93 results on '"Iwamoto, Y."'
Search Results
2. Contact stress at the anterior aspect of the tibial post in posterior-stabilized total knee replacement.
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Hamai S, Miura H, Matsuda S, Shimoto T, Higaki H, Iwamoto Y, Hamai, Satoshi, Miura, Hiromasa, Matsuda, Shuichi, Shimoto, Takeshi, Higaki, Hidehiko, and Iwamoto, Yukihide
- Abstract
Background: Retrieval studies have demonstrated polyethylene wear and deformation of the anterior aspect of the tibial post of posterior-stabilized total knee replacements. We are not aware of any study that has analyzed the effects of the design of the femoral notch and the anterior aspect of the tibial post of posterior-stabilized total knee replacements on contact area, stress, and location. The purpose of the present study was to determine the levels of contact stress generated in three posterior-stabilized total knee replacement designs when the femoral intercondylar notch impinges on the anterior aspect of the tibial post.Methods: The contact area, mean and peak contact stresses, and contact location at the anterior aspect of the tibial post were determined when a posterior force of 100 N was applied to a NexGen LPS Flex, Genesis II, and Scorpio NRG total knee replacement. Measurements were performed at -15 degrees, -10 degrees, -5 degrees, 0 degrees, and 5 degrees of flexion of the femoral component both in neutral and with 5 degrees of rotation of the tibial component. Each measurement was sequentially performed five times, and the data were compared within and between the designs with use of analysis of variance and a post-hoc Scheffé F test.Results: The NexGen LPS Flex exhibited two contact areas on the medial and lateral corners of the anterior aspect of the post, whereas both the Genesis II and Scorpio NRG exhibited a single horizontal band. The NexGen LPS Flex showed the largest total contact area of the three designs at -15 degrees, -10 degrees, and 5 degrees of flexion. The NexGen LPS showed the lowest mean contact stress at -15 degrees and 5 degrees but showed the highest peak contact stress at -5 degrees and 0 degrees. The Scorpio NRG showed the highest mean contact stress under all conditions and showed the highest peak contact stress at -15 degrees, -10 degrees, and 5 degrees. With 5 degrees of rotation of the tibial component, peak contact stress increased, relative to neutral, 1.2 to twofold (depending on the flexion angle) in the Genesis II design.Conclusions: The mean and peak contact stresses were variable for all three designs and the test conditions, approaching and in some cases exceeding the compressive yield stress for polyethylene. The geometry of the metal femoral notch and polyethylene tibial post in the axial and sagittal planes significantly affected contact area, mean and peak stresses, and contact location at the anterior aspect of the tibial post. [ABSTRACT FROM AUTHOR]- Published
- 2010
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3. Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation.
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Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Handschumacher MD, Sullivan S, Johnson B, Titus JS, Iwamoto Y, Wylie-Sears J, Levine RA, Carpentier A, Dal-Bianco, Jacob P, Aikawa, Elena, Bischoff, Joyce, Guerrero, J Luis, Handschumacher, Mark D, Sullivan, Suzanne, Johnson, Benjamin, and Titus, James S
- Published
- 2009
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4. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease.
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Aikawa E, Aikawa M, Libby P, Figueiredo JL, Rusanescu G, Iwamoto Y, Fukuda D, Kohler RH, Shi GP, Jaffer FA, Weissleder R, Aikawa, Elena, Aikawa, Masanori, Libby, Peter, Figueiredo, Jose-Luiz, Rusanescu, Gabriel, Iwamoto, Yoshiko, Fukuda, Daiju, Kohler, Rainer H, and Shi, Guo-Ping
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- 2009
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5. Transtrochanteric anterior rotational osteotomy for osteonecrosis of the femoral head in patients 20 years or younger.
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Ikemura S, Yamamoto T, Nakashima Y, Mawatari T, Motomura G, Iwamoto Y, Ikemura, Satoshi, Yamamoto, Takuaki, Nakashima, Yasuharu, Mawatari, Taro, Motomura, Goro, and Iwamoto, Yukihide
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- 2009
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6. Intraarticular findings in symptomatic developmental dysplasia of the hip.
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Fujii M, Nakashima Y, Jingushi S, Yamamoto T, Noguchi Y, Suenaga E, and Iwamoto Y
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- 2009
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7. Pitavastatin may reduce risk of steroid-induced osteonecrosis in rabbits: a preliminary histological study.
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Nishida K, Yamamoto T, Motomura G, Jingushi S, Iwamoto Y, Nishida, Kenjiro, Yamamoto, Takuaki, Motomura, Goro, Jingushi, Seiya, and Iwamoto, Yukihide
- Abstract
Several animal and human studies suggest pharmacological approaches may prevent steroid-induced osteonecrosis (ON). We asked whether the newly developed 3-hydroxymethyl-3-glutaryl-CoA (HMG-CoA) reductase inhibitor, pitavastatin, could prevent steroid-induced ON in rabbits. We injected 65 adult male Japanese white rabbits once with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle. The rabbits were divided into two groups; one group of 35 rabbits received pitavastatins (PS), and the other group of 30 rabbits received no prophylaxis (CTR). Hematological examinations were performed just before the steroid injection (0 weeks) and at 1 and 2 weeks after steroid injection; both the femora and the humeri were histologically examined 2 weeks postinjection. The incidence of histologic changes consistent with early ON in the PS group (13 of 35; 37%) was lower in comparison to the CTR group (21 of 30; 70%). The size of the bone marrow fat cells in the PS group (56.6 +/- 10 microm) was smaller than those in the CTR group (60 +/- 4 microm). The data suggest pitavastatin has the potential to lower the incidence of steroid-induced ON in rabbits. [ABSTRACT FROM AUTHOR]
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- 2008
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8. Minimally invasive versus standard approach in total knee arthroplasty.
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Tashiro Y, Miura H, Matsuda S, Okazaki K, and Iwamoto Y
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- 2007
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9. The effect of ankle rotation on cutting of the tibia in total knee arthroplasty.
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Mizu-uchi H, Matsuda S, Miura H, Higaki H, Okazaki K, Iwamoto Y, Mizu-uchi, Hideki, Matsuda, Shuichi, Miura, Hiromasa, Higaki, Hidehiko, Okazaki, Ken, and Iwamoto, Yukihide
- Abstract
Background: Extramedullary alignment guides are commonly used to prepare the tibia during total knee arthroplasty. One disadvantage is that the guide is easily affected by the position of the ankle joint. The tibia may have a rotational mismatch between its proximal and distal ends. We hypothesized that a rotational mismatch might cause incorrect positioning of an extramedullary alignment guide and evaluated such a mismatch on the predicted postoperative coronal alignment of the tibia.Methods: Fifty-three osteoarthritic knees with varus deformity in fifty-one patients were evaluated with use of computerized tomography scans before total knee arthroplasty. We defined one anteroposterior axis of the ankle joint and five different anteroposterior axes of the proximal aspect of the tibia using three-dimensional bone models from the computerized tomography data. We measured the rotational angle between the anteroposterior axis of the ankle joint and the proximal part of the tibia. The distal end of the extramedullary guide was placed in front of the center of the ankle joint (on the line of the extended anteroposterior axis of the ankle joint), and the proximal end was placed on the line of the extended anteroposterior axis of the proximal part of the tibia. We established spatial coordinates to evaluate the effect of the rotational angle on the predicted postoperative coronal alignment of the tibia and calculated the presumed tibial coronal alignment.Results: The rotational angle was positive (3.6 degrees to 19.7 degrees) for all of the anteroposterior axes of the proximal aspect of the tibia, indicating that the ankle joint was externally rotated relative to the proximal part of the tibia. The predicted tibial coronal alignment was varus (0.5 degrees to 5.1 degrees) for all of the anteroposterior axes of the proximal part of the tibia.Conclusions: When an extramedullary alignment guide is used to prepare the tibia in total knee arthroplasty, varus alignment of the tibial component can occur because of a rotational mismatch between the proximal part of the tibia and the ankle joint. [ABSTRACT FROM AUTHOR]- Published
- 2006
10. In vivo evaluation of antiplatelet agents in gerbil model of carotid artery thrombosis.
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Nishimura, H, Naritomi, H, Iwamoto, Y, Tachibana, H, and Sugita, M
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- 1996
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11. Successful salvage after necrotizing fasciitis in a lower extremity with hip and knee replacement.
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Tashiro Y, Shuto T, Yoshida T, Sakamoto A, Yamamoto S, Hashizume M, and Iwamoto Y
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- 2010
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12. Lymphangioma presenting as a dumbbell tumor in the epidural space of the lumbar spine.
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Saito, T, Terada, K, Tsuchiya, K, Oda, Y, Tsuneyoshi, M, and Iwamoto, Y
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- 1999
13. Immunoreactive Endothelin Levels in the Vitreous Fluid Are Decreased in Diabetic Patients with Proliferative Retinopathy.
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Ogata, M., Naruse, M., Iwasaki, N., Katoh, S., Ohta, Y., Hori, S., Demura, H., and Iwamoto, Y.
