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ABSTRACT: Muscle biopsy is used in the diagnosis of mitochondrial disorders. There are limited data on the normal ranges, so interpretation of findings can be difficult.
We evaluated the percentage of fibers showing mitochondrial abnormalities using Gomori trichrome staining, succinate dehydrogenase, and cytochrome oxidase histochemistry in autopsy samples taken from 45 individuals without evidence of muscle disease and biopsies from 17 patients with mitochondrial disorders.
In controls, mitochondrial abnormalities were rare before the fifth decade, and most had <0.1% abnormal fibers. The proportion of abnormal fibers increased with age and was higher in deltoid than quadriceps. Most patients with mitochondrial disorders had >0.5% abnormal fibers.
Although some patients with mitochondrial disease have very few muscle fibers that show mitochondrial abnormalities, a rate of abnormality of >0.5% fibers, in the absence of a primary muscle disease this should raise the possibility of a mitochondrial disorder.
Muscle & Nerve 06/2011; 43(6):795-800. · 2.37 Impact Factor
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Jonathan D F Wadsworth,
Inmaculada Dalmau-Mena,
Susan Joiner,
Jacqueline M Linehan,
Catherine O'Malley,
Caroline Powell,
Sebastian Brandner,
Emmanuel A Asante,
James W Ironside, David A Hilton,
John Collinge
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ABSTRACT: Anonymous screening of lymphoreticular tissues removed during routine surgery has been applied to estimate the UK population prevalence of asymptomatic vCJD prion infection. The retrospective study of Hilton et al (J Pathol 2004; 203: 733-739) found accumulation of abnormal prion protein in three formalin-fixed appendix specimens. This led to an estimated UK prevalence of vCJD infection of ∼1 in 4000, which remains the key evidence supporting current risk reduction measures to reduce iatrogenic transmission of vCJD prions in the UK. Confirmatory testing of these positives has been hampered by the inability to perform immunoblotting of formalin-fixed tissue. Animal transmission studies offer the potential for 'gold standard' confirmatory testing but are limited by both transmission barrier effects and known effects of fixation on scrapie prion titre in experimental models. Here we report the effects of fixation on brain and lymphoreticular human vCJD prions and comparative bioassay of two of the three prevalence study formalin-fixed, paraffin-embedded (FFPE) appendix specimens using transgenic mice expressing human prion protein (PrP). While transgenic mice expressing human PrP 129M readily reported vCJD prion infection after inoculation with frozen vCJD brain or appendix, and also FFPE vCJD brain, no infectivity was detected in FFPE vCJD spleen. No prion transmission was observed from either of the FFPE appendix specimens. The absence of detectable infectivity in fixed, known positive vCJD lymphoreticular tissue precludes interpreting negative transmissions from vCJD prevalence study appendix specimens. In this context, the Hilton et al study should continue to inform risk assessment pending the outcome of larger-scale studies on discarded surgical tissues and autopsy samples.
The Journal of Pathology 03/2011; 223(4):511-8. · 6.32 Impact Factor
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ABSTRACT: Cannabinoids have been shown to have a beneficial effect in both animal models of multiple sclerosis (MS) and human disease, although the mechanisms of action are unclear. We examined expression of the major cannabinoid receptors [(CBRs) cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)] and a key enzyme involved in synthesis of the endocannabinoid anandamide [N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD)] in autopsy brain samples from patients with MS. CB1 was expressed in neurons, injured axons, oligodendrocytes, macrophages/microglia, some astrocytes, endothelial cells, smooth muscle cells and pericytes. CB2 and NAPE-PLD were localized to cerebral endothelial cells, pericytes, smooth muscle cells, astrocytes and macrophages/microglia. NAPE-PLD immunoreactivity was also seen in neurons. Endothelial CB2 expression was greatest in chronic inactive plaques, and in areas was seen in segments of endothelium where the endothelial expression of adhesion molecules (VCAM-1 and ICAM-1) was focally undetectable, and was often expressed in areas of blood-brain barrier damage. Vascular density was increased in chronic active plaques and normal-appearing white matter compared with controls. These data support findings from animal models which suggest a role for the endocannabinoid system in the MS, particularly in the regulation of endothelial leukocyte adhesion and the cellular response to injury.
Brain Pathology 01/2011; 21(5):544-57. · 3.99 Impact Factor
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ABSTRACT: The detection of viral infection in paraffin-embedded, formalin-fixed tissue is notoriously difficult and often requires inherent knowledge about the specific virus being sought. For this reason, there is an ongoing need for reagents and methods which can identify a range of different virus types in paraffin embedded tissue.
The aim of this study was to optimise and validate the use of antisera directed against dsRNA (>50 bp in length) in paraffin-embedded formalin-fixed tissue samples.
dsRNA antisera were optimised for use in a range of virally-infected tissue culture cells, Coxsackie-infected mice and human tissues. The specificity of labelling was confirmed by pre-adsorption of antisera with poly-IC and by digestion of dsRNA with RNaseIII.
Two different polyclonal dsRNA antisera (J2 and K1) were capable of recognising dsRNA encoded by all the multiple different viral types (including (+) ssRNA viruses, dsRNA viruses and DNA viruses) tested in paraffin-embedded formalin fixed infected cells and tissues. In contrast, the enteroviral vp1 antisera detected only a subset of the (+) ssRNA viruses tested. Staining was not seen in uninfected cells or in uninfected control tissues. Positive staining was ablated following incubation of antisera with poly-IC or by pre-treating sections with RNaseIII prior to staining.
The dsRNA antisera J2 and K1 are useful for the detection of viral infection in formalin-fixed, paraffin-embedded, human tissue samples.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 11/2010; 49(3):180-5. · 3.12 Impact Factor
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ABSTRACT: A 41-year-old female patient was admitted with streptococcal meningitis on a background of 5-month history of CSF rhinorrhoea. Imaging revealed an extensive skull base lesion involving the sphenoid and ethmoid sinuses, the pituitary fossa with suprasellar extension and bony destruction. Histological examination of an endonasal transethmoidal biopsy suggested a diagnosis of olfactory neuroblastoma. A profuse CSF leak occurred and the patient developed coliform meningitis. A second endonasal endoscopic biopsy was undertaken which demonstrated the tumour to be a prolactinoma. Following endonasal repair of the CSF leak and lumbar drainage, she developed profound pneumocephalus. The patient underwent three further unsuccessful CSF leak repairs. Definitive control of the CSF leak was finally achieved through a transcranial approach with prolonged lumbar drainage. This case illustrates some of the potentially devastating complications which can occur as a consequence of complex skull base lesions. A multidisciplinary approach may be required to successfully manage such cases.
Case Reports in Medicine 01/2010; 2010.
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ABSTRACT: Schwannomas are common tumours that may be multiple in neurofibromatosis type 2, when they may be difficult to treat without significant morbidity using surgery and radiosurgery. Previous in vitro work has suggested that merlin loss is associated with activation of the JNK/JUN, PI3K/AKT and MEK/ERK pathways and that these pathways may be susceptible to pharmacological inhibition. The aim was to investigate the expression of proteins involved in these pathways in human schwannomas in situ.
Immunohistochemistry using antibodies to AKT, pAKT, MEK, pMEK, ERK, pERK, JUN and pJUN was applied to 16 schwannomas (sporadic and NF2), and the results were compared with those seen in traumatic neuromas. Increased expression of pMEK, pERK and pJUN was seen in the schwannomas samples and of pAKT in schwannomas and controls.
These findings provide further direct evidence for activation of the JNK/JUN, PI3K/AKT and MEK/ERK signalling pathways in schwannomas and support the development of therapeutic agents directed against these pathways for the treatment of this group of tumours.
Histopathology 11/2009; 55(6):744-9. · 3.08 Impact Factor
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ABSTRACT: Deficiency of the tumor suppressor merlin leads to the development of multiple tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas. Due to the benign character of these tumors, classical chemotherapy is ineffective. Current therapies, surgery, and radiosurgery are local and quite invasive, thus new systemic treatments are required. We have previously described the Raf/mitogen-activated kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway activation and its role in schwannoma growth. Here, we targeted MEK1/2 known as a convergence point for multiple cascades towards ERK1/2 activation and cell proliferation, using MEK1/2 inhibitor AZD6244 (ARRY-142886; Astra Zeneca). We show that AZD6244 at low concentration completely abolished platelet-derived growth factor-DD-mediated ERK1/2 activation and cell proliferation in human primary schwannoma cells. Moreover, this drug was not toxic for either schwannoma or Schwann cells and has been reported to be safe with tolerable side effects. Thus, AZD6244 can be considered as a drug candidate for schwannoma treatment.
Neurobiology of Disease 10/2009; 37(1):141-6. · 5.40 Impact Factor
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Jonathan P Clewley,
Carole M Kelly,
Nick Andrews,
Kelly Vogliqi,
Gary Mallinson,
Maria Kaisar, David A Hilton,
James W Ironside,
Philip Edwards,
Linda M McCardle,
Diane L Ritchie,
Reza Dabaghian,
Helen E Ambrose,
O Noel Gill
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ABSTRACT: To establish with improved accuracy the prevalence of disease related prion protein (PrP(CJD)) in the population of Britain and thereby guide a proportionate public health response to limit the threat of healthcare associated transmission of variant Creutzfeldt-Jakob disease (vCJD).
Cross sectional opportunistic survey. Study samples Anonymised tonsil pairs removed at elective tonsillectomy throughout England and Scotland.
National anonymous tissue archive for England and Scotland.
Presence of PrP(CJD) determined by using two enzyme immunoassays based on different analytical principles, with further investigation by immunohistochemistry or immunoblotting of any samples reactive in either assay.
Testing of 63 007 samples was completed by the end of September 2008. Of these, 12 753 were from the birth cohort in which most vCJD cases have arisen (1961-85) and 19 908 were from the 1986-95 cohort that would have been also exposed to bovine spongiform encephalopathy through infected meat or meat products. None of the samples tested was unequivocally reactive in both enzyme immunoassays. Only two samples were reactive in one or other enzyme immunoassay and equivocal in the other, and nine samples were equivocally reactive in both enzyme immunoassays. Two hundred and seventy six samples were initially reactive in one or other enzyme immunoassay; the repeat reactivity rate was 15% or less, depending on the enzyme immunoassay and cut-off definition. None of the samples (including all the 276 initially reactive in enzyme immunoassay) that were investigated by immunohistochemistry or immunoblotting was positive for the presence of PrP(CJD).
The observed prevalence of PrP(CJD) in tonsils from the 1961-95 combined birth cohort was 0/32 661 with a 95% confidence interval of 0 to 113 per million. In the 1961-85 cohort, the prevalence of zero with a 95% confidence interval of 0 to 289 per million was lower than, but still consistent with, a previous survey of appendix tissue that showed a prevalence of 292 per million with a 95% confidence interval of 60 to 853 per million. Continuing to archive and test tonsil specimens, especially in older birth cohorts, and other complementary large scale anonymous tissue surveys, particularly of post-mortem tissues, will further refine the calculated prevalence of PrP(CJD).
BMJ (Clinical research ed.). 02/2009; 338:b1442.
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Henry Houlden,
Janel Johnson,
Christopher Gardner-Thorpe,
Tammaryn Lashley,
Dena Hernandez,
Paul Worth,
Andrew B Singleton, David A Hilton,
Janice Holton,
Tamas Revesz,
Mary B Davis,
Paola Giunti,
Paolo Giunti,
Nicholas W Wood
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ABSTRACT: The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration.
Nature Genetics 01/2008; 39(12):1434-6. · 35.53 Impact Factor
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ABSTRACT: Nerve biopsy is used as part of the investigation of patients with peripheral neuropathy and is particularly useful in confirming the diagnosis of peripheral nerve vasculitis. Previous studies have suggested that sampling the peroneal nerve, in combination with peroneus brevis, is more sensitive than the sural nerve for this diagnosis but there are no published data on the complication rate of peroneal nerve biopsies. We have assessed the complications in 50 patients undergoing nerve biopsy, and have shown that although biopsy of the peroneal nerve may result in a larger area of sensory loss in some patients, other complications are not increased when compared with sural nerve biopsy.
Journal of neurology, neurosurgery, and psychiatry 12/2007; 78(11):1271-2. · 4.87 Impact Factor
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ABSTRACT: To perform prion protein gene (PRNP) codon 129 analysis in DNA extracted from appendix tissue samples that had tested positive for disease associated prion protein.
Reanalysis of positive cases identified in a retrospective anonymised unlinked prevalence study of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom. STUDY SAMPLES: Three positive appendix tissue samples out of 12,674 samples of appendix and tonsil tested for disease associated prion protein. The patients from whom these samples were obtained were aged 20-29 years at the time of surgery, which took place in 1996-9.
Pathology departments in two tertiary centres in England and Scotland.
Adequate DNA was available for analysis in two of the three specimens, both of which were homozygous for valine at codon 129 in the PRNP.
This is the first indication that the valine homozygous subgroup at codon 129 in the PRNP is susceptible to vCJD infection. All tested clinical cases of vCJD have so far occurred in the methionine homozygous subgroup, and a single case of probable iatrogenic vCJD infection has been identified in one patient who was a methionine/valine heterozygote at this genetic locus. People infected with vCJD with a valine homozygous codon 129 PRNP genotype may have a prolonged incubation period, during which horizontal spread of the infection could occur either from blood donations or from contaminated surgical instruments used on these individuals during the asymptomatic phase of the illness.
BMJ (Clinical research ed.). 06/2006; 332(7551):1186-8.
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David A Hilton
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ABSTRACT: In the late 1980s and early 1990s, there was widespread exposure of the UK population to bovine spongiform encephalopathy (BSE)-contaminated food products, which has led to over 150 deaths from variant Creutzfeldt-Jakob disease (vCJD). Although the pathogenesis in humans is not fully understood, data from animal models and, to a lesser extent, patients with vCJD suggest that oral exposure to BSE is rapidly followed by accumulation of PrP(res) in gut-associated lymphoid tissue, then, after haematogenous spread, throughout the lymphoreticular system. Spread to the central nervous system may not occur for several years, but blood from individuals in the pre-clinical phase appears to be able to transmit disease. The incidence of vCJD has remained low and is in decline, but it is known from iatrogenic CJD and kuru that human prion disease can have incubation periods of up to 40 years. Cases of vCJD are therefore likely to occur for many more years and alternative phenotypes may develop in individuals with different PRNP genotypes to those seen to date. Studies in transgenic mice have shown that sub-clinical infection is frequent following oral exposure to BSE and a study looking at the accumulation of PrP in anonymized human lymphoid tissue samples found positive cases. There are likely to be a number of asymptomatic 'carriers' of disease within the UK and although it is unclear whether these individuals will develop clinical disease, there is a potential for iatrogenic spread to others. These uncertainties highlight the importance of developing a reliable blood test for vCJD and the continued need for surveillance.
The Journal of Pathology 02/2006; 208(2):134-41. · 6.32 Impact Factor
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Neil J Scolding,
Fady Joseph,
Patricia A Kirby,
Ingrid Mazanti,
Françoise Gray,
Jacqueline Mikol,
David Ellison, David A Hilton,
Timothy L Williams,
James M MacKenzie,
John H Xuereb,
Seth Love
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ABSTRACT: Idiopathic or primary angiitis of the CNS (PACNS) and cerebral amyloid angiopathy (CAA) are unusual vasculopathies generally regarded as unrelated disorders. A few case reports have, however, described granulomatous angiitis in patients with sporadic, amyloid beta peptide (Abeta)-related CAA. Here we describe the clinical, neuroradiological and neuropathological features of nine patients with Abeta-related angiitis (ABRA). Combining these with the individual case reports drawn from the literature has allowed us to define ABRA as a clinical entity and to compare its features with those of PACNS. The mean age of presentation of ABRA (67 years) is higher than that of PACNS but lower than that of sporadic non-inflammatory Abeta-related CAA. Alterations in mental status (59%), headaches (35%), seizures and focal neurological deficits (24%) are common. Hallucinations are a presenting manifestation in 12% of cases. Most patients have white matter hyperintensities on MRI but these are of similar appearance to those in PACNS. Cerebrospinal fluid usually shows modest elevation of protein and pleocytosis. Neuropathology reveals angiodestructive inflammation, often granulomatous, and meningeal lymphocytosis. Abeta is consistently present in abundance in affected blood vessels but usually scanty within the parenchyma of the cerebral cortex. However, the cortex includes numerous activated microglia, occasionally in a plaque-like distribution and containing cytoplasmic Abeta. The cerebral white matter shows patchy gliosis and rarefaction, in some cases marked. Our findings (i) help to dissect one separate clinicopathological entity from what is likely to be a spectrum of primary angiitides of the CNS; (ii) have important therapeutic implications for one category of patients with amyloid-related vasculopathy; and (iii) may provide valuable insights into the development of amyloid-associated inflammation, of relevance not only to ABRA but also to Abeta-immunization-related encephalitis and to Alzheimer's disease.
Brain 04/2005; 128(Pt 3):500-15. · 9.46 Impact Factor
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ABSTRACT: This study aims to provide an estimate of the number of individuals in the UK who may be incubating variant Creutzfeldt-Jakob disease and at risk of causing iatrogenic spread of the disease. Lymphoreticular accumulation of prion protein is a consistent feature of variant Creutzfeldt-Jakob at autopsy and has also been demonstrated in the pre-clinical phase. Immunohistochemical accumulation of prion protein in the lymphoreticular system remains the only technique that has been shown to predict neurological disease reliably in animal prion disorders. In this study, immunohistochemistry was used to demonstrate the presence of prion protein, with monoclonal antibodies KG9 and 3F4, in surgically removed tonsillectomy and appendicectomy specimens. The samples were collected from histopathology departments across the UK and anonymised prior to testing. Samples were tested from 16 703 patients (14 964 appendectomies, 1739 tonsillectomies), approximately 60% of whom were from the age group 20-29 years at operation. Twenty-five per cent of the samples were excluded from the final analyses because they contained inadequate amounts of lymphoid tissue. Three appendicectomy samples showed lymphoreticular accumulation of prion protein, giving an estimated prevalence of 3/12 674 or 237 per million (95% CI 49-692 per million). The pattern of lymphoreticular accumulation in two of these samples was dissimilar from that seen in known cases of variant Creutzfeldt-Jakob disease. Although it is uncertain whether immunohistochemical accumulation of prion protein in the lymphoreticular system is specific for variant Creutzfeldt-Jakob disease, it has not been described in any other disease, including other forms of human prion disease or a range of inflammatory and infective conditions. These findings reinforce the importance of measures taken by the UK Department of Health to reduce the risk of spread of variant Creutzfeldt-Jakob via blood products and surgical instruments, and of the urgency to proceed with large-scale screening of fresh tonsil specimens for the presence of prion protein.
The Journal of Pathology 08/2004; 203(3):733-9. · 6.32 Impact Factor
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ABSTRACT: The authors report the neuropathologic findings in a case of Sneddon's syndrome. There were multiple small, predominantly cortical, infarcts, with focal hyperplasia and fibrotic occlusion of arterial vessels in the superficial white matter, cortex, and leptomeninges. A very occasional arterial thrombus was seen. These findings suggest that Sneddon's syndrome is caused by a noninflammatory arteriopathy affecting superficial cerebral vessels.
Neurology 05/2003; 60(7):1181-2. · 8.31 Impact Factor
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BMJ (Clinical research ed.). 10/2002; 325(7365):633-4.
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ABSTRACT: Variant Creutzfeldt-Jakob disease is almost certainly caused by the bovine spongiform encephalopathy agent, and although the disease is rare (115 deaths to date) there is uncertainty about future numbers of cases.1 The lack of a conventional immune response and the inability to detect abnormal prion protein in blood has hampered the development of a blood test.1 Lymphoreticular accumulation of prion protein has been used as a preclinical test for scrapie (the form of the disease in sheep and goats) and is a consistent feature of variant Creutzfeldt-Jakob disease, occurring before the onset of symptoms.2–4 We screened large numbers of specimens from appendicectomies and tonsillectomies for the presence of prion protein in lymphoreticular tissue to determine the number of people with preclinical variant Creutzfeldt-Jakob disease.
Methods and results
We retrieved appendix and tonsil samples removed between 1995 and 1999 from patients aged 10-50 from histopathology departments across the United Kingdom. The samples were anonymised before testing. We also examined appendix samples removed at autopsy or at surgery from patients with variant Creutzfeldt-Jakob disease. Prion protein was detected by immunohistochemistry with monoclonal antibodies 3F4 (Dako, Ely, Cambridge) and KG9 (Institute for Animal Health, Newbury) and visualised with the catalysed signal amplification system (Dako). We excluded cases with fewer than five secondary lymphoid follicles from the final analyses because in the previously reported case and those examined at autopsy, prion protein was present in around 20% of follicles.4 We tested 11 228 samples, of which 2910 were excluded. Most samples were appendixes and 70% were from patients aged 20-29. In one case we identified prion protein immunoreactivity in a single lymphoid follicle stained with KG9 (figure). The pattern of staining was similar to that seen in the two other patients who developed variant Creutfeldt-Jakob disease (figure1).4 This positive staining was less evident in sections stained with 3F4 antibody. The reason for this discrepancy is not clear but may be due to sampling error because of the focal nature of prion protein deposition. In the appendixes removed before the onset of symptoms in three patients with variant Creutfeldt-Jakob disease, two (removed in 1995 and 1996; see figure) were positive, and the third (removed in 1987) was negative.4 Overall, 19 of 20 appendixes removed at autopsy from cases of variant Creutzfeldt-Jakob disease with adequate numbers of lymphoid follicles had lymphoreticular accumulation of prion protein.
View larger version:In a new windowDownload as PowerPoint SlideView larger version:In a new windowDownload as PowerPoint Slide(Left) Distribution of coarse granular prion protein within lymphoid follicle of appendix, suggestive of follicular dendritic cells. (Right) Lymphoreticular accumulation of prion protein in appendix tissue from patient with Creutzfeldt-Jakob disease, removed two years before onset of symptoms
Comment
One appendix showing the lymphoreticular accumulation of prion protein out of 8318 samples tested gives an estimated detectable prevalence of prion protein accumulation of 120 per million (95% confidence interval, 0.5 to 900) among people aged 10-50 between 1995 and 1999. Our study design precluded transmission studies, but the accumulation of prion protein in lymphoreticular tissue detected by the immunohistochemical technique correlates with the detection of abnormal prion protein by western blotting and remains the only technique shown to reliably predict disease in animals. 2 3 5 The sensitivity and specificity of preclinical lymphoreticular accumulation of prion protein in predicting variant Creutzfeldt-Jakob disease are unknown, but in sheep exposed to scrapie are estimated to be 87% and 94%, respectively.5 At autopsy, 95% of appendixes from patients with variant Creutzfeldt-Jakob disease with adequate amounts of lymphoid tissue showed accumulation of prion protein, as did both appendixes removed during the 1990s from patients who later developed the disease.
We provide the first estimate of the number of people who may be a potential source of variant Creutzfeldt-Jakob disease by iatrogenic spread. Large scale prospective screening of tissue from tonsillectomies is needed to obtain precise data on prevalence. The use of fresh tissue would allow for a semi-automated western blot assay and verification of positive samples by transmission studies. As half of tonsillectomies are in children under 10, who will have had little or no exposure to bovine spongiform encephalopathy, the opportunity for such a study will diminish over time.
Acknowledgments
We thank histopathology departments and relatives of patients with variant Creutzfeldt-Jakob disease who gave consent for autopsy tissues to be used as positive control material.
Contributors: DAH designed the English study, screened samples tested at Plymouth, and drafted the manuscript; he will act as guarantor for the paper. JWI designed the Scottish study, screened samples tested at Edinburgh, and contributed to the manuscript. ACG performed the statistical analyses and contributed to the manuscript. MP, LC, and PE performed the technical work at Plymouth. LMcC and DR performed the technical work and assisted in screening samples at Edinburgh.
Footnotes
Funding Department of Health and the Royal Society. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.
Competing interests None declared.References1.↵Collinge J.Variant Creutzfeldt-Jakob disease.Lancet 1999;354: 317–323.OpenUrlCrossRefMedlineWeb of Science2.↵Schreuder BEC, van Keulen LJM, Vromans MEW, Langeveld JPM, Smits MA.Preclinical test for prion diseases.Nature 1996;381: 563.OpenUrlCrossRefMedline3.↵Hill AF, Butterworth RJ, Joiner S, Jackson G, Rosser MN, Thomas DJ, et al.Investigation of variant Creutzfeldt-Jakob disease and other human prion disease with tonsil biopsy samples.Lancet 1999;353: 183–189.OpenUrlCrossRefMedlineWeb of Science4.↵Hilton DA, Fathers E, Edwards P, Ironside JW, Zajicek J.Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease.Lancet 1998;352: 703–704.OpenUrlCrossRefMedlineWeb of Science5.↵O'Rourke KI, Baszler TV, Besser TE, Miller JM, Cutlip RC, Wells GAH, et al.Preclinical diagnosis of scrapie by immunohistochemistry of third eyelid lymphoid tissue.J Clin Microbiol 2000;38: 3254–3259.OpenUrlFREE Full Text
BMJ. 09/2002; 325(7365):633 - 634.
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ABSTRACT: Diffuse astrocytomas have a median survival of 6-8 years. However, in a minority of cases that are histologically low grade, progression is rapid, leading to death within 2 years. Loss of p16, retinoblastoma protein, and deleted-in-colon-carcinoma protein expression, and monosomy of chromosome 10 have been shown to occur in malignant astrocytic tumors. We have investigated the prognostic value of expression of these markers, using techniques applicable in many histopathology laboratories, in diffuse astrocytomas that are histologically low grade. Paraffin sections from 71 diffuse, supratentorial, low-grade astrocytomas, from patients with at least 8-year survival data, were immunostained with antibodies to p16, deleted-in-colon-carcinoma protein, p53, Ki67, and retinoblastoma protein. In situ hybridization with a digoxigenin-labeled probe to chromosome 10 was used to assess chromosomal loss. In most cases there was immunostaining of virtually all tumor cell nuclei with antibodies to p16 and retinoblastoma protein. Three of the 68 tumors in which assessment of p16 was possible included discrete foci with lack of detectable immunoreactivity in tumor cells. The three patients concerned had a significantly shortened median survival (1.1 years vs 4.4 years in those without loss of p16; p <0.01). In six of the 61 cases where assessment of retinoblastoma protein was possible, <70% of tumor cell nuclei showed immunoreactivity. These six patients had a shorter survival (4.0 years) than had the remaining patients (5.4 years), although this difference was not statistically significant. The tumor from one of these patients included areas where only 36% of tumor cells showed retinoblastoma protein immunoreactivity, and this patient survived only 1.5 years. Tumors showing loss of both p16 and retinoblastoma were not seen. p53 and deleted-in-colon-carcinoma protein expression was highly variable and did not correlate with survival. Tumors with monosomy for chromosome 10 were not identified. Both polyploidy and the Ki67 labeling index were significantly associated with the p53 labeling index but not with survival. Focal loss of p16 or retinoblastoma protein is demonstrable in approximately 5% and 10% of diffuse low-grade diffuse astrocytomas, respectively. Tumors with focal loss of immunoreactivity for these proteins are associated with shorter survival than those without, suggesting that immunohistochemistry for p16 and retinoblastoma protein may be a useful adjunct to other methods for assessing the prognosis of astrocytomas.
American Journal of Surgical Pathology 05/2002; 26(4):472-8. · 4.35 Impact Factor
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ABSTRACT: A 25-year-old woman presented with rapidly progressive motor weakness necessitating ventilation 10 months after the onset. Despite immunosuppressive therapy she died 27 months later, without developing significant extramotor features. Autopsy revealed evidence of both upper and lower motor neuron loss with wide-spread motor and extramotor intraneuronal basophilic inclusions, most of which did not show ubiquitin immunoreactivity. Motor neuron disease with basophilic inclusions appears to be a rare, but distinctive pathological subtype, with most reported cases occurring sporadically in young women and having a rapid clinical progression.
Brain Pathology 05/2002; 12(2):267-8, 269. · 3.99 Impact Factor
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ABSTRACT: We have examined the ultrastructure of the trigeminal sensory nerve root in three patients with medically intractable trigeminal neuralgia. In one patient, the nerve root was sandwiched between a large vein and a small pontine artery, in the others compression was due to marked dolichoectasia of a verterbal artery. Because these were not amenable to microvascular decompression, a caudal rhizotomy was performed, by excising a short inferior segment of nerve root in the region of indentation. In all cases, examination revealed a zone of chronic demyelination in the proximal (centrally myelinated) part of the root, near its junction with peripheral nerve. The zone of demyelination contained closely packed axons without intervening glial cytoplasm. Also present were small numbers of thinly myelinated axons. In some cases a single thin myelin sheath encircled several adjacent axons that were still in close apposition. These findings indicate that the trigeminal neuralgia associated with vascular compression is due to demyelination. The demyelination is associated with some evidence of remyelination. The latter phenomenon may account in part for the long periods of remission, especially during the inital period after the onset of trigeminal neuralgia. The partly aberrant nature of the myelination within the region of vascular compression may contribute to the persistence of symptoms in some patients after decompressive surgery.
Brain Pathology 12/1997; 8(1):1 - 11. · 3.99 Impact Factor
