α7 nicotinic acetylcholine receptor signaling modulates the inflammatory phenotype of fetal brain microglia: first evidence of interference by iron homeostasis.

Neuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on α7 nicotinic acetylcholine receptor (α7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of α7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep microglia cultures re-exposed to LPS in presence of a selective α7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with α7nAChR agonistic stimulation. Conversely, antagonistic α7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated α7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of α7nAChR agonists in early re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Future studies will assess the role of interactions between inflammation-triggered microglial iron sequestering and α7nAChR signaling in neurodevelopment.

Automatic exposure control calibration and optimisation for abdomen, pelvis and lumbar spine imaging with an Agfa computed radiography system.

The use of three physical image quality metrics, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and mean effective noise equivalent quanta (eNEQm) have recently been examined by our group for their appropriateness in the calibration of an automatic exposure control (AEC) device for chest radiography with an Agfa computed radiography (CR) imaging system. This study uses the same methodology but investigates AEC calibration for abdomen, pelvis and spine CR imaging. AEC calibration curves were derived using a simple uniform phantom (equivalent to 20 cm water) to ensure each metric was held constant across the tube voltage range. Each curve was assessed for its clinical appropriateness by generating computer simulated abdomen, pelvis and spine images (created from real patient CT datasets) with appropriate detector air kermas for each tube voltage, and grading these against reference images which were reconstructed at detector air kermas correct for the constant detector dose indicator (DDI) curve currently programmed into the AEC device. All simulated images contained clinically realistic projected anatomy and were scored by experienced image evaluators. Constant DDI and CNR curves did not provide optimized performance but constant eNEQm and SNR did, with the latter being the preferred calibration metric given that it is easier to measure in practice. This result was consistent with the previous investigation for chest imaging with AEC devices. Medical physicists may therefore use a simple and easily accessible uniform water equivalent phantom to measure the SNR image quality metric described here when calibrating AEC devices for abdomen, pelvis and spine imaging with Agfa CR systems, in the confidence that clinical image quality will be sufficient for the required clinical task. However, to ensure appropriate levels of detector air kerma the advice of expert image evaluators must be sought.

Correlation between the signal-to-noise ratio improvement factor (KSNR) and clinical image quality for chest imaging with a computed radiography system.

This work assessed the appropriateness of the signal-to-noise ratio improvement factor (KSNR) as a metric for the optimisation of computed radiography (CR) of the chest. The results of a previous study in which four experienced image evaluators graded computer simulated chest images using a visual grading analysis scoring (VGAS) scheme to quantify the benefit of using an anti-scatter grid were used for the clinical image quality measurement (number of simulated patients = 80). The KSNR was used to calculate the improvement in physical image quality measured in a physical chest phantom. KSNR correlation with VGAS was assessed as a function of chest region (lung, spine and diaphragm/retrodiaphragm), and as a function of x-ray tube voltage in a given chest region. The correlation of the latter was determined by the Pearson correlation coefficient. VGAS and KSNR image quality metrics demonstrated no correlation in the lung region but did show correlation in the spine and diaphragm/retrodiaphragmatic regions. However, there was no correlation as a function of tube voltage in any region; a Pearson correlation coefficient (R) of -0.93 (p = 0.015) was found for lung, a coefficient (R) of -0.95 (p = 0.46) was found for spine, and a coefficient (R) of -0.85 (p = 0.015) was found for diaphragm. All demonstrate strong negative correlations indicating conflicting results, i.e. KSNR increases with tube voltage but VGAS decreases. Medical physicists should use the KSNR metric with caution when assessing any potential improvement in clinical chest image quality when introducing an anti-scatter grid for CR imaging, especially in the lung region. This metric may also be a limited descriptor of clinical chest image quality as a function of tube voltage when a grid is used routinely.

A practical method to standardise and optimise the Philips DoseRight 2.0 CT automatic exposure control system.