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- 1998
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14. Comparison of the amounts of canal encroachment between semisitting and supine position of computed tomography-myelography for vertebral fractures of the elderly involving the posterior vertebral wall.
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Hayashi T, Maeda T, Ueta T, Shiba K, Iwamoto Y, Hayashi, Tetsuo, Maeda, Takeshi, Ueta, Takayoshi, Shiba, Keiichiro, and Iwamoto, Yukihide
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- 2012
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15. Extradural nodular fasciitis arising in the spinal canal.
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Kubota K, Okada S, Maeda T, Matsumoto Y, Sakamoto A, Harimaya K, Saiwai H, Kumamaru H, Oda Y, Iwamoto Y, Kubota, Kensuke, Okada, Seiji, Maeda, Takeshi, Matsumoto, Yoshihiro, Sakamoto, Akio, Harimaya, Katsumi, Saiwai, Hirokazu, Kumamaru, Hiromi, Oda, Yoshinao, and Iwamoto, Yukihide
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- 2012
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16. Transtrochanteric rotational osteotomy for late-onset legg-calve-perthes disease.
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Nakashima Y, Kubota H, Yamamoto T, Mawatari T, Motomura G, and Iwamoto Y
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- 2011
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17. IMPACT OF HSCRP AND ADIPO-CYTOKINE IN CORONARY ARTERY CALCIFICATIONS IN TYPE 2 DIABETES.
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Kunugi, T., Sato, A., Nagai, K., Era, M., Sakai, K., Hasumi, S., and Iwamoto, Y.
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- 2011
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18. PREVALENCE AND CORRELATION OF LEFT ATRIAL ENLARGEMENT IN TYPE 2 DIABETES WITH AND WITHOUT CHRONIC KIDNEY DISEASE.
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Sato, A., Sakai, K., Kunugi, T., Harada, M., Nagai, K., and Iwamoto, Y.
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- 2011
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19. Ventricular-vascular stiffening in patients with repaired coarctation of aorta: integrated pathophysiology of hypertension.
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Senzaki H, Iwamoto Y, Ishido H, Masutani S, Taketazu M, Kobayashi T, Katogi T, and Kyo S
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- 2008
20. Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature.
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Harimaya K, Oda Y, Matsuda S, Tanaka K, Chuman H, and Iwamoto Y
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- 2003
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21. ANALYSIS OF IEMG ACTIVITIES OF LOWER EXTREMITY AND TRUNK MUSCLES DURING WALKING BACKWARD UNDERWATER.
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Masumoto, K, Takasugi, S, Hotta, N, Fujishima, K, and Iwamoto, Y
- Published
- 2002
22. Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart.
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Grune J, Bajpai G, Ocak PT, Kaufmann E, Mentkowski K, Pabel S, Kumowski N, Pulous FE, Tran KA, Rohde D, Zhang S, Iwamoto Y, Wojtkiewicz GR, Vinegoni C, Green U, Swirski FK, Stone JR, Lennerz JK, Divangahi M, Hulsmans M, and Nahrendorf M
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- Animals, Humans, Mice, Male, Female, Macrophages immunology, Macrophages pathology, Macrophages metabolism, Inflammation pathology, Middle Aged, Myocardium pathology, Myocardium immunology, Mice, Inbred C57BL, Aged, COVID-19 immunology, COVID-19 complications, COVID-19 pathology, Respiratory Distress Syndrome immunology, Respiratory Distress Syndrome etiology, Respiratory Distress Syndrome pathology, Respiratory Distress Syndrome virology, SARS-CoV-2, Cardiomyopathies immunology, Cardiomyopathies etiology, Cardiomyopathies pathology, Cardiomyopathies virology
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Background: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation., Methods: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2-associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor., Results: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2
+ (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2+ macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α-neutralizing antibody reduced cardiac monocytes and inflammatory MHCIIlo CCR2+ macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure., Conclusions: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2+ macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart., Competing Interests: Disclosures M.N. has received funds or material research support from Alnylam, Biotronik, CSL Behring, GlycoMimetics, GSK, Medtronic, Novartis, and Pfizer, as well as consulting fees from Lilly, Biogen, Gimv, IFM Therapeutics, Molecular Imaging, Sigilon, and Verseau Therapeutics. The other authors report no conflicts.- Published
- 2024
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23. What Happens 20 to 30 years After Radial Keratotomy? Case Series.
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Iwamoto Y, Koh S, Inoue R, Maeda N, McDonald M, and Nishida K
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- Humans, Retrospective Studies, Male, Female, Middle Aged, Adult, Aged, Astigmatism surgery, Astigmatism physiopathology, Refraction, Ocular physiology, Follow-Up Studies, Contact Lenses, Young Adult, Keratotomy, Radial, Visual Acuity
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Abstract: Radial keratotomy (RK) was commonly performed in the 1980s and 1990s. We aimed to clarify the current status of post-RK refractive correction and treatment. We retrospectively reviewed the charts of 70 patients with a history of RK. Of the 70 patients, 44 were identified for clinical outcomes. Refractive or therapeutic intervention (rigid gas-permeable contact lens fit, spectacle prescription, corneal surgery, and use of pilocarpine hydrochloride for photophobia) was possible in 59% of patients with postoperative visual deterioration after RK; in the remaining 41%, therapeutic intervention was not possible. Rigid gas-permeable contact lens fit for corneal irregular astigmatism was the most common refractive intervention and was effective in 36% of cases in the university hospital., (Copyright © 2024 Contact Lens Association of Ophthalmologists.)
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- 2024
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24. A case of Empty Sella syndrome with adrenal insufficiency masked by prednisolone after administration of immune checkpoint inhibitors.
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Iwamoto Y, Tatsumi F, Ohnishi M, Katakura Y, Kimura T, Shimoda M, Nakanishi S, Mune T, and Kaneto H
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- Male, Humans, Middle Aged, Prednisolone therapeutic use, Hydrocortisone, Immune Checkpoint Inhibitors therapeutic use, Adrenocorticotropic Hormone, Carcinoma, Non-Small-Cell Lung drug therapy, Empty Sella Syndrome chemically induced, Lung Neoplasms drug therapy, Adrenal Insufficiency chemically induced, Adrenal Insufficiency drug therapy
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Introduction: The use of immune checkpoint inhibitors (ICIs) is gradually increasing; ICIs produce a variety of immune-related adverse events (irAEs), especially ICI-induced hypoadrenocorticism, which can be a lethal complication if treatment is delayed., Patient Concerns: A 63-year-old man received chemotherapy with pembrolizumab for nonsmall cell lung cancer. He developed drug-induced interstitial pneumonia 366 days after receiving pembrolizumab and was treated with prednisolone. Five hundred thirty-seven days later, he developed drug-induced eosinophilic enteritis, and pembrolizumab was discontinued and prednisolone was continued. After discontinuation of prednisolone, general malaise and edema of the lower extremities appeared, and adrenal insufficiency was suspected., Diagnosis: In blood tests on admission adrenocorticotropic hormone (ACTH) was 2.2 pg/mL and cortisol was 15 μg/dL, with no apparent cortisol deficiency. However, the cortisol circadian rhythm disappeared and remained low throughout the day; a corticotropin-releasing hormone stimulation test showed decreased reactive secretion of ACTH. Pituitary magnetic resonance imaging showed pituitary emptying, suggesting Empty Sella syndrome., Interventions and Outcomes: We started hydrocortisone and his symptoms were improved., Conclusions: The administration of high-dose steroids after ICI administration may mask the symptoms of hypoadrenocorticism as irAEs. Therefore, we should bear in mind the possibility of hypoadrenocorticism when we stop steroid therapy in patients who are treated with steroids after ICI administration., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2024
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25. Case report: Acute submandibular sialadenitis in poorly controlled diabetes mellitus patient fed twenty days by enteral tube.
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Iwamoto Y, Anno T, Koyama K, Tomoda K, Kimura T, and Kaneto H
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- Humans, Female, Aged, 80 and over, Intubation, Gastrointestinal, Enteral Nutrition methods, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 therapy, Autoimmune Diseases, Sialadenitis etiology, Sialadenitis therapy
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Introduction: Enteral tube feeding is an effective method of providing nutrients for patients who are unable to meet their nutritional requirements, and patients with parenteral nutrition are at an increased risk of infection. The submandibular gland is one of the major salivary glands and sialadenitis are often caused by obstruction of the salivary outflow tract., Patient Concerns: A 91-year-old woman had parenteral nutrition with nasogastric tube feeding. Her history includes angina pectoris, myocardial infarction, type 2 diabetes mellitus (T2DM), heart failure, atrial fibrillation, sick sinus syndrome, and she recently had a pacemaker implanted. She was continued parenteral nutrition with nasogastric tube feeding for 20 days, and her fasting blood glucose ranged from 200 to 400 mg/dL. In the midst of poor glycemic control, she suddenly had high fever and elevated infection markers under poorly glycemic control., Diagnoses: She had neck swelling with a feeling of heat. We performed cervical computed tomography, and it revealed swelling of the bilateral submandibular glands and fluffing of surrounding tissue. She was diagnosed with acute submandibular glanditis., Interventions: We treated her with antibiotics therapy, extubation, daily massage of the submandibular gland and strict glycemic control., Outcomes: Her neck swelling disappeared about 11 days after such treatment., Lessons: We reported acute submandibular glanditis induced by nasogastric tube feeding under poorly controlled diabetes mellitus. We have to keep good oral hygiene and also pay attention to glycemic control in subjects under parenteral nutrition with tube feeding management., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
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26. Long-Term Corneal Refractive Power Changes Two Decades After Radial Keratotomy With Microperforations.
