miR-486-5p protects against rat ischemic kidney injury and prevents the transition to chronic kidney disease and vascular dysfunction.

AIM: Acute kidney injury (AKI) increases the risk for progressive chronic kidney disease (CKD). MicroRNA (miR)-486-5p protects against kidney ischemia-reperfusion (IR) injury in mice, although its long-term effects on the vasculature and development of CKD are unknown. We studied whether miR-486-5p would prevent the AKI to CKD transition in rat, and affect vascular function. METHODS: Adult male rats were subjected to bilateral kidney IR followed by i.v. injection of liposomal-packaged miR-486-5p (0.5 mg/kg). Kidney function and histologic injury were assessed after 24 h and 10 weeks. Kidney endothelial protein levels were measured by immunoblot and immunofluorescence, and mesenteric artery reactivity was determined by wire myography. RESULTS: In rats with IR, miR-486-5p blocked kidney endothelial cell increases in intercellular adhesion molecule-1 (ICAM-1), reduced neutrophil infiltration and histologic injury, and normalized plasma creatinine (P<0.001). However, miR-486-5p attenuated IR-induced kidney endothelial nitric oxide synthase (eNOS) expression (P<0.05). At 10 weeks, kidneys from rats with IR alone had decreased peritubular capillary density and increased interstitial collagen deposition (P<0.0001), and mesenteric arteries showed impaired endothelium-dependent vasorelaxation (P<0.001). These changes were inhibited by miR-486-5p. Delayed miR-486-5p administration (96 h, 3 weeks after IR) had no impact on kidney fibrosis, capillary density, or endothelial function. CONCLUSION: In rats, administration of miR-486-5p early after kidney IR prevents injury, and protects against CKD development and systemic endothelial dysfunction. These protective effects are associated with inhibition of endothelial ICAM-1 and occur despite reduction in eNOS. miR-486-5p holds promise for the prevention of ischemic AKI and its complications.

miRNA-486-5p: signaling targets and role in non-malignant disease.

MicroRNAs (miRNAs) are short non-coding RNAs, highly conserved between species, that are powerful regulators of gene expression. Aberrant expression of miRNAs alters biological processes and pathways linked to human disease. miR-486-5p is a muscle-enriched miRNA localized to the cytoplasm and nucleus, and is highly abundant in human plasma and enriched in small extracellular vesicles. Studies of malignant and non-malignant diseases, including kidney diseases, have found correlations with circulating miR-486-5p levels, supporting its role as a potential biomarker. Pre-clinical studies of non-malignant diseases have identified miR-486-5p targets that regulate major signaling pathways involved in cellular proliferation, migration, angiogenesis, and apoptosis. Validated miR-486-5p targets include phosphatase and tensin homolog (PTEN) and FoXO1, whose suppression activates phosphatidyl inositol-3-kinase (PI3K)/Akt signaling. Targeting of Smad1/2/4 and IGF-1 by miR-486-5p inhibits transforming growth factor (TGF)-ß and insulin-like growth factor-1 (IGF-1) signaling, respectively. Other miR-486-5p targets include matrix metalloproteinase-19 (MMP-19), Sp5, histone acetyltransferase 1 (HAT1), and nuclear factor of activated T cells-5 (NFAT5). In this review, we examine the biogenesis, regulation, validated gene targets and biological effects of miR-486-5p in non-malignant diseases.

Laparoscopic-guided distal loco-regional anesthetic infiltration technique in TAPP inguinal hernia repair: a double-blind randomized clinical trial.

BACKGROUND: Ultrasound-guided transversus abdominis plane block (US-TAP) is an important component of multimodal analgesia in laparoscopic inguinal hernia repair, although it has certain limitations. To overcome them, surgeons have developed several techniques to perform local anesthetic infiltration under laparoscopic guidance, but no trials evaluating these in transabdominal preperitoneal (TAPP) hernia repair were conducted till the date. The aim of this study was to compare the efficacy of a novel laparoscopic-guided local anesthetic infiltration technique (LDAI) with US-TAP in postoperative pain control and analgesic consumption for patients undergoing elective TAPP hernia repair. METHODS: This was a double-blind randomized controlled trial conducted at a single tertiary academic center between 2019 and 2020 on adult patients undergoing elective laparoscopic TAPP inguinal hernia repair. Postoperative pain and analgesic consumption were compared for LDAI vs. US-TAP up to 30 postoperative days. RESULTS: 62 patients were included (31 LDAI, 31 US-TAP). Female gender was significantly higher in the LDAI group (8, 25.81%; US-TAP 0; p = 0.005). Mean anesthetic time (US-TAP group: 142.2 min, SD = 17.7; LDAI group: 127.1 min, SD = 15.5; p < 0.001) and mean operative time (US-TAP group: 117.2 min, SD = 15.9; LDAI group: 103.8 min, SD = 15.2; p < 0.001) were significantly shorter in the LDAI group. Pain scores assessed at the first-hour postoperative, at the moment of discharge, and at 8, 24, and 48 postoperative hours showed no significant differences between both groups. No significant difference was found regarding postoperative analgesic rescue administration in the recovery room and analgesic consumption after discharge between groups. CONCLUSION: LDAI is a safe and effective local anesthetic technique in elective TAPP hernia repair. Pain control is similar to US-TAP block, with shorter anesthesthetic and surgical time and better health resources allocation.

Towards a Non-Contact Method for Identifying Stress Using Remote Photoplethysmography in Academic Environments.

Stress has become a common condition and is one of the chief causes of university course disenrollment. Most of the studies and tests on academic stress have been conducted in research labs or controlled environments, but these tests can not be extended to a real academic environment due to their complexity. Academic stress presents different associated symptoms, anxiety being one of the most common. This study focuses on anxiety derived from academic activities. This study aims to validate the following hypothesis: by using a non-contact method based on the use of remote photoplethysmography (rPPG), it is possible to identify academic stress levels with an accuracy greater than or equal to that of previous works which used contact methods. rPPG signals from 56 first-year engineering undergraduate students were recorded during an experimental task. The results show that the rPPG signals combined with students' demographic data and psychological scales (the State-Trait Anxiety Inventory) improve the accuracy of different classification methods. Moreover, the results demonstrate that the proposed method provides 96% accuracy by using K-nearest neighbors, J48, and random forest classifiers. The performance metrics show better or equal accuracy compared to other contact methods. In general, this study demonstrates that it is possible to implement a low-cost method for identifying academic stress levels in educational environments.

micro-RNA-486-5p protects against kidney ischemic injury and modifies the apoptotic transcriptome in proximal tubules.

Acute kidney injury (AKI) carries high morbidity and mortality, and effective treatments are lacking. Preclinical models support involvement of micro-RNAs (miRs) in AKI pathogenesis, although effects on the kidney transcriptome are unclear. We previously showed that injection of cord blood endothelial colony forming cell-derived exosomes, enriched in miR-486-5p, prevented ischemic AKI in mice. To further define this, we studied direct effects of miR-486-5p in mice with kidney ischemia-reperfusion injury. RNA-Seq was used to compare the impact of miR-486-5p and exosomes on the transcriptome of proximal tubules and kidney endothelial cells 24 hours after ischemia-reperfusion. In mice with AKI, injection of miR-486-5p mimic increased its levels in proximal tubules and endothelial cells, and improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis. Additionally, miR-486-5p inhibited expression of its target phosphatase and tensin homolog, and activated protein kinase B. In proximal tubules, miR-486-5p or exosomes reduced expression of genes associated with ischemic injury and the tumor necrosis factor (TNF) pathway, and altered distinct apoptotic genes. In endothelial cells, genes associated with metabolic processes were altered by miR-486-5p or exosomes, although TNF pathway genes were not affected. Thus, our results suggest that miR-486-5p may have therapeutic potential in AKI.

Sex diversity in proximal tubule and endothelial gene expression in mice with ischemic acute kidney injury.

Female sex protects against development of acute kidney injury (AKI). While sex hormones may be involved in protection, the role of differential gene expression is unknown. We conducted gene profiling in male and female mice with or without kidney ischemia-reperfusion injury (IRI). Mice underwent bilateral renal pedicle clamping (30 min), and tissues were collected 24 h after reperfusion. RNA-sequencing (RNA-Seq) was performed on proximal tubules (PTs) and kidney endothelial cells. Female mice were resistant to ischemic injury compared with males, determined by plasma creatinine and neutrophil gelatinase-associated lipocalin (NGAL), histologic scores, neutrophil infiltration, and extent of apoptosis. Sham mice had sex-specific gene disparities in PT and endothelium, and male mice showed profound gene dysregulation with ischemia-reperfusion compared with females. After ischemia PTs from females exhibited smaller increases compared with males in injury-associated genes lipocalin-2 (Lcn2), hepatitis A virus cellular receptor 1 (Havcr1), and keratin 18 (Krt18), and no up-regulation of SRY-Box transcription factor 9 (Sox9) or keratin 20 (Krt20). Endothelial up-regulation of adhesion molecules and cytokines/chemokines occurred in males, but not females. Up-regulated genes in male ischemic PTs were linked to tumor necrosis factor (TNF) and Toll-like receptor (TLR) pathways, while female ischemic PTs showed up-regulated genes in pathways related to transport. The data highlight sex-specific gene expression differences in male and female PTs and endothelium before and after ischemic injury that may underlie disparities in susceptibility to AKI.

Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.

Administration of human cord blood endothelial colony-forming cells (ECFCs) or their exosomes protects mice against kidney ischemia/reperfusion injury. Here we studied the microRNA (miRNA) content of ECFC exosomes and the role of miRNA transfer in kidney and endothelial cell protection. ECFC exosomes were enriched in miR-486-5p, which targets the phosphatase and tensin homolog (PTEN) and the Akt pathway. In cultured endothelial cells exposed to hypoxia, incubation with ECFC exosomes increased miR-486-5p, decreased PTEN, and stimulated Akt phosphorylation. Exposure of hypoxic endothelial cells to conditioned medium from ECFCs pretreated with anti-miR-486-5p blocked increases in miR-486-5p and phosphorylated Akt, restored expression of PTEN, and enhanced apoptosis. Coculture of endothelial cells with ECFCs enhanced endothelial miR-486-5p levels. Targeting of PTEN by miR-486-5p was observed in endothelial cells, and PTEN knockdown blocked apoptosis. In mice with ischemic kidney injury, infusion of ECFC exosomes induced potent functional and histologic protection, associated with increased kidney miR-486-5p levels, decreased PTEN, and activation of Akt. Infusion of exosomes from ECFCs transfected with anti-miR-486-5p had no protective effect. Thus, delivery of ECFC exosomes reduces ischemic kidney injury via transfer of miR-486-5p targeting PTEN. Exosomes enriched in miR-486-5p could represent a therapeutic tool in acute kidney injury.

Human endothelial colony-forming cells protect against acute kidney injury: role of exosomes.

The administration of certain progenitor cells is protective in experimental acute kidney injury (AKI), and mechanisms may involve the release of paracrine factors. Endothelial colony-forming cells (ECFCs) are endothelial precursor cells with a high proliferative capacity and pro-angiogenic potential. We examined the effects of human umbilical cord blood-derived ECFCs and their extracellular vesicles in a mouse model of ischemic AKI and in cultured human umbilical vein endothelial cells subjected to hypoxia/reoxygenation. In mice with ischemic AKI, administration of ECFCs (i.v.) at the time of reperfusion significantly attenuated increases in plasma creatinine, tubular necrosis, macrophage infiltration, oxidative stress, and apoptosis, without cell persistence in the kidneys. In cultured human umbilical vein endothelial cells, hypoxia/reoxygenation stimulated apoptosis. This effect was inhibited by incubation with conditioned medium or exosomes (40- to 100-nm diameter) derived from ECFCs, but not by microparticles (100- to 1000-nm diameter) or vesicle-depleted conditioned medium. Administration of exosomes (i.v.) directly to mice with ischemic AKI attenuated renal injury, as assessed by plasma creatinine, tubular necrosis, and apoptosis. Taken together, these studies indicate protective effects of human cord blood-derived ECFCs in experimental AKI and suggest that ECFC-derived exosomes may mediate the protective response via inhibition of endothelial cell apoptosis.

Three-Dimensional Printing in Breast Reconstruction: Current and Promising Applications.

Three-dimensional (3D) printing is dramatically improving breast reconstruction by offering customized and precise interventions at various stages of the surgical process. In preoperative planning, 3D imaging techniques, such as computer-aided design, allow the creation of detailed breast models for surgical simulation, optimizing surgical outcomes and reducing complications. During surgery, 3D printing makes it possible to customize implants and precisely shape autologous tissue flaps with customized molds and scaffolds. This not only improves the aesthetic appearance, but also conforms to the patient's natural anatomy. In addition, 3D printed scaffolds facilitate tissue engineering, potentially favoring the development and integration of autologous adipose tissue, thus avoiding implant-related complications. Postoperatively, 3D imaging allows an accurate assessment of breast volume and symmetry, which is crucial in assessing the success of reconstruction. The technology is also a key educational tool, enhancing surgeon training through realistic anatomical models and surgical simulations. As the field evolves, the integration of 3D printing with emerging technologies such as biodegradable materials and advanced imaging promises to further refine breast reconstruction techniques and outcomes. This study aims to explore the various applications of 3D printing in breast reconstruction, addressing current challenges and future opportunities.

Incarcerated left-sided Amyand's hernia and synchronous ipsilateral femoral hernia: first case report.

BACKGROUND: The finding of a vermiform appendix within the peritoneal sac of an inguinal hernia is called Amyand's hernia. The reported incidence of Amyand's hernia and femoral hernia is 1% and 3.8%, respectively. To our knowledge, no cases have been reported in the literature that associate these two entities. We present the first case of incarcerated left-sided Amyand's hernia and synchronous ipsilateral femoral hernia found during emergency surgery. CASE PRESENTATION: A 72-year-old woman was admitted to the Emergency Department for a complicated left inguinal hernia. An inguinotomy was performed that detected a large direct hernial sac and a synchronous femoral hernia. The opening of the inguinal hernia showed the presence of the cecum and the appendix, both without signs of inflammation. The femoral space was evaluated transinguinally, identifying the larger omentum that had slipped into the femoral canal. The primary closure of the posterior wall defect was performed with the McVay technique due to its large size, and then the hernioplasty was completed with a polypropylene mesh. No postoperative complications were reported. CONCLUSIONS: In the context of an incarcerated Amyand's hernia, the decision to perform an appendectomy in addition to hernia repair with or without mesh will depend on intraoperative findings.

Androgen-induced exosomal miR-379-5p release determines granulosa cell fate: cellular mechanism involved in polycystic ovaries.

Polycystic ovarian syndrome (PCOS) is a complex multi-factorial syndrome associated with androgen excess and anovulatory infertility. In the current study, we investigated the role of dihydrotestosterone-induced exosomal miR-379-5p release in determining the destiny of the developing follicles. Our hypothesis was that androgen regulates granulosa cell miR-379-5p content by facilitating its exosomal release in a follicular-stage dependent manner, a process which determines granulosa cell fate. Compared to human non-PCOS subjects, individuals with PCOS exhibit higher follicular fluid free testosterone levels, lower exosomal miR-379-5p content and granulosa cell proliferation. Androgenized rats exhibited lower granulosa cell miR-379-5p but higher phosphoinositide-dependent kinase-1 (PDK1; a miR-379-5p target) content and proliferation. Androgen reduced granulosa cell miR-379-5p content by increasing its exosomal release in preantral follicles, but not in antral follicles in vitro. Studies with an exosomal release inhibitor confirmed that androgen-induced exosomal miR-379-5p release decreased granulosa cell miR-379-5p content and proliferation. Ovarian overexpression of miR-379-5p suppressed granulosa cell proliferation, and basal and androgen-induced preantral follicle growth in vivo. These findings suggest that increased exosomal miR-379-5p release in granulosa cells is a proliferative response to androgenic stimulation specific for the preantral stage of follicle development and that dysregulation of this response at the antral stage is associated with follicular growth arrest, as observed in human PCOS.

Infusion of IL-10-expressing cells protects against renal ischemia through induction of lipocalin-2.

Ischemia/reperfusion injury is a leading cause of acute renal failure triggering an inflammatory response associated with infiltrating macrophages, which determine disease outcome. To repair the inflammation we designed a procedure whereby macrophages that overexpress the anti-inflammatory agent interleukin (IL)-10 were adoptively transferred. These bone marrow-derived macrophages were able to increase their intracellular iron pool that, in turn, augmented the expression of lipocalin-2 and its receptors. Infusion of these macrophages into rats after 1 h of reperfusion resulted in localization of the cells to injured kidney tissue, caused increases in regenerative markers, and a notable reduction in both blood urea nitrogen and creatinine. Furthermore, IL-10 therapy decreased the local inflammatory profile and upregulated the expression of pro-regenerative lipocalin-2 and its receptors. IL-10-mediated protection and subsequent renal repair were dependent on the presence of iron and lipocalin-2, since the administration of a neutralizing antibody for lipocalin-2 or administration of IL-10 macrophages pretreated with the iron chelating agent deferoxamine abrogated IL-10-mediated protective effects. Thus, adoptive transfer of IL-10 macrophages to ischemic kidneys blunts acute kidney injury. These effects are mediated through the action of intracellular iron to induce lipocalin-2.

Therapeutic effects of micro-RNAs in preclinical studies of acute kidney injury: a systematic review and meta-analysis.

AKI has a high mortality rate, may lead to chronic kidney disease, and effective therapies are lacking. Micro-RNAs (miRNAs) regulate biologic processes by potently inhibiting protein expression, and pre-clinical studies have explored their roles in AKI. We conducted a systematic review and meta-analysis of miRNAs as therapeutics in pre-clinical AKI. Study screening, data extraction, and quality assessments were performed by 2 independent reviewers. Seventy studies involving 42 miRNA species were included in the analysis. All studies demonstrated significant effects of the miRNA intervention on kidney function and/or histology, with most implicating apoptosis and phosphatase and tensin homolog (PTEN) signaling. Fourteen studies (20.0%) examined the effect of miRNA-21 in AKI, and meta-analysis demonstrated significant increases in serum creatinine and kidney injury scores with miR-21 antagonism and pre-conditioning. No studies reported on adverse effects of miRNA therapy. Limitations also included lack of model diversity (100% rodents, 61.4% ischemia-reperfusion injury), and predominance of male sex (78.6%). Most studies had an unclear risk of bias, and the majority of miRNA-21 studies were conducted by a single team of investigators. In summary, several miRNAs target kidney function and apoptosis in pre-clinical AKI models, with data suggesting that miRNA-21 may mediate protection and kidney repair.Systematic review registration ID: CRD42019128854.

MicroRNA in Human Acute Kidney Injury: A Systematic Review Protocol.

BACKGROUND: Acute kidney injury (AKI) is a common complication of hospitalization with high morbidity and mortality for which no effective treatments exist and for which current diagnostic tools have limitations for earlier identification. MicroRNAs (miRNAs) are small non-coding RNAs that have been implicated in the pathogenesis of AKI, and some miRNAs have shown promise as therapeutic tools in animal models of AKI. However, less is known about the role of miRNAs in human AKI. OBJECTIVE: To evaluate the role of miRNAs in human subjects with AKI. DESIGN: Systematic review and meta-analysis. MEASUREMENTS: Quantification of miRNA levels from human blood, urine, or kidney biopsy samples, and measures of renal function as defined in the study protocol. METHODS: A comprehensive search strategy for Ovid MEDLINE All, Embase, Web of Science, and CENTRAL will be developed to identify investigational studies that evaluated the relationship between miRNA levels and human AKI. Primary outcomes will include measurements of kidney function and miRNA levels. Study screening, review and data extraction will be performed independently by 2 reviewers. Study quality and certainty of evidence will be assessed with validated tools. A narrative synthesis will be included and the possibility for meta-analysis will be assessed according to characteristics of clinical and statistical heterogeneity between studies. LIMITATIONS: These include (1) lack of randomized trials of miRNAs for the prevention or treatment of human AKI, (2) quality of included studies, and (3) sources of clinical and statistical heterogeneity that may affect strength and reproducibility of results. CONCLUSION: Previous studies of miRNAs in different animal models of AKI have generated strong interest on their use for the prevention and treatment of human AKI. This systematic review will characterize the most promising miRNAs for human research and will identify methodological constraints from miRNA research in human AKI to help inform the design of future studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020201253.

CONTEXTE: L'insuffisance rénale aiguë (IRA) est une complication fréquente des hospitalisations avec morbidité et mortalité élevées. Il n'existe aucun traitement efficace contre l'IRA et les outils diagnostiques actuels qui permettent son dépistage précoce comportent des limites. Les microARN (miARN) sont de petits ARN non codants ayant été impliqués dans la pathogenèse de l'IRA; certains d'entre eux se sont révélés prometteurs comme outils thérapeutiques dans les modèles animaux de l'IRA. Le rôle des miARN dans l'IRA chez l'humain est cependant moins connu. OBJECTIF: Évaluer le rôle des miARN chez les sujets humains atteints d'IRA. TYPE D'ÉTUDE: Examen systématique et méta-analyze. MESURES: La quantification des taux de miARN chez l'humain à partir d'échantillons de sang, d'urine ou de biopsie rénale, et mesure de la fonction rénale telle que définie dans le protocole de l'étude. MÉTHODOLOGIE: Une stratégie de recherche exhaustive des bases de données Ovid MEDLINE All, Embase, Web of Science et CENTRAL sera élaborée afin de répertorier les études expérimentales ayant évalué la relation entre les taux de miARN et l'IRA chez l'humain. Les principaux critères d'évaluation comprendront la mesure de la fonction rénale et des taux de miARN. Deux examinateurs procéderont de façon indépendante à la sélection des études, à leur examen et à l'extraction des données. La qualité des études et la robustesse des données seront évaluées à l'aide d'outils validés. Une synthèse descriptive sera incluse et la possibilité d'une méta-analyze sera évaluée en fonction des caractéristiques de l'hétérogénéité clinique et statistique entre les études. LIMITES: Les limites de l'étude concernent notamment (i) le manque d'essais randomisés examinant les miARN pour la prévention ou le traitement de l'IRA humaine; (ii) la qualité des études incluses; et (iii) les sources d'hétérogénéité clinique et statistique susceptibles d'affecter la robustesse et la reproductibilité des résultats. CONCLUSION: Des études antérieures sur les miARN dans différents modèles animaux de l'IRA ont suscité un vif intérêt pour leur utilization dans la prévention et le traitement de l'IRA chez l'humain. Cet examen systématique caractérisera les miARN les plus prometteurs pour la recherche sur l'IRA humaine et définira les contraintes méthodologiques de telles études, ce qui aidera à orienter la conception des études futures.

Inhibitory action of Wnt target gene osteopontin on mitochondrial cytochrome c release determines renal ischemic resistance.

Certain determinants of ischemic resistance in the Brown Norway rat strain have been proposed, but no studies to date have focused on the role of the Wnt pathway in the ischemic resistance mechanism. We performed a comparative genomic study in Brown Norway vs. Sprague-Dawley rats. Selective manipulations of the Wnt pathway in vivo and in vitro allowed us to study whether the action of the Wnt pathway on apoptosis through the regulation of osteopontin was critical to the maintenance of inherent ischemic resistance mechanisms. The results revealed a major gene upregulation of the Wnt family in Brown Norway rats after renal ischemia-reperfusion. Manipulation of the Wnt signaling cascade by selective antibodies increased mitochondrial cytochrome c release and caspase 3 activity. The antiapoptotic role of Wnt was mediated by osteopontin, a direct Wnt target gene. Osteopontin was reduced by Wnt antibody administration in vivo, and osteopontin gene silencing in vitro significantly increased mitochondrial cytochrome c release. The overexpression of Wnt pathway genes detected in Brown Norway rats is critical in the maintenance of their inherent ischemic resistance. Activation of the Wnt signaling cascade reduces mitochondrial cytochrome c release and caspase 3 activity through the action of osteopontin.

Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects.

Pelizaeus-Merzbacher Disease is an X-linked hypomyelinatiing leukodystrophy. We report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53 families affected by hypomyelinating leukodystrophies of unknown aetiology. The 12 MCT8 mutated patients express initially a Pelizaeus-Merzbacher-Like disease phenotype with a latter unusual improvement of magnetic resonance imaging white matter signal despite absence of clinical progression. This observation underlines the interest of determining both free T3 and free T4 serum concentrations to screen for MCT8 mutations in young patients (<3 y) with a severe Pelizaeus-Merzbacher-Like disease presentation or older severe mentally retarded male patients with "hypomyelinated" regions.

Thoracic Aortic Pseudoaneurysm Due to Screw Dislodgment Following Anterior Spinal Approach. Complex Surgical Management of Both Issues: A Case Report and Review of Literature.

A few descriptions about anterior thoracic arthrodesis causing thoracic aortic pseudoaneurysms due to late screw loosening are mentioned in the literature. We report a case that describes a hybrid approach complicated with an aortic injury when removing a screw from the aortic wall. A 57-year-old man was initially operated on for scoliosis due to poliomyelitis using dorsal thoracolumbar in situ fusion at an early age. At adulthood, the patient complained of spinal cord compression and severe myelopathy due to D9-D10 nonunion, and the patient required a double surgical approach. Almost a year later, he was diagnosed with a thoracic aneurysm caused by late screw loosening from the anterior plate. A hybrid approach was used to treat the aortic pseudoaneurysm (endograft stent) and for anterior vertebral hardware removal (rethoracotomy). Although an aortic stent was covering the aortic lumen, during the open part of the procedure, an aortic injury took place when removing the screw, requiring quick cross clamping and repair. Anterior vertebral hardware removal after a previous anterior spinal approach is a technically highly demanding procedure. As unexpected life-threatening complications can occur, this procedure should be performed in a setting with the capacity for both endovascular and open aortic repair.

Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury.

The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process.

The therapeutic effects of microRNAs in preclinical studies of acute kidney injury: a systematic review protocol.

BACKGROUND: Acute kidney injury (AKI) causes significant morbidity and mortality in humans, and there are currently no effective treatments to enhance renal recovery. MicroRNAs (miRNAs) are short chain nucleotides that regulate protein expression and have been implicated in the pathogenesis of AKI. Recently, preclinical studies in vivo have uncovered a therapeutic role for administration of specific miRNAs in AKI. However, the overall benefits of this strategy in preclinical studies have not been systematically reviewed, and the potential for translation to human studies is unclear. AIM: The primary aim is to conduct a systematic review of the therapeutic properties of miRNAs in preclinical studies of AKI. The secondary aim is to determine potential adverse effects of miRNA administration in these studies. METHODS: A comprehensive search strategy will identify relevant studies in AKI in vivo models, using the MEDLINE, EMBASE, OVID, PUBMED, and Web of Science databases. The search strategy will include terms for mammalian (non-human) AKI models, including injury related to ischemia/reperfusion, nephrotoxicity, sepsis, contrast agents, cardio-pulmonary bypass, and hemorrhagic shock. Interventions will be defined as direct administration of exogenous miRNAs or antagonists of miRNAs, as well as maneuvers that alter expression of miRNAs that are mechanistically linked to AKI outcomes. The primary outcomes will be indices of kidney function and structure, and there will be no restriction on comparator interventions. Two independent investigators will initially screen abstracts, and selected articles that meet eligibility criteria will be reviewed for data abstraction and analysis. The SYRCLE RoB tool for animal studies will determine risk of bias, and meta-analysis will be performed as appropriate. The GRADE methodology will assess the quality of evidence. DISCUSSION: The administration of selective miRNA mimics or antagonists exerts beneficial effects in mammalian models of AKI, although multiple obstacles must be addressed prior to translation to human clinical trials. The proposed systematic review will document key miRNA candidates, and determine effect size estimates and sources of outcome bias. The review will also identify gaps in knowledge and guide future directions in AKI research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128854.