Efectos del precondicionamiento isquémico abdominal multiorgánico en modelos experimentales de isquemia-reperfusión

El origen de esta línea de investigación se relaciona con la problemática observada en la clínica del trasplante de órganos sólidos en humanos. Desde el momento en que se inicia el procedimiento quirúrgico de extracción del órgano en el donante, la isquemia se asocia a un conjunto de mecanismos plausibles de lesionar al órgano a implantar, y surge entonces el precondicionamiento isquémico (PCI) como una posible herramienta de atenuación a la injuria en cuestión. El PCI consiste en someter al tejido a uno o más periodos de isquemia breve seguido de períodos de reperfusión previamente a un periodo de isquemia prolongado, con el fin de generar una respuesta adaptativa que enlentezca la tasa de muerte celular, y de este modo proteja al órgano en cuestión. Una forma de realizar PCI es por medio del clampeo de la vasculatura nutricia del órgano implicado. El PCI fue ampliamente estudiado asociado al trasplante de los distintos órganos abdominales en forma aislada en roedores, obteniéndose resultados alentadores tanto en intestino delgado, como en hígado, y riñón. Es de notar que, en la práctica clínica, el momento de la extracción implica el accionar de un grupo quirúrgico de ablacionistas para cada órgano que luego se va a implantar. Sumando a esto el escaso tiempo con que se cuenta para la procuración de órganos, debido a que la celeridad en la procuración se objetiva en una mejor funcionalidad del injerto en el paciente, se requiere entonces de una coordinación óptima tanto en el seno de cada grupo quirúrgico como así también en la articulación entre cada uno de ellos. Esto conlleva que de incorporarse el precondicionamiento como procedimiento quirúrgico en la práctica clínica, sea necesario para su implementación, que cumpla ciertos criterios. Entre los que se incluyen: que el método sea sencillo, fácilmente reproducible, que genere un beneficio al conjunto de órganos o al menos no genere daño o perjuicio en ninguno de ellos, y que no prolongue innecesariamente el proceso de procuración. De este modo, se planteó en el presente trabajo la posibilidad de aplicación del precondicionamiento, pero en forma multiorgánica. Realizando el clampeo de la arteria aorta abdominal en su origen, a fin de precondicionar en un tiempo todos los órganos abdominales, simplificando así el método.Facultad de Ciencias Médica

Optimización de un modelo de trasplante intestinal heterotópico en ratas utilizando la combinación Sprague Dawley-Wistar para el estudio del proceso de rechazo celular agudo

El rechazo del injerto (RI) constituye una de las principales complicaciones pos-quirúrgicas en pacientes que reciben un trasplante intestinal (TI), ya que puede comprometer la vida del receptor y del órgano trasplantado. Por tal motivo, comprender de mejor manera la patogenia del rechazo intestinal y establecer estrategias para prevenirlo, diagnosticarlo de manera temprana y tratarlo representan un gran desafío en el área clínica y experimental. En este sentido, los modelos de TI en roedores constituyen una herramienta de gran utilidad para estudiar temas inherentes a este tipo de trasplante.Facultad de Ciencias Médica

Optimización de un modelo de trasplante intestinal heterotópico en ratas utilizando la combinación Sprague Dawley-Wistar para el estudio del proceso de rechazo celular agudo

El rechazo del injerto (RI) constituye una de las principales complicaciones pos-quirúrgicas en pacientes que reciben un trasplante intestinal (TI), ya que puede comprometer la vida del receptor y del órgano trasplantado. Por tal motivo, comprender de mejor manera la patogenia del rechazo intestinal y establecer estrategias para prevenirlo, diagnosticarlo de manera temprana y tratarlo representan un gran desafío en el área clínica y experimental. En este sentido, los modelos de TI en roedores constituyen una herramienta de gran utilidad para estudiar temas inherentes a este tipo de trasplante.Facultad de Ciencias Médica

Small bowel transplantation in rats, a multicenter experience summarizing the pitfalls to be overcome