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Iwamoto Y, Koh S, Inoue R, Soma T, Oie Y, Maeda N, and Nishida K
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- Humans, Retrospective Studies, Cornea surgery, Postoperative Period, Keratotomy, Radial methods
- Abstract
Abstract: We retrospectively examined corneal refractive power in three patients who had been followed up for more than 20 years after radial keratotomy (RK) with microperforations (MPs). All patients underwent RK in both eyes and were referred to our clinic because of postoperative decreased vision. MP was observed in five of the six eyes at the initial visit. The corneal refractive power of the anterior and posterior surfaces of the 6-mm-diameter cornea was examined using Fourier analysis based on corneal shape analysis using anterior segment optical coherence tomography. The spherical components decreased in all three cases. The asymmetry and higher-order irregularity components and fluctuations in corneal refractive power were markedly greater in the two cases with MP in both eyes. Fluctuations in corneal refractive power were observed at more than 20 years after RK with MP. Therefore, careful observation is necessary, even after a long-term postoperative follow-up period., (Copyright © 2023 Contact Lens Association of Ophthalmologists.)
- Published
- 2023
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27. Comparison of Ocular Wavefront Aberration Measurements Obtained Using Two Hartmann-Shack Wavefront Aberrometers.
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Koh S, Inoue R, Iwamoto Y, Mihashi T, Soma T, Maeda N, and Nishida K
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- Humans, Case-Control Studies, Visual Acuity, Pupil, Vision Disorders, Refraction, Ocular, Keratoconus
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Objectives: To assess agreement between measurements of ocular wavefront aberrations obtained using the Pentacam AXL Wave (Oculus Optikgeräte GmbH) (Aberrometer A) and KR-1W (Topcon Corp) (Aberrometer B), both of which are based on the Hartmann-Shack principle., Methods: In this prospective case-control study, ocular wavefront aberrations measurements were obtained using both aberrometers in patients with keratoconus (KC) and control participants. Ocular wavefront aberrations were measured through the natural pupil without dilation using both devices in a dark room. For both aberrometers, accommodation was inhibited by automatically adding fogging. The individual Zernike coefficients from the second to fourth order were compared between the two aberrometers for a 4-mm pupil diameter., Results: Twenty-six KC and 29 control eyes were assessed. Statistically significant correlations ( P <0.05) were observed for all Zernike coefficients, except for Z 4-2 in the control group. Bland-Altman analysis indicated good agreement between aberrometers and no statistically significant differences in the control group. However, in the KC group, patterns of proportional error were observed in vertical coma Z 3-1 (r=0.338, P =0.008), trefoil Z 4-4 (r=0.701, P =0.003), secondary astigmatism Z 4-2 (r=0.348, P =0.025), and spherical aberrations Z 40 (r=0.407, P =0.012)., Conclusions: The Zernike coefficient values measured by the two aberrometers were well correlated in the control and KC groups. However, in eyes with KC, Aberrometer B tended to present greater values in several Zernike coefficients than Aberrometer A, suggesting that wavefront measurements obtained using the two aberrometers are not interchangeable in patients with KC., (Copyright © 2022 Contact Lens Association of Ophthalmologists.)
- Published
- 2023
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28. Dramatic recovery without steroid therapy and withdrawal from insulin therapy in a subject with hyperglycemic and hyperosmolar syndrome and depletion of insulin secretory capacity induced by type 2 autoimmune pancreatitis: A case report.
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Iwamoto Y, Tatsumi F, Kohara K, Shimoda M, Nakanishi S, Mune T, Kaku K, and Kaneto H
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- Aged, 80 and over, Female, Humans, Insulin therapeutic use, Pancreas, Steroids, Autoimmune Pancreatitis drug therapy, Diabetes Mellitus, Hyperglycemic Hyperosmolar Nonketotic Coma diagnosis
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Introduction: Autoimmune pancreatitis (AIP) is characterized by the involvement of autoimmune mechanisms and is classified as type 1, together with infiltration of IgG4-positive cells, and type 2 with poor serological abnormal findings. In clinical practice, AIP is often treated with steroid therapy., Patient Concerns: An 81-year-old Japanese woman had thirst and appetite loss in the previous 5 days; thus, she visited a local doctor. The patient had no abdominal or back pain. She had no history of diabetes mellitus, but at that time blood glucose level and HbA1c were as high as 633 mg/dL and 9.7%, respectively, and she was referred to our institution., Diagnosis: Based on various clinical findings in this patient, we diagnosed her with hyperglycemic and hyperosmolar syndrome and depletion of insulin secretory capacity induced by type 2 AIP., Interventions and Outcomes: The patient completely recovered without steroid therapy and was withdrawn from insulin therapy., Conclusions: We should bear in mind the possibility of AIP when the sudden onset of hyperglycemia together with enlargement of the pancreas are observed in subjects without a history of diabetes mellitus., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2022
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29. Vitamin D deficiency osteomalacia triggered by long-term social withdrawal and unbalanced diet in a Japanese middle-aged subject: A case report.
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Iwamoto Y, Tatsumi F, Dan K, Katakura Y, Shimoda M, Kimura T, Nakanishi S, Mune T, Kaku K, and Kaneto H
- Subjects
- Adult, Alkaline Phosphatase, Calcium, Fibroblast Growth Factor-23, Humans, Japan, Male, Middle Aged, Parathyroid Hormone, Vitamin D, Vitamins, Dermatitis, Atopic, Diet, Osteomalacia etiology, Social Isolation, Vitamin D Deficiency complications
- Abstract
Introduction: Osteomalacia is caused by an increase in the number of osteoids owing to mineralization failure. There are various causes of osteomalacia, such as hypophosphatemia due to excess production of fibroblast growth factor 23, vitamin D deficiency, insufficient vitamin D action, and renal tubular disorders., Patient Concerns: A 53-year-old man with bone pain and gait disturbance was referred to our institution. At the age of 35, he developed atopic dermatitis. He had eyesight deterioration due to atopic cataracts when he was 37 years old. Subsequently, he stayed home all the time, and his eating habits were unbalanced for a long period of time. Although he had atopic dermatitis, he did not take allergen-free diets, and he did not use sunscreen. Furthermore, when he was 43 years old, he failed to flex his legs and suffered gait disturbance., Diagnosis: Hypocalcemia and hypophosphatemia were observed as follow: calcium, 5.5 mg/dL; adjusted calcium, 6.9 mg/dL; inorganic phosphorous, 1.9 mg/dL. In addition, intact parathyroid hormone levels were as high as 277.4 pg/mL, and 1, 25-(OH)2 vitamin D and 25-(OH) vitamin D levels were markedly reduced: 1, 25-(OH)2 vitamin D, ≤4 pg/mL; 25-(OH) vitamin D, 11.0 ng/mL. Fibroblast growth factor 23 levels did not increase. Alkaline phosphatase (ALP) and bone-type ALP (BAP) levels were high: ALP, 784 U/L; BAP, 159.2 μg/L (reference range: 3.7-20.9 μg/L). Based on these findings, we diagnosed this patient with vitamin D-deficient osteomalacia triggered by long-term social withdrawal and an unbalanced diet., Interventions and Outcomes: After hospitalization, to treat vitamin D-deficient osteomalacia, we started to administer 1 μg/day of alfacalcidol and 3 g/day of calcium lactate. Approximately one month later, 1,25-(OH)2 vitamin D levels increased to 214 pg/mL. Consequently, calcium and inorganic phosphorus were also increased up to 7.8 mg/dL and 3.9 mg/dL, respectively, and intact parathyroid hormone was decreased to 132.0 pg/mL., Conclusions: We should bear in mind the possibility of osteomalacia triggered by social withdrawal and vitamin D deficiency even in middle-aged subjects., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2022
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30. Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase.
