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Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant *** infection with osseointegration in murine models of implant-associated osteomyelitis

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Bone Research 2023年第4期11卷 751-763页

作者： Youliang Ren Jason Weeks Thomas Xue Joshua Rainbolt Karen L.de mesy Bentley Ye Shu Yuting Liu Elysia masters Philip Cherian Charles E.mcKenna Jeffrey Neighbors Frank H.Ebetino Edward m.schwarz Shuting Sun Chao Xie Center for musculoskeletal Research University of Rochester Medical CenterRochesterNY 14642USA Department of Orthopaedics University of Rochester Medical CenterRochesterNY 14642USA Department of Pathology and Center for Advanced Research Technologies University of Rochester Medical CenterRochesterNY 14642USA BioVinc LLCPasadenaCA 91107USA Department of Chemistry University of Southern CaliforniaLos AngelesCA 90089USA Department of Pharmacology Pennsylvania State UniversityHersheyPA 17033USA Department of Chemistry University of RochesterRoche

Eradication of mRSA osteomyelitis requires elimination of distinct *** overcome this,we developed bisphosphonateconjugated sitafloxacin(BCS,BV600072)and hydroxybisphosphonate-conjugate sitafloxacin(HBCS,BV63072),which achieve“target-and-release”drug delivery proximal to the bone infection and have prophylactic efficacy against mRSA static biofilm in vitro and in *** we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent mRSA(USA300LAC::lux).Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging(BLI)after debridement and implant exchange surgery on day 7,and mice were randomized into seven groups:1)Baseline(harvested at day7,no treatment);2)HPBP(bisphosphonate control for BCS)+vancomycin;3)HPHBP(hydroxybisphosphonate control for HBCS)+vancomycin;4)vancomycin;5)sitafloxacin;6)BCS+vancomycin;and 7)HBCS+*** confirmed infection persisted in all groups except for mice treated with BCS or HBCS+*** revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS+vancomycin,which also displayed decreases in peri-implant bone loss,osteoclast numbers,and *** confirm this,we assessed the efficacy of vancomycin,sitafloxacin,and HBCS monotherapy in a transtibial implant *** results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control,and some had evidence of osseous integrated septic implants,suggestive of biofilm *** together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate mRSA osteomyelitis.

关键词： implant infection overcome

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Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts

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Cellular & molecular Immunology 2022年第10期19卷 1185-1195页

作者： Ruby J.Siegel Anil K.Singh Paul m.Panipinto Farheen S.Shaikh Judy Vinh Sang U.Han H.mark Kenney Edward m.schwarz Cynthia S.Crowson Sadik A.Khuder Basil S.Khuder David A.Fox Salahuddin Ahmed Department of Pharmaceutical Sciences Washington State University College of Pharmacy and Pharmaceutical SciencesSpokaneWAUSA Department of Pathology and Laboratory medicine University of Rochester Medical CenterRochesterNYUSA Center for musculoskeletal Research University of Rochester Medical CenterRochesterNYUSA Department of Quantitative Health Sciences and Division of Rheumatology Mayo ClinicRochesterMNUSA Department of medicine and Public Health University of ToledoToledoOHUSA Department of Pathology and Laboratory medicine Phoenix Children’s HospitalPhoenixAZUSA Department of medicine Division of Rheumatology and Clinical Autoimmunity Center of ExcellenceUniversity of Michigan Medical SystemAnn ArborMIUSA Division of Rheumatology University of Washington School of MedicineSeattleWAUSA

Extracellular sulfatase-2(Sulf-2)influences receptor-ligand binding and subsequent signaling by chemokines and growth factors,yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis(RA).In the present study,we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts(RASFs).Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg *** sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated~2500 genes compared to scrambled *** Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in *** blot,ELISA,and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAm1,VCAm1,CAD11,PDPN,CCL5,CX3CL1,CXCL10,and *** studies identified the protein kinase C-delta(PKCδ)and c-Jun N-terminal kinase(JNK)pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and *** of Sulf-2 abrogated TNF-α-induced RASF ***-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδand JNK,thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human ***,Sulf-2 expression positively correlated with the expression of TNF receptor 1,and coimmunoprecipitation assays demonstrated the binding of these two proteins,suggesting they exhibit crosstalk in TNF-α*** study identified a novel role of Sulf-2 in TNF-αsignaling and the activation of RA synoviocytes,providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA.

