ResearchPad - routes-of-administration https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Oral administration with a traditional fermented multi-fruit beverage modulates non-specific and antigen-specific immune responses in BALB/c mice]]> https://www.researchpad.co/article/elastic_article_7730 Fruits have been widely considered as the default “health foods” because they contain numerous vitamins and minerals needed to sustain human health. Fermentation strategies have been utilized to enhance the nutritive and flavor features of healthy and readily consumable fruit products while extending their shelf lives. A traditional fermented multi-fruit beverage was made from five fruits including kiwi, guava, papaya, pineapple, and grape fermented by Saccharomyces cerevisiae along with lactic acid bacteria and acetic acid bacteria. The immunomodulatory properties of the fermented multi-fruit beverage, in vivo nonspecific and ovalbumin (OVA)-specific immune response experiments using female BALB/c mice were performed. Administration of the fermented multi-fruit beverage reduced the calorie intake, thus resulting in a less weight gain in mice compared to the water (placebo)-fed mice. In the nonspecific immune study model, the fermented multi-fruit beverage enhanced phagocytosis and T cell proliferation but did not affect B cell proliferation and immunoglobulin G (IgG) production. Analysis of cytokine secretion profile also revealed that the fermented multi-fruit beverage enhanced proinflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and T helper (Th)1-related cytokine interferon (IFN)-γ production, thus creating an immunostimulatory effect. Nonetheless, in the specific immune study model, the results showed that the fermented multi-fruit beverage decreased the production of proinflammatory cytokines IL-6 and TNF-α production in OVA-immunized mice. Moreover, it also caused a decrease in the production of anti-OVA IgG1, which was accompanied by a decrease in Th2-related cytokines IL-4 and IL-5 production and an increase in Th1-related cytokine IFN-γ production, indicating that it may have the potential to shift the immune system from the allergen‐specific Th2 responses toward Th1-type responses. The results indicate that fermented multi-fruit beverage has the potential to modulate immune responses both in a nonspecific and specific manners.

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<![CDATA[Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak]]> https://www.researchpad.co/article/5c8c194bd5eed0c484b4d370

Clinical and model studies indicate that low nitric oxide (NO) bioavailability due in part to profound hypoargininemia contributes to cerebral malaria (CM) pathogenesis. Protection against CM pathogenesis may be achieved by altering the diet before infection with Plasmodium falciparum infection (nutraceutical) or by administering adjunctive therapy that decreases CM mortality (adjunctive therapy). This hypothesis was tested by administering citrulline or arginine in experimental CM (eCM). We report that citrulline injected as prophylaxis immediately post infection (PI) protected virtually all mice by ameliorating (i) hypoargininemia, (ii) urea cycle impairment, and (iii) disruption of blood brain barrier. Citrulline prophylaxis inhibited plasma arginase activity. Parasitemia was similar in citrulline- and vehicle control-groups, indicating that protection from pathogenesis was not due to decreased parasitemia. Both citrulline and arginine administered from day 1 PI in the drinking water significantly protected mice from eCM. These observations collectively indicate that increasing dietary citrulline or arginine decreases eCM mortality. Citrulline injected ip on day 4 PI with quinine-injected ip on day 6 PI partially protected mice from eCM; citrulline plus scavenging of superoxide with pegylated superoxide dismutase and pegylated catalase protected all recipients from eCM. These findings indicate that ameliorating hypoargininemia with citrulline plus superoxide scavenging decreases eCM mortality.

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<![CDATA[Economic benefits of subcutaneous trastuzumab administration: A single institutional study from Karolinska University Hospital in Sweden]]> https://www.researchpad.co/article/5c61e8f9d5eed0c48496f56c

Introduction

Adjuvant trastuzumab is a standard of care in the treatment of Human Epidermal growth factor Receptor 2 (HER2) positive early breast cancer (eBC). Initially trastuzumab could only be administered intravenously (IV), however since 2013, a subcutaneous (SC) formulation with comparable efficacy and safety profile is available and preferred by patients. Trastuzumab SC does not require pharmacy preparation and has shorter administration time. The objective of this study was to estimate the economic efficiency of the SC formulation of trastuzumab by assessing the economic benefits of actual SC-driven process changes at one single Swedish healthcare institution.

