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The learning system Thermopr@ctice represents an internet-based learning environment for calculating exercises using the computer algebra system Mathcad. This new working method for the learner consists of replacing the conventional paper worksheet with the Mathcad working screen. The exercises-here for those learning Technical Thermodynamics-are provided to the learner via the internet in individual variations and with individual numerical values in the Mathcad format. The exercises are solved during supervised seminars or on the computer at home. The teaching materials which are necessary for the solution are provided in Mathcad format. After calculating each subtask, the learner sends the solution to Thermopr@ctice. If an error occurs, the system will request interim results. The learning system takes the students closer to modern working methods in the workplace by using a computer algebra system and subject-related property libraries. Since the system has been designed for the purpose of self-study, it is particularly suitable for further education and distance learning. It can be applied to other subjects in which the acquisition or consolidation of knowledge takes place by calculating exercises. Thermopr@ctice was developed within the scope of the joint research project “Saxon Education Portal” from the Saxon Ministry of Science and Art and since then it has been continuously improved and enhanced.

To describe the clinical syndrome and diagnostic tests in patients with genetic prion diseases (gPD) in Germany. Clinical features, MRI, EEG, and CSF markers were studied in 91 patients (28 D178N, 20 E200K, 17 inserts, 13 V210I, 8 P102L, 5 E196K). Dementia (35 %) and ataxia (29 %) were the most common initial symptoms and signs. A wide variety and high frequency of neurological/psychiatric symptoms and signs was found during disease course in all patients independently of the type of the mutation. Psychiatric manifestations were frequent (87 %). Neuropsychological abnormalities were observed in 67 %, and aphasia was the most common disturbance (45 %). In E200K, V210I and D178N patients, visual/oculomotor deficits were followed by ataxia early in the disease. Dementia followed by ataxia at onset was common in patients with insert and E196K mutation. P102L patients had isolated ataxia over a longer time period followed by pyramidal signs. Dementia was present only late in the disease course. All clinical routine tests such as MRI, EEG and CSF tests were less sensitive than in sporadic CJD. We provide the first detailed analysis of clinical signs and symptoms in a large group of patients with gPD. Frequency of clinical symptoms and signs was similar in different mutations in a later disease course, but the sequence of occurrence may be of great diagnostic importance. CSF markers were shown to be more sensitive than MRI and EEG.

In suspected grade II gliomas, three distinct patterns of time-activity curves (TAC) on O-(2-[(18)F]fluoroethyl)-1-tyrosine ((18)F-FET) positron emission tomography (PET) have been delineated (i) increasing TAC homogeneously throughout the tumor, and decreasing TAC, (ii) either homogeneously throughout the tumor or (iii) only focally within otherwise increasing TAC patterns. Increasing TAC was associated with low-grade histology and decreasing TAC with high-grade histology. This prospective study analyzed whether these patterns correlate with distinct biological tumor subtypes and differential outcome. (18)F-FET PET-guided biopsies were used for stepwise histopathological evaluation. Molecular-genetic evaluation included O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, isocitrate dehydrogenase (IDH1/2) mutational and 1p/19q codeletion status. Progression-free survival (PFS) was estimated with the Kaplan-Meier method. Prognostic factors were obtained from multivariate regression models. 98 adult patients were included. Homogeneous increasing, focal decreasing and homogeneous decreasing TAC were seen in 51, 19 and 28 patients. The corresponding 1-year (2-years) PFS were 92% (85%), 89% (51%) and 50% (28%; p = 0.002). IDH1/2 mutations were more frequent in tumors with homogeneous increasing (90%) and focal decreasing (79%) TAC, but were rare in those exhibiting homogeneous decreasing TAC (25%; p < 0.001). Overall, TAC patterns, IDH1/2 mutational and 1p/19q codeletion status were powerful and independent prognostic factors. Dynamic (18)F-FET PET might be an important and independent imaging biomarker for patients with suspected WHO grade II gliomas and offers perspectives for stratified diagnostic and therapeutic strategies. Tumors with focal decreasing TAC need highly targeted surgical interventions to avoid undergrading and undertreatment.

A collaborative study of human transmissible spongiform encephalopathies has been carried out from 1993 to 2000 and includes data from 10 national registries, the majority in Western Europe. In this study, we present analyses of predictors of survival in sporadic (n = 2304), iatrogenic (n = 106) and variant Creutzfeldt-Jakob disease (n = 86) and in cases associated with mutations of the prion protein gene (n = 278), including Gerstmann-Sträussler-Scheinker syndrome (n = 24) and fatal familial insomnia (n = 41). Overall survival for each disease type was assessed by the Kaplan-Meier method and the multivariate analyses by the Cox proportional hazards model. In sporadic disease, longer survival was correlated with younger age at onset of illness, female gender, codon 129 heterozygosity, presence of CSF 14-3-3 protein and type 2a prion protein type. The ability to predict survival based on patient covariates is important for diagnosis and counselling, and the characterization of the survival distributions, in the absence of therapy, will be an important starting point for the assessment of potential therapeutic agents in the future.

