Targeting IL-6 trans-signalling by sgp130Fc attenuates severity in SARS-CoV-2 -infected mice and reduces endotheliopathy.

BACKGROUND: SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling. METHODS: To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc. FINDINGS: We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling. INTERPRETATION: IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19. FUNDING: The project was supported by ISCIII, Spain (COV-20/00792 to MB, PI23/01351 to MARH) and the European Commission-Next generation EU (European Union) (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global, SGL2103029 to MB). PID2019-110587RB-I00 (MB) supported by MICIN/AEI/10.13039/501100011033/and PID2022-143034OB-I00 (MB) by MICIN/AEI/10.13039/501100011033/FEDER. MAR-H acknowledges support from ISCIII, Spain and the European Commission-Next generation EU (European Union), through CSIC's Global Health PTI.

Proof of concept, design, and manufacture via 3-D printing of a mesh with bactericidal capacity: Behaviour in vitro and in vivo.

Currently, hernia treatment involves implantation of a mesh prosthesis, usually made of polypropylene, and the primary complication is infection of the device, which leads to an exponential increase in morbidity. Three-dimensional printing offers a method of dealing with complications of this magnitude. Therefore, in this study, the bactericidal properties and effectiveness of three-dimensional-printed meshes with polycaprolactone (PCL) and gentamicin were evaluated in vitro in Escherichia coli cultures, and their histological behaviour was examined in vivo. Different PCL meshes were implanted into four groups of rats, with 10 rats in each group: PCL meshes, PCL meshes with alginate and calcium chloride, PCL meshes with gentamicin, and PCL meshes with alginate and gentamicin. Thirty-six microporous meshes were manufactured, and their bactericidal properties were assessed. When the meshes did not include an antibiotic, an inhibition halo was not observed; when the gentamicin was free, an asymmetric inhibition area of 5.65 ± 0.46 cm2 was present; when the gentamicin was encapsulated, a rectangular area of 5.40 ± 0.38 cm2 was observed. In the rats, macroporous and microporous mesh implants produced mild inflammation and substantial fibrosis with collagen and neovascular foci. A significant difference was observed in fibroblastic activity between the PCL with alginate group and the PCL with alginate and gentamicin group microporous meshes (p = .013) and in collagen deposits between the macroporous and microporous meshes in the PCL mesh group (p = .033). The feasibility of manufacturing drug-doped printed PCL meshes containing alginate and gentamicin was verified, and the meshes exhibited bactericidal effects and good histopathological behaviour.

Platelet-rich plasma (PRP) versus fibrin glue in cryptogenic fistula-in-ano: a phase III single-center, randomized, double-blind trial.

PURPOSE: To compare the clinical outcome of autologous platelet-rich growth factor (PRP) with commercial fibrin glue in the management of high cryptogenic fistulae-in-ano. METHOD: The study was conducted at a single center between July 2012 and July 2015 and performed as a phase III, randomized, double-blind comparison of autologously prepared PRP versus fibrin glue for cryptoglandular anal fistulae without active sepsis. Patients were assessed with clinical and endosonographic follow-up. Patients were followed up at 1 week and then at 3, 6, and 12 postoperative months. The primary outcome measure was the fistula healing rate (complete, partial, and non-healing) with secondary outcome measures assessing fistula recurrence, continence status, quality of life, and visual analog pain scores. RESULTS: Of the 56 enrolled patients, 32 were PRP-treated and 24 were fibrin-treated. The groups were well matched for fistula type with an improved overall healing rate for PRP-treated over fibrin-treated cases (71% vs. 58.3%, respectively; P = 0.608); a complete healing rate of 48.4% vs. 41.7%, respectively; and a partial healing rate of 22.6% vs. 16.7%, respectively. The median pain scores of PRP-treated patients were lower at the first visit with a greater initial pain decrease early during follow-up. Improvements in pain reduction impacted the quality of life measures (P = 0.035). All adverse events were minor and no patient experienced a negative impact on continence. CONCLUSION: Treatment of complex cryptoglandular anal fistula with autologous PRP is as effective as fibrin glue with less cost and no adverse effect on continence.

Local Mesenchymal Stem Cell Therapy in Experimentally Induced Colitis in the Rat.

BACKGROUND: Multipotent mesenchymal stem cells (MSCs) have been used in inflammatory bowel diseases because of their immunomodulatory and regenerative properties. We investigated their local use in an experimental model of colitis in the rat. MATERIALS AND METHODS: Colitis was induced into 20 Wistar rats with local TNBS instillation. Allogeneic stem cells were derived from rat adipose tissue and labeled with PKH2 linker dye with creation of a control and a second group treated by a local injection into the rectal wall of 2×106 allogeneic adipose tissue-derived stem cells (ADSCs). The thicknesses of different components of the rectum were measured with comparisons made in different parts of the colon of the Hunter inflammatory score. PKH2-dyed ADSCs were detected by fluorescence microscopy. RESULTS AND CONCLUSIONS: Total colitis was induced in 19/20 rats with homing of fluorescent ADSCs. to the crypt base and perivascular space of the submucosa. There were no differences in component rectal wall thicknesses with a higher Hunter score in the treated group compared with the controls, in the rectum (3.8±2.74 vs. 1.5±2.37, respectively; p=0.017) and in right colon (2.5±1.08 vs. 0.20±0.42, respectively; p=0.0001). Local colonic injection of allogeneic adipose stem cells. in experimental colitis is feasible and safe. There is demonstrable homing of cells in chemically-induced colitis both to the treated region and parts of the colon distant to the MSC treatment site. Such cells readily proliferate in vitro and could potentially be a source for future treatment of resistant disease.

Post-transplant lymphoproliferative disease in liver transplant recipients.

INTRODUCTION: Post-transplant lymphoproliferative syndrome (PTLD) is a rare and potentially life-threatening complication after liver transplantation. The aim of this study was to analyze the clinicopathologic features related to PTLD in a single institution after liver transplantation. METHODS: Observational study where we have retrospectively analyzed 851 cases who underwent liver transplantation. Ten cases have developed PTLD. Their clinical-pathological characteristics and the treatment received have been analyzed. RESULTS: PTLD incidence was 1.2% (10/851). The mean time from liver transplantation to PTLD diagnosis was 36 months (range 1.2 to 144 months). PTLD localization was extranodal in all cases, the most frequent location being intestinal. Seven cases showed a monomorphic lymphoma which in all cases was differentiated B cell lymphomas. Fifty per cent of the series were seropositive for Epstein-Barr virus. Five patients were alive at the time of the review. Among these patients, we observed three cases of complete remission and two cases of disease stabilization. The death rate was higher in the first year after diagnosis of PTLD. CONCLUSION: PTLD is a rare complication after liver transplantation, but it may pose a threat to the life of a liver transplant recipient. It is essential to identify patients at risk, to establish an early diagnosis and treatment that can change the outcome of the disease.

Oxidative stress influence on renal dysfunction in patients with obstructive jaundice: A case and control prospective study.

BACKGROUND: Obstructive Jaundice (OJ) is associated with a significant risk of developing acute renal failure (ARF). The involvement of oxidative stress in the development of cholestasis has been demonstrated in different experimental models. However, its role in the morbidity of human cholestasis is far to be elucidated. The aim of the study was the evaluation of oxidative stress markers in blood from patients with OJ and its relation to complications and benign/malignant evolution of cholestasis. METHODS: A prospective cross-sectional study of 105 patients with OJ and 34 control subjects were included. Several markers of liver function and oxidative stress, such as lipoperoxides (LPO), as well as reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were assessed. RESULTS: The patients with OJ showed a marked increase in plasma levels of LPO, SOD and GSH, while GSH-Px levels were decreased. The increase in lipid peroxidation products and the depletion of SOD activity in blood were also related to renal dysfunction. The highest level of LPO was associated with malignant etiology of the disease. The logistic regression analysis showed that the age of the patient and the levels of LPO in blood were predictors of renal dysfunction in OJ patients. CONCLUSIONS: This study demonstrates a correlation between oxidative stress and renal dysfunction patients with OJ.

Magnetic-assisted single-port sleeve gastrectomy.

BACKGROUND: Sleeve gastrectomy is a recent, purely restrictive procedure in bariatric surgery that has shown results similar to gastric bypass over the short and middle term. At the same time, single-port access surgery has fostered the development of new techniques and methods seeking better cosmetic results and less postoperative pain, while maintaining the satisfactory results obtained by the standard laparoscopic approach. One of the problems associated to single-access surgery is the lack of traction and the difficulties to retract the liver. The authors' aim was to try to avoid additional trocars or sutures in order to perform pure single-incision surgery, using 2 magnetic forceps. METHODS: The authors present the case of a 51-year-old morbidly obese female (body mass index = 44.82) who underwent a pure single-access laparoscopic sleeve gastrectomy with no additional trocars or sutures and assisted by 2 neodymium magnetic forceps: one to retract the liver and the other to retract the stomach in order to provide sufficient triangulation for adequate exposure of the surgical field during dissection. RESULTS: The procedure was completed in 120 minutes. No preoperative or postoperative complications were recorded, and the patient was discharged 2 days after surgery. CONCLUSION: Single-port access sleeve gastrectomy assisted by magnetic forceps is feasible and safe in the hands of experienced laparoscopic surgeons, solving one of the problems associated to this type of surgery, that is, the need for an additional trocar and needles or sutures to retract the liver and stomach in order to perform the operation.

Adenocarcinoma mucinoso sobre fístula anorrectal en paciente con enfermedad de Crohn / No disponible

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Conservative management of perforated duodenal diverticulum: a case report and review of the literature.

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.

Beneficial properties of melatonin in an experimental model of pancreatic cancer.

Pancreatic cancer is a major health problem because of the aggressiveness of the disease and the lack of effective systemic therapies. Melatonin has antioxidant activity and prevents experimental genotoxicity. However, the effect of melatonin in pancreatic cancer has not been tested. Pancreatic carcinogenesis was induced by N-nitrosobis (2-oxopropyl)amine (BOP) in Syrian hamsters. Melatonin was administered during the BOP-induction phase (12 wk) and/or following the postinduction phase (12 wk). Different parameters of oxidative stress including lipid peroxides (LPO) and antioxidants (superoxide dismutase, catalase, reduced glutathione and glutathione peroxidase) were determined in pancreatic tissue. Also, the presence of atypical hyperplasia (AH), well and moderately differentiated adenomacarcinoma (ADC-WD and ADC-MD, respectively) were studied. The administration of BOP induced an intense oxidative stress and ADC induction in the pancreas. The administration of melatonin during the induction or postinduction phase reduced LPO and improved the antioxidant status, as well as drastically reducing the presence of ADC but some AH remained. In conclusion, treatment with melatonin reduced oxidative damage and cancer nodules induced by BOP in the pancreas.