Assessment of prophylactic antibiotics administration for acute pancreatitis: a meta-analysis of randomized controlled trials.

BACKGROUND: Recent evidence has shown that prophylactic antibiotic treatment in patients with acute pancreatitis is not associated with a significant decrease in mortality or morbidity. The use and efficacy of prophylactic antibiotic treatment in acute pancreatitis remain controversial. This meta-analysis was conducted to assess whether antibiotic prophylaxis is beneficial in patients with acute pancreatitis. METHODS: We searched randomized controlled trials (RCTs) of prophylactic use of antibiotics using Medline (PubMed), Embase, the Cochrane Library, and Web of Science. The data were analyzed using Review Manager 5.3 software. We performed pooled analyses for infected pancreatic necrosis, mortality, surgical intervention, and non-pancreatic infection. Odds ratios (ORs) from each trial were pooled using a random or fixed effects model, depending on the heterogeneity of the included studies. Sub-group analysis or sensitivity analysis was conducted to explore potential sources of heterogeneity, when necessary. RESULTS: Totally, 11 RCTs involving 747 participants were included, with an intervention group (prophylactic use of antibiotics, n = 376) and control group (n = 371). No significant differences were found regarding antibiotic prophylaxis with respect to incidence of infected pancreatic necrosis (OR, 0.74; 95% confidence interval [CI], 0.50-1.09; P = 0.13), surgical intervention (OR, 0.92; 95% CI, 0.62-1.38; P = 0.70), and morality (OR, 0.71; 95% CI, 0.44-1.15; P = 0.16). However, antibiotic prophylaxis was associated with a statistically significant reduction in the incidence of non-pancreatic infection (OR, 0.59; 95% CI, 0.42-0.84; P = 0.004). CONCLUSIONS: Prophylactic antibiotics can reduce the incidence of non-pancreatic infection in patients with AP.

MicroRNA-34c Suppresses Breast Cancer Migration and Invasion by Targeting GIT1.

Abnormal expression of microRNAs plays important role in tumor metastasis. Migration and invasion of cancer cells accord for the metastasis and deterioration of breast cancer. However, the regulatory role of microRNAs in the invasion and migration of breast cancer cells has not completely understood yet. Here we found that microRNA-34c (miR-34c) was significantly downregulated in metastatic tissue of breast cancer. In vitro study showed that miR-34c negatively regulated GIT1 protein expression by binding to the 3'UTR of GIT1 mRNA. Consistently, GIT1 protein expression was found upregulated significantly in metastatic breast cancer. Moreover, miR-34c overexpression suppressed the expression of GIT1 protein, and this effect was restored by AMO-miR-34c in breast cancer cells. Overexpression of miR-34c suppressed cell migration and invasion in both MCF-7 and MDA-MD-231 breast cancer cells. Furthermore, knockdown of endogenous GIT1 expression reduced the migration and invasion of both two breast cancer cells. Collectively, miR-34c downregulation in breast cancer cells resulted in the upregulation of GIT1, which in turn enhanced the migration and invasion of breast cancer. This study highlights molecular mechanism of migration and invasion of breast cancer cells.

A diversity-oriented synthesis of bioactive benzanilides via a regioselective C(sp2)-H hydroxylation strategy.

A diversity-oriented synthesis of bioactive benzanilides via C(sp2)-H hydroxylation has been studied. Different regioselectivity was observed with Ru(ii) and Pd(ii) catalysts. The reaction demonstrates excellent regioselectivity, good tolerance of functional groups, and high yields. A wide range of ortho-hydroxylated-benzanilides can be readily synthesized with excellent regioselectivity via this new synthetic strategy. Computational investigations revealed that the regioselectivity was controlled mainly by both steric and electronic factors. Steric effects determine the regioselective outcomes in the Ru-catalyzed reaction, while electronic effects are dominant in the Pd-catalyzed reaction.

[Effect of mild moxibustion on macrophage number and collagen expression of raw surface tissue in chronic refractory skin ulcer rats].

OBJECTIVE: To observe the effect of mild moxibustion on the number of macrophages and contents of collagen I and III in the raw surface tissue in chronic skin ulcer rats so as to study its mechanism underlying promoting scar formation. METHODS: Eighty male SD rats were randomly divided into normal (n = 8), model (n = 24), TDP (n = 24) and moxibustion (n = 24) groups. Chronic refractory skin ulcer was established by making an open wound at the back and local intramuscular injection of hydrocortisone sodium succinate. For rats of the TDP and moxibustion groups, TDP irradiation or mild moxibustion was applied to the raw surface, bilateral "Shenshu" (BL 23) and "Zusanli" (ST 36) for 15 min, once daily for 7, 10 and 14 days, respectively. The number of macrophages in the raw surface tissue was counted under light microscope after H. E. staining and col- lagen I and III expressions of the raw surface tissue were detected by immunohistochemistry. RESULTS: In comparison with the normal group, the numbers of macrophages in the raw surface tissue were increased significantly in the model group on day 7, 10 and 14 (P < 0.05); while compared with the model group, the numbers of macrophages were increased further obviously in the moxibustion group on day 7 and 10 and in the TDP group on day 10 after the treatment (P < 0.05). Compared with the model group, the numbers of macrophages in both TDP and moxibustion groups were down-regulated obviously (P < 0. 05). In regard to collagen I and III expression of the raw surface tissue, compared with the normal group, the collagen I protein expression level was down-regulated markedly in the model group on the 7th day (P < 0.01); whereas in comparison with the model group, the expression levels of collagen I and III were increased considerably in the TDP and moxibustion groups on day 7 and 14 after the treatment (P < 0.05, P < 0.01). The ratios of collagen I/III expression were remarkably higher in the model group than in the normal group on day 7 and 14 (P < 0.05), and significantly lower in the TDP group on day 7 and 14 and in the moxibustion group on day 14 than in the model group (P < 0.05, P < 0.01). The effects of moxibustion were obviously superior to those of TDP in up-regulating macrophage number on day 10, up-regulating collagen I and III expressions on day 14, and down-regulating macrophage number on day 14 after the treatment (P < 0.05, P < 0.01). No significant differences were found between the TDP and moxibustion groups in up-regulating macrophage number, and collagen I and III protein expressions, and in down-regulating the ratios of collagen I/III expression on day 7 after the treatment (P > 0.05). CONCLUSION: Mild moxibustion can regulate the number of macrophages and strengthen the expression of collagen proteins in the raw surface tissue in the chronic skin ulcer rats, which may contribute to its effect in promoting wound healing and reducing scar formation.

[Effect of mild-warm moxibustion on microcirculation in the raw surface tissue of chronic refractory wound in skin ulcer rats].

OBJECTIVE: To observe the effects of mild-warm moxibustion on dynamic blood flow, microvessel count (MVC)and vascular endothelial growth factor (VEGF) expression in the wound tissue of the chronic skin ulcer in rats, so as to reveal its underlying mechanism in promoting wound recovery. METHODS: A total of 104 male SD rats with skin injury were randomly divided into control group (n=8), model group (n=32), TDP (far-infrared heating device) group (n=32) and moxibustion group (n=32). Chronic refractory raw surface wound model was established by muscular injection of Hydrocortisone Sodium Succinate. For rats of the TDP and moxibustion groups, TDP irridiation and mild-warm moxibustion were applied to the raw surface, bilateral "Shenshu" (BL 23) and "Zusanli" (ST 36) for 15 min, once daily for 3, 7 and 14 days respectively. The healing rate and the healing time of raw surface of the wound were observed. The blood flow of the raw surface of the wound tissue was measured by laser Doppler flowmeter and the MVC in granulation tissue of chronic skin ulcer was counted under light microscope. VEGF expression was detected by immunohistochemistry. RESULTS: In comparison with the control group, the healing rate of the wound raw surface was significantly lower and the healing time was prolonged in the model group (P < 0.01). Compared with the model group, the healing rates on day 3, 7, 10 and 14 were significantly higher and the healing time was strikingly faster in both TDP and moxibustion groups (P < 0.01, P < 0.05), and the effects of the moxibustion group in increasing the healing rate and shortening the healing time were significantly better than those of TDP group (P < 0.01). In comparison with the model group, the blood flow volume, MVC and VEGF expression levels on day 3 and 7 were upregulated significantly in both TDP and moxibustion groups (P < 0.01, P < 0.05); while the blood flow volume, MVC and VEGF expression level in the moxibustion group and the blood flow volume and VEGF expression level in the TDP group downregulated considerably on day 14 (P < 0.01). No significant difference was found between the TDP and moxibustion groups in the MVC on day 14 after the treatment (P > 0.05). CONCLUSION: Mild-warm moxibustion can promote wound healing, which is closely with its effects in increasing blood flow and MVC, and upregulating VEGF expression in the wound granulation tissue of the chronic skin ulcer.

[Antireflux anastomosis following resection of esophageal cancer].

OBJECTIVE: To investigate the antireflux effects of a modified Nissen fundoplication following esophagectomy for cancer. METHODS: From March 2006 to March 2007, 70 patients with esophageal cancer were divided into two groups randomly. Esophagogastrostomy with a stapler only was perform in 35 patients as controls (group C), and a modified Nissen fundoplication was added after esophagogastrostomy with stapler in the other 35 patients as observed group (group O). There were 48 male and 22 female, ranging in age from 47 to 77 years (mean 60.1 years). The operative morbidity and mortality were recorded. Fourty-nine patients were followed at 3 months after surgery, and the questionnaire of life quality (EORTC QLQ C-30) was conducted in 24 patients in group C and 25 patients in group O. Thirty patients were examined with esophageal manometry, 24 h pH monitoring and gastroscopy. There were 16 patients in group C and 14 patients in group O. RESULTS: There was no significant difference in postoperative morbidity between the two groups (P > 0.05). However, the scores of heart burn and regurgitation in the group O were less than in group C (P = 0.041 and 0.034 respectively), but there was no difference in scores of dysphagia between the two groups (P = 0.677). The pressure at the anastomotic site was higher than that in the stomach in group O (P = 0.032), but not in group C (P = 0.448). DeMeester score in group O was 53 ± 46, compared to 140 ± 103 in group C (P = 0.043). The score of esophagitis was 0.9 ± 0.8 in group O, which was lower than 1.6 ± 1.0 in group C (P = 0.041). CONCLUSIONS: Addition of modified Nissen fundoplication after esophagectomy and esophagogastrostomy for cancer significantly increases the pressure at the anastomotic site, thus reduces the extent of gastroesophageal reflux, which leads to the reduction of the extent of reflux esophagitis and the improvement of the quality of life.

Selective modulation of protein C affinity for EPCR and phospholipids by Gla domain mutation.

Uniquely amongst vitamin K-dependent coagulation proteins, protein C interacts via its Gla domain both with a receptor, the endothelial cell protein C receptor (EPCR), and with phospholipids. We have studied naturally occurring and recombinant protein C Gla domain variants for soluble (s)EPCR binding, cell surface activation to activated protein C (APC) by the thrombin-thrombomodulin complex, and phospholipid dependent factor Va (FVa) inactivation by APC, to establish if these functions are concordant. Wild-type protein C binding to sEPCR was characterized with surface plasmon resonance to have an association rate constant of 5.23 x 10(5) m(-1).s(-1), a dissociation rate constant of 7.61 x 10(-2) s(-1) and equilibrium binding constant (K(D)) of 147 nm. It was activated by thrombin over endothelial cells with a K(m) of 213 nm and once activated to APC, rapidly inactivated FVa. Each of these interactions was dramatically reduced for variants causing gross Gla domain misfolding (R-1L, R-1C, E16D and E26K). Recombinant variants Q32A, V34A and D35A had essentially normal functions. However, R9H and H10Q/S11G/S12N/D23S/Q32E/N33D/H44Y (QGNSEDY) variants had slightly reduced (< twofold) binding to sEPCR, arising from an increased rate of dissociation, and increased K(m) (358 nm for QGNSEDY) for endothelial cell surface activation by thrombin. Interestingly, these variants had greatly reduced (R9H) or greatly enhanced (QGNSEDY) ability to inactivate FVa. Therefore, protein C binding to sEPCR and phospholipids is broadly dependent on correct Gla domain folding, but can be selectively influenced by judicious mutation.

Enhanced rate of cleavage at Arg-306 and Arg-506 in coagulation factor Va by Gla domain-mutated human-activated protein C.

A Gla domain-mutated protein C variant, QGNSEDY, modified at positions 10-12, 23, 32-33, and 44, having enhanced affinity for negatively charged phospholipid and increased anticoagulant potential, was used to elucidate the importance of the interaction between the Gla domain and the phospholipid for the ability of activated protein C (APC) to inactivate factor Va (FVa). FVa degradation by wild type (WT)-APC and QGNSEDY-APC yielded similar fragments on Western blotting; QGNSEDY-APC was, however, considerably more efficient. The kinetic parameters for individual APC-mediated cleavages in FVa, i.e. at Arg-306 and Arg-506, were investigated at high and low phospholipid concentrations in the presence and absence of protein S. FVa variants 306Q679Q and 506Q679Q, which can only be cleaved at Arg-506 and Arg-306, respectively, were used. In the absence of protein S, QGNSEDY-APC was 17.8- and 4-fold more efficient than WT-APC in cleaving at Arg-306 and Arg-506, respectively, at high phospholipid. Similar values were obtained at low phospholipid. In the presence of protein S, QGNSEDYAPC was 6.8- and 3.2-fold more active than WT-APC in cleaving at Arg-306 and Arg-506, respectively, at high phospholipid. At low phospholipid, the corresponding values were 14- and 6.5-fold. In conclusion, the modification of the Gla domain in QGNSEDY-APC yielded increased rates of cleavage at both sites in FVa, the increase being particularly pronounced for the Arg-306 site in the absence of protein S. The results obtained with QGNSEDY-APC provide insights into the importance of the APC-phospholipid interaction for the APC-mediated cleavages at Arg-306 and Arg-506 in FVa.

Gla domain-mutated human protein C exhibiting enhanced anticoagulant activity and increased phospholipid binding.

Protein C is a member of the vitamin K- dependent protein family. Proteins in this family have similar gamma-carboxyglutamic acid (Gla)-rich domains, but their affinities for negatively charged phospholipid membranes vary more than 1000-fold. We have shown that it is possible to enhance anticoagulant activity and membrane affinity of protein C by selective mutagenesis of the Gla domain. In this study, 3 new mutants, Q10G11N12 (QGN), S23E32D33Y44 (SEDY), and Q10G11N12S23E32D33Y44 (QGNSEDY), were created. In plasma-based coagulation assays, the activated form of QGNSEDY (QGNSEDY-APC) demonstrated approximately 20-fold higher anticoagulant activity than wild-type activated protein C (WT APC), while QGN-APC and SEDY-APC did not. Both normal activated factor V (FVa) and FVa Leiden (Arg506Gln) were degraded much more efficiently by QGNSEDY-APC than by WT APC in the presence as well as in the absence of protein S. Binding of protein C variants to negatively charged phospholipid membranes was investigated using light scattering and the BIAcore technique. QGNSEDY demonstrated 3- to 7-fold enhanced binding as compared with WT protein C, suggesting the membrane affinity to be influenced by several residues located at different parts of the Gla domain. The anticoagulant activity as well as phospholipid binding ability was only enhanced when multiple regions of the Gla domain were modified. The results provide insights into the molecular mechanisms that are involved in determining the binding affinity of the interaction between Gla domains and phospholipid membranes. The unique properties of QGNSEDY-APC suggest this APC variant possibly to have greater therapeutic potential than WT APC.