A giant cause of stroke.

An 80 year old man presented subacutely with drowsiness and confusion. Subsequent MRI brain imaging demonstrated multiple posterior circulation infarcts. Extracranial vasculitis was suspected when his ESR was found to be high and vascular imaging showed multifocal irregular narrowing of both vertebral arteries. This was confirmed by targeted temporal artery biopsy, which showed chronic granulomatous inflammation typical of giant cell arteritis (GCA). The patient made a significant recovery following treatment with prednisolone.

Isolated intracranial Rosai-Dorfman disease in a child, a case report and review of the literature.

BACKGROUND: Rosai-Dorfman disease (RDD), otherwise known as sinus histiocytosis with massive lymphadenopathy (SHML), usually affects young adults and commonly presents with massive painless cervical lymphadenopathy. Extranodal disease is present in a third of patients, and it is recognised that this can involve the central nervous system. Intracranial RDD is rare in adults and fewer than 10 paediatric cases have been reported. CASE: A 10-year-old boy with isolated intracranial RDD presents with a painless forehead mass. The management is discussed and the literature reviewed. CONCLUSION: This case of isolated intracranial RDD highlights the importance of considering RDD in the differential of paediatric intracranial mass lesions and outlines the diagnostic and treatment challenges faced when managing this rare condition.

Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia.

Pancreatic cancer remains as one of the most deadly cancers with few treatment options at late stages and little information about how it develops through earlier stages. Activating mutation of the Kras gene has been implicated in, but is not sufficient for, tumorigenesis. In mouse models of pancreatic cancer, loss of tumor suppressor genes in conjunction with Kras mutation leads to gradual stochastic acquisition of neoplastic precursors and carcinomas, whereas many cells remain phenotypically unaltered in younger mice. Here, we demonstrate that two oncogenic events, mutation of Kras and production of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF), are sufficient for rapid and complete neoplastic transformation of the exocrine pancreas. We found that macrophages are the major source of HB-EGF production in pancreatic cancer tissue samples, and that macrophages are present in high density and in close association with human pancreatic cancer lesions. In a mouse model, high macrophage density was observed at the earliest stages of neoplastic transformation. The consequence of elevated HB-EGF signaling was investigated without the confounding effects of other macrophage-produced factors via transgenic overexpression of the active form of HB-EGF. In this model, HB-EGF was sufficient to promote Kras-initiated tumorigenesis, inducing rapid and complete neoplastic transformation of the entire exocrine pancreas shortly after birth. HB-EGF overexpression and Kras(G12D) together, but neither alone, increased proliferation with increased cyclinD1 and decreased Cdkn2a/2d (p16/p19(Ink4A/Arf)). These findings establish the importance of oncogenic synergy in cancer initiation and promotion, and establish a molecular link between inflammation and the earliest stages of tumor induction.

Quantitative evaluation of MRI and histological characteristics of the 5xFAD Alzheimer mouse brain.

Assessment of ß-amyloid (Aß) plaque load in Alzheimer's disease by MRI would provide an important biomarker to monitor disease progression or treatment response. Alterations in tissue structure caused by the presence of Aß may cause localised changes that can be detected by quantitative T1 and T2 relaxation time measurements averaged over larger areas of tissue than that of individual plaques. We constructed depth profiles of the T1 and T2 relaxation times of the cerebral cortex with subjacent white matter and hippocampus in six 5xFAD transgenic and six control mice at 11 months of age. We registered these profiles with corresponding profiles of three immunohistochemical markers: ß-amyloid; neuron-specific nuclear protein (NeuN), a marker of neuronal cell load; and myelin basic protein (MBP), a marker of myelin load. We found lower T1 in the 5xFAD transgenic mice compared to wild type control mice at all depths, with maximum sensitivity for detection at specific layers. T1 negatively correlated with Aß staining intensity in the 5xFAD mice which had no changes in NeuN and MBP staining compared to wild type mice. We postulate that these relaxation time changes are due to the presence of ß-amyloid in the transgenic mice. It may be clinically feasible to develop a similar layered analysis protocol as a biomarker for Alzheimer's disease in humans.