Small Bowel transplantation in rats is a highly complex microsurgical procedure because several technical complications may lead to recipient mortality and transplant failure. Our aim was to report the most common complications associated with orthotopic and heterotopic intestinal transplantation in rats in order to identify the “pitfalls” of the procedure and prevent them. A retrospective multicenter study was performed. All participant centers have established rodent transplant procedures and trained surgeons. Two hundred ninety-three complications from 264 unsuccessful intestinal transplants were reported, representing an overall failure rate of 15% of the procedures performed. Recipient complications were most frequent than donor (257 vs. 36 p<0.0001). Excessive surgical time (11/36); severe hemorrhage (12/36) and inappropriate infusion of the preservation solution in the intestinal graft (11/36) were the most common donor complications. Arterial anastomosis bleeding (50/257), venous anastomosis bleeding (35/257) and portal vein stenosis (26/257) were the most common intraoperative complications in the recipient. To maximize success rate, surgeons should optimize time and avoid bleeding during graft dissection in the donor surgery. After performing a bloodless vascular anastomosis an adequate post-operative management of the animal is mandatory to guarantee survival.Facultad de Ciencias MédicasLaboratorio y Programa de Trasplante de Organos, Tejidos y CélulasInstituto de Estudios Inmunológicos y Fisiopatológico

Gut Permeability and Glucose Absorption Are Affected at Early Stages of Graft Rejection in a Small Bowel Transplant Rat Model

Background. Intestinal transplantation (ITx) faces many challenges due to the complexity of surgery and to the multiple immunological reactions that lead to the necessity of rigorous follow-up for early detection of acute cellular rejection (ACR). Our aim was to determine the kinetics of ACR using an experimental ITx model, with emphasis in the characterization of the process using different approaches, including the use of functional assays of absorptive and barrier function.Methods. ITx in rats conducting serial sampling was performed. Clinical monitoring, graft histology, proinflammatory gene expression, and nitrosative stress determination were performed. Also, glucose absorption, barrier function using ovalbumin translocation, and contractile function were analyzed. Results. The model used reproduced the different stages of ACR. Allogeneic ITx recipients showed signs of rejection from postoperative day (POD) 5, with increasing severity until 12 POD. Histological evaluation showed mild rejection in early sampling and severe rejection at late stages, with alterations in all graft layers. IL-6, CXCL 10, IFNg, and nitrite plasmas levels showed behavior coincident with histopathology. Remarkably, allogeneic grafts showed a marked alteration of glucose absorptive capacity from POD 5 that was sustained until endpoint. Coincidently, barrier function alteration was evidenced by luminal ovalbumin translocation to serum. Contractile function was progressively impaired along ACR. Conclusions. Glucose absorption and barrier function are altered at early stages of ACR when histological alterations or gene expression changes were much subtle. This observation may provide simple evaluation tools that could be eventually translated to the clinics to contribute to early ACR diagnosis.Facultad de Ciencias MédicasInstituto de Estudios Inmunológicos y FisiopatológicosLaboratorio y Programa de Trasplante de Organos, Tejidos y CélulasInstituto de Investigaciones Bioquímicas de La Plat

Migration of cations induces reversible performance losses over day/night cycling in perovskite solar cells

Perovskites have been demonstrated in solar cells with a power conversion efficiency of well above 20​%, which makes them one of the strongest contenders for next generation photovoltaics. While there are no concerns about their efficiency, very little is known about their stability under illumination and load. Ionic defects and their migration in the perovskite crystal lattice are some of the most alarming sources of degrdn., which can potentially prevent the commercialization of perovskite solar cells (PSCs)​. In this work, we provide direct evidence of elec. field-​induced ionic defect migration and we isolate their effect on the long-​term performance of state-​of-​the-​art devices. Supported by modeling, we demonstrate that ionic defects, migrating on timescales significantly longer (above 103 s) than what has so far been explored (from 10-​1 to 102 s)​, abate the initial efficiency by 10-​15​% after several hours of operation at the max. power point. Though these losses are not negligible, we prove that the initial efficiency is fully recovered when leaving the device in the dark for a comparable amt. of time. We verified this behavior over several cycles resembling day​/night phases, thus probing the stability of PSCs under native working conditions. This unusual behavior reveals that research and industrial stds. currently in use to assess the performance and the stability of solar cells need to be adjusted for PSCs. Our work paves the way for much needed new testing protocols and figures of merit specifically designed for PSCs

Gut Permeability and Glucose Absorption Are Affected at Early Stages of Graft Rejection in a Small Bowel Transplant Rat Model

