Supplemental Digital Content is Available in the Text.This unique multicenter approach provides high-quality evidence validating burrowing as a robust and reproducible outcome measure to infer the global effect of pain on rodents.
Background:Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)–extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised.Methods:Modulation of ERK5 expression or function in human PCa PC3 and PC3–ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT–PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry.Results:Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P<0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P=0.013 and P<0.0001, respectively).Conclusion:Our in vitro, in vivo and clinical data support an important role for the MEK5–ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa.
We report a systematic review and meta-analysis of research using animal models of chemotherapy-induced peripheral neuropathy (CIPN). We systematically searched 5 online databases in September 2012 and updated the search in November 2015 using machine learning and text mining to reduce the screening for inclusion workload and improve accuracy. For each comparison, we calculated a standardised mean difference (SMD) effect size, and then combined effects in a random-effects meta-analysis. We assessed the impact of study design factors and reporting of measures to reduce risks of bias. We present power analyses for the most frequently reported behavioural tests; 337 publications were included. Most studies (84%) used male animals only. The most frequently reported outcome measure was evoked limb withdrawal in response to mechanical monofilaments. There was modest reporting of measures to reduce risks of bias. The number of animals required to obtain 80% power with a significance level of 0.05 varied substantially across behavioural tests. In this comprehensive summary of the use of animal models of CIPN, we have identified areas in which the value of preclinical CIPN studies might be increased. Using both sexes of animals in the modelling of CIPN, ensuring that outcome measures align with those most relevant in the clinic, and the animal’s pain contextualised ethology will likely improve external validity. Measures to reduce risk of bias should be employed to increase the internal validity of studies. Different outcome measures have different statistical power, and this can refine our approaches in the modelling of CIPN.
Background and aims: Chemotherapy-induced peripheral neuropathy (CIPN) can be a severely disabling side-effect of commonly used cancer chemotherapeutics, requiring cessation or dose reduction, impacting on survival and quality of life. Our aim was to conduct a systematic review and meta-analysis of research using animal models of CIPN to inform robust experimental design. Methods: We systematically searched 5 online databases (PubMed, Web of Science, Citation Index, Biosis Previews and Embase (September 2012) to identify publications reporting in vivo CIPN modelling. Due to the number of publications and high accrual rate of new studies, we ran an updated search November 2015, using machine-learning and text mining to identify relevant studies. All data were abstracted by two independent reviewers. For each comparison we calculated a standardised mean difference effect size then combined effects in a random effects metaanalysis. The impact of study design factors and reporting of measures to reduce the risk of bias was assessed. We ran power analysis for the most commonly reported behavioural tests. Results: 341 publications were included. The majority (84%) of studies reported using male animals to model CIPN; the most commonly reported strain was Sprague Dawley rat. In modelling experiments, Vincristine was associated with the greatest increase in pain-related behaviour (-3.22 SD [-3.88; -2.56], n=152, p=0). The most commonly reported outcome measure was evoked limb withdrawal to mechanical monofilaments. Pain-related complex behaviours were rarely reported. The number of animals required to obtain 80% power with a significance level of 0.05 varied substantially across behavioural tests. Overall, studies were at moderate risk of bias, with modest reporting of measures to reduce the risk of bias. Conclusions: Here we provide a comprehensive summary of the field of animal models of CIPN and inform robust experimental design by highlighting measures to increase the internal and external validity of studies using animal models of CIPN. Power calculations and other factors, such as clinical relevance, should inform the choice of outcome measure in study design.
Clear reporting of research is crucial to the scientific process. Poorly designed and reported studies are damaging not only to the efforts of individual researchers, but also to science as a whole. Standardised reporting methods, such as those already established for reporting randomised clinical trials, have led to improved study design and facilitated the processes of clinical systematic review and meta-analysis. Such standards were lacking in the pre-clinical field until the development of the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines. These were prompted following a survey which highlighted a widespread lack of robust and consistent reporting of pre-clinical in vivo research, with reports frequently omitting basic information required for study replication and quality assessment. The resulting twenty item checklist in ARRIVE covers all aspects of experimental design with particular emphasis on bias reduction and methodological transparency. Influential publishers and research funders have already adopted ARRIVE. Further dissemination and acknowledgement of the importance of these guidelines is vital to their widespread implementation. Conclusions and implications Wide implementation of the ARRIVE guidelines for reporting of in vivo preclinical research, especially pain research, are essential for a much needed increased transparency and quality in publishing such research. ARRIVE will also positively influence improvements in experimental design and quality, assist the conduct of accurate replication studies of important new findings and facilitate meta-analyses of preclinical research.
Understanding the non-sensory components of the pain experience is crucial to developing effective treatments for pain conditions. Chronic pain is associated with increased incidence of anxio-depressive disorders, and patients often report feelings of vulnerability which can decrease quality of life. In animal models of pain, observation of behaviours such as thigmotaxis can be used to detect such affective disturbances by exploiting the influence of nociceptive stimuli on the innate behavioural conflict between exploration of a novel space and predator avoidance behaviour. This study investigates whether acute and repeated bladder inflammation in adult female Wistar rats increases thigmotactic behaviour in the open field paradigm, and aims to determine whether this correlates with activation in the central amygdala, as measured by c-Fos immunoreactivity. Additionally, up-regulation of inflammatory mediators in the urinary bladder was measured using RT-qPCR array featuring 92 transcripts to examine how local mediators change under experimental conditions. We found acute but not repeated turpentine inflammation of the bladder increased thigmotactic behaviour (decreased frequency of entry to the inner zone) in the open field paradigm, a result that was also observed in the catheter-only instrumentation group. Decreases in locomotor activity were also observed in both models in turpentine and instrumentation groups. No differences were observed in c-Fos activation, although a general increased in activation along the rostro-caudal axis was seen. Inflammatory mediator up-regulation was greatest following acute inflammation, with CCL12, CCL7, and IL-1β significantly up-regulated in both conditions when compared to naïve tissue. These results suggest that acute catheterisation, with or without turpentine inflammation, induces affective alterations detectable in the open field paradigm accompanied by up-regulation of multiple inflammatory mediators.
BackgroundPain is associated with affective, cognitive and sensory dysfunction. Animal models can be used to observe ethologically relevant behaviours such as thigmotaxis, giving insight into how ongoing sensory abnormalities influence natural rodent behaviours. The amygdala is a complex group of nuclei implicated in the integration and generation of emotional behavioural responses, including those associated with pain, and a region known as the central amygdala is particularly associated with generation of behavioural responses, due to its links to the descending pain modulation pathways; as such, study of amygdalar c‐Fos immunoreactivity can help identify the neuronal circuits involved.MethodThis study investigated changes in both nociceptive evoked responses and open field behaviour following spinal nerve transection (SNT) in male Wistar rats, and attempted to correlate these with changes in central amygdala c‐Fos immunoreactivity.ResultsFourteen days after SNT, mechanical hypersensitivity was present in the hind paw ipsilateral to site of injury. Thigmotactic behaviour was significantly increased in both SNT and sham surgery animals, with c‐Fos immunoreactivity in the central amygdala significantly greater in SNT animals compared to both sham and naive groups. Activation was greatest in the capsular and lateral subnuclei of the central amygdala, and in the caudal‐most regions. There was a strong correlation between thigmotactic behaviour and central amygdala activation following SNT surgery not seen in sham animals suggesting a role for the amygdala in behavioural responses to peripheral nerve injury.ConclusionsThis study provides evidence to support the role of the amygdala in thigmotactic open field behaviour following SNT.What does this study add?Thigmotaxis and amygdala activation are positively correlated in rats following spinal nerve transection.Behavioural changes seen in sham animals did not correlate with amygdala activation, suggesting amygdala activation is related to nociceptive input.Evoked measures, such as hindpaw withdrawal, are not correlated with either thigmotaxis or amygdala activation, emphasizing the importance of complex behaviours when studying pain.
A quality assurance programme was used to evaluate community and primary care based preschool surveillance using the National Child Health Computer System in 40 examination centres. Quarterly reports were generated from returns from clinical medical officers and general practitioners to list non-attenders, uptake, and timeliness for the four preschool checks. These provided rapid and comparative feedback on personal performance for participating health professionals and led to marked rises in recorded timeliness and uptake against preset targets.Pre-existing uptake was highest at the 6 week check with least overall improvement. Greatest improvements occurred at the 18 month health visitor check but, in general, results plateaued when the programme had been in use for 12 to 18 months. Particular problems such as data legibility and mobile populations were identified and solutions formulated. It is postulated that improvements in performance were due to enhanced professional motivation as no other factors changed. This system provides a valuable contribution in the light of changing patterns of service provision.
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