Given the increasing use of computed tomography (CT) in the UK over the last 30 years, it is essential to ensure that all imaging protocols are optimised to keep radiation doses as low as reasonably practicable, consistent with the intended clinical task. However, the complexity of modern CT equipment can make this task difficult to achieve in practice. Recent results of local patient dose audits have shown discrepancies between two Philips CT scanners that use the DoseRight 2.0 automatic exposure control (AEC) system in the 'automatic' mode of operation. The use of this system can result in drifting dose and image quality performance over time as it is designed to evolve based on operator technique. The purpose of this study was to develop a practical technique for configuring examination protocols on four CT scanners that use the DoseRight 2.0 AEC system in the 'manual' mode of operation. This method used a uniform phantom to generate reference images which form the basis for how the AEC system calculates exposure factors for any given patient. The results of this study have demonstrated excellent agreement in the configuration of the CT scanners in terms of average patient dose and image quality when using this technique. This work highlights the importance of CT protocol harmonisation in a modern Radiology department to ensure both consistent image quality and radiation dose. Following this study, the average radiation dose for a range of CT examinations has been reduced without any negative impact on clinical image quality.

Retrospective review of locally set tolerances for VMAT prostate patient specific QA using the COMPASS(®) system.

PURPOSE: This study retrospectively reviewed locally set pass rates/tolerances for COMPASS(®) pre-treatment quality assurance results for RapidArc prostate plans to determine if these are appropriate. This was performed via quantifying the agreement between treatment planning system calculations and measurements based on absolute dose comparisons (3% tolerance for all dose points) and global gamma index assessment (3%/3 mm criterion for 97% of points). METHOD: Seventy-three prostate one-arc RapidArc plans, delivered by four dosimetrically matched linacs, were measured using the MatriXX Evolution two-dimensional array and analysed using COMPASS(®) (v.3, IBA Dosimetry). For the planning target volumes (PTV) considered, the D99%, D50%, D1% and DMean differences were analysed. The percentage volume with gamma greater than 1, average gamma and DMean difference were investigated for all structures. Nine plans were also assessed across the linac fleet to investigate potential linac dependence of results. RESULTS AND CONCLUSIONS: Regarding PTV DMean differences, all plans fell within the 3% tolerance and mostly within 2%, although there was a relatively small systematic difference. The absolute percentage differences of average and median doses suggested a weak linac dependence of the results which was found to be clinically insignificant. New stricter tolerances were established both for dose comparisons and gamma evaluation. Correlation between the gamma pass rates and the differences in the D99%, D50% and D1% was found to be moderate suggesting that gamma analysis in isolation has questionable clinical meaning and should only be used to indicate outliers for further analysis.

Investigating the use of an antiscatter grid in chest radiography for average adults with a computed radiography imaging system.

OBJECTIVE: The aim of this study was to investigate via simulation a proposed change to clinical practice for chest radiography. The validity of using a scatter rejection grid across the diagnostic energy range (60-125 kVp), in conjunction with appropriate tube current-time product (mAs) for imaging with a computed radiography (CR) system was investigated. METHODS: A digitally reconstructed radiograph algorithm was used, which was capable of simulating CR chest radiographs with various tube voltages, receptor doses and scatter rejection methods. Four experienced image evaluators graded images with a grid (n = 80) at tube voltages across the diagnostic energy range and varying detector air kermas. These were scored against corresponding images reconstructed without a grid, as per current clinical protocol. RESULTS: For all patients, diagnostic image quality improved with the use of a grid, without the need to increase tube mAs (and therefore patient dose), irrespective of the tube voltage used. Increasing tube mAs by an amount determined by the Bucky factor made little difference to image quality. CONCLUSION: A virtual clinical trial has been performed with simulated chest CR images. RESULTS indicate that the use of a grid improves diagnostic image quality for average adults, without the need to increase tube mAs, even at low tube voltages. ADVANCES IN KNOWLEDGE: Validated with images containing realistic anatomical noise, it is possible to improve image quality by utilizing grids for chest radiography with CR systems without increasing patient exposure. Increasing tube mAs by an amount determined by the Bucky factor is not justified.

Validation of a technique for estimating organ doses for kilovoltage cone-beam CT of the prostate using the PCXMC 2.0 patient dose calculator.

The use of cone beam CT in common radiotherapy treatments is increasing with the growth of image guided radiotherapy. Whilst the benefits that this technology offers are clear, such as improved patient positioning prior to treatment, it is always important to consider the implications of such intensive imaging regimes on the patient, especially when considering the fundamental radiation protection requirements for justification and optimisation.The purpose of this study was to develop a technique that uses readily available dose calculation software (PCXMC 2.0) to estimate the organ and effective doses that result from these types of examination in prostate treatments on the Varian OBI system. It has been shown that by separating these types of examinations into 28 different projections, with a range of x-ray beam qualities, it is possible to reproduce the complex geometry that is used on these imaging systems in PCXMC i.e. asymmetric radiation field with a half bowtie filter rotating 360° around the patient.This new technique has been validated with thermo-luminescent dosimeter measurements in the Rando anthropomorphic phantom, and has been shown to give excellent agreement with this established method (R(2) = 0.995). This technique will prove to be valuable to radiotherapy departments that are looking to optimise their CBCT imaging protocols as it allows a rapid evaluation of the impact of any changes on patient dose. It also serves to further highlight the levels of dose that these types of patient are subject to when having daily CBCT scans as part of the treatment, which further reinforces the need for optimisation of both patient dose and image quality on these systems.

An investigation of automatic exposure control calibration for chest imaging with a computed radiography system.

The purpose of this study was to examine the use of three physical image quality metrics in the calibration of an automatic exposure control (AEC) device for chest radiography with a computed radiography (CR) imaging system. The metrics assessed were signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and mean effective noise equivalent quanta (eNEQm), all measured using a uniform chest phantom. Subsequent calibration curves were derived to ensure each metric was held constant across the tube voltage range. Each curve was assessed for its clinical appropriateness by generating computer simulated chest images with correct detector air kermas for each tube voltage, and grading these against reference images which were reconstructed at detector air kermas correct for the constant detector dose indicator (DDI) curve currently programmed into the AEC device. All simulated chest images contained clinically realistic projected anatomy and anatomical noise and were scored by experienced image evaluators. Constant DDI and CNR curves do not appear to provide optimized performance across the diagnostic energy range. Conversely, constant eNEQm and SNR do appear to provide optimized performance, with the latter being the preferred calibration metric given as it is easier to measure in practice. Medical physicists may use the SNR image quality metric described here when setting up and optimizing AEC devices for chest radiography CR systems with a degree of confidence that resulting clinical image quality will be adequate for the required clinical task. However, this must be done with close cooperation of expert image evaluators, to ensure appropriate levels of detector air kerma.

Correlation of the clinical and physical image quality in chest radiography for average adults with a computed radiography imaging system.

OBJECTIVE: The purpose of this study was to examine the correlation between the quality of visually graded patient (clinical) chest images and a quantitative assessment of chest phantom (physical) images acquired with a computed radiography (CR) imaging system. METHODS: The results of a previously published study, in which four experienced image evaluators graded computer-simulated postero-anterior chest images using a visual grading analysis scoring (VGAS) scheme, were used for the clinical image quality measurement. Contrast-to-noise ratio (CNR) and effective dose efficiency (eDE) were used as physical image quality metrics measured in a uniform chest phantom. Although optimal values of these physical metrics for chest radiography were not derived in this work, their correlation with VGAS in images acquired without an antiscatter grid across the diagnostic range of X-ray tube voltages was determined using Pearson's correlation coefficient. RESULTS: Clinical and physical image quality metrics increased with decreasing tube voltage. Statistically significant correlations between VGAS and CNR (R=0.87, p<0.033) and eDE (R=0.77, p<0.008) were observed. CONCLUSION: Medical physics experts may use the physical image quality metrics described here in quality assurance programmes and optimisation studies with a degree of confidence that they reflect the clinical image quality in chest CR images acquired without an antiscatter grid. ADVANCES IN KNOWLEDGE: A statistically significant correlation has been found between the clinical and physical image quality in CR chest imaging. The results support the value of using CNR and eDE in the evaluation of quality in clinical thorax radiography.

Use of a digitally reconstructed radiograph-based computer simulation for the optimisation of chest radiographic techniques for computed radiography imaging systems.

OBJECTIVES: The purpose of this study was to derive an optimum radiographic technique for computed radiography (CR) chest imaging using a digitally reconstructed radiograph computer simulator. The simulator is capable of producing CR chest radiographs of adults with various tube potentials, receptor doses and scatter rejection. METHODS: Four experienced image evaluators graded images of average and obese adult patients at different potentials (average-sized, n=50; obese, n=20), receptor doses (n=10) and scatter rejection techniques (average-sized, n=20; obese, n=20). The quality of the images was evaluated using visually graded analysis. The influence of rib contrast was also assessed. RESULTS: For average-sized patients, image quality improved when tube potential was reduced compared with the reference (102 kVp). No scatter rejection was indicated. For obese patients, it has been shown that an antiscatter grid is indicated, and should be used in conjunction with as low a tube potential as possible (while allowing exposure times <20 ms). It is also possible to reduce receptor air kerma by 50% without adversely influencing image quality. Rib contrast did not interfere at any tube potential. CONCLUSIONS: A virtual clinical trial has been performed with simulated chest CR images. Results indicate that low tube potentials (<102 kVp) are optimal for average and obese adults, the former acquired without scatter rejection, the latter with an anti-scatter grid. Lower receptor (and therefore patient doses) than those used clinically are possible while maintaining adequate image quality.

Validation of a large-scale audit technique for CT dose optimisation.

The expansion and increasing availability of computed tomography (CT) imaging means that there is a greater need for the development of efficient optimisation strategies that are able to inform clinical practice, without placing a significant burden on limited departmental resources. One of the most fundamental aspects to any optimisation programme is the collection of patient dose information, which can be compared with appropriate diagnostic reference levels. This study has investigated the implementation of a large-scale audit technique, which utilises data that already exist in the radiology information system, to determine typical doses for a range of examinations on four CT scanners. This method has been validated against what is considered the 'gold standard' technique for patient dose audits, and it has been demonstrated that results equivalent to the 'standard-sized patient' can be inferred from this much larger data set. This is particularly valuable where CT optimisation is concerned as it is considered a 'high dose' technique, and hence close monitoring of patient dose is particularly important.

A method to produce and validate a digitally reconstructed radiograph-based computer simulation for optimisation of chest radiographs acquired with a computed radiography imaging system.

OBJECTIVES: The purpose of this study was to develop and validate a computer model to produce realistic simulated computed radiography (CR) chest images using CT data sets of real patients. METHODS: Anatomical noise, which is the limiting factor in determining pathology in chest radiography, is realistically simulated by the CT data, and frequency-dependent noise has been added post-digitally reconstructed radiograph (DRR) generation to simulate exposure reduction. Realistic scatter and scatter fractions were measured in images of a chest phantom acquired on the CR system simulated by the computer model and added post-DRR calculation. RESULTS: The model has been validated with a phantom and patients and shown to provide predictions of signal-to-noise ratios (SNRs), tissue-to-rib ratios (TRRs: a measure of soft tissue pixel value to that of rib) and pixel value histograms that lie within the range of values measured with patients and the phantom. The maximum difference in measured SNR to that calculated was 10%. TRR values differed by a maximum of 1.3%. CONCLUSION: Experienced image evaluators have responded positively to the DRR images, are satisfied they contain adequate anatomical features and have deemed them clinically acceptable. Therefore, the computer model can be used by image evaluators to grade chest images presented at different tube potentials and doses in order to optimise image quality and patient dose for clinical CR chest radiographs without the need for repeat patient exposures.

Intravenous administration of human embryonic stem cell-derived neural precursor cells attenuates cuprizone-induced central nervous system (CNS) demyelination.

AIMS: Previous studies have demonstrated the therapeutic potential for human embryonic stem cell-derived neural precursor cells (hES-NPCs) in autoimmune and genetic animal models of demyelinating diseases. Herein, we tested whether intravenous (i.v.) administration of hES-NPCs would impact central nervous system (CNS) demyelination in a cuprizone model of demyelination. METHODS: C57Bl/6 mice were fed cuprizone (0.2%) for 2 weeks and then separated into two groups that either received an i.v. injection of hES-NPCs or i.v. administration of media without these cells. After an additional 2 weeks of dietary cuprizone treatment, CNS tissues were analysed for detection of transplanted cells and differences in myelination in the region of the corpus callosum (CC). RESULTS: Cuprizone-induced demyelination in the CC was significantly reduced in mice treated with hES-NPCs compared with cuprizone-treated controls that did not receive stem cells. hES-NPCs were identified within the brain tissues of treated mice and revealed migration of transplanted cells into the CNS. A limited number of human cells were found to express the mature oligodendrocyte marker, O1, or the astrocyte marker, glial fibrillary acidic protein. Reduced apoptosis and attenuated microglial and astrocytic responses were also observed in the CC of hES-NPC-treated mice. CONCLUSIONS: These findings indicated that systemically administered hES-NPCs migrated from circulation into a demyelinated lesion within the CNS and effectively reduced demyelination. Observed reductions in astrocyte and microglial responses, and the benefit of hES-NPC treatment in this model of myelin injury was not obviously accountable to tissue replacement by exogenously administered cells.

Dietary strategy to manipulate ad libitum macronutrient intake, and glycaemic index, across eight European countries in the Diogenes Study.

The aim of this study was to describe the development and implementation of a multifaceted, low-fat, weight-loss strategy for a Pan-European randomized controlled dietary intervention study, Diogenes. There were 891 families with at least one overweight/obese parent who underwent screening. Eligible, overweight/obese adults followed an 8-week weight-loss phase with a fixed low-energy diet (800 kcal). On attaining weight loss of > or = 8%, families were randomized to a 6- or 12-month low-fat (25-30%E) diet either based on national dietary guidelines or one of four interventions: low protein (LP)/low glycaemic index (LGI), LP/high GI (HGI), high protein (HP)/LGI and HP/HGI. The impact of each diet in preventing weight (re)gain was tested. A points-based system was used to manipulate dietary protein and carbohydrate. Manipulating carbohydrate composition involved substituting foods with a relatively high or low GI. A questionnaire was designed and completed by study investigators, providing feedback on the dietary intervention methods used to inform future interventions. The points system allowed macronutrient manipulations without compromising dietary flexibility or enforcing energy restrictions. Reported centre/participant differences in the ease of implementing the intervention may reflect dietary diversity and personal preferences for specific weight-management strategies. The points system provides a useful starting point for designing improved experimental paradigms for the manipulation of dietary intake in future trials.

Investigating the exposure class of a computed radiography system for optimisation of physical image quality for chest radiography.

The purpose of this study was to investigate whether the exposure (speed) class (EC) of an Agfa computed radiography (CR) system could be used to optimise chest radiography. The frequency-dependent normalised noise-power spectra (NNPS(f)) were determined for a range of EC settings (25-1200) for a receptor dose of 4 microGy. Signal-to-noise ratios (SNRs) were measured in the lung, heart and diaphragm areas of a chest phantom with ECs of 400 and 600 at four tube voltages (60, 75, 90 and 125 kVp). As anatomical background can be a factor in detection of lung nodules, a tissue to rib ratio (TRR), which measures the ratio of pixel values in the nodule to that of rib, was measured in the lung region of the phantom to assess the suppression of the rib at ECs of 400 and 600. The NNPS(f) at ECs lower than 400 was relatively high. The NNPS(f) at EC 600 was found to be 7% lower when averaged over all frequencies than that at EC 400. The statistical significance of this difference was verified. The EC 800 and EC 1200 settings offered no extra advantages in terms of lowering frequency-dependent noise. The EC 600 setting offered improvements in SNR of between 10% and 18% in the lung, 11% and 16% in the heart, and 15% and 20% in the diaphragm compared with EC 400. Statistical analysis verified the significant difference. The EC 600 setting increased the TRR, thereby helping to suppress rib. This work indicates that an exposure class setting of 600 is the most appropriate for standard chest radiography, but clinical verification is required.

Investigation of optimum X-ray beam tube voltage and filtration for chest radiography with a computed radiography system.

The purpose of this study was to determine the optimum tube voltage and amount of added copper (Cu) filtration for processed chest radiographs obtained with an Agfa 75.0 Computed Radiography (CR) system. The contrast-to-noise ratio (CNR) was measured in the lung, heart/spine and diaphragm compartments of a validated chest phantom using various tube voltages and amounts of Cu filtration. The CNR was derived as a function of air kerma at the CR plate and with the effective dose. As rib contrast can interfere with detection of nodules in chest radiography, a tissue-to-rib ratio (TRR) was derived to investigate which tube voltages suppress the contrast of rib. Although processing algorithms affect the signal and noise in a way that is hard to predict, we found that, for a given set of processing parameters, the CNR was related to the plate air kerma and effective dose in a logarithmic manner (all R(2) >or=0.97). For imaging of the lung region, a low voltage (60 kVp) produced the highest CNR, whereas a high voltage (125 kVp) produced the highest TRR. In the heart/spine region, 80-125 kVp produced the highest CNR, while in the diaphragm region 60-90 kVp produced the highest CNR. For chest radiography with this CR system, the optimal tube voltage depends upon the region of interest. Of the filters tested, a 0.1 mm Cu thickness was found to provide a statistically significant increase in the CNR in the diaphragm region with tube potentials of 60 kVp and 80 kVp, without affecting the CNR in the other anatomical compartments.

Expression of the inhibitor of apoptosis protein family in multiple sclerosis reveals a potential immunomodulatory role during autoimmune mediated demyelination.

A failure of autoreactive T cells to undergo apoptosis may contribute to the pathogenesis of multiple sclerosis (MS). The role of the inhibitor of apoptosis (IAP) family of anti-apoptotic proteins such as X-linked IAP (XIAP), human inhibitor of apoptosis-1 (HIAP-1), human inhibitor of apoptosis-2 (HIAP-2), neuronal apoptosis inhibitory protein (NAIP) and Survivin in relapsing-remitting, secondary-progressive, primary-progressive or benign forms of MS is unclear. We report here that expression of the IAP family of genes in peripheral blood samples and brain tissues from MS cases support a role for differential regulation of these potent anti-apoptotic proteins in the pathology of MS. XIAP mRNA and protein levels were elevated in peripheral blood mononuclear cells from patients with active disease relative to normal subjects. In patients with active MS, HIAP-1 and HIAP-2 mRNA levels were elevated in resting T cells while NAIP mRNA was increased in whole blood. In post-mortem MS brain tissue, XIAP and HIAP-1 in myelin lesions were co-localized with microglia and T cells, respectively. Only in primary-progressive patients was Survivin expression elevated suggestive of a distinct pathological basis for this subtype of MS. Taken together, these results suggest that patterns of inhibitor of apoptosis expression in immune cells may have value in distinguishing between MS subtypes and offer insight into the mechanisms responsible for their distinct clinical courses.

A method to optimize the processing algorithm of a computed radiography system for chest radiography.

A test methodology using an anthropomorphic-equivalent chest phantom is described for the optimization of the Agfa computed radiography "MUSICA" processing algorithm for chest radiography. The contrast-to-noise ratio (CNR) in the lung, heart and diaphragm regions of the phantom, and the "system modulation transfer function" (sMTF) in the lung region, were measured using test tools embedded in the phantom. Using these parameters the MUSICA processing algorithm was optimized with respect to low-contrast detectability and spatial resolution. Two optimum "MUSICA parameter sets" were derived respectively for maximizing the CNR and sMTF in each region of the phantom. Further work is required to find the relative importance of low-contrast detectability and spatial resolution in chest images, from which the definitive optimum MUSICA parameter set can then be derived. Prior to this further work, a compromised optimum MUSICA parameter set was applied to a range of clinical images. A group of experienced image evaluators scored these images alongside images produced from the same radiographs using the MUSICA parameter set in clinical use at the time. The compromised optimum MUSICA parameter set was shown to produce measurably better images.

The impact of long chain n-3 polyunsaturated fatty acid supplementation on inflammation, insulin sensitivity and CVD risk in a group of overweight women with an inflammatory phenotype.

BACKGROUND: Inflammation is strongly related to obesity and the risk of cardiovascular disease (CVD). The metabolic benefits of long chain (LC) n-3 polyunsaturated fatty acid (PUFA) may be attributable to its anti-inflammatory properties. OBJECTIVE: To investigate whether an individual's habitual inflammatory status influences the impact of a LC n-3 PUFA intervention on CVD risk. DESIGN: The study was a randomized crossover design. Subjects received LC n-3 PUFA capsules or a placebo for 12 weeks, with 4-week washout between phases. Thirty women, in the top and bottom tertiles of baseline sialic acid concentration, formed raised inflammatory status (top, n = 12) and reference (bottom, n = 18) groups. Baseline data were analysed using one-way anova, differences between treatment phases were calculated at each timepoint and analysed using a random effects model. RESULTS: At baseline, the raised inflammatory status group had significantly higher body mass index and area under the curve (AUC) insulin than the reference group. With LC n-3 PUFA supplementation, both groups showed significantly higher plasma eicosapentaenoic acid and docosahexaenoic acid at 4 and 12 weeks (p < 0.001), and lower triacylglycerols (4 weeks p < 0.01 and 12 weeks p < 0.05). The difference in AUC insulin between the two treatment phases at 12 weeks was significantly greater in the raised inflammatory status group compared to the reference group (p < 0.05). Inflammatory markers were significantly lower after 12 weeks LC n-3 PUFA supplementation compared to baseline (C-reactive protein p < 0.05 and interleukin-6 p < 0.01), but there was no significant group effect. CONCLUSIONS: Habitual inflammatory status influences the impact of LC n-3 PUFA supplementation, but it is not clear whether the effect of LC n-3 PUFA on AUC insulin is mediated through inflammatory mechanisms.

Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline.

A major obstacle in the therapeutic development of phosphodiesterase-4 (PDE4) inhibitors is the production of adverse side effects such as nausea and vomiting. Immunohistochemical detection of Fos-like immunoreactivity (FLI) was used to address the neuroanatomical basis for the pharmacological actions of PDE4 inhibitors. The potent and selective PDE4 inhibitors 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline (PMNPQ) and rolipram elevated FLI in brain regions potentially relevant to the anti-depressant and emetic effects of PDE4 inhibition. PMNPQ and rolipram elevated FLI in the locus coeruleus, habenula, paraventricular nucleus of the thalamus, amygdala and nucleus accumbens, all structures with strong limbic connectivity implicated in arousal, memory and affective aspects of behaviour. Consistent with the emetic effects of PDE4 inhibitors such as PMNPQ and rolipram, these compounds elevated FLI in caudal brainstem nuclei such as the area postrema and nucleus of the solitary tract. Administration of the NK(1) antagonist RP 67580 prior to PMNPQ reversed increases in FLI produced by PMNPQ in these regions. RP 67580 did not, however, reduce PMNPQ-induced FLI in limbic structures. These findings suggest that PDE4 inhibitors produce emesis by increasing NK(1) receptor activation in the AP/NTS and implicate brain regions associated with reward and mood such as the amygdala, paraventricular nucleus of the thalamus, habenula and nucleus accumbens in the anti-depressant activity of such compounds.