In-Vitro Activity of Polymyxin B, Rifampicin, Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii in Singapore

OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CR-AB) is an emerging cause of nosocomial infections worldwide. Combination therapy may be the only viable option until new antibiotics become available. The objective of this study is to identify potential antimicrobial combinations against CR-AB isolated from our local hospitals. METHODS: AB isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All CR-AB isolates were genotyped using a PCR-based method. Clonal relationship was elucidated. Time-kill studies (TKS) were conducted with polymyxin B, rifampicin and tigecycline alone and in combination using clinically relevant (achievable) unbound concentrations. RESULTS: 31 CR AB isolates were identified. They are multidrug-resistant, but are susceptible to polymyxin B. From clonal typing, 8 clonal groups were identified and 11 isolates exhibited clonal diversity. In single TKS, polymyxin B, rifampicin and tigecycline alone did not exhibit bactericidal activity at 24 hours. In combination TKS, polymyxin plus rifampicin, polymyxin B plus tigecycline and tigecycline plus rifampicin exhibited bactericidal killing in 13/31, 9/31 and 7/31 isolates respectively at 24 hours. Within a clonal group, there may be no consensus with the types of antibiotics combinations that could still kill effectively. CONCLUSION: Monotherapy with polymyxin B may not be adequate against polymyxin B susceptible AB isolates. These findings demonstrate that in-vitro synergy of antibiotic combinations in CR AB may be strain dependant. It may guide us in choosing a pre-emptive therapy for CR AB infections and warrants further investigations

Targeting dyslipidemia in the Metabolic Syndrome: An update

Background: The management of the Metabolic Syndrome (MetS) includes lifestyle interventions (e.g. diet and exercise for weight reduction), as well as drug treatment to normalize blood pressure, high-density lipoprotein cholesterol, triglycerides and glucose values. Treatment of atherogenic dyslipidemia should comprise a primary therapeutic target since it is associated with an increased risk of cardiovascular disease. Objective: To review the efficacy of the drugs available for the management of the dyslipidemia associated with MetS. Methods: MEDLINE was searched up to May 10, 2009 for studies in English using the mesh-terms "metabolic syndrome", "hypercholesterolemia", "dyslipidemia", "treatment", "statins" and "cardiovascular disease" in various combinations to identify treatment strategies for the management of the dyslipidemia of the MetS. Results/Conclusions: Several drugs have been described for the management of the dyslipidemia of the MetS, namely statins, fibrates, ezetimibe, niacin, bile acid sequestrants, cholesteryl ester transfer protein inhibitors, as well as combined treatment regimes. Although each of these may deal to some extent with some aspect of the dyslipidemia of the MetS compared with placebo, a direct comparison of all these agents has not been carried out. A head-to-head comparison between the suggested regimes could identify the mono- or combination therapy for the optimal management of dyslipidemia associated with MetS. © 2010 Bentham Science Publishers Ltd

Beneficial effects of sildenafil on tissue perfusion and inflammation in a murine model of limb ischemia and atherosclerosis

Background: Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has endothelium protective and angiogenic effects. Objectives: To test if sildenafil improves tissue perfusion and neovascularization and downregulates proinflammatory molecules following limb ischemia. Methods: 30 ApoE-/- male mice, bred with cholesterol rich diet for 4 weeks, were anesthetized and underwent unilateral hind-limb ischemia with ligation of the left femoral artery. Mice were randomized in 2 groups: sildenafil (1 mg/Kg for 7 days intraperitoneally, i.p.) or normal saline (0.4 ml for 7 days, i.p.). Bilateral hind-limb perfusion was estimated by laser Doppler imaging after surgery on days 0, 7 and 28. Results: Sildenafil significantly reduced at day 28 compared with day 0 levels of soluble intracellular adhesion molecule-1(sICAM-1) [2.24(1.81-2.41) vs. 1.29(0.87-1.45) ng/ml, p=0,01], soluble E-selectin (sE-Selectin) [5.52 (3.67-6.14) vs 1.71 (1.42-2.86) ng/ml, p=0.02] and tissue plasminogen activator inhibitor- 1 (tPAI-1) [0.13(0.07-0.21) vs 0.08 (0.04-0.10) ng/ml, p=0.01] while normal saline had no effect on the levels of sICAM-1, sE-Selectin and tPAI-1. Treatment with sildenafil was associated with increased perfusion in the ischemic limb compared with controls. Conclusion: Sildenafil exerts significant beneficial effects on tissue perfusion and inflammatory status after limb ischemia, a finding implying neovascularization and potential vascular protective properties of sildenafil. © 2017 Bentham Science Publishers

Adiponectin and interleukin-6 levels in insulin-treated diabetic rats with experimental periodontitis

The aim of the study was to compare the serum levels of adiponectin and interleukin-6 (IL-6) in insulin-treated diabetic rats with or without periodontitis. Forty male Wistar rats were randomly divided into 2 groups (20 rats each): a) insulin-treated diabetic group (control, DI) and b) insulin-treated diabetic periodontitis group (test, DIP). Diabetes was induced, and insulin treatment was initiated on day 5. On day 16, periodontitis was induced in the DIP group. All rats were euthanized on day 77. Adiponectin and IL-6 were assessed on days 16 and 77. At the end of the experiment, 14 and 11 rats survived in the DI and DIP groups, respectively. Adiponectin levels were statistically significantly higher at the end of the experiment compared with levels on day 16 in the periodontitis group (p < 0.05), but not in the control group. At the end of the experiment, adiponectin levels were statistically significantly higher in the periodontitis group compared with the control group (p < 0.05). Within-group and between-group comparisons of IL-6 levels showed no statistically significant difference. In conclusion, serum adiponectin was increased in insulin-treated diabetic rats with periodontitis in comparison with insulin-treated diabetic rats, while IL-6 levels did not differ between groups

Experimental replacement of pig trachea with novel bioprosthesis from harp Seal

Tracheal replacement has been a challenging problem for thoracic surgeons for over half of a century. We evaluated the in-vivo performance of a new tracheal bioprosthesis derived from Harp seal (Phoca groelandica) trachea that was fixed and preserved in 0.625% buffered glutaraldehyde solution for 3 months. Ten young male pigs weighing 27-32 kg (mean, 28.7 kg) underwent replacement of a tracheal segment with this new bioprosthesis. The length of replaced trachea was 1.8-2.4 cm (mean, 2.17 cm), representing 2-3 cartilage rings. All pigs survived the operation uneventfully. No immunosuppression drugs were used. The pigs eventually developed dyspnea and were euthanized on postoperative day 17-39 (mean, 30.8 days). Macroscopic and histological analysis showed an intact bioprosthesis but near-total occlusion of the native trachea by a ring of inflammatory infiltration at the site of distal anastomosis. More experiments involving a different concentration of the preservation agent, different management, and perhaps the use of bioengineering techniques are needed to improve the performance of this novel bioprosthesis. © 2010 SAGE Publications

Oral supplementation with L-aspartate and L-glutamate inhibits atherogenesis and fatty liver disease in cholesterol-fed rabbit

Previous studies have shown that dietary supplementation with L-aspartate and L-glutamate inhibits fatty streak initiation in cholesterol-fed rabbit. The present study investigates the role of dicarboxylic amino acids on the progression of fatty streaks and the development of fatty liver disease, which were caused in New Zealand White rabbits after a 0.5% w/w cholesterol diet for 7 weeks. A group of animals additionally received a combination of 12.5 mM L-aspartate and 12.5 mM L-glutamate per day through drinking water. Total cholesterol (TC), high-density lipoproteins cholesterol (HDLC), non-HDLC and triacylglycerol (TAG) concentrations were measured in plasma. Serum gamma-glutamyl transferase (γ-GT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were also determined. At the end of dietary intervention, animals were sacrificed. Aortic, hepatic and brain lesions were evaluated after staining with hematoxylin and eosin. Supplementation with dicarboxylic amino acids inhibited the progression of aortic intima thickness (P < 0.05) and the development of liver lesions (P < 0.05). TC, non-HDLC and TAG were similarly increased in both cholesterol-fed groups. Serum γ-GT and AST activities elevated during the study in all cholesterolfed animals but the elevation of γ-GT was milder and significantly lower in rabbits treated with L-aspartate and L-glutamate (P < 0.05). ALT activity was not affected by cholesterol feeding. In conclusion, oral supplementation with L-aspartate and L-glutamate inhibits the progression of atherogenesis and the development of fatty liver disease in the animal model of cholesterol-fed rabbit. The beneficial effects of dicarboxylic amino acids reflect the limited elevation of serum γ-GT activity. © Springer-Verlag 2009

Infusion of lin-/sca-1+ and endothelial progenitor cells improves proinflammatory and oxidative stress markers in atherosclerotic mice

Background: The effects of direct infusion or indirect mobilization of progenitor cells on atherosclerotic plaque development and progression are not clear. We sought to investigate the effects of hematopoietic progenitors lineage negative/stem cell antigen-1 positive (lin-/sca-1+) cells, endothelial progenitor cells and G-CSF administration on the inflammatory and oxidative component of atherosclerosis. Methods: Splenectomized ApoE-/- C57BL/6 J mice (6-8 weeks of age) fed with a high-fat, cholesterol-rich diet for 6 weeks, were divided in four groups (n = 10/group) and received two intravenous injections of 5 × 105 cells (lin-/sca-1+ or EPCs), or granulocyte colony-stimulating factor (G-CSF 100 μg/kg/day) for 7 days or normal saline. sVCAM-1 (Vascular cell adhesion protein 1), sICAM-1 (soluble intercellular adhesion molecule-1), sE-Selectin, Metalloproteinase 9 (MMP-9), Plasminogen activator inhibitor (PAI-1), Interleukin 6 (IL-6), oxidized LDL (ox-LDL) levels and lipid PEROX were evaluated at the day of the first infusion, 7 days later and 6 weeks post-treatment with ELISA. Results: The administration of both G-CSF and progenitor cells significantly decreased the levels of sICAM-1, sVCAM-1,sE-Selectin, IL-6, ox-LDL and lipid Perox 6 weeks after the initiation of treatment. No significant effects of lin-/sca-1+ cells, EPCs and G-CSF on PAI-1 and MMP-9 levels were observed. The effects of all treatments on the levels of pro-inflammatory molecules and oxidative stress parameters 7 days post-treatment were not significant. Interestingly, the levels of sICAM-1and sE-selectin were increased 7 days post-treatment. Conclusions: Direct infusion of progenitor cells and indirect mobilization of hematopoietic progenitor cells significantly decreased the levels of proinflammatory molecules and oxidative stress parameters in a murine model of atherosclerosis. The principal novelty of this work is that treatment with hematopoietic progenitors, EPCs or G-CSF may exert beneficial effects on vascular inflammation and atherosclerotic plaque development. © 2012 Elsevier Ireland Ltd

A surgical rat model of sleeve gastrectomy with staple technique: Long-term weight loss results

Background: Sleeve gastrectomy (SG) is one of the surgical procedures applied for treating morbid obesity consisting of removing the gastric fundus and transforming the stomach into a narrow gastric tube. The aim of this experimental study is to create a functional model of SG and to present the long-term weight loss results. Methods: Twenty adult Wistar rats were fed with high fat diet for 12 weeks before being divided randomly in two groups of ten rats each. One group underwent SG performed with the use of staples, and the other group underwent a sham operation (control group). The animals' weight was evaluated weekly for 15 weeks after the operation. Results: All animals survived throughout the experiment. After the operation both groups started to lose weight with maximum weight loss on the seventh postoperative day (POD) for the sham-operated group and on the 15th POD for the SG group. Thereafter, both groups started to regain weight but with different rates. By the fourth postoperative week (POW), the average weight of the sham group did not differ statistically significantly compared to the preoperative weight, while after the eighth POW, rats' average weight was statistically significantly increased compared to the preoperative value. On the other hand, average weight of the SG group was lower postoperatively until the end of the study compared to the preoperative average weight. Conclusion: We have created a surgical rat model of experimental SG model, enabling the further study of biochemical and hormonal parameters. © 2009 Springer Science + Business Media, LLC