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1.  Mandatory vaccination 
PMCID: PMC3735749  PMID: 23922359
2.  Neurobiology of secure infant attachment and attachment despite adversity: a mouse model 
Genes, brain, and behavior  2013;12(7):673-680.
Attachment to an abusive caregiver has wide phylogenetic representation, suggesting that animal models are useful in understanding the neural basis underlying this phenomenon and subsequent behavioral outcomes. We previously developed a rat model, in which we use classical conditioning to parallel learning processes evoked during secure attachment (odor-stroke, with stroke mimicking tactile stimulation from the caregiver) or attachment despite adversity (odor-shock, with shock mimicking maltreatment). Here we extend this model to mice. We conditioned infant mice (postnatal day (PN) 7–9 or 13–14) with presentations of peppermint odor and either stroking or shock. We used 14C 2-deoxyglucose (2-DG) to assess olfactory bulb and amygdala metabolic changes following learning. PN7-9 mice learned to prefer an odor following either odor-stroke or shock conditioning, whereas odor-shock conditioning at PN13-14 resulted in aversion/fear learning. 2-DG data indicated enhanced bulbar activity in PN7-9 preference learning, whereas significant amygdala activity was present following aversion learning at PN13-14. Overall, the mouse results parallel behavioral and neural results in the rat model of attachment, and provide the foundation for the use of transgenic and knockout models to assess the impact of both genetic (biological vulnerabilities) and environmental factors (abusive) on attachment-related behaviors and behavioral development.
PMCID: PMC4047794  PMID: 23927771
Animal model; attachment; infant; learning; maltreatment; memory
3.  Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease 
Neurology  2004;63(8):1376-1384.
Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity.
To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases.
Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted.
The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and α-internexin.
NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.
PMCID: PMC3516854  PMID: 15505152
4.  Staging and natural history of cerebrovascular pathology in dementia 
Neurology  2012;78(14):1043-1050.
Most pathologic studies indicate that significant vascular changes are found in the majority of elderly persons, either alone or in association with neurodegenerative processes such as Alzheimer disease (AD) or dementia with Lewy bodies (DLB). Cumulative burden of cerebrovascular lesions can explain cognitive decline described as vascular cognitive impairment, but because there is a lack of consensus in the best way to quantify vascular pathology, the relationship between cognitive decline and cerebrovascular disease remains uncertain. We developed a rating scheme for cerebrovascular lesions using postmortem brains from patients with dementia from 2 European tertiary care memory clinics.
A total of 135 brains with a neuropathologic diagnosis of vascular dementia (VaD) (n = 26), AD + VaD (n = 39), DLB + VaD (n = 21), AD + DLB + VaD (n = 9), AD (n = 19), and DLB (n = 21) were investigated in this study. Cerebrovascular lesions were rated on large sections from the hippocampus, the temporal lobe, the frontal lobe, and basal ganglia.
In patients with dementia, vessel wall modifications such as arteriolosclerosis or amyloid angiopathy are the most common and presumably the earliest changes. Modifications in perivascular spaces and myelin loss are the next most common. Lacunar or regional infarcts may occur as a consequence of an independent process or in the final phase of small vessel diseases.
A staging system based on this conceptual model of cerebrovascular pathology could enable the neuropathologic quantification of the cerebrovascular burden in dementia. Further studies are needed to determine whether this system can be used in large-scale studies to understand clinical–cerebrovascular pathologic correlations.
PMCID: PMC3317531  PMID: 22377814
5.  Re-implantation of suboptimal prostate seed implantation: technique with intraoperative treatment planning 
Post-implant dosimetry following prostate seed implantation (PSI) occasionally reveals suboptimal dosimetric coverage of the gland. Published reports of re-implantation techniques have focused on earlier-generation techniques, including preplanned approaches and stranded seeds. The purpose of this case report is to describe a customizable approach to perform corrective re-implantation using loose seeds and intraoperative planning technique.