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Xiao L, Salem JE, Clauss S, Hanley A, Bapat A, Hulsmans M, Iwamoto Y, Wojtkiewicz G, Cetinbas M, Schloss MJ, Tedeschi J, Lebrun-Vignes B, Lundby A, Sadreyev RI, Moslehi J, Nahrendorf M, Ellinor PT, and Milan DJ
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- Action Potentials drug effects, Adenine toxicity, Agammaglobulinaemia Tyrosine Kinase deficiency, Agammaglobulinaemia Tyrosine Kinase genetics, Animals, Atrial Fibrillation enzymology, Atrial Fibrillation physiopathology, CSK Tyrosine-Protein Kinase genetics, CSK Tyrosine-Protein Kinase metabolism, Databases, Genetic, Heart Atria enzymology, Heart Atria physiopathology, Humans, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Risk Assessment, Risk Factors, Adenine analogs & derivatives, Antineoplastic Agents toxicity, Atrial Fibrillation chemically induced, Atrial Function, Left drug effects, CSK Tyrosine-Protein Kinase antagonists & inhibitors, Heart Atria drug effects, Heart Rate drug effects, Piperidines toxicity, Protein Kinase Inhibitors toxicity
- Abstract
Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood., Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF., Results: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; P <0.0001)., Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.
- Published
- 2020
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31. Imaging Cardiovascular and Lung Macrophages With the Positron Emission Tomography Sensor 64 Cu-Macrin in Mice, Rabbits, and Pigs.
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Nahrendorf M, Hoyer FF, Meerwaldt AE, van Leent MMT, Senders ML, Calcagno C, Robson PM, Soultanidis G, Pérez-Medina C, Teunissen AJP, Toner YC, Ishikawa K, Fish K, Sakurai K, van Leeuwen EM, Klein ED, Sofias AM, Reiner T, Rohde D, Aguirre AD, Wojtkiewicz G, Schmidt S, Iwamoto Y, Izquierdo-Garcia D, Caravan P, Swirski FK, Weissleder R, and Mulder WJM
- Subjects
- Animals, Atherosclerosis diagnostic imaging, Atherosclerosis pathology, Disease Models, Animal, Injections, Intravenous, Lung pathology, Macrophages, Alveolar pathology, Mice, Myocardial Infarction diagnostic imaging, Myocardial Infarction pathology, Nanoparticles, Pneumonia diagnostic imaging, Pneumonia pathology, Predictive Value of Tests, Rabbits, Swine, Swine, Miniature, Time Factors, Copper Radioisotopes administration & dosage, Copper Radioisotopes pharmacokinetics, Dextrans administration & dosage, Dextrans pharmacokinetics, Heart diagnostic imaging, Lung diagnostic imaging, Macrophages pathology, Molecular Imaging, Positron Emission Tomography Computed Tomography, Radiopharmaceuticals administration & dosage, Radiopharmaceuticals pharmacokinetics
- Abstract
Background: Macrophages, innate immune cells that reside in all organs, defend the host against infection and injury. In the heart and vasculature, inflammatory macrophages also enhance tissue damage and propel cardiovascular diseases., Methods: We here use in vivo positron emission tomography (PET) imaging, flow cytometry, and confocal microscopy to evaluate quantitative noninvasive assessment of cardiac, arterial, and pulmonary macrophages using the nanotracer
64 Cu-Macrin-a 20-nm spherical dextran nanoparticle assembled from nontoxic polyglucose., Results: PET imaging using64 Cu-Macrin faithfully reported accumulation of macrophages in the heart and lung of mice with myocardial infarction, sepsis, or pneumonia. Flow cytometry and confocal microscopy detected the near-infrared fluorescent version of the nanoparticle (VT680 Macrin) primarily in tissue macrophages. In 5-day-old mice,64 Cu-Macrin PET imaging quantified physiologically more numerous cardiac macrophages. Upon intravenous administration of64 Cu-Macrin in rabbits and pigs, we detected heightened macrophage numbers in the infarcted myocardium, inflamed lung regions, and atherosclerotic plaques using a clinical PET/magnetic resonance imaging scanner. Toxicity studies in rats and human dosimetry estimates suggest that64 Cu-Macrin is safe for use in humans., Conclusions: Taken together, these results indicate64 Cu-Macrin could serve as a facile PET nanotracer to survey spatiotemporal macrophage dynamics during various physiological and pathological conditions.64 Cu-Macrin PET imaging could stage inflammatory cardiovascular disease activity, assist disease management, and serve as an imaging biomarker for emerging macrophage-targeted therapeutics.- Published
- 2020
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32. Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes Mellitus.
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Hoyer FF, Zhang X, Coppin E, Vasamsetti SB, Modugu G, Schloss MJ, Rohde D, McAlpine CS, Iwamoto Y, Libby P, Naxerova K, Swirski FK, Dutta P, and Nahrendorf M
- Subjects
- Animals, Diabetes Mellitus, Experimental, Disease Models, Animal, Epidermal Growth Factor metabolism, ErbB Receptors metabolism, Gene Expression Profiling, Gene Expression Regulation, Male, Mice, Models, Biological, Myeloid Cells metabolism, Signal Transduction, Transcriptome, Bone Marrow Cells metabolism, Endothelial Cells metabolism, Myelopoiesis genetics
- Abstract
Background: Diabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production., Methods: In 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling., Results: In diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12 , a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr ( Cdh5
Cre Egfrfl/fl ). We found enhanced HSPC proliferation and increased myeloid cell production in Cdh5Cre Egfrfl/fl mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5Cre Egfrfl/fl mice, significantly delaying wound closure. Atherosclerosis was accelerated in Cdh5Cre Egfrfl/fl mice, leading to larger and more inflamed atherosclerotic lesions in the aorta., Conclusions: In diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.- Published
- 2020
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33. A Miniaturized, Programmable Pacemaker for Long-Term Studies in the Mouse.
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Hulsmans M, Aguirre AD, Bonner MD, Bapat A, Cremer S, Iwamoto Y, King KR, Swirski FK, Milan DJ, Weissleder R, and Nahrendorf M
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- Animals, Electrodes, Implanted, Equipment Design, Female, Male, Mice, Mice, Inbred C57BL, Miniaturization, Software, Time, Arrhythmias, Cardiac physiopathology, Pacemaker, Artificial, Telemetry methods
- Abstract
Rationale: Cardiac pacing is a critical technology for the treatment of arrhythmia and heart failure. The impact of specific pacing strategies on myocardial function is an area of intense research and high clinical significance. Mouse models have proven extremely useful for probing mechanisms of heart disease, but there is currently no reliable technology for long-term pacing in the mouse., Objective: We sought to develop a device for long-term pacing studies in mice. We evaluated the device for (1) treating third-degree atrioventricular block after macrophage depletion, (2) ventricular pacing-induced cardiomyopathy, and (3) high-rate atrial pacing., Methods and Results: We developed a mouse pacemaker by refashioning a 26 mm×6.7 mm clinical device powered by a miniaturized, highly efficient battery. The electrode was fitted with a single flexible lead, and custom software extended the pacing rate to up to 1200 bpm. The wirelessly programmable device was implanted in the dorsal subcutaneous space of 39 mice. The tunneled lead was passed through a left thoracotomy incision and attached to the epicardial surface of the apex (for ventricular pacing) or the left atrium (for atrial pacing). Mice tolerated the implantation and both long-term atrial and ventricular pacing over weeks. We then validated the pacemaker's suitability for the treatment of atrioventricular block after macrophage depletion in Cd11b
DTR mice. Ventricular pacing increased the heart rate from 313±59 to 550 bpm ( P<0.05). In addition, we characterized tachypacing-induced cardiomyopathy in mice. Four weeks of ventricular pacing resulted in reduced left ventricular function, fibrosis, and an increased number of cardiac leukocytes and endothelial activation. Finally, we demonstrated the feasibility of chronic atrial pacing at 1200 bpm., Conclusions: Long-term pacing with a fully implantable, programmable, and battery-powered device enables previously impossible investigations of arrhythmia and heart failure in the mouse.- Published
- 2018
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34. Prevalence, Concomitance, and Distribution of Ossification of the Spinal Ligaments: Results of Whole Spine CT Scans in 1500 Japanese Patients.
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Fujimori T, Watabe T, Iwamoto Y, Hamada S, Iwasaki M, and Oda T
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- Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Female, Humans, Japan epidemiology, Male, Middle Aged, Ossification, Heterotopic diagnostic imaging, Prevalence, Spinal Diseases diagnostic imaging, Tomography, X-Ray Computed, Young Adult, Ligaments, Articular diagnostic imaging, Ossification, Heterotopic epidemiology, Spinal Diseases epidemiology
- Abstract
Study Design: Cross-sectional study., Objective: To investigate the prevalence, concomitance, and distribution of various types of ossification of the spinal ligaments in healthy subjects using computed tomography (CT)., Summary of Background Data: CT has better diagnostic accuracy for ossification of the spinal ligaments compared to plain radiography. Currently there is no study that examines the prevalence of ossification of the spinal ligaments using whole spine CT scans., Methods: One thousand five hundred Japanese patients (888 men and 612 women) who underwent positron emission tomography and CT (PETCT) in a private health check center between 2006 and 2013 were included. This PETCT was performed on self-paying participants as a preventive cancer screen. Existence of ossification of the posterior longitudinal ligament (OPLL), ligamentum flavum (OLF), anterior longitudinal ligament (OALL), diffuse idiopathic skeletal hyperostosis (DISH), and nuchal ligament (ONL) was examined., Results: The prevalence of spinal ligament ossifications was found to be 6.3% in cervical OPLL (8.3% in men and 3.4% in women), 23% in ONL (33% in men and 8.8% in women), 1.6% in thoracic OPLL (1.4% in men and 2.0% in women), 12% in thoracic OLF (15% in men and 7.7% in women), 37% in thoracolumbar OALL (45% in men and 26% in women), and 12% in DISH (16% in men and 6.2% in women). Thirteen percent of patients with cervical OPLL had thoracic OPLL, 34% of cervical OPLL had thoracic OLF, 45% of cervical OPLL had ONL, and 36% of cervical OPLL had DISH. The most common level was C5 for cervical OPLL, T1/2 for thoracic OPLL, T11 for thoracic OLF, and T8/9 for OALL., Conclusion: Accurate prevalence of various types of ossification of the spinal ligaments evaluated by CT was revealed. High concomitance was observed in each classification of spinal ligament ossification., Level of Evidence: 3.