关键词： Sulfatase-2 TNF-α Rheumatoid arthritis Synovial fibroblasts Signal transduction

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The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies

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Bone Research 2023年第2期11卷 273-291页

作者： Hengwei Zhang Jane LLiesveld Laura mCalvi Brea CLipe Lianping Xing michael WBecker Edward mschwarz Shu-Chi A.Yeh Center for musculoskeletal Research University of Rochester Medical Center601 Elmwood AveBox 665RochesterNY14642USA Department of Pathology and Laboratory medicine University of Rochester Medical CenterRochesterNYUSA Wilmot Cancer Center University of Rochester Medical CenterRochesterNYUSA Department of medicine Division of Hematology/Oncology and Bone Marrow Transplantation ProgramUniversity of Rochester Medical CenterRochesterNYUSA Department of medicine Division of Endocrinology/MetabolismUniversity of Rochester Medical CenterRochesterNYUSA Department of Orthopaedics University of Rochester Medical CenterRochesterNYUSA Department of medicine Division of Allergy/Immunology/RheumatologyUniversity of Rochester Medical CenterRochesterNYUSA Department of Biomedical Engineering University of RochesterNYUSA Department of Physiology/Pharmacology University of Rochester Medical CenterRochesterNYUSA

Prior research establishing that bone interacts in coordination with the bone marrow microenvironment(BmmE)to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell *** advances in intravital imaging has suggested that the expansion of hematopoietic stem cells(HSCs)and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone *** findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BmmE to yield differential clonal responses.A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel *** advance this understanding,herein,we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic ***,we elaborate on the coupling between bone remodeling and the BmmE in homeostasis and age-related hematological malignancies and after treatment with bone-targeting *** then discuss unresolved questions and ambiguities that remain in the field.

关键词： remodeling homeostasis likely

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Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation

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Bone Research 2022年第4期10卷 826-837页

作者： Yugo morita motoo Saito Javier Rangel-moreno Anthony m.Franchini John R.Owen John C.martinez John L.Daiss Karen L.de mesy Bentley Stephen L.Kates Edward m.schwarz Gowrishankar muthukrishnan Center for musculoskeletal Research University of Rochester Medical CenterRochesterNYUSA Division of Allergy Immunology and RheumatologyDepartment of MedicineUniversity of Rochester Medical CenterRochesterNYUSA Department of Environmental medicine University of Rochester School of Medicine and DentistryRochesterNYUSA Department of Orthopedic Surgery Virginia Commonwealth UniversityRichmondVAUSA Department of Orthopedics University of Rochester Medical CenterRochesterNYUSA Department of Pathology and Laboratory medicine University of Rochester Medical CenterRochesterNYUSA

Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial,and its role in patients with *** osteomyelitis is *** address this knowledge gap,we completed a clinical study and observed elevated serum IL-27 levels(20-fold higher,Pmpared with healthy ***,IL-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients(Pmyelitis in WT and IL-27Rα^(−/−)mice with and without exogenous IL27 induction by intramuscular injection of rAAV-IL-27p28 or rAAV-GFP,*** found that IL-27 was induced at the surgical site within 1 day of *** infection of bone and was expressed by m0,m1 and m2 macrophages and osteoblasts but not by ***,exogenous IL-27p28(~2 ng·mL^(−1) in serum)delivery ameliorated soft tissue abscesses and periimplant bone loss during infection,accompanied by enhanced local IL-27 expression,significant accumulation of RORγt^(+)neutrophils at the infection site,a decrease in RANK^(+) cells,and compromised osteoclast *** effects were not observed in IL-27Rα^(−/−)mice compared with WT mice,suggesting that IL-27 is dispensable for immunity but mediates redundant immune and bone cell functions during *** vitro studies and bulk RNA-seq of infected tibiae showed that IL-27 increased nos1,nos2,il17α,il17f,and rorc expression but did not directly stimulate ***,these results identify a novel phenomenon of IL-27 expression by osteoblasts immediately following *** infection of bone and suggest a protective role of systemic IL-27 in osteomyelitis.

