecectomy, but the dose-response curve for time to onset of diarrhea by i.p. PGE2 was displaced to the right in animals with ligations of the ileo-ceco-colonic (ICC) junctions. The intraluminal fluid accumulation in the colon, evaluated in mice with ICC ligations, was increased by PGE2 administration within 2 min and remained greater than in vehicle-treated animals until the onset of diarrhea. The stimulation of colonic bead expulsion produced by i.p. PGE2 in control mice was not observed in animals with acute ICC ligations, even at i.p. doses up to 800 micrograms/kg.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1993994

  6. Chemical Inhibition of Histone Deacetylases 1 and 2 Induces Fetal Hemoglobin through Activation of GATA2

    PubMed Central

    Golonzhka, Olga; Chonkar, Apurva; Tamang, David; van Duzer, John H.; Jones, Simon S.; Jarpe, Matthew B.

    2016-01-01

    Therapeutic intervention aimed at reactivation of fetal hemoglobin protein (HbF) is a promising approach for ameliorating sickle cell disease (SCD) and β-thalassemia. Previous studies showed genetic knockdown of histone deacetylase (HDAC) 1 or 2 is sufficient to induce HbF. Here we show that ACY-957, a selective chemical inhibitor of HDAC1 and 2 (HDAC1/2), elicits a dose and time dependent induction of γ-globin mRNA (HBG) and HbF in cultured primary cells derived from healthy individuals and sickle cell patients. Gene expression profiling of erythroid progenitors treated with ACY-957 identified global changes in gene expression that were significantly enriched in genes previously shown to be affected by HDAC1 or 2 knockdown. These genes included GATA2, which was induced greater than 3-fold. Lentiviral overexpression of GATA2 in primary erythroid progenitors increased HBG, and reduced adult β-globin mRNA (HBB). Furthermore, knockdown of GATA2 attenuated HBG induction by ACY-957. Chromatin immunoprecipitation and sequencing (ChIP-Seq) of primary erythroid progenitors demonstrated that HDAC1 and 2 occupancy was highly correlated throughout the GATA2 locus and that HDAC1/2 inhibition led to elevated histone acetylation at well-known GATA2 autoregulatory regions. The GATA2 protein itself also showed increased binding at these regions in response to ACY-957 treatment. These data show that chemical inhibition of HDAC1/2 induces HBG and suggest that this effect is mediated, at least in part, by histone acetylation-induced activation of the GATA2 gene. PMID:27073918

  7. Protective effects of veskamide, enferamide, becatamide, and oretamide on H2O2-induced apoptosis of PC-12 cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Veskamide, enferamide, becatamide, and oretamide are phenolic amides whose analogues are found in plants. In this study, the four amides were prepared by chemical synthesis and their protective effects on H(2)O(2)-induced apoptosis in PC-12 cells were investigated. The syntheses were relatively si...

  8. Inhibition of prothrombin kringle-2-induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo.

    PubMed

    Nam, Jin Han; Leem, Eunju; Jeon, Min-Tae; Kim, Young-Je; Jung, Un Ju; Choi, Myung-Sook; Maeng, Sungho; Jin, Byung Kwan; Kim, Sang Ryong

    2014-05-01

    Prothrombin kringle-2 (pKr-2), a domain of prothrombin, can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation. However, the chemical products that inhibit pKr-2-induced inflammatory activities in the brain are still not well known. The present study investigated whether minocycline, a semisynthetic tetracycline derivative, could inhibit pKr-2-induced microglial activation and prevent the loss of nigral dopaminergic (DA) neurons in vivo. To address this question, rats were administered a unilateral injection of pKr-2 in the substantia nigra in the presence or absence of minocycline. Our results show that pKr-2 induces the production of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inducible nitric oxide synthase from the activated microglia. In parallel, 7 days after pKr-2 injection, tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons. This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor-α, interleukin-1β, and nitric oxide synthase. These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr-2-induced microglial activation. PMID:24488033

  9. Use of indomethacin as an adjuvant to surgery for recurrent temporomandibular joint ankylosis in adults

    PubMed Central

    Bhatt, Krushna; Pandey, Sandeep; Bhutia, Ongkila; Roychoudhury, Ajoy

    2014-01-01

    Two cases with multiple recurrences of temporomandibular joint ankylosis and multiple failed interposition/gap arthroplasty procedures are presented here. Heterotopic bone formation was thought to be the reason. Indomethacin prophylaxis for prevention of heterotopic new bone formation at the osteoarthrectomy site was used as an adjuvant to surgery, in dosages of 75 mg/day for six weeks. Indomethacin is used frequently in hip and elbow arthroplasties to prevent heterotopic ossification, but its use in temporomandibular joint is not routine. The presented cases did not develop further recurrence and attained stable mouth opening over two-year follow-up after osteoarthrectomy and oral indomethacin. PMID:25937735

