Physiologic Effects of Exogenous Dextrose in Murine Klebsiella pneumoniae Sepsis Vary by Route of Provision

Sepsis is characterized by a dysregulated immune response to infection. Nutrition is important in the care of septic patients, but the effects of specific nutrients on inflammation in sepsis are not well defined. Our prior work has shown benefits from early enteral dextrose infusion in a preclinical endotoxemia model of sepsis. In the current study, we extend our initial work to examine the effects of dextrose infusions, varying by route of administration, on inflammation and glycemic control in a more clinically relevant and translational model of Klebsiella pneumoniae (KP) bacteremia. Ten-week old C57BL6/J male mice (n = 31) underwent the implantation of indwelling vascular catheters, followed by inoculation with oropharyngeal KP. The mice were randomized 24 h after inoculation to (1) intravenous (IV) dextrose, (2) enteral dextrose, or (3) enteral saline (control) to study the effects on systemic inflammation, hemodynamics, and glycemic control. At 72 h, 77% of the control mice died, whereas IV dextrose induced 100% mortality, associated with increased inflammation, hyperglycemia, and hypotension. Enteral dextrose reduced mortality to 27%, promoted euglycemia, and reduced inflammation compared to IV dextrose. We conclude, in a bacteremic model of sepsis, that enteral (but not IV) dextrose administration is protective, suggesting that the route of nutrient support influences inflammation in sepsis.

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Effects of the Antitumor Drug OSI-906, a Dual Inhibitor of IGF-1 Receptor and Insulin Receptor, on the Glycemic Control, β-Cell Functions, and β-Cell Proliferation in Male Mice

Endocrinology ◽

10.1210/en.2013-2032 ◽

2014 ◽

Vol 155 (6) ◽

pp. 2102-2111 ◽

Cited By ~ 21

Author(s):

Jun Shirakawa ◽

Tomoko Okuyama ◽

Eiko Yoshida ◽

Mari Shimizu ◽

Yuka Horigome ◽

...

Keyword(s):

Insulin Resistance ◽

Cell Proliferation ◽

Insulin Secretion ◽

Glycemic Control ◽

Insulin Receptor ◽

Cell Mass ◽

Male Mice ◽

Β Cell ◽

Dual Inhibitor ◽

Cell Functions

The IGF-1 receptor has become a therapeutic target for the treatment of cancer. The efficacy of OSI-906 (linstinib), a dual inhibitor of IGF-1 receptor and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β-cell functions have not yet been reported. We investigated the impact of OSI-906 on glycemic control, insulin secretion, β-cell mass, and β-cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. Insulin receptor substrate (IRS)-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β-cell mass and β-cell proliferation rate were significantly increased. The insulin signals in the β-cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand, the results suggest that the β-cell mass may expand in response to chemotherapy with this drug.

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Klebsiella pneumoniae liver abscess in diabetic patients: association of glycemic control with the clinical characteristics

BMC Infectious Diseases ◽

10.1186/1471-2334-13-56 ◽

2013 ◽

Vol 13 (1) ◽

Cited By ~ 48

Author(s):

Yi-Tsung Lin ◽

Fu-Der Wang ◽

Ping-Feng Wu ◽

Chang-Phone Fung

Keyword(s):

Glycemic Control ◽

Klebsiella Pneumoniae ◽

Liver Abscess ◽

Clinical Characteristics ◽

Diabetic Patients

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Efficacy and Pharmacokinetics of the Combination of OP0595 and Cefepime in a Mouse Model of Pneumonia Caused by Extended-Spectrum-Beta-Lactamase-Producing Klebsiella pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00828-17 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 3

Author(s):

Norihito Kaku ◽

Kosuke Kosai ◽

Kazuaki Takeda ◽

Naoki Uno ◽

Yoshitomo Morinaga ◽

...

Keyword(s):

Combination Therapy ◽

Klebsiella Pneumoniae ◽

Mouse Model ◽

Therapy Group ◽

Saline Control ◽

Pharmacokinetic Analysis ◽

Beta Lactamase ◽

Extended Spectrum Beta Lactamase ◽

Extended Spectrum

ABSTRACT OP0595 (RG6080) is a novel diazabicyclooctane that inhibits class A and C serine beta-lactamases. Although the combination of OP0595 and cefepime (FEP) showed good in vitro activity against extended-spectrum-beta-lactamase (ESBL)-producing pathogens, the effect of the combination therapy against severe infections, such as pneumonia or bacteremia, remains unknown in vivo. In this study, we investigated the efficacy and pharmacokinetics of the combination therapy of OP0595 and FEP in a mouse model of pneumonia caused by Klebsiella pneumoniae harboring SHV- and CTX-M-9-type ESBLs. The infected BALB/c mice were intraperitoneally administered saline (control), 100 mg/kg of body weight of FEP, 20 mg/kg of OP0595, or both FEP and OP0595, twice a day. The MIC of FEP against the bacteria was 8 mg/liter and markedly improved to 0.06 mg/liter with the addition of 0.5 mg/ml of OP0595. In the survival study, the combination of FEP and OP0595 significantly improved the survival rate compared with that reported with either OP0595 or FEP alone (P < 0.001). The number of bacteria in the lungs and blood significantly decreased in the combination therapy group compared to that reported for the monotherapy groups (P < 0.001). In addition, the in vivo effect depended on the dose of FEP. However, pharmacokinetic analysis revealed that the percentage of time above MIC remained constant when increasing the dose of FEP in combination with 20 mg/kg of OP0595. The results of our study demonstrated the in vivo effectiveness of the combination of OP0595 and FEP.

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Immunohistochemical Expression of P16 Protein and TGF β1 in Mice Liver Exposed to Fumonisin B1

Baghdad Science Journal ◽

10.21123/bsj.2020.17.2.0401 ◽

2020 ◽

Vol 17 (2) ◽

pp. 0401

Author(s):

Sinai Mohammed et al.

Keyword(s):

Fusarium Species ◽

Critical Role ◽

Fumonisin B1 ◽

Structural Similarity ◽

Saline Control ◽

Control Group ◽

Male Mice ◽

P16 Protein ◽

Mice Liver ◽

Tgf Β1

Fumonisin B1 (FB1) is a mycotoxin produced in some grains (mainly corn) by Fusarium species. Due to a structural similarity between FB1 and sphinganine, sphingolipids metabolism is inhibited. Such inhibition plays a critical role in cell to cell singling and structure of lipoprotein; therefore FB1 has been suggested to have a relationship with human and animal cancer. This research is planned to study the effect of FB1 on male mice at two doses (20 and 30 µg/ ml) on the expression of TGF-β1 and p16 in liver cells. Three groups of Swiss albino male mice; each group was orally administrated with FB1 toxin as the following: normal saline (control group); 20 and 30 µg/ ml. All groups were sacrificed after two weeks of oral management. Liver samples were collected and prepared for immunohistochemistry technique (IHC) using anti-TGF-β1 and anti-p16 antibodies. The results showed that exposure to FB1 caused significant elevation of TGF-β1 in both doses (76.74 ± 2.387% and 80.62 ± 7.277%, respectively) in comparison with the control group (46.79 ± 2.404%). The level of p16 protein was decreased at 20 µg/ml (76.63 ± 2.349%) and then increased at 30 µg/ml (81.25 ± 6.263%) but the expression was lower than that of control (90.00 ± 0.805%). In conclusion, FB1 has a significant effect on TGF-β1 and p16 protein expression at both doses (20 and 30 µg/ml), and therefore, its role in cancer development is suggested.

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Cisplatin-induced neurotoxicity in cerebellar cortex of male mice involves oxidative stress and histopathology

The Journal of Basic and Applied Zoology ◽

10.1186/s41936-021-00220-3 ◽

2021 ◽

Vol 82 (1) ◽

Author(s):

Azza Attia ◽

Cecil Matta ◽

Reda ElMazoudy ◽

Hanan Khalifa

Keyword(s):

Oxidative Stress ◽

Cerebellar Cortex ◽

Molecular Layer ◽

Nerve Fibers ◽

The Body ◽

Saline Control ◽

Control Group ◽

Cortical Region ◽

Male Mice ◽

Stress Dependent

Abstract Background Despite evidence of neurotoxicity, cisplatin is still considered the most potent drug prescribed in human chemotherapy for a broad spectrum of malignancies. The objective was to evaluate the cerebellar cortex damage including oxidative stress biomarkers and histopathology aspects in male mice. One saline control group and two cisplatin groups were intraperitoneally injected with 0, 5, and 10 mg/kg body weight (bw) cisplatin, twice per week for four successive weeks, respectively. Results Cisplatin decreased the body weights of treated mice. Serum levels of superoxide dismutase and glutathione peroxidase were significantly reduced in the 5 and 10 mg/kg dose, twice weekly for 4 weeks treatment; in contrast, there was a significant increase of lipid peroxidation. 5 and 10 mg/kg bw of cisplatin caused histopathological damage in the cerebellum tissue characterized by disruption, disorganization, and degeneration with dense pyknotic nuclei of the granular cells. Ultrastructurally, in the cortical region of the cerebellum, the Purkinje cells showed irregular pyknotic nuclei with indistinct nucleoli, cytoplasmic vacuolation, marked indentation of the nuclear membrane, dilatation of the endoplasmic reticulum, and breakdown and disappearance of mitochondrial cristae. Moreover, the molecular layer showed cellular necrosis and an increased number of lysosomal particles. The myelinated nerve fibers showed degenerative areas distinct by splitting, disruption, and loss of the lamellar pattern of the myelin sheath. Conclusion These findings provide a confirmed foresight that the in vivo potential treatment of mice with cisplatin induces cerebellum deficits and impairment in neuronal histology. The identified mechanism which evokes neurotoxicity is oxidative stress-dependent status. This mechanism is pharmacologically boosted by great production of free radical reactive oxygen species.

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Novel colistin-EDTA combination for successful eradication of colistin-resistant Klebsiella pneumoniae catheter-related biofilm infections

Scientific Reports ◽

10.1038/s41598-021-01052-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aye Mya Sithu Shein ◽

Dhammika Leshan Wannigama ◽

Paul G. Higgins ◽

Cameron Hurst ◽

Shuichi Abe ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Bacterial Load ◽

In Vivo Studies ◽

Adaptive Responses ◽

Colistin Resistance ◽

Internal Organs ◽

Vascular Catheters ◽

Hostile Environments

AbstractDevelopment of an effective therapy to overcome colistin resistance in Klebsiella pneumoniae, a common pathogen causing catheter-related biofilm infections in vascular catheters, has become a serious therapeutic challenge that must be addressed urgently. Although colistin and EDTA have successful roles for eradicating biofilms, no in vitro and in vivo studies have investigated their efficacy in catheter-related biofilm infections of colistin-resistant K. pneumoniae. In this study, colistin resistance was significantly reversed in both planktonic and mature biofilms of colistin-resistant K. pneumoniae by a combination of colistin (0.25–1 µg/ml) with EDTA (12 mg/ml). This novel colistin-EDTA combination was also demonstrated to have potent efficacy in eradicating colistin-resistant K. pneumoniae catheter-related biofilm infections, and eliminating the risk of recurrence in vivo. Furthermore, this study revealed significant therapeutic efficacy of colistin-EDTA combination in reducing bacterial load in internal organs, lowering serum creatinine, and protecting treated mice from mortality. Altered in vivo expression of different virulence genes indicate bacterial adaptive responses to survive in hostile environments under different treatments. According to these data discovered in this study, a novel colistin-EDTA combination provides favorable efficacy and safety for successful eradication of colistin-resistant K. pneumonia catheter-related biofilm infections.

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L-alanyl-glutamine pretreatment attenuates acute inflammatory response in children submitted to palatoplasty

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502011000700015 ◽

2011 ◽

Vol 26 (suppl 1) ◽

pp. 72-76 ◽

Cited By ~ 6

Author(s):

José Ferreira da Cunha Filho ◽

Isabelle Ivo Gonçalves ◽

Sergio Botelho Guimarães ◽

Francisco Vagnaldo Fechine Jamacaru ◽

José Huygens Parente Garcia ◽

...

Keyword(s):

Glycemic Control ◽

Inflammatory Response ◽

Surgical Procedure ◽

Infusion Pump ◽

Venous Blood ◽

Thiobarbituric Acid ◽

Saline Control ◽

Control Group ◽

Group A ◽

Group B

PURPOSE: To evaluate the effects of L-alanyl-glutamine (L-Ala-Gln) pretreatment on oxidative stress, glycemic control and inflammatory response in children submitted to palatoplasty. METHODS: Thirty male children scheduled for routine palatoplasty, age range 2-10 years, were randomly assigned to 2 groups (n=15): Group A (saline, control) and Group B (L-Ala-Gln). Group A received normal saline 100 ml, delivered intravenously by infusion pump over 3 hours preceding surgical procedure. Group B was treated with L-Ala-Gln, 20% solution (0.5g/Kg), adding saline to complete 100ml. Peripheral venous blood samples were collected at 5 different time-points: T1- at the beginning of the study, 3 h prior to the surgical procedure; T2- at the end of the infusion (before the surgical procedure), T3- at the end of the surgical procedure, T4- 6 h postoperative and T5- 12 h postoperative. Parameters analyzed included glutathione (GSH), thiobarbituric acid reactive substances (TBARS), glucose, insulin, C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS: No statistically significant differences were found between groups comparing glucose, insulin, TBARS, GSH and IL-6 levels. However, glucose levels increased (P <0.001) in T4 and T5 as compared to baseline (T1) in control group as opposed to L-Ala-Gln group. IL-6 increased in both groups during the postoperative period, indicating an increased inflammatory response. L-Ala-Gln pretreatment did not suppress the increase of IL-6, but reduced the increase of postoperative CRP levels (T5, p <0.01). CONCLUSION: Pretreatment with L-Ala-Gln in children submitted to palatoplasty attenuates the inflammatory response in early post-operative period and promoted a better glycemic control.

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An open source tool to compute measures of inpatient glycemic control: translating from healthcare analytics research to clinical quality improvement

JAMIA Open ◽

10.1093/jamiaopen/ooab033 ◽

2021 ◽

Vol 4 (2) ◽

Author(s):

Ying Chen ◽

Yilin Ning ◽

Prem Thomas ◽

Mark Salloway ◽

Maudrene Luor Shyuan Tan ◽

...

Keyword(s):

Glycemic Control ◽

Open Source ◽

Graphical Interface ◽

Prior Work ◽

Healthcare Analytics ◽

Privacy Concerns ◽

Open Source Tool ◽

Extended Code ◽

User Friendly

Abstract Objectives The objective of this study is to facilitate monitoring of the quality of inpatient glycemic control by providing an open-source tool to compute glucometrics. To allay regulatory and privacy concerns, the tool is usable locally; no data are uploaded to the internet. Materials and Methods We extended code, initially developed for healthcare analytics research, to serve the clinical need for quality monitoring of diabetes. We built an application, with a graphical interface, which can be run locally without any internet connection. Results We verified that our code produced results identical to prior work in glucometrics. We extended the prior work by including additional metrics and by providing user customizability. The software has been used at an academic healthcare institution. Conclusion We successfully translated code used for research methods into an open source, user-friendly tool which hospitals may use to expedite quality measure computation for the management of inpatients with diabetes.

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Effect of Feeding Lactic Acid Bacteria and Fermented Milk on Specific and Nonspecific Immune Reponses of Mice Infected With Klebsiella pneumoniae AD-1

Journal of Food Protection ◽

10.4315/0362-028x-55.8.595 ◽

1992 ◽

Vol 55 (8) ◽

pp. 595-600 ◽

Cited By ~ 6

Author(s):

L. SAUCIER ◽

M. JULIEN ◽

F. CHEÓUR ◽

R. LETARTE ◽

J. GOULET

Keyword(s):

Lactic Acid ◽

Immune System ◽

Lactic Acid Bacteria ◽

Klebsiella Pneumoniae ◽

Immunoglobulin G ◽

Fermented Milk ◽

Assay Method ◽

Saline Control ◽

Enzyme Linked Immunosorbent Assay ◽

Uht Milk

The diets of six groups of weaned mice were supplemented with ultra high temperature (UHT) milk containing a washed suspension of lactic acid bacteria (mixture of 8 strains) or with UHT milk fermented by the same strains and heat-treated or not. Control groups received physiological saline or UHT milk only. The mice were infected intranasally by Klebsiella pneumoniae AD-1 on the 13th d of feeding. The effect on the immune system (specific and nonspecific) before and after infection was evaluated by measuring the phagocytosis of alveolar macrophages (using zymosan particles) and by measuring of total immunoglobulin G and A levels in serum and in pulmonary fluid (using the enzyme-linked immunosorbent assay method). Postinfection survival was 0.7 d longer for mice receiving fermented milk than for the saline control group. The percent phagocytosis did not vary significantly, while serum immunoglobulin G levels differed between mice fed fermented milk and those fed bacterial suspensions in unfermented milk. Fermentation appears to be essential for the beneficial effects on the immune system and survival time; this effect no longer occurs after pasteurization of fermented milk.

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