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- 2016
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35. Dumbbell Scoring System: A New Method for the Differential Diagnosis of Malignant and Benign Spinal Dumbbell Tumors.
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Matsumoto Y, Harimaya K, Kawaguchi K, Hayashida M, Okada S, Doi T, and Iwamoto Y
- Subjects
- Adult, Diagnosis, Differential, Female, Hemangiopericytoma diagnostic imaging, Hemangiopericytoma pathology, Humans, Lymphoma diagnostic imaging, Lymphoma pathology, Magnetic Resonance Imaging methods, Male, Middle Aged, Neurilemmoma diagnostic imaging, Neurilemmoma pathology, Retrospective Studies, Sensitivity and Specificity, Spinal Neoplasms diagnostic imaging, Spinal Neoplasms pathology, Tomography, X-Ray Computed methods, Hemangiopericytoma diagnosis, Lymphoma diagnosis, Neurilemmoma diagnosis, Spinal Neoplasms diagnosis
- Abstract
Study Design: Retrospective diagnostic analysis., Objective: The aim of the study was to establish a new scoring system, the dumbbell scoring system (DSS), for preoperative evaluation of the malignant potential of spinal dumbbell tumors (SDTs)., Summary of Background Data: Among SDTs, benign tumors such as schwannomas occur frequently, whereas malignant SDTs, including malignant peripheral nerve sheath tumors, are uncommon. No scoring system has been developed to preoperatively diagnose the malignant potential of SDTs., Methods: We retrospectively reviewed the records of 59 consecutive patients with SDTs. The following imaging features were recorded: tumor size, tumor shape, tumor boundary, pattern of enhancement of intratumoral lesions (homogeneous or heterogeneous), cyst formation in the tumors on magnetic resonance imaging, and enlargement of neural foramina and scalloping or osteolytic destruction of surrounding bones on computed tomography. The prevalence of characteristic imaging features in malignant and benign SDTs were evaluated, and appropriate cut-off points for the DSS score were obtained using receiver operating characteristics., Results: Twenty cases were confirmed to be malignant tumors. Pathological diagnoses of the malignant SDTs were as follows: 11 cases of malignant peripheral nerve sheath tumor; 3 cases of malignant lymphoma; and 1 case each of extraskeletal Ewing sarcoma, hemangiopericytoma, hemangioendothelioma, malignant myoepithelioma, neuroblastoma, and plasmacytoma. The DSS was based on four characteristic imaging features confirmed as significant predictors of malignant SDTs, namely, maximal diameter greater than 5 cm, irregularly lobulated tumor, tumor boundary indistinguishable from surrounding tissues, and osteolytic bone destruction. Malignant SDTs showed a higher DSS score (median 5.5 points) than did benign SDTs (median 0 point). The optimum cut-off value for the DSS score was 3 points, and the sensitivity and specificity for the diagnosis of malignant SDTs were 90% and 84.6%, respectively., Conclusion: This scoring system may be helpful for preoperative decision making. If the DSS score is equal to or higher than 3, biopsies was recommended to confirm the histological diagnosis., Level of Evidence: 4.
- Published
- 2016
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36. Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure.
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Sager HB, Hulsmans M, Lavine KJ, Moreira MB, Heidt T, Courties G, Sun Y, Iwamoto Y, Tricot B, Khan OF, Dahlman JE, Borodovsky A, Fitzgerald K, Anderson DG, Weissleder R, Libby P, Swirski FK, and Nahrendorf M
- Subjects
- Animals, Cells, Cultured, Chronic Disease, Female, Heart Failure physiopathology, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Biomechanical Phenomena physiology, Cell Proliferation physiology, Heart Failure pathology, Macrophages physiology, Myocardium cytology
- Abstract
Rationale: Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic remote myocardium, however, remain unclear., Objective: This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation., Methods and Results: Eight weeks post MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6C(high) monocytes rose from 64±5 to 108±9 per microliter of blood (P<0.05). Cardiac monocyte recruitment declined in Ccr2(-/-) mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the mitogen-activated protein kinase pathway, whereas specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (P<0.05). Steady-state cardiac macrophages, monocyte-derived macrophages, and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 versus 19.1±2%; P<0.05)., Conclusions: Myocardial failure is influenced by an altered myeloid cell repertoire., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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37. E-Selectin Inhibition Mitigates Splenic HSC Activation and Myelopoiesis in Hypercholesterolemic Mice With Myocardial Infarction.
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Dutta P, Hoyer FF, Sun Y, Iwamoto Y, Tricot B, Weissleder R, Magnani JL, Swirski FK, and Nahrendorf M
- Subjects
- Animals, Aortic Diseases genetics, Aortic Diseases metabolism, Aortic Diseases pathology, Apolipoproteins E deficiency, Apolipoproteins E genetics, Atherosclerosis genetics, Atherosclerosis metabolism, Atherosclerosis pathology, Cell Proliferation drug effects, Diet, High-Fat, Disease Models, Animal, Fibrosis, Hematopoietic Stem Cells metabolism, Hypercholesterolemia genetics, Male, Mice, Inbred C57BL, Mice, Knockout, Myocardial Infarction genetics, Myocardial Infarction metabolism, Myocardial Infarction pathology, Necrosis, Plaque, Atherosclerotic, Signal Transduction drug effects, Spleen metabolism, Aortic Diseases drug therapy, Atherosclerosis drug therapy, E-Selectin metabolism, Hematopoietic Stem Cells drug effects, Hypercholesterolemia metabolism, Myelopoiesis drug effects, Myocardial Infarction drug therapy, Spleen drug effects
- Abstract
Objective: Atherosclerosis is a chronic disease characterized by lipid accumulation in the arterial wall. After myocardial infarction (MI), atherosclerotic plaques are infiltrated by inflammatory myeloid cells that aggravate the disease and increase the risk of secondary myocardial ischemia. Splenic myelopoiesis provides a steady flow of myeloid cells to inflamed atherosclerotic lesions after MI. Therefore, targeting myeloid cell production in the spleen could ameliorate increased atherosclerotic plaque inflammation after MI., Approach and Results: Here we show that MI increases splenic myelopoiesis by driving hematopoietic stem and progenitor cells into the cell cycle. In an atherosclerotic mouse model, E-selectin inhibition decreased hematopoietic stem and progenitor cell proliferation in the spleen after MI. This led to reduced extramedullary myelopoiesis and decreased myeloid cell accumulation in atherosclerotic lesions. Finally, we observed stable atherosclerotic plaque features, including smaller plaque size, reduced necrotic core area, and thicker fibrous cap after E-selectin inhibition., Conclusions: Inhibiting E-selectin attenuated inflammation in atherosclerotic plaques, likely by reducing leukocyte recruitment into plaques and by mitigating hematopoietic stem and progenitor cell activation in the spleen of mice with MI., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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38. The Position of the Aorta Relative to the Vertebrae in Patients With Lenke Type 1 Adolescent Idiopathic Scoliosis.
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Bekki H, Harimaya K, Matsumoto Y, Hayashida M, Okada S, Doi T, and Iwamoto Y
- Subjects
- Adolescent, Adult, Child, Cohort Studies, Female, Humans, Male, Pedicle Screws, Scoliosis surgery, Spine surgery, Tomography, X-Ray Computed, Young Adult, Aorta diagnostic imaging, Scoliosis diagnostic imaging, Spine diagnostic imaging
- Abstract
Study Design: A computed tomography study., Objective: The aim of the study was to clarify the position of the aorta relative to the spine in patients with Lenke type 1 adolescent idiopathic scoliosis., Summary of Background Data: Several authors have examined the position of the aorta in patients with scoliosis; however, their analysis included several types of curve. There is a possibility that the position of the aorta differs according to the scoliosis curve type., Methods: Thirty-eight patients with Lenke type 1 were analyzed. The angle (left pedicle aorta [LtP-Ao] angle) and distance (LtP-Ao distance) from the insertion point of the left pedicle screw to the aorta were measured from T4 through L2. The measured data were evaluated from 4 levels above to 4 levels below the apical vertebra. The difference between lumbar modifiers A and C was examined. Dangerous pedicles, which were defined as those in which the aorta entered the expected area based on the screw direction error and length, were counted from T10 to L2., Results: The aorta was located posterolaterally and adjacent to the vertebra at the middle thoracic level, and anteromedially and distant at the thoracolumbar level. LtP-Ao angle was largest at 1 level above the apical vertebra, and LtP-Ao distance was shortest at 2 levels above. LtP-Ao angle of Lenke 1A was significantly larger than 1C from T11 to L2, and LtP-Ao distance of 1A was significantly shorter than 1C from T11 to L1. When the screw length was 40 mm and the direction error was within 10°, there were a large number of dangerous pedicles at T11, regardless of the lumbar modifier., Conclusion: The direction error has a potential risk of injuring the aorta around the apical vertebra. The selection of screws of the proper length is necessary to avoid a breach of the anterior vertebral wall at thoracolumbar level, especially at T11., Level of Evidence: 3.
