The transverse aortic constriction heart failure animal model: a systematic review and meta-analysis

The transverse aortic constriction (TAC) model is frequently used to study adverse cardiac remodeling upon pressure overload. We set out to define the most important characteristics that define the degree of cardiac remodeling in this model. A systematic review and meta-analyses were performed on studies using the TAC mouse/rat model and reporting echocardiographic outcome parameters. We included all animal studies in which a constriction around the transverse aorta and at least one of the predefined echocardiography or MRI outcome parameters were assessed. A total of 502 articles and > 3000 wild-type, untreated animals undergoing TAC were included in this study and referenced to a control group. The duration of aortic constriction correlated to the degree of adverse remodeling. However, the mouse data is strongly biased by the preferential use of male C57Bl/6 mice (66% of studies). Furthermore, mostly ketamine/xylazine anesthetics, 27G needle constriction, and silk sutures are used. Nonetheless, despite the homogeneity in experimental design, the model contained a substantial degree of heterogeneity in the functional outcome measures. When looking at study quality, only 12% reported randomization, 23% mentioned any sort of blinding, 25% adequately addressed the outcomes, and an amazingly low percentage (2%) showed sample size calculation. Meta-analyses did not detect specific study characteristics that explained the heterogeneity in the reported outcome measures, however this might be related to the strong bias towards the use of specific mouse lines, sex as well as age or to poor reporting of characteristics of study quality

Improving the conduct, reporting, and appraisal of animal research

Contains fulltext : 190714.pdf (publisher's version ) (Open Access

Pharmacological and methodological aspects of the separation-induced vocalization test in guinea pig pups; a systematic review and meta-analysis

Contains fulltext : 153647.pdf (Publisher’s version ) (Open Access)The separation-induced vocalization test in guinea pig pups is one of many that has been used to screen for anxiolytic-like properties of drugs. The test is based on the cross-species phenomenon that infants emit distress calls when placed in social isolation. Here we report a systematic review and meta-analysis of pharmacological intervention in the separation-induced vocalization test in guinea pig pups. Electronic databases were searched for original research articles, yielding 32 studies that met inclusion criteria. We extracted data on pharmacological intervention, animal and methodological characteristics, and study quality indicators. Meta-analysis showed that the different drug classes in clinical use for the treatment of anxiety disorders, have comparable effects on vocalization behaviour, irrespective of their mechanism of action. Of the experimental drugs, nociception (NOP) receptor agonists proved very effective in this test. Analysis further indicated that the commonly used read-outs total number and total duration of vocalizations are equally valid. With regard to methodological characteristics, repeated testing of pups as well as selecting pups with moderate or high levels of vocalization were associated with larger treatment effects. Finally, reporting of study methodology, randomization and blinding was poor and Egger's test for small study effects showed that publication bias likely occurred. This review illustrates the value of systematic reviews and meta-analyses in improving translational value and methodological aspects of animal models. It further shows the urgent need to implement existing publication guidelines to maximize the output and impact of experimental animal studies

Renal Perfusion and Function during Pneumoperitoneum: A Systematic Review and Meta-Analysis of Animal Studies

Both preclinical and clinical studies indicate that raised intra-abdominal pressure (IAP) associated with pneumoperitoneum during laparoscopic surgical procedures can cause renal damage, the severity of which may be influenced by variables such as pressure level and duration. Several of these variables have been investigated in animal studies, but synthesis of all preclinical data has not been performed. This systematic review summarizes all available pre-clinical evidence on this topic, including an assessment of its quality and risk of bias. We performed meta-analysis to assess which aspects of the pneumoperitoneum determine the severity of its adverse effects. A systematic search in two databases identified 55 studies on the effect of pneumoperitoneum on renal function which met our inclusion criteria. There was high heterogeneity between the studies regarding study design, species, sex, pressure and duration of pneumoperitoneum, and type of gas used. Measures to reduce bias were poorly reported, leading to an unclear risk of bias in the majority of studies. Details on randomisation, blinding and a sample size calculation were not reported in >/=80% of the studies. Meta-analysis showed an overall increase in serum creatinine during pneumoperitoneum, and a decrease in urine output and renal blood flow. Subgroup analysis indicated that for serum creatinine, this effect differed between species. Subgroup analysis of pressure level indicated that urine output decreased as IAP level increased. No differences between types of gas were observed. Data were insufficient to reliably assess whether sex or IAP duration modulate the effect of pneumoperitoneum. Four studies assessing long-term effects indicated that serum creatinine normalized >/=24 hours after desufflation of pneumoperitoneum at 15mmHg. We conclude that harmful effects on renal function and perfusion during pneumoperitoneum appear to be robust, but evidence on long-term effects is very limited. The reliability and clinical relevance of these findings for healthy patients and patients at high risk of renal impairment remain uncertain. We emphasize the need for rigorous reporting of preclinical research methodology, which is of vital importance for clinical translation of preclinical data

Towards evidence-based translational research: the pros and cons of conducting systematic reviews of animal studies

Contains fulltext : 117875.pdf (publisher's version ) (Open Access

The usefulness of systematic reviews of animal studies: shooting the messenger

Contains fulltext : 171781.pdf (publisher's version ) (Closed access

Regarding "Remote and local ischemic preconditioning equivalently protects rat skeletal muscle mitochondrial function during experimental aortic cross-clamping".

Item does not contain fulltext1 september 201

Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport

Contains fulltext : 185825.pdf (publisher's version ) (Closed access)The kidney of vertebrates plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion, mediated by carrier proteins including multidrug resistance protein 2 (Mrp2). We previously showed that Mrp2 function is reduced by endothelin-1 (ET-1) through a basolateral B-type receptor, nitric oxide (NO), cGMP, and PKC (Notenboom S, Miller DS, Smits P, Russel FGM, Masereeuw R. Am J Physiol Renal Physiol 282: F458-F464, 2002; Notenboom S, Miller DS, Smits P, Russel FG, Masereeuw R. Am J Physiol Renal Physiol 287: F33-F38, 2004). This pathway was rapidly activated by several nephrotoxicants and appeared to be calcium dependent. In the present study, we studied the effect of the calciotropic hormones parathyroid hormone (PTH), PTH-related protein (PTHrP), and stanniocalcin (STC) to interfere with ET-regulated Mrp2 transport. Like ET-1, PTH reduces Mrp2-mediated transport by 40% in killifish renal proximal tubules. When given in combination, an additive effect was seen, which is partially reversed by the PKC inhibitor calphostin C. Recombinant PTHrP shows a comparable inhibitory effect, which is concentration dependent and additive to the inhibition by ET. STC fully reverses PTHrP-inhibited transport as does a guanylyl cyclase inhibitor. Finally, to confirm PTHrP bioactivity in a homologous assay, we performed immunolocalization and transport studies in sea bream kidney tubules. Mrp2 immunoreactivity was observed in approximately 40% of the tubules and is associated with the brush-border and apical plasma membrane of cells. Both proximal tubules and distal (collecting) tubules express the antigen. A highly significant 40% inhibition of Mrp2-mediated transport was observed with PTHrP in sea bream tubules. In conclusion, ET-regulated Mrp2 transport is influenced by calciotropic hormones and involves PKC and cGMP signaling

Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2 (Mrp2-) mediated transport

Item does not contain fulltextThe kidney of vertebrates plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion, mediated by carrier proteins including multidrug resistance protein 2 (Mrp2). We previously showed that Mrp2 function is reduced by endothelin-1 (ET-1) through a basolateral B-type receptor, nitric oxide (NO), cGMP and protein kinase C (PKC). This pathway was rapidly activated by several nephrotoxicants and appeared to be calcium dependent. In the present study we studied the effect of the calciotropic hormones, parathyroid hormone (PTH), PTH-related protein (PTHrP) and stanniocalcin (STC), to interfere with ET-regulated Mrp2 transport. Like ET-1, PTH reduces Mrp2-mediated transport for 40% in killifish renal proximal tubules. When given combined an additive effect was seen, which is partially reversed by the PKC inhibitor calphostin C. Recombinant PTHrP shows a comparable inhibitory effect, which is concentration-dependent and additive to the inhibition by ET. STC fully reverses PTHrP inhibited transport as does a guanylyl cyclase inhibitor. Finally, to confirm PTHrP bioactivity in a homologous assay we performed immunolocalization and transport studies in sea bream kidney tubules. Mrp2 immunoreactivity was observed in about 40% of the tubules and is associated with the brush border and apical plasma membrane of cells. Both proximal tubules and distal (collecting) tubules express the antigen. A highly significant 40% inhibition of Mrp2-mediated transport was observed with PTHrP in sea bream tubules. In conclusion, ET-regulated Mrp2 transport is influenced by calciotropic hormones and involves PKC and cGMP signaling. Key words: endothelin, stanniocalcin., parathyroid hormone related protein, parathyroid hormone, multidrug resistance-associated protein 2

The protective effect of anterior cruciate ligament reconstruction on articular cartilage: a systematic review of animal studies

Contains fulltext : 203275.pdf (publisher's version ) (Closed access)OBJECTIVE: It is unclear if anterior cruciate ligament (ACL) reconstruction can prevent the onset of degenerative changes in the knee. Previous studies were inconclusive on this subject. The aim of this study was to systematically review all studies on the effect of ACL reconstruction on articular cartilage in animals. DESIGN: Pubmed and Embase were searched to identify all original articles concerning the effect of ACL reconstruction on articular cartilage compared with both its positive (ACL transection) and negative (sham and/or non-operated) control in animals. Subsequently a Risk of bias and meta analysis was conducted based on five outcomes (gross macroscopic assessment, medical imaging, histological histochemical grading, histomophometrics and biomechanical characterization) related to articular cartilage. RESULTS: From the 19 included studies, 29 independent comparisons could be identified which underwent ACL reconstruction with an average timing of data collection of 23 weeks (range 1-104 weeks). Due to limited data availability meta-analysis could only be conducted for gross macroscopic damage. ACL reconstruction caused significant gross macroscopic damage compared with intact controls (SMD 2.0 [0.88; 3.13]). These findings were supported by individual studies reporting on histomorphometrics, histology and imaging. No significant gross macroscopic damage was found when ACL reconstruction was compared with ACL transection (SMD -0.64 [-1.85; 0.57]). CONCLUSION: This systematic review with an average follow up of included studies of 23 weeks (range 1-104 weeks) demonstrates that, in animals, ACL reconstruction does not protect articular cartilage from degenerative changes. The consistency of the direction of effect, provides some reassurance that the direction of effect in humans might be the same