scholarly journals Azithromycin in Combination with Ceftriaxone Reduces Systemic Inflammation and Provides Survival Benefit in a Murine Model of Polymicrobial Sepsis

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Anasuya Patel ◽  
Jiji Joseph ◽  
Hariharan Periasamy ◽  
Santosh Mokale
Keyword(s):  
Blood Glucose ◽  
Body Temperature ◽  
Murine Model ◽  
Survival Benefit ◽  
Blood Glucose Concentration ◽  
Bacterial Load ◽  
Cecal Ligation ◽  
The Body ◽  
Immunomodulatory Activity ◽  
Necrosis Factor Alpha

ABSTRACTSepsis is a life-threatening systemic inflammatory condition triggered as a result of an excessive host immune response to infection. In the past, immunomodulators have demonstrated a protective effect in sepsis. Azithromycin (a macrolide antibiotic) has immunomodulatory activity and was therefore evaluated in combination with ceftriaxone in a clinically relevant murine model of sepsis induced by cecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered the vehicle or a subprotective dose of ceftriaxone (100 mg/kg of body weight subcutaneously) alone or in combination with an immunomodulatory dose of azithromycin (100 mg/kg intraperitoneally). Survival was monitored for 5 days. In order to assess the immunomodulatory activity, parameters such as plasma and lung cytokine (interleukin-6 [IL-6], IL-1β, tumor necrosis factor alpha) concentrations, the plasma glutathione (GSH) concentration, plasma and lung myeloperoxidase (MPO) concentrations, body temperature, blood glucose concentration, and total white blood cell count, along with the bacterial load in blood, peritoneal lavage fluid, and lung homogenate, were measured 18 h after CLP challenge. Azithromycin in the presence of ceftriaxone significantly improved the survival of CLP-challenged mice. Further, the combination attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature and blood glucose and GSH concentrations, which were otherwise markedly decreased in CLP-challenged mice. Ceftriaxone produced a significant reduction in the bacterial load, while coadministration of azithromycin did not produce a further reduction. Therefore, the survival benefit offered by azithromycin was due to immunomodulation and not its antibacterial action. The findings of this study indicate that azithromycin, in conjunction with appropriate antibacterial agents, could provide clinical benefits in sepsis.

scholarly journals Azithromycin reduces systemic inflammation and provides survival benefit in murine model of polymicrobial sepsis

2018 ◽  
Author(s):  
Anasuya Patel ◽  
Jiji Joseph ◽  
Hariharan Periasamy ◽  
Santosh Mokale
Keyword(s):  
Blood Glucose ◽  
Body Temperature ◽  
Murine Model ◽  
Peritoneal Fluid ◽  
Survival Benefit ◽  
Bacterial Load ◽  
Lung Homogenate ◽  
The Body ◽  
Combination Group ◽  
Immunomodulatory Activity

ABSTRACTSepsis is a life threatening systemic inflammatory condition triggered as a result of excessive host immune response to infection. In the past, drugs modulating immune reactions have demonstrated protective effect in sepsis. Azithromycin (macrolide antibiotic) with immunomodulatory activity was therefore evaluated in combination with ceftriaxone in a more clinically relevant murine model of sepsis induced by caecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered with vehicle, sub-effective dose of ceftriaxone (100 mg/kg,subcutaneous) alone or in combination with immunomodulatory dose of azithromycin (100 mg/kg,intraperitoneal). Survival was then monitored for 5 days. Parameters like body temperature, blood glucose, total white blood cell count, plasma glutathione (GSH), plasma and lung myeloperoxidase (MPO) as well as cytokine (interleukin IL-6, IL-1β, tumor necrosis factor-α) levels along with bacterial load in blood, peritoneal fluid and lung homogenate were measured 18 h after CLP challenge. Combination group significantly improved the survival of CLP mice. It attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature, blood glucose and GSH which were otherwise markedly decreased in CLP mice. Ceftriaxone exhibited significant reduction of bacterial count in blood, peritoneal fluid and lung homogenate, while co-administration of azithromycin did not further reduce it. This confirms that survival benefit by azithromycin was due to immunomodulation and not by its antibacterial action. Findings of this study indicate that azithromycin in combination with ceftriaxone could exhibit clinical benefit in sepsis.

scholarly journals Impact of Hypothermia on Differentiation and Maturation of Neutrophils

