TSPO and amyloid deposits in sub-regions of the hippocampus in the 3xTgAD mouse model of Alzheimer's disease.

The involvement of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in Alzheimer's disease (AD) remains controversial. In the present report, we used [125I]-CLINDE, a SPECT TSPO radiotracer never before used in AD, and we investigated the relationship between TSPO and amyloid plaque density (using [125I]-DRM106) in a triple transgenic mouse model of AD (3xTgAD, APPSWE, PS1M146V and TauP301L). Our results show that TSPO increases appear before those of amyloid deposits. Moreover, the different parts of the hippocampus are differentially affected. Indeed, for both TSPO and amyloid, the subiculum is affected earlier and the ventral hippocampus later than the dorsal hippocampus. In the subiculum and the dorsal hippocampus of 3xTgAD mice, a positive correlation between TSPO and of amyloid deposit levels is observed. This data supports the hypothesis that TSPO could be used as a predictive marker of amyloid pathology. In addition, our immunohistochemical data shows a segregation of TSPO in the hippocampus and immunofluorescence imaging revealed a mainly microglial origin of the TSPO expression. Thus, imaging TSPO with CLINDE may be a good alternative to PET radiotracers.

Non-steroidal anti-inflammatory drugs (NSAIDs) for cancer-related pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for persisting pain in children acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Specific mortality and morbidity data relating to children are not currently identified. All childhood cancer rates are on the rise; for example, in the USA approximately 10,380 children aged under 15 years were expected to be diagnosed with cancer by the end of 2016. However, with survival rates also increasing, over 80% of paediatric cancer patients are expected to survive for five years or more, thus identifying the need to address pain management in this population.Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammatory properties. They are commonly used within paediatric pain management. NSAIDs are currently licensed for use in western countries, however not approved for infants aged under three months. Primary adverse effects include gastrointestinal issues and possible renal impairment with long term use. Other adverse effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain. OBJECTIVES: To assess the analgesic efficacy, and adverse events, of non-steroidal anti-inflammatory drugs (NSAIDs) used to treat cancer-related pain in children and adolescents aged from birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 21 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised, double-blind trials of any dose, and any route, treating cancer-related pain in children and adolescents, comparing NSAIDs with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were eligible for inclusion in this review (very low quality evidence). We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials that non-steroidal anti-inflammatory drugs (NSAIDs) reduce cancer-related pain in children and adolescents. This means that no reliance or conclusions can be made about efficacy or harm in the use of NSAIDs to treat chronic cancer-related pain in children and adolescents.

Opioids for cancer-related pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is to start with a low dose gradually titrated to effect or unacceptable adverse effect in the child. OBJECTIVES: To assess the analgesic efficacy, and adverse events, of opioids used to treat cancer-related pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid and Embase via Ovid from inception to 22 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials (RCTs), with or without blinding, of any dose, and any route, treating cancer-related pain in children and adolescents, comparing opioids with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were identified that were eligible for inclusion in this review (very low quality evidence). Several studies tested opioids on adults with cancer-related pain, but none in participants aged from birth to 17 years.We rated the quality of evidence as very low, downgraded due to a lack of available data; no analyses could be undertaken. AUTHORS' CONCLUSIONS: No conclusions can be drawn about efficacy or harm in the use of opioids to treat cancer-related pain in children and adolescents. As a result, there is no RCT evidence to support or refute the use of opioids to treat cancer-related pain in children and adolescents.

In vivo PET imaging with [(18)F]FDG to explain improved glucose uptake in an apolipoprotein A-I treated mouse model of diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by decreased HDL levels, as well as the level of apolipoprotein A-I (apoA-I), the main apolipoprotein of HDLs. Pharmacological elevation of HDL and apoA-I levels is associated with improved glycaemic control in patients with type 2 diabetes. This is partly due to improved glucose uptake in skeletal muscle. METHODS: This study used kinetic modelling to investigate the impact of increasing plasma apoA-I levels on the metabolism of glucose in the db/db mouse model. RESULTS: Treatment of db/db mice with apoA-I for 2 h significantly improved both glucose tolerance (AUC 2574 ± 70 mmol/l × min vs 2927 ± 137 mmol/l × min, for apoA-I and PBS, respectively; p < 0.05) and insulin sensitivity (AUC 388.8 ± 23.8 mmol/l × min vs 194.1 ± 19.6 mmol/l × min, for apoA-I and PBS, respectively; p < 0.001). ApoA-I treatment also increased glucose uptake by skeletal muscle in both an insulin-dependent and insulin-independent manner as evidenced by increased uptake of fludeoxyglucose ([(18)F]FDG) from plasma into gastrocnemius muscle in apoA-I treated mice, both in the absence and presence of insulin. Kinetic modelling revealed an enhanced rate of insulin-mediated glucose phosphorylation (k 3) in apoA-I treated mice (3.5 ± 1.1 × 10(-2) min(-1) vs 2.3 ± 0.7 × 10(-2) min(-1), for apoA-I and PBS, respectively; p < 0.05) and an increased influx constant (3.7 ± 0.6 × 10(-3) ml min(-1) g(-1) vs 2.0 ± 0.3 × 10(-3) ml min(-1) g(-1), for apoA-I and PBS, respectively; p < 0.05). Treatment of L6 rat skeletal muscle cells with apoA-I for 2 h indicated that increased hexokinase activity mediated the increased rate of glucose phosphorylation. CONCLUSIONS/INTERPRETATION: These findings indicate that apoA-I improves glucose disposal in db/db mice by improving insulin sensitivity and enhancing glucose phosphorylation.

4D PET iterative deconvolution with spatiotemporal regularization for quantitative dynamic PET imaging.

Quantitative measurements in dynamic PET imaging are usually limited by the poor counting statistics particularly in short dynamic frames and by the low spatial resolution of the detection system, resulting in partial volume effects (PVEs). In this work, we present a fast and easy to implement method for the restoration of dynamic PET images that have suffered from both PVE and noise degradation. It is based on a weighted least squares iterative deconvolution approach of the dynamic PET image with spatial and temporal regularization. Using simulated dynamic [(11)C] Raclopride PET data with controlled biological variations in the striata between scans, we showed that the restoration method provides images which exhibit less noise and better contrast between emitting structures than the original images. In addition, the method is able to recover the true time activity curve in the striata region with an error below 3% while it was underestimated by more than 20% without correction. As a result, the method improves the accuracy and reduces the variability of the kinetic parameter estimates calculated from the corrected images. More importantly it increases the accuracy (from less than 66% to more than 95%) of measured biological variations as well as their statistical detectivity.

Challenging neurological symptoms in paediatric palliative care: An approach to symptom evaluation and management in children with neurological impairment.

Neurological symptoms are very common in children with life-limiting conditions and are challenging in terms of burden of illness. Moreover, neurological symptoms can significantly impact the child's quality of life and contribute to distress among parents, families, caregivers and health care providers. Knowing how to manage and alleviated these symptoms is essential for providing good palliative care. In the present article, the more common neurological symptoms of agitation/irritability, spasticity and dystonia will be reviewed. The aim of the present brief review is to provide a basic approach to both the identification and treatment of these neurological symptoms. A medication table is provided for quick reference. A brief commentary and guidance for the management of pain are also incorporated, with reference to further literature sources.

Les symptômes neurologiques sont très courants chez les enfants ayant des problèmes limitant l'espérance de vie, et le fardeau de la maladie est difficile à prendre en charge. De plus, les symptômes neurologiques peuvent avoir des effets marqués sur la qualité de vie de l'enfant et contribuer à la détresse des parents, des familles, des soignants et des dispensateurs de soins. Il est essentiel de savoir comment prendre en charge et soulager ses symptômes pour offrir de bons soins palliatifs. Dans le présent article, les symptômes neurologiques plus courants d'agitation ou d'irritabilité, de spasticité et de dystonie sont abordés. L'analyse qui y est présentée vise à proposer une conduite de base pour déterminer et traiter ces symptômes neurologiques. Un tableau de médicaments facilite la consultation. Un bref commentaire et des conseils sur la prise en charge de la douleur sont également proposés, de même que des références vers d'autres publications.

A data driven method for estimation of B(avail) and appK(D) using a single injection protocol with [¹¹C]raclopride in the mouse.

PURPOSE: The partial saturation approach (PSA) is a simple, single injection experimental protocol that will estimate both B(avail) and appK(D) without the use of blood sampling. This makes it ideal for use in longitudinal studies of neurodegenerative diseases in the rodent. The aim of this study was to increase the range and applicability of the PSA by developing a data driven strategy for determining reliable regional estimates of receptor density (B(avail)) and in vivo affinity (1/appK(D)), and validate the strategy using a simulation model. METHODS: The data driven method uses a time window guided by the dynamic equilibrium state of the system as opposed to using a static time window. To test the method, simulations of partial saturation experiments were generated and validated against experimental data. The experimental conditions simulated included a range of receptor occupancy levels and three different B(avail) and appK(D) values to mimic diseases states. Also the effect of using a reference region and typical PET noise on the stability and accuracy of the estimates was investigated. RESULTS: The investigations showed that the parameter estimates in a simulated healthy mouse, using the data driven method were within 10±30% of the simulated input for the range of occupancy levels simulated. Throughout all experimental conditions simulated, the accuracy and robustness of the estimates using the data driven method were much improved upon the typical method of using a static time window, especially at low receptor occupancy levels. Introducing a reference region caused a bias of approximately 10% over the range of occupancy levels. CONCLUSIONS: Based on extensive simulated experimental conditions, it was shown the data driven method provides accurate and precise estimates of B(avail) and appK(D) for a broader range of conditions compared to the original method.

Simulation-based optimisation of the PET data processing for partial saturation approach protocols.

Positron emission tomography (PET) with [(11)C]Raclopride is an important tool for studying dopamine D2 receptor expression in vivo. [(11)C]Raclopride PET binding experiments conducted using the Partial Saturation Approach (PSA) allow the estimation of receptor density (B(avail)) and the in vivo affinity appK(D). The PSA is a simple, single injection, single scan experimental protocol that does not require blood sampling, making it ideal for use in longitudinal studies. In this work, we generated a complete Monte Carlo simulated PET study involving two groups of scans, in between which a biological phenomenon was inferred (a 30% decrease of B(avail)), and used it in order to design an optimal data processing chain for the parameter estimation from PSA data. The impact of spatial smoothing, noise removal and image resolution recovery technique on the statistical detection was investigated in depth. We found that image resolution recovery using iterative deconvolution of the image with the system point spread function associated with temporal data denoising greatly improves the accuracy and the statistical reliability of detecting the imposed phenomenon. Before optimisation, the inferred B(avail) variation between the two groups was underestimated by 42% and detected in 66% of cases, while a false decrease of appK(D) by 13% was detected in more than 11% of cases. After optimisation, the calculated B(avail) variation was underestimated by only 3.7% and detected in 89% of cases, while a false slight increase of appK(D) by 3.7% was detected in only 2% of cases. We found during this investigation that it was essential to adjust a factor that accounts for difference in magnitude between the non-displaceable ligand concentrations measured in the target and in the reference regions, for different data processing pathways as this ratio was affected by different image resolutions.

Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?

PURPOSE: Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE. METHODS: Adult male Wistar rats underwent LFPI or sham injury. Serial magnetic resonance (MR) and positron emission tomography (PET) imaging, and behavioral analyses were performed over 6 months postinjury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video-electroencephalography (EEG) to assess for PTE. Of the LFPI rats, 52% (n = 12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings. KEY FINDINGS: MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, (18) F-fluorodeoxyglucose (FDG)-PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at 1 week, and 1, 3, and 6 months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and nonepileptic groups. However, hippocampal surface shape analysis using large-deformation high-dimensional mapping identified significant changes in the ipsilateral hippocampus at 1 week postinjury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the 1 week, and 1 and 3 month (18) F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination. SIGNIFICANCE: These findings suggest that PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest that more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and nonepileptic animals into the correct group.

Drugs for chronic pain in children: a commentary on clinical practice and the absence of evidence.

Pediatric chronic pain is widespread, under-recognized and undertreated. Best management usually involves a multimodal approach coordinated by a multidisciplinary team. The present commentary specifically discusses common pharmacological approaches to chronic pain in children, identifies gaps in knowledge and suggests several research directions that would benefit future clinical care.

Characterisation of partial volume effect and region-based correction in small animal positron emission tomography (PET) of the rat brain.

Accurate quantification of PET imaging data is required for a useful interpretation of the measured radioactive tracer concentrations. The partial volume effect (PVE) describes signal dilution and mixing due to spatial resolution and sampling limitations, which introduces bias in quantitative results. In the present study we investigated the magnitude of PVE for volumes of interest (VOIs) in the rat brain and the effect of positron range. In simulated (11)C-raclopride studies we examined the influence of PVE on time activity curves in striatal and cerebellar VOIs and binding potential estimation. The performance of partial volume correction (PVC) was studied using the region-based geometric transfer matrix (GTM) method including the question of whether a spatially variant point spread function (PSF) is necessary for PVC of a rat brain close to the centre of the field of view. Furthermore, we determined the effect of spillover from activity outside the brain. The results confirmed that PVE is significant in rat brain PET and showed that positron range is an important factor that needs to be included in the PSF. There was considerable bias in time activity curves for the simulated (11)C-raclopride studies and significant underestimation of binding potential even for very small centred VOIs. Good activity recovery was achieved with the GTM PVC using a spatially invariant simulated PSF when no activity was present outside the brain. PVC using a simple Gaussian fit point spread function was not sufficiently accurate. Spillover from regions outside the brain had a significant impact on measured activity concentrations and reduced the accuracy of PVC with the GTM method using rat brain regions alone, except for the smallest VOI size but at the cost of increased noise. Voxel-based partial volume correction methods which inherently compensate for spillover from outside the brain might be a more suitable choice.

Evaluation of [¹²³I]-CLINDE as a potent SPECT radiotracer to assess the degree of astroglia activation in cuprizone-induced neuroinflammation.

PURPOSE: The purpose of this study was to assess the feasibility and sensitivity of the high-affinity translocator protein (TSPO) ligand [(123)I]-CLINDE in imaging TSPO changes in vivo and characterise and compare astroglial and TSPO changes in the cuprizone model of demyelination and remyelination in C57BL/6 mice. METHODS: C57BL/6 mice were fed with cuprizone for 4 weeks to induce demyelination followed by 2-4 weeks of standard diet (remyelination). Groups of mice were followed by in vivo single photon emission computed tomography (SPECT)/CT imaging using [(123)I]-CLINDE and uptake correlated with biodistribution, autoradiography, immunohistochemistry, immunofluorescence and real-time polymerase chain reaction (RT-PCR). RESULTS: The uptake of [(123)I]-CLINDE in the brain as measured by SPECT imaging over the course of treatment reflects the extent of the physiological response, with significant increases observed during demyelination followed by a decrease in uptake during remyelination. This was confirmed by autoradiography and biodistribution studies. A positive correlation between TSPO expression and astrogliosis was found and both activated astrocytes and microglial cells expressed TSPO. [(123)I]-CLINDE uptake reflects astrogliosis in brain structures such as corpus callosum, caudate putamen, medium septum and olfactory tubercle as confirmed by both in vitro and in vivo results. CONCLUSION: The dynamics in the cuprizone-induced astroglial and TSPO changes, observed by SPECT imaging, were confirmed by immunofluorescence, RT-PCR and autoradiography. The highly specific TSPO radioiodinated ligand CLINDE can be used as an in vivo marker for early detection and monitoring of a variety of neuropathological conditions using noninvasive brain imaging techniques.

[Validation of the French version of the non-communicating children's pain checklist - postoperative version]. / Validation francophone de la grille d'évaluation de la douleur-déficience intellectuelle - version postopératoire.

PURPOSE: The aim of the study was to test the validity of a French language version of the Non-Communicating Children's Pain Checklist - Postoperative Version (NCCPC-PV): grille d'évaluation de la douleur-déficience intellectuelle (GED-DI). METHODS: We assessed the intensity of pain in 87 intellectually disabled surgical patients recruited in four Canadian and French hospitals in the pre- and post-operative settings using the GED-DI, a 100-mm visual analogue pain scale (VAS) and the Rosen sedation scale. The validity of the GED-DI was measured by the difference in scores between pre- and postoperative conditions. The checklist was made up of 30 items divided into seven subgroups. Items were rated from 0 to 3 for a total score ranging from 0 to 90 points. RESULTS: The mean (standard deviation) age of the patients was 17 (11) yr and the mean mental age 24.5 (24) months. The total GED-DI score was 6.1 (4.9) pre- and 13.4 (11.2) post-surgery (P < 0.001). All subgroups had a higher score after surgery (P < 0.001). The receiver operating characteristic (ROC) curves, comparing the absence of pain to mild pain scores and moderate to severe pain scores, showed a cutoff at 6 (mild pain) and 11 (moderate to severe pain). CONCLUSION: The French version of the NCCPC-PV can be used to assess pain in non-communicating patients with intellectual disabilities in a postoperative setting. It has good content validity, as the total pre-surgery score for the GED-DI was significantly lower than the postoperative score, and showed a good concurrent validity when compared to the VAS.

Optimising the process for conducting scoping reviews.

Knowledge synthesis constitutes a key part of evidence-based medicine and a scoping review is a type of knowledge synthesis that maps the breadth of literature on a topic. Conducting a scoping review is resource intensive and, as a result, it can be challenging to maintain best practices throughout the process. Much of the current guidance describes a scoping review framework or broad ways to conduct a scoping review. However, little detailed guidance exists on how to complete each stage to optimise the process. We present five recommendations based on our experience when conducting a particularly challenging scoping review: (1) engage the expertise of a librarian throughout the process, (2) conduct a truly systematic search, (3) facilitate communication and collaboration, (4) explore new tools or repurpose old ones, and (5) test every stage of the process. These recommendations add to the literature by providing specific and detailed advice on each stage of a scoping review. Our intent is for these recommendations to aid other teams that are undertaking knowledge synthesis projects.