Evaluation of a therapeutic vaccine for the prevention of recurrent urinary tract infections versus prophylactic treatment with antibiotics.

INTRODUCTION AND HYPOTHESIS: Urinary tract infections (UTIs) are considered the most common bacterial infections, especially in women. The objective of this study was to evaluate the use of the sublingual bacterial vaccine Uromune® in order to prevent recurrent UTIs (RUTIs). METHODS: This study was conceived as a multicenter observational study. The clinical history of 319 women who presented at least 2 episodes of UTI in the last 6 months or 3 in 12 months was reviewed. Data related to treatment and clinical evolution were recorded and analyzed. A total of 159 patients received prophylactic treatment with Uromune® for a period of 3 months (group A) and 160 with sulfamethoxazole/trimethoprim 200/40 mg/day for a period of 6 months (group B). Uromune® contained an inactivated bacterial cell suspension of selected strains of Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Enterococcus faecalis. RESULTS: Patients in group A experienced a highly significant reduction in the number of infections compared to patients in group B. In the first 3 months, the mean number of infections was 0.36 versus 1.60 (P < 0.0001), respectively. A significant reduction was also observed after 9 and 15 months (P < 0.0001). The numbers of patients who did not have any UTI at 3, 9, and 15 months were 101, 90, and 55 in group A versus 9, 4, and 0 in group B (P < 0.0001). CONCLUSIONS: The results obtained in this study favor the use of this bacterial-based therapeutic vaccine as an effective strategy to reduce frequency, duration, severity, and costs of RUTIs.

[Treatment of stress urinary incontinence with perineal biofeedback by using superficial electrodes]. / Tratamiento de la incontinencia urinaria de esfuerzo con biofeedback perineal con electrodos de superficie.

PURPOSE: We analyze the pelvic floor muscles treatment outcomes by using biofeedback (BFB) with electromyography with superficial electrodes in women diagnosed as having stress urinary incontinence (SUI). Besides, we compare this treatment with pelvic floor muscle exercises (PFME) plus vaginal electrostimulation. METHODS: 85 women with stress urinary incontinence, aged 42 - 74 years. We divided the patients in two groups: Group 1 (N = 50): This patients carry out a perineal biofeedback with superficial electrodes without electrostimulation, and Group 2 (N = 35): This patients were treated with pelvis floor muscle exercices and vaginal electrostimulation. All patients carry out two session per week (of 30 minutes each one) during ten weeks. We assess the outcomes through international urinary incontinence questionnaires (IU-5 and ICIQ-SF) and urinary incontinence related quality of life test (King's questionnaire). Student t-test and Fisher Exact test were used, p < 0.05 was considered statistically significant. RESULTS: No difference was found in the age average of both groups. 84% of patients of group 1 and 80% of patients of group 2 were cured with the treatment. We assumed they were cured when incontinence episodes not happened or they do not need to use absorbent materials. In the Group 1, 50% of patients in the fourth week and 84% in the tenth week were cured. In the Group 2, 71.42% of patients in the fourth week and 80% in the tenth week were cured. In the Group 2, eight patients (22.85%) complained side effects. Both groups improved the quality of life similarly. CONCLUSION: Grade 1 and grade 2 stress urinary incontinence treatment by using perineal biofeedback with superficial electrodes electromyography is better or similar to more invasive treatments. Also pelvic floor muscle exercices plus vaginal electrostimulation have good outcomes although some patients complain side effects. Both conservative treatments are effective and feasible.

Experimental murine model of renal cancer. / Modelo murino experimental de cáncer renal.