  10. Effect of plant extracts on H2O2-induced inflammatory gene expression in macrophages

    PubMed Central

    Pomari, Elena; Stefanon, Bruno; Colitti, Monica

    2014-01-01

    Background Arctium lappa (AL), Camellia sinensis (CS), Echinacea angustifolia, Eleutherococcus senticosus, Panax ginseng (PG), and Vaccinium myrtillus (VM) are plants traditionally used in many herbal formulations for the treatment of various conditions. Although they are well known and already studied for their anti-inflammatory properties, their effects on H2O2-stimulated macrophages are a novel area of study. Materials and methods Cell viability was tested after treatment with increasing doses of H2O2 and/or plant extracts at different times of incubation to identify the optimal experimental conditions. The messenger (m)RNA expression of TNFα, COX2, IL1β, NFκB1, NFκB2, NOS2, NFE2L2, and PPARγ was analyzed in macrophages under H2O2 stimulation. The same genes were also quantified after plant extract treatment on cells pre-stimulated with H2O2. Results A noncytotoxic dose (200 μM) of H2O2 induced active mRNA expression of COX2, IL1β, NFE2L2, NFκB1, NFκB2, NOS2, and TNFα, while PPARγ was depressed. The expression of all genes tested was significantly (P<0.001) regulated by plant extracts after pre-stimulation with H2O2. COX2 was downregulated by AL, PG, and VM. All extracts depressed IL1β expression, but upregulated NFE2L2. NFκB1, NFκB2, and TNFα were downregulated by AL, CS, PG, and VM. NOS2 was inhibited by CS, PG, and VM. PPARγ was decreased only after treatment with E. angustifolia and E. senticosus. Conclusion The results of the present study indicate that the stimulation of H2O2 on RAW267.4 cells induced the transcription of proinflammatory mediators, showing that this could be an applicable system by which to activate macrophages. Plant extracts from AL, CS, PG, and VM possess in vitro anti-inflammatory activity on H2O2-stimulated macrophages by modulating key inflammation mediators. Further in vitro and in vivo investigation into molecular mechanisms modulated by herbal extracts should be undertaken to shed light on the development of novel

  11. LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

    PubMed Central

    2013-01-01

    Introduction Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigated the effects of LOXL2 expression in normal mammary epithelial cells to gain insight into how LOXL2 mediates cancer progression. Methods LOXL2 was expressed in MCF10A normal human mammary epithelial cells. The 3D acinar morphogenesis of these cells was assessed, as well as the ability of the cells to form branching structures on extracellular matrix (ECM)-coated surfaces. Transwell-invasion assays were used to assess the invasive properties of the cells. Clinically relevant inhibitors of ErbB2, lapatinib and Herceptin (traztuzumab), were used to investigate the role of ErbB2 signaling in this model. A retrospective study on a previously published breast cancer patient dataset was carried out by using Disease Specific Genomic Analysis (DSGA) to investigate the correlation of LOXL2 mRNA expression level with metastasis and survival of ErbB2-positive breast cancer patients. Results Fluorescence staining of the acini revealed increased proliferation, decreased apoptosis, and disrupted polarity, leading to abnormal lumen formation in response to LOXL2 expression in MCF10A cells. When plated onto ECM, the LOXL2-expressing cells formed branching structures and displayed increased invasion. We noted that LOXL2 induced ErbB2 activation through reactive oxygen species (ROS) production, and ErbB2 inhibition by using Herceptin or lapatinib abrogated the effects of LOXL2 on MCF10A cells. Finally, we found LOXL2 expression to be correlated with decreased overall survival and metastasis-free survival in breast cancer patients with ErbB2-positive tumors. Conclusions These findings suggest that LOXL2 expression in normal epithelial cells can induce abnormal changes that resemble oncogenic transformation and cancer progression

  12. Sphingosine 1-phosphate receptor activation enhances BMP-2-induced osteoblast differentiation

    SciTech Connect

    Sato, Chieri; Iwasaki, Tsuyoshi; Kitano, Sachie; Tsunemi, Sachi; Sano, Hajime

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer We investigated the role of S1P signaling for osteoblast differentiation. Black-Right-Pointing-Pointer Both S1P and FTY enhanced BMP-2-stimulated osteoblast differentiation by C2C12 cells. Black-Right-Pointing-Pointer S1P signaling enhanced BMP-2-stimulated Smad and ERK phosphorylation by C2C12 cells. Black-Right-Pointing-Pointer MEK/ERK signaling is a pathway underlying S1P signaling for osteoblast differentiation. -- Abstract: We previously demonstrated that sphingosine 1-phosphate (S1P) receptor-mediated signaling induced proliferation and prostaglandin productions by synovial cells from rheumatoid arthritis (RA) patients. In the present study we investigated the role of S1P receptor-mediated signaling for osteoblast differentiation. We investigated osteoblast differentiation using C2C12 myoblasts, a cell line derived from murine satellite cells. Osteoblast differentiation was induced by the treatment of bone morphogenic protein (BMP)-2 in the presence or absence of either S1P or FTY720 (FTY), a high-affinity agonist of S1P receptors. Osteoblast differentiation was determined by osteoblast-specific transcription factor, Runx2 mRNA expression, alkaline phosphatase (ALP) activity and osteocalcin production by the cells. Smad1/5/8 and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was examined by Western blotting. Osteocalcin production by C2C12 cells were determined by ELISA. Runx2 expression and ALP activity by BMP-2-stimulated C2C12 cells were enhanced by addition of either S1P or FTY. Both S1P and FTY enhanced BMP-2-induced ERK1/2 and Smad1/5/8 phosphorylation. The effect of FTY was stronger than that of S1P. S1P receptor-mediated signaling on osteoblast differentiation was inhibited by addition of mitogen-activated protein kinase/ERK kinase (MEK) 1/2 inhibitor, indicating that the S1P receptor-mediated MEK1/2-ERK1/2 signaling pathway enhanced BMP-2-Smad signaling. These results indicate that S1P

