bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of 5‐lipoxygenase activity protects mice against paracetamol‐induced liver toxicity
Authors: Pu Shiyun , Ren Lin , Liu Qinhui , Kuang Jiangying , Shen Jing , Cheng Shihai , Zhang Yuwei , Jiang Wei , Zhang Zhiyong , Jiang Changtao , He Jinhan 
Published: September 2015

Background and PurposeParacetamol (acetaminophen) is the most widely used over‐the‐counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5‐Lipoxygenase (5‐LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5‐LO could protect mice against paracetamol‐induced hepatic toxicity.Experimental ApproachBoth genetic deletion and pharmacological inhibition of 5‐LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real‐time PCR were used to assess liver toxicity.Key ResultsDeletion or pharmacological inhibition of 5‐LO in mice markedly ameliorated paracetamol‐induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5‐LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro‐toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5‐LO−/− mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5‐LO−/− mice.Conclusions and ImplicationsThe activity of 5‐LO may play a critical role in paracetamol‐induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress.
The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI‐101 prevents cisplatin‐induced nephrotoxicity
Authors: Mukhopadhyay Partha , Baggelaar Marc , Erdelyi Katalin , Cao Zongxian , Cinar Resat , Fezza Filomena , Ignatowska‐Janlowska Bogna , Wilkerson Jenny , van Gils Noortje , Hansen Thomas , Ruben Marc , Soethoudt Marjolein , Heitman Laura , Kunos George , Maccarrone Mauro , Lichtman Aron , Pacher Pál , Van der Stelt Mario 
Published: September 2015

Background and PurposeHere, we have characterized 3‐cyclopropyl‐1‐(4‐(6‐((1,1‐dioxidothiomorpholino)methyl)‐5‐fluoropyridin‐2‐yl)benzyl)imidazolidine‐2,4‐dione hydrochloride (LEI‐101) as a novel, peripherally restricted cannabinoid CB2 receptor agonist, using both in vitro and in vivo models.Experimental ApproachWe investigated the effects of LEI‐101 on binding and functional activity. We assessed its in vitro and in vivo selectivity. Efficacy of LEI‐101 was determined in a mouse model of cisplatin‐induced nephrotoxicity.Key ResultsLEI‐101 behaved as a partial agonist at CB2 receptors using β‐arrestin and GTPγS assays and was ~100‐fold selective in CB2 /CB1 receptor‐binding assays. It did not display any activity on endocannabinoid hydrolases and nor did it react with serine hydrolases in an activity‐based protein profiling assay. In mice, LEI‐101 had excellent oral bioavailability reaching high concentrations in the kidney and liver with minimal penetration into the brain. LEI‐101 up to a dose of 60 mg·kg−1 (p.o.) did not exert any CNS‐mediated effects in the tetrad assay, in mice. LEI‐101 (p.o. or i.p.) at 3 or 10 mg·kg−1 dose‐dependently prevented kidney dysfunction and/or morphological damage induced by cisplatin in mice. These protective effects were associated with improved renal histopathology, attenuated oxidative stress and inflammation in the kidney. These effects were absent in CB2 receptor knockout mice.Conclusion and ImplicationsThese results indicate that LEI‐101 is a selective, largely peripherally restricted, orally available CB2 receptor agonist with therapeutic potential in diseases that are associated with inflammation and/or oxidative stress, including kidney disease.
High avidity chimeric monoclonal antibodies against the extracellular domains of human aquaporin‐4 competing with the neuromyelitis optica autoantibody, NMO‐IgG
Authors: Miyazaki‐Komine Kaori , Takai Yoshiki , Huang Ping , Kusano‐Arai Osamu , Iwanari Hiroko , Misu Tatsuro , Koda Katsushi , Mitomo Katsuyuki , Sakihama Toshiko , Toyama Yoshiaki , Fujihara Kazuo , Hamakubo Takao , Yasui Masato , Abe Yoichiro 
Published: September 2015