关键词： abscess protective immunity

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小鼠离体工作心脏模型及功能评价

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中国病理生理杂志 2002年第7期18卷 878-880页

作者：朱莹 m.schwarz 单江 T.Kurz G.Richardt 浙江大学医学院附属第二医院心内科浙江杭州310009 德国吕贝克医科大学临床二所心内科

目的 :为心力衰竭的基因研究提供理想的实验模型。方法 :建立小鼠离体工作心脏模型 ,并评价心功能状态。结果 :后负荷固定 (5 0mmHg) ,前负荷 5mmHg至 2 5mmHg范围内 ,左室收缩压 (LVPsys)、最大左室压力上升 /下降速率 (dLVPdtmax/dLVP... 详细信息

目的 :为心力衰竭的基因研究提供理想的实验模型。方法 :建立小鼠离体工作心脏模型 ,并评价心功能状态。结果 :后负荷固定 (5 0mmHg) ,前负荷 5mmHg至 2 5mmHg范围内 ,左室收缩压 (LVPsys)、最大左室压力上升 /下降速率 (dLVPdtmax/dLVPdtmin)、冠状动脉流量 (CFlow)在前负荷 10mmHg时达最大值 ;平均主动脉压力 (AP mean)、平均主动脉流量 (AFmean)在前负荷 2 0mmHg达最大值 ;左室舒张末压 (LVEDP)与前负荷正相关 ,r=0 986 1。前负荷固定 (10mmHg) ,后负荷 4 0mmHg至 10 0mmHg范围内 ,LVEDP、CFlow与后负荷无关 ;LVPsys、dLVPdtmax、dLVPdtmin分别于后负荷 90、6 0、70mmHg时达最大值 ;APmean随后负荷的递增而增加 ;AFmean随后负荷的递增而减少。结论 :小鼠离体工作心脏在不同前后负荷下功能的改变完全符合Frank -Starling定律。

关键词：小鼠离体工作心脏模型心力衰竭心功能评价动物模型前负荷后负荷

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masquelet技术治疗感染性骨缺损的研究进展

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中国矫形外科杂志 2017年第20期25卷 1867-1871页

作者：黄进成刘曦明蔡贤华 Edward m.schwarz Chao Xie 中国人民解放军总医院骨科湖北武汉430070 三峡大学第二人民医院湖北宜昌443000 罗彻斯特大学医学院骨科研究中心美国纽约14642

在感染性骨缺损的治疗过程中对感染控制与骨重建是制约临床疗效的两大难题。尽管Ilizarov骨搬移技术、带血管的自体骨移植技术、Papineau技术等能够成功修复骨缺损,但仍存在明显的不足。masquelet骨重建技术虽在其他国家报道较多,但国... 详细信息

在感染性骨缺损的治疗过程中对感染控制与骨重建是制约临床疗效的两大难题。尽管Ilizarov骨搬移技术、带血管的自体骨移植技术、Papineau技术等能够成功修复骨缺损,但仍存在明显的不足。masquelet骨重建技术虽在其他国家报道较多,但国内尚未予以足够重视。本文综述近年来masquelet技术治疗感染性骨缺损的相关文献,旨在提高对其疗效的认识及重视。

关键词：骨缺损感染 masquelet技术预防治疗

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線蟲及線蟲捕捉菌之交互作用分子機制的研究

線蟲及線蟲捕捉菌之交互作用分子機制的研究

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第十二届海峡两岸真菌学学术研讨会

作者：薛雁冰 matthew R.Gronquist Erich m.schwarz Ravi Nath Frank C.Schroeder Paul Sternberg 中央研究院分子生物研究所 Howard Hughes medical Institute and Division of Biology California Institute of Technology Department of Chemistry SUNY Fredonia Department of molecular Biology and Genetics Cornell University Boyce Thompson Institute and Department of Chemistry and Chemical Biology Cornell University

線蟲捕捉菌***在自然界中是線蟲的天敵。利用模式線蟲***,我們希望了解***和線蟲之間交互作用的分子機制,以期對獵食者和獵物之間的共同演化有更深入的了解。大部份的線蟲捕捉菌只有在偵測到線蟲獵物時才會發育捕捉器。線蟲捕捉菌是如...