  13. Glucagon like peptide-2 induces intestinal restitution through VEGF release from subepithelial myofibroblasts.

    PubMed

    Bulut, Kerem; Pennartz, Christian; Felderbauer, Peter; Meier, Juris J; Banasch, Matthias; Bulut, Daniel; Schmitz, Frank; Schmidt, Wolfgang E; Hoffmann, Peter

    2008-01-14

    repair, whereas no such effects were observed in colonic cells. The mechanisms underlying GLP-2 induced intestinal wound repair seem to involve the secretion of VEGF and, subsequently, TGF-beta from subepithelial fibroblasts, whereas KGF appeared to be less important. PMID:17920582

  14. Bile acid accelerates erbB2-induced pro-tumorigenic activities in biliary tract cancer.

    PubMed

    Kitamura, Takuya; Srivastava, Jaya; DiGiovanni, John; Kiguchi, Kaoru

    2015-06-01

    erbB2 activation in epithelial cell proliferation; bile acid appears to accelerate erbB2-induced pro-tumorigenic activities in the biliary tract and skin. PMID:24839254

  15. A compound heterozygote SLC26A2 mutation resulting in robin sequence, mild limbs shortness, accelerated carpal ossification, and multiple epiphysial dysplasia in two Brazilian sisters. A new intermediate phenotype between diastrophic dysplasia and recessive multiple epiphyseal dysplasia.

    PubMed

    Zechi-Ceide, Roseli Maria; Moura, Priscila Padilha; Raskin, Salmo; Richieri-Costa, Antonio; Guion-Almeida, Maria Leine

    2013-08-01

    Mutations in solute carrier family 26 (sulfate transporter), member 2 (SLC26A2) gene result in a spectrum of autosomal recessive chondrodysplasias that range from the mildest recessive form of multiple epiphysial dysplasia (rMED) through the most common diastrophic dysplasia (DTD) to lethal atelosteogenesis type II and achondrogenesis IB. The clinical variability has been ascribed to quantitative effect of mutations of the sulfate transporter activity. Here we describe two Brazilian sisters, born to healthy and non consanguineous parents, with Robin sequence, mild shortening of upper and lower limbs, brachymetacarpalia/tarsalia, additional and accelerated carpal ossification, marked genu valgum, and multiple epiphysial dysplasia. This phenotype was intermediate between DTD and rMED, and both girls have a compound heterozygous mutations for the SLC26A2, a Finnish founder mutation (c.-26 + 2T>C), and R279W. This combination of mutations has been observed in individuals with different phenotypes, including DTD, DTD variant, and rMED. The distinct phenotype of our cases reinforces the hypothesis that other factors may be influencing the phenotype as previously suggested. PMID:23840040

  16. The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo

    PubMed Central

    Grace, M S; Lieu, T; Darby, B; Abogadie, F C; Veldhuis, N; Bunnett, N W; McIntyre, P

    2014-01-01

    BACKGROUND AND PURPOSE Protease-activated receptor 2 (PAR2) is expressed on nociceptive neurons, and can sensitize transient receptor potential (TRP) ion channels to amplify neurogenic inflammation and pain. The mechanisms by which this occurs are not fully understood. PAR2 causes receptor-operated activation of TRPV4 channels and TRPV4 null mice have attenuated PAR2-stimulated neurogenic inflammation and mechanical hyperalgesia. Here we investigate the intracellular signalling mechanisms underlying PAR2-induced TRPV4 channel activation and pain. EXPERIMENTAL APPROACH Responses of non-transfected and TRPV4-transfected HEK293 cells to agonists of PAR2 (trypsin and SLIGRL) and TRPV4 channels (GSK1016790A) were determined using calcium imaging. Inhibitors of TRPV4 channels (HC067047), sarcoendoplasmic reticulum calcium transport ATPase (thapsigargin), Gαq (UBO-QIC), tyrosine kinases (bafetinib and dasatinib) or PI3 kinases (wortmannin and LY294002) were used to investigate signalling mechanisms. In vivo effects of tyrosine kinase inhibitors on PAR2-induced mechanical hyperalgesia were assessed in mice. KEY RESULTS In non-transfected HEK293 cells, PAR2 activation transiently increased intracellular calcium ([Ca2+]i). Functional expression of TRPV4 channels caused a sustained increase of [Ca2+]i, inhibited by HC067047, bafetinib and wortmannin; but not by thapsigargin, UBO-QIC, dasatinib or LY294002. Bafetinib but not dasatinib inhibited PAR2-induced mechanical hyperalgesia in vivo. CONCLUSIONS AND IMPLICATIONS This study supports a role for tyrosine kinases in PAR2-mediated receptor-operated gating of TRPV4 channels, independent of Gαq stimulation. The ability of a tyrosine kinase inhibitor to diminish PAR2-induced activation of TRPV4 channels and consequent mechanical hyperalgesia identifies bafetinib (which is in development in oncology) as a potential novel analgesic therapy. PMID:24779362