Neuropathologic evidence of endothelial changes in cerebral small vessel disease.

OBJECTIVES: Cerebral small vessel disease (SVD) is common in aged brains and causes lacunar stroke, diffuse white matter lesions (leukoaraiosis), and vascular cognitive impairment. The pathogenesis is unknown. Endothelial dysfunction is a possible causal factor, and circulating markers of endothelial activation (intercellular adhesion molecule-1, thrombomodulin) and inflammation (interleukin [IL]-6) are elevated in patients with SVD. In this case-control study, we tested whether brain endothelial ICAM1, thrombomodulin, and IL-6 are altered in SVD. METHODS: We examined small penetrating cerebral arteries of pathologically diagnosed SVD cases, aged controls without SVD, young control cases with no brain pathology, and cases with early-onset hereditary SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]). All tissues had minimal cerebral amyloid angiopathy or other Alzheimer pathology. RESULTS: Thrombomodulin immunoreactivity was present in all aged SVD, aged control, and CADASIL cases, primarily in small artery endothelium. Thrombomodulin was augmented in aged SVD cases compared with aged controls (p = 0.012) and in vessels with higher sclerotic index (an indicator of SVD severity; p < 0.01). Thrombomodulin was sparse/absent in young controls. Endothelial ICAM1 and IL-6 were rarely seen, and were not related to SVD. CONCLUSIONS: Our data suggest that cerebral endothelial activation in deep penetrating arteries is not associated with SVD. Endothelial thrombomodulin increased with SVD severity, and CADASIL data suggest that this may be a cerebral response to SVD. Elevated thrombomodulin may be a protective agent in SVD. Our data confirm endothelial involvement in SVD.

Laing early onset distal myopathy: slow myosin defect with variable abnormalities on muscle biopsy.

BACKGROUND: Laing early onset distal myopathy (MPD1) is an autosomal dominant myopathy caused by mutations within the slow skeletal muscle fibre myosin heavy chain gene, MYH7. It is allelic with myosin storage myopathy, with the commonest form of familial hypertrophic cardiomyopathy, and with one form of dilated cardiomyopathy. However, the clinical picture of MPD1 is distinct from these three conditions. OBJECTIVE: To collate and discuss the histological features reported in the muscle biopsies of MPD1 patients and to outline the clinical features. RESULTS: The phenotype of MPD1 was consistent, with initial weakness of great toe/ankle dorsiflexion, and later development of weakness of finger extension and neck flexion. Age of onset was the only variable, being from birth up to the 20 s, but progression was always very slow. The pathological features were variable. In this retrospective series, there were no pathognomonic diagnostic features, although atrophic type I fibres were found in half the families. Rimmed vacuoles are consistently seen in all other distal myopathies with the exception of Myoshi distal myopathy. However, they were found in a minority of patients with MPD1, and were not prominent when present. Immunohistochemical staining for slow and fast myosin showed co-expression of slow and fast myosin in some type I fibres, possibly indicating a switch to type II status. This may be a useful aid to diagnosis. CONCLUSIONS: The pathological findings in MPD1 are variable and appear to be affected by factors such as the specific muscle biopsied, the age of the patient at biopsy, and the duration of disease manifestations.

Progressive myoclonus epilepsy with polyglucosans (Lafora disease): evidence for a third locus.

Lafora disease (LD) is the most common teenage-onset progressive myoclonus epilepsy. It is caused by recessive mutations in the EPM2A or EPM2B genes. The authors describe a family with three affected members with no mutations in either gene. Linkage and haplotype analyses exclude both loci from causative involvement in this family. Therefore, a third LD locus is predicted. Its identification will be a crucial element in the understanding of the biochemical pathway underlying the generation of Lafora bodies and LD.

Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular surface disease.

AIMS: To evaluate the efficacy of 50% autologous serum drops against conventional treatment in ocular surface disorders refractory to normal treatments in a prospective randomised crossover trial. METHOD: Patients fulfilling ophthalmological and haematological entry criteria were randomised to either 3 months of autologous serum 50% followed by 3 months of their conventional treatment, or 3 months of conventional treatment, followed by 3 months of autologous serum. Clinical assessments, including Schirmer's test, rose Bengal, and fluorescein staining, were carried out on entry and at monthly intervals. Impression cytology was performed at entry, 3 and 6 months. Grading was carried out on degrees of squamous metaplasia and goblet cell density. Subjective comfort was recorded daily using the "faces" scale. These categorical scores were converted to linear measurement using Rasch analysis. Statistical analysis was carried out using Wilcoxon's signed rank test and ANOVA. RESULTS: 16 patients were recruited with 31 eyes studied. The ocular surface diseases chiefly included Sjögren's syndrome (n = 6) and keratoconjunctivitis sicca (n = 5). Impression cytology available in 25 of 31 eyes showed significant improvement on serum treatment, p<0.02. Rasch weighted faces scores were statistically significantly better with serum, p<0.01. CONCLUSION: The results of this randomised study provide further evidence of the beneficial effects of autologous serum in severe ocular surface disorders. For most of these patients, autologous serum was superior to conventional treatment for improving ocular surface health and subjective comfort.

Epidemiology of central nervous system tumors in children and young adults (0-29 years), Yorkshire, United Kingdom.

The authors describe the incidence and survival of 480 patients diagnosed under 30 years with a CNS tumor in Yorkshire, UK, between 1990 and 2001. The effect on survival from deprivation and other prognostic factors was examined. Young adults (aged 15-29) were significantly less likely to develop CNS tumors than children (p = .001), largely because of an excess of medulloblastoma and ependymoma in the pediatric age range. No significant temporal trends in incidence were present apart from young adults with "other CNS" tumors showing an average annual increase of 10.7% (95% CI 1.3-21.0%; p = .03). Young adults had significantly lower survival rates than children (hazard ratio = 1.52, 95% CI 1.10-2.10). The highest risk of death was observed for patients from the most affluent areas. The overall burden of CNS tumors appears to be relatively constant, but the significantly poorer survival for young people needs further rapid investigation.

Neuromuscular hamartoma of the cochlear nerve: a rare occurrence in the internal auditory meatus.

The authors present a case of neuromuscular hamartoma of the cochlear nerve, an unusual occurrence in the internal auditory meatus (IAM). A review of the literature shows no previous report of neuromuscular hamartoma of the cochlear nerve. This tumour was clinically and radiologically difficult to distinguish from acoustic neuroma. It is important to consider the diagnosis of these rare small tumours pre-operatively, as it may be appropriate to manage this conservatively.

Tau, beta-amyloid and beta-amyloid precursor protein distribution in the entorhinal-hippocampal alvear and perforant pathways in the Alzheimer's brain.

It has been suggested that the pathological lesions of Alzheimer's disease (AD) spread along neuronal connections. This study was designed to examine this hypothesis in the alvear and perforant pathways, two well-defined neuroanatomical pathways that project from the entorhinal cortex to the hippocampus. Paraffin-sections of hippocampal-entorhinal cortex from 25 AD cases were immunolabelled for tau, beta-amyloid (Abeta) and beta-amyloid precursor protein (betaAPP). We used image-analysis to quantify immunolabelling at both ends of the alvear and perforant pathways. At the beginning and the end of the alvear pathway, area of immunolabelling in microm2 per area of field (72000 microm2) were as follows: tau 349 and 821 (P<0.01), Abeta 349 and 61 (P<0.05) and betaAPP 18 and 73 (P<0.01). Corresponding values for the perforant pathway were tau 421 and 387, Abeta 382 and 115 (P<0.05) and betaAPP 55 and 83. Tau was significantly greater at the end than at the beginning of the alvear pathway, but similar at both ends of the perforant pathway. There was significantly more Abeta at the beginning than at the end of the alvear and perforant pathway. These results at least in part reinforce previous work [19] that tau-rich areas may be neuronally connected to Abeta-rich areas.

Primary diffuse leptomeningeal gliomatosis predominantly affecting the spinal cord: case report and review of the literature.

Primary leptomeningeal gliomatosis is a rare, fatal neoplastic syndrome. A 71 year old man is reported on, who after a 2 month history of back stiffness, epigastric pain, and weight loss developed visual blurring. Cranial CT and MRI studies showed no leptomeningeal enhancement. Examination of CSF 10 weeks premortem showed an increase in protein and decrease in glucose but no malignant cells. He became increasingly confused and repeated CSF examination showed inflammation and a few suspicious cells but no definitive evidence of neoplasia. He died 7 months after onset of his initial symptoms. At postmortem meningeal whitening was seen at the base of the brain and over the spinal cord. Histology disclosed diffuse leptomeningeal gliomatosis (GFAP positive, cytokeratin negative) over the brain, optic nerves, and spinal cord without parenchymal involvement. No tumour was found in internal organs. The diagnosis of primary leptomeningeal gliomatosis was not evident after cranial CT and MRI and CSF examination premortem. Suspected cases need MRI scanning of the entire neuraxis and meningeal biopsy.

Inherited prion disease with an alanine to valine mutation at codon 117 in the prion protein gene.

A large English family with autosomal dominant segregation of presenile dementia, ataxia and other neuropsychiatric features is described. Diagnoses of demyelinating disease, Alzheimer's disease, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome have been attributed to particular individuals at different times. An Irish family, likely to be part of the same kindred, is also described, in which diagnoses of multiple sclerosis, dementia, corticobasal degeneration and new variant CJD have been considered in affected individuals. Molecular genetic studies have enabled the classification of this disease at the molecular level as one of the group of inherited prion diseases, with the substitution of valine for alanine at codon 117 of the prion protein gene (PRNP). Only three other kindreds have been described world-wide with this mutation and only limited phenotypic information has been reported. Here we describe the phenotypic spectrum of inherited prion disease (PrPA117V). The diversity of phenotypic expression seen in this kindred emphasizes the logic of molecular classification of the inherited prion diseases rather than classification by specific clinicopathological syndrome. Indeed, inherited prion disease should be excluded by PRNP analysis in any individual presenting with atypical presenile dementia or neuropsychiatric features and ataxia, including suspected cases of new variant CJD.

Correlation of survival time with size of axonal swellings in diffuse axonal injury.

Widespread damage to axons in the white matter of the brain is a well-recognised consequence of non-missile head injury. This diffuse axonal injury is characterised by a gradual swelling of the axon associated with an accumulation of cellular organelles and proteins. We have investigated the relationship between the size of the swellings of the damaged axon with survival time in post-mortem brain tissue. Sixty-six cases of head injury with known length of post-traumatic survival were selected for study, and immunohistochemistry for beta-amyloid precursor protein (betaAPP) was carried out. The minimum diameter of the betaAPP-immunolabelled damaged axons was measured in micrometers using the IBAS image analysis system. There was a strong, positive and significant relationship between the mean size of axonal swelling and survival time which plateaued at around 85 h post injury. With longer survival times the situation becomes more complex. betaAPP immunolabelling of damaged axons can contribute evidence about trauma and post-injury survival time in the forensic setting but should always be assessed with other evidence.

Malignant transformation in pleomorphic xanthoastrocytoma--a report of two cases.

Pleomorphic xanthoastrocytomas (PXA) with malignant transformation are reported in two adult men with a long history of seizures, recent onset of neurological symptoms and superficially located, temporal lobe lesions. Although PXA is generally described as having relatively benign behaviour, this report adds two further cases of malignant transformation to the literature.

Regional distribution of tau, beta-amyloid and beta-amyloid precursor protein in the Alzheimer's brain: a quantitative immunolabelling study.