線蟲捕捉菌***在自然界中是線蟲的天敵。利用模式線蟲***,我們希望了解***和線蟲之間交互作用的分子機制,以期對獵食者和獵物之間的共同演化有更深入的了解。大部份的線蟲捕捉菌只有在偵測到線蟲獵物時才會發育捕捉器。線蟲捕捉菌是如何辨識線蟲的?我們發現,線蟲的費洛蒙ascarosides能夠刺激***捕捉器的發育,代表***可以辨識線蟲的費洛蒙。此現象在其他具有類似構造的線蟲捕捉菌都有觀察到,代表這在演化上是保守的（evolutionarily conserved）。此外,我們也發現***必須要在營養缺乏的狀態之下才能夠偵測到ascarosides。以***而言,已經有超過一百種以上的ascarosides被發現,其中有許多種,都會被不同線蟲補捉菌辨識。因此,我們推測線蟲捕捉菌會促進線蟲費洛蒙多樣性的不斷演化。另一方面,我們也致力於了解線蟲在遇到線蟲捕捉菌時,會有什麼反應。我們發現***和其他線蟲都會被***所吸引。利用系統生物學的方法,包括遺傳學,基因體學,顯微影像及雷射剝離神經細胞技術,我們發現***被吸引的行為主要是經由一對嗅覺神經來調控。這對嗅神經會被真菌所產生的揮發性物質所激化而產生受吸引的行為。失去此對嗅神經的功能的***突變株在遇到***時,有較高的存活率。

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四肢创伤性骨折术后细菌感染及耐药的地域性特征分析

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中华创伤骨科杂志 2016年第3期18卷 226-232页

作者：任有亮彭笳宸李政道刘曦明杨晋 Stephen L. Kates Edward m.schwarz Chao Xie 遵义医学院附属医院骨科贵州省遵义市563000 广州军区总医院骨科 430070 美国纽约罗彻斯特大学医学院骨科研究中心 14642

目的探讨四肢创伤性骨折术后Gram阳性和阴性细菌感染的地域性分布态势及耐药率，旨在为手术前、后经验性使用抗菌素提供循证医学依据。方法回顾性分析筛查2012年1月至2015年1月因四肢创伤性骨折住院治疗的3728例患者，按照CLSIm．100-S2... 详细信息

目的探讨四肢创伤性骨折术后Gram阳性和阴性细菌感染的地域性分布态势及耐药率，旨在为手术前、后经验性使用抗菌素提供循证医学依据。方法回顾性分析筛查2012年1月至2015年1月因四肢创伤性骨折住院治疗的3728例患者，按照CLSIm．100-S22标准，收集经手术、病理及细菌培养证实细菌感染的51例患者的病历资料，整理其病理、窦道分泌物或病灶穿刺标本的细菌培养和药敏试验数据，对金黄色葡萄球菌（***）等主要菌株的分布及耐药性进行分析。结果四肢创伤性骨折术后细菌感染率为1．37％（51／3728）。常见感染骨折部位依次为胫腓骨（25例，49．02％）、股骨（11例，21．57％）、尺桡骨（8例，15．69％）。单株菌感染45例（88．23％），混合感染6例（11．76％）。Gram阳性细菌感染以***（27例，47．37％）、表皮葡萄球菌（4例，7．02％）、鸟肠球菌（2例，3．51％）为主；Gram阴性细菌感染以大肠埃希菌（***）（9例，15．79％）、阴沟肠杆菌（4例，7．02％）、肺炎克雷伯氏菌（2例，3．51％）为主。药敏试验发现主要Gram阳性菌耐药率为40．74％-100．00％，以耐林可霉素、红霉素、青霉素、四环素、头孢西丁和苯唑西林为主，未检出对万古霉素、替加环素、呋喃妥因耐药的***、表皮葡萄球菌和鸟肠球菌。主要Gram阴性细菌耐药率为44．44％～100．00％，以耐左氧氟沙星、氨苄西林、氨曲南、头孢曲松、头孢替坦、头孢他啶等为主，未检出对亚硫胺霉素耐受的主要Gram阴性菌。***感染的27例患者中耐甲氧西林金黄色葡萄球菌（mRSA）占11例（40．74％），全部对吗啉恶酮、氨苄西林、替加环素、万古霉素等敏感。结论创伤性四肢骨折术后感染以下肢长骨和尺桡骨感染单株***、***、表皮葡萄球菌或阴沟肠杆菌为主，有明显的地域性特点。不仅mRSA感染率较高，且混合感染多以***合并其他细菌感染为主。根据耐药谱结果分析、对本地区感染病灶彻底清除术前后经验性抗生素治疗的选择建议为：Gram阳性细菌感染选用替加环素、呋喃妥因、万古霉素，Gram阴性细菌感染选用亚胺硫霉素为宜。