  17. Protective effect of bioactive compounds from Lonicera japonica Thunb. against H2O2-induced cytotoxicity using neonatal rat cardiomyocytes

    PubMed Central

    Wang, Chen; Wang, Gang; Liu, Hong; Hou, Yun-long

    2016-01-01

    Objective(s): Pharmacological studies showed that the extracts of Jin Yin Hua and its active constituents have lipid lowering, antipyretic, hepatoprotective, cytoprotective, antimicrobial, antibiotic, antioxidative, antiviral, and anti-inflammatory effects. The purpose of the present study was to investigate the protective effects of caffeoylquinic acids (CQAs) from Jin Yin Hua against hydrogen peroxide (H2O2)-induced and hypoxia-induced cytotoxicity using neonatal rat cardiomyocytes. Materials and Methods: Seven CQAs (C1 to C7) isolated and identified from Jin Yin Hua were used to examine the effects of H2O2-induced and hypoxia-induced cytotoxicity. We studied C4 and C6 as preventative bioactive compounds of the reactive oxygen species (ROS) production, apoptotic pathway, and apoptosis-related gene expression. Results: C4 and C6 were screened as bioactive compounds to exert a cytoprotective effect against oxidative injury. Pretreatment with C4 and C6, dose-dependently attenuated hypoxia-induced ROS production and reduced the ratio of GSSG/GStotal. Western blot data revealed that the inhibitory effect of C4 on H2O2-induced up and down-regulation of Bcl-2, Bax, caspase-3, and cleaved caspase-3. Apoptosis was evaluated by detection of DNA fragmentation using TUNEL assay, and quantified with Annexin V/PI staining. Conclusion: In vitro experiments revealed that both C4 and C6 protect cardiomyocytes from necrosis and apoptosis during H2O2-induced injury, via inhibiting the generation of ROS and activation of caspase-3 apoptotic pathway. These results demonstrated that CQAs might be a class of compounds which possess potent myocardial protective activity against the ischemic heart diseases related to oxidative stress. PMID:27096070

  18. Hg2+ signaling in trout hepatoma (RTH-149) cells: involvement of Ca2+-induced Ca2+ release.

    PubMed

    Burlando, Bruno; Bonomo, Marco; Fabbri, Elena; Dondero, Francesco; Viarengo, Aldo

    2003-09-01

    Mercury is a non-essential heavy metal affecting intracellular Ca2+ dynamics. We studied the effects of Hg2+ on [Ca2+]i in trout hepatoma cells (RTH-149). Confocal imaging of fluo-3-loaded cells showed that Hg2+ induced dose-dependent, sustained [Ca2+]i transient, triggered intracellular Ca2+ waves, stimulated Ca2+-ATPase activity, and promoted InsP3 production. The effect of Hg2+ was reduced by the Ca2+ channel blocker verapamil and totally abolished by extracellular GSH, but was almost unaffected by cell loading with the heavy metal chelator TPEN or esterified GSH. In a Ca2+-free medium, Hg2+ induced a smaller [Ca2+]i transient, that was unaffected by TPEN, but was abolished by U73122, a PLC inhibitor, and by cell loading with GDP-betaS, a G protein inhibitor, or heparin, a blocker of intracellular Ca2+ release. Data indicate that Hg2+ induces Ca2+ entry through verapamil-sensitive channels, and intracellular Ca2+ release via a G protein-PLC-InsP3 mechanism. However, in cells loaded with heparin and exposed to Hg2+ in the presence of external Ca2+, the [Ca2+]i rise was maximally reduced, indicating that the global effect of Hg2+ is not a mere sum of Ca2+ entry plus Ca2+ release, but involves an amplification of Ca2+ release operated by Ca2+ entry through a CICR mechanism. PMID:12887976

  19. The orphan nuclear receptor estrogen receptor-related receptor gamma negatively regulates BMP2-induced osteoblast differentiation and bone formation.