- Published
- 2016
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39. Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction.
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Sager HB, Heidt T, Hulsmans M, Dutta P, Courties G, Sebas M, Wojtkiewicz GR, Tricot B, Iwamoto Y, Sun Y, Weissleder R, Libby P, Swirski FK, and Nahrendorf M
- Subjects
- Animals, Cell Proliferation drug effects, Cell Proliferation physiology, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Interleukin-1beta metabolism, Leukocytes metabolism, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardial Infarction metabolism, Recombinant Proteins administration & dosage, Drug Delivery Systems methods, Interleukin-1beta antagonists & inhibitors, Leukocytes pathology, Myocardial Infarction pathology, Myocardial Infarction prevention & control
- Abstract
Background: Myocardial infarction (MI) is an ischemic wound that recruits millions of leukocytes. MI-associated blood leukocytosis correlates inversely with patient survival, yet the signals driving heightened leukocyte production after MI remain incompletely understood., Methods and Results: With the use of parabiosis surgery, this study shows that soluble danger signals, among them interleukin-1β, increase bone marrow hematopoietic stem cell proliferation after MI. Data obtained in bone marrow reconstitution experiments reveal that interleukin-1β enhances hematopoietic stem cell proliferation by both direct actions on hematopoietic cells and through modulation of the bone marrow's hematopoietic microenvironment. An antibody that neutralizes interleukin-1β suppresses these effects. Anti-interleukin-1β treatment dampens the post-MI increase in hematopoietic stem cell proliferation. Consequently, decreased leukocyte numbers in the blood and infarct reduce inflammation and diminish post-MI heart failure in ApoE(-/-) mice with atherosclerosis., Conclusions: The presented insight into post-MI bone marrow activation identifies a mechanistic target for muting inflammation in the ischemically damaged heart., (© 2015 American Heart Association, Inc.)
- Published
- 2015
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40. Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis.
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Ye YX, Calcagno C, Binderup T, Courties G, Keliher EJ, Wojtkiewicz GR, Iwamoto Y, Tang J, Pérez-Medina C, Mani V, Ishino S, Johnbeck CB, Knigge U, Fayad ZA, Libby P, Weissleder R, Tawakol A, Dubey S, Belanger AP, Di Carli MF, Swirski FK, Kjaer A, Mulder WJ, and Nahrendorf M
- Subjects
- Animals, Aorta, Thoracic diagnostic imaging, Aortic Diseases diagnostic imaging, Aortic Diseases genetics, Aortic Diseases metabolism, Apolipoproteins E deficiency, Apolipoproteins E genetics, Atherosclerosis diagnostic imaging, Atherosclerosis genetics, Atherosclerosis metabolism, Bone Marrow diagnostic imaging, Carotid Artery Diseases diagnostic imaging, Carotid Artery Diseases genetics, Carotid Artery Diseases metabolism, Cholesterol, Dietary, Dideoxynucleosides, Diet, High-Fat, Disease Models, Animal, Female, Fluorodeoxyglucose F18, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Multimodal Imaging, Plaque, Atherosclerotic, Predictive Value of Tests, Rabbits, Radiopharmaceuticals, Retrospective Studies, Spleen diagnostic imaging, Time Factors, Aortic Diseases diagnosis, Atherosclerosis diagnosis, Carotid Artery Diseases diagnosis, Cell Proliferation, Hematopoietic Stem Cells diagnostic imaging, Macrophages diagnostic imaging, Positron-Emission Tomography, Tomography, X-Ray Computed
- Abstract
Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention., Objective: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis., Methods and Results: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta., Conclusions: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis., (© 2015 American Heart Association, Inc.)
- Published
- 2015
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41. Lp-PLA2 Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative Macrophages.
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He S, Chousterman BG, Fenn A, Anzai A, Nairz M, Brandt M, Hilgendorf I, Sun Y, Ye YX, Iwamoto Y, Tricot B, Weissleder R, Macphee C, Libby P, Nahrendorf M, and Swirski FK
- Subjects
- 1-Alkyl-2-acetylglycerophosphocholine Esterase biosynthesis, Animals, Disease Models, Animal, Female, Flow Cytometry, Heart Ventricles metabolism, Heart Ventricles pathology, Macrophages metabolism, Magnetic Resonance Imaging, Cine, Mice, Mice, Inbred C57BL, Myocardial Infarction diagnosis, Myocardial Infarction metabolism, Reverse Transcriptase Polymerase Chain Reaction, Wound Healing, 1-Alkyl-2-acetylglycerophosphocholine Esterase genetics, Gene Expression Regulation, Heart Ventricles physiopathology, Macrophages pathology, Myocardial Infarction genetics, RNA genetics, Ventricular Remodeling genetics
- Abstract
Background: Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6C(high) and reparative Ly-6C(low) monocytes/macrophages. Excessive inflammation disrupts the balance between the 2 phases, impairs infarct healing, and contributes to left ventricle remodeling and heart failure. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of the phospholipase A2 family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA2 levels associate with increased risk of cardiovascular events across diverse patient populations, but the mechanisms by which the enzyme elicits its effects remain unclear. This study tested the role of Lp-PLA2 in healing after MI., Methods and Results: In response to MI, Lp-PLA2 levels markedly increased in the circulation. To test the functional importance of Lp-PLA2, we generated chimeric mice whose bone marrow-derived leukocytes were Lp-PLA2-deficient (bmLp-PLA2 (-/-)). Compared with wild-type controls, bmLp-PLA2 (-/-) mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly, bmLp-PLA2 (-/-) mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6C(high) monocytes. During the later, reparative phase, infarcts of bmLp-PLA2 (-/-) mice contained Ly-6C(low) macrophages with a skewed M2-prone gene expression signature, increased collagen deposition, fewer inflammatory cells, and improved indices of angiogenesis. Consequently, the hearts of bmLp-PLA2 (-/-) mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction., Conclusions: Lp-PLA2 augments the inflammatory response after MI and antagonizes healing by disrupting the balance between inflammation and repair, providing a rationale for focused study of ventricular function and heart failure after targeting this enzyme acutely in MI., (© 2015 The Authors.)
- Published
- 2015
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42. Scintigraphic assessments of the reparative process in osteonecrosis of the femoral head using SPECT/CT with 99mTc hydroxymethylene diphosphonate.
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Motomura G, Yamamoto T, Abe K, Nakashima Y, Ohishi M, Hamai S, Doi T, Honda H, and Iwamoto Y
- Subjects
- Adult, Bone and Bones metabolism, Female, Femur metabolism, Femur Head Necrosis metabolism, Hip diagnostic imaging, Humans, Male, Osteotomy, Retrospective Studies, Technetium Tc 99m Medronate pharmacokinetics, Bone and Bones diagnostic imaging, Femur diagnostic imaging, Femur Head Necrosis diagnostic imaging, Radiopharmaceuticals pharmacokinetics, Technetium Tc 99m Medronate analogs & derivatives, Tomography, Emission-Computed methods, Tomography, Emission-Computed, Single-Photon methods
- Abstract
Objective: The aim of the study was to assess the degree and location of the reparative process in early osteonecrosis of the femoral head on the basis of single-photon emission computed tomography/computed tomography (SPECT/CT) with technetium-99m hydroxymethylene diphosphonate., Materials and Methods: This study was approved by the institutional review board. We retrospectively evaluated SPECT/CT scans of 23 consecutive hips. On the basis of the classification system used, 12 hips were classified as stage 1 (no radiographic abnormality), six hips as stage 2 (demarcating sclerosis without femoral head collapse), and five hips as stage 3A (<3 mm femoral head collapse). In each femoral head, the area with the maximum uptake count was defined as the region of maximum uptake. The degree of maximum uptake was assessed by the count ratio, which was defined as the maximum count within the femoral head divided by the mean uptake count of the cross-sectional region of the ipsilateral femur at the level of the distal end of the lesser trochanter., Results: In stage 1, the maximum uptake count tended to occur in the anterior region of the femoral head. Meanwhile, in both stage 2 and stage 3A, the maximum uptake count was more likely to be observed in the lateral region. The mean count ratio of stage 2 was significantly higher than that of stage 1., Conclusion: We speculate that osteoblastic activity in the precollapsed stage may gradually increase around the necrotic lesion, with a tendency to advance toward the lateral region of the femoral head.
