Image_1_Establishment of an optimized guinea pig model of cisplatin-induced ototoxicity.TIFF

BackgroundCisplatin is among the most effective antineoplastic agents and has revolutionized the treatment of many cancer diseases. However, one of its serious side effects is a progressive and irreversible hearing loss, occurring in both adults and children. For the development of otoprotective therapies that prevent this side effect, cisplatin-induced hearing loss animal models are indispensable. Due to the high toxicity of cisplatin, the establishment of such animal models is a difficult and time-consuming task. Here we introduce the detailed protocol of a sophisticated guinea pig model with a sufficient and permanent hearing loss induced by cisplatin. This manuscript is intended to provide guidance in the development of future cisplatin guinea pig models which may reduce the mortality rate of the animals and help to gain more reproducible results.MethodsPigmented and unpigmented guineapigs were treated with an intravenous single application of 8 mg/kg cisplatin under general anesthesia. An extensive and long-term intensive care protocol consisting of scheduled application of fluids, antiemetics, analgesics, glucose and supportive feeding among others, was used to ensure wellbeing of the animals. Hearing tests were performed prior to and 5 days after cisplatin application. Animals were then euthanized.ResultsThe ABR audiometry 5 days after cisplatin application revealed a hearing threshold ranging from 70 dB to 90 dB in the frequencies from 1 kHz to 32 kHz respectively.All animals presented a good health condition despite the treatment with cisplatin.DiscussionThe introduced care protocol in this manuscript is intended to serve as a guidance for the establishment of a stable guinea pig model for short- and long-term investigation regarding the inner ear and its protection in the frame work of cisplatin-induced damage.</p

Correlation between plasma endothelin-1 levels and severity of septic liver failure quantified by maximal liver function capacity (LiMAx test). A prospective study

<div><p>Aim</p><p>To investigate the relationship between the degree of liver dysfunction, quantified by maximal liver function capacity (LiMAx test) and endothelin-1, TNF-α and IL-6 in septic surgical patients.</p><p>Methods</p><p>28 septic patients (8 female, 20 male, age range 35–80y) were prospectively investigated on a surgical intensive care unit. Liver function, defined by LiMAx test, and measurements of plasma levels of endothelin-1, TNF-α and IL-6 were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Patients were divided into 2 groups (group A: LiMAx ≥100 μg/kg/h, moderate liver dysfunction; group B: LiMAx <100 μg/kg/h, severe liver dysfunction) for analysis and investigated regarding the correlation between endothelin-1 and the severity of liver failure, quantified by LiMAx test.</p><p>Results</p><p>Group B showed significant higher results for endothelin-1 than patients in group A (P = 0.01, d5; 0.02, d10). For TNF-α, group B revealed higher results than group A, with a significant difference on day 10 (P = 0.005). IL-6 showed a non-significant trend to higher results in group B. The Spearman's rank correlation coefficient revealed a significant correlation between LiMAx and endothelin-1 (-0.434; P <0.001), TNF-α (-0.515; P <0.001) and IL-6 (-0.590; P <0.001).</p><p>Conclusions</p><p>Sepsis-related hepatic dysfunction is associated with elevated plasma levels of endothelin-1, TNF-α and IL-6. Low LiMAx results combined with increased endothelin-1 and TNF-α and a favourable correlation between LiMAx and cytokine values support the findings of a crucial role of Endothelin-1 and TNF-α in development of septic liver failure.</p></div

Clinical characteristics.

<p>Clinical characteristics.</p

Relationship between liver function and cytokines in septic patients using Spearman’s rank correlation coefficient.

<p><b>(A)</b> LiMAx vs. CT-proET-1, <b>(B)</b> LiMAx vs. TNF-a, <b>(C)</b> LiMAx vs. IL-6.</p

Progression of CT-proET-1 and cytokines by severity of liver dysfunction in sepsis.

<p><b>(A)</b> CT-proET-1, <b>(B)</b> TNF-α, <b>(C)</b> IL-6. White box: group A; LiMAx ≥100μg/kg/h; Shaded box: group B; LiMAx <100μg/kg/h. Bold lines, medians; box plots, 25th to 75th percentiles. Horizontal broken lines indicate the normal range. Outliers are illustrated as circles.</p

Clinical characteristics and severity of illness in the study groups.

<p>Clinical characteristics and severity of illness in the study groups.</p

Progression of liver function, CT-proET-1 and cytokines in septic patients.

<p><b>(A)</b> Maximal liver function capacity (LiMAx), <b>(B)</b> CT-proET-1, <b>(C)</b> TNF-α, <b>(D</b>) IL-6. Bold lines: medians; box plots: 25th to 75th percentiles. Horizontal broken lines indicate the normal range. Outliers are illustrated as circles.</p