    PubMed

    Jeong, Byung-Chul; Lee, Yong-Soo; Park, Yun-Yong; Bae, In-Ho; Kim, Don-Kyu; Koo, Seung-Hoi; Choi, Hong-Ran; Kim, Sun-Hun; Franceschi, Renny T; Koh, Jeong-Tae; Choi, Hueng-Sik

    2009-05-22

    Estrogen receptor-related receptor gamma (ERRgamma/ERR3/NR3B3) is a member of the orphan nuclear receptor with important functions in development and homeostasis. Recently it has been reported that ERRalpha is involved in osteoblast differentiation and bone formation. In the present study we examined the role of ERRgamma in osteoblast differentiation. Here, we showed that ERRgamma is expressed in osteoblast progenitors and primary osteoblasts, and its expression is increased temporarily by BMP2. Overexpression of ERRgamma reduced BMP2-induced alkaline phosphatase activity and osteocalcin production as well as calcified nodule formation, whereas inhibition of ERRgamma expression significantly enhanced BMP2-induced osteogenic differentiation and mineralization, suggesting that endogenous ERRgamma plays an important role in osteoblast differentiation. In addition, ERRgamma significantly repressed Runx2 transactivity on osteocalcin and bone sialoprotein promoters. We also observed that ERRgamma physically interacts with Runx2 in vitro and in vivo and competes with p300 to repress Runx2 transactivity. Notably, intramuscular injection of ERRgamma strongly inhibited BMP2-induced ectopic bone formation in a dose-dependent manner. Taken together, these results suggest that ERRgamma is a novel negative regulator of osteoblast differentiation and bone formation via its regulation of Runx2 transactivity. PMID:19324883

  20. The Orphan Nuclear Receptor Estrogen Receptor-related Receptor γ Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation*

    PubMed Central

    Jeong, Byung-Chul; Lee, Yong-Soo; Park, Yun-Yong; Bae, In-Ho; Kim, Don-Kyu; Koo, Seung-Hoi; Choi, Hong-Ran; Kim, Sun-Hun; Franceschi, Renny T.; Koh, Jeong-Tae; Choi, Hueng-Sik

    2009-01-01

    Estrogen receptor-related receptor γ (ERRγ/ERR3/NR3B3) is a member of the orphan nuclear receptor with important functions in development and homeostasis. Recently it has been reported that ERRα is involved in osteoblast differentiation and bone formation. In the present study we examined the role of ERRγ in osteoblast differentiation. Here, we showed that ERRγ is expressed in osteoblast progenitors and primary osteoblasts, and its expression is increased temporarily by BMP2. Overexpression of ERRγ reduced BMP2-induced alkaline phosphatase activity and osteocalcin production as well as calcified nodule formation, whereas inhibition of ERRγ expression significantly enhanced BMP2-induced osteogenic differentiation and mineralization, suggesting that endogenous ERRγ plays an important role in osteoblast differentiation. In addition, ERRγ significantly repressed Runx2 transactivity on osteocalcin and bone sialoprotein promoters. We also observed that ERRγ physically interacts with Runx2 in vitro and in vivo and competes with p300 to repress Runx2 transactivity. Notably, intramuscular injection of ERRγ strongly inhibited BMP2-induced ectopic bone formation in a dose-dependent manner. Taken together, these results suggest that ERRγ is a novel negative regulator of osteoblast differentiation and bone formation via its regulation of Runx2 transactivity. PMID:19324883

  1. A polysaccharide isolated from Cynomorium songaricum Rupr. protects PC12 cells against H2O2-induced injury.

    PubMed

    Wang, Fengxia; Liu, Qin; Wang, Wei; Li, Xibo; Zhang, Ji

    2016-06-01

    As a great deal of interest is developed to study novel bioactive components with health benefit effects from natural resources, in this paper, a rat pheochromocytoma line 12 (PC12) cell is built to observe the protective effect of a Cynomorium songaricum Rupr. polysaccharide (CSP) against H2O2-induced oxidative stress. Fluorescence microscope, flow cytometry and micro-plate reader are used to assess cell viability and apoptosis. And the levels of reactive oxygen species (ROS), 8-hydroxy-2'-deoxyguanosine (8-OH-dG), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and lactate dehydrogenase (LDH) are evaluated. The results show that, the CSP can significantly protect PC12 cells against H2O2-induced oxidative stress, increase the intracellular antioxidase system load and inhibit H2O2-induced apoptosis by scavenging of ROS, regulating cell cycle, preventing DNA damage and protecting the cell membrane. This research would be benefit for preventing and curing the oxidation-related diseases in polysaccharide study. PMID:26853824

  2. Design and Synthesis of Novel Xyloketal Derivatives and Their Protective Activities against H2O2-Induced HUVEC Injury

    PubMed Central

    Liu, Shixin; Luo, Rong; Xiang, Qi; Xu, Xianfang; Qiu, Liqin; Pang, Jiyan

    2015-01-01

    In this work, we designed and synthesized a series of amide derivatives (1–13), benzoxazine derivatives (16–28) and amino derivatives (29–30) from xyloketal B. All 28 new derivatives and seven known compounds (14, 15, 31–35) were evaluated for their protection against H2O2-induced HUVEC injury. 23 and 24 exhibited more potential protective activities than other derivatives; and the EC50 values of them and the leading compound 31 (xyloketal B) were 5.10, 3.59 and 15.97 μM, respectively. Meanwhile, a comparative molecular similarity indices analysis (CoMSIA) was constructed to explain the structural activity relationship of these xyloketal derivatives. This 3D QSAR model from CoMSIA suggested that the derived model exhibited good predictive ability in the external test-set validation. Derivative 24 fit well with the COMSIA map, therefore it possessed the highest activity of all compounds. Compounds 23, 24 and 31 (xyloketal B) were further to examine in the JC-1 mitochondrial membrane potential (MMP) assay of HUVECs using flow cytometry (FCM). The result indicated that 23 and 24 significantly inhibited H2O2-induced decrease of the cell mitochondrial membrane potential (ΔΨm) at 25 μM. Collectively, the protective effects of xyloketals on H2O2-induced endothelial cells may be generated from oxidation action by restraining ROS and reducing the MMP. PMID:25686273

  3. NPR1-dependent salicylic acid signaling is not involved in elevated CO2-induced heat stress tolerance in Arabidopsis thaliana

    PubMed Central

    Ahammed, Golam Jalal; Li, Xin; Yu, Jingquan; Shi, Kai

    2015-01-01

    Elevated CO2 can protect plants from heat stress (HS); however, the underlying mechanisms are largely unknown. Here, we used a set of Arabidopsis mutants such as salicylic acid (SA) signaling mutants nonexpressor of pathogenesis-related gene 1 (npr1-1 and npr1-5) and heat-shock proteins (HSPs) mutants (hsp21 and hsp70-1) to understand the requirement of SA signaling and HSPs in elevated CO2-induced HS tolerance. Under ambient CO2 (380 µmol mol−1) conditions, HS (42°C, 24 h) drastically decreased maximum photochemical efficiency of PSII (Fv/Fm) in all studied plant groups. Enrichment of CO2 (800 µmol mol−1) with HS remarkably increased the Fv/Fm value in all plant groups except hsp70-1, indicating that NPR1-dependent SA signaling is not involved in the elevated CO2-induced HS tolerance. These results also suggest an essentiality of HSP70-1, but not HSP21 in elevated CO2-induced HS mitigation. PMID:25874349

  4. Fractured diaphyseal tibiofibular synostosis in an adolescent soccer player.

    PubMed

    Santa Maria, Daniel L; Shaw, Thomas; Allen, Marque; Marin, James

    2015-01-01

    Diaphyseal tibiofibular synostosis is a rare cause of symptomatic shin pain with exertion. In this case, a 14-year-old male soccer player presented with atraumatic right shin pain made worse with running. Computed tomography revealed heterotopic ossification, or synostosis, of the tibial-fibular syndesmosis. The patient's symptoms improved with rest, without the need for operative intervention. PMID:25171880

  5. The impact of escitalopram on IL-2-induced neuroendocrine, immune, and behavioral changes in patients with malignant melanoma: preliminary findings.

    PubMed

    Musselman, Dominique; Royster, Erica B; Wang, Ming; Long, Qi; Trimble, Lisa M; Mann, Tara K; Graciaa, Daniel S; McNutt, Marcia D; Auyeung, N S Freda; Oliver, Lindsay; Lawson, David H; Miller, Andrew H

    2013-09-01

    Interleukin (IL)-2, a T-cell cytokine used to treat malignant melanoma, can induce profound depression. To determine whether pretreatment with the antidepressant escitalopram could reduce IL-2-induced neuroendocrine, immune, and neurobehavioral changes, 20 patients with Stage IV melanoma were randomized to either placebo or the serotonin reuptake inhibitor, escitalopram (ESC) 10-20 mg/day, 2 weeks before, and during IL-2 treatment (720 000 units/kg Q8 h × 5 days (1 cycle) every 3 weeks × 4 cycles). Generalized estimation equations were used to examine HPA axis activity (plasma ACTH and cortisol), immune activation (plasma IL-6), and depressive symptoms (Hamilton Depression Rating Scale (HDRS) score). Tolerance of IL-2 treatment (concomitant medications required) and adherence (number of IL-2 doses received) were also assessed. Both the groups (ESC (n=9), placebo (n=11)) exhibited significant IL-2-induced increases in plasma cortisol, IL-6, and depressive symptoms (p<0.05), as well as a temporal trend for increases in plasma ACTH (p=0.054); the effects of age and treatment were not significant. Higher plasma ACTH concentrations were associated with higher depressive symptoms during cycles 1-3 of IL-2 therapy (p<0.01). Although ESC had no significant effects on ACTH, cortisol, IL-6, tolerance of, or adherence to IL-2, ESC treatment was associated with lower depressive symptoms, ie, a maximal difference of ∼3 points on the HDRS, which, though not statistically significant (in part, due to small sample size), represents a clinically significant difference according to the National Institute for Health and Clinical Excellence guidelines. A larger sample size will establish whether antidepressant pretreatment can prevent IL-2-induced neurobehavioral changes. PMID:23575741

  6. Gangliosides inhibit bee venom melittin cytotoxicity but not phospholipase A{sub 2}-induced degranulation in mast cells

    SciTech Connect

    Nishikawa, Hirofumi; Kitani, Seiichi

    2011-05-01

    Sting accident by honeybee causes severe pain, inflammation and allergic reaction through IgE-mediated anaphylaxis. In addition to this hypersensitivity, an anaphylactoid reaction occurs by toxic effects even in a non-allergic person via cytolysis followed by similar clinical manifestations. Auto-injectable epinephrine might be effective for bee stings, but cannot inhibit mast cell lysis and degranulation by venom toxins. We used connective tissue type canine mast cell line (CM-MC) for finding an effective measure that might inhibit bee venom toxicity. We evaluated degranulation and cytotoxicity by measurement of {beta}-hexosaminidase release and MTT assay. Melittin and crude bee venom induced the degranulation and cytotoxicity, which were strongly inhibited by mono-sialoganglioside (G{sub M1}), di-sialoganglioside (G{sub D1a}) and tri-sialoganglioside (G{sub T1b}). In contrast, honeybee venom-derived phospholipase A{sub 2} induced the net degranulation directly without cytotoxicity, which was not inhibited by G{sub M1}, G{sub D1a} and G{sub T1b}. For analysis of distribution of G{alpha}{sub q} and G{alpha}{sub i} protein by western blotting, lipid rafts were isolated by using discontinuous sucrose gradient centrifuge. Melittin disrupted the localization of G{alpha}{sub q} and G{alpha}{sub i} at lipid raft, but gangliosides stabilized the rafts. As a result from this cell-based study, bee venom-induced anaphylactoid reaction can be explained with melittin cytotoxicity and phospholipase A{sub 2}-induced degranulation. Taken together, gangliosides inhibit the effect of melittin such as degranulation, cytotoxicity and lipid raft disruption but not phospholipase A{sub 2}-induced degranulation in mast cells. Our study shows a potential of gangliosides as a therapeutic tool for anaphylactoid reaction by honeybee sting.

  7. Earthworms repair H2O2-induced oxidative DNA adducts without removing UV-induced pyrimidine dimers.

    PubMed

    Chang, Wen-Shin; Tsai, Chia-Wen; Lin, Cheng-Chieh; Lin, Chih-Hsueh; Shen, Wu-Chung; Lin, Song-Shei; Bau, Da-Tian

    2011-01-01

    Ultraviolet (UV) radiation is a natural insult to various organisms. Earthworms, although possessing similar biomolecules to those in mammalian skin, do not suffer from skin cancer nor any other types of cancer as humans do. However, little is known about the molecular mechanism of the earthworm's tolerance to UV. In this study, we evaluated the genotoxicity of UV and the capacity of earthworm cell to repair UV-induced damage. The T4 UV endonuclease UV-incorporated comet assay was used to examine the excision and rejoining steps of UV-induced pyrimidine dimer. Earthworm testis cells were treated with a combination of 5 mM hydroxyurea plus 50 μM cytosine-β-D-arabinofuranoside for 6 h to block DNA rejoining capacity and to investigate excision dynamics. Compared with H(2)O(2)-induced oxidative repair capacity, the excision step of repair of UV-induced lesions in earthworm testis cells was significantly lower. After 6-h treatment of 5 mM hydroxyurea plus 50 μM cytosine-β-D-arabinofuranoside, the medium was totally replaced with fresh medium and cells were allowed to rejoin the accumulated DNA strand breaks. We found that the capacity for rejoining UV-induced breaks was also significantly lower than that for the H(2)O(2)-induced breaks. Our results strongly suggest that earthworms seem to be efficient at repairing H(2)O(2)-induced oxidative DNA adducts, but not so capable of removing UV-induced pyrimidine dimers from their genome. PMID:22021692

  8. IL-2 induces STAT4 activation in primary NK cells and NK cell lines, but not in T cells.

    PubMed

    Wang, K S; Ritz, J; Frank, D A

    1999-01-01

    IL-2 exerts potent but distinct functional effects on two critical cell populations of the immune system, T cells and NK cells. Whereas IL-2 leads to proliferation in both cell types, it enhances cytotoxicity primarily in NK cells. In both T cells and NK cells, IL-2 induces the activation of STAT1, STAT3, and STAT5. Given this similarity in intracellular signaling, the mechanism underlying the distinct response to IL-2 in T cells and NK cells is not clear. In this study, we show that in primary NK cells and NK cell lines, in addition to the activation of STAT1 and STAT5, IL-2 induces tyrosine phosphorylation of STAT4, a STAT previously reported to be activated only in response to IL-12 and IFN-alpha. This activation of STAT4 in response to IL-2 is not due to the autocrine production of IL-12 or IFN-alpha. STAT4 activated in response to IL-2 is able to bind to a STAT-binding DNA sequence, suggesting that in NK cells IL-2 is capable of activating target genes through phosphorylation of STAT4. IL-2 induces the activation of Jak2 uniquely in NK cells, which may underlie the ability of IL-2 to activate STAT4 only in these cells. Although the activation of STAT4 in response to IL-2 occurs in primary resting and activated NK cells, it does not occur in primary resting T cells or mitogen-activated T cells. The unique activation of the STAT4-signaling pathway in NK cells may underlie the distinct functional effect of IL-2 on this cell population. PMID:9886399

  9. New monoterpene glycosides from sunflower seeds and their protective effects against H2O2-induced myocardial cell injury.