Material and methods
This case report describes a 63-year-old male with favorable risk prostate adenocarcinoma receiving PSI. Thirty day post-implant dosimetric evaluation revealed suboptimal coverage of the base of the gland. Using guidance from post-implant CT-images and real-time planning, the patient received a corrective re-implantation with intraoperative planning.
Post-implant dosimetry after re-implantation procedure with intraoperative planning yielded improved target volume coverage that achieved standard dosimetric criteria.
Re-implantation as a salvage treatment technique after sub-optimal PSI is a valid treatment option performed with intraoperative real-time planning.
PMCID: PMC3551375  PMID: 23346147
low-dose-rate brachytherapy; prostate cancer; re-implantation; salvage therapy; seeds
6.  Improving community health and safety in Canada through evidence-based policies on illegal drugs 
Open Medicine  2012;6(1):e35-e40.
Illegal drug use remains a serious threat to community health in Canada, yet there has been a remarkable discordance between scientific evidence and policy in this area, with most resources going to drug use prevention and drug law enforcement activities that have proven ineffective. Conversely, evidence-based drug treatment programs have been chronically underfunded, despite their cost-effectiveness. Similarly, various harm reduction strategies, such as needle exchange, supervised injecting programs and opioid substitution therapy, have also proven effective at reducing drug-related harm but receive limited government support. Accordingly, Canadian society would greatly benefit from reorienting its drug policies on addiction, with consideration of addiction as a health issue, rather than primarily a criminal justice issue. In this context, and in light of the simple reality that drug prohibition has not effectively reduced the availability of most illegal drugs and has instead contributed to a vast criminal enterprise and related violence, among other harms, alternatives should be prioritized for evaluation.
PMCID: PMC3329118  PMID: 22567081
7.  Comparative analysis of marine ecosystems: international production modelling workshop 
Biology Letters  2010;6(6):723-726.
Understanding the drivers that dictate the productivity of marine ecosystems continues to be a globally important issue. A vast literature identifies three main processes that regulate the production dynamics of such ecosystems: biophysical, exploitative and trophodynamic. Exploring the prominence among this ‘triad’ of drivers, through a synthetic analysis, is critical for understanding how marine ecosystems function and subsequently produce fisheries resources of interest to humans. To explore this topic further, an international workshop was held on 10–14 May 2010, at the National Academy of Science's Jonsson Center in Woods Hole, MA, USA. The workshop compiled the data required to develop production models at different hierarchical levels (e.g. species, guild, ecosystem) for many of the major Northern Hemisphere marine ecosystems that have supported notable fisheries. Analyses focused on comparable total system biomass production, functionally equivalent species production, or simulation studies for 11 different marine fishery ecosystems. Workshop activities also led to new analytical tools. Preliminary results suggested common patterns driving overall fisheries production in these ecosystems, but also highlighted variation in the relative importance of each among ecosystems.
PMCID: PMC3001386  PMID: 20610416
production modelling; triad of drivers; ecosystem comparisons; trophodynamics; biophysical forcing; fisheries
8.  Direct Interaction between Myocyte Enhancer Factor 2 (MEF2) and Protein Phosphatase 1α Represses MEF2-Dependent Gene Expression▿ † 
Molecular and Cellular Biology  2009;29(12):3355-3366.
The myocyte enhancer factor 2 (MEF2) transcription factors play important roles in neuronal, cardiac, and skeletal muscle tissues. MEF2 serves as a nuclear sensor, integrating signals from several signaling cascades through protein-protein interactions with kinases, chromatin remodeling factors, and other transcriptional regulators. Here, we report a novel interaction between the catalytic subunit of protein phosphatase 1α (PP1α) and MEF2. Interaction occurs within the nucleus, and binding of PP1α to MEF2 potently represses MEF2-dependent transcription. The interaction utilizes uncharacterized domains in both PP1α and MEF2, and PP1α phosphatase activity is not obligatory for MEF2 repression. Moreover, a MEF2-PP1α regulatory complex leads to nuclear retention and recruitment of histone deacetylase 4 to MEF2 transcription complexes. PP1α-mediated repression of MEF2 overrides the positive influence of calcineurin signaling, suggesting PP1α exerts a dominant level of control over MEF2 function. Indeed, PP1α-mediated repression of MEF2 function interferes with the prosurvival effect of MEF2 in primary hippocampal neurons. The PP1α-MEF2 interaction constitutes a potent locus of control for MEF2-dependent gene expression, having potentially important implications for neuronal cell survival, cardiac remodeling in disease, and terminal differentiation of vascular, cardiac, and skeletal muscle.