INTRODUCTION: The objective of this study was to determine the reproducibility in a murine model of renal tumours of various histological strains that could be useful for investigating the response to target drugs. MATERIAL AND METHODS: Development and analysis of the "in vivo" model: tumour xenograft of renal cell carcinomas with Balb/c nude athymic mice. Nontumourous human renal tissue was implanted in the interscapular region of 5 mice, chromophobe renal cell carcinoma was implanted in 5 mice (which, after checking its growth, was prepared for implantation in another 10 mice) and Fuhrman grade 2 clear cell renal cell carcinoma (CCRCC) was implanted in 5 mice (which was also subsequently implanted in 10 mice). We monitored the tumour size, onset of metastases and increase in size and number of tumours. When the size had reached a point greater than or equal to locally advanced or metastatic carcinoma, the animals were euthanised for a pathological and immunohistochemical study and a second phase of implantation. RESULTS: The subcutaneous xenograft of the healthy tissue did not grow. The animals were euthanised at 6 months and no renal tissue was found. The chromophobe renal cell carcinoma cells grew in the initial phase (100%); however, in the second phase, we observed a chronic lymphomonocyte inflammatory reaction and a foreign body reaction. The CCRCC grew at 5-8 months both in the first and second phase (100%), maintaining the tumour type and grade. CONCLUSIONS: The model with athymic Balb/c nude mice is useful for reproducing CCRCC, with the same histological characteristics and aggressiveness as native human tumours, promoting the development of the second experimental phase.

Effect of preoperative oral pravastatin reload in systemic inflammatory response and myocardial damage after coronary artery bypass grafting. A pilot double-blind placebo-controlled study.

AIM: Statins exert pleiotropic effects that result in cardioprotective and antiinflammatory properties. There is a lack of information about the effect of preoperative reloading statin administration in surgical coronary patients regarding myocardial protection, systemic inflammatory response (SIR) attenuation and nitric oxide (NO) metabolism. METHODS: Thirty consecutive dyslipidemic patients under chronic treatment with statins were randomized to orally receive pravastatin 80 mg (N.=10), 40 mg (N.=10) or placebo (N.=10) two hours before anesthetic induction for non-emergent on-pump coronary artery bypass grafting (CABG) procedures. Perioperative peripheral venous and intraoperative CS blood samples were collected for determination of drug-related adverse effects, NO metabolism and both myocardial damage and SIR biomarkers. RESULTS: Pravastatin reloading resulted in a significant and dose-related intense attenuation of SIR, but no differences in cardiac damage biomarker levels were demonstrated. NO release and inducible nitric oxide synthase expression was significantly reduced in both treatment groups. Highest pravastatin doses significantly increased systemic creatine phosphokinase (CPK) concentration compared with intermediate doses but no other adverse effects were observed. CONCLUSION: Oral pravastatin reloading before non-emergent CABG significantly attenuates postoperative SIR and systemic NO/iNOS concentrations with no effect in perioperative myocardial damage. Highest pravastatin doses increase CPK levels and must be avoided in susceptible patients.

Tacrolimus (FK506) down-regulates free radical tissue levels, serum cytokines, and neutrophil infiltration after severe liver ischemia.

BACKGROUND: Liver ischemia and reperfusion injury is associated with activation of multiple inflammatory pathways, including free radicals, cytokines, and neutrophil-mediated tissue damage among others. Tacrolimus (FK506) has shown important regulatory effects on some inflammatory pathways, such as cytokines, neutrophils, and adhesion molecules. In this study, we explored a new potential protective mechanism for tacrolimus in the liver inflammatory response after ischemia and reperfusion, specifically its effect on liver tissue free radicals. METHODS: Total hepatic ischemia was produced in the rat for 90 min with an extracorporeal portosystemic shunt. Animals (n=96) were divided into four groups: group 1 comprised normal rats for reference values; group 2 comprised sham operated rats; in group 3, ischemic control rats received only the vehicle; and the experimental treatment group, group 4, received tacrolimus at a dose of 0.3 mg/kg, 4 hr before ischemia. Animal survival was followed up to 7 days. Liver function tests were performed and liver tissue free radicals and myeloperoxidase, serum cytokines (interleukin 1, tumor necrosis factor-alpha), and liver histology were measured 4 hr after reperfusion. RESULTS: Seven-day survival was significantly improved from only 20% in the control group to 55% in the tacrolimus group (P<0.01). Liver function tests, histology, and myeloperoxidase tissue values were significantly improved (P<0.05) with tacrolimus pretreatment. Furthermore, a significant (P<0.05) down-regulation of serum cytokines and liver tissue free radicals was observed. CONCLUSIONS: These data indicate a new and different protective mechanism for FK506 in regard to its ability to down-regulate free radical levels in livers subjected to severe ischemia and reperfusion. Tacrolimus, also confirmed to be a potent suppressor of the cytokine response, specifically interleukin 1 and tumor necrosis, decreased neutrophil tissue migration as well.

Protective effect of exogenous nitric oxide on the renal function and inflammatory response in a model of ischemia-reperfusion.

BACKGROUND: Tissue subjected to a period of ischemia undergoes morphological and functional damage that increases during the reperfusion phase. The aim of the present work was to assess the possible improvement induced by exogenous administration of nitric oxide (NO) on renal injury and inflammatory reaction in an experimental animal model of renal ischemia-reperfusion (I-R). METHODS: Ischemia was achieved by ligation of the left arteria and vein for 60 min, followed first by contralateral nephrectomy and then reestablishment of blood flow. Molsidomine, used as an NO donor, was administered by systemic injection 30 min before reperfusion. The effect of molsidomine was compared with the effect of hydralazine, a non-NO donor hypotensive agent. RESULTS: Treatment with molsidomine improved the renal dysfunction (increase in plasma creatinine and urea levels) caused by I-R. Moreover, molsidomine blunted the enhanced production of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin [IL] 1alpha), the increase in tissular levels of superoxide anions and oxygen free radical scavengers, and the neutrophilic infiltration observed in the ischemic kidney. One hundred percent survival was achieved in the group of animals treated with the NO donor, whereas the groups of animals undergoing I-R that did not receive molsidomine showed a 40% mortality from the second day after reperfusion. CONCLUSIONS: The present work demonstrated that systemic treatment with an NO donor before reperfusion improved renal function and diminished inflammatory responses in a kidney subjected to an I-R process.

Levels of serum cathepsin L and several glycosidases in patients operated for colorectal cancer.

The activities of several glycosidases and cathepsin L were determined in the blood serum of a control group of ten healthy humans in comparison with a group (group I: 32 subjects) of preoperative colorectal cancer patients (1 week before surgical exeresis) and with another two groups: group II, comprising 18 operated subjects (1 week after surgery), and group III, of 15 operated subjects (4 months after surgery). All subjects were 48-88 years old. Both 'enzyme activity' and 'specific activity' determinations of serum beta-galactosidase, alpha-L-fucosidase and cathepsin L revealed peculiar profiles that differed from one another. Control values differed from those of some stages of the pathological groups, but not of others. These values were compared also with the levels of total, lipid- and glycoprotein-associated serum sialic acid. The usefulness of some assays (especially cathepsin L activity measurement) in the follow-up of the health status of humans operated for colorectal cancer is discussed.

Role of P-selectin in total hepatic ischemia and reperfusion.

BACKGROUND: Ischemia and reperfusion of the liver are associated with changes in the interaction of leukocyte-endothelium cells. The role of an adhesion molecule, P-selectin, is studied in ischemia and reperfusion injury of the liver. STUDY DESIGN: Total hepatic ischemia was produced in the rat for 90 minutes, using a portosystemic shunt. To determine the role of P-selectin in ischemia and reperfusion, a murine IgG1 monoclonal antibody to P-selectin (1 mg/kg) was used at different times (30 minutes before and at reperfusion and five minutes and 24 hours after reperfusion). Rats survived for seven days, and tests showing hepatic injury, myeloperoxidase in hepatic tissue, and histologic studies were analyzed at four hours postreperfusion. RESULTS: Survival improved from 15 percent for the rats in the ischemia control group to 55 percent for those in the group receiving anti-P-selectin antibody given 30 minutes before reperfusion (p < 0.05). We observed an improved statistically significant difference in tests demonstrating hepatic injury, myeloperoxidase in hepatic tissue, and histologic studies in the treated and ischemia control groups. The other groups did not show consistent significant differences. CONCLUSIONS: P-selectin has a significant role in ischemia and reperfusion injury of the liver. Early modulation of the interaction between P-selectin and its ligand decreased neutrophil adhesion and migration and consequently diminished damage to the liver.

[Nutrition and bacterial translocation]. / Nutrición y translocación bacteriana.

The present work is part of a presentation given at the Scientific Meeting of the Association for Surgical Nutrition and Metabolism, during the XX National Congress for Surgery (Madrid, November 1994). The authors, prior to presenting their experiences, define and high light the importance of the phenomenon of "Bacterial Translocation" (BT). Afterwards, and based on several experimental studies performed by them, they attempt to answer two questions: 1) Is the term BT correct? 2) Is BT a physiological or a pathological state? Finally they review the relationship which exists between bacterial translocation and nutrition, both from a causative point of view as from the prevention and therapy of the same.

[An experimental model of bacterial translocation]. / Modelo experimental sobre translocación bacteriana.

The authors submit an experimental model for bacterial translocation (administering OF-1 mice Zymosan intra-peritoneally at a dose of 1 mg/kg weight). The existence is confirmed of this new mechanism of infection (0% of translocation in control groups, as against 80% in the trial group -p < 0.001). The bacteria in the translocated organs coincide with those present in the fecal flora of the experimental animal. This study is the point of departure for subsequent research to study the physiopathological mechanisms of the phenomenon, which will enable us subsequently to reach better preventive and/or therapeutic decisions.

Effects and mechanism of organ protection by cardiotrophin-1.

Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and profibrotic effects of CT-1 on the heart. Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them. Although many effects of CT-1 have been described on the heart, CT-1 has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system. CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFRß) and a common signal transducer, the glycoprotein 130 (gp130). The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway(s) is involved in each particular effect of CT-1. In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated.

[Risk factors for failure after transobturator vaginal tape for urinary incontinence]. / Factores de riesgo de fracaso de la corrección quirúrgica de la incontinencia urinaria de esfuerzo mediante cinta suburetral transobturatriz.

OBJECTIVE: To identify risk factors leading to treatment failure in a sample of 302 women with stress urinary incontinence (SUI) treated by transobturator vaginal tape (TOT) with a medium follow-up of 4 years (range 1-6). MATERIAL AND METHODS: A population based cohort study with prospectively data from 302 women, aged 41-81 years underwent TOT between April 2003-November 2010. Data were collected by validated questionnaire on urinary incontinence, the International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF), and clinical data-records. Continence was achieved in 262 (Group A) and 40 continued with incontinence (Group B). We investigated the relationship between age, SUI evolution time, type and number of childbirths (eutocic, dystocic, nulliparous, multiparous status) and medical and/or surgical backgrounds. The ICIQ-SF questionnaire was used to describe whether the surgery outcomes were successful or not. RESULTS: Group A were younger (p=0.0001), had less SUI evolution time (p=0.017); more eutocic childbirths (p=0.000018). Group B had more dystocic childbirth (p=0.022), previous tension free vaginal tape (TVT) or TOT (p=0.03.), antidepressant-anxiolytic drugs (p=0.003), antihypertensive drugs (p=0.0005), type 1 diabetes (p=0.02), arterial hypertension (p=0.0007), respiratory diseases (p=0.025). Differences were not found with regard to nulliparous (p=0.701), multiparous status (p=0.42), obesity (p=0.18), intestinal disorders (p=0.59), oophorectomy (p=0.19), caesarean (p=0.17), prolapse surgery (p=0.29), hysterectomy (p=0.57), allergies (p=0.48), arthritis (p=0.22), arthrosis (p=0.44), depression (p=0.74), type 2 diabetes (p=0.44), smoking patterns (p=0.28), fibromyalgia (p=0.47). CONCLUSIONS: Elderly women, with long evolution SUI, dystocic delivery, previous TVT or TOT appear as independent risk factors associated to TOT failure. These factors may make the indication of another surgical approach recommendable.

Study of the efficacy of Coated VICRYL Plus Antibacterial suture (coated Polyglactin 910 suture with Triclosan) in two animal models of general surgery.

OBJECTIVES: To evaluate the efficacy in vitro and in vivo of a new antibacterial suture (PGAB) compared with a traditional braided suture (PG). Our primary goals were to study microbiological effectiveness and impact on wound healing of PGAB vs PG. Secondary goal was to analyze influence on inflammatory response. METHODS: In vitro study: clinical samples of Staphylococcus epidermidis, Staphylococcus aureus, S. hominis, Staphylococcus haemolyticus, Staphylococcus auricularis, Enterococcus faecalis, Corynebacterium spp. and Escherichia coli were studied. We also implanted a flat mesh in 10 minipigs, four incisions each (two PG and two PGAB) two contaminated with S. epidermidis and two not contaminated. Finally, we performed four colic anastomosis in each of 10 minipigs, two contaminated with E. coli and two not contaminated (two PG and two PGAB). We studied the inflammatory and wound healing processes in both models. RESULTS: We observed a bactericidal efficacy of PGAB against grampositive, and bacteriostatic effect against E. coli. Mesh study: recovered CFU were lower in the group PGAB vs PG. In the group PGAB, inflammatory mediators' concentrations were lower. In the group PGAB, concentrations of wound healing mediators were normal. Colic anastomosis: recovered CFU were lower in the group PGAB vs the group PG. In the group PGAB we observed a reduction of inflammatory mediators. In the group PGAB we observed normalized concentrations of wound healing mediators. CONCLUSIONS: This study demonstrates microbiological efficacy of PGAB, that normalizes wound healing process, and an anti-inflammatory effect.

Factores de riesgo de fracaso de la corrección quirúrgica de la incontinencia urinaria de esfuerzo mediante cinta suburetral transobturatriz / Risk Factors for Failure After Transobturator Vaginal Tape for Urinary Incontinence

Objetivos: Identificar factores que llevaron al fracaso del tratamiento quirúrgico en 302 mujeres con incontinencia urinaria de esfuerzo (IUE) tratadas mediante cinta suburetral transobturatriz (TOT) con seguimiento de 4 años (rango 1-6).Material y métodos302 mujeres incontinentes de 41-81 años fueron intervenidas mediante TOT entre abril de 2003 y noviembre de 2010. Los datos se recogieron mediante el cuestionario validado para incontinencia de orina, el International Consultation on Incontinence Questionnaire — Short Form (ICIQ-SF), y los registros clínicos de la historia. En 262 se consiguió continencia (grupo A) y 40 siguieron incontinentes (grupo B). Se investigó: edad, tiempo de evolución de IUE, tipo y número de partos (eutócicos, distócicos, nuliparidad, multiparidad) y antecedentes médicos y/ o quirúrgicos. Se empleó el cuestionario ICIQ-SF para asignar si los resultados de la cirugía fueron o no exitosos. Resultados: El grupo A presentó menor edad (p=0,0001), menos tiempo de evolución de IUE (p=0,017) y más partos eutócicos (p=0,00002). El grupo B presentó más partos distócicos (p=0,002), colocación previa de cinta vaginal libre de tensión (TVT) o TOT (p=0,03), tratamiento antidepresivo-ansiolítico (p=0,003), tratamiento antihipertensivo (p=0,0005), DMID (p=0.02), HTA (p=0,0007), trastornos respiratorios (p=0,025). No hubo diferencia en nuliparidad (p=0,7), multiparidad (p=0,4), obesidad (p=0,18), trastornos intestinales (p=0,59), anexectomía (p=0,19), cesárea (p=0,17), colposuspensión (p=0,29), histerectomía (p=0,57), alergias (p=0,48), artritis (p=0,22), artrosis (p=0,44), depresión (p=0,74), DMNID (p=0,44), tabaquismo (p=0,28) o fibromialgia (p=0,47). Conclusiones: Edad avanzada, largo tiempo de evolución de la incontinencia urinaria, antecedentes de partos distócicos y la colocación de TVT o TOT previamente aparecen como los factores independientes más asociados al fracaso del TOT, y pueden hacer aconsejable la indicación de otra técnica quirúrgica (AU)

Objective: To identify risk factors leading to treatment failure in a sample of 302 women with stress urinary incontinence (SUI) treated by transobturator vaginal tape (TOT) with a medium follow-up of 4 years (range 1-6). Material and Methods: A population based cohort study with prospectively data from 302 women, aged 41-81 years underwent TOT between April 2003-November 2010. Data were collected by validated questionnaire on urinary incontinence, the International Consultation on Incontinence Questionnaire — Short Form (ICIQ-SF), and clinical data-records. Continence was achieved in 262 (Group A) and 40 continued with incontinence (Group B). We investigated the relationship between age, SUI evolution time, type and number of childbirths (eutocic, dystocic, nulliparous, multiparous status) and medical and/or surgical backgrounds. The ICIQ-SF questionnaire was used to describe whether the surgery outcomes were successful or not. Results: Group A were younger (p=0.0001), had less SUI evolution time (p=0.017); more eutocic childbirths (p=0.000018). Group B had more dystocic childbirth (p=0.022), previous tension free vaginal tape (TVT) or TOT (p=0.03.), antidepressant-anxiolytic drugs (p=0.003), antihypertensive drugs (p=0.0005), type 1 diabetes (p=0.02), arterial hypertension (p=0.0007), respiratory diseases (p=0.025). Differences were not found with regard to nulliparous (p=0.701), multiparous status (p=0.42), obesity (p=0.18), intestinal disorders (p=0.59), oophorectomy (p=0.19), caesarean (p=0.17), prolapse surgery (p=0.29), hysterectomy (p=0.57), allergies (p=0.48), arthritis (p=0.22), arthrosis (p=0.44), depression (p=0.74), type 2 diabetes (p=0.44), smoking patterns (p=0.28), fibromyalgia (p=0.47). Conclusions: Elderly women, with long evolution SUI, dystocic delivery, previous TVT or TOT appear as independent risk factors associated to TOT failure. These factors may make the indication of another surgical approach recommendable (AU)

Nitric oxide prevents the bacterial translocation and inhibits the systemic inflammatory response produced by implantation of a vascular prosthesis followed by Zymosan A.

OBJECTIVE AND DESIGN: To evaluate the beneficial effects of exogenous NO and its levels of action in a model of SIRS/Bacterial Translocation (BT) induced by two sequential insults. MATERIAL OR SUBJECTS: Eighty-six Wistar rats were submitted to different treatments and their tissue and blood samples were accessed at the end of the experiment. TREATMENT: Nitric Oxide was compared to Gentamicin as the tested guideline for our study. METHODS: Dacron graft implantation (first insult) and subsequent administration of Zymosan A((R)) (second insult) were performed in Wistar rats. The animals were divided into 6 groups: I) No manipulation (BASAL: ); II) Laparotomy (L) + mineral oil (SHAM: ); III) L + Graft-Zymosan (GZ) (CONTROL: ); IV) L + GZ + Antibiotic (A) (ASSAY: I); V) L + GZ + NO (ASSAY: II) and VI) L + GZ + A + NO (ASSAY: III). Determinations: Survival, Bacterial Translocation, myeloperoxidase (MPO), Cytokines (TNF-alpha, IL-1beta, IFN-gamma), Oxygen Free Radical (OFR) SOA and detoxifying enzymes (SOD, Superoxide Dismutase, CAT, Catalase and GPX, Glutathione Peroxidase), Cell Adhesion Molecules, CAMs (ICAM-1, VCAM-1 and PECAM-1) and Nuclear Transcription Factor, NFkappaB. RESULTS: The model established induced a mortality rate of 20% and generated BT in all samples. It also significantly increased all variables, with P < 0.001 for MPO and all Cytokines; P < 0.01 for all OFR, and P < 0.05 for CAMs and for NFkappaB. Treatment with A reduced mortality to 0%, significantly decreased BT, MPO, Cytokines and OFR (P < 0.05), but did not reduce CAMs or NFkappaB. NO, either alone or associated, reduced mortality to 0% and abolished BT, significantly decreasing nearly all the variables studied (P < 0.001 for MPO and all Cytokines; P < 0.01 for OFR, and P < 0.05 for CAMs and for NFkappaB). CONCLUSIONS: The exogenous administration of NO before the two sequential insults prevented BT and controlled SIRS peripherally and at both cellular and transcriptional level in a lasting manner. In contrast, antibiotic treatment only exerted its action at peripheral level. The association of both treatments did not provide any important advantages.

21-Aminosteroids block neutrophil infiltration and provide liver protection independent of NO2-/NO3- levels.

21-Aminosteroids are antioxidant compounds that prevent iron-dependent lipid peroxidation and improve cell viability. In this work we attempt to define the role of 21-aminosteroids in liver ischemia and reperfusion and assess their possible mode of action, specifically their effect on neutrophil infiltration and nitrite/nitrate levels. Total liver ischemia for 90 min was produced in the rat with the use of a portosystemic shunt. Three groups of animals were studied. One group received the 21-aminosteroid U-74389G (10 mg/ kg) divided into two equal doses 10 min prior to ischemia (7 mg/kg) and 10 min before reperfusion (3 mg/ kg). The two other groups included the sham and the control animals. We studied survival at 7 days and serum liver enzymes, liver myeloperoxidase, plasma nitrites, nitrates, and liver histology at 6 hr postreperfusion. Animal survival improved from 13% in the ischemic control to 52% in the lazaroid treated group (P < 0.05). We observed significant improvements in liver function tests, liver myeloperoxidase levels, as well as in the liver histology (P < 0.05). We could not find statistical difference in plasma nitrite/nitrate (P > 0.1). The 21-aminosteroids significantly improved animal survival after total liver ischemia, through a mechanism that includes blocking neutrophil infiltration which is independent from nitrite/nitrate levels.

The sialyl Lewis X analogue, CY-1503, down-regulates leucocyte-endothelium interactions and the inflammatory response.

OBJECTIVE: To elucidate mechanisms of protection of ischaemic liver with the sialyl Lewis X analogue CY-1503 by regulation of inflammatory mediators such as oxygen free radicals and cytokines as well as blocking the migration of leucocytes. DESIGN: Laboratory study. SETTING: Teaching hospital, Spain. ANIMALS: 122 male Sprague-Dawley rats divided into four groups: normal (n = 18), sham-operated (n = 28), ischaemic controls (n = 38), and CY-1503 (n = 38). INTERVENTIONS: Warm total hepatic ischaemia for 90 minutes followed by various periods of reperfusion. MAIN OUTCOME MEASURES: Survival, liver histology, liver function, neutrophil infiltration, and free radical and cytokine concentrations. RESULTS: 2/20 ischaemic controls survived, compared with 14/20 given CY-1503. Liver function was better, as was histological appearance judged by the Suzuki score); myeloperoxidase activity was significantly decreased (n = 6 in each group, p<0.01) as were concentrations of free radicals (n = 12 in each group, p<0.05) in the group given CY-1503. CY-1503 had no effect on concentrations of the cytokines tumour necrosis factor-alpha or interleukin 1-alpha. CONCLUSIONS: CY-1503 exerts a protective effect in that it able to down-regulate concentrations of free radicals in our rat model. It is a potent inhibitor of neutrophil migration, but has no effect on cytokine concentrations.