关键词：感染骨折葡萄球菌,金黄色耐药性

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Prospective cohort study on facial profile changes in infants with Robin sequence and healthy controls

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World Journal of Pediatrics 2024年第6期20卷 581-589页

作者： Cornelia Wiechers Julian Sowula Karen Kreutzer Christoph E.schwarz Christina Weismann michael Krimmel Christian F.Poets Bernd Koos Department of Neonatology Tuebingen University HospitalCalwerstrasse 772076 TuebingenGermany Center for Cleft Lip Palate and Craniofacial MalformationsTuebingen University HospitalTuebingenGermany Department of Orthodontics Tuebingen University HospitalTuebingenGermany Department of Oral and maxillofacial Surgery Tuebingen University HospitalTuebingenGermany

Background Various conservative and surgical approaches exist to treat Robin sequence(RS),but their effects on facial profile and mandibular catch-up growth are unclear.A functional treatment concept,used in our centre for 25 years,includes an individualized palatal plate with a velo-pharyngeal extension and intensive feeding *** We performed a prospective study to objectively describe facial profiles in infants with RS treated with the above *** with isolated RS were admitted to our tertiary perinatal and national referral centre for craniofacial malformations between may 2018 and Nov *** with RS received 3D-photographs during clinically indicated *** controls were recruited from Dec 2018 to Sep 2019 and received 3D-photographs every 3 *** digitally measured jaw index(JI),defined as alveolar overjet(O)x maxillary arch(U)/mandibular arch(L),and the soft tissue reference points A’-point,Nasion’,B’-point angle(ANB’),describing the relative position of maxilla to mandible,were *** mixed models were used to examine time trajectories in JI and ANB’.Results A total of 2073D images,obtained in 19 infants with RS and 32 controls,were *** and ANB’decreased over time in both groups[for JI−0.18(95%CI−0.25 to−0.10);for ANB’:−0.40°per month[(95%CI−0.48 to−0.32)]]but remained lower in controls[for JI−2.5(95%CI−3.2 to−1.8);for ANB’-1.7°(95%CI−2.4 to−1.0)].Also,the ANB’model showed a significant effect of the interaction term diagnosis x *** Based on longitudinal 3D images,we describe changes in objective parameters of facial profile in infants with and without RS during the first year of *** findings indicate catch-up growth in infants treated for RS.

关键词： Infant mandibular catch-up growth Pre-epiglottic Baton Plate Robin sequence Three-dimensional photography

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坏死性胰腺炎的抗生素应用

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德国医学 1998年第2期15卷 94-96页

作者： m.schwarz R.Isenmann H.meyer H.G.Beger 彭小楚 Chirurgische Klinik Ⅰ der Universitt Steinhovelstr.9D-89075 UlmGermany 湖北省襄樊市护士学校

对急性坏死性胰腺炎应用抗生素的价值迄今尚缺乏对照性研究,对坏死感染病例无疑应应用抗菌治疗,对缺乏坏死细菌感染证据的病例是否要补充应用抗生素治疗则存有争议。细菌感染对坏死性胰腺炎的临床经过有决定性作用。在坏死性胰腺炎病... 详细信息

对急性坏死性胰腺炎应用抗生素的价值迄今尚缺乏对照性研究,对坏死感染病例无疑应应用抗菌治疗,对缺乏坏死细菌感染证据的病例是否要补充应用抗生素治疗则存有争议。细菌感染对坏死性胰腺炎的临床经过有决定性作用。在坏死性胰腺炎病程的第1周即已证实坏死伴有细菌感染的发生。

关键词：胰腺炎坏死性胰腺炎药物疗法抗生素

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