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PURPOSE Ostomy creation is often an integral part of the surgical management of various diseases including colorectal malignancies and inflammatory bowel disease. Stoma and peristomal complications may occur in up to 70% of patients following ostomy surgery. The aim of this scoping literature review was to synthesize evidence on the risk factors for developing complications following creation of a fecal ostomy. DESIGN Scoping literature review. SEARCH STRATEGY Two independent researchers completed a search of the online bibliographic databases PubMed, MEDLINE, Cochrane, Google Scholar, and EMBASE for all articles published between January 1980 and December 2018. The search comprised multiple elements including systematic literature reviews with meta-analysis of pooled findings, randomized controlled trials, cohort studies, observational studies, other types of review articles, and multiple case reports. We screened 307 unique titles and abstracts; 68 articles met our eligibility criteria for inclusion. The methodological rigor of study quality included in our scoping review was variable. FINDINGS/CONCLUSIONS We identified 6 risk factors associated with an increased likelihood of stoma or peristomal complications (1) age more than 65 years; (2) female sex; (3) body mass index more than 25; (4) diabetes mellitus as a comorbid condition; (5) abdominal malignancy as the underlying reason for ostomy surgery; and (6) lack of preoperative stoma site marking and WOC/ostomy nurse specialist care prior to stoma surgery. We also found evidence that persons with a colostomy are at a higher risk for prolapse and parastomal hernia. IMPLICATIONS Health care professionals should consider these risk factors when caring for patients undergoing fecal ostomy surgery and manage modifiable factors whenever possible. For example, preoperative stoma site marking by an ostomy nurse or surgeon familiar with this task, along with careful perioperative ostomy care and education of the patient by an ostomy nurse specialist, are essential to reduce the risk of modifiable risk factors related to creation of a fecal ostomy.

Morphine and related drugs, which are the most effective analgesics for the relief of severe pain, act through activating opioid receptors. The endogenous ligands of these receptors are opioid peptides which cannot be used as antinociceptive agents due to their low bioactivity and stability in biological fluids. The major goal of opioid research is to understand the mechanism of action of opioid receptor agonists in order to improve therapeutic utility of opioids. Analgesic effects of morphine are mediated mostly through activation of the mu opioid receptor. However, in the search for safer and more effective drug candidates, analogs with mixed opioid receptor profile gained a lot of interest. Recently, the concept of biased agonists able to differentially activate GPCR downstream pathways, became a new approach in the design of novel drug candidates. It is hypothesized that compounds promoting G-protein signaling may produce analgesia while β-arrestin recruitment may be responsible for opioid side effects. In this report we showed that replacement of the tyrosine residue in the mu-selective ligand Tyr-c[d-Lys-Phe-Asp]NH2 with 2',6'-dimethyltyrosine (Dmt) produced a cyclopeptide Dmt-c[d-Lys-Phe-Asp]NH2 with mu/delta opioid receptor agonist profile. This analog showed improved antinociception in the hot-plate test, probably due to the simultaneous activation of mu and delta receptors but also significantly inhibited the gastrointestinal transit. Using the bioluminescence resonance energy transfer (BRET) assay it was shown that this analog was a mu receptor agonist biased toward β-arrestin. β-Arrestin-dependent signaling is most likely responsible for the observed inhibition of gastrointestinal motility exerted by the novel cyclopeptide. This work was supported by the Polpharma Scientific Foundation grant (11/XIII/2014 to KG) and grants from the Medical University of Lodz (No 503/1-156-02/503-11-002 and 502-03/1-156-02/502-14-301) and from the University of Ferrara (FAR grant to G.C.). KG is recipients of the Polish L’Oréal UNESCO Awards for Women in Science.

Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure&ndash, activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.

Bacterial cellulose modified with chitosan (MBC) is an innovative biomaterial used in regenerative medicine which may potentially improve treatment outcomes mesh for hernia repair surgery by facilitating better absorption in native tissue with less risk of mesh-related infections. The aim of the present study was to evaluate the biocompatibility of mesh based on MBC, and determine whether immunological reactions occur due to hypersensitivity to the implants. Forty five Imp:WIST rats were randomly assigned to be implanted with one of three mesh types: simple polypropylene mesh (n = 15), mesh modified by bacterial cellulose only (n = 15) and MBC mesh (n = 15) and evaluated after one and three months following intramuscular implantation. For MBC mesh, basic toxicological studies, i.e. Acute Dermal Irritation, Intradermal Reactivity and Acute Sensitization (GPMT), were also carried out on 9 Imp:BN albino rabbits and 15 Imp:D-H guinea pigs. The lowest immune response and the highest degree of fibroplasia were observed for MBC mesh both after one and three months after implantation. Toxicological studies classified the tested MBC mesh as a barely perceptible irritant with no signs of sensitization or allergic reactions observed during the studies. The findings indicate that MBC mesh does not irritate, does not sensitize and does not cause hypersensitivity in the implant site, and therefore presents a low risk of provoking such reactions in humans.

Morphine and related drugs, which are the most effective analgesics for the relief of severe pain, act through activating opioid receptors. The endogenous ligands of these receptors are opioid peptides which cannot be used as antinociceptive agents due to their low bioactivity and stability in biological fluids. The major goal of opioid research is to understand the mechanism of action of opioid receptor agonists in order to improve therapeutic utility of opioids. Analgesic effects of morphine are mediated mostly through activation of the mu opioid receptor. However, in the search for safer and more effective drug candidates, analogs with mixed opioid receptor profile gained a lot of interest. Recently, the concept of biased agonists able to differentially activate GPCR downstream pathways, became a new approach in the design of novel drug candidates. It is hypothesized that compounds promoting G-protein signaling may produce analgesia while β-arrestin recruitment may be responsible for opioid side effects. In this report we showed that replacement of the tyrosine residue in the mu-selective ligand Tyr-c[d-Lys-Phe-Asp]NH

Background Many employees working outside are exposed to the harmful effects of UV radiation. A growing problem is also sensitization to textile materials and allergic reactions to active compounds. Groups of inorganic UV blockers with nanoparticles may provide superior properties over organic UV absorbers with relatively less potential of provoking dermatitis. Objectives To assess acute dermal irritation and sensitization of nano UV absorbers. Materials & methods Five UV absorbers with nano-sized particles (Z11, TiO2 - SiO2 [TDPK], TK44, TK11, A8G) and 2 vehicles (paste-based on 10% PEG, and dispersion with 1% HEC) were tested. Acute dermal irritation was tested using group of 3 rabbits for each absorber. The sensitization study was carried out on groups of 15 guinea pigs for each tested textile with a UV absorber showing an Ultraviolet Protection Factor (UPF)>40. This research was designed according to OECD Test Guideline No. 404 and 406, and 21 rabbits and 60 guinea pigs were used in the study. Results In acute dermal irritation, Z11 and A8G modifiers and the analyzed paste gave results of 0.047 to 0.33 which classifies them as barely perceptible irritants, whereas the other analyzed modifiers and dispersion gave results of 0.00 and were classified as nonirritating. Only the textile with TK 11 did not have UPF>40. The analyzed barrier materials were classified as nonsenitizers (TDPK, A8G) or mild sensitizers (TK44, Z11). Conclusions None of the analyzed materials or modifiers induced major skin reactions in animals. Therefore, they present low risk of provoking skin reactions in humans.

Purpose Oxidative stress generated by anticancer drugs in non-targeted tissues, is considered as a significant factor responsible for their severe side effects, e.g. cardiotoxicity, neurotoxicity and hepatotoxicity. Lack of data on the effect of concurrent administration of commonly used anticancer drugs: doxorubicin (DOX), paclitaxel (PTX) and docetaxel (DTX) on normal tissue, prompted us to examine the markers of oxidative stress in the liver of rats treated with these drugs. Material/Methods Male Wistar rats of average weight 200 g were injected intraperitoneally (i.p.) with 10 mg/kg of body weight (b.w.) of DOX, PTX and DTX. The drugs were given alone or in combinations DOX+taxane. The activities of superoxide dismutase (SOD), catalase (CAT), low molecular weight and total thiols and thiobarbituric acid-reactive substances (TBARS) were estimated. Results Combination of two drugs generated greater changes than single agents. Concurrent administration of DOX and PTX increased SOD activity and TBARS, decreased the amount of low molecular weight and total thiols, but did not cause any changes in the activity of catalase. Combination of DOX and DTX induced similar changes except for the activity of catalase, which decreased after the treatment. Of the three drugs only DTX significantly decreased the activity of SOD. However, both taxanes increased the activity of catalase. Although a decrease in concentration of –SH groups, depletion of glutathione and an increase of TBARS were observed after treatment with single drugs, the changes were not statistically significant. Conclusion Concurrent administration of DOX and taxane induced enhanced oxidative stress in comparison to single drugs, which suggests their synergistic prooxidant mode of action in liver.

Background: Vitamin C (vit C) is an antioxidant involved in scavenging free radicals generated during cellular metabolism. It has been found that isocyanate-induced lung disease is an oxidant stress-dependent pulmonary inflammation. The goal of this study was to evaluate the antioxidant effect of vit C on the course of allergic inflammation in the lungs in an experimental murine model of toluene diisocyanate (TDI-)induced asthma. Methods: BALB/cJ/Han/IMP mice were divided into six different groups: Group I: unsensitized control; Group II: TDI control; Group III -VI:TDI + vitamin C in four different doses. All mice were exposed first intranasally and then in an inhalation chamber to TDI in the air. After the final exposure, bronchoalveolar lavage fluid (BALF) was collected and changes induced in levels of inflammatory cells, and some key cytokines (IL-4, TNFa, IFNg) were evaluated. In addition, thiobarbituric acid reactive substance (TBARS) levels in plasma and liver homogenates were evaluated. Results: Total number of cells in the BALF of vit C-treated mice were lower than in the BALF of the TDI controls. A significant decrease in BALF neutrophil levels and IL-4, TNFa, IFNg levels were decreased in the BALF of most of vit C-treated mice compared to TDI controls. TBARS levels were decreased in the serum of vit C-supplemented mice as compared to TDI control. There was an increase in TBARS levels in the livers of mice that received the highest dose of the vitamin. Conclusion: The results of this experiment suggest that vitamin C may reduce inflammation and oxidative stress in the lungs of TDI-treated mice.

Background Considering the role of oxidative stress in carcinogenesis, we investigated the effect of synthetic antioxidant Pirolin (3-carbamoyl-2,2,5,5-tetramethylpyrroline-1-oxyl) on breast cancer progression. Since the anticancer drugs may cause cardiotoxicity due to oxidative stress in the heart muscle, we also evaluated Pirolin performance in heart tissue and compared its effect with that of the natural dietary flavonoid quercetin. Methods Sprague-Dawley rats were administered with 7,12-dimethylbenz( a )anthracene (DMBA) and then treated ip with an antioxidant (each at a dose of 10 mg/kg b.w.) for 14 days. The histopathology of tumors, their size and multiplicity were assesed. The effect of antioxidants on heart tissue was evaluated by the oxidative stress markers and poly (ADP-ribose) polymerase 1 (PARP 1) cleavage. Results The median number of tumors and their volume, at the end of the study, were considerably smaller in both antioxidant-treated groups. We found a better antioxidative performance of quercetin in the heart, since a restoration of the GSH pool and decreased amount of hydroperoxides were observed. Antioxidants did not prevent cardiomyocytes from apoptosis. Conclusion The attenuation of tumor progression by Pirolin was comparable with the action of quercetin. No negative changes were observed in the heart of animals after Pirolin treatment. Thus, its use in targeting deregulated redox pathways should be further studied.

Highly reactive, low-molecular-weight diisocyanates (DIC) are the most commonly identified cause of occupational asthma (OA). Animal/clinical studies of DIC asthma have been more limited compared with atopic asthma, and an understanding of DIC pathogenesis is less clear. The aim of this study was to investigate in a mouse model, toluene diisocyanate (TDI, as 2,4-TDI isomer)-induced inflammatory reactions/cytokine profile changes in the lungs and accompanying changes in lymph node lymphocyte sub-populations. The study used female BALB/cJ/Han/IMP mice that were exposed first intra-nasally and then in an inhalation chamber to TDI or air. After the final exposure, bronchoalveolar lavage fluid (BALF) was collected and changes induced in inflammatory cell composition, levels of key cytokines (i.e. IL-4, TNFα, IFNγ), and lymphocyte sub-population profiles within auricular lymph nodes, were evaluated. Total number of cells in the BALF of treated mice was significantly higher than in control mice BALF. There was also a significant increase in BALF neutrophil and eosinophil levels with TDI mice compared to in controls; lymphocyte and macrophage numbers did not significantly differ. A significant increase in BALF levels of TNFα and IFNγ was also noted in mice exposed to TDI relative to levels in controls. BALF IL-4 levels were also increased, but the change from control was not significant. Lastly, the levels/percentages of CD3(+)CD4(+) (T-helper [TH]) lymphocytes significantly increased in the lymph nodes of TDI-exposed groups while those of the CD3(+)CD8(+) cells decreased as compared to in control mice. These studies, the first to assess TDI-induced changes in levels of three key cytokines in BALF in conjunction with changes in local lymph nodes following first an intra-nasal and then a general inhalation exposure to a low-level of TDI, confirm that TDI inhalation induces a pathology manifested by airway inflammation, TH cell-derived cytokine production, and shifts in lymph node lymphocytes sub-populations toward increases in TH cells.

The development of side-effects during doxorubicin-docetaxel (DOX-DTX) chemotherapy is considered as related to generation of oxidative stress by DOX. The addition of docetaxel potenti - ates this effect. Thus, antioxidants are assumed as a promising remedy for neutralizing deteriorating effects of reactive oxygen species (ROS) in pathological conditions and polyphenolic antioxidants are suitable candidates for such a therapeutic approach. We evaluated the ability of quercetin to attenuate oxidative stress developed during the process of DMBA carcinogenesis and DOX-DTX chemotherapy in the blood plasma of rats bearing mammary tumors. We have found that quercetin significantly improved the plasma nonenzymatic antioxidant capacity (NEAC) and reduced lipid peroxidation, which suggest the beneficial effect of flavonoid. The inclusion of quercetin to the DOX-DTX chemotherapy was also advantageous. A considerable decrease of carbonyls and lipid peroxidation products (TBARS) and improvement of the endogenous antioxidant defense system (an increase of NEAC, thiols and SOD activity) were observed compared to rats treated with DOX-DTX chemotherapy. These results suggest that quercetin could protect blood plasma constituents against oxidative damage evoked by DOX and DTX.

Background: Organophosphates are cholinesterase (ChE) inhibitors with worldwide use as insecticides. Stress response, evidenced by a dramatic and relatively long-lasting (several hours) rise in the plasma glucocorticoid concentration is an integral element of the organophosphate (OP) poisoning symptomatology. In rodents, corticosterone (CORT) is the main glucocorticoid. There are several reports suggesting a relationship between the stressor-induced rise in CORT concentraion (the CORT response) and the activity of the cerebral and peripheral ChE. Thus, it seems reasonable to presume that, in OP intoxication, the rise in plasma CORT concentration may somehow affect the magnitude of the OP-induced ChE inhibition. Metyrapone (MET) [2-methyl-1,2-di(pyridin-3-yl)propan-1-one] blocks CORT synthesis by inhibiting steoid 11β-hydroxylase, thereby preventing the CORT response. Chlorfenvinphos (CVP) [2-chloro-1-(2,4-dichlorophenyl) ethenyl diethyl phosphate] is an organophosphate insecticide still in use in some countries. Material and Methods: The purose of the present work was to compare the CVP-induced effects - the rise of the plasma CORT concentration and the reduction in ChE activity - in MET-treated and MET-untreated rats. Chlorfenvinphos was administered once at 0.0, 0.5, 1.0 and 3.0 mg/kg i.p. Metyrapone, at 100 mg/kg i.p., was administered five times, at 24-h intervals. The first MET dose was given two hours before CVP. Conclusion: The following was observed in the MET-treated rats: i) no rise in plasma CORT concentration after the CVP administration, ii) a reduced inhibition and a faster restitution of blood and brain ChE activities. The results suggest that MET treatment may confer significant protection against at least some effects of OP poisoning. The likely mechanism of the protective MET action has been discussed.

The aim of the study was the assessment of local tolerance to nickel implants during 9 months observation in guinea pigs sensitized to nickel before implantation and non-sensitized ones.Three groups of guinea pigs were included in the study: 10 sensitized to nickel by the guinea pig maximization test; 10 previously non-sensitized and 10 in control group. In 20 animals (except control group) the nickel implants were inserted in the muscle of the back. After 9 months of observation, the animals were patch-tested with 5% nickel sulfate. Also percentage of eosinophils in peripheral blood was examined. Next, the tissue surrounding the implant and skin from the area of patch tests were collected for the histological examination.In 70% of previously sensitized animals, the patch test confirmed the sensitivity to nickel. In 60% of previously non-sensitized animals, a positive reaction to nickel occurred. The results of patch tests in control group were negative. Percentage of eosinophils in peripheral blood was fourfold higher in animals sensitized to nickel than in control group. In histological examination, in the tissue surrounding the implant a dissimilarity concerning the intensity of cellular infiltration was observed between animals previously allergic and non-allergic to nickel. In the 2 of 10 previously sensitized guinea pigs quite severe inflammatory reactions in the inside of connective tissue capsule were noted which may indicate a local allergic reaction. The histological images of skin collected from the positive patch test site corresponded with the typical allergic contact dermatitis.Nickel implants may cause primary sensitization to nickel. The nature of the histological changes in the tissues around the implants in guinea pigs sensitized to nickel may correspond to an allergic reaction. The examination of percentage of eosinophils in blood of guinea pigs may be useful in assessing the allergenic activity of metal alloys containing nickel.

Diisocyanates (DIC) are highly reactive, low-molecular-weight chemicals which are the leading cause of occupational asthma (OA). The aim of the study was to analyze certain aspects of the pathogenesis of allergic inflammation in the airways induced by toluene diisocyanate (TDI) in an experimental model in mice.The experiment was carried out on 50 female BALB/cJ/Han/IMP mice, which were exposed by inhalation (intranasal and in the inhalation chamber) to toluene diisocyanate (2,4-TDI). After the experiment, the bronchoalveolar lavage fluid (BALF) was collected from the animals, and the composition of the induced inflammatory cells, and the concentrations of certain cytokines (IL-4, IL-5, TNF-α) were evaluated.The total number of cells in BALF of the examined group of mice was significantly higher compared to the control mice. There was also a significant increase in neutrophils and eosinophils in the study group compared to the controls. The number of lymphocytes and macrophages did not differ significantly between the two groups. A statistically significant increase in the level of TNF-α was shown to occur in the group exposed to toluene diisocyanate in comparison to the control group. The concentration of IL-4 increased in the study group, compared to the control one, but the differences did not reach the level of significance, p0.05. Such difference was not observed for IL-5.We developed a murine model of TDI-induced asthma which caused the influx of inflammatory cells like eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF) in the TDI-treated mice. The increase of the concentration of some proinflammatory cytokines (TNF-α, IL-4) in BALF from the exposed mice was also observed.