The T309G MDM2 gene polymorphism is a novel risk factor for proliferative vitreoretinopathy

Proliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism (rs2279744) in PVR. Distribution of T309G MDM2 genotypes among European subjects undergoing RD surgery was evaluated. Proportions of genotypes between subsamples from different countries were analyzed. Also, a genetic interaction between rs2279744 in MDM2 and rs1042522 in p53 gene was analyzed. Significant differences were observed comparing MDM2 genotype frequencies at position 309 of intron 1 between cases (GG: 21.6%, TG: 54.5%, TT: 23.8%) and controls (GG: 7.3%, TG: 43.9%, TT: 48.7%). The proportions of genotypes between sub-samples from different countries showed a significant difference. Distribution of GG genotype revealed differences in Spain (35.1-53.0)/(22.6-32.9), Portugal (39.0-74.4)/(21.4-38.9), Netherlands (40.6-66.3)/(25.3-38.8) and UK (37.5-62.4)/(23.3-34.2). The OR of G carriers in the global sample was 5.9 (95% CI: 3.2 to 11.2). The OR of G carriers from Spain and Portugal was 5.4 (95% CI: 2.2-12.7), whereas in the UK and the Netherlands was 7.3 (95% CI: 2.8-19.1). Results indicate that the G allele of rs2279744 is associated with a higher risk of developing PVR in patients undergoing a RD surgery. Further studies are necessary to understand the role of this SNP in the development of PVR. Copyright

Cell Therapy Replacement for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice. Sources include human fetal retinal stem cells, allogenic cadaveric human cells, adult hippocampal neural stem cells, human CNS stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), human pluripotent stem cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). Of these, RPCs, PSCs and MSCs have already entered early-stage clinical trials since they can all differentiate into RPE, photoreceptors or ganglion cells, and have demonstrated safety, while showing some indicators of efficacy. Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long-term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical translation of cell-based therapy, including (1) the ability to enrich for specific retinal subtypes; (2) cell survival; (3) cell delivery, which may need to incorporate a scaffold to induce correct cell polarization, which increases the size of the retinotomy in surgery and, therefore, the chance of severe complications; (4) the need to induce retinal detachment to perform the subretinal placement of the transplanted cell; and (5) the evaluation of the risk of tumor formation caused by the undifferentiated stem cells and prolific progenitor cells. Despite these challenges, stem/progenitor cells represent the most promising strategy for retinal and optic nerve disease treatment in the near future, and therapeutics assisted by gene techniques, neuroprotective compounds and artificial devices can be applied to fulfil clinical needs.</jats:p

Functional characterization of rs2229094 (T&gt;C) polymorphism in the tumor necrosis factor locus and lymphotoxin alpha expression in human retina: the Retina 4 project

Abstract Purpose: The objective of this study is to determine the expression and localization of lymphotoxin alpha (LTA) in human retinas and the functionality of one of its polymorphisms rs2229094 (C13R) (T>C), previously associated with proliferative vitreoretinopathy (PVR) development. Materials and methods: Total RNA from three healthy human retinas were extracted and subjected to reverse transcription-polymerase chain reaction (RT-PCR) analysis, using flanking primers of LTA cDNA. In addition, three human eyes with retinal detachment (RD) and three healthy control eyes were subjected to immunohistochemistry (IHC) with a specific antibody against LTA. The functionality of T and C alleles was assessed by using pCEFL-Flag expression vector and transient transfection assays in COS-1 cell line. In addition, expression analysis by RT-PCR, Western blot and subcellular localization of both alleles and by immunofluorescence assay was performed. Results: RT-PCR analysis revealed no significant levels of messenger RNA (mRNA) LTA in healthy human retinas. Sequential IHC staining showed differences between healthy human and RD retinas. No differences in mRNA and protein expression levels and in subcellular localization between both alleles were found. Both alleles were located in the cytoplasm of COS-1 cells. Conclusion: Although results suggest lack of functionality, the differences found in IHC study and its strong association with PVR and its relationship with tumor necrosis factor locus, warrant further studies and could justify the use of this polymorphism as a valid biomarker to identify high-risk patients to develop PVR after RD. Keywords: cytokines; inflammation; lymphotoxin alpha; polymorphism; proliferative vitreoretinopathy; tumor necrosis factor alpha

Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical consequences.

During the last four decades, proliferative vitreoretinopathy (PVR) has defied the efforts of many researchers to prevent its occurrence or development. Thus, PVR is still the major complication following retinal detachment (RD) surgery and a bottle-neck for advances in cell therapy that require intraocular surgery. In this review we tried to combine basic and clinical knowledge, as an example of translational research, providing new and practical information for clinicians. PVR was defined as the proliferation of cells after RD. This idea was used for classifying PVR and also for designing experimental models used for testing many drugs, none of which were successful in humans. We summarize current information regarding the pathogenic events that follow any RD because this information may be the key for understanding and treating the earliest stages of PVR. A major focus is made on the intraretinal changes derived mainly from retinal glial cell reactivity. These responses can lead to intraretinal PVR, an entity that has not been clearly recognized. Inflammation is one of the major components of PVR, and we describe new genetic biomarkers that have the potential to predict its development. New treatment approaches are analyzed, especially those directed towards neuroprotection, which can also be useful for preventing visual loss after any RD. We also summarize the results of different surgical techniques and clinical information that is oriented toward the identification of high risk patients. Finally, we provide some recommendations for future classification of PVR and for designing comparable protocols for testing new drugs or techniques

Histopathological changes associated to an absorbable fibrin patch (Tachosil®) covering in an experimental model of high-risk colonic anastomoses

Background. TachoSil® is a fibrin sponge that contains fibrinogen and thrombin and is a useful adjuvant to enhance control of air leaks in thoracic surgery and to control bleeding in vascular and general surgery. Its use in intestinal surgery to prevent suture dehiscence is currently under investigation. Material and Methods. We report the results of a prospective randomized experimental study on 33 large white pigs in which a high-risk suture was created by induction of ischemia. We randomly employed TachoSil® to cover the anastomosis in half of the animals compared to a control group of uncovered anastomosis. After euthanasia, postmortem analysis was performed describing the findings related to anastomotic leakage, peritonitis and grade of adhesions. The entire anastomosis was resected in bloc and sent for histopathological analysis. A single blinded-pathologist evaluated the histopathological features of the specimens. Results. We found statistically significant differences favouring the patch in decreasing leakage in the covered group. The healing process did not show significant differences between groups, although a higher rate of microscopic abscess was observed in the covered group. Conclusion. The use of fibrin sealants covering highrisk intestinal sutures has a positive effect in avoiding macroscopic anastomotic leakage. The patch did not have any influence in the anastomotic healing process, however, as a result of the effect in containing the inflammatory response, it may increase the rate of abscess

Trasplante pancreático

La diabetes mellitus constituye una preocupación sanitaria de primer orden, dado el alto índice de morbimortalidad asociada. El objetivo para frenar el avance de sus complicaciones, antes de que éstas sean irreversibles, se basa en un control metabólico correcto. La alta tasa de morbilidad asociada a la cirugía del trasplante vascularizado de páncreas y el alto índice de rechazo ha constituido durante tres décadas un obstáculo para que se considerara a éste como una alternativa válida en el tratamiento de estos pacientes. El trasplante de páncreas hoy día ha pasado a ocupar un lugar primordial, gracias a los nuevos regímenes de inmunosupresión y al perfeccionamiento de la técnica quirúrgica. En este capítulo revisamos la evolución del trasplante de páncreas desde sus inicios y su situación actual

Cirugía mínimamente invasiva de la hernia inguinal

El abordaje mínimamente invasivo de la hernia inguinal presenta ventajas respecto a los abordajes convencionales anteriores en las hernias inguinales bilaterales y recurrentes, si bien los resultados iniciales fueron malos, se sumaron nuevos problemas derivados del abordaje laparoscópico. El objetivo de este artículo es describir la técnica quirúrgica y analizar los resultados preliminares de nuestra serie de 600 hernioplastias totalmente extraperitoneales realizadas en la Clínica Universitaria de Navarra. La complicación intraoperatoria más frecuente (25,7%) fue la apertura accidental del peritoneo. No hubo complicaciones intrabdominales asociadas. En el seguimiento hubo 9 (1,5%) recidivas y 13 reintervenciones. Once (1,8%) pacientes desarrollaron dolor neuropático transitorio en el territorio del fémoro-cutáneo. En nuestra experiencia el abordaje totalmente extraperitoneal es una técnica especialmente indicada en hernias recidivadas y bilaterales. Las ventajas presentes en cuanto a dolor y disconfort postoperatorio, recuperación de la actividad física y laboral, y los buenos resultados en cuanto a recidivas y dolor neuropático nos animan a indicarla no sólo en las hernias inguinales recidivadas o bilaterales sino en las primarias. Palabras clave. Hernia. Hernioplastia. Laparoscopia. Abordaje mínimamente invasivo. Hernia totalmente extraperitoneal

Additional file 2 of Intravitreal allogeneic mesenchymal stem cells: a non-randomized phase II clinical trial for acute non-arteritic optic neuropathy

Additional file 2. Supplementary Table T1. Follow-up Schedul