José Miguel Lloris-Carsí

Pentoxifylline in Liver Ischemia and Reperfusion

ABSTRACT Pentoxifylline is a methylxanthine compound which was first filed in 1973 and registered in 1974 in the United States by Sanofi-Aventis Deustchland Gmbh for the treatment of intermittent claudication for chronic occlusive arterial disease. This methylxanthine was later discovered to be a phosphodiesterase inhibitor. Furthermore, its hemorheological properties and its function as an inhibitor of inflammatory cytokines, like TNF-α, allowed researchers to study its effects in organ ischemia and reperfusion and transplantation. Although this drug has demonstrated beneficial effects, the mechanisms by which Pentoxifylline exerts a protective effect are not fully understood. This paper focuses on reviewing the literature to define the effect of Pentoxifylline when used in liver ischemia and reperfusion injury. Our research shows different animal models in which Pentoxifylline has been used as well as different doses and time of administration, as the ideal dose and timing have not yet been ascertained in liver ischemia and reperfusion. In conclusion, Pentoxifylline has shown positive effects in liver ischemia and reperfusion injury, and the main mechanism seems to be associated with the inhibition of TNF-α.

Allopurinol Protective Effect of Renal Ischemia by Downregulating TNF-α, IL-1β, and IL-6 Response

ABSTRACT Allopurinol is a well-known antioxidant that protects tissue against ischemia and reperfusion injury, blocking purine catabolism, and possibly reducing TNF-α and other cytokines. It also plays a significant role in reducing the inflammatory processes by inhibiting chemotaxis and other inflammatory mediators. The objective of this study was to define the role of allopurinol regarding kidney ischemic injury particularly as to its effect on inflammatory molecules such as TNF-α, IL-1β, and IL-6 response. One hundred and twenty five rats were subjected to warm renal ischemia. Five more animals were included as sham. Animal survival and plasma levels of lipid peroxidation, myeloperoxidase, lactate dehydrogenase, glutathione, urea, creatinine, and cytokines were determined. Inflammatory parameters (TNF-α, IL-1β, and IL-6) were measured in all groups by quantitative immunosorbent assay. Further, immunohistological and histopathological studies were carried out on animals treated prior to, or following reperfusion with 10 and 50 mg/kg of Allopurinol. The statistical analysis included ANOVA and Fisher test as well as χ2 test. Significance was reached at a p < 0.05. The results of this study indicated that Allopurinol protected against kidney ischemia–reperfusion injury since significantly better results of survival, biochemical analysis, and histopathological testing were observed in treated animals as compared to ischemic controls. In conclusion, Allopurinol protected ischemic kidneys through a mechanism associated with downregulation of TNF-α, IL-1 β, and IL-6, in addition to other well-known effects such as decreased lipid peroxidation and neutrophil activity. It also increased antioxidant capacity and diminished endogenous peroxidase stain in renal ischemic tissue. Therefore, this experiment showed an effectiveness of allopurinol protection against proteomic and morphological damage.

Antioxidant potential of Himanthalia elongata for protection against ischemia-reperfusion injury in the small bowel

Background: Seaweed has been associated with the prevention and/or treatment of various diseases related to oxidative stress because of its antioxidant activity. We investigated the protective potential of extract of Himanthalia elongata against ischemia‐reperfusion (I/R) injury in the intestine of rats. Methods: Seventy‐two (72) male Wistar albino rats were randomly assigned into 12 groups as follows: sham, I/R only, I/R plus vehicle at 3 time points, and I/R plus extract at 3 time points. The degree of intestinal injury was determined by oxidative stress using lipid peroxidation, superoxide dismutase, catalase, and glutathione peroxidase after mesenteric ischemia‐reperfusion. A histological study was also performed. Results: The algae extract helps to maintain normal enzymatic levels because, for all the studied parameters, groups treated with the extract showed significant differences (P < .05) compared with the I/R groups, and there were no differences compared with the sham group. The histological study showed that damage to the intestinal mucosa was less severe in animals treated with extract of H elongata after up to 24 hours of reperfusion compared with the I/R group. Conclusion: These results suggest that the extract of H elongata can protect intestinal tissue against ischemia‐reperfusion injury.

Randomized clinical trial of a new cyanoacrylate flexible tissue adhesive (Adhflex) for repairing surgical wounds.

The use of synthetic adhesives such as cyanoacrylates for closing surgical wounds remains controversial. In a multicenter, prospective and randomized clinical trial, we compared a new cyanoacrylate elastic tissue adhesive, Adhflex, with standard suturing methods for repairing surgical wounds. Sixty patients who underwent surgery for inguinal hernia were randomly chosen for Adhflex or standard silk suture. We evaluated wound closure time and parameters related to wound healing and complications using the Hollander Scale; overall surgeon, patient, and independent evaluator satisfaction with scar appearance using a visual analog scale; and scar cosmesis and cosmetic outcome using the Patient and Observer Scar Assessment Scale. The major finding of this study was that surgical wound closure time (minutes) was significantly lower (p < 0.05) when using Adhflex (1.50 ± 0.63) than when using sutures (2.23 ± 0.66), reducing surgery costs. Patient, surgeon and independent evaluator satisfaction was greater with Adhflex (p < 0.05). No differences were found in the final cosmetic outcome of surgical wounds (p > 0.05). The results of this clinical trial showed that Adhflex could be considered a promising and suitable wound closure method. Undoubtedly, lower operating room times will reduce overall surgical costs. Cosmetic outcomes in the medium term are comparable to those seen with sutures, yet there is no need for dressing changes, postoperative wound checks, or removal of stitches or clips. The comfort of the patient is an important factor when considering wound closure methods. Registration number: Eudra CT2012‐002701‐22.

Pharmacology of Ischemia-Reperfusion. Translational Research Considerations.

ABSTRACT Ischemia–reperfusion (IRI) is a complex physiopathological mechanism involving a large number of metabolic processes that can eventually lead to cell apoptosis and ultimately tissue necrosis. Treatment approaches intended to reduce or palliate the effects of IRI are varied, and are aimed basically at: inhibiting cell apoptosis and the complement system in the inflammatory process deriving from IRI, modulating calcium levels, maintaining mitochondrial membrane integrity, reducing the oxidative effects of IRI and levels of inflammatory cytokines, or minimizing the action of macrophages, neutrophils, and other cell types. This study involved an extensive, up-to-date review of the bibliography on the currently most widely used active products in the treatment and prevention of IRI, and their mechanisms of action, in an aim to obtain an overview of current and potential future treatments for this pathological process. The importance of IRI is clearly reflected by the large number of studies published year after year, and by the variety of pathophysiological processes involved in this major vascular problem. A quick study of the evolution of IRI-related publications in PubMed shows that in a single month in 2014, 263 articles were published, compared to 806 articles in the entire 1990.

Behaviour of the Biological Adhesives TachoSil®, GelitaSpon®, and a New Elastic Cyanoacrylate (Adhflex®) in Experimental Renal Trauma and Wound Healing

Background: Renal injuries are relatively frequent in abdominal trauma. In some cases, adhesives and sealants can be used to repair and preserve injured organs. This paper describes the behaviour of three biomaterials - TachoSil®, GelitaSpon®, and a new elastic cyanoacrylate (CyA), Adhflex® - in standardized experimental renal injuries. Methods: Ninety male Wistar rats (300-350 g) were used. A Stiefel Biopsy Punch (8 mm diameter, 3 mm depth) was used to create injuries to the anterior kidney to evaluate wound healing. The animals were divided into five groups: (1) sham (n = 3); (2) control (n = 6), untreated, standard punch injury created on the anterior left kidney; (3) TachoSil® (n = 27), punch injury treated with TachoSil®; (4) GelitaSpon® (n = 27), punch injury treated with GelitaSpon®, and (5) Adhflex® (n = 27), punch injury treated with the new elastic CyA adhesive. The parameters studied were bleeding time, peritoneal adhesions, and histopathological evaluation of wound healing on days 2, 6, and 18, including measurements of the gap between wound edges, inflammatory reaction (CD68), and vascular neoformation (CD31). Results: The bleeding time was significantly shorter (27.7 ± 12.9 s) in the Adhflex® group than in the control (135.8 ± 11.6 s; p < 0.01), TachoSil® (77.5 ± 7.4 s; p < 0.05), and GelitaSpon® (82.5 ± 14.4 s; p < 0.05) groups. The incidence of intraperitoneal adhesions in the animals treated with Adhflex® was 3.6 times higher than in the non-treated group. It was also higher (p < 0.04) than in the groups treated with TachoSil® and GelitaSpon®. The time point with the largest gap between the wound edges and most abundant granulation tissue was at day 6. The largest gap after 18 days was reported for the Adhflex® adhesive. With regard to the markers CD31 and CD68, Adhflex® showed the largest areas 2 days after surgery, but no differences were found after 6 and 18 days versus the other treatments. The expression of the immunomarkers on the renal samples treated with Adhflex® was consistent with a normal healing process. Conclusions: In this experimental model of renal injuries, the new elastic CyA (Adhflex®) resulted in the shortest bleeding time. It offers rapid sealing of the bleeding produced by renal injuries, fixation to adjacent tissues, and reduced occurrences of relapse. The evolution of the scarring is similar to other procedures. Given that traumatic renal injuries are always an emergency due to haemorrhage, Adhflex® might offer additional benefits over conventional treatment methods in human clinical practice.

Multivariate methods in research.

ABSTRACT Univariate methods are very helpful when utilized appropriately within the research analysis. However, there are many occasions in which only multivariate methods will satisfy an optimal assessment. In this case, multivariate methods will permit the researcher to incorporate many variables within a single research analysis. This work reviews the use of multivariate methods and how to apply them in clinical medicine.

The effect of adhesives on inflammatory immune-markers during renal injury healing: ADHESIVES AND INFLAMMATORY IMMUNE-MARKERS IN RENAL INJURY HEALING

Renal injury is common in abdominal trauma. Adhesives and sealants can be used to repair and preserve damaged organs. We describe the effect of three biomaterial treatments (TachoSil, GelitaSpon, and Adhflex) on injured renal tissue. Renal traumatic injuries were experimentally induced in male Wistar rats (n = 90) using a punch. Animals were divided into five groups: (1) sham noninjured (n = 3) and punch injury groups; (2) nontreated (n = 6); (3) TachoSil (n = 27); (4) GelitaSpon (n = 27); and (5) Adhflex (n = 27). Wound healing was evaluated 2, 6, and 18 days postinjury by inflammatory cytokines response, histopathological evolution of lesions, inflammatory reaction markers (CD68), and vascular neoformation (CD31). The TachoSil group showed the least inflammatory reaction among the three treated groups, which showed similarly low inflammatory reaction 18 days postinjury. Ciliary neurotrophic factor, soluble intercellular adhesion molecule-1, L-selectin, thymus chemokine, and TIMP metallopeptidase inhibitor 1 expression peaked between 2 and 6 days postinjury. TachoSil promoted the highest cytokine expression. The Adhflex group had the highest CD31 inflammatory immune-marker levels at 2 and 6 days postinjury, but there was a similar decrease in CD31 levels in all three groups at 18 days postinjury. The results show that all three sealant treatments induced a normal healing process with the typical pattern of proinflammatory cytokine and immune-marker expression. Each tested sealant substance could be suitable treatment for renal lacerations. The findings of this study indicate that Adhflex® elastic cyanoacrylate does not induce an adverse inflammatory reaction, and therefore, could be considered as one of the first-line treatments for renal injuries.

The effect of biological sealants and adhesive treatments on matrix metalloproteinase expression during renal injury healing

Background Renal injuries are relatively common in cases of abdominal trauma. Adhesives and sealants can be used to repair and preserve damaged organs. Using a rat model, this study explores the activity of different matrix metalloproteinases (MMP) during the healing of renal injuries treated by two biological adhesives (TachoSil and GelitaSpon) and a new synthetic elastic cyanoacrylate (Adhflex). Methods Renal traumatic injuries were experimentally induced in 90 male Wistar rats by a Stiefel Biopsy Punch in the anterior aspect of the left kidney. Animals were divided into five groups: 1, sham non-injured (n = 3); 2, non-treated standard punch injury (n = 6); 3, punch injury treated with TachoSil (n = 27); 4, punch injury treated with GelitaSpon (n = 27); and, 5, punch injury treated with Adhflex (n = 27). Wound healing was evaluated 2, 6, and 18 days after injury by determining the expression of MMPs, and the histopathological evolution of lesions. Findings Histologically, the wound size at 6 days post-injury was larger in Adhflex-treated samples than in the other treatments, but the scarring tissue was similar at 18 days post-injury. Only the MMPs subtypes 1, 2, 8, 9, and 13 were sufficiently expressed to be quantifiable. Both time since injury and treatment type had a significant influence on MMPs expression. Two days after injury, the expression of MMP8 and MMP9 was predominant. MMP2 expression was greater 6 days after injury. The Adhflex-treated group had a significantly higher MMPs expression than the other treatment groups at all healing stages. Conclusions All three sealant treatments induced almost similar expression of MMPs than untreated animals indicating a physiological healing process. Given that all renal trauma injuries must be considered emergencies, both biological and synthetic adhesives, such as Adhflex, should be considered as a treatment options.

Contents Vol. 56, 2016

I. Alwayn, Halifax D.K. Bartsch, Marburg C. Bassi, Verona W.O. Bechstein, Frankfurt am Main J.A. Bradley, Cambridge M. Cikirikcioglu, Geneva P.-A. Clavien, Zurich U. Dahmen, Jena R.W.F. de Bruin, Rotterdam S. Fichtner-Feigl, Regensburg H. Friess, Munich G. Galata, London D.J. Gouma, Hilversum J.K. Habermann, Lübeck M. Heberer, Basel M. Heger, Amsterdam T. Hubert, Lille W.R. Jarnagin, New York, N.Y. J.C. Kalff, Bonn M.W. Laschke, Homburg/Saar H.-A. Lehr, Friedrichshafen C.M. Malata, Cambridge T. Minor, Bonn M. Morino, Torino J. Pirenne, Leuven A. Schachtrupp, Melsungen T. Schmitz-Rixen, Frankfurt a.M. R. Schramm, Munich L. Steinstraesser, Oldenburg A. Szijártó, Budapest R.H. Tolba, Aachen M. van Griensven, Munich T.M. van Gulik, Amsterdam M.A. Venermo, Helsinki M.H. Wilhelmi, Hannover D.C. Winter, Dublin Y. Yamamoto, Akita Clinical and Experimental Surgery