Use of an acellular collagen-elastin matrix to support bladder regeneration in a porcine model of peritoneocystoplasty

Bladder reconstruction without using the intestine remains a challenge to this day despite the development of new biomaterials and cell cultures. Human bladder engineering is merely anecdotic, and mostly in vitro and animal studies have been conducted. In our study using a porcine model, we performed a bladder augmentation using an autologous parietal peritoneum graft (peritoneocystoplasty) and determined whether the attachment of an acellular collagen-elastin matrix (Group 1) or lack of (Group 2) had better histologic and functional results. Thus far, peritoneocystoplasty has rarely been performed or combined with a biomaterial. After 6 weeks, we observed different degrees of retraction of the new bladder wall in both groups, although the retraction was lower and the histological analysis showed more signs of regeneration (neoangiogenesis and less fibrosis) in Group 1 than when compared with Group 2. No transitional cells were found in the new bladder wall in any of the groups, and no differences were observed in the functional test results. Performing a peritoneocystoplasty is an easy and safe procedure. The data supports the benefit of an acellular collagen-elastin matrix to reinforce bladder regeneration. However, in our study we observed too much retraction of the new wall and the histologic results were not acceptable to consider it an appropriate cystoplasty technique

Malignant infarction of the middle cerebral artery in a porcine model. A pilot study

Animal models; Central nervous system; InfarctionModels animals; Sistema nerviós central; InfartModelos animales; Sistema nervioso central; InfartoBackground and purpose Interspecies variability and poor clinical translation from rodent studies indicate that large gyrencephalic animal stroke models are urgently needed. We present a proof-of-principle study describing an alternative animal model of malignant infarction of the middle cerebral artery (MCA) in the common pig and illustrate some of its potential applications. We report on metabolic patterns, ionic profile, brain partial pressure of oxygen (PtiO2), expression of sulfonylurea receptor 1 (SUR1), and the transient receptor potential melastatin 4 (TRPM4). Methods A 5-hour ischemic infarct of the MCA territory was performed in 5 2.5-to-3-month-old female hybrid pigs (Large White x Landrace) using a frontotemporal approach. The core and penumbra areas were intraoperatively monitored to determine the metabolic and ionic profiles. To determine the infarct volume, 2,3,5-triphenyltetrazolium chloride staining and immunohistochemistry analysis was performed to determine SUR1 and TRPM4 expression. Results PtiO2 monitoring showed an abrupt reduction in values close to 0 mmHg after MCA occlusion in the core area. Hourly cerebral microdialysis showed that the infarcted tissue was characterized by reduced concentrations of glucose (0.03 mM) and pyruvate (0.003 mM) and increases in lactate levels (8.87mM), lactate-pyruvate ratio (4202), glycerol levels (588 μM), and potassium concentration (27.9 mmol/L). Immunohistochemical analysis showed increased expression of SUR1-TRPM4 channels. Conclusions The aim of the present proof-of-principle study was to document the feasibility of a large animal model of malignant MCA infarction by performing transcranial occlusion of the MCA in the common pig, as an alternative to lisencephalic animals. This model may be useful for detailed studies of cerebral ischemia mechanisms and the development of neuroprotective strategies.The Neurotraumatology and Neurosurgery Research Unit is supported by a grant from the Departament d'Universitats, Recerca i Societat de la Informació de la Generalitat de Catalunya (SGR 2014-844). This work has been supported in part by the Fondo de Investigación Sanitaria (Instituto de Salud Carlos III) with grant FIS PI11/00700, which was co-financed by the European Regional Development Fund (ERDF) and awarded to Dr. J. Sahuquillo. A. Sánchez-Guerrero is the recipient of a personal pre-doctoral grant from the Instituto de Salud Carlos III (grant number grant number FI12/00074)

Single Intracoronary Injection of Encapsulated Antagomir-92a Promotes Angiogenesis and Prevents Adverse Infarct Remodeling