PMCID: PMC2698741  PMID: 19364819
9.  Combined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning 
Archives of Disease in Childhood  2006;91(12):972-976.
Thyroid imaging is helpful in confirming the diagnosis of congenital hypothyroidism and in establishing the aetiology. Although isotope scanning is the standard method of imaging, ultrasound assessment may be complementary.
To determine the strengths and weaknesses of thyroid ultrasound and isotope scanning in neonates with thyroid stimulating hormone (TSH) elevation.
Babies from the West of Scotland with raised capillary TSH (>15 mU/l) on neonatal screening between January 1999 and 2004 were recruited. Thyroid dimensions were measured using ultrasonography, and volumes were calculated. Isotope scanning was carried out with a pinhole collimator after an intravenous injection of 99m‐technetium pertechnetate.
40 infants (29 female) underwent scanning at a median of 17 days (range 12 days to 15 months). The final diagnosis was athyreosis (n = 11), ectopia (n = 12), hypoplasia (n = 8; 3 cases of hemi‐agenesis), dyshormonogenesis (n = 5), transient hypothyroidism (n = 2), transient hyperthyrotropinaemia (n = 1) and uncertain status with gland in situ (n = 1). 6 infants had discordant scans with no isotope uptake but visualisation of thyroid tissue on ultrasound. This was attributed to TSH suppression from thyroxine (n = 3); maternal blocking antibodies (n = 1); cystic degeneration of the thyroid (n = 1); and possible TSH receptor defect (n = 1).
Isotope scanning was superior to ultrasound in the detection of ectopic tissue. However, ultrasound detected tissue that was not visualised on isotope scanning, and showed abnormalities of thyroid volume and morphology. We would therefore advocate dual scanning in newborns with TSH elevation as each modality provides different information.
PMCID: PMC2082992  PMID: 16864597
10.  Optical Protein Sensor for Detecting Cancer Markers in Saliva 
Biosensors & bioelectronics  2008;24(2):266-271.
A surface immobilized optical protein sensor has been utilized to detect Interleukin-8 (IL-8) protein, an oral cancer marker, and can reach limit of detection (LOD) at 1.1 pM in buffer without using enzymatic amplification. Only after applying enzymatic amplification to increase the signal level by a few orders of magnitude, ELISA can reach the LOD of 1pm level. We then develop the confocal optics based sensor for further reducing the optical noise and can extend the LOD of the surface immobilized optical protein sensor two orders in magnitude. These improvements have allowed us to detect IL-8 protein at 4.0 fM in buffer. In addition, these sensitive LODs were achieved without the use of enzymatic signal amplification, such that the simplified protocol can further facilitate the development of point-of-care devices.
The ultra sensitive optical protein sensor presented in this paper has a wide number of applications in disease diagnoses. Measurements for detecting biomarkers in clinical sample are much more challenging than the measurements in buffer, due to high background noise contributed by large collections of non-target molecules. We used clinical salvia samples to validate the functionality of the optical protein sensor. Clinical detection of disease-specific biomarkers in saliva offers a non-invasive, alternative approach to using blood or urine. Currently, the main challenge of using saliva as a diagnostic fluid is its inherently low concentration of biomarkers. We compare the measurements of 40 saliva samples; half from oral cancer patients and half from a control group. The data measured by the optical protein sensor is compared with the traditional Enzyme-Linked Immunosorbant Assay (ELISA) values to validate the accuracy of our system. These positive results enable us to proceed to using confocal optical protein sensor to detect other biomarkers, which have much lower concentrations.
PMCID: PMC2584973  PMID: 18479906
Optical biosensor; Diagnostics; IL-8 protein; Oral cancer; Surface immobilization
11.  Carotid sinus hypersensitivity associated with focal α‐synucleinopathy of the autonomic nervous system 
A case of an 82‐year‐old woman who experienced repeated falls is described. She exhibited a cardioinhibitory carotid sinus hypersensitivity after right carotid sinus massage (CSM), but without evidence of orthostatic hypotension. After a pacemaker was implanted, she did not experience any falls, dizziness or syncope. Her balance eventually deteriorated, but she remained cognitively intact and died from lung cancer at the age of 89 years. Neuropathological examination showed only age‐related Alzheimer's disease pathology and a few α‐synuclein‐positive granular deposits and neurites in the dorsal nucleus of the vagus and solitary tract nucleus in the medulla, but a marked α‐synuclein pathology in the stellate ganglia. The cardioinhibitory element of her CSM was possibly because of the α‐synuclein pathology in the ganglion, which impaired sympathetic transmission. This case shows another phenotype among patients with α‐synucleinopathy.
PMCID: PMC2077727  PMID: 16914754
12.  Cost effectiveness of drug eluting coronary artery stenting in a UK setting: cost–utility study 
Heart  2005;92(1):68-74.
To assess the cost effectiveness of drug eluting stents (DES) compared with conventional stents for treatment of symptomatic coronary artery disease in the UK.
Cost–utility analysis of audit based patient subgroups by means of a simple economic model.
Tertiary care.
12 month audit data for 2884 patients receiving percutaneous coronary intervention with stenting at the Cardiothoracic Centre Liverpool between January 2000 and December 2002.
Main outcome measures
Risk of repeat revascularisation within 12 months of index procedure and reduction in risk from use of DES. Economic modelling was used to estimate the cost–utility ratio and threshold price premium.
Four factors were identified for patients undergoing elective surgery (n  =  1951) and two for non‐elective surgery (n  =  933) to predict risk of repeat revascularisation within 12 months. Most patients fell within the subgroup with lowest risk (57% of the elective surgery group with 5.6% risk and 91% of the non‐elective surgery group with 9.9% risk). Modelled cost–utility ratios were acceptable for only one group of high risk patients undergoing non‐elective surgery (only one patient in audit data). Restricting the number of DES for each patient improved results marginally: 4% of stents could then be drug eluting on economic grounds. The threshold price premium justifying 90% substitution of conventional stents was estimated to be £112 (US$212, [euro ]162) (sirolimus stents) or £89 (US$167, [euro ]130) (paclitaxel stents).
At current UK prices, DES are not cost effective compared with conventional stents except for a small minority of patients. Although the technology is clearly effective, general substitution is not justified unless the price premium falls substantially.
PMCID: PMC1861007  PMID: 15831599
drug eluting stents; cost–benefit analysis; percutaneous coronary intervention
13.  Prior CABG does not prevent pericardial tamponade following saphenous vein graft perforation associated with angioplasty 
Heart  2005;91(8):1052.
PMCID: PMC1769021  PMID: 16020595
Images in cardiology
14.  Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study 
Objectives: Depression is a common psychiatric disorder in late life. Cerebrovascular disease has been postulated as an important aetiological factor in many cases (the "vascular depression" hypothesis). Consistent with this, an inflammatory response, most probably representing ischaemia, has been reported with increases in intercellular adhesion molecule 1 (ICAM-1), in the dorsolateral prefrontal cortex (DLPFC) in postmortem tissue from elderly depressed subjects. As ischaemia is known to cause astrogliosis, this study has further tested the "vascular depression hypothesis" by investigating the distribution of the astrocytic marker glial fibrillary acidic protein (GFAP) in the DLPFC and in the anterior cingulate cortex (ACC).
Methods: Postmortem tissue was obtained from 20 elderly patients with a history of major depressive disorder (MDD) and 20 control subjects. Sections were stained for GFAP using standard immunocytochemistry. Sets of images were obtained from all cortical layers in the DLPFC and ACC with the exception of layer IV in the ACC, and from gyral and deep white matter in both regions. The percentage of the area of each image occupied by GFAP was calculated using true colour image analysis, and mean values obtained for each region examined.
Results: Immunoreactivity for GFAP was low in grey matter (for example, Mean (SEM) 0.76 (0.2)% in DLPFC layer V in depressed subjects), but higher in white matter (for example, 12.02 (2.2)% in DLPFC deep white matter in depressed subjects). Pronounced gliosis was observed within grey matter in a few cases only. GFAP immunoreactivity was significantly higher in layer I of the DLPFC in depressed subjects 15.8 (2.6)% than in controls 9.7 (1.3)% (t=2.2; df=27.5, p=0.04). No difference was detected in any other region.
Conclusions: The data suggest any increase in GFAP in elderly MDD patients is limited to layer 1 of the DLPFC. These results provide some support for the vascular depression hypothesis and further implicate DLPFC abnormalities in depression.
PMCID: PMC1738142  PMID: 12397151
15.  Ultrasound of the thyroid gland in the newborn: normative data 
Objective: To establish reference ranges for thyroid length, breadth, depth, and volume in healthy term Scottish infants.
Design: Prospective observational study of 100 (49 male) neonates. Length, breadth, and depth were measured, and the volume of each lobe was calculated using the formula for a prolate ellipsoid (volume = length x breadth x depth x π/6).
Results: All measurements showed gaussian distribution, with no significant differences between the right and the left lobes. Values (mean (SD) range) were: length (cm), 1.94 (0.24) 0.9–2.5; breadth (cm), 0.88 (0.16) 0.5–1.4; depth (cm), 0.96 (0.17) 0.6–2.0; volume (ml), 0.81 (0.24) 0.3–1.7; combined volume (ml), 1.62 (0.41) 0.7–3.3. Although there was no difference in mean volume between right and left lobes, there was considerable variation (-0.8 to + 0.7 ml) between the two lobes in individual babies.
Conclusions: Both lobes should be measured to give a combined volume. Our findings provide a reference against which thyroid hypoplasia or goitre can be evaluated.
PMCID: PMC1721466  PMID: 12390993
16.  Cushing's syndrome, growth impairment, and occult adrenal suppression associated with intranasal steroids 
Nine cases (including the original two cases) are reviewed to show the varied clinical manifestations of adrenal suppression caused by intranasal steroids. Four presented with Cushing's syndrome, three with growth failure, while two asymptomatic patients were discovered in the course of pituitary function testing.
Four children had dysmorphic syndromes—Down's, Treacher–Collins, CHARGE association, and campomelic dysplasia—reflecting the vulnerability of such children to ENT problems, together with the difficulty of interpreting steroid induced growth failure in this context.
Adrenal suppression was seen not only with betamethasone but also with budesonide, beclomethasone and flunisolide nasal preparations.
A careful enquiry as to the use of intranasal steroids should be routine in children presenting with unexplained growth failure or Cushing's syndrome. Particular vigilance/awareness is required in children with dysmorphic syndromes.
PMCID: PMC1751129  PMID: 12089123
18.  An echocardiographic assessment of cardiac morphology and common ECG findings in teenage professional soccer players: reference ranges for use in screening 
Heart  2001;85(6):649-654.
OBJECTIVE—To assess physiological cardiac adaptation in adolescent professional soccer players.
SUBJECTS AND DESIGN—Over a 32 month period 172 teenage soccer players were screened by echocardiography and ECG at a tertiary referral cardiothoracic centre. They were from six professional soccer teams in the north west of England, competing in the English Football League. One was excluded because of an atrial septal defect. The median age of the 171 players assessed was 16.7 years (5th to 95th centile range: 14-19) and median body surface area 1.68 m2 (1.39-2.06 m2).
MAIN OUTCOME MEASURES—Standard echocardiographic measurements were compared with predicted mean, lower, and upper limits in a cohort of normal controls after matching for age and surface area. Univariate regression analysis was used to assess the correlation between echocardiographic variables and the age and surface area of the soccer player cohort. ECG findings were also assessed.
RESULTS—All mean echocardiographic variables were greater than predicted for age and surface area matched controls (p < 0.001). All variables except left ventricular septal and posterior wall thickness showed a modest linear correlation with surface area (r = 0.2 to 0.4, p < 0.001); however, left ventricular mass was the only variable that was significantly correlated with age (r = 0.2, p < 0.01). Only six players (3.5%) had structural anomalies, none of which required further evaluation. All had normal left ventricular systolic function. Sinus bradycardia was found in 65 (39%). The Solokow-Lyon voltage criteria for left ventricular hypertrophy were present in 85 (50%) and the Romhilt-Estes points score (five or more) in 29 (17%). Repolarisation changes were present in 19 (11%), mainly in the inferior leads.
CONCLUSIONS—Chamber dimensions, left ventricular wall thickness and mass, and aortic root size were all greater than predicted for controls after matching for age and surface area. Sinus bradycardia and the ECG criteria for left ventricular hypertrophy were common but there was poor correlation with echocardiographic left ventricular hypertrophy. The type of hypertrophy found reflected the combined endurance and strength based training undertaken.

Keywords: cardiac morphology; professional soccer players; echocardiography; ECG findings
PMCID: PMC1729780  PMID: 11359746
19.  Cardiac rupture caused by Staphylococcus aureus septicaemia and pericarditis: an incidental finding 
Heart  2001;85(3):e4.
A 35 year old woman with a long history of intravenous drug abuse presented to a local hospital with severe anaemia, fever, raised markers of inflammation, and positive blood cultures for Staphylococcus aureus. She responded to treatment with antibiotics with improvement in her symptoms and markers of inflammation. Four weeks later a "routine" echocardiogram showed a rupture of her left ventricular apex and a large pseudoaneurysm. There had been no deterioration in her symptoms or haemodynamic status to herald this new development. It was successfully repaired surgically and the patient made a good recovery.

Keywords: ventricular rupture; pseudoaneurysm; staphylococcal septicaemia
PMCID: PMC1729660  PMID: 11179283
20.  Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer's disease 
OBJECTIVE—To test the hypotheses that visuoperceptual and attentional ability are disproportionately impaired in patients having dementia with Lewy Bodies (DLB) compared with Alzheimer's disease (AD).
METHODS—A comprehensive battery of neuropsychological tasks designed to assess working, episodic, and semantic memory, and visuoperceptual and attentional functions was given to groups of patients with DLB (n=10) and AD (n=9), matched for age, education, and mini mental state examination (MMSE), and to normal controls (n=17).
RESULTS—Both patient groups performed equally poorly on tests of episodic and semantic memory with the exception of immediate and delayed story recall, which was worse in the AD group. Digit span was by contrast spared in AD. The most striking differences were on tests of visuoperceptual/spatial ability and attention. Whereas patients with AD performed normally on several subtests of the visual object and space perception battery, the DLB group showed substantial impairments. In keeping with previous studies, the AD group showed deficits in selective attention and set shifting, but patients with DLB were more impaired on virtually every test of attention with deficits in sustained, selective, and divided attention.
CONCLUSIONS—Patients with DLB have substantially greater impairment of attention, working memory, and visuoperceptual ability than patients with AD matched for overall dementia severity. Semantic memory seems to be equally affected in DLB and AD, unlike episodic memory, which is worse in AD. These findings may have relevance for our understanding of the genesis of visual hallucinations, and the differential diagnosis of AD and DLB.

PMCID: PMC1737215  PMID: 11160462
21.  A neuropathological study of vascular factors in late-life depression 
OBJECTIVES—Depression is a common psychiatric disorder in late life and it may be associated with vascular disease processes. Although there are clinical and neuroimaging studies lending support to such a "vascular depression" hypothesis there have been no neuropathological studies to directly test this. Postmortem tissue was investigated to determine whether late life depression was associated with atheromatous change in large and medium vessels and microvascular disease in the brain.
METHODS—Postmortem tissue wae obtained from 20 patients with a history of at least one episode of DSM-IV major depression and 20 control subjects. Standard procedures were carried out to analyze and quantify Alzheimer type pathology (plaques, tangles, Braak staging) and cortical Lewy bodies. Coronary arteries, cerebral vessels, and aorta were rated for atheromatous disease on a 0-3 scale and the four neocortical areas were rated for microvascular disease.
RESULTS—The two groups showed no significant differences in age, sex, or postmortem delay. There was a significant increase in atheromatous disease in the depressed group (p=0.023). No differences were found for microvascular disease, either in the brain generally or locally in the frontal lobes. No subject had any significant Alzheimer type or Lewy body pathology.
CONCLUSIONS—Neuropathological evidence was found for an excess of atheromatous disease, related to the aortic and cerebral vessels, in late life depression. However, there was no evidence of an increase in microvascular disease. The findings broadly support the vascular depression hypothesis.

PMCID: PMC1763463  PMID: 11118253
22.  The molecular pathology of p53 in primitive neuroectodermal tumours of the central nervous system 
British Journal of Cancer  2002;86(7):1117-1123.
One hundred and one pre-treatment primary central primitive neuroectodermal tumours were analysed for the expression of p53 protein by immunohistochemistry using the monoclonal antibody DO-7. The staining intensity was classified into four groups: strong, medium, weak and negative and strong staining intensity was associated with the poorest survival. DNA sequencing of the p53 gene was performed in 28 cases representing all four staining groups. Mutations were found in only three of the strong staining tumours suggesting that DNA mutations were not common events and that in the majority of the tumours with over-expressed p53, the protein was likely to be wild-type. Results of immunohistochemistry showed a significantly positive relationship between the expression of p53 and Bax and Bcl-2 proteins, but not Waf-1. Multivariate analyses supported the prognostic value of p53 immunostaining in central primitive neuroectodermal tumours and also of age and gender of patients.
British Journal of Cancer (2002) 86, 1117–1123. DOI: 10.1038/sj/bjc/6600151
© 2002 Cancer Research UK
PMCID: PMC2364191  PMID: 11953859
central primitive neuroectodermal tumours; p53 protein; DNA sequencing; Waf-1; Bax; Bcl-2
23.  Genetic abnormalities detected in ependymomas by comparative genomic hybridisation 
British Journal of Cancer  2002;86(6):929-939.
Using comparative genomic hybridisation, we have analysed genetic imbalance in a series of 86 ependymomas from children and adults. Tumours were derived from intracranial and spinal sites, and classified histologically as classic, anaplastic or myxopapillary. Ependymomas showing a balanced profile were significantly (P<0.0005) more frequent in children than adults. Profiles suggesting intermediate ploidy were common (44% of all tumours), and found more often (P<0.0005) in tumours from adults and the spinal region. Loss of 22q was the most common specific abnormality, occurring in 50% of spinal (medullary) ependymomas and 26% of tumours overall. Genetic profiles combining loss of 22q with other specific abnormalities – gain of 1q, loss of 6q, loss of 10q/10, loss of 13, loss of 14q/14 – varied according to site and histology. In particular, we showed that classic ependymomas from within the cranium and spine have distinct genetic profiles. Classic and anaplastic ependymomas with gain of 1q tended to occur in the posterior fossa of children and to behave aggressively. Our extensive data on ependymomas demonstrate significant associations between genetic aberrations and clinicopathological variables, and represent a starting point for further biological and clinical studies.
British Journal of Cancer (2002) 86, 929–939. DOI: 10.1038/sj/bjc/6600180
© 2002 Cancer Research UK
PMCID: PMC2364143  PMID: 11953826
ependymoma; CGH; gain 1q; loss 22; intermediate ploidy
24.  Clinical and molecular stratification of disease risk in medulloblastoma 
British Journal of Cancer  2001;85(5):705-712.
The accurate assessment of disease risk among children with medulloblastoma remains a major challenge to the field of paediatric neuro-oncology. In the current study we investigated the capacity of molecular abnormalities to increase the accuracy of disease risk stratification above that afforded by clinical staging alone. 41 primary medulloblastoma tumour samples were analysed for ErbB2 receptor expression using immunohistochemistry, and for aberrations of chromosome 17 and amplification of the MYC oncogene using fluorescence in situ hybridisation. The ErbB2 receptor and deletion of 17p were detected in 80% and 49% of tumours, respectively. 17p loss occurred either in isolation (20%), or in association with gain of 17q (29%), compatible with an isochromosome of 17q. Amplification of MYC was detected in only 2 tumours. Significant prognostic factors included, ‘metastatic disease’ (P = 0.0006), ‘sub-total tumour resection’ (P = 0.007), ‘high ErbB2 receptor expression’ (P = 0.003) and ‘isolated 17p loss’ (P = 0.003). Combined analysis of clinical and molecular factors enabled greater resolution of disease risk than clinical factors alone, identifying a sub-population of patients with particularly favourable disease outcome. These data support the hypothesis that a combination of clinical and molecular factors may afford a more reliable means of assigning disease risk in patients with medulloblastoma, thereby providing a more accurate basis for targeting therapy in children with this disease. © 2001 Cancer Research Campaign
PMCID: PMC2364121  PMID: 11531256
medulloblastoma; prognosis; ErbB2; MYC; chromosome 17
25.  White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer's disease, vascular dementia, and normal aging 
OBJECTIVES—Alzheimer's disease and vascular dementia are associated with an increase in changes in white matter on MRI. The aims were to investigate whether white matter changes also occur in dementia with Lewy bodies and to examine the relation between white matter lesions and the cognitive and non-cognitive features of dementia with Lewy bodies, Alzheimer's disease, and vascular dementia.
METHODS—Proton density and T2 weighted images were obtained on a 1.0 Tesla MRI scanner in patients with dementia with Lewy bodies (consensus criteria; n=27, mean age=75.9 years), Alzheimer's disease (NINCDS/ADRDA; n=28, mean age=77.4 years), vascular dementia (NINDS/AIREN; n=25, mean age=76.8 years), and normal controls (n=26, mean age=76.2 years). Cognitive function, depressive symptoms, and psychotic features were assessed using a standardised protocol. Periventricular hyperintensities (PVHs), white matter hyperintensities (WMHs) and basal ganglia hyperintensities (BGHs) were visually rated blind to diagnosis using a semiquantitative scale.
RESULTS—Periventricular hyperintensities were positively correlated with age and were more severe in all dementia groups than controls. Total deep hyperintensities scores (WMHs plus BGHs) were significantly higher in all dementia groups than controls and higher in patients with vascular dementia than those with dementia with Lewy bodies or Alzheimer's disease. In all patients with dementia, frontal WMHs were associated with higher depression scores and occipital WMHs were associated with an absence of visual hallucinations and delusions.
CONCLUSION—In common with Alzheimer's disease and vascular dementia, PVHs and WMHs were significantly more extensive in dementia with Lewy bodies than in controls. This overlap between different dementias may reflect shared pathological mechanisms. The link between frontal WMHs and depression and the absence of occipital WMHs and psychotic symptoms has important implications for understanding the neurobiological basis of these symptoms.

PMCID: PMC1736409  PMID: 10369824

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