Background and PurposeMost of the cases of neuromyelitis optica (NMO) are characterized by the presence of an autoantibody, NMO‐IgG, which recognizes the extracellular domains of the water channel, aquaporin‐4. Binding of NMO‐IgG to aquaporin‐4 expressed in end‐feet of astrocytes leads to complement‐dependent disruption of astrocytes followed by demyelination. One therapeutic option for NMO is to prevent the binding of NMO‐IgG to aquaporin‐4, using high‐avidity, non‐pathogenic–chimeric, monoclonal antibodies to this water channel. We describe here the development of such antibodies.Experimental ApproachcDNAs encoding variable regions of heavy and light chains of monoclonal antibodies against the extracellular domains of human aquaporin‐4 were cloned from hybridoma total RNA and fused to those encoding constant regions of human IgG1 and Igκ respectively. Then mammalian expression vectors were constructed to establish stable cell lines secreting mature chimeric antibodies.Key ResultsOriginal monoclonal antibodies showed high avidity binding to human aquaporin‐4, as determined by ELISA. Live imaging using Alexa‐Fluor‐555‐labelled antibodies revealed that the antibody D15107 more rapidly bound to cells expressing human aquaporin‐4 than others and strongly enhanced endocytosis of this water channel, while D12092 also bound rapidly to human aquaporin‐4 but enhanced endocytosis to a lesser degree. Chimeric D15107 prevented complement‐dependent cytotoxicity induced by NMO‐IgG from patient sera in vitro.Conclusions and ImplicationsWe have established non‐pathogenic, high‐avidity, chimeric antibodies against the extracellular domains of human aquaporin‐4, which provide a novel therapeutic option for preventing the progress and recurrence of NMO/NMO spectrum disorders.
Diverse applications for near infra‐red intraoperative imaging
Authors: Gossedge G. , Vallance A. , Jayne D. 
Published: September 2015

AbstractBackgroundNear infra‐red angiography using Indocyanine Green (ICG) has increasingly used as a tool for intraoperative diagnostics.AimsThe aim of this review is to explore the applications of ICG fluorescence angiography with particular emphasis on general surgical applications.Materials and MethodsA literature review was conducted to identify and summarise the diverse range of applications of ICG fluorescence.ResultsICG fluorescence angiography is increasingly used in a number of general surgical applications, including identification of colorectal liver metastases, assessment of skin flap perfusion, diagnosis of peritoneal endometriosis, ureteric identification, and localisation of colonic pathology.DiscussionICG fluorescence angiography has clinical application in many areas as a tool for guiding surgical resection.ConclusionWith the technological developments in near infra‐red imaging it is likely that ICG fluorescence will play an increasing role in many routine surgical procedures.
Discriminatory influence of Pinpoint perfusion imaging on diversion ileostomy after laparoscopic low anterior resection
Authors: Ris F. , Buchs N. C. , Morel P. , Mortensen N. J. , Hompes R. 
Published: September 2015

AbstractWhile still debated, it was advised to perform a protective temporary ileostomy after a low anterior resection (LAR). This might help to decrease the leak rate and therefore offers the patient better outcomes. Anastomotic leak can occur in many situations after a LAR and the control of the risk factors helps to adapt the need of an ileostomy. Near infrared technology allows assessing the microvascularisation of the anastomosis at the time of surgery and therefore might be an important tool to avoid a stoma in given situation. This article reviews the evidences with the use of this technology.
Near‐infrared laparoscopic fluorescence for pelvic side wall delta mapping in patients with rectal cancer‐ ‘PINPOINT’ nodal assessment
Authors: Kazanowski M. , Al Furajii H. , Cahill R. A. 
Published: September 2015