Small and large preclinical animal models have shown that antagomir-92a-based therapy reduces early postischemic loss of function, but its effect on postinfarction remodeling is not known. In addition, the reported remote miR-92a inhibition in noncardiac organs prevents the translation of nonvectorized miR-targeted therapy to the clinical setting. We investigated whether a single intracoronary administration of antagomir-92a encapsulated in microspheres could prevent deleterious remodeling of myocardium 1 month after acute myocardial infarction AUTHOR: Should "acute" be added before "myocardial infarction" (since abbreviation is AMI)? Also check at first mention in main text (AMI) without adverse effects. In a percutaneous pig model of reperfused AMI, a single intracoronary administration of antagomir-92a encapsulated in specific microspheres (9 μm poly-d,-lactide-co-glycolide [PLGA]) inhibited miR-92a in a local, selective, and sustained manner (n=3 pigs euthanized 1, 3, and 10 days after treatment; 8×, 2×, and 5×-fold inhibition at 1, 3, and 10 days). Downregulation of miR-92a resulted in significant vessel growth (n=27 adult minipigs randomly allocated to blind receive encapsulated antagomir-92a, encapsulated placebo, or saline [n=8, 9, 9]; P =0.001), reduced regional wall-motion dysfunction (P =0.03), and prevented adverse remodeling in the infarct area 1 month after injury (P =0.03). Intracoronary injection of microspheres had no significant adverse effect in downstream myocardium in healthy pigs (n=2), and fluorescein isothiocyanate albumin-PLGA microspheres were not found in myocardium outside the left anterior descending coronary artery territory (n=4) or in other organs (n=2). Early single intracoronary administration of encapsulated antagomir-92a in an adult pig model of reperfused AMI prevents left ventricular remodeling with no local or distant adverse effects, emerging as a promising therapeutic approach to translate to patients who suffer a large AMI

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Refinamiento anestésico en un modelo de defecto óseo segmentario diafisiario en oveja

La investigación con animales sigue siendo esencial para el avance del conocimiento de los procesos biológicos, especialmente los relacionados con la salud y la enfermedad humana y animal. Los animales más usados en investigación biomédica son los pequeños mamíferos, y más particularmente, los pequeños roedores. Sin embargo, entre estos y el humano hay diferencias esenciales derivadas del tamaño corporal y la longevidad, por lo que el uso de modelos animales de gran tamaño, como la oveja, proporciona en muchos casos una alternativa idónea, principalmente en modelos de ortopedia. Para ello, los animales son normalmente sometidos a anestesia general y por lo tanto, resulta necesario desarrollar nuevas técnicas de refinamiento que disminuyan el dolor en procedimientos experimentales, especialmente en el ovino, cuya evaluación del dolor supone un desafío debido a su especial comportamiento. El presente estudio tuvo como objetivo buscar un refinamiento de la técnica anestésica en ovejas sometidas a un procedimiento ortopédico de defecto óseo segmentario (DOSD), mejorando el bienestar animal y permitiendo disminuir la aplicación de fármacos de rescate, minimizando así el uso de aquellos fármacos que podrían interferir con los objetivos de la investigación. Para la realización de esta tesis se realizó, en primer lugar, una descripción del estudio anatómico correlacionado con la imagen ecográfica de forma detallada del nervio ciático y femoral en la oveja. En segundo lugar, se desarrolló la técnica de bloqueo nervioso ciático y femoral guiado por ultrasonografía y con neuroestimulación. Finalmente, el bloqueo nervioso periférico del nervio ciático pudo aplicarse en la oveja intraoperatoriamente, y prolongarse de forma continua durante el primer periodo postoperatorio con un sistema de infusión. Como conclusión podemos decir que se consiguió reducir el dolor postoperatorio tras la cirugía para la creación del DOSD, haciendo que los animales recuperaran con rapidez la capacidad de carga de la extremidad pélvica. Esto supone un refinamiento de la técnica anestésica, que repercute en una mejora del bienestar animal durante el procedimiento experimental. Creemos, además, que la aplicación de esta técnica podría ser útil en otros procedimientos ortopédicos experimentales en oveja.Animal research remains essential to advance the understanding of biological processes, especially those related to health and human and animal diseases. The most common animals used in biomedical research are small mammals. However, there are some studies that require larger animals, as rodents often do not faithfully replicate the human disease. Furthermore, between mice and humans there are essential differences in body size and longevity, for which the use of large animal models, among which includes sheep, provides a suitable alternative. Animal models in orthopedic research are usually induced under general anesthesia. Therefore, it is necessary to develop new refining techniques that reduce pain in experimental procedures, especially in sheep, which pain assessment involves a challenge because of the special behavior of these animals. The main objective of this study was to refine the anesthetic technique in sheep that have been included in a segmental diaphyseal bone defect orthopedic study. This suppose a refinement of the anesthetic technique, which results in an improved animal welfare during the experimental procedures, it can allow providing lower doses of rescue medication and also minimizing the use of those drugs that could interfere with the objectives of scientific research. In this Thesis Project, a detailed anatomical description was done, correlated with the echography images of the sciatic and femoral nerves in sheep. Secondly, that peripheral nerve blocking of the sciatic nerve guided with ultrasonography and neurostimulation was applied intraoperatively in sheep. Finally, peripheal nerve blocking of sciatic nerve could be applied intraoperatively and could be extended continuously during the first postoperatory period with an infusion system. As a conclusion, we can expose that pain lowering was achieved after surgery of the segmental diaphyseal bone defect. So, the animals could present a rapid recovery of the load bearing ability of the pelvic limb. This suppose a refinement of the anesthetic technique, which results in an improved animal welfare during the experimental procedures. This new refinement of experimental anesthesia with continuing blockading in sheep could be useful in orthopedic procedures