Methods

This study analyzes changes in trastuzumab administration practice after the SC formulation was introduced at the Karolinska University Hospital. Process changes were identified and introduced in order to capitalize on the inherent work efficiency benefits of the SC formulation. Actual hospital data for 2015 were used to quantitatively estimate the annual economic impact of the changes. It encompassed administrative (i.e. non-medical) data of 178 newly diagnosed HER2-positive eBC patients and a total of 2,769 SC administrations. Realized economic benefits were expressed in hours saved by nurses, direct monetary cost savings and potential infusion fee revenue that could be earned through infrastructural revenue gains.

Results

In 2015, the replacement of IV infusion to SC administration generated total time savings of more than 1,100 hours, and led to direct monetary cost savings of 603,000 EUR. It unlocked a capacity gain of 1–2 additional administrations daily within the existing facility infrastructure. Given the current remuneration structure per administration, this revenue gain translated into an incremental revenue potential of up to 3 million EUR.

Conclusion

Data from this study showed that the shift from trastuzumab IV to SC formulation resulted in significant economic effects in terms of departmental resources related to time, direct monetary cost savings, and infrastructural revenue gains.

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<![CDATA[The use of initial dosing of gentamicin in the management of pyelonephritis/urosepsis: A retrospective study]]> https://www.researchpad.co/article/5c5217c6d5eed0c484794564

Objective

The primary objective was to determine if initial empirical intravenous dosing of gentamicin improved patient's outcomes in pyelonephritis/urosepsis compared with alternative IV antibiotic management.

Design

Retrospective cross-sectional descriptive study.

Setting

Public TertiaryTeaching Hospital serving adults in an urban centre.

Participants

All adult patient records with a recorded diagnosis of any of pyelonephritis/urosepsis, urinary tract infection, UTI, complicated urinary tract infection, bacteriuria, symptomatic bacteriuria and asymptomatic bacteriuria from 2nd February 2012 to 10th May 2014 were reviewed. Only patients treated with an empirical regimen of one or more IV antibiotics were included in the study.

Main outcomes

The primary outcomes were: duration of IV antibiotic treatment, time to resolution of symptoms and length of hospital stay (LOS). Secondary end points were: compliance with Therapeutic Guidelines: Antibiotic (electronic version) (eTG) for severe pyelonephritis/urosepsis and appropriateness of gentamicin use.

Data analysis

Univariate and multivariable associations between baseline and demographic variables and the main outcomes were performed using Chi-square tests and a General Linear Model using the SAS version 9.2 software.

Results

Of 295 patients reviewed 152 were prescribed one or more IV antibiotics and included in the study. Approximately half of the patients (n = 73, 48%) were prescribed IV piperacillin/tazobactam (Tazocin), while gentamicin was prescribed for 66 patients (43.4%). Of the 152 patients evaluated, 49 (32%) were given gentamicin first. Multivariable regression analysis showed that duration of IV treatment was shorter for those aged over 70 (40.2 hours vs 85.5 hours for those aged up to 70; p = 0.0074), and those who received gentamicin as first line treatment (41.3 hours vs 89.8 hours for those not receiving any gentamicin; p = 0.0312). After adjustment for age and gentamicin administration, there appeared to be no significant difference in duration of IV treatment for any other independent variables. No significant associations between the independent variables (gentamicin, age, gender, comorbidities, and eTG compliance) and either time to resolution of symptoms (median: 68 hours) or hospital LOS (median: 5 days) were observed.

Conclusions

Neither time to resolution of abnormal symptoms nor length of stay were significantly influenced by an initial dose of gentamicin when the data were subjected to multivariable analysis. The age of the patient and pattern of gentamicin treatment were the dominant factors associated with duration of IV antibiotics. Piperacillin/tazobactam is not recommended in treatment guidelines for pyelonephritis/urosepsis but was the most commonly prescribed IV antibiotic. This requires review by the appropriate hospital clinicians.

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<![CDATA[Polypharmacy in outpatients with relapsing-remitting multiple sclerosis: A single-center study]]> https://www.researchpad.co/article/5c53699fd5eed0c484a4620b

Background

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. Given the chronic and heterogenous nature of the disease, treatment with various therapies is a frequent scenario in clinical practice. In persons with chronic morbidity such as MS patients, polypharmacy can give rise to considerable health problems.

Objectives

The aim of the present study was to examine the frequency of polypharmacy among relapsing-remitting (RR) MS patients as well as to analyse sociodemographic and clinical factors, which might be associated with polypharmacy (use of five or more medications). Differences in medication between MS patients with and without secondary illnesses (PwSI and Pw/oSI), between men and women and between patients with and without polypharmacy (PwP and Pw/oP) were examined.

Methods

For 145 RRMS outpatients, we prospectively collected data by means of anamnesis, patient records, clinical examination and a structured patient interview. This was followed by comparative analyses of various patient subgroups (PwP vs. Pw/oP, PwSI vs. Pw/oSI, men vs. women).

Results

The proportion of included MS patients with polypharmacy (use of ≥5 medications) was 30.3%. PwP were significantly older than Pw/oP (45.9 vs. 41.7 years), had a lower level of education and showed a significantly higher median EDSS score (3.0 vs. 2.0). Comorbidities (p<0.001; odds ratio [OR] = 6.293) and higher EDSS scores (p = 0.029; OR = 1.440) were associated with a higher risk of polypharmacy. The proportion of polypharmacy among PwSI was approximately four times higher than among Pw/oSI (46.8% vs. 11.8%). Particularly in the use of antihypertensives, gastrointestinal drugs and dietary supplements, there were differences between Pw/oP and PwP.

Conclusion

We found a high burden of polypharmacy in patients with RRMS. This particularly applies to more severely disabled MS patients who suffer from comorbidities.

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<![CDATA[Cross-sectional survey of off-label and unlicensed prescribing for inpatients at a paediatric teaching hospital in Western Australia]]> https://www.researchpad.co/article/5c3e4f70d5eed0c484d754d2

Objectives

To evaluate the prevalence of off-label and unlicensed prescribing in inpatients at a major paediatric teaching hospital in Western Australia and to identify which drugs are commonly prescribed off-label or unlicensed, including factors influencing such prescribing.

Methods

A retrospective cross-sectional study was conducted in June, 2013. Patient and prescribing data were collected from 190 inpatient medication chart records which had been randomly selected from all admissions during the second week of February 2013. Drugs were categorised as licensed, off-label or unlicensed, according to their approved Australian registration product information (PI). All drugs were classified according to the Anatomical Therapeutic Chemical (ATC) code.

Results

There were 120 male and 70 female inpatients. The average age was 6.0 years (± 4.7). The study included 1160 prescribed drugs suitable for analysis. The number of drugs prescribed per patient ranged from 1 to 25 with an average of 6.1 (± 4.3). More than half (54%) were prescribed off-label. Oxycodone, clonidine, parecoxib and midazolam were always prescribed off-label. The most common off-label drugs were ondansetron (18.5%), fentanyl (12.9%), oxycodone (8.8%) and paracetamol (6.1%). Many ATC classifications included high off-label proportions especially the genitourinary system and sex hormones, respiratory system drugs, systemic hormonal preparations and alimentary tract and metabolism drugs.

Conclusions

This study highlights that prescribing of paediatric drugs needs to be better supported by existing and new evidence. Incentives should be established to foster the conduct of evidence-based studies in the paediatric population. The current level of off-label prescribing raises issues of unexpected toxicity and adverse drug effects in children that are in some cases severely ill.