Background. Intestinal transplantation (ITx) faces many challenges due to the complexity of surgery and to the multiple immunological reactions that lead to the necessity of rigorous follow-up for early detection of acute cellular rejection (ACR). Our aim was to determine the kinetics of ACR using an experimental ITx model, with emphasis in the characterization of the process using different approaches, including the use of functional assays of absorptive and barrier function.Methods. ITx in rats conducting serial sampling was performed. Clinical monitoring, graft histology, proinflammatory gene expression, and nitrosative stress determination were performed. Also, glucose absorption, barrier function using ovalbumin translocation, and contractile function were analyzed. Results. The model used reproduced the different stages of ACR. Allogeneic ITx recipients showed signs of rejection from postoperative day (POD) 5, with increasing severity until 12 POD. Histological evaluation showed mild rejection in early sampling and severe rejection at late stages, with alterations in all graft layers. IL-6, CXCL 10, IFNg, and nitrite plasmas levels showed behavior coincident with histopathology. Remarkably, allogeneic grafts showed a marked alteration of glucose absorptive capacity from POD 5 that was sustained until endpoint. Coincidently, barrier function alteration was evidenced by luminal ovalbumin translocation to serum. Contractile function was progressively impaired along ACR. Conclusions. Glucose absorption and barrier function are altered at early stages of ACR when histological alterations or gene expression changes were much subtle. This observation may provide simple evaluation tools that could be eventually translated to the clinics to contribute to early ACR diagnosis.Facultad de Ciencias MédicasInstituto de Estudios Inmunológicos y FisiopatológicosLaboratorio y Programa de Trasplante de Organos, Tejidos y CélulasInstituto de Investigaciones Bioquímicas de La Plat

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6&nbsp;years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P &lt; 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100&nbsp;years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Global, regional, and national burden of neurological disorders, 1990–2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background: Neurological disorders are increasingly recognised as major causes of death and disability worldwide. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 is to provide the most comprehensive and up-to-date estimates of the global, regional, and national burden from neurological disorders. Methods: We estimated prevalence, incidence, deaths, and disability-adjusted life-years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs]) by age and sex for 15 neurological disorder categories (tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease and other dementias, Parkinson's disease, multiple sclerosis, motor neuron diseases, idiopathic epilepsy, migraine, tension-type headache, and a residual category for other less common neurological disorders) in 195 countries from 1990 to 2016. DisMod-MR 2.1, a Bayesian meta-regression tool, was the main method of estimation of prevalence and incidence, and the Cause of Death Ensemble model (CODEm) was used for mortality estimation. We quantified the contribution of 84 risks and combinations of risk to the disease estimates for the 15 neurological disorder categories using the GBD comparative risk assessment approach. Findings: Globally, in 2016, neurological disorders were the leading cause of DALYs (276 million [95% UI 247–308]) and second leading cause of deaths (9·0 million [8·8–9·4]). The absolute number of deaths and DALYs from all neurological disorders combined increased (deaths by 39% [34–44] and DALYs by 15% [9–21]) whereas their age-standardised rates decreased (deaths by 28% [26–30] and DALYs by 27% [24–31]) between 1990 and 2016. The only neurological disorders that had a decrease in rates and absolute numbers of deaths and DALYs were tetanus, meningitis, and encephalitis. The four largest contributors of neurological DALYs were stroke (42·2% [38·6–46·1]), migraine (16·3% [11·7–20·8]), Alzheimer's and other dementias (10·4% [9·0–12·1]), and meningitis (7·9% [6·6–10·4]). For the combined neurological disorders, age-standardised DALY rates were significantly higher in males than in females (male-to-female ratio 1·12 [1·05–1·20]), but migraine, multiple sclerosis, and tension-type headache were more common and caused more burden in females, with male-to-female ratios of less than 0·7. The 84 risks quantified in GBD explain less than 10% of neurological disorder DALY burdens, except stroke, for which 88·8% (86·5–90·9) of DALYs are attributable to risk factors, and to a lesser extent Alzheimer's disease and other dementias (22·3% [11·8–35·1] of DALYs are risk attributable) and idiopathic epilepsy (14·1% [10·8–17·5] of DALYs are risk attributable). Interpretation: Globally, the burden of neurological disorders, as measured by the absolute number of DALYs, continues to increase. As populations are growing and ageing, and the prevalence of major disabling neurological disorders steeply increases with age, governments will face increasing demand for treatment, rehabilitation, and support services for neurological disorders. The scarcity of established modifiable risks for most of the neurological burden demonstrates that new knowledge is required to develop effective prevention and treatment strategies. Funding: Bill & Melinda Gates Foundation