Refinamiento anestésico en un modelo de defecto óseo segmentario diafisiario en oveja

La investigación con animales sigue siendo esencial para el avance del conocimiento de los procesos biológicos, especialmente los relacionados con la salud y la enfermedad humana y animal. Los animales más usados en investigación biomédica son los pequeños mamíferos, y más particularmente, los pequeños roedores. Sin embargo, entre estos y el humano hay diferencias esenciales derivadas del tamaño corporal y la longevidad, por lo que el uso de modelos animales de gran tamaño, como la oveja, proporciona en muchos casos una alternativa idónea, principalmente en modelos de ortopedia. Para ello, los animales son normalmente sometidos a anestesia general y por lo tanto, resulta necesario desarrollar nuevas técnicas de refinamiento que disminuyan el dolor en procedimientos experimentales, especialmente en el ovino, cuya evaluación del dolor supone un desafío debido a su especial comportamiento. El presente estudio tuvo como objetivo buscar un refinamiento de la técnica anestésica en ovejas sometidas a un procedimiento ortopédico de defecto óseo segmentario (DOSD), mejorando el bienestar animal y permitiendo disminuir la aplicación de fármacos de rescate, minimizando así el uso de aquellos fármacos que podrían interferir con los objetivos de la investigación. Para la realización de esta tesis se realizó, en primer lugar, una descripción del estudio anatómico correlacionado con la imagen ecográfica de forma detallada del nervio ciático y femoral en la oveja. En segundo lugar, se desarrolló la técnica de bloqueo nervioso ciático y femoral guiado por ultrasonografía y con neuroestimulación. Finalmente, el bloqueo nervioso periférico del nervio ciático pudo aplicarse en la oveja intraoperatoriamente, y prolongarse de forma continua durante el primer periodo postoperatorio con un sistema de infusión. Como conclusión podemos decir que se consiguió reducir el dolor postoperatorio tras la cirugía para la creación del DOSD, haciendo que los animales recuperaran con rapidez la capacidad de carga de la extremidad pélvica. Esto supone un refinamiento de la técnica anestésica, que repercute en una mejora del bienestar animal durante el procedimiento experimental. Creemos, además, que la aplicación de esta técnica podría ser útil en otros procedimientos ortopédicos experimentales en oveja.Animal research remains essential to advance the understanding of biological processes, especially those related to health and human and animal diseases. The most common animals used in biomedical research are small mammals. However, there are some studies that require larger animals, as rodents often do not faithfully replicate the human disease. Furthermore, between mice and humans there are essential differences in body size and longevity, for which the use of large animal models, among which includes sheep, provides a suitable alternative. Animal models in orthopedic research are usually induced under general anesthesia. Therefore, it is necessary to develop new refining techniques that reduce pain in experimental procedures, especially in sheep, which pain assessment involves a challenge because of the special behavior of these animals. The main objective of this study was to refine the anesthetic technique in sheep that have been included in a segmental diaphyseal bone defect orthopedic study. This suppose a refinement of the anesthetic technique, which results in an improved animal welfare during the experimental procedures, it can allow providing lower doses of rescue medication and also minimizing the use of those drugs that could interfere with the objectives of scientific research. In this Thesis Project, a detailed anatomical description was done, correlated with the echography images of the sciatic and femoral nerves in sheep. Secondly, that peripheral nerve blocking of the sciatic nerve guided with ultrasonography and neurostimulation was applied intraoperatively in sheep. Finally, peripheal nerve blocking of sciatic nerve could be applied intraoperatively and could be extended continuously during the first postoperatory period with an infusion system. As a conclusion, we can expose that pain lowering was achieved after surgery of the segmental diaphyseal bone defect. So, the animals could present a rapid recovery of the load bearing ability of the pelvic limb. This suppose a refinement of the anesthetic technique, which results in an improved animal welfare during the experimental procedures. This new refinement of experimental anesthesia with continuing blockading in sheep could be useful in orthopedic procedures