AbstractLow rectal cancers metastase lymphatically to the pelvic side wall in addition to cephalad spread alongside the superior rectal/inferior mesenteric arterial axis. Radical surgery in the West has focused resectional intent and effort on the midline en bloc oncological package by Total Mesorectal Excision. While neoadjuvant chemo/radiotherapy (now often administered to patients with radiologically locally advanced cancer) may contribute significant therapeutic effect to the lateral pelvic side walls, many patients with earlier preoperative stage low rectal cancer are offered surgery first (and indeed solely). Furthermore, some of those pretreated may have residual in situ lateral nodal disease and so risk understaging and undertreatment. Routine extended lymphadenectomy is on the otherhand unproven with respect to survival benefit and has likely no added role in the absence of definite (rather than possible) side‐wall involvement. Near‐infrared fluorescence pelvic side‐wall delta mapping, as illustrated here in five patients undergoing abdominoperineal resection for rectal cancer after neoadjuvant therapy, may give the technological capacity to identify tumor site‐draining nodes on the pelvic side and the focus the operating surgeon on this potential target for surgical resection (whether by berry picking or nerve sparing clearance) and prompt individualized diagnostic and therapeutic selection.
Provenance of global seafood
Authors: Watson Reg A , Green Bridget S , Tracey Sean R , Farmery Anna , Pitcher Tony J 
Published: September 2015

AbstractKnowing where and how seafood is caught or farmed is central to empowering consumers, and the importers that supply them, with informed choices. Given the wide‐ranging, complex and at times commercially sensitive nature of global seafood trade, it can prove very challenging to link imported seafood with information about its provenance. The databases involved are incomplete, at times vague and not harmonized. Here, we present a first attempt to link all global seafood imports through a virtual marketplace to exports and map their origins. Considerable work remains to ground‐truth the specific origins of all seafood commodities. We illustrate the flow of seafood and its evolution since the 1970s when supporting records began. This work allows the impact of fishing or marine farming to be associated with seafood imports.
How to calculate toric intraocular lenses in clinical practice?
Authors: Langenbucher A. , Szentmáry N. , Seitz B. , Spira C. , Eppig T. 
Published: September 2015

SummaryThere are several options for calculation of toric intraocular lenses, some are based on the classical intraocular lens calculation formulas and others utilize paraxial or numerical ray tracing techniques. Most online calculators use a two‐step system based on precalculated data for the equivalent monofocal lens. Other methods calculate intraocular lens power separately for both cardinal meridians. Advanced methods directly calculate spherocylindrical power by matrix or ray tracing techniques. Especially when considering superposition of regular and irregular astigmatic components, postoperative implant rotation or anisometropia and aniseikonia, the classical formula approach might be inadequate for estimating toric intraocular lens power. Therefore surgeons dealing with toric intraocular lenses require deeper knowledge on advanced calculation techniques to improve patient satisfaction.
Limbal stem cells and their application in ocular surface reconstruction
Authors: Meller D. 
Published: September 2015

SummaryVarious ocular surface diseases are caused by loss of corneal epithelial stem cells or dysfunction of limbal niche. Besides conventional transplantation of autologous or allogeneic limbal tissue recent advances in tissue‐engineering have led to the development of new culture and expansion techniques of human limbal stem and progenitor cells as a new strategy to treat successfully limbal stem cell deficiency (LSCD). From a small limbal biopsy with a limited amount of LSPC an epithelium ready for transplantation is achieved. Autologous grafting of cultured limbal epithelium led in most of the treated cases to a successful reconstruction of the corneal surface. However, allogeneic grafts of cultivated limbal epithelium show a higher graft failure. The etiology of the disease causing LSCD seems to influence the outcome of the procedure. In this presentation challenges and limitations associated with stem cell culture techniques for ocular surface reconstruction are reviewed.
Which margins for which tumors?
Authors: Mouriaux F. 
Published: September 2015

Traditional surgical treatment of non‐melanoma skin cancer includes excision with subsequent surgical margins, the “security” margins leading to determine the theoretical level of recurrences. Thus, some authors favor a clinical excision margin of 4 mm for basal cell carcinoma and 6 mm for squamous cell carcinoma. However, such “security” margins could not be applied in all cases of eyelids tumors for anatomic and functional considerations because such recommendations may lead to severe ocular complications. Thus the best assurance of minimal excision with complete excision is obtained by extemporaneous examination of the resection margins by frozen section or by surgery in two times. The aim of this paper is to review these two techniques for eyelids (lid margins) and medial canthus. This article will discuss the concept of surgical margins in excisions of non‐melanoma skin cancer and the role of frozen section of the margins for minimizing the amount of tissue that must be excised.
Pluripotent stem cells, cornea fate and physiopathology
Authors: Aberdam D. 
Published: September 2015

SummaryThe human corneal surface epithelium is continuously repopulated by limbal stem cells (LSCs). Limbal Stem Cell Deficiency (LSCD) can lead to corneal opacity and vascularization, with consequent visual impairment or blindness. Chemical or thermal trauma and congenital diseases, such as congenital aniridia, can lead to LCSD by destruction of the LSC niche. Grafted autologous limbus or cultivated LCS can restore the vision, unless the two eyes are affected. We have recently developed novel culture systems to reprogram hair follicles into induced pluripotent stem cells (iPSCs) and differentiate them into LSC that could become an alternative to animal models for drug cytotoxicity and an alternative autologous source to the shortage of post‐mortem cornea transplantation.Moreover, we identified miR‐450 as specific repressor of PAX‐6, the eye master gene responsible for proper embryonic eye formation and LSC pool maintenance. As most of the aniridia patients carry mutations on PAX‐6 that lead to haploinsufficiency, we are testing if manipulating the level or activity of miR‐450 could be used as a therapeutic strategy in aniridia.Thus, iPSCs are valuable for modeling corneal pathologies, and pave the way for future therapy.
Role of High‐mobility group box‐1 in diabetic retinal vasculopathy and neuropathy
Authors: Abu El Asrar A. 
Published: September 2015

SummaryHigh‐mobility mobility group box‐1 (HMGB1) is a non‐histone DNA‐binding protein that plays an important role in chromatin organization and transcriptional regulation. Extracellular HMGB1 functions as a proinflammatory cytokine and triggers the inflammatory response through the activation of multiple receptors such as the receptor for advanced glycation end products (RAGE), toll‐like receptor‐2 (TLR2), TLR4 and TLR9. We demonstrated that HMGB1 and RAGE were expressed in fibrovascular epiretinal membranes from patients with proliferative diabetic retinopathy (PDR). In addition, we demonstrated increased levels of HMGB1 in the vitreous samples from patients with PDR and that there were significant positive correlations between the vitreous levels and HMGB1 and the levels of the biomarkers of inflammation and oxidative injury. Furthermore, we demonstrated that diabetes induced significant upregulation of the expression of HMGB1 and RAGE in the retinas of rats and mice and that HMGB1 mediates diabetes‐induced oxidative stress, activation of inflammatory signaling pathways, breakdown of the blood‐retinal barrier and neuropathy in the retina. Therefore, compounds inhibiting HMGB1 may be novel therapeutic agents for diabetic retinopathy.
Neuro‐vascular coupling – molecular mechansims and potential clinical applications
Authors: Garhofer G. 
Published: September 2015

SummaryThe coupling between neural activity, metabolism and blood flow is an essential physiological mechanism to assure constant supply of the tissue with oxygen and nutrients. Further, it has been shown that several ocular diseases, such as glaucoma or diabetic retinopathy are accompanied by a breakdown of this physiological mechanism. Despite many efforts, the signaling pathways that trigger the hyperemic response of the vasculature are still incompletely understood, which makes the significance of changes in the response during disease difficult to interpret. Recent experimental data from animal studies challenges the current view that NO is the key mediator of flicker induced vasodilatation and indicates a more complex interaction between neurons, blood vessels, vasodilating and vasoconstricting factors at the level of the retina.This talk aims to summarize our current understanding of the mechanisms underlying neuro‐vascular coupling in the human retina. Further, the role of neuro‐vascular coupling and its potential application in the diagnosis and follow up in neuro‐degenerative diseases such as glaucoma will be discussed.
Caffeine, an in vivo oxidation protectant in the lens
Authors: Kronschläger M. , Yu Z. , Talebizadeh N. , Söderberg P. 
Published: September 2015

SummaryThe major avoidable cause of cataract is ultraviolet radiation (UVR). We aimed at investigating topical caffeine in UVR‐induced cataract.Topical caffeine and a placebo were applied to the eyes of separate groups of Sprague Dawley rats that were exposed to sub‐doses of UVR and protective effect was evaluated. Penetration of topical caffeine in the rats to lens and blood was analysed by HPLC. Influence of topical caffeine on pupil diameter was measured in ketamine/xylazine anesthetized rats.Topically administered caffeine protected against UVR‐induced cataract development with a Protection Factor, an objective relative measure of protective properties, of 1.23 and inhibited UVR‐induced apoptosis. Topical caffeine peaked at 30 min in the lens, increased up to 120 min in the blood and antagonized ketamine/xylazine‐induced mydriasis. Eyes treated with caffeine reacted with quick dilatation after tropicamide application.In conclusion, topically applied caffeine protects against ultraviolet radiation cataract, reducing lens sensitivity 1.23 times. Considering that caffeine is a powerful antioxidant that is easily available and well tolerated our finding implicates that caffeine may be a clinically useful anticataract agent.
Migration of lens epithelial cells and IOL drug soaking
Authors: Wertheimer C. , Kueres A. , Mayer W. , Liegl R. , Eibl‐Lindner K. 
Published: September 2015

SummaryPurposeTo assess the effect of EGFR Inhibitor Erlotinib and the downstream Inhibitor Erufosin (PI3K) soaked into intraocular lenses (IOLs) on human lensepithelialcell (LEC) proliferation in vitro.MethodsFoldable IOLs were incubated with Erufosin or Erlotinib. Intraocular lenses of the same lot served as uncoated controls. Each IOL was placed into cell cultre containing proliferating human LECs. Cell survival was tested by the XTT‐dye reduction assay 5 days later. Furthermore IOLs were put into the Gotoh anterior chamber model. In addition, soaked IOLs were implanted into the human capsular bags and braught to cell‐culture. The time until full cell‐coverage of the capsular bag was measured.ResultsErufosin (P<0.05) and Erlotinib (P<0.05) coated IOLs attenuated human LEC proliferation in all above described models. For both substances soaked hydrophilic acrylic IOLs were more effective inhibitors of human LEC proliferation than coated hydrophobic acrylic.ConclusionsResults show that both substances are suitable agents for IOL‐soaking without linker molecules. Soaked IOLs can inhibit human LEC proliferation in our models and might become of clinical relevance in future.
TGF beta and fibrosis‐ironing out the wrinkles
Authors: Eldred J. , Wormstone M. 
Published: September 2015

SummaryThe fibrotic disorder Posterior Capsule Opacification (PCO) is the leading secondary ocular complication following cataract surgery. PCO causes a significant loss of vision for approximately 10–30% of patients, 2–5 years post cataract removal. The formation of PCO requires additional surgical treatment, presenting an additional and substantial burden on health care providers and affects the overall well‐being of cataract patients. Fibrotic disorders affect many organs of the body and are associated with hyperproliferation, cell transdifferentiation, matrix modification and contraction. Identifying the major control of these features is essential to our understanding of PCO development. Transforming growth factor beta (TGFβ) has long been implicated in fibrotic disorders and is commonly defined as the “master switch” of fibrosis. However the actions governed by TGFβ can be complex and diverse involving multiple signalling pathways and cross‐talk between many signalling cascades. Significant understanding of the key pathways regulating TGFβ induced modifications in PCO has been identified using human cell and tissue culture models. These important findings and how they may be used as therapeutic targets will be presented.
Therapeutic management of uveitis
Authors: Dick A. 
Published: September 2015

SummaryThis talk will overview the contemporary therapeutic approaches to treatment of noninfectious non‐infective ocular inflammatory disease. Treatment of non‐infectious uveitis has over past 15 years expanded from the use of traditional therapies including corticosteroids and immunosuppressants to the deployment of targetting the immune response with biologic therapies with monoclonal antibodies and immunoadhesins. Such use will be exemplified with case reports during the talk. Evidence of efficacy of immunosuppressants in the treatment of uveitis, the role of predicting steroid responsiveness, the use of monotherapy with immunosuppression and finally the pathways and evidence of success of biologic therapy will be provided.