- Published
- 2014
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43. Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction.
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Heidt T, Courties G, Dutta P, Sager HB, Sebas M, Iwamoto Y, Sun Y, Da Silva N, Panizzi P, van der Laan AM, Swirski FK, Weissleder R, and Nahrendorf M
- Subjects
- Adoptive Transfer, Animals, Apoptosis drug effects, Bone Marrow Transplantation, CX3C Chemokine Receptor 1, Cell Division, Diphtheria Toxin toxicity, Female, Genes, Reporter, Humans, Macrophage Activation, Mice, Mice, Inbred C57BL, Myocardial Infarction pathology, Myocardial Ischemia pathology, Myocardium pathology, Parabiosis, Phagocytosis, Radiation Chimera, Receptors, Chemokine genetics, Receptors, Chemokine physiology, Macrophages physiology, Monocytes physiology, Myocardial Infarction immunology, Myocardial Ischemia immunology, Myocardium immunology
- Abstract
Rationale: Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that, in several organs, tissue-resident macrophages may self-maintain through local proliferation., Objective: Our aim was to study the contribution of monocytes to cardiac-resident macrophages in steady state, after macrophage depletion in CD11b(DTR/+) mice and in myocardial infarction., Methods and Results: Using in vivo fate mapping and flow cytometry, we estimated that during steady state the heart macrophage population turns over in ≈1 month. To explore the source of cardiac-resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3±3.4%, whereas heart macrophages showed a much lower chimerism of 2.7±0.5% (P<0.01). Macrophages self-renewed locally through proliferation: 2.1±0.3% incorporated bromodeoxyuridine 2 hours after a single injection, and 13.7±1.4% heart macrophages stained positive for the cell cycle marker Ki-67. The cells likely participate in defense against infection, because we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue-resident macrophages died locally, whereas some also migrated to hematopoietic organs. If the steady state was perturbed by coronary ligation or diphtheria toxin-induced macrophage depletion in CD11b(DTR/+) mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation., Conclusions: In this study, we show differential contribution of monocytes to heart macrophages during steady state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure., (© 2014 American Heart Association, Inc.)
- Published
- 2014
- Full Text
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44. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium.
- Author
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Hilgendorf I, Gerhardt LM, Tan TC, Winter C, Holderried TA, Chousterman BG, Iwamoto Y, Liao R, Zirlik A, Scherer-Crosbie M, Hedrick CC, Libby P, Nahrendorf M, Weissleder R, and Swirski FK
- Subjects
- Animals, Antigens, Ly blood, Cell Movement physiology, Female, Inflammation metabolism, Inflammation pathology, Inflammation Mediators metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes pathology, Myocardial Infarction pathology, Nuclear Receptor Subfamily 4, Group A, Member 1 blood, Antigens, Ly physiology, Inflammation Mediators physiology, Monocytes metabolism, Myocardial Infarction blood, Myocardial Infarction prevention & control, Nuclear Receptor Subfamily 4, Group A, Member 1 physiology
- Abstract
Rationale: Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C)(high) and reparative Ly-6C(low) monocytes/macrophages (Mo/MΦ). According to 1 model, Mo/MΦ heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6C(low) monocyte production but dispensable to Ly-6C(low) macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity., Objective: This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/MΦ accumulation scenarios., Methods and Results: We show that Ly-6C(high) monocytes infiltrate the infarcted myocardium and, unlike Ly-6C(low) monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6C(high) monocytes accrue in response to a brief C-C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6C(high) monocytes give rise to reparative Ly-6C(low) F4/80(high) macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C(high) monocytes express heightened levels of C-C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function., Conclusions: Ly-6C(high) monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.
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- 2014
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45. Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity.
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Hilgendorf I, Theurl I, Gerhardt LM, Robbins CS, Weber GF, Gonen A, Iwamoto Y, Degousee N, Holderried TA, Winter C, Zirlik A, Lin HY, Sukhova GK, Butany J, Rubin BB, Witztum JL, Libby P, Nahrendorf M, Weissleder R, and Swirski FK
- Subjects
- Animals, Atherosclerosis genetics, Atherosclerosis pathology, B-Lymphocytes pathology, Bone Marrow Cells immunology, Bone Marrow Cells pathology, Cholesterol, Dietary administration & dosage, Cholesterol, Dietary adverse effects, Coculture Techniques, Humans, Lymphocyte Activation genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Radiation Chimera, Th1 Cells pathology, Adaptive Immunity genetics, Atherosclerosis immunology, B-Lymphocytes immunology, Immunity, Innate genetics, Lymphocyte Activation immunology, Th1 Cells immunology
- Abstract
Background: Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other's function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor-secreting cells of hitherto unknown function in atherosclerosis., Methods and Results: Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell-derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon γ-producing T helper-1 cells. This IRA B cell-dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins., Conclusions: Granulocyte macrophage colony-stimulating factor-producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1-associated milieu that aggravates atherosclerosis.
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- 2014
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46. Nanoparticle PET-CT detects rejection and immunomodulation in cardiac allografts.
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Ueno T, Dutta P, Keliher E, Leuschner F, Majmudar M, Marinelli B, Iwamoto Y, Figueiredo JL, Christen T, Swirski FK, Libby P, Weissleder R, and Nahrendorf M
- Subjects
- Angiotensin-Converting Enzyme Inhibitors pharmacology, Animals, Copper Radioisotopes, Enalapril pharmacology, Female, Flow Cytometry, Graft Rejection prevention & control, Graft Survival drug effects, Heart drug effects, Heart Transplantation adverse effects, Immunosuppressive Agents pharmacology, Macrophages diagnostic imaging, Macrophages immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Predictive Value of Tests, Radiopharmaceuticals, Time Factors, Graft Rejection diagnostic imaging, Graft Rejection immunology, Heart diagnostic imaging, Heart Transplantation immunology, Multimodal Imaging, Myocardium immunology, Nanomedicine methods, Nanoparticles, Positron-Emission Tomography, Tomography, X-Ray Computed
- Abstract
Background: Macrophages predominate among the inflammatory cells in rejecting allografts. These innate immune cells, in addition to allospecific T cells, can damage cardiomyocytes directly., Methods and Results: We explored whether sensitive positron emission tomography-computed tomography (PET-CT) imaging of macrophages-avid nanoparticles detects rejection of heart allografts in mice. In addition, we used the imaging method to follow the immunomodulatory impact of angiotensin-converting enzyme inhibitor therapy on myeloid cells in allografts. Dextran nanoparticles were derivatized with the PET isotope copper-64 and imaged 7 days after transplantation. C57BL/6 recipients of BALB/c allografts displayed robust positron emission tomography signal (standard uptake value allograft, 2.8±0.3; isograft control, 1.7±0.2; P<0.05). Autoradiography and scintillation counting confirmed the in vivo findings. We then imaged the effects of angiotensin-converting enzyme inhibitor (5 mg/kg enalapril). Angiotensin-converting enzyme inhibitor significantly decreased nanoparticle signal (P<0.05). Histology and flow cytometry showed a reduced number of myeloid cells in the graft, blood, and lymph nodes and diminished antigen presentation (P<0.05 versus untreated allografts). Angiotensin-converting enzyme inhibitor also significantly prolonged allograft survival (12 versus 7 days; P<0.0001)., Conclusions: Nanoparticle macrophage PET-CT detects heart transplant rejection and predicts organ survival by reporting on myeloid cells.
- Published
- 2013
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47. Nitroglycerine-induced vasodilation for assessment of vascular function: a comparison with flow-mediated vasodilation.