    PubMed

    Fei, Yonghe; Zhao, Jianping; Liu, Yanli; Li, Xiaoran; Xu, Qiongming; Wang, Taoyun; Khan, Ikhlas A; Yang, Shilin

    2015-11-15

    Three new monoterpene glycosides (1-3) and eleven known compounds (4-14) were isolated from seeds of Helianthus annuus L. (sunflower). Their structures were determined by spectroscopic and chemical methods. All the compounds were isolated from sunflower seeds for the first time. Protective effects of compounds 1-14 against H2O2-induced H9c2 cardiomyocyte injury were evaluated, and compounds 1 and 2 showed some cell-protective effects. No significant DPPH radical scavenging activity was observed for compounds 1-14. PMID:25977041

  10. Research project on CO{sub 2}-induced climate change. Annual progress report, March 1, 1994--February 28, 1995

    SciTech Connect

    Cess, R.D.; Hameed, S.

    1995-01-01

    This summarizes current progress in the research project at SUNY Stony Brook on CO2-induced climate change. Three tasks are described, corresponding to the task categories in the USDOE/PRC CAS cooperative project on climate change. Task 1, led by Dr. Robert Cess, concerns the intercomparison of CO2 related climatic warming in contemporary general circulation models. Task 2, directed by Dr. Sultan Hameed, looks at understanding the natural variability in climatic data and comparing its significant features between observations and model simulations. Task 3, also directed by Dr. Hameed focuses on analysis of historical climate data developed at the institute of Geography of the Chinese Academy of Sciences.

  11. Association of miR-146a, miR-149, miR-196a2, and miR-499 Polymorphisms with Ossification of the Posterior Longitudinal Ligament of the Cervical Spine

    PubMed Central

    Jeon, Young Joo; Kumar, Hemant; Sohn, Seil; Min, Hyoung Sik; Lee, Jang Bo; Kuh, Sung Uk; Kim, Keung Nyun; Kim, Jung Oh; Kim, Ok Joon; Ropper, Alexander E.; Kim, Nam Keun; Han, In Bo

    2016-01-01

    Background Ossification of the posterior longitudinal ligament (OPLL) of the spine is considered a multifactorial and polygenic disease. We aimed to investigate the association between four single nucleotide polymorphisms (SNPs) of pre-miRNAs [miR-146aC>G (rs2910164), miR-149T>C (rs2292832), miR-196a2T>C (rs11614913), and miR-499A>G (rs3746444)] and the risk of cervical OPLL in the Korean population. Methods The genotypic frequencies of these four SNPs were analyzed in 207 OPLL patients and 200 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Findings For four SNPs in pre-miRNAs, no significant differences were found between OPLL patients and controls. However, subgroup analysis based on OPLL subgroup (continuous: continuous type plus mixed type, segmental: segmental and localized type) showed that miR-499GG genotype was associated with an increased risk of segmental type OPLL (adjusted odds ratio = 4.314 with 95% confidence interval: 1.109–16.78). In addition, some allele combinations (C-T-T-G, G-T-T-A, and G-T-C-G of miR-146a/-149/-196a2/-499) and combined genotypes (miR-149TC/miR-196a2TT) were associated with increased OPLL risk, whereas the G-T-T-G and G-C-C-G allele combinations were associated with decreased OPLL risk. Conclusion The results indicate that GG genotype of miR-499 is associated with significantly higher risks of OPLL in the segmental OPLL group. The miR-146a/-149/-196a2/-499 allele combinations may be a genetic risk factor for cervical OPLL in the Korean population. PMID:27454313

  12. Peptide drugs accelerate BMP-2-induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling.

    PubMed

    Sugamori, Yasutaka; Mise-Omata, Setsuko; Maeda, Chizuko; Aoki, Shigeki; Tabata, Yasuhiko; Murali, Ramachandran; Yasuda, Hisataka; Udagawa, Nobuyuki; Suzuki, Hiroshi; Honma, Masashi; Aoki, Kazuhiro

    2016-08-01

    Both W9 and OP3-4 were known to bind the receptor activator of NF-κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide-induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3-4 accelerated BMP-2-induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL-binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP-2-induced bone regeneration by the RANKL-binding peptides. PMID:27345003

  13. Inhibition of Store-Operated Calcium Entry Protects Endothelial Progenitor Cells from H2O2-Induced Apoptosis

    PubMed Central

    Wang, Yan-Wei; Zhang, Ji-Hang; Yu, Yang; Yu, Jie; Huang, Lan

    2016-01-01

    Store-operated calcium entry (SOCE), a major mode of extracellular calcium entry, plays roles in a variety of cell activities. Accumulating evidence indicates that the intracellular calcium ion concentration and calcium signaling are critical for the responses induced by oxidative stress. The present study was desi