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<![CDATA[Adenosine stimulates hepatic glycogenolysis via adrenal glands–liver crosstalk in mice]]> https://www.researchpad.co/article/5c269740d5eed0c48470f09f

Adenosine signaling is involved in glucose metabolism in hepatocytes and myocytes in vitro. However, no information is available regarding the effect of adenosine on glucose metabolism in vivo. Thus, we examined how extracellular adenosine acts on glucose metabolism using mice. Subcutaneous injections of adenosine (10, 25, and 50 mg/kg bodyweight) dose-dependently increased blood glucose levels, with the peak occurring at 30 min post injection. At 30 min after adenosine injection (25 mg/kg bodyweight), glycogen content in the liver, but not the skeletal muscle, was significantly decreased. Hepatic glycogen depletion by fasting for 12 h suppressed the increase of blood glucose levels at 30 min after adenosine injection. These results suggest that adenosine increases blood glucose levels by stimulating hepatic glycogenolysis. To investigate the effect of adenosine on the adrenal gland, we studied the glycogenolysis signal in adrenalectomized (ADX) mice. Adenosine significantly increased the blood glucose levels in sham mice but not in the ADX mice. The decrease in hepatic glycogen content induced by adenosine in the sham mice was partially suppressed in the ADX mice. The level of plasma corticosterone, the main glucocorticoid in mice, was significantly increased in the sham mice by adenosine but its levels were low in ADX mice injected with either PBS or adenosine. These results suggest that adenosine promotes secretion of corticosterone from the adrenal glands, which causes hepatic glycogenolysis and subsequently the elevation of blood glucose levels. Our findings are useful for clarifying the physiological functions of adenosine in glucose metabolism in vivo.

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<![CDATA[Vitamin A to prevent bronchopulmonary dysplasia in extremely low birth weight infants: a systematic review and meta-analysis]]> https://www.researchpad.co/article/5c2400e1d5eed0c484099929

Background

Vitamin A (VA) supplementation reduces the risk of developing bronchopulmonary dysplasia (BPD). However, a previous meta-analysis showed that VA had minimal efficacy for preventing BPD in very low birth weight infants (VLBWIs).

Aims

To elucidate the effects of VA supplementation for BPD prevention in extremely low birth weight infants (ELBWIs).

Study design

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We registered the protocol on PROSPERO, the international prospective registry of systematic reviews (registration number: CRD42016050887). We searched the following five databases: CINAHL, CENTRAL, EMBASE, MEDLINE, and PubMed; screened the reference lists of retrieved articles to identify randomized controlled trials (RCTs); and assessed the Cochrane Risk of Bias for each study. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines.

Results

Four studies (total, 1,011 infants) were included. VA was administered intramuscularly in 3 studies and orally in 1 study. VA supplementation for ELBWIs had benefited oxygen dependency at the postmenstrual age of 36 weeks in survivors (pooled risk ratio, 0.88; 95% confidence intervals (CI), 0.77–0.99; 4 trials, 841 infants, moderate certainty of evidence), which is similar to the meta-analysis in VLBWIs. Length of hospital stay was reduced in the VA group (mean difference, −49.9; 95% CI, −88.78 to −11.02; 1 trial, 20 infants, low certainty of evidence). The meta-analysis showed no reduction in the risk of neonatal death, oxygen use at 28 days in survivors, duration of mechanical ventilation, intraventricular hemorrhage, retinopathy in prematurity, and necrotizing enterocolitis.

Conclusions

VA supplementation for ELBWIs is potentially effective in decreasing oxygen dependency at the postmenstrual age of 36 weeks.

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<![CDATA[Biological Activity and Antidiabetic Potential of C-Terminal Octapeptide Fragments of the Gut-Derived Hormone Xenin]]> https://www.researchpad.co/article/5989da6fab0ee8fa60b941c6

Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18–25 and xenin 18–25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18–25 and xenin 18–25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18–25 or xenin 18–25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18–25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18–25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18–25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18–25 Gln, have potential therapeutic utility for type 2 diabetes.

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<![CDATA[Intravenous S-Ketamine Does Not Inhibit Alveolar Fluid Clearance in a Septic Rat Model]]> https://www.researchpad.co/article/5989daecab0ee8fa60bbfaa1

We previously demonstrated that intratracheally administered S-ketamine inhibits alveolar fluid clearance (AFC), whereas an intravenous (IV) bolus injection had no effect. The aim of the present study was to characterize whether continuous IV infusion of S-ketamine, yielding clinically relevant plasma concentrations, inhibits AFC and whether its effect is enhanced in acute lung injury (ALI) which might favor the appearance of IV S-ketamine at the alveolar surface. AFC was measured in fluid-instilled rat lungs. S-ketamine was administered IV over 6 h (loading dose: 20 mg/kg, followed by 20 mg/kg/h), or intratracheally by addition to the instillate (75 µg/ml). ALI was induced by IV lipopolysaccharide (LPS; 7 mg/kg). Interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant (CINC)-3 were measured by ELISA in plasma and bronchoalveolar lavage fluid. Isolated rat alveolar type-II cells were exposed to S-ketamine (75 µg/ml) and/or LPS (1 mg/ml) for 6 h, and transepithelial ion transport was measured as short circuit current (ISC). AFC was 27±5% (mean±SD) over 60 min in control rats and was unaffected by IV S-ketamine. Tracheal S-ketamine reduced AFC to 18±9%. In LPS-treated rats, AFC decreased to 16±6%. This effect was not enhanced by IV S-ketamine. LPS increased IL-6 and CINC-3 in plasma and bronchoalveolar lavage fluid. In alveolar type-II cells, S-ketamine reduced ISC by 37% via a decrease in amiloride-inhibitable sodium transport. Continuous administration of IV S-ketamine does not affect rat AFC even in endotoxin-induced ALI. Tracheal application with direct exposure of alveolar epithelial cells to S-ketamine decreases AFC by inhibition of amiloride-inhibitable sodium transport.

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<![CDATA[Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart]]> https://www.researchpad.co/article/5989db5cab0ee8fa60be02a6

Background

We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury.

Methods

Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining.

Results

Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine.

Conclusions

Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse.

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<![CDATA[Polymer micelle formulation for the proteasome inhibitor drug carfilzomib: Anticancer efficacy and pharmacokinetic studies in mice]]> https://www.researchpad.co/article/5989db50ab0ee8fa60bdbd77

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic acid (CFZ-PM) and assessed its in vivo anticancer efficacy and pharmacokinetic profiles. Despite in vitro metabolic protection of CFZ, CFZ-PM did not display in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) superior to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD and the residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, our results showed that despite its favorable in vitro performances, the current CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Careful consideration of the current results and potential confounding factors may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for solid cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers.

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<![CDATA[Alterations of the Blood-Brain Barrier and Regional Perfusion in Tumor Development: MRI Insights from a Rat C6 Glioma Model]]> https://www.researchpad.co/article/5989d9f4ab0ee8fa60b6fb88

Objectives

Angiogenesis and anti-angiogenetic medications play an important role in progression and therapy of glioblastoma. In this context, in vivo characterization of the blood-brain-barrier and tumor vascularization may be important for individual prognosis and therapy optimization.

Methods

We analyzed perfusion and capillary permeability of C6-gliomas in rats at different stages of tumor-growth by contrast enhanced MRI and dynamic susceptibility contrast (DSC) MRI at 7 Tesla. The analyses included maps of relative cerebral blood volume (CBV) and signal recovery derived from DSC data over a time period of up to 35 days after tumor cell injections.

Results

In all rats tumor progression was accompanied by temporal and spatial changes in CBV and capillary permeability. A leakage of the blood-brain barrier (slow contrast enhancement) was observed as soon as the tumor became detectable on T2-weighted images. Interestingly, areas of strong capillary permeability (fast signal enhancement) were predominantly localized in the center of the tumor. In contrast, the tumor rim was dominated by an increased CBV and showed the highest vessel density compared to the tumor center and the contralateral hemisphere as confirmed by histology.

Conclusion

Substantial regional differences in the tumor highlight the importance of parameter maps in contrast or in addition to region-of-interest analyses. The data vividly illustrate how MRI including contrast-enhanced and DSC-MRI may contribute to a better understanding of tumor development.

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<![CDATA[Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality]]> https://www.researchpad.co/article/5989db29ab0ee8fa60bd0fb6

Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8+ T cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.

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<![CDATA[Lipopolysaccharide Cross-Tolerance Delays Platelet-Activating Factor-Induced Sudden Death in Swiss Albino Mice: Involvement of Cyclooxygenase in Cross-Tolerance]]> https://www.researchpad.co/article/5989d9f9ab0ee8fa60b713d9

Lipopolysaccharide (LPS) signaling through Toll-like receptor-4 (TLR-4) has been implicated in the pathogenesis of many infectious diseases. Some believe that TLR-mediated pathogenicity is due, in part, to the lipid pro-inflammatory mediator platelet-activating factor (PAF), but this has been questioned. To test the direct contribution of PAF in endotoxemia in murine models, we injected PAF intraperitoneally into Swiss albino mice in the presence and absence of LPS. PAF alone (5 μg/mouse) caused death within 15–20 min, but this could be prevented by pretreating mice with PAF-receptor (PAF-R) antagonists or PAF-acetylhydrolase (PAF-AH). A low dose of LPS (5 mg/kg body wt) did not impair PAF-induced death, whereas higher doses (10 or 20 mg/kg body wt) delayed death, probably via LPS cross-tolerance. Cross-tolerance occurred only when PAF was injected simultaneously with LPS or within 30 min of LPS injection. Tolerance does not appear to be due to an abundant soluble mediator. Histologic examination of lungs and liver and measurement of circulating TNF-α and IL-10 levels suggested that the inflammatory response is not diminished during cross-tolerance. Interestingly, aspirin, a non-specific cyclooxygenase (COX) inhibitor, partially blocked PAF-induced sudden death, whereas NS-398, a specific COX-2 inhibitor, completely protected mice from the lethal effects of PAF. Both COX inhibitors (at 20 mg/kg body wt) independently amplified the cross-tolerance exerted by higher dose of LPS, suggesting that COX-derived eicosanoids may be involved in these events. Thus, PAF does not seem to have a protective role in endotoxemia, but its effects are delayed by LPS in a COX-sensitive way. These findings are likely to shed light on basic aspects of the endotoxin cross-tolerance occurring in many disease conditions and may offer new opportunities for clinical intervention.

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<![CDATA[Comparison of renal response to four different induction therapies in Japanese patients with lupus nephritis class III or IV: A single-centre retrospective study]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc215

The recent recommendations for the management of lupus nephritis suggest that racial background should be considered while choosing induction therapy. However, the responses to different induction regimens have been poorly studied in Japanese population. Here, we assessed the renal response to different induction therapies in Japanese patients with lupus nephritis class III or IV. The records of 64 patients with biopsy-proven lupus nephritis class III or IV were retrospectively evaluated according to therapy received: monthly intravenous cyclophosphamide (IVCY), the Euro-lupus nephritis trial (ELNT) protocol-IVCY, tacrolimus (TAC), or mycophenolate mofetil (MMF). We investigated cumulative complete renal response (CR) rates and relapse rates for each group for 3 years. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). There were 22 patients on monthly IVCY, 18 on ELNT-IVCY, 13 on TAC, and 11 on MMF. Lower systemic lupus erythematosus disease activity index (SLEDAI) and higher CH50 were found in the TAC group at baseline (p<0.01 and p<0.01, respectively). There were no significant differences of cumulative CR rates and relapse free survival for 3 years among the four different therapeutic regimens (p = 0.2 and p = 0.2, respectively). There was a tendency to have early response and early relapse in TAC group and late response in MMF group. The SDI increase over 3 years was found more frequently in the TAC group than in the monthly-IVCY group (p = 0.04). Multivariate analysis indicated that CR at 3 months was independent prognosticator for low damage accrual. Regarding lower damage accrual, early CR achievement might be essential in induction therapy regardless of immunosuppressant choice.

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<![CDATA[Klotho and S100A8/A9 as Discriminative Markers between Pre-Renal and Intrinsic Acute Kidney Injury]]> https://www.researchpad.co/article/5989db4bab0ee8fa60bda581

Early detection and accurate differentiation of the cause of AKI may improve the prognosis of the patient. However, to date, there are few reliable biomarkers that can discriminate between pre-renal and intrinsic AKI. In this study, we determined whether AKI is associated with altered serum and urinary levels of Klotho, S100A8/A9 (an endogenous ligand of toll-like receptor 4), and neutrophil gelatinase-associated lipocalin (NGAL), which may allow differentiation between pre-renal and intrinsic AKI. A volume-depleted pre-renal AKI model was induced in male Sprague Dawley rats fed a low-salt diet (0.03%) without water 96 h before two intraperitoneal (IP) injections of furosemide (20 mg/kg) at a 24 h interval. In contrast, in the cisplatin-induced intrinsic AKI model, animals were given a single IP injection of cisplatin (5 mg/kg). All of the animals were euthanized 72 h after the first IP injection. Serum and urinary levels of Klotho, S100A8/A9, and NGAL were measured using an enzyme-linked immunosorbent assay. We also performed a proof-of-concept cross-sectional study to measure serum and urinary biomarkers in 61 hospitalized patients with established AKI. Compared to the intrinsic AKI group, the pre-renal AKI group showed a marked depression in urinary Klotho levels (13.21±17.32 vs. 72.97±17.96 pg/mL; P = 0.002). In addition, the intrinsic AKI group showed marked elevation of S100A8/A9 levels compared to the pre-renal AKI group (2629.97±598.05 ng/mL vs. 685.09±111.65 ng/mL; P = 0.002 in serum; 3361.11±250.86 ng/mL vs. 741.72±101.96 ng/mL; P = 0.003 in urine). There was no difference in serum and urinary NGAL levels between the pre-renal and intrinsic AKI groups. The proof-of-concept study with the hospitalized AKI patients also demonstrated decreased urinary Klotho in pre-renal AKI patients and increased urinary S100A8/A9 concentrations in intrinsic AKI patients. The attenuation of urinary Klotho and increase in urinary S100A8/A9 may allow differentiation between pre-renal and intrinsic AKI.

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<![CDATA[A Comparison of Human Neutrophils Acquired from Four Experimental Models of Inflammation]]> https://www.researchpad.co/article/5989db3bab0ee8fa60bd4bce

Defects in neutrophil function have been implicated in a wide spectrum of clinical conditions. Several models are employed to study activated human neutrophils akin to those found at a site of inflammation. These include whole blood (WB) ex vivo stimulation with lipopolysaccharide (LPS) and in vivo techniques: cantharidin blister, skin windows and intra-dermal injection of UV-killed E.coli (UVKEc). Neutrophils obtained from these have never been compared. We compared the activation status of neutrophils from each technique in order to inform the optimal model for use in human studies. Healthy male volunteers were randomised to undergo one of the four techniques (n = 5/group). LPS: WB stimulated with 1ng/ml of LPS for 4 hours. Cantharidin: 12.5μl of 0.1% cantharidin elicited a single blister, aspirated at 24 hours. Skin windows: four 6mm mechanical-suction blisters created, de-roofed and an exudate-collection chamber placed over the windows for 4 hours before aspiration. UVKEc: 1.5 x 107 UVKEc injected intra-dermally. A single 10mm mechanical-suction blister formed and aspirated at 4 hours. Unstimulated WB used as the control. Flow cytometry was used to determine activation status using CD16, CD11b, CD54, CD62L and CD88. Functional status was assessed with a phagocytosis assay. The pattern of neutrophil activation was similar in all models. Neutrophil CD11b was elevated in all models, most markedly in UVKEc (p<0.0001), and CD54 was also elevated but only significant in the LPS model (p = 0.001). CD62L was significantly reduced in all 4 models (p<0.0001) and CD88 was also suppressed in all. There were no changes in CD16 in any model, neither was there any significant difference in the phagocytic capacity of the neutrophils. In summary, there are no significant differences in activation marker expression or phagocytic capacity in the neutrophils obtained from each technique. Therefore we believe whole blood stimulation is the best model in experimentally challenging inpatient populations.

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<![CDATA[Assessment of Free Radical Scavenging Activity of Dimethylglycine Sodium Salt and Its Role in Providing Protection against Lipopolysaccharide-Induced Oxidative Stress in Mice]]> https://www.researchpad.co/article/5989da02ab0ee8fa60b7460f

In the present study, the free radical scavenging activities (against 1,1-diphenyl-2-pierylhydrazy (DPPH), 2,2'-Azinobis-(3-ethylbenzthiazoline-6- sulphonate) (ABTS+), Hydrogen peroxide (H2O2)) of dimethylglycine sodium salt (DMG-Na) were measured and compared with those of Trolox (6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid), a commonly used antioxidant. The radical scavenging activities of DMG-Na were found to be the highest at 40 mg/ml. In Experiment 2, gastric intubation in mice with 12 mg DMG-Na/0.3 ml sterile saline solution significantly increased (P < 0.05) the body weight (BW) (28 d), organ proportion (liver and spleen), and antioxidant capacity in serum and the liver (Superoxide dismutase (SOD), Hydrogen peroxidase (CAT), Glutathione peroxidase (GPx), and Total antioxidant capacity (T-AOC)), and significantly decreased (P < 0.05) the activities of serum Glutamic-pyruvic transaminase (ALT) and Glutamic oxalacetic transaminase (AST) and Methane Dicarboxylic Aldehyde (MDA) contents in the serum and liver. Specifically, the effect of 12 mg DMG-Na/0.3 ml sterile saline solution, which showed the highest antioxidant capacity, was further studied using a mice model. In Experiment 3, the mice CL (CON+ lipopolysaccharide (LPS)) group showed a significant decrease (P < 0.05) in the serum ALT and AST content; hepatic mitochondrial antioxidant capacity (Manganese Superoxide dismutase (MnSOD), Glutathione reductase (GR), GPx, Glutathione (GSH)); MDA and Protein carbonyl (PC) content; Reactive oxygen species (ROS) level, Mitochondrial membrane potential (MMP) level, and expression of liver antioxidant genes (Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme oxygenase 1 (HO-1), Manganese superoxide dismutase (MnSOD), Glutathione peroxidase 1 (Gpx1), Sirtuin 1 (Sirt1)) relative to the mice CS (CON+ sterile saline) group. The DL (DMG+LPS) group showed a significant decrease (P < 0.05) in serum ALT and AST content, ROS level, and expression of liver antioxidant gene MnSOD, Gpx1, Sirt1 and a significant increase (P < 0.05) in the hepatic mitochondrial antioxidant capacity (MnSOD, GSH, GPx, GR) and MMP level relative to the CL group. These results indicate that DMG-Na could protect against the LPS-induced oxidative stress by enhancing the free radical scavenging capacity, and increasing the activity of antioxidant defense system.

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<![CDATA[The epidemiology and clinical features of melioidosis in Far North Queensland: Implications for patient management]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdcefe

Background

The epidemiology, clinical presentation and management of melioidosis vary around the world. It is essential to define the disease’s local features to optimise its management.

Principal findings

Between 1998 and 2016 there were 197 cases of culture confirmed melioidosis in Far North Queensland; 154 (78%) presented in the December-April wet season. 145 (74%) patients were bacteraemic, 58 (29%) were admitted to the Intensive Care Unit and 27 (14%) died; nine (33%) of these deaths occurred within 48 hours of presentation. Pneumonia was the most frequent clinical finding, present in 101 (61%) of the 166 with available imaging. A recognised risk factor for melioidosis (diabetes, hazardous alcohol use, chronic renal disease, chronic lung disease, immunosuppression or malignancy) was present in 148 (91%) of 162 patients with complete comorbidity data. Despite representing only 9% of the region’s population, Aboriginal and Torres Strait Island (ATSI) people comprised 59% of the cases. ATSI patients were younger than non-ATSI patients (median (interquartile range): 46 (38–56) years versus 59 (43–69) years (p<0.001) and had a higher case-fatality rate (22/117 (19%) versus 5/80 (6.3%) (p = 0.01)). In the 155 patients surviving the initial intensive intravenous phase of treatment, eleven (7.1%) had disease recurrence, despite the fact that nine (82%) of these patients had received prolonged intravenous therapy. Recurrence was usually due to inadequate source control or poor adherence to oral eradication therapy. The case fatality rate declined from 12/44 (27%) in the first five years of the study to 7/76 (9%) in the last five (p = 0.009), reflecting national improvements in sepsis management.

Conclusions

Melioidosis in Far North Queensland is a seasonal, opportunistic infection of patients with specific comorbidities. The ATSI population bear the greatest burden of disease. Although the case-fatality rate is declining, deaths frequently occur early after hospitalisation, reinforcing the importance of prompt, targeted therapy in high-risk patients.

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