Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease

Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes.     

Immune privilege in the gut: the establishment and maintenance of non-responsiveness to dietary antigens and commensal flora

Summary:  Immune privilege in the gut is the result of a complex interplay between the gut microbiome, gut luminal antigens, and the intestinal epithelial barrier. Composed of both physical and immunochemical components, the intestinal barrier secretes immunoregulatory mediators that promote the generation of tolerogenic antigen-presenting cells, phagocytic innate immune cells characterized by 'inflammatory anergy', and regulatory cells of the adaptive immune system. Innate immune cells mediate controlled transepithelial transport of luminal antigens as far as the mesenteric lymph nodes, where the intestinal and peripheral immune systems intersect. This promotes the generation of adaptive regulatory lymphocytes that actively suppress effector cell responses against gut luminal antigens and flora. The net result is the generation of tolerance to dietary antigens and the maintenance of gut homeostasis. Dysregulation of this complex immunoregulatory network leads to diseases such as food allergy and inflammatory bowel disease. Future therapies for these diseases will likely involve the functional restoration of the barrier and regulatory cell functions at the epithelial/luminal interface.     

Enteroenterale Invagination des Dünndarms beim Erwachsenen

Zusammenfassung Es wird über eine 43jährige Patientin berichtet, die mehrere Wochen lang über inkonstant auftretende, krampfartige Mittelbauchschmerzen klagte. Die Diagnose einer ileoilealen Invagination konnte bei der Patientin erst beim dritten stationären Aufenthalt gestellt werden. Folgende Fehldiagnosen waren während des 4wöchigen Verlaufs bei der Patientin gestellt worden: Nierenbeckenentzundung, acute Appendizitis, chronische Appendizitis und zuletzt psychosomatische Bauchschmerzen. Die Patientin wurde zunächst antibiotisch, zuletzt mit Psychopharmaka medikamentös behandelt. Schließlich wurde die Diagnose einer Invagination des Dünndarms mittels Sonographie vermutet und in der konventionellen fortlaufenden Magen-Darm-Passage röntgenologisch gesichert. Bei der Patientin wurde daraufhin eine Dünndarmsegmentresektion durchgeführt. Die enteroenterale Invagination ist im Erwachsenenalter ein sehr seltenes Ereignis, bei der meistens eine Ursache (oft Tumore) als Auslöser der Invagination ermittelt werden kann. Durch Peristaltik und Ingesta wird der nach aboral bewegte Tumor zum Motor der Invagination. Prädilektionsorte sind die Übergänge eines beweglichen zu einem retroperitoneal fixierten Darmabschnitts (z. B. Ileozökalregion). Die Sonographie des Abdomens ist die Methode der ersten Wahl bei der Diagnose einer enteroenteralen Invagination. Beim Erwachsenen ist die operative Beseitigung der Invagination und deren Ursache (meist Tumore) angezeigt.

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Entero-enteric invagination of the small intestine in adultsA rare cause of abdominal distress

The present paper reports on a 43-year-old female patient who complained over a number of weeks of paroxysms of crampy pain in the mesogastrium. The diagnosis of ileoileal invagination was only made after she had been admitted to hospital for the third time. The following false diagnoses had been made during the 4-week course of the condition: pyelonephritis, acute appendicitis, chronic appendicitis and, most recently psychosomatic abdominal distress. The patient was initially treated with antibiotics and finally with psychotropic drugs. Eventually ultrasound suggested the diagnosis of invagination of the small intestine, which was then verified by conventional barium follow-through radiography. The patient subsequently underwent resection of a segment of the small intestine. Entero-enteric invagination is a very rare event in adults, in which a single (often malignant) cause is identified as triggering the invagination. Peristalsis and ingested food push the tumor distad, thus acting as a motor for invagination. The preferred localizations are the junctions between freely moving segments to retroperitoneally fixed segments (e.g., ileocecal region). Ultrasound of the abdomen is the examination of choice for diagnosis of enteroenteric invagination. Surgical resection of the invagination and its cause (generally tumors) is indicated in adults.

     

Coronary endothelium-protective effects of defibrotide in ischaemia and reperfusion

Summary Defibrotide is known to enhance prostacyclin (PGI₂) release from the vascular endothelium. We investigated the vasoactive effects of defibrotide in isolated rat hearts perfused at constant flow subjected to ischaemia and reperfusion. Defibrotide at 10^–7 or 100 g/ml did not exert any direct vasoactive effect on normal rats hearts. However, ischaemia and reperfusion resulted in an impaired vasodilation to acetylcholine, an endothelium-dependent vasodilator. In contrast, the vasodilator response to the endothelium-independent dilator, nitroglycerin, was unaffected. Defibrotide, at 10^–7 or 100 g/ml, markedly restored the vasodilation to acetylcholine 10^–7 nmol/l to 1 mol/l (P < 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 g/1). Haemoglobin (150 nmol/l) inhibited the dilation to acetylcholine in response to defibrotide. However, no evidence of (PGI₂) release was observed with acetylcholine-induced vasodilation in the presence or absence of defibrotide. Additionally, 10–100 g/ml of defibrotide did not significantly decrease superoxide radicals generated by a xanthine-xanthine oxidase synthetic system under conditions in which superoxide dismutase was effective. Thus, defibrotide appears to exert an endothelium-protective effect preserving endothelium-derived relaxing factor (EDRF) without directly scavenging free signals.Supported in part by Research Grant No. HL-25575 from the National Heart, Lung and Blood Institute of the NIH Send offprint requests to A. M. Lefer at the above address     

临床活体部分小肠移植术移植肠的处理

目的 报告我国首例活体小肠移植术的移植肠处理体会。方法 为１例１８岁男性超短肠综合征患放行了活体部分小肠移植术,供肠来自患的父亲（４４岁）,切取供体回肠１５０ｃｍ,ＵＷ液灌洗血管,将移植肠动、静脉车受体腹主动及及下腔静脉而吻合,移植肠近端与受体空肠近端行端端吻合,远端与受体空肠远端行侧端吻合,末端造口,术后给子抗排斥,抗感染,抗凝及营养支持等治疗。结果 术后管出现贫血,单纯疱疹病感染和急性排斥     

The basal and stimulated release of the endothelium-derived relaxing factor from isolated pig coronary arteries does not interfere with the vascular release of superoxide

Oxygen-derived free radicals, in particular superoxide anions, are known to inactivate the endogenous vasodilator endothelium-derived relaxing factor (EDRF) which is probably identical with the gaseous radical nitric oxide. It is possible that EDRF is not the target of superoxide anions but may also be an endogenous scavenger of this radical.Superoxide anions generated by the vessel wall were measured by a modified lucigenin-enhanced chemiluminescence technique in isolated pig coronary artery rings with intact endothelium.The addition of bovine superoxide dismutase, a scavenger of superoxide anions, decreased the chemiluminescence signal by 40 ± 26% (mean ± SD; P < 0.05; n = 21) indicating reduced generation/release of superoxide anions. In contrast, pretreatment of coronary artery rings with diethyldithiocarbamate, an inhibitor of the intrinsic copper-zinc superoxide dismutase, increased the chemiluminescence response by 136 ± 128°10 (P < 0.05; n = 21). This increase in the chemiluminescence response induced by diethyldithiocarbamate-pretreatment was almost abolished in the presence of added bovine superoxide dismutase. Specific inhibition of the EDRF release with nitro-l-arginine (100 M) did not affect the chemiluminescence response. On the other hand, stimulation of the EDRF release by substance P (10 nM) or addition of the endothelium-mediated relaxant bradykinin (0.1 M) did not affect the chemiluminescence response. Stimulation of the EDRF release with serotonin (0.1 M) significantly reduced the photon emission by 15 ± 16% (n = 27). However, this effect of serotonin on the chemiluminescence response could not be prevented by specific inhibition of the EDRF release with nitro-l-arginine (100 M) but could be prevented by buffering the acidic serotonin solution with NaOH to pH 7.4.Our results suggest that basal and agonist-stimulated release of EDRF in isolated pig coronary artery rings does not interfere with the basal generation/release of superoxide anions derived from the vascular wall. Correspondence to: A. Mugge at the above address     

The endothelium-derived relaxing factormediated acetylcholine response of the arterial perfusion pressure after cold storage of the isolated rabbit kidney

The vasodilatation induced by acetylcholine (ACh) in a rabbit isolated perfused kidney was abolished when the tissue was exposed to cold ischemia for 72 h in Euro-Collins (EC) solution. This vasodilatation is due to the release of endothelium-derived relaxing factor (EDRF) from renal vasculature as evidenced by the attenuation following methylene blue pretreatment. When kidneys were preserved in EC solution containing UK 38 485, a thromboxane synthase inhibitor, or nicardipine, a calcium channel blocker, ACh-induced vasodilatation persisted after 72 h of cold ischemia. These results were taken as evidence of tissue protective activity of UK 38 485 and nicardipine and have promising implications for cadaveric kidney transplantation.This paper was presented at the 35th World Congress of the International Society of Surgery in Hong Kong in August 1993     

Unsere Erfahrungen mit der Infektionsprophylaxe und -therapie nach 53 Lebertransplantationen

Summary An attempt was made to reduce the risk of infection following liver transplantation by means of selective bowel decontamination with tobramycin, polymyxin E and amphotericin B, as well as short-term systemic antibiotics with cephotaxim and tobramycin. After 53 consecutive orthotopec hepatic transplants performed in 51 patients between 1985 and 1987, a total of eight pneumonias occurred as the clinically most significant infection. Two pneumonias were caused by cytomegalovirus, one by Pneumocystis carinii, one by Candida and the remaining four by various bacteria. In 6 patients, bacteria were cultured from the blood, but only in one case was an indwelling catheter identified as the source of the septicemia. Taking all samples together, Streptococcus faecalis was the bacterium most frequently cultured, which was not covered by the prophylactic antimicrobial regime applied. Pseudomonas, however, and gram-negative bacteria were demonstrated much less frequently. Vaginal and oral Candida infections, as well as oral and genital herpes simplex infections, responded well to topical therapy with fungicide and aciclovir, respectively. Three patients developed cytomegalovirus (CMV) hepatitis. All five CMV infections were successfully treated with ganciclovir and hyperimmunoglobulin, as well as reduction of prophylactic immunosuppression. Out of 15 patients transplanted for posthepatitic cirrhosis, 7 developed a recurrence of the infection (5 hepatitis B virus) 2 hepatitis C virus) in the graft. Two died of the cirrhosis, three are still alive with cirrhosis but sufficient graft function, and one patient is suffering from chronic active hepatitis. One patient grafted for acute hepatic failure was able to clear the delta virus within 1 year post-transplant. During the perioperative phase, however, we never lost a single patient to infectious complications. Therefore, bowel decontamination and antibiotic prophylaxis, including Streptococcus faecalis, are recommended.

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Unsere Erfahrungen mit der Infektionsprophylaxe und -therapie nach 53 Lebertransplantationen

Zusammenfassung Durch selektive Darmdekontamination mit Tobramycin, Polymyxin E and Amphotericin B über 8 Tage and kurzzeitige Antibiotikatherapie mit Cefotaxim und Tobramycin wurde versucht, die hohe Infektionsrate nach Lebertransplantation zu reduzieren. Nach 53 konsekutiven orthotopen Leberverpflanzungen bei 51 Patienten zwischen 1985 and 1987 traten als klinisch bedeutsamste Infekte 8 Pneumonien auf. Bei 4 Patienten waren these bakterieller Natur, 2 durch Cytomegalovirus verursacht, 1 durch Pneumocystis carnii and 1 durch Candida. 6 Patienten hatten eine Septikämie, wobei nur in 1 Fall ein Venenkatheter als Ausgangspunkt identifiziert werden konnte. Alle Proben zusammengenommen wurde am häufigsten Streptokokkus faecalis kultiviert, ein Keim, der durch das angewendete antimikrobielle Regime nicht erfaßt wird. Pseudomonaden hingegen und gramnegative Stäbchen wurden in einem wesentlich geringeren Prozentsatz nachgewiesen. Vaginale and orale Candidainfektionen erlangten ebenso wie orale and genitale Herpes simplex-Infektionen kaum Krankheitswert und wurden jeweils topisch mit einem Antimykotikum bzw. Acyclovir behandelt. Neben den 2 CMV-Pneumonien wurden auch 3 durch CMV verursachte Hepatitiden beobachtet. Alle CMV-Infekte konnten mit Gancyclovir und Hyperimmunglobulin bei gleichzeitiger Reduktion der Basisimmunosuppression beherrscht werden. Von 15 Patienten, die wegen posthepatitischer Zirrhose transplantiert wurden waren, entwickelten 7 eine Reinfektion des Transplantates (5 HBV, 2 HCV), wovon 2 an der Zirrhose verstarben, 3 mit einer Zirrhose and noch ausreichender Transplantatfunktion leben, wie auch der Patient, der eine chronisch aktive Hepatitis entwickelt hatte. Eine im akuten Leberversagen transplantierte Patientin hat das Deltavirus innerhalb eines Jahres eliminiert. In der perioperativen Phase wurde jedoch kein einziger Patient an einer infektiösen Komplikation verloren, so da auch bei fehlender Kontrollgruppe die Darmdekontamination sowie die antibiotische Kurzzeitprophylaxe empfohlen werden können.

     

Carnitine depletion during total parenteral nutrition despite oral L-carnitine supplementation

Carnitine (CAR) plays an important role in the β-oxidation of fatty acids. Less attention, however, has been paid to CAR compared to other nutrients even in total parenteral nutrition (TPN). To examine CAR metabolism during TPN and the effect of simultaneous oral L-CAR supplementation on CAR levels, the blood CAR level was measured in a 3-year-old boy receiving long-term TPN because of short bowel syndrome. Both the total and acyl CAR in the serum were evaluated under various nutritional conditions including oral supplementation of L-CAR. Low CAR concentrations were observed especially when lipid containing TPN regimens were in place. Oral L-CAR supplementation was not sufficient to restore the low CAR levels in the present index patient even when the dose was increased to 120 mg/kg in accordance with the result of the L-CAR absorption test that revealed poor intestinal absorption of this nutrient. Moreover, a markedly low CAR level was measured during the onset of sepsis in the patient, and the blood CAR was depleted when lipid metabolism was activated by lipid loading or sepsis. To date, the late effects of CAR depletion on child growth have not been well examined. It is recommended that the blood CAR level be maintained at normal levels before any prominent manifestations of the deficiency have developed. The intravenous administration of CAR appears to be necessary to supply a sufficient amount of CAR for patients with severe malabsorption.