Regional variation in the distribution of SP and NFT within the brain is well documented. Consideration of such variation is potentially of help in formulating models of disease progression. Several models propose that pathological changes in Alzheimer's disease (AD) progress in a step-wise fashion along neuronally connected regions. In this study, we measured tau, Abeta and betaAPP load in different brain regions and examined our results against models of AD progression. Blocks of brain tissue from 45 AD and 15 control cases were immunolabelled for tau, Abeta and betaAPP. Immunolabelled areas were measured as a proportion of the area of the field. Tau load was almost twice as great in the entorhinal cortex than elsewhere in the brain and was least in the cingulate gyrus. In contrast, Abeta was greatest in the cingulate gyrus and least in the entorhinal cortex. BetaAPP rankings were similar to those of tau. Thus the site with the greatest Abeta load (cingulate cortex) had the least tau and the site with the greatest tau load (entorhinal cortex) had the least Abeta. The entorhinal and cingulate cortex are neuronally interconnected. Our results might be explained on the basis that a neurone with its cell body in the entorhinal cortex and axonal terminals in the cingulate cortex shows predominately tau pathology in relation to the cell body and predominately Abeta pathology in relation to its axonal terminals. We conclude that our observations are consistent with previously described models of AD progression. It is possible that tau-rich neurones are associated through their projections to Abeta rich sites. Further work of this kind analysing differential pathological profiles in interconnected brain regions may contribute to refining this model.

Segregation of malignant hyperthermia, central core disease and chromosome 19 markers.

Malignant hyperthermia (MH) is an autosomal dominant disorder presenting under general anaesthesia. It is occasionally associated with a myopathy, central core disease (CCD), named after its predominant histochemical characteristic. The penetration of CCD is variable, but typically affected individuals show delayed motor milestones in infancy and remain physically compromised. It was thought until recently that individuals with CCD were always susceptible to MH. Individuals from eight CCD families were screened for the presence of 13 mutations in the skeletal muscle ryanodine receptor gene, reported previously to be associated with MH and/or CCD: none was detected. In seven of these families, where CCD and MH co-existed, we examined the segregation of CCD, MH susceptibility and chromosome 19q markers. In four families, there was complete co-segregation between MH, CCD and the chromosome 19 markers, but in one large pedigree there was a clear lack of segregation of CCD with either MH or chromosome 19 markers and there was no segregation between MH and these markers. This is unequivocal evidence that CCD, in common with MH, is genetically heterogeneous. In the two other families, CCD segregated with chromosome 19 markers but not all individuals with CCD were susceptible to MH. We recommend determination of MH susceptibility in all patients with CCD, irrespective of the MH status of their relatives with CCD.

Immunohistochemical analysis of cyclin A in astrocytic tumours.

Cyclins are important regulators of the cell cycle; there is increasing evidence that some cyclins are positively involved in carcinogenesis. Amplification and translocation of the cyclin genes and overexpression of their mRNAs and proteins have been observed in a variety of tumours. We studied cyclin A protein in astrocytic tumours by immunohistochemical analysis. Immunohistochemistry with microwave antigen retrieval was carried out on formalin fixed, paraffin embedded material from 15 glioblastomas (WHO grade IV), 10 anaplastic astrocytomas (WHO grade III), seven diffuse low grade astrocytomas (WHO grade II) and nine pilocytic astrocytomas (WHO grade I) using antibodies against cyclin A and a proliferation marker MIB1. Staining for these antibodies was seen mainly in the tumour cell nuclei; 66% of all cases showing staining for cyclin A and 95% of all cases staining for MIB1. Mean labelling indices (LI) for cyclin a were higher in glioblastoma (mean LI-6.7) and anaplastic astrocytoma (mean LI-5.9) than low grade diffuse astrocytoma (mean LI-1.7) and pilocytic astrocytoma (mean LI-0.12), although there was no clear cut off point between the various tumour types. A good correlation was seen between labelling indices of cyclin A and MIB1 (Pearson correlation coefficient r = 0.59, P < 0.0001). Cyclin A is variably expressed in astrocytic tumours, either reflecting increased tumour proliferation (cyclin A being an integral component of the cell cycle), an alteration of its gene, protein upregulation or regulation of apoptosis. The genetic basis of expression of cyclin A in astrocytic tumours remains to be determined.