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2393-2393
Author(s):  
Yusuke Torikoshi ◽  
Asumi Yokota ◽  
Naoka Kamio ◽  
Atsushi Sato ◽  
Tsukimi Shouji ◽  
...  
Keyword(s):  
Body Temperature ◽  
Host Defense ◽  
Research Funding ◽  
Molecular Mechanisms ◽  
Environmental Temperature ◽  
Cecal Ligation ◽  
The Body ◽  
Neutrophil Differentiation ◽  
The Impact

Abstract Accumulating evidence has suggested that low body temperature is associated with the risk of infection. Unintentional drops in the body temperature known as "accidental hypothermia" are occasionally accompanied with infections. Patients under therapeutic hypothermia for post-cardiac arrest care are also susceptible to infections. In addition, secondary hypothermia caused by severe sepsis is significantly associated with higher mortality. These observations suggest the negative impact of hypothermia on host defense. Neutrophils are continuously produced in the bone marrow (BM) and supplied to the peripheral blood (PB) or tissues, where they fight against microorganisms. In addition to the neutrophil functions, sufficient supply of neutrophils is a critical determinant of host defense. However, little is known about the impact of hypothermia on granulopoiesis, the process of neutrophil production in the BM. In this study, we investigated the changes in granulopoiesis under hypothermic conditions. We first analyzed the neutrophils in the PB of mice exposed to low environmental temperature (4 °C). Under this condition, rectal temperature of the mice significantly declined from 36.7±0.4 °C to 35.5±0.4 °C. After 72-hour exposure to the low environmental temperature, PB neutrophil counts were significantly decreased. In order to understand the reason for the decrease, we analyzed their BMs by flow cytometry. Previously we developed a unique strategy to divide cells undergoing granulopoiesis into 5 subpopulations based on the expression of c-kit and Ly6G, which reflect successive differentiation/maturation from #1 (c-kithi Ly6G-) to #5 (c-kit- Ly6Ghi) (Satake S and Hirai H et al. J Immunol, 2012). In BM cells of the mice exposed to the low environmental temperature, a significant decrease in mature neutrophils (#5) and a significant increase in cellular intermediates (#3 and #4) were observed, while total BM cell numbers were unchanged. In order to clarify whether these changes were cell-intrinsic or -extrinsic, total BM cells were cultured in vitro at either 35 °C or 37 °C in the presence of G-CSF. Flow cytometric analysis of these cultured BM cells at 72 hours revealed the increase in the intermediates (#2 to #4) and a decrease in the mature subpopulation (#5), suggesting that these alterations were cell-intrinsic phenomena. When neutrophil precursors (#1 or #2) were purified by cell sorter and subjected to in vitro culture at 35 °C for 48 hours, the number of resultant mature neutrophils (#5) were significantly less than those induced at 37 °C. These results clearly indicate that hypothermia delayed neutrophil differentiation/maturation. Interestingly, mice with sepsis induced by cecal ligation and puncture (CLP) accompanied with lower body temperature revealed significantly fewer PB granulocytes and shorter survival when compared to those mice which maintained normal body temperature after CLP. In order to understand the molecular mechanisms underlying the differentiation/maturation delay induced by hypothermia, we performed RNA sequencing of purified neutrophil precursors (#2) after 24-hour culture either at 35 °C or 37 °C. Interestingly, we found alterations in amino acid metabolic pathways and target genes of C/EBP, which is the transcription factor family required for granulopoiesis and cellular metabolism. Collectively, these results indicate hypothermia causes neutropenia through delayed neutrophil differentiation/maturation. We are currently analyzing metabolic changes to understand more precise molecular mechanisms by which hypothermia regulates granulopoiesis. This study will facilitate the understanding of host defense at low body temperature, and shed novel insight into the management of hypothermia in patients. Disclosures Kashiwagi: Takara Bio Inc.: Employment. Hirai:Kyowa Hakko Kirin: Research Funding; Novartis Pharma: Research Funding.

scholarly journals THE POST-MORTEM EVALUATION OF GLUCOSE CONCENTRATION IN BLOOD AND ITS DIAGNOSTICAL VALUE

2019 ◽  
Vol 7 ◽  
Author(s):  
Gintarė Lukočiūtė ◽  
Karolina Ginčienė ◽  
Sigitas Chmieliauskas ◽  
Sigitas Laima ◽  
Jurgita Stasiūnienė ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Sudden Death ◽  
Forensic Medicine ◽  
Glucose Concentration ◽  
Blood Glucose Concentration ◽  
Diagnostic Value ◽  
The Body ◽  
Glucose Metabolism Disorders ◽  
Post Mortem ◽  
Glucose Levels

Introduction:  Hyperglycemia is a consequence of uncontrolled diabetes and over a long period of time can lead to serious violations of the various systems of the body. In daily clinical practice, glucose level in blood and glycated hemoglobin are major and frequently used worldwide laboratory findings for the diagnosis of glucose metabolism disorders. In forensic medicine, the diagnostic value of post-mortem blood glucose levels is questionable because of its significant and rapid variation after death. Our research was aimed to analyse glucose concentration in blood after death and to estimate its diagnostic value. Methods: Data analysis of the State Forensic Medicine Service (SFMS) of Vilnius region of sudden death cases was performed. 238 autopsy findings were analysed. A retrospective analysis was performed using the R commander program. Results: The analysis included 238 individuals, 161 (67.6%) were men and 77 (32.4%) women. Mean age was 52.28 ± 15.45 yeras. Mean  alcohol level in blood was 2.257 ± 1.482 g/L. Mean post-mortem glucose concentration in blood was 6.716 ± 5.800 mmol/l. The lowest glucose concentration was 0.600 mmol/l and the highest - 33.300 mmol/l. There were no significant glycemia level difference between men and women (p = 0.279). In 6 cases, glucose concentrations were compared before and after death. The difference in blood glucose was insignificant (p = 0.90). There was no strong correlation between ethyl alcohol and glucose concentration (r = 0.037, p = 0.667). There was a weak correlation between age and blood glucose concentration (r = 0.03, p = 0.639). Conclusions: According to SFMS autopsy data, post-mortem glucose levels remain within the normal values. Evaluation of glucose after death remains a valuable diagnostic criterion for sudden death due to hyperglycaemia, when the hyperglycaemic episode is first and fatal to the subject.

scholarly journals Antimicrobial and Immunologic Activities of Clarithromycin in a Murine Model of Mycoplasma pneumoniae-Induced Pneumonia

2003 ◽  
Vol 47 (5) ◽  
pp. 1614-1620 ◽  
Author(s):  
Robert D. Hardy ◽  
Ana Maria Rios ◽  
Susana Chavez-Bueno ◽  
Hasan S. Jafri ◽  
Jeanine Hatfield ◽  
...  
Keyword(s):  
Mycoplasma Pneumoniae ◽  
Murine Model ◽  
Tumor Necrosis ◽  
Airway Resistance ◽  
Immunomodulatory Activity ◽  
Necrosis Factor Alpha ◽  
Once Daily ◽  
Beneficial Effects ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Because macrolide antibiotics are hypothesized to possess immunomodulatory activity independent of their antimicrobial activity, we evaluated the immunomodulatory effect of clarithromycin in a murine model of lung inflammation induced by either live or UV-killed Mycoplasma pneumoniae. BALB/c mice were intranasally inoculated once with live or UV-killed M. pneumoniae. Clarithromycin (25 mg/kg of body weight) or placebo was subcutaneously administered once daily in both groups of mice. In mice infected with live M. pneumoniae, clarithromycin treatment significantly reduced quantitative M. pneumoniae bronchoalveolar lavage (BAL) culture, pulmonary histopathologic scores (HPS), and airway resistance-obstruction (as measured by plethysmography) compared with placebo. Concentrations of tumor necrosis factor alpha, gamma interferon, interleukin-6 (IL-6), mouse KC (functional IL-8), JE/MCP-1, and MIP-1α in BAL fluid were also significantly decreased in mice infected with live M. pneumoniae given clarithromycin. In contrast, mice inoculated with UV-killed M. pneumoniae had no significant reduction in HPS, airway resistance-obstruction, or BAL cytokine or chemokine concentrations in response to clarithromycin administration. Clarithromycin therapy demonstrated beneficial effects (microbiologic, histologic, respiratory, and immunologic) on pneumonia in the mice infected with live M. pneumoniae; this was not observed in the mice inoculated with UV-killed M. pneumoniae.

The intrinsic and interactive effects of RO 15-4513 and ethanol on locomotor activity, body temperature, and blood glucose concentration

Life Sciences ◽  
1989 ◽  
Vol 45 (16) ◽  
pp. 1467-1473 ◽  
Author(s):  
Angela L. Wood ◽  
Philip A. Healey ◽  
JoséA. Menéndez ◽  
Sarah L. Verne ◽  
Dale M. Atrens
Keyword(s):  
Blood Glucose ◽  
Locomotor Activity ◽  
Body Temperature ◽  
Glucose Concentration ◽  
Blood Glucose Concentration ◽  
Interactive Effects

85 PREGNANCIES AND VIABILITY OF THE OFFSPRING AFTER TRANSFER OF HANDMADE CLONED PORCINE EMBRYOS

2007 ◽  
Vol 19 (1) ◽  
pp. 160
Author(s):  
M. Schmidt ◽  
I. B. Bøgh ◽  
Y. Du ◽  
Y. Zhang ◽  
J. Li ◽  
...  
Keyword(s):  
Weight Gain ◽  
Blood Glucose ◽  
Birth Weight ◽  
Body Temperature ◽  
Pregnancy Rate ◽  
Uterine Horn ◽  
The Body ◽  
Daily Weight Gain ◽  
High Birth Weight ◽  
The Mean

In several species, nuclear transfer causes a high frequency of fetal loss, high birth weight, malformations, and neonatal death. This study investigates the fetal development of porcine embryos produced by handmade cloning (HMC) and compares the piglets with littermates produced by traditional cloning (TC). HMC embryos were produced from one fetal cell line, LYxD (Landrace/Yorkshire x Duroc) and TC from another (LYDxLYD). For transfer, 11 sows were weaned, and at cycle stage Day 4 after heat, they were anesthetized in lateral recumbence. Through an abdominal incision 40–60 Days 5–7 embryos (69% HMC + 31% TC) were transferred to the upper uterine horn. The tip of the uterine horn was punctured with a blunt 18G needle and a temporary catheter introduced to absorb the blood before inserting an insemination catheter (J-IUIC-351341 Insemi-Cath; Cook Ireland Ltd., Limerick, Ireland) 5–6 cm into the horn and releasing the embryos. Pregnancy was examined by ultrasonography every second week to Day 100. Caesarian sections were performed at Day 115, 24 h after injection of PGF2 (175 �g Estrumate�; Pitman-Moore Ltd., Harefield, UK). The piglets were fed with 15 mL kg-1/3 h colostrum through a stomach tube for the first 12–24 h, until they were left with their dam. Body weight, blood values (oxygen tension, and glucose and hemoglobin concentrations), and body temperature were recorded at birth, 24 h, and 3 weeks of age. The data were analyzed by Fisher's Exact test and are given as LS means � SEM values with a significance level of P < 0.05. The pregnancy rate was 6/11 (55%), with 2 pregnancies developing to term, 2 ongoing (Day 100 and Day 60), and 2 lost (about Day 35). So far, the litter sizes were 3 (1 TC, 2 HMC) and 10 (2 TC, 8 HMC) live piglets, respectively. The mean birth weight of the TC offspring (1045 � 135 g) was lower than that of the HMC piglets (1614 � 177 g) and that of normal piglets on the farm (1520 � 240 g; P < 0.05). One of the HMC piglets of the first litter was rather oversized (2690 g) and another showed rigid flexure of a carpal joint. All other piglets appeared normal on gross morphology and behavior. Blood values were similar for HMC and TC piglets, but the body temperature at Day 0 (36.3 � 0.2 vs. 35.1 � 1.1�C; P < 0.05) and the daily weight gain during the first week (129 � 21 vs. 74 � 13 g; P = 0.06) tended to be higher for the HMC piglets. After 24 hrs, the mean blood glucose concentration was higher in the HMC than in the TC piglets (6.09 � 0.74 vs. 3.67 � 0.19 mmol L-1) and similar to farm piglets of the same age (6.93 � 0.44 mmol L-1), but the difference was not significant after 3 weeks. These preliminary results demonstrate for the first time that HMC in pigs can result in an acceptable pregnancy rate, birth rate, and litter size. The minor differences in birth weight, weight gain, and blood glucose observed between HMC and TC offspring may be explained by the different cell lines used for the 2 methods, and are under current investigation.

Anti-inflammatory response is associated with mortality and severity of infection in sepsis

2005 ◽  
Vol 288 (4) ◽  
pp. L633-L640 ◽  
Author(s):  
Alix Ashare ◽  
Linda S. Powers ◽  
Noah S. Butler ◽  
Kevin C. Doerschug ◽  
Martha M. Monick ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Murine Model ◽  
Bacterial Load ◽  
Cecal Ligation ◽  
Proinflammatory Response ◽  
Inflammatory Phase ◽  
Anti Inflammatory ◽  
Soluble Tnf Receptor

Using a murine model of sepsis, we found that the balance of tissue pro- to anti-inflammatory cytokines directly correlated with severity of infection and mortality. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Liver tissue was analyzed for levels of IL-1β, IL-1 receptor antagonist (IL-1ra), tumor necrosis factor (TNF)-α, and soluble TNF receptor 1 by ELISA. Bacterial DNA was measured using quantitative real-time PCR. After CLP, early predominance of proinflammatory cytokines (6 h) transitioned to anti-inflammatory predominance at 24 h. The elevated anti-inflammatory cytokines were mirrored by increased tissue bacterial levels. The degree of anti-inflammatory response compared with proinflammatory response correlated with the bacterial concentration. To modulate the timing of the anti-inflammatory response, mice were treated with IL-1ra before CLP. This resulted in decreased proinflammatory cytokines, earlier bacterial load, and increased mortality. These studies show that the initial tissue proinflammatory response to sepsis is followed by an anti-inflammatory response. The anti-inflammatory phase is associated with increased bacterial load and mortality. These data suggest that it is the timing and magnitude of the anti-inflammatory response that predicts severity of infection in a murine model of sepsis.

scholarly journals Comparative efficacy of two medicinal plants and Amaryl® tablet (Glimepiride) in induced diabetes mellitus in rat

1970 ◽  
Vol 6 (2) ◽  
pp. 297-300
Author(s):  
PC Das ◽  
M Mostofa ◽  
AK Sarkar ◽  
M Ali
Keyword(s):  
Diabetes Mellitus ◽  
Body Weight ◽  
Blood Glucose ◽  
Blood Glucose Concentration ◽  
The Body ◽  
Antidiabetic Activity ◽  
Herbal Extracts ◽  
Comparative Efficacy ◽  
Trigonella Foenum Graecum ◽  
Coccinia Indica

Comparative efficacy of two indigenous herbal extracts, (Trigonella foenum-graecum seed & Coccinia indica leaves) with the commonly used drug Glimepiride were studied. Healthy young rats (n=30) of both sexes weighting between 150 to 200 gm were selected and divided into six equal groups, as A (Control), B (diabetic), experimental diabetic groups were-C, D, E and F, treated with combined extract of Methi seed and Telakucha leaves- @ 250mg, 500mg, 750mg and Glimepiride 800μg/kg body weight, respectively. The substances were given orally once daily for14 days. The blood glucose concentration were decreased significantly (P<0.01) in groups C, D, E, and F. The body weight increased significantly (P<0.05) by 2.3%, 3.9%, 4.8% and 10.4%, respectively. The herbal extracts significantly reduced in blood glucose level with the increased in body weight. It is indicated that antidiabetic activity of Trigonella foenum-graecum and Coccinia indica are evident that are traditionally used as the herbal preparations by the Ayurvedic practitioners for the control of diabetes mellitus. Keywords: Trigonella foenum graecum; Coccinia indica; Amaryl® Tablet (Glimepiride); Streptozotocin and antidiabetic effect; Diabetes mellitus; Rat DOI: 10.3329/jbau.v6i2.4825 J. Bangladesh Agril. Univ. 6(2): 297-300, 2008

scholarly journals 5-HT Drives Mortality in Sepsis Induced by Cecal Ligation and Puncture in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Jingyao Zhang ◽  
Jianbin Bi ◽  
Sushun Liu ◽  
Qing Pang ◽  
Ruiyao Zhang ◽  
...  
Keyword(s):  
Body Temperature ◽  
Organ Dysfunction ◽  
Tryptophan Hydroxylase ◽  
Cecal Ligation ◽  
Clinical Score ◽  
The Body ◽  
Sepsis Group ◽  
Cecal Ligation And Puncture ◽  
Lower Survival Rate ◽  
Sepsis And Septic Shock

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection with a high mortality. 5-Hydroxytryptamine (5-HT) is an important regulatory factor in inflammation. The aim of this study is to investigate the role of 5-HT on cecal ligation and puncture- (CLP-) induced sepsis in the mouse model. CLP was performed on C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout (KO) mice. The results showed that the 5-HT-sufficient group mice had a significantly lower survival rate than the 5-HT-deficient group in CLP-induced sepsis and septic shock. The KO-CLP sepsis group received a lower clinical score than the WT-CLP sepsis group. Meanwhile, the body temperature of mice in the KO-CLP sepsis group was higher than that in the WT-CLP sepsis group and was much closer to the normal body temperature 24 hours after CLP. The tissue histopathology analysis revealed that 5-HT markedly exacerbated histological damages in the peritoneum, lung, liver, kidney, intestinal tissue, and heart in sepsis. Moreover, significant lower levels of TNF-α, IL-6, bacterial loads, MPO, and ROS were discovered in the KO-CLP sepsis group in contrast to the WT-CLP sepsis group. In conclusion, 5-HT drives mortality and exacerbates organ dysfunction by promoting serum cytokines and bacterial loads as well as facilitating oxidative stress in the process of sepsis.

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