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Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Hidaka T, Kihara Y, Chayama K, Noma K, Nakashima A, Goto C, and Higashi Y
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Analysis of Variance, Angiography methods, Atherosclerosis diagnostic imaging, Atherosclerosis pathology, Blood Flow Velocity, Cardiovascular Diseases diagnostic imaging, Cardiovascular Diseases pathology, Cohort Studies, Endothelium, Vascular physiology, Female, Humans, Male, Middle Aged, Multivariate Analysis, Predictive Value of Tests, Prospective Studies, Reference Values, Risk Assessment, Sensitivity and Specificity, Severity of Illness Index, Sex Factors, Vascular Patency physiology, Young Adult, Atherosclerosis epidemiology, Cardiovascular Diseases epidemiology, Endothelium, Vascular drug effects, Nitroglycerin pharmacology, Vasodilation drug effects
- Abstract
Objective: Nitroglycerine-induced vasodilation has been used as a control test for flow-mediated vasodilation (FMD) to differentiate endothelium-dependent from endothelium-independent response when evaluating endothelial function in humans. Recently, nitroglycerine-induced vasodilation has also been reported to be impaired in patients with atherosclerosis. The purpose of this study was to determine the relationships between nitroglycerine-induced vasodilation and cardiovascular risk factors., Approach and Results: We measured nitroglycerine-induced vasodilation and FMD in 436 subjects who underwent health examinations (mean age, 53 ± 19 years; age range, 19-86 years), including patients with cardiovascular diseases. There was a significant relationship between nitroglycerine-induced vasodilation and FMD (r=0.42; P<0.001). Univariate regression analysis revealed that nitroglycerine-induced vasodilation correlated with age (r=-0.34; P<0.001), systolic blood pressure (r=-0.32; P<0.001), diastolic blood pressure (r=-0.24; P<0.001), heart rate (r=-0.21; P<0.001), glucose (r=-0.23; P<0.001), and smoking pack-year (r=-0.12; P=0.01), as well as Framingham risk score (r=-0.30; P<0.001). Nitroglycerine-induced vasodilation was significantly smaller in patients with cardiovascular disease than in both subjects with and without cardiovascular risk factors (10.5 ± 5.6% versus 13.7 ± 5.4% and 15.3 ± 4.3%; P<0.001, respectively), whereas there was no significant difference in nitroglycerine-induced vasodilation between subjects with and without cardiovascular risk factors. Multivariate analysis revealed that male sex, body mass index, hypertension, diabetes mellitus, baseline brachial artery diameter, and FMD were independent predictors of nitroglycerine-induced vasodilation., Conclusions: These findings suggest that nitroglycerine-induced vasodilation may be a marker of the grade of atherosclerosis. FMD should be interpreted as an index of vascular function reflecting both endothelium-dependent vasodilation and endothelium-independent vasodilation in subjects with impaired nitroglycerine-induced vasodilation.
- Published
- 2013
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48. Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice.
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Majmudar MD, Keliher EJ, Heidt T, Leuschner F, Truelove J, Sena BF, Gorbatov R, Iwamoto Y, Dutta P, Wojtkiewicz G, Courties G, Sebas M, Borodovsky A, Fitzgerald K, Nolte MW, Dickneite G, Chen JW, Anderson DG, Swirski FK, Weissleder R, and Nahrendorf M
- Subjects
- Amino Acid Sequence, Animals, Atherosclerosis genetics, Atherosclerosis pathology, Female, Genetic Predisposition to Disease, Genetic Therapy methods, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Monocytes pathology, Myocardial Infarction pathology, Random Allocation, Receptors, CCR2 antagonists & inhibitors, Receptors, CCR2 metabolism, Atherosclerosis therapy, Gene Targeting methods, Monocytes metabolism, Myocardial Infarction genetics, Myocardial Infarction therapy, RNA Interference physiology, Receptors, CCR2 genetics, Wound Healing genetics
- Abstract
Background: Exaggerated and prolonged inflammation after myocardial infarction (MI) accelerates left ventricular remodeling. Inflammatory pathways may present a therapeutic target to prevent post-MI heart failure. However, the appropriate magnitude and timing of interventions are largely unknown, in part because noninvasive monitoring tools are lacking. Here, we used nanoparticle-facilitated silencing of CCR2, the chemokine receptor that governs inflammatory Ly-6C(high) monocyte subset traffic, to reduce infarct inflammation in apolipoprotein E-deficient (apoE(-/-)) mice after MI. We used dual-target positron emission tomography/magnetic resonance imaging of transglutaminase factor XIII (FXIII) and myeloperoxidase (MPO) activity to monitor how monocyte subset-targeted RNAi altered infarct inflammation and healing., Methods and Results: Flow cytometry, gene expression analysis, and histology revealed reduced monocyte numbers and enhanced resolution of inflammation in infarcted hearts of apoE(-/-) mice that were treated with nanoparticle-encapsulated siRNA. To follow extracellular matrix cross-linking noninvasively, we developed a fluorine-18-labeled positron emission tomography agent ((18)F-FXIII). Recruitment of MPO-rich inflammatory leukocytes was imaged with a molecular magnetic resonance imaging sensor of MPO activity (MPO-Gd). Positron emission tomography/magnetic resonance imaging detected anti-inflammatory effects of intravenous nanoparticle-facilitated siRNA therapy (75% decrease of MPO-Gd signal; P<0.05), whereas (18)F-FXIII positron emission tomography reflected unimpeded matrix cross-linking in the infarct. Silencing of CCR2 during the first week after MI improved ejection fraction on day 21 after MI from 29% to 35% (P<0.05)., Conclusion: CCR2-targeted RNAi reduced recruitment of Ly-6C(high) monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling.
- Published
- 2013
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49. Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques.
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Majmudar MD, Yoo J, Keliher EJ, Truelove JJ, Iwamoto Y, Sena B, Dutta P, Borodovsky A, Fitzgerald K, Di Carli MF, Libby P, Anderson DG, Swirski FK, Weissleder R, and Nahrendorf M
- Subjects
- Animals, Aorta diagnostic imaging, Aorta pathology, Apolipoproteins E deficiency, Apolipoproteins E genetics, Dextrans, Disease Models, Animal, Disease Progression, Feasibility Studies, Mice, Mice, Knockout, Radioisotopes, Sensitivity and Specificity, Zirconium, Macrophages diagnostic imaging, Macrophages pathology, Magnetic Resonance Imaging methods, Nanoparticles, Plaque, Atherosclerotic diagnostic imaging, Plaque, Atherosclerotic pathology, Positron-Emission Tomography methods
- Abstract
Rationale: Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocytes and macrophages could serve as a biomarker of disease progression and therapeutic intervention., Objective: To noninvasively assess plaque inflammation with dextran nanoparticle (DNP)-facilitated hybrid positron emission tomography/magnetic resonance imaging (PET/MRI)., Methods and Results: Using clinically approved building blocks, we systematically developed 13-nm polymeric nanoparticles consisting of cross-linked short chain dextrans, which were modified with desferoxamine for zirconium-89 radiolabeling ((89)Zr-DNP) and a near-infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in monocytes and macrophages (76.7%) and lower signal originating from other leukocytes, such as neutrophils and lymphocytes (11.8% and 0.7%, P<0.05 versus monocytes and macrophages). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of (89)Zr-DNP in the aortic root of apolipoprotein E knock out (ApoE(-/-)) mice (standard uptake value, ApoE(-/-) mice versus wild-type controls, 1.9±0.28 versus 1.3±0.03; P<0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor C-C chemokine receptor type 2 with short-interfering RNA decreased (89)Zr-DNP plaque signal (P<0.05) and inflammatory gene expression (P<0.05)., Conclusions: Hybrid PET/MRI with a 13-nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy.
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- 2013
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50. Early histologic lesions and risk factors for recurrence of diabetic kidney disease after kidney transplantation.
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Nyumura I, Honda K, Tanabe K, Teraoka S, and Iwamoto Y
- Subjects
- Adult, Aged, Albuminuria etiology, Biomarkers blood, Biopsy, Blood Pressure, Case-Control Studies, Diabetic Nephropathies blood, Diabetic Nephropathies pathology, Diabetic Nephropathies physiopathology, Female, Glomerular Basement Membrane ultrastructure, Glycated Hemoglobin metabolism, Humans, Japan, Kidney Glomerulus blood supply, Kidney Glomerulus ultrastructure, Linear Models, Lipids blood, Male, Microscopy, Electron, Middle Aged, Multivariate Analysis, Neovascularization, Pathologic, Recurrence, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Diabetic Nephropathies surgery, Kidney Glomerulus pathology, Kidney Transplantation adverse effects
- Abstract
Background: Recurrence of diabetic kidney disease (DKD) after diabetic kidney transplantation has been reported. The aim of this study was to determine the early histologic lesions, focusing especially on abnormal glomerular angiogenesis, and clinical risk factors of recurrent DKD after kidney transplantation., Methods: The authors studied 34 renal transplant recipients with diabetes and 30 without diabetes. All patients had undergone both baseline and posttransplant follow-up biopsies. Glomerular morphometric analyses of the mesangial area, the capillary number, and the capillary area were performed with a computer-assisted image analyzer, and glomerular basement membrane (GBM) thickness was evaluated by electron microscopy. The incidence of polar vasculosis as an angiogenic phenomenon was also evaluated. Clinical data including hemoglobin (Hb)A1c, blood pressure, urinary albumin excretion, and serum lipid profiles were compared with histologic parameters., Results: Together with the increased glomerular mesangial area and GBM thickness, the glomerular capillary number and area and the incidence of polar vasculosis were significantly higher in patients with diabetes. Most of these alterations were significantly associated with the mean posttransplant HbA1c levels but not with blood pressure or lipid profiles. In the multiple regression analysis, HbA1c level remained significantly associated with these histologic parameters., Conclusions: Similar to mesangial expansion and GBM thickening, glomerular neovascularization represented by increased capillary number and area and glomerular polar vasculosis can occur as an early diabetic lesion in recurrent DKD. Posttransplant hyperglycemia is a significant risk factor predictive of the progression of recurrent DKD in kidney allografts.
- Published
- 2012
- Full Text
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