Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling

The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-alpha and TNF-alpha release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.     

Laparoscopic Pouch Resizing and Redo of Gastro-jejunal Anastomosis for Pouch Dilatation following Gastric Bypass

Background: With a dramatically increasing number of bariatric operations performed world-wide in the recent years, more late complications have been noticed. Proximal gastric pouch dilatation is a known late complication after laparoscopic or open restrictive surgery for morbid obesity. In the present paper, we report our experience with laparoscopic re-operation of enlarged gastric pouches after laparoscopic gastric bypass, with emphasis on technique and outcome. Methods: Data were retrieved from a prospective database of 334 patients who underwent a laparoscopic gastric bypass operation at the University Hospital of Zurich from July 2000 to December 2004. Five laparoscopic revisions for pouch dilatation after primary bypass were performed. Results: 3 female and 2 male patients with median age 40 years (range 32-55) underwent a laparoscopic pouch resizing. At the time of the re-operation, the median BMI was 32.0 kg/m² (range 28.4-48.4). All procedures were performed laparoscopically with no conversion to open surgery. The median operating-time was 110 minutes (95-120). The median hospital stay was 6 days (range 5-14). The median BMI in the follow-up of 12 months (9-14) was 28.0 kg/m² (25.5-45.8). Diabetes mellitus improved in 4 cases during follow-up. Conclusion: Laparoscopic pouch resizing with redo of the gastro-jejunal anastomosis was feasible, safe and effective in this small series. It led to further weight loss and improved symptoms of poor pouch emptying.     

A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning

OBJECTIVE: To evaluate the protective effects of ischemic preconditioning in a prospective randomized study involving a large population of unselected patients and to identify factors affecting the protective effects. SUMMARY BACKGROUND DATA: Ischemic preconditioning is an effective protective strategy in several animal models. Protection has also been suggested in a small series of patients undergoing a hemihepatectomy with 30 minutes of inflow occlusion. Whether preconditioning confers protection in other types of liver resection and longer periods of ischemia is unknown. Therefore, we conducted a prospective randomized study to evaluate the impact of ischemic preconditioning in liver surgery. METHODS: A total of 100 unselected patients undergoing major liver resection (> bisegmentectomy) under inflow occlusion for at least 30 minutes were randomized during surgery to either receive or not receive an ischemic preconditioning protocol (10 minutes of ischemia followed by 10 minutes of reperfusion). Univariate and multivariate analyses were performed to identify independent factors affecting the protective effects of ischemic preconditioning. ATP contents in liver were measured as a possible mechanism of protection. RESULTS: Both groups (n = 50 in each) were comparable regarding age, gender, duration of inflow occlusion, and resected liver volumes. Postoperative serum transaminase levels were significantly lower in preconditioned than in control patients (median peak AST 364 U/L vs. 520 U/L, P = 0.028; ALT 406 vs. 519 U/L, P = 0.049). Regression multivariate analysis revealed an increased benefit of ischemic preconditioning in younger patients, in patients with longer duration of inflow occlusion (up to 60 minutes), and in cases of lower resected liver volume (<50%). Patients with steatosis were also particularly protected by ischemic preconditioning. ATP content in liver tissue was preserved by ischemic preconditioning in young but not older patients. CONCLUSIONS: This study establishes ischemic preconditioning as a protective strategy against hepatic ischemia in humans. The strategy is particularly effective in young patients requiring a prolonged period of inflow occlusion, and in the presence of steatosis, and is possibly related to preservation of ATP content in liver tissue. Other strategies are needed in older patients.     

Inhibition of c-Jun N-terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anaesthetized rats

1 Myocardial ischemia/reperfusion is associated with inflammation, apoptosis and necrosis. During this process, c-jun N-terminal kinase is activated in cardiac myocytes resulting in apoptosis. 2 This study investigates the effects of AS601245, a nonpeptide ATP competitive JNK inhibitor, on infarct size caused by myocardial ischemia/reperfusion in anaesthetized rats. The left descending coronary artery of anaesthetized rats was occluded for 30 min and then reperfused for 3 h. AS601245 was administered 5 min before the end of the ischemia period as an i.v. bolus (1.5, 4.5 or 15 mg kg(-1) i.v.) followed by continuous i.v. infusion (18, 55 and 183 microg kg(-1) min(-1), respectively) during reperfusion. Controls received saline only. 3-Aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, was used as reference compound at 10 mg kg(-1) i.v. bolus plus 0.17 mg kg(-1) min(-1) continuous infusion. 3 AS601245 significantly reduced infarct size at 4.5 mg kg(-1) (-44%; P<0.001) and 15 mg kg(-1) i.v. (-40.3%; P<0.001) similarly to 3-aminobenzamide (-44.2%; P<0.001). This protective effect was obtained without affecting hemodynamics or reducing ST-segment displacement. 4 The beneficial effects on infarct size correlated well with the reduction of c-jun phosphorylation (-85%; P<0.001 versus control) and of TUNEL-positive cells (-82.1%; P<0.001) in post-ischemic cardiomyocytes. No change in the phosphorylation state of p38 MAPK and ERK in post-ischemic heart was observed in the presence of AS601245 in comparison to the vehicle-treated group. 5 These results demonstrate that blocking the JNK pathway may represent a novel therapeutic approach for treating myocardial ischemia/reperfusion-induced cardiomyocyte death.     

A study of interlaboratory influence on column evaluation

A liquid chromatography method for the characterization of base deactivated columns was investigated in a collaborative study involving six laboratories. This work was carried out on two chromatographic supports (Xterra RP 18 and Symmetry Shield). Different cooling systems, namely water bath and air oven, were tested and it was shown that column thermoregulation did not significantly influence chromatographic data. In order to control the mobile phase composition, the latter was prepared by weight rather than volume. Thanks to the injection of a set of selected neutral compounds, extra-column effects were evaluated in each of the participating laboratories. The results showed that chromatographic supports tested in different laboratories and following the same test protocol could be effectively compared.     

X-tox: an atypical defensin derived family of immune-related proteins specific to Lepidoptera

We report here the isolation in Spodoptera frugiperda (Lepidoptera) of an immune-related protein (hereafter named Spod-11-tox), characterized by imperfectly conserved tandem repeats of 11 cysteine-stabilized alpha beta motifs (CS-alphabeta), the structural scaffold characteristic of invertebrate defensins and scorpion toxins. Spod-11-tox orthologs were only found in Lepidopteran species, suggesting that this new protein family (named X-tox) is specific to this insect order. Moreover, phylogenetic analysis suggests that X-tox proteins represent a new class of proteins restricted to Lepidoptera and likely derived from Lepidopteran defensins. In S. frugiperda, analysis of gene expression revealed that spod-11-tox is rapidly induced by infection. However, and conversely to what is known for most insect antimicrobial peptides (AMP), spod-11-tox is mainly expressed in blood cells. Moreover, recombinant Spod-11-tox produced in the Sf9 cell line does not show any antimicrobial activity. Altogether, these results suggest that although X-tox proteins are derived from defensins, they may play a different and still unknown role in Lepidoptera immune response.     

Intravesical glucidic capsaicin versus glucidic solvent in neurogenic detrusor overactivity: a double blind controlled randomized study

AIMS: Many studies report the use of alcoholic capsaicin instillation to treat neurogenic detrusor overactivity (NDO) in spinal cord injured (SCI) and multiple sclerosis (MS) patients. However, poor tolerability due to the irritative effect of the ethanol solvent limits its use. Our study aimed to evaluate the efficacy and tolerability of a new formulation of capsaicin in a glucidic solution in a multicenter clinical trial. MATERIALS AND METHODS: Thirty-three patients (26MS/7SCI) suffering from urinary incontinence due to refractory NDO were prospectively enrolled in a double-blind placebo controlled study and randomized to capsaicin group (CG, N = 17) or solvent group (SG, N = 16). They respectively received an intravesical instillation of 100 ml capsaicin diluted in glucidic solvent (CG) or glucidic solvent alone (SG). Efficacy (voiding chart, maximum cystometric capacity (MCC)) and tolerability were evaluated on days 0 (D0), 30 and 90. RESULTS: On D0, groups were homogeneous. On D30, significant improvement of overactive bladder syndrome and an increase in MCC were shown in CG, whereas there were no improvement in SG. No significant improvement was shown on D90 in both groups. There were no significant differences between groups regarding prevalence, duration, or intensity of side effects, except for short duration pubic pain during instillation more often reported in CG (58.8%) than in SG (12.5%) (P < 0.01). CONCLUSION: This placebo controlled study using glucidic capsaicin confirms its short-term efficacy in NDO patients. Global tolerance of glucidic capsaicin appeared satisfactory. Long-term efficacy and tolerance of repeated glucidic capsaicin instillations need to be evaluated.