Factor XII and prekallikrein promote microvascular inflammation and psoriasis in mice.

BACKGROUND AND PURPOSE: Psoriasis is an autoimmune inflammatory skin disease, featuring microvascular abnormalities and elevated levels of bradykinin. Contact activation of Factor XII can initiate the plasma kallikrein-kinin cascade, producing inflammation and angioedema. The role of Factor XII in psoriasis is unknown. EXPERIMENTAL APPROACH: The effects of deficiency of Factor XII or its enzymatic substrate, prekallikrein, were examined in the imiquimod-induced mouse model of psoriasis. Skin microcirculation was assessed using intravital confocal microscopy and laser Doppler flowmeter. A novel antibody blocking Factor XII activation was evaluated for psoriasis prevention. KEY RESULTS: Expression of Factor XII was markedly up-regulated in human and mouse psoriatic skin. Genetic deletion of Factor XII or prekallikrein, attenuated imiquimod-induced psoriatic lesions in mice. Psoriatic induction increased skin microvascular blood perfusion, causing vasodilation, hyperpermeability and angiogenesis. It also promoted neutrophil-vascular interaction, inflammatory cytokine release and enhanced Factor XII / prekallikrein enzymatic activity with elevated bradykinin. Factor XII or prekallikrein deficiency ameliorated these microvascular abnormalities and abolished bradykinin increase. Antagonism of bradykinin B2 receptors reproduced the microvascular protection of Factor XII / prekallikrein deficiency, attenuated psoriatic lesions, and prevented protection by Factor XII / prekallikrein deficiency against psoriasis. Furthermore, treatment of mice with Factor XII antibody alleviated experimentally induced psoriasis and suppressed microvascular inflammation. CONCLUSION AND IMPLICATIONS: Activation of Factor XII promoted psoriasis via prekallikrein-dependent formation of bradykinin, which critically mediated psoriatic microvascular inflammation. Inhibition of contact activation represents a novel therapeutic strategy for psoriasis.

Microsomal prostaglandin E synthase-1 inhibition prevents adverse cardiac remodelling after myocardial infarction in mice.

BACKGROUND AND PURPOSE: Heart failure with reduced ejection fraction (HFrEF) is a major consequence of myocardial infarction (MI). The microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway has been shown to constrain reperfusion injury after acute myocardial ischaemia. However, it is unknown whether pharmacological inhibition of mPGES-1, a target with lower risk of thrombosis compared with selective inhibition of cyclooxygenase-2, affects chronic cardiac remodelling after MI. EXPERIMENTAL APPROACH: Mice were subjected to left anterior descending coronary artery ligation, followed by intraperitoneal treatment with the mPGES-1 inhibitor compound III (CIII) or 118, celecoxib (cyclooxygenase-2 inhibitor) or vehicle, once daily for 28 days. Urinary prostanoid metabolites were measured by liquid chromatography-tandem mass spectrometry. KEY RESULTS: Chronic administration of CIII improved cardiac function in mice after MI compared with vehicle or celecoxib. CIII did not affect thrombogenesis or blood pressure. In addition, CIII reduced infarct area, augmented scar thickness, decreased collagen I/III ratio, decreased the expression of fibrosis-related genes and increased capillary density in the ischaemic area. Shunting to urinary metabolites of PGI2 , not thromboxane B2 or PGD2 , after inhibition of mPGES-1 was positively correlated with cardiac function after MI. CIII administration significantly increased urinary PGI2 /PGE2 metabolite ratio compared to vehicle or celecoxib. The PGI2 /PGE2 metabolite ratio correlated positively with ejection fraction, fractional shortening and scar thickness. Treatment with 118 also improved cardiac function. CONCLUSION AND IMPLICATIONS: Inhibition of mPGES-1 prevented chronic adverse cardiac remodelling via an augmented PGI2 /PGE2 metabolite ratio and therefore represents a potential therapeutic strategy for development of HFrEF after MI.

"Fast Track" nasogastric decompression of rectal cancer surgery.

This study evaluates the application of fast track (FT) nasogastric decompression in patients who underwent anterior resection of rectal cancer. A randomized control trial was performed comparing the group with the fast track treatment (n = 57) and the group with traditional nasogastric decompression (n = 84). Preoperative characteristics and postoperative recovery indices were recorded and analyzed. The results indicate no significant differences in gender (P = 0.614), age (P = 0.653), tumor location (P = 0.113), and TNM stages (P = 0.054) were observed between the 2 groups. The differences in the type of resection, anastomosis, and adoption of protective colostomy were all not significant between the FT and the traditional group. During the first 24 hours after surgery, the volume of nasogastric drainage averaged 197 ml in the FT group and 155 ml in the traditional group (P = 0.197). The initiation of test-meal (P = 0.000), semiliquid diet (P = 0.002), and ordinary diet (P = 0.008) were all significantly shorter in the FT group. Furthermore, compared with the other group, the patients in the FT group enjoyed earlier removal of the abdominal drainage, urinary catheter, and shorter hospital stays (P = 0.000). Based on a correlation test, the duration of nasogastric decompression is related to the time of test-meal and semiliquid diet. The routine usage of nasogastric decompression in rectal surgery is unnecessary. The fast track procedure might help in facilitating postoperative functional and diet recovery, reducing the time of catheterization, and shortening hospital stay.

