PET imaging of the neurovascular interface in cerebrovascular disease

Cerebrovascular disease encompasses a range of pathologies affecting different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate metabolic processes that are key to pathogenesis. Although structural imaging has been a mainstay of stroke clinical care and research, it has limited ability to detect these pathophysiological processes in vivo. Positron emission tomography (PET) provides a means to detect and quantify metabolic processes in each facet of cerebrovascular disease non-invasively. The use of PET has helped shape the understanding of key concepts in cerebrovascular medicine, including the vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult, and the relationships between chronic hypoxia, neuroinflammation, and amyloid deposition in cerebral small vessel disease. This review considers how the ability to image these processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease and facilitated translational research to advance clinical care.N.R.E. is supported by a research training fellowship from The Dunhill Medical Trust (grant number RTF44/0114). J.M.T. is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). J.H.F.R. is part-supported by the Higher Education Funding Council for England (HEFCE), the British Heart Foundation, and the Wellcome Trust. H.S.M. is supported by the Medical Research Council (MRC) as a National Institute for Health Research (NIHR) Senior Investigator. E.A.W. is supported by the British Heart Foundation. H.S.M., J.H.F.R., and E.A.W. are supported by the NIHR Cambridge Biomedical Research Centre

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Effectiveness of a clinical pathway for acute stroke care in a district general hospital: an audit

BACKGROUND: Organised stroke care saves lives and reduces disability. A clinical pathway might be a form of organised stroke care, but the evidence for the effectiveness of this model of care is limited. METHODS: This study was a retrospective audit study of consecutive stroke admissions in the setting of an acute general medical unit in a district general hospital. The case-notes of patients admitted with stroke for a 6-month period before and after introduction of the pathway, were reviewed to determine data on length of stay, outcome, functional status, (Barthel Index, BI and Modified Rankin Scale, MRS), Oxfordshire Community Stroke Project (OCSP) sub-type, use of investigations, specific management issues and secondary prevention strategies. Logistic regression was used to adjust for differences in case-mix. RESULTS: N = 77 (prior to the pathway) and 76 (following the pathway). The median (interquartile range, IQR) age was 78 years (67.75–84.25), 88% were European NZ and 37% were male. The median (IQR) BI at admission for the pre-pathway group was less than the post-pathway group: 6 (0–13.5) vs. 10 (4–15.5), p = 0.018 but other baseline variables were statistically similar. There were no significant differences between any of the outcome or process of care variables, except that echocardiograms were done less frequently after the pathway was introduced. A good outcome (MRS<4) was obtained in 66.2% prior to the pathway and 67.1% after the pathway. In-hospital mortality was 20.8% and 23.1%. However, using logistic regression to adjust for the differences in admission BI, it appeared that admission after the pathway was introduced had a significant negative effect on the probability of good outcome (OR 0.29, 95%CI 0.09-0.99). CONCLUSION: A clinical pathway for acute stroke management appeared to have no benefit for the outcome or processes of care and may even have been associated with worse outcomes. These data support the conclusions of a recent Cochrane review

Lower limb arterial calcification (LLAC) scores in patients with symptomatic peripheral arterial disease are associated with increased cardiac mortality and morbidity

Aims The association of coronary arterial calcification with cardiovascular morbidity and mortality is well-recognized. Lower limb arterial calcification (LLAC) is common in PAD but its impact on subsequent health is poorly described. We aimed to determine the association between a LLAC score and subsequent cardiovascular events in patients with symptomatic peripheral arterial disease (PAD). Methods LLAC scoring, and the established Bollinger score, were derived from a database of unenhanced CT scans, from patients presenting with symptomatic PAD. We determined the association between these scores outcomes. The primary outcome was combined cardiac mortality and morbidity (CM/M) with a secondary outcome of all-cause mortality. Results 220 patients (66% male; median age 69 years) were included with follow-up for a median 46 [IQR 31–64] months. Median total LLAC scores were higher in those patients suffering a primary outcome (6831 vs. 1652; p = 0.012). Diabetes mellitus (p = 0.039), ischaemic heart disease (p = 0.028), chronic kidney disease (p = 0.026) and all-cause mortality (p = 0.012) were more common in patients in the highest quartile of LLAC scores. The area under the curve of the receiver operator curve for the LLAC score was greater (0.929: 95% CI [0.884–0.974]) than for the Bollinger score (0.824: 95% CI [0.758–0.890]) for the primary outcome. A LLAC score ≥ 4400 had the best diagnostic accuracy to determine the outcome measure. Conclusion This is the largest study to investigate links between lower limb arterial calcification and cardiovascular events in symptomatic PAD. We describe a straightforward, reproducible, CT-derived measure of calcification—the LLAC score.M.M.C. is supported by the Royal College of Surgeons of England Fellowship Programme and a British Heart Foundation Research Fellowship award FS/16/29/31957. J.M.T. is supported by a Wellcome Trust Research Training Fellowship (104492/Z/14/Z). J.H.F.R. is part-supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, HEFCE and the Wellcome Trust

Paediatric radiology seen from Africa. Part I: providing diagnostic imaging to a young population

Article approval pendingPaediatric radiology requires dedicated equipment, specific precautions related to ionising radiation, and specialist knowledge. Developing countries face difficulties in providing adequate imaging services for children. In many African countries, children represent an increasing proportion of the population, and additional challenges follow from extreme living conditions, poverty, lack of parental care, and exposure to tuberculosis, HIV, pneumonia, diarrhoea and violent trauma. Imaging plays a critical role in the treatment of these children, but is expensive and difficult to provide. The World Health Organisation initiatives, of which the World Health Imaging System for Radiography (WHIS-RAD) unit is one result, needs to expand into other areas such as the provision of maintenance servicing. New initiatives by groups such as Rotary and the World Health Imaging Alliance to install WHIS-RAD units in developing countries and provide digital solutions, need support. Paediatric radiologists are needed to offer their services for reporting, consultation and quality assurance for free by way of teleradiology. Societies for paediatric radiology are needed to focus on providing a volunteer teleradiology reporting group, information on child safety for basic imaging, guidelines for investigations specific to the disease spectrum, and solutions for optimising imaging in children

Utility of Atherosclerosis Imaging in the Evaluation of High-Density Lipoprotein–Raising Therapies

Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C–raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C–raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C–raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C–raising drugs

Information overload : the differences that age makes

Information overload has long been studied as a phenomenon that causes problems at the personal, social and organisational level. This study investigates overload from a new angle, that of the influence of age on perceptions of information overload. A combination of questionnaires, interviews and diaries were used to gain insight into people’s perceptions towards information overload. It was found that people of all ages suffer from information overload but young people are primarily affected by information literacy levels while older people are affected by technology. There was evidence of a link between age and technology use. A link was also found between job role and information overload and the impact technology has had on the quantity of information available. This research will benefit anyone, either individually or within an organisation, looking for ways to combat information overload. It identifies the influence of age on various factors and recommends actions that may be taken to reduce information overload. In particular, recommendations were made for further training in technology and information literacy. The paper is based on an approach not seen before in the literature as it investigates the effects of age on information overload by seeking to understand how perceptions towards information overload may differ between different age groups. It is anticipated that this paper will trigger further studies that could focus on the effect of job role on information overload and the likelihood of information addiction becoming a future concern

Intrinsic gain modulation and adaptive neural coding

In many cases, the computation of a neural system can be reduced to a receptive field, or a set of linear filters, and a thresholding function, or gain curve, which determines the firing probability; this is known as a linear/nonlinear model. In some forms of sensory adaptation, these linear filters and gain curve adjust very rapidly to changes in the variance of a randomly varying driving input. An apparently similar but previously unrelated issue is the observation of gain control by background noise in cortical neurons: the slope of the firing rate vs current (f-I) curve changes with the variance of background random input. Here, we show a direct correspondence between these two observations by relating variance-dependent changes in the gain of f-I curves to characteristics of the changing empirical linear/nonlinear model obtained by sampling. In the case that the underlying system is fixed, we derive relationships relating the change of the gain with respect to both mean and variance with the receptive fields derived from reverse correlation on a white noise stimulus. Using two conductance-based model neurons that display distinct gain modulation properties through a simple change in parameters, we show that coding properties of both these models quantitatively satisfy the predicted relationships. Our results describe how both variance-dependent gain modulation and adaptive neural computation result from intrinsic nonlinearity.Comment: 24 pages, 4 figures, 1 supporting informatio

The Evolutionary Origin of Man Can Be Traced in the Layers of Defunct Ancestral Alpha Satellites Flanking the Active Centromeres of Human Chromosomes

Alpha satellite domains that currently function as centromeres of human chromosomes are flanked by layers of older alpha satellite, thought to contain dead centromeres of primate progenitors, which lost their function and the ability to homogenize satellite repeats, upon appearance of a new centromere. Using cladistic analysis of alpha satellite monomers, we elucidated complete layer patterns on chromosomes 8, 17, and X and related them to each other and to primate alpha satellites. We show that discrete and chronologically ordered alpha satellite layers are partially symmetrical around an active centromere and their succession is partially shared in non-homologous chromosomes. The layer structure forms a visual representation of the human evolutionary lineage with layers corresponding to ancestors of living primates and to entirely fossil taxa. Surprisingly, phylogenetic comparisons suggest that alpha satellite arrays went through periods of unusual hypermutability after they became “dead” centromeres. The layer structure supports a model of centromere evolution where new variants of a satellite repeat expanded periodically in the genome by rounds of inter-chromosomal transfer/amplification. Each wave of expansion covered all or many chromosomes and corresponded to a new primate taxon. Complete elucidation of the alpha satellite phylogenetic record would give a unique opportunity to number and locate the positions of major extinct taxa in relation to human ancestors shared with extant primates. If applicable to other satellites in non-primate taxa, analysis of centromeric layers could become an invaluable tool for phylogenetic studies