Refinamiento anestésico en un modelo de defecto óseo segmentario diafisiario en oveja

La investigación con animales sigue siendo esencial para el avance del conocimiento de los procesos biológicos, especialmente los relacionados con la salud y la enfermedad humana y animal. Los animales más usados en investigación biomédica son los pequeños mamíferos, y más particularmente, los pequeños roedores. Sin embargo, entre estos y el humano hay diferencias esenciales derivadas del tamaño corporal y la longevidad, por lo que el uso de modelos animales de gran tamaño, como la oveja, proporciona en muchos casos una alternativa idónea, principalmente en modelos de ortopedia. Para ello, los animales son normalmente sometidos a anestesia general y por lo tanto, resulta necesario desarrollar nuevas técnicas de refinamiento que disminuyan el dolor en procedimientos experimentales, especialmente en el ovino, cuya evaluación del dolor supone un desafío debido a su especial comportamiento. El presente estudio tuvo como objetivo buscar un refinamiento de la técnica anestésica en ovejas sometidas a un procedimiento ortopédico de defecto óseo segmentario (DOSD), mejorando el bienestar animal y permitiendo disminuir la aplicación de fármacos de rescate, minimizando así el uso de aquellos fármacos que podrían interferir con los objetivos de la investigación. Para la realización de esta tesis se realizó, en primer lugar, una descripción del estudio anatómico correlacionado con la imagen ecográfica de forma detallada del nervio ciático y femoral en la oveja. En segundo lugar, se desarrolló la técnica de bloqueo nervioso ciático y femoral guiado por ultrasonografía y con neuroestimulación. Finalmente, el bloqueo nervioso periférico del nervio ciático pudo aplicarse en la oveja intraoperatoriamente, y prolongarse de forma continua durante el primer periodo postoperatorio con un sistema de infusión. Como conclusión podemos decir que se consiguió reducir el dolor postoperatorio tras la cirugía para la creación del DOSD, haciendo que los animales recuperaran con rapidez la capacidad de carga de la extremidad pélvica. Esto supone un refinamiento de la técnica anestésica, que repercute en una mejora del bienestar animal durante el procedimiento experimental. Creemos, además, que la aplicación de esta técnica podría ser útil en otros procedimientos ortopédicos experimentales en oveja.Animal research remains essential to advance the understanding of biological processes, especially those related to health and human and animal diseases. The most common animals used in biomedical research are small mammals. However, there are some studies that require larger animals, as rodents often do not faithfully replicate the human disease. Furthermore, between mice and humans there are essential differences in body size and longevity, for which the use of large animal models, among which includes sheep, provides a suitable alternative. Animal models in orthopedic research are usually induced under general anesthesia. Therefore, it is necessary to develop new refining techniques that reduce pain in experimental procedures, especially in sheep, which pain assessment involves a challenge because of the special behavior of these animals. The main objective of this study was to refine the anesthetic technique in sheep that have been included in a segmental diaphyseal bone defect orthopedic study. This suppose a refinement of the anesthetic technique, which results in an improved animal welfare during the experimental procedures, it can allow providing lower doses of rescue medication and also minimizing the use of those drugs that could interfere with the objectives of scientific research. In this Thesis Project, a detailed anatomical description was done, correlated with the echography images of the sciatic and femoral nerves in sheep. Secondly, that peripheral nerve blocking of the sciatic nerve guided with ultrasonography and neurostimulation was applied intraoperatively in sheep. Finally, peripheal nerve blocking of sciatic nerve could be applied intraoperatively and could be extended continuously during the first postoperatory period with an infusion system. As a conclusion, we can expose that pain lowering was achieved after surgery of the segmental diaphyseal bone defect. So, the animals could present a rapid recovery of the load bearing ability of the pelvic limb. This suppose a refinement of the anesthetic technique, which results in an improved animal welfare during the experimental procedures. This new refinement of experimental anesthesia with continuing blockading in sheep could be useful in orthopedic procedures

Comparison of subacute vascular damage caused by ADAPT versus stent retriever devices after thrombectomy in acute ischemic stroke. Histological and ultrastructural study in an animal model

OBJECTIVES: To assess the delayed (15 days) histological and ultrastructural changes occurring following endovascular treatment with a direct aspiration first pass technique (ADAPT) or stent retrievers (SRs) and to compare the findings in order to determine which is the least harmful technique and what changes occur. MATERIALS AND METHODS: Damage to the wall of swine extracranial arteries was evaluated after ADAPT with the Penumbra system or thrombectomy with various SRs. The procedures were performed using two pigs as animal models; extracranial cervical arteries were selected based on their diameters in order to reproduce the procedures as in human intracranial arteries, and endovascular thrombectomies were done after the injection of autologous thrombi. Two weeks later, the animals were euthanized, and 60 arterial samples were obtained for analysis by optical and electron microscopy. RESULTS: Optical and electron microscopy revealed that both techniques cause, in different way, alterations to the structure of the vessel wall. CONCLUSIONS: Both techniques caused damage to the vessel wall. The main damages were localized at the level of the tunica media and adventitia, instead of the tunica intima as in the acute phase. Further investigation is required to better understand whether these alterations could have chronic consequences

Use of an acellular collagen-elastin matrix to support bladder regeneration in a porcine model of peritoneocystoplasty

Bladder reconstruction without using the intestine remains a challenge to this day despite the development of new biomaterials and cell cultures. Human bladder engineering is merely anecdotic, and mostly in vitro and animal studies have been conducted. In our study using a porcine model, we performed a bladder augmentation using an autologous parietal peritoneum graft (peritoneocystoplasty) and determined whether the attachment of an acellular collagen-elastin matrix (Group 1) or lack of (Group 2) had better histologic and functional results. Thus far, peritoneocystoplasty has rarely been performed or combined with a biomaterial. After 6 weeks, we observed different degrees of retraction of the new bladder wall in both groups, although the retraction was lower and the histological analysis showed more signs of regeneration (neoangiogenesis and less fibrosis) in Group 1 than when compared with Group 2. No transitional cells were found in the new bladder wall in any of the groups, and no differences were observed in the functional test results. Performing a peritoneocystoplasty is an easy and safe procedure. The data supports the benefit of an acellular collagen-elastin matrix to reinforce bladder regeneration. However, in our study we observed too much retraction of the new wall and the histologic results were not acceptable to consider it an appropriate cystoplasty technique