[A prospective study on quality of life in post-operative colorectal cancer patients with fast-track].

OBJECTIVE: To explore the impact of postoperative recovery and short term quality of life in the patients with colorectal cancer in fast track model. METHODS: There were 122 patients enrolled into this prospective study in Gastrointestinal Surgery Center, West China Hospital of Sichuan University, from October 2008 to January 2009, and 121 patients completed the whole study. The patients were divided into the fast track group (62 cases) and the tradition track group (59 cases), postoperative recovery and the QLQ-C30 scores were evaluated at one week after the surgery. RESULTS: The fast track group showed earlier recovery than the tradition group in first aerofluxus [(3.96 +/- 1.40) d vs. (5.66 +/- 3.11) d, P < 0.05], first intake [(3.12 +/- 1.93) d vs. (5.96 +/- 3.23) d, P < 0.05], first ambulation [(2.05 +/- 1.16) d vs. (5.13 +/- 1.36) d, P < 0.05] and in-hospital time post-operation [(7.85 +/- 5.31) d vs. (10.11 +/- 3.37) d, P < 0.05]. The incidence of wound infection (1.61% vs. 6.78%, P < 0.05) and intestinal obstruction (1.61% vs. 8.47%, P < 0.05) in fast track were significantly lower than those in the traditional track group. The general health of fast track in C30 is better too (80.46 +/- 15.54 vs. 76.58 +/- 15.28, P < 0.05). In the functional assessment of C30, the physical function (87.35 +/- 5.12 vs. 85.02 +/- 8.70, P < 0.05) and emotional function (90.00 +/- 0.00 vs. 85.35 +/- 12.39, P < 0.05) both were better in the fast track group. In the symptom assessment of C30, fast track group is less fatigue (71.70 +/- 2.86 vs. 87.12 +/- 10.80, P < 0.05) and pain (71.78 +/- 3.76 vs. 77.63 +/- 8.33, P < 0.05). Better sleep (75.78 +/- 11.68 vs. 82.70 +/- 19.40, P < 0.05) and less loss of appetite(73.24 +/- 8.60 vs. 78.02 +/- 16.42, P < 0.05) were found in fast track group. CONCLUSION: The fast track group manifested faster in postoperative recovery and can improve the quality of life in postoperative patients with colorectal cancer.

[Relationships among interleukin-1beta, interleukin-1 receptor antagonist gene polymorphism and susceptibility to gastric cancer].

OBJECTIVES: To investigate the genetic polymorphisms of interleukin-1B (IL-1B) and interleukin-1 receptor antagonist gene (IL-1RN) in gastric cancer, and to explore the relationships of these genetic polymorphisms to the susceptibility of gastric cancer. METHODS: The polymorphisms of IL-1B and IL-1RN genes were analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) after extracting the genomic DNA from 140 gastric cancer patients and 165 age- and sex-matched healthy controls. RESULTS: The polymorphisms of IL-1B promoter region -31, -511 and +3954 locus have no significant difference between gastric cancer patients and healthy subjects. Four kinds of polymorphisms of IL-1RN were found as 2R/2R, 2R/4R, 3R/4R and 4R/4R, and the frequency in gastric cancer patients were 0.7%, 15.7%, 2.9% and 80.7%, respectively, while the frequency in healthy controls were 0, 5.5%, 0 and 94.5%, respectively. Compared to 4R/4R genotype, a 3.37 fold increased risk of gastric cancer were found in 2R/4R genotype, but the difference was not significant (P = 0.557, chi2 = 2.076). IL-1RN 2R allele frequencies in gastric cancer and healthy controls were 8.6% and 2.7%, respectively, which showed the risk to be gastric cancer increased 3.4 times, but the difference was not significant (P = 0.781, chi2 = 0.494). CONCLUSION: There is no evidence to support that the polymorphism of IL-1B and IL-1RN gene had relationship with gastric cancer. However, the risk of developing gastric cancer might be raised when the IL-1RN 2R allele exist.

[Impact of mesorectal involvement on the outcome of patients with rectal cancer].

OBJECTIVE: To assess the relationship between the incidence and prognostic significance of mesorectal involvement. METHODS: 328 cases of rectal cancer resected with total or subtotal mesorectal excision in our hospital from Jan. 1997 to Dec. 1998 were followed up and analyzed in this study. The neoplastic foci were identified at the pathologic examination of the mesorectum. RESULTS: Neoplastic mesorectal metastasis was found in 234 cases (71.3%); node involvement in 59.8% and microscopic foci involvement in 36% of all cases (isolated in 11.6%, microfoci alone without any kind of other mesorectal involvement). Microscopic deposits were found in 10.3% of TNM Stage I tumors, in 18.4% of Stage II and in 45.1% of Stage III cancers. Five-year disease-free survival rate (49.6% vs. 91.4%) were observed in patients with mesorectal involvement, compared with those without deposits. CONCLUSION: The incidence of neoplastic foci in the mesorectum seem to affect prognosis, even in early staged tumors. The presence of mesorectal foci should be considered an index in modifying the conventional staging of the rectal tumor.