To describe the first symptom/sign and first diagnosis in patients with sporadic Creutzfeldt-Jakob disease (sCJD) in Germany with respect to M129V polymorphism of the prion protein gene and prion protein type. Data on the first symptom/sign and first diagnosis were studied in 492 sCJD patients with probable and definite sCJD and known M129V polymorphism. Unspecific prodromal symptoms such as headache, fatigue, sleep disturbances, 'peculiar feeling in the head', photophobia or weight loss were found in about 10 % of the patients. No prodromal symptoms were found in MV2 and VV1 patients. Dementia was the most common first symptom (37 %) followed by cerebellar (34 %), visual (15 %), and psychiatric disturbances (14 %). The CJD diagnosis was the first diagnosis in only 35 % of the patients (in 42 % of MM, 28 % of MV, and 24.5 % of VV patients). We provide a detailed analysis on clinical presentation and first diagnosis in a large group of patients with sCJD with respect to M129V genotype and prion protein type. These data emphasize the importance of knowledge about CJD and especially rare CJD types among physicians of different specializations. Our findings may improve early recognition of atypical CJD forms.

Neurodegenerative disease is a general designation for the disorders that are progressive loss of structure or function and final death of neurons, including Alzheimer's, Parkinson's, Huntington's, prion diseases, etc. In this study, we comparatively analyzed 21 individual microarray data sets of the cortex tissues from 11 sporadic Creutzfeldt-Jakob disease (sCJD), 3 fatal familial insomnia (FFI), 3 Alzheimer's disease (AD), and 4 normal controls. After normalization, a collection of 730 differently expressed sets (DESets) were obtained by comparison of the data of three diseases with their original controls. Principal component analysis (PCA) showed a background-related distribution within the groups of FFI, AD, and normal control, but two apparently different subgroups within the group of sCJD were observed. Review of the clinical materials of 11 sCJD patients identified the difference in brain PrP(Sc) deposits between two subgroups. Hierarchical cluster analysis illustrated the relatively independent clusters of normal controls, FFIs, six sCJD cases (subgroup 1) with more PrP(Sc) deposits, respectively, while an overlapped cluster of five cases of sCJD2 (subgroup 2) with less PrP(Sc) deposits and AD patients. Despite of the presence of special gene expressions, many common features were found among those neurodegenerative diseases. The most commonly changed biological processes (BPs) were signal transduction, synaptic transmission, and neuropeptide signaling pathway. The most commonly changed pathways were MAPK signaling pathway, Parkinson's disease, and oxidative phosphorylation. Our data here provide the similarity and difference in global gene expressions among the patients with sCJD, FFI, and AD, which may help to understand the common mechanism of neurodegenerative diseases.

Object Chordomas of the skull base are rare and locally invasive and have a poor prognosis. The aim of this retrospective multicenter study was to evaluate the current pattern of care and clinical course and to identify prognostic factors. Methods A total of 47 patients (26 men; mean age 48.5 years) treated in 5 centers were included. Histology was centrally reviewed; additionally, semiquantitative N- and E-cadherin expression analysis was performed. Prognostic factors were obtained from multivariate regression models. For survival analysis the Kaplan-Meier method was used. Results The median follow-up period was 5.2 years. Complete resection, incomplete resection, and extended biopsy were performed in 14.9%, 80.9%, and 4.3% of patients, respectively. Surgical morbidity was not associated with extent of resection. Adjuvant radiation therapy was performed in 30 (63.8%) of 47 patients. The median progression-free survival (PFS) was 7.3 years. Complete resection prolonged median overall survival (OS) (p = 0.04). Male patients presented with worse PFS (4.8 years vs 9.8 years; p = 0.04) and OS (8.3 years vs not reached; p = 0.03) even though complete resection was exclusively achieved in the male subpopulation. Multivariate analysis confirmed male sex as the most important risk factor for tumor progression (p = 0.04) and death (p = 0.02). Age, duration of symptoms, initial Karnofsky Performance Scale score, brainstem compression, involvement of the petrous bone, infiltration of the dura mater, modality and dose of radiation therapy, and the E- and N-cadherin expression patterns did not gain prognostic relevance. Conclusions In skull base chordomas, male patients bear a higher risk of progressive disease and death. Male patients might benefit from more aggressive adjuvant therapy and/or from a closer follow-up schedule.

In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10–12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies. All molecular stereotactic biopsies were performed according to a detailed workflow. The selection of specimens best suited for molecular analyses was intra-operatively guided by the attending neuropathologist. Postoperative screening was done by methylation specific PCR using two distinct cryopreserved specimens to test for reproducibility of the findings and to rule out contamination. The DNA of a single best-suited specimen (1 mm3) was subjected to detailed molecular analysis (MGMT promoter methylation, IDH1/2 mutational status, LOH 1p and/or 19q). 159 consecutively enrolled untreated gliomas were analyzed (94 glioblastomas, 2 gliosarcomas, 24 anaplastic astrocytomas, 10 oligo-tumors grade II/III, 20 grade II astrocytomas and 9 pilocytic astrocytomas). Transient morbidity was 2 %. Overall, the drop-out rate due to tissue contamination was 0.4 %. Median time from biopsy to histological and molecular genetic analyses was 3 and 5 days, respectively. Distributions of the respective biomarker status for tumor subgroups were consistent with the literature. The final histological diagnosis was changed/modified in 5/159 patients according to molecular findings. Treatment after molecular biopsy was highly personalized. Molecular stereotactic biopsy is feasible and safe, can be implemented in daily clinical practice, improves diagnostic precision and enables personalized treatment.

Hereditary diffuse leukencephalopathy with spheroids (HDLS) is a rare progressive form of leukodystrophy with variable clinical presentation and little known pathophysiology. Characteristic pathological features at brain biopsy or postmortem can support the diagnosis. The genetic basis of HDLS was elusive until 2011 when mutations in the colony-stimulating factor 1 receptor (CSF1R) gene were identified as the cause. Mutations in the CSF1R gene had previously been associated with tumor development, including hematological malignancies. We report three patients with HDLS who carried missense mutations in the CSF1R gene, two of them novel (p.L582P and p.V383L). Particularly in younger patients with rapid cognitive decline and/or leukencephalopathy of unknown origin, HDLS appears to be more common than previously thought. Various compounds acting on the CSF1 receptor are available from the treatment of hemato-oncological malignancies, so novel therapeutic approaches could be developed for this devastating condition.

Summary Brain banks are used to gather, store, and provide human brain tissue for research and have been fundamental to improving our knowledge of the brain in health and disease. To maintain this role, the legal and ethical issues relevant to the operations of brain banks need to be more widely understood. In recent years, researchers have reported that shortages of high-quality brain tissue samples from both healthy and diseased people have impaired their efforts. Closer collaborations between brain banks and improved strategies for brain donation programmes will be essential to overcome these problems as the demand for brain tissue increases and new research techniques become more widespread, with the potential for substantial scientific advances in increasingly common neurological disorders.

Background: Parkinsonism with dopa-sensitivity and a correlating DaTSCAN turned out to be due to a D202N mutation which is associated with Gerstmann-Straussler-Scheinker (GSS) disease. Methods/Results: We report a 51-year old female who presented with left-dominant parkinsonism and a positive DaTSCAN. She was diagnosed with idiopathic Parkinson's syndrome. Dopaminergic medication reduced her symptoms. In addition, punding-like behavior, deficits in organizing daily life and abnormal sleep behavior were reported. Neuropsychological testing, EEG, polysomnography as well as PET imaging with fluorodexyglucose (FDG), [F-18]-desmethoxyfallypride (DMFP), and [C-11]-6-OH-BTA-1 (PIB) were not diagnostic. Cerebral spinal fluid analysis revealed no 14-3-3 protein, but elevated neuron-specific enolase (NSE) and S100-beta and a very low phospho-tau/total-tau ratio. Analysis of the prion gene disclosed the rare D202N mutation. Conclusions: The D202N prion mutation has been associated with GSS pathology and up to now was only reported post mortem. Our patient is the very first case diagnosed in vivo. © 2013 Movement Disorder Society

Magnetic resonance imaging (MRI), with diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR), is a useful diagnostic investigation for Creutzfeldt-Jakob disease (CJD). Amendment of the diagnostic criteria for sporadic CJD (sCJD) to include defined MRI alterations has just recently been proposed. We analyzed MRI scans with FLAIR and/or DWI available of 29 patients with the E200K or the V210I mutation, and a control group of 29 sCJD patients to compare the MRI lesion profile and evaluate the applicability of new MRI criteria to genetic CJD patients. FLAIR images of all 29 patients and controls and DWI images of 15 genetic CJD and 13 sCJD were rated by 2 neuroradiologists blinded to diagnosis and genetic testing. In genetic CJD (gCJD) patients, hyperintensities on FLAIR could be found in the putamen in 55% and the caudate nucleus in 66% and on DWI in 33% and 60%, respectively. Lesion profile and frequency of hyperintensities did not differ significantly from the findings in sCJD. New diagnostic MRI criteria yield similar sensitivity for gCJD and sCJD, being 79% and 72%, respectively. MRI provides useful information in E200K and V210I gCJD patients. The alterations strongly resembled those seen in sCJD, once again demonstrating the similarity of the clinical syndrome in patients with these particular mutations.

Autopsy is the diagnostic gold standard for progressive supranuclear palsy (PSP). The National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP) criteria for the clinical diagnosis of probable PSP are thought to possess high specificity and low sensitivity. The NINDS-SPSP criteria for possible PSP are considered to increase sensitivity at the expense of specificity. The Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) criteria are intended to improve sensitivity while maintaining high specificity. The aim of this study was to conduct a clinicopathological evaluation of the NINDS-SPSP and NNIPPS criteria in tertiary neurological centers. Defined clinical features and their year of onset were recorded by chart review in neuropathologically diagnosed patients with PSP, Parkinsons's disease (PD), MSA parkinsonism and corticobasal degeneration from four European brain banks. Fulfilment of the clinical diagnostic criteria was verified for each year after disease onset and for the final antemortem record. We analyzed 98 PSP patients and 46 disease controls. The NINDS-SPSP probable criteria yielded shorter time to diagnosis, slightly higher specificity and positive predictive value (PPV), and similar sensitivity, compared with the NNIPPS criteria. Unexpectedly, the NINDS-SPSP possible criteria yielded the lowest sensitivity, specificity, and PPV. A combination of NINDS-SPSP possible and probable criteria yielded the highest sensitivity. We suggest that the NINDS-SPSP probable criteria might be preferred for recruitment of patients for clinical trials, where an early and specific diagnosis is important. For routine clinical care, where high sensitivity is crucial, a combination of NINDS possible and probable criteria might be preferred. (c) 2013 Movement Disorder Society

Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.

A 31-year-old man presented to his local hospital in Germany with subacute holocephalic headaches and bilateral retro-orbital pain with blurry vision and soon developed clumsiness in his right hand. Neurologic examination revealed mild upper motor neuron weakness of the right arm with impaired fine motor movements and increased muscle tendon reflexes. Examination of cranial nerves and sensation was normal. Physical examination and his past medical history were unremarkable. He smoked cigarettes, consumed alcohol infrequently, and denied any medication or drug abuse. He worked in the passenger security check at Munich airport. His family history was significant only for migraine headaches. Brain MRI showed a single tumor-like, contrast-enhancing lesion in the left paramedian midbrain (figure, A) with prominent perifocal edema and slight compression of the third ventricle. Chest radiography and abdominal ultrasound were normal. Blood tests revealed slightly elevated liver enzymes (alanine aminotransferase 55 U/L [normal

BACKGROUND: The favorable prognostic impact of mutations in the IDH1 gene is well documented for malignant gliomas; its influence on World Health Organization (WHO) grade II astrocytomas, however, is still under debate. METHODS: A previously published database of 127 predominantly surgically treated patients harboring WHO grade II astrocytomas was revisited. Patients were screened for TP53 mutations (sequencing analysis), IDH1 mutations (pyrosequencing), and MGMT promoter methylation (methylation-specific polymerase chain reaction and bisulfite sequencing). Endpoints were overall survival, progression-free survival (PFS), time to malignant transformation, and postrecurrence survival. Radiotherapy was usually withheld until tumor progression/malignant transformation occurred. RESULTS: IDH1 mutations, TP53 mutations, and methylated MGMT promoters were seen in 78.1%, 51.2%, and 80.0% of the analyzed tumors, respectively. IDH1 mutations, which were significantly associated with TP53 mutations and/or MGMT promoter methylation (P < .001), resulted in shortened PFS (median, 47 vs 84 months; P = .004); postrecurrence survival, however, was significantly increased in those patients undergoing malignant transformation (median, 49 vs 13.5 months; P = .006). Overall survival was not affected by IDH1. A similar pattern of influence was seen for MGMT promoter methylation. Methylated tumors did significantly worse (better) in terms of PFS (postrecurrence survival); a low number of unmethylated tumors, however, limited the power of this analysis. Conversely, TP53 mutations were stringently associated with a worse prognosis throughout the course of the disease. CONCLUSIONS: IDH1 mutations are associated with a Janus headlike phenomenon; unfavorable prognostic influence on PFS turns into favorable impact on postrecurrence survival. A similar pattern of influence might exist for MGMT methylation. Cancer 2011;. © 2011 American Cancer Society.

Department of Neurology, Ludwig-Maximilians-Universitat, Munich, Germany Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universitat, Munich, Germany Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tubingen, Germany German Research Center for Neurodegenerative Diseases (DZNE), University of Tubingen, Germany CeGaT GmbH, Center for Genomics and Transcriptomics, Tubingen, Germany Department of Neurosurgery, Ludwig-Maximilians-Universitat, Munich, Germany Department of nuclear medicine, Ludwig-Maximilians-Universitat, Munich, Germany Department of Neuroradiology, Ludwig-Maximilians-Universitat, Munich, Germany Department of Child Neurology, VU Medical Center, Amsterdam, The Netherlands German Research Center for Neurodegenerative Diseases (DZNE), Ludwig-Maximilians-Universitat, Munich, Germany

The kinetics of amyloid plaque formation and growth as one of the characteristic hallmarks of Alzheimer’s disease (AD) are fundamental issues in AD research. Especially the question how fast amyloid plaques grow to their final size after they are born remains controversial. By long-term two-photon in vivo imaging we monitored individual methoxy-X04-stained amyloid plaques over 6 weeks in 12 and 18 months old Tg2576 mice. We found that in 12 months old mice, newly appearing amyloid plaques were initially small in volume and subsequently grew over time. The growth rate of plaques was inversely proportional to their volume; thus amyloid plaques that were already present at the first imaging time point grew over time but slower compared to new plaques. Additionally, we analyzed 18 months old Tg2576 mice in which we neither found newly appearing plaques nor a significant growth of pre-existing plaques over 6 weeks of imaging. In conclusion, newly appearing amyloid plaques are initially small in size but grow over time until plaque growth can not be detected anymore in aged mice. These results suggest that drugs that target plaque formation should be most effective early in the disease, when plaques are growing. Electronic supplementary material The online version of this article (doi:10.1007/s00401-010-0787-6) contains supplementary material, which is available to authorized users.

Patients with non-resectable glioblastoma generally exhibit a poor prognosis, even after radiotherapy plus concomitant and adjuvant temozolomide (XRT/TMZ→TMZ). Unfortunately, no data are available concerning the predictive value of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation for this important subpopulation. For clarification, a prospective study was conducted.Adult patients with a non-resectable glioblastoma were included. A molecular stereotactic biopsy technique was used for tumour characterisation combining histopathological diagnosis with small sample size adjusted methylation-specific PCR (MSP) and sodium bisulfite sequencing. Treatment included XRT (60 Gy in 30 fractions)/TMZ (daily dose of 75 mg/m(2))→TMZ (150-200 mg/m(2) per day for 5 days of every 28-day cycle). The primary end point was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and treatment response (TR). Patients were categorised in the Radiation Therapy Oncology Group (RTOG)-recursive partitioning analysis (RPA) Classes III (N=4), IV (N=12), V (N=28) and VI (N=12).The success rates of MSP and sequence analyses were 100%. The MGMT promoter was methylated in 30/56 tumours, which was associated with an increased PFS (median 56 versus 20 weeks; hazard ratio 0.15; range 0.07 to 0.33; p0.0001), higher frequency of TR (93.3% vs 46.2%; p=0.0008) and increased OS (median 104 vs 28 weeks; hazard ratio 0.18; range 0.08 to 0.38; p0.0001). The transient perioperative morbidity was 1.8%.MGMT promoter methylation has a predominant favourable influence even for the important subpopulation with non-resectable glioblastoma. The molecular stereotactic biopsy technique is safe and effective for predictive evaluation and helps to avoid both over- and undertreatment.

At present there is no routinely available decontamination procedure in washer-disinfectors to allow the reliable inactivation and/or elimination of prions present on reusable surgical instruments. This means that is not possible to provide assurance for preventing iatrogenic transmission of prion diseases. We need effective procedures in prion decontamination that can be integrated into the usual routine of reprocessing surgical instruments. This article reports on the evaluation of an automated process designed to decontaminate prions in washer-disinfectors using a quantitative, highly sensitive in vivo assay for surface-adherent 22L prions. The automated process showed great advantages when compared with conventional alkaline cleaning. In contrast, the new process was as effective as autoclaving at 134 degrees C for 2h and left no detectable prion infectivity, even for heavily contaminated surfaces. This indicates a reduction of surface-adherent prion infectivity of >7 log units. Due to its compatibility with even delicate surgical instruments, the process can be integrated into the large scale reprocessing of instruments in a central sterile supply department. The system could potentially make an important contribution to the prevention of iatrogenic transmission of prions.

Progressive multifocal leukoencephalopathy (PML) is a subaute encephalitis caused by the JC polyomavirus almost always in atients with severe cellular immune deficiency, nowadays most requently in patients with human immunodeficiency virus (HIV) nfection or recently as a complication of Natalizumab treatment or Multiple Sclerosis. Occasionally cases in immunocompetent atients have been reported. MRI displays a typical pattern of ultiple subcortical areas of high signal on FLAIR images in both emispheres. Single cases of purely infratentorial involvement ave been reported but are very infrequent [1]. Here we report a ase of primary brainstem involvement of PML in an immunocometent patient with a deleterious course and negative JC-virus but ositive BK-virus PCR in the CSF. The use and findings of PET-MRI re discussed.

There is growing evidence that GVHD affects the central nervous system (CNS). In this study, we describe the long-term follow-up of four allogeneic BM recipients who developed cerebral angiitis-like disease probably due to GVHD. The patients developed focal neurological signs, cognitive deficits and/or coma in association with GVHD, 2-18 years after transplantation, following reduction of immunosuppressive therapy. Magnetic resonance imaging was variable, showing generalized brain atrophy, ischemic lesions or leukoencephalopathy. Diagnosis of cerebral angiitis was confirmed by histopathological analysis of bioptic brain tissue and response to immunosuppressive therapy. By means of immunohistochemistry and immunofluorescence, perivascular lymphomononuclear cerebral infiltrates were shown to express the adhesion receptor, CD11a, and the chemokine receptor, CCR5. Our findings imply that GVHD should be considered in the differential diagnosis of noninfectious angiitis-like disease of the CNS in long-term survivors after allogeneic BMT. Infiltrating cells, in analogy to typical target organs of GVHD such as skin or liver, expressed CD11a and CCR5. These findings could be of etiopathological, diagnostic and therapeutic relevance.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson–dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Brain banks collect post-mortem human brains to foster research into human CNS function and disease. They have been indispensable for uncovering the secrets of many diseases, including Alzheimer's and Parkinson's. At a time when there are so many open questions in neuroscience and the incidence of brain diseases continues to increase in parallel with the aging of the population, brain banking remains at the heart of brain research. However, the major source of brain banks, the clinical autopsy, is rapidly falling into limbo. New strategies, including donor programmes, medico-legal autopsies and banking in networks, as well as fresh considerations of the ethics and public relations, are required.

Because accumulation of alpha-synuclein (alphaS) in the brain is a hallmark of Parkinson disease (PD) and related disorders, we examined its occurrence in human cerebrospinal fluid (CSF). Following affinity enrichment and trypsin digestion of CSF collected from a neurologically healthy donor, we identified several alphaS-derived peptides by mass spectrometry. The concentration of alphaS amounted to

Object Creutzfeldt–Jakob disease (CJD) is a rare neurodegenerative disorder with diagnostic criteria defined as a combination of clinical symptoms, electroencephalography findings, cerebrospinal fluid (CSF) analysis, and MR imaging results. Special subtypes are known to present with an atypical course and test findings that can complicate the clinical diagnosis. In such patients a brain biopsy can support the clinical approach. Methods The authors studied the records on 26 brain biopsies conducted in patients with suspected CJD who had been referred to the CJD Surveillance Unit in Germany between 1993 and 2005. Results Of the 26 included patients, 11 suffered from neuropathologically confirmed CJD, which in 5 cases had been deemed clinically “probable” and in 2 had been deemed “possible.” The disease in the remaining 4 patients had been categorized as “other” prior to neuropathological confirmation of CJD. The results of 15 brain biopsies showed no features of prion disease. None of these 15 patients had received a probable diagnosis of CJD, 4 had a possible diagnosis, and 11 had received a diagnosis of “other.” Three of the cases classified as other and none of those with CJD presented with pleocytosis in the CSF. In 73% of the other cases, biopsy sampling did not reveal any results characteristic of CJD but did not provide specific findings on which to base a differential diagnosis. Autopsy confirmed the biopsy diagnosis of CJD in all cases, and additionally confirmed that CJD was not present in 3 patients who had nondiagnostic biopsy results. Conclusions Biopsy sampling may be helpful in the diagnostic approach to rare cases of dementia for which a reliable diagnosis cannot be established on the basis of clinical symptoms, CSF parameters, electroencephalography, and MR imaging results.

So far only the detection of 14-3-3 proteins in cerebrospinal fluid (CSF) is included in the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD). However, this assay cannot be used for screening because of the high rate of false positive results in sCJD, and often negative results in variant CJD. To facilitate the differential diagnosis of CJD, we applied 2-D differential gel-electrophoresis (2-D DIGE) as a quantitative proteomic screening system for CSF proteins. We compared 36 patients suffering from sCJD with 30 patients suffering from other neurodegenerative diseases. Sample preparation was optimized in consideration of the fact that CSF is composed of blood- and brain-derived proteins, and an improved 2-D DIGE protocol was established. Using this method in combination with protein identification by MALDI-TOF-MS, several known surrogate markers of sCJD like 14-3-3 protein, neuron-specific enolase, and lactate dehydrogenase were readily identified. Moreover, a not yet identified protein with an approximate molecular mass of 85 kDa was found as marker for sCJD with high diagnostic specificity and sensitivity. We conclude that our proteomic approach is useful to differentiate CJD from other neurodegenerative diseases and expect that CSF-optimized 2-D DIGE will find broad application in the search for other brain derived proteins in CSF.

The audience for this paper includes researchers, educators, and engineers in the fields of air conditioning, atmospheric physics, meteorology, psychrometrics, standards, and thermodynamics. This paper provides a brief history of the molar mass of dry air, Mda, followed by the composition of Earth's atmosphere for the year 2008 and the calculation of Mda. A single equation is given to calculate Mda based on the actual abundance of CO2 in the atmosphere, which is currently increasing at an annual rate of 1.9 imol·mol−1. This causes an increase in the value of Mda at a rate of 0.0001 kg·kmol−1 (lb·lbmol−1) for every 8.33 imol·mol−1 increase in the abundance of CO2. It is practical for many calculations to use the average projected Mda value over a period of a half-century, during which time the value of Mda will increase by approximately 0.0010 kg·kmol−1 (lb·lbmol−1). For most psychrometric calculations, the authors recommend an Mda value of 28.966 kg·kmol−1 (lb·lbmol−1), which is projected for the year 203...

Background and purpose: To establish radiological features in the atypical MV2 subtype of sCJD compared with the classical MM1 subtype, as well as region- and sequence-dependent inter-observer correlation. Methods: MRI hyperintensity of basal ganglia (BG), cortex and thalamus was evaluated in 31 MM1 and 32 MV2 patients. Each MR scan was analyzed independently by two neuroradiologists blinded to PRNP genotype/prion protein type. Results: Cumulative T2-sensitivity for BG hyperintensity was higher in the MV2 subtype (84% for both observers versus 61% in observer 1/42% in observer 2 in MM1 patients). Significant inter-observer agreement was found for BG and thalamus on T2, FLAIR, PD and DWI, but for cortex only on DWI. Thalamic changes were significantly more frequent in MV2 than in MM1 patients (cumulative sensitivity 86% vs. 12.5% on DWI). Discussion: The high frequency of thalamic hyperintensity in the MV2 subtype allowed differentiation from MM1 patients. Good inter-observer agreement was found for BG and thalamus in all sequences. DWI showed the highest inter-observer correlation independent of the investigated brain region and was therefore not only highly sensitive but also relatively independent of investigator bias. Since inter-observer correlation for cortical hyperintensity in T2, FLAIR and PD is relatively low, the cortical changes should not be over-interpreted with these sequences.

Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.

Background Prospective epidemiological studies are being employed to determine the incidence and possible risk factors of Creutzfeldt-Jakob disease (CJD) in five European countries in which bovine spongiform encephalopathy (BSE) occurs at different rates of incidence. Patients and methods Using a voluntary reporting system throughout the Federal Republic of Germany, suspected cases of CJD were investigated and the incidence calculated. Possible risk factors in patients and control groups were obtained by questionnaire. Serum and cerebrospinal fluid samples served to delineate genetic forms and distinguish the disease from other major dementias. Results A total of 544 patients with suspected CJD, reported in Germany between 1993 and 1997, were examined. 232 (plus 27 investigated only neuropathologically) were confirmed as definite or probable, an annual incidence per million population of between 0.76 (for 1994) and 0.98 (for 1995), similar to figures from other European countries. In Great Britain, the cases of "new variant" CJD, not yet observed in Germany, were excluded from the calculation of incidence. So far, dementia in the family and handling of horn shavings have been identified as risk factors. A rise in the concentrations of neurone-specific enolase and of S100 protein as well as the demonstration of certain proteins in cerebrospinal fluid (p130/ 131 and 14-3-3, respectively) have been shown as being diagnostically superior to EEG changes. Interpretation There has so far been no increase in the incidence of CJD within Europe. However, the occurrence of the new variant in Great Britain requires long-term monitoring. The diagnostic criteria used for this can be improved by biochemical methods.

Treatment and prognosis of gliomas depend on their histological tumour grade. The aim of the study was to evaluate the potential of [(18)F]fluoroethyltyrosine (FET) PET for non-invasive tumour grading in untreated patients.Dynamic FET PET studies were performed in 54 patients who, based on MRI, were estimated to have low grade (LG; n = 20), intermediate (WHO II-III; n = 4) or high grade (HG; n = 30) tumours. For standard evaluation, tumour SUV(max) and the ratio to background (SUV(max)/BG) were calculated (sum image: 20-40 min). For dynamic evaluation, mean SUV values within a 90% isocontour ROI (SUV90) and the SUV90/BG ratios were determined for each time frame to evaluate the course of FET uptake. Results were correlated with histopathological findings from PET-guided stereotactic biopsies.Histology revealed gliomas in all patients. Using the standard method a statistically significant difference (p = 0.001) was found between LG (n = 20; SUV(max)/BG: 2.16 +/- 0.98) and HG (n = 34; SUV(max)/BG: 3.29 +/- 1.06) gliomas (opt. threshold 2.58: SN71%/SP85%/area under ROC curve [AUC]:0.798), however, with a marked overlap between WHO II to IV tumours. Time activity curves showed slight increase in LG, whereas HG tumours presented with an early peak (10-20 min) followed by a decrease. Dynamic evaluation successfully separated LG from HG gliomas with higher diagnostic accuracy (SN94%/SP100%/AUC:0.967).Based on the ratio-based method, a statistically significant difference was found between LG and HG gliomas. Due to the interindividual variability, however, no reliable individual grading was possible. In contrast, dynamic evaluation allowed LG and HG gliomas to be differentiated with high diagnostic power and, thus, should supplement the conventional method.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare transmissible disease caused by accumulation of pathological prion protein (PrP(sc)) in the CNS. According to the codon 129 polymorphism (methionine or valine) and the prion protein type 1 or 2, a classification into distinct subtypes was established. Further analysis of these subtypes detected atypical clinical forms with longer disease duration or younger age at onset. The CJD subtype influences sensitivity of the technical investigations such as 14-3-3 in CSF, periodic sharp wave complexes in the EEG or hyperintense basal ganglia in MRI. A further characterization of these subtypes is important for reliable diagnosis and identification of rare disease variants. The aim is to establish specific patterns of test results and clinical findings. These improvements in diagnostics may be the reason for the apparent increase in sCJD incidence in Germany from 0.9 in 1994 to 1.6 in a million in 2005. Despite careful surveillance, no patient with variant CJD has been detected to date in Germany. Here we present the data of the CJD surveillance of the last 13 years. Additionally, the improvements in diagnostics and differential diagnosis are discussed.

Objective Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies. We recently identified TDP-43 as the major pathological protein in sporadic ALS. In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations. Methods Ubiquitin and TDP-43 immunohistochemistry was performed on postmortem tissue from sporadic ALS (n = 59), ALS with SOD1 mutations (n = 15), SOD-1–negative FALS (n = 11), and ALS with dementia (n = 26). Biochemical analysis was performed on representative cases from each group. Results All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43. Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43. Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations. Interpretation These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS. Ann Neurol 2007;61:427–434

Background: The measurement of biomarkers in cerebrospinal fluid (CSF) has gained increasing acceptance in establishing the diagnosis of some neurodegenerative diseases. Heart-type fatty acid-binding protein (H-FABP) was recently discovered in CSF and serum of patients with neurodegenerative diseases. Objective: We investigated H-FABP in CSF and serum alone and in combination with CSF tau protein to evaluate these as potential biomarkers for the differentiation between dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Methods: We established H-FABP and tau protein values in a set of 144 persons with DLB (n = 33), Parkinson disease with dementia (PDD; n = 25), AD (n = 35) and nondemented neurological controls (NNC; n = 51). Additionally, serum H-FABP levels were analyzed in idiopathic Parkinson disease patients without evidence of cognitive decline (n = 45) using commercially available enzyme-linked immunosorbent assays. We calculated absolute values of H-FABP and tau protein in CSF and serum and established relative ratios between the two to obtain the best possible match for the clinical working diagnosis. Results: Serum H-FABP levels were elevated in DLB and PDD patients compared with NNC and AD subjects. To better discriminate between DLB and AD, we calculated the ratio of serum H-FABP to CSF tau protein levels. At the arbitrary chosen cutoff ratio ≧8 this quotient reached a sensitivity of 91% and a specificity of 66%. Conclusion: Our results suggest that the measurement of CSF tau protein, together with H-FABP quantification in serum and CSF, and the ratio of serum H-FABP to CSF tau protein represent marker candidates for the differentiation between AD and DLB.

The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

Accurate simulations of non-stationary processes in steam turbines by means of Computational Fluid Dynamics (CFD) require precise and extremely fast algorithms for computing real fluid properties. To fulfill these requirements, the International Association for the Properties of Water and Steam (IAPWS) issues the “Guideline on the Fast Calculation of Steam and Water Properties with the Spline-Based Table Look-Up Method (SBTL)” as an international standard. Through the use of this method, spline functions for the independent variables specific volume and specific internal energy (v,u) are generated for water and steam based on the industrial formulation IAPWS-IF97. With these spline functions, thermodynamic and transport properties can be computed. The desired backward functions of the variables pressure and specific volume (p,v), and specific internal energy and specific entropy (u,s) are numerically consistent with the spline functions from (v,u). The properties calculated from these SBTL functions are in agreement with those of IAPWS-IF97 within a maximum relative deviation of 10 to 100 ppm depending on the property and the range of thermodynamic states spanned under the given conditions (range of state). Consequently, the differences between the results of process simulations using the SBTL method and those obtained through the use of IAPWS-IF97 are negligible. Moreover, the computations from the (v,u) spline functions are more than 200 times faster than the iterative calculations with IAPWS-IF97. In order to demonstrate the efficiency and applicability of the SBTL method, the SBTL functions have been implemented into the CFD software TRACE, developed by the German Aerospace Center (DLR). As a result, the computing times required for the simulations of steam flow in a turbine cascade considering real fluid behavior are reduced by a factor of 6–10 in comparison to the calculations based on IAPWS-IF97. Furthermore, computing times are increased by a factor of 1.4 only with respect to CFD calculations where steam is considered to be an ideal gas, through the use of the SBTL method.

Presenilin 1 (PSEN1) mutations are the major cause of autosomal dominant Alzheimer's disease (ADAD). Here we report three novel PSEN1 mutations: Ile238_Lys239insIle, Ala246Pro and Ala164Val from patients who manifested in their twenties, forties and seventies, respectively, with variant clinical presentations of dementia. These cases exemplify the tremendous heterogeneity of clinical phenotypes and age of onset associated with PSEN1 mutations. The possibility of ADAD--not previously suspected in two of our patients--should always be considered in neurodegenerative conditions albeit they might neither exhibit the typical clinical picture of Alzheimer's disease nor early onset dementia, which is regarded the primary clinical sign of hereditary neurodegeneration.

Ubiquitin-positive, tau- and α-synuclein–negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

Assessment of Alzheimer's disease (AD)-related neurofibrillary pathology requires a procedure that permits a sufficient differentiation between initial, intermediate, and late stages. The gradual deposition of a hyperphosphorylated tau protein within select neuronal types in specific nuclei or areas is central to the disease process. The staging of AD-related neurofibrillary pathology originally described in 1991 was performed on unconventionally thick sections (100 mum) using a modern silver technique and reflected the progress of the disease process based chiefly on the topographic expansion of the lesions. To better meet the demands of routine laboratories this procedure is revised here by adapting tissue selection and processing to the needs of paraffin-embedded sections (5-15 mum) and by introducing a robust immunoreaction (AT8) for hyperphosphorylated tau protein that can be processed on an automated basis. It is anticipated that this revised methodological protocol will enable a more uniform application of the staging procedure.

This interlaboratory study evaluated the reproducibility of the assessments of neuritic plaques and neurofibrillary tangles (NFTs)-the hallmark lesions of Alzheimer disease-and compared the staining between the BrainNet Europe centers. To reduce the topography-related inconsistencies in assessments, we used a 2-mm tissue microarray (TMA) technique. The TMA block included 42 core samples taken from 21 paraffin blocks. The assessments were done on Bielschowsky and Gallyas silver stains using an immunohistochemical (IHC) method with antibodies directed to beta-amyloid (IHC/Aβ) and hyperphosphorylated tau (IHC/HPtau). The staining quality and the assessments differed between the participants, being most diverse with Bielschowsky (good/acceptable stain in 53% of centers) followed by Gallyas (good/acceptable stain in 57%) and IHC/Aβ (good/acceptable stain in 71%). The most uniform staining quality and assessment was obtained with the IHC/HPtau method (good/acceptable stain in 94% of centers). The neuropathologic diagnostic protocol (Consortium to Establish a Registry for Alzheimer Disease, Braak and Braak, and the National Institute of Aging and Reagan [NIA-Reagan] Institute) that was used significantly influenced the agreement, being highest with NIA-Reagan (54%) recommendations. This agreement was improved by visualization of NFTs using the IHC/HPtau method. Therefore, the IHC/HPtau methodology to visualize NFTs and neuropil threads should be considered as a method of choice in a future diagnostic protocol for Alzheimer disease. Copyright © 2006 by the American Association of Neuropathologists, Inc.

To study the potential diagnostic value of abnormally phosphorylated tau protein in Creutzfeldt-Jakob disease (CJD) compared to Alzheimer's disease (AD), we determined levels of tau phosphorylated at threonine 231 (p-tau231) and of total tau (t-tau) in cerebrospinal fluid (CSF) of CJD patients, AD patients, and healthy controls (HC). CJD patients showed excessively high t-tau levels but relatively low p-tau(231) concentrations compared to the AD group. t-tau alone yielded the best diagnostic accuracy to differentiate between CJD and AD patients, when compared to p-tau231 and the p-tau231/t-tau ratio (97, 78, and 95% correctly allocated cases, respectively). Our findings indicate a dissociation in the direction of change in CSF levels of t-tau and p-tau231 in CJD when compared to AD.

The optical transmission loss behavior was investigated for commercially available poly(methyl methacrylate) (PMMA) based polymer optical fibers (POFs). POFs were exposed to various climates of temperature and humidