Amelioration of renal damage by administration of anti-thymocyte globulin to potential donors in a brain death rat model

Brain death (BD), a non-immunological factor of renal injury, triggers an inflammatory process causing pathological signs of cell death in the kidney, such as necrosis and apoptosis. Kidneys from brain dead donors show lower success rates than kidneys from living donors and one strategy to improve transplantation outcome is to precondition the donors. For the first time, anti-rat thymoglobulin (rATG) was administered in an experimental brain death animal model to evaluate if it could ameliorate histopathological damage and improve organ function. Animals were divided into three groups: V (n = 5) ventilated for 2 h; BD (n = 5) brain death and ventilated for 2 h; and BD+rATG (n = 5) brain death, ventilated for 2 h, rATG was administered during brain death (10 mg/kg). We observed lower creatinine levels in treatment groups (means): V, 0·88 ± 0·22 mg/dl; BD, 1·37 ± 0·07 mg/dl; and BD+rATG, 0·64 ± 0·02 mg/dl (BD versus BD+rATG, P < 0·001). In the BD group there appeared to be a marked increase of ATN, whereas ATN was decreased significantly in the rATG group (V, 2·25 ± 0·5 versus BD, 4·75 ± 0·5, P < 0·01; BD+rATG, 2·75 ± 0·5 versus BD 4·75 ± 0·5 P < 0·01). Gene expression was evaluated with reverse transcription–polymerase chain reaction; tumour necrosis factor (TNF)-α, interleukin (IL)-6, C3, CD86 showed no significant difference between groups. Increased IL-10 and decreased CCL2 in BD+rATG compared to BD (both cases P < 0·01). Myeloperoxidase was increased significantly after the brain death setting (V: 32 ± 7·5 versus BD: 129 ± 18). Findings suggest that rATG administered to potential donors may ameliorate renal damage caused by BD. These findings could contribute in the search for specific cytoprotective interventions to improve the quality and viability of transplanted organs.Facultad de Ciencias Médica

Preconditioning donor with a combination of tacrolimus and rapamacyn to decrease ischaemia-reperfusion injury in a rat syngenic kidney transplantation model

Reperfusion injury remains one of the major problems in transplantation. Repair from ischaemic acute renal failure (ARF) involves stimulation of tubular epithelial cell proliferation. The aim of this exploratory study was to evaluate the effects of preconditioning donor animals with rapamycin and tacrolimus to prevent ischaemia–reperfusion (I/R) injury. Twelve hours before nephrectomy, the donor animals received immunosuppressive drugs. The animals were divided into four groups, as follows: group 1 control: no treatment; group 2: rapamycin (2 mg/kg); group 3 FK506 (0, 3 mg/kg); and group 4: FK506 (0, 3 mg/kg) plus rapamycin (2 mg/kg). The left kidney was removed and after 3 h of cold ischaemia, the graft was transplanted. Twenty-four hours after transplant, the kidney was recovered for histological analysis and cytokine expression. Preconditioning treatment with rapamycin or tacrolimus significantly reduced blood urea nitrogen and creatinine compared with control [blood urea nitrogen (BUN): P < 0·001 versus control and creatinine: P < 0·001 versus control]. A further decrease was observed when rapamycin was combined with tacrolimus. Acute tubular necrosis was decreased significantly in donors treated with immunosuppressants compared with the control group (P < 0·001 versus control). Moreover, the number of apoptotic nuclei in the control group was higher compared with the treated groups (P < 0·001 versus control). Surprisingly, only rapamycin preconditioning treatment increased anti-apoptotic Bcl2 levels (P < 0·001). Finally, inflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, showed lower levels in the graft of those animals that had been pretreated with rapamycin or tacrolimus. This exploratory study demonstrates that preconditioning donor animals with rapamycin or tacrolimus improves clinical outcomes and reduce necrosis and apoptosis in kidney I/R injury.Facultad de Ciencias MédicasComisión de Investigaciones Científicas de la provincia de Buenos Aire

Amelioration of renal damage by administration of anti-thymocyte globulin to potential donors in a brain death rat model

Brain death (BD), a non-immunological factor of renal injury, triggers an inflammatory process causing pathological signs of cell death in the kidney, such as necrosis and apoptosis. Kidneys from brain dead donors show lower success rates than kidneys from living donors and one strategy to improve transplantation outcome is to precondition the donors. For the first time, anti-rat thymoglobulin (rATG) was administered in an experimental brain death animal model to evaluate if it could ameliorate histopathological damage and improve organ function. Animals were divided into three groups: V (n = 5) ventilated for 2 h; BD (n = 5) brain death and ventilated for 2 h; and BD+rATG (n = 5) brain death, ventilated for 2 h, rATG was administered during brain death (10 mg/kg). We observed lower creatinine levels in treatment groups (means): V, 0·88 ± 0·22 mg/dl; BD, 1·37 ± 0·07 mg/dl; and BD+rATG, 0·64 ± 0·02 mg/dl (BD versus BD+rATG, P < 0·001). In the BD group there appeared to be a marked increase of ATN, whereas ATN was decreased significantly in the rATG group (V, 2·25 ± 0·5 versus BD, 4·75 ± 0·5, P < 0·01; BD+rATG, 2·75 ± 0·5 versus BD 4·75 ± 0·5 P < 0·01). Gene expression was evaluated with reverse transcription–polymerase chain reaction; tumour necrosis factor (TNF)-α, interleukin (IL)-6, C3, CD86 showed no significant difference between groups. Increased IL-10 and decreased CCL2 in BD+rATG compared to BD (both cases P < 0·01). Myeloperoxidase was increased significantly after the brain death setting (V: 32 ± 7·5 versus BD: 129 ± 18). Findings suggest that rATG administered to potential donors may ameliorate renal damage caused by BD. These findings could contribute in the search for specific cytoprotective interventions to improve the quality and viability of transplanted organs.Facultad de Ciencias Médica

Preconditioning donor with a combination of tacrolimus and rapamacyn to decrease ischaemia-reperfusion injury in a rat syngenic kidney transplantation model

Reperfusion injury remains one of the major problems in transplantation. Repair from ischaemic acute renal failure (ARF) involves stimulation of tubular epithelial cell proliferation. The aim of this exploratory study was to evaluate the effects of preconditioning donor animals with rapamycin and tacrolimus to prevent ischaemia–reperfusion (I/R) injury. Twelve hours before nephrectomy, the donor animals received immunosuppressive drugs. The animals were divided into four groups, as follows: group 1 control: no treatment; group 2: rapamycin (2 mg/kg); group 3 FK506 (0, 3 mg/kg); and group 4: FK506 (0, 3 mg/kg) plus rapamycin (2 mg/kg). The left kidney was removed and after 3 h of cold ischaemia, the graft was transplanted. Twenty-four hours after transplant, the kidney was recovered for histological analysis and cytokine expression. Preconditioning treatment with rapamycin or tacrolimus significantly reduced blood urea nitrogen and creatinine compared with control [blood urea nitrogen (BUN): P < 0·001 versus control and creatinine: P < 0·001 versus control]. A further decrease was observed when rapamycin was combined with tacrolimus. Acute tubular necrosis was decreased significantly in donors treated with immunosuppressants compared with the control group (P < 0·001 versus control). Moreover, the number of apoptotic nuclei in the control group was higher compared with the treated groups (P < 0·001 versus control). Surprisingly, only rapamycin preconditioning treatment increased anti-apoptotic Bcl2 levels (P < 0·001). Finally, inflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, showed lower levels in the graft of those animals that had been pretreated with rapamycin or tacrolimus. This exploratory study demonstrates that preconditioning donor animals with rapamycin or tacrolimus improves clinical outcomes and reduce necrosis and apoptosis in kidney I/R injury.Facultad de Ciencias MédicasComisión de Investigaciones Científicas de la provincia de Buenos Aire

European Glaucoma Society - A guide on surgical innovation for glaucoma

Prologue Glaucoma surgery has been, for many decades now, dominated by the universal gold standard which is trabeculectomy augmented with antimetabolites. Tubes also came into the scene to complement what we use to call conventional or traditional glaucoma surgery. More recently we experienced a changing glaucoma surgery environment with the "advent"of what we have become used to calling Minimally Invasive Glaucoma Surgery (MIGS). What is the unmet need, what is the gap that these newcomers aim to fill? Hippocrates taught us "bring benefit, not harm"and new glaucoma techniques and devices aim to provide safer surgery compared to conventional surgery. For the patient, but also for the clinician, safety is important. Is more safety achieved with new glaucoma surgery and, if so, is it associated with better, equivalent, or worse efficacy? Is new glaucoma surgery intended to replace conventional surgery or to complement it as an € add-on' to what clinicians already have in their hands to manage glaucoma? Which surgery should be chosen for which patient? What are the options? Are they equivalent? These are too many questions for the clinician! What are the answers to the questions? What is the evidence to support answers? Do we need more evidence and how can we produce high-quality evidence? This EGS Guide explores the changing and challenging glaucoma surgery environment aiming to provide answers to these questions. The EGS uses four words to highlight a continuum: Innovation, Education, Communication, and Implementation. Translating innovation to successful implementation is crucially important and requires high-quality evidence to ensure steps forward to a positive impact on health care when it comes to implementation. The vision of EGS is to provide the best possible well-being and minimal glaucomainduced visual disability in individuals with glaucoma within an affordable healthcare system. In this regard, assessing the changes in glaucoma surgery is a pivotal contribution to better care. As mentioned, this Guide aims to provide answers to the crucial questions above. However, every clinician is aware that answers may differ for every person: an individualised approach is needed. Therefore, there will be no uniform answer for all situations and all patients. Clinicians would need, through the clinical method and possibly some algorithm, to reach answers and decisions at the individual level. In this regard, evidence is needed to support clinicians to make decisions. Of key importance in this Guide is to provide an overview of existing evidence on glaucoma surgery and specifically on recent innovations and novel devices, but also to set standards in surgical design and reporting for future studies on glaucoma surgical innovation. Designing studies in surgery is particularly challenging because of many subtle variations inherent to surgery and hence multiple factors involved in the outcome, but even more because one needs to define carefully outcomes relevant to the research question but also to the future translation into clinical practice. In addition this Guide aims to provide clinical recommendations on novel procedures already in use when insufficient evidence exists. EGS has a long tradition to provide guidance to the ophthalmic community in Europe and worldwide through the EGS Guidelines (now in their 5th Edition). The EGS leadership recognized that the changing environment in glaucoma surgery currently represents a major challenge for the clinician, needing specific guidance. Therefore, the decision was made to issue this Guide on Glaucoma Surgery in order to help clinicians to make appropriate decisions for their patients and also to provide the framework and guidance for researchers to improve the quality of evidence in future studies. Ultimately this Guide will support better Glaucoma Care in accordance with EGS's Vision and Mission. Fotis Topouzis EGS President Contributors All contributors have provided the appropriate COI visible in detail at www.eugs.org/pages/guidesurgical/ This manuscript reflects the work and thoughts of the list of individuals recognized above, but importantly, it reflects EGS views on the subject matter. Its strength originates from a team effort, where a cohesive group of authors and reviewers have worked towards a common goal and now stand behind the text in its entirety. The EGS nevertheless wishes to thank the following external contributors for their additional expertise, which was particularly valuable to the development of this Surgical Guide: Amanda Bicket, Jonathan Bonnar, Catey Bunce, Kuan Hu, Sheffinea Koshy, Jimmy Le, Tianjing Li, Francisco Otarola, Riaz Qureshi, Anupa Shah, Richard Stead and Marta Toth. A particular appreciation goes to Ian Saldanha for drafting the introductory overview on Core Outcomes onchapter 8. Finally, EGS would like to acknowledge Augusto Azuara Blanco, Chair of the Scientific and Guidelines Committee, for his expertise and advisory role throughout the entire process. Luis Abegao Pinto, Centro Hospitalar Universitário Lisboa Norte Editor Gordana Sunaric Mégevand, Eye Research Centre, Adolphe de Rothschild Hospital, Geneva, Switzerland and Centre Ophtalmologique de Florissant, Geneva, Switzerland Editor Ingeborg Stalmans, Ingeborg Stalmans, University Hospitals UZ Leuven, Catholic University KU Leuven Editor Luis Abegao Pinto, Centro Hospitalar Universitário Lisboa Norte Hana Abouzeid, Clinical Eye Research Centre Adolph de Rothschild, AZ Ophthalmologie Eleftherios Anastasopoulos, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece Augusto Azuara Blanco, Centre for Public Health, Queen's University Belfast Luca Bagnasco, Clinica Oculistica, DiNOGMI University of Genoa Alessandro Bagnis, Clinica Oculistica, IRCCS Ospedale Policlinico San Martino Joao Barbosa Breda, Faculty of Medicine of the University of Porto, Porto, Portugal. Centro Hospitalar e Universitário São João, Porto, Portugal. KULeuven, Belgium Keith Barton, University College London, Moorfields Eye Hospital Amanda Bicket, University of Michigan (Ann Arbor, MI, USA) Jonathan Bonnar, Belfast Health and Social Care Trust Chiara Bonzano, Clinica Oculistica, IRCCS Ospedale Policlinico San Martino Rupert Bourne, Cambridge University Hospital Alain Bron, University Hospital Dijon Catey Bunce, King's College London Carlo Cutolo, Clinica Oculistica, DiNOGMI University of Genoa, and IRCCS Ospedale Policlinico San Martino Barbara Cvenkel, University Medical Centre Ljubljana Faculty of Medicine, University of Ljubljana Antonio Fea, University of Turin Theodoros Filippopoulos, Athens Vision Eye Institute Panayiota Founti, Moorfields Eye Hospital NHS Foundation Trust Stefano Gandolfi, U.O.C. Oculistica, University of Parma Julian Garcia Feijoo, Hospital Clinico San Carlos, Universidad Complutense, Madrid Gerhard Garhoefer, Medical University of Vienna, Austria David Garway Heath, Moorfields Eye Hospital NHS Foundation Trust, London. Institute of Ophthalmology, University College London. Gus Gazzard, Moorfields Eye Hospital NHS Foundation Trust, London. Institute of Ophthalmology, University College London. Stylianos Georgoulas, Addenbrooke's, Cambridge University Hospitals Dimitrios Giannoulis, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece Franz Grehn, University Hospitals Wuerzburg Kuang Hu, NIHR Moorfields Biomedical Research Centre, London - Institute of Ophthalmology - University College London Michele Iester, Clinica Oculistica, DiNOGMI University of Genoa, and IRCCS Ospedale Policlinico San Martino Hari Jayaram, Moorfields Eye Hospital Gauti Johannesson, Umea University Stylianos Kandarakis, National and Kapodistrian University of Athens, G. Gennimatas Hospital, Athens, Greece. Efthymios Karmiris, Hellenic Air Force General Hospital National and Kapodistrian University of Athens, G. Gennimatas Hospital, Athens Alan Kastner, Clinica Oftalmologica Pasteur, Santiago, Chile Andreas Katsanos, University of Ioannina, Greece Christina Keskini, Aristotle University of Thessaloniki, AHEPA Hospital Anthony Khawaja, Moorfields Eye Hospital and UCL Institute of Ophthalmology Anthony King, Nottingham University Hospitals NHS Trust James Kirwan, Portsmouth hospitals university NHS trust Miriam Kolko, University of Copenhagen, Copenhagen University Hospital Rigshospitalet Sheffinea Koshy, University of Galway Antoine Labbe, Quinze-Vingts ­ National Ophthalmology Hospital Jimmy Le, Johns Hopkins Bloomberg School of Public Health, Baltimore Sanna Leinonen, Tays Eye Centre, Tampere University Hospital Sophie Lemmens, University Hospitals UZ Leuven Tianjing Li, School of Medicine, University of Colorado Anschutz Medical Campus Giorgio Marchini, Clinica Oculistica, University Hospital, AOUI, Verona, Italy José Martinez De La Casa, Hospital Clinico San Carlos. Universidad Complutense Andy McNaught, Gloucestershire Eye Unit Frances Meier Gibbons, Eye Center Rapperswil, Switzerland Karl Mercieca, University Hospitals Eye Clinic, Bonn, Germany Manuele Michelessi, IRCCS - Fondazione Bietti Stefano Miglior, University of Milan Bicocca Eleni Nikita, Moorfields Eye Hospital NHS Foundation Trust Francesco Oddone, IRCCS ­ Fondazione Bietti Francisco Otarola, Universidad de La Frontera Marta Pazos, Institute of Ophthalmology. Hospital Clínic Barcelona. Researcher at Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Norbert Pfeiffer, Mainz University Medical Center Verena Prokosh, University of Cologne, Center for ophthalmology. Riaz Qureshi, Johns Hopkins Medicine, Baltimore Gokulan Ratnarajan, Queen Victoria Hospital, East Grinstead, UK Herbert Reitsamer, University Clinic Salzburg / SALK Luca Rossetti, University of Milan, ASST Santi Paolo e Carlo, Milano, Italy Ian Saldanha, Johns Hopkins Bloomberg School of Public Health, Baltimore Cedric Schweitzer, CHU Bordeaux, Univ. Bordeaux, ISPED, INSERM, U1219 - Bordeaux Population Health Research Centre, France Andrew Scott, Moorfields Eye Hospital London Riccardo Scotto, Clinica Oculistica, DiNOGMI University of Genoa Anupa Shah, Queen's University Belfast George Spaeth, Wills Eye Hospital/Sidney Kimmel Medical College/Thomas Jefferson University Richard Stead, Nottingham University Hospitals NHS Trust Francesco Stringa, University Hospital Southampton NHS FT Gordana Sunaric, Centre Ophtalmologique de Florissant, Centre de Recherche Clinique en Ophtalmologie Mémorial Adolphe de Rothschild Andrew Tatham, University of Edinburgh, Princess Alexandra Eye Pavilion Mark Toeteberg, University Hospital Zurich Fotis Topouzis, Aristotle University of Thessaloniki, AHEPA Hospital Marta Toth, Moorfields Eye Hospital NHS Foundation Trust Carlo Traverso, Clinica Oculistica, DiNOGMI University of Genoa, and IRCCS Ospedale Policlinico San Martino Anja Tuulonen, Tays Eye Centre, Tampere University Hospital Clemens Vass, Medical University of Vienna Ananth Viswanathan, Moorfields Eye Hospital NHSFT and UCL Institute of Ophthalmology Richard Wormald, UCL Institute of Ophthalmology External Reviewers American Glaucoma Society Asia-Pacific Glaucoma Society Middle East Africa Glaucoma Society World Glaucoma Society www.eugs.org/pages/externalreviewers The team of Clinica Oculistica of the University of Genoa for medical editing and illustration Luca Bagnasco Alessandro Bagnis Chiara Bonzano Carlo Cutolo Michele Iester Riccardo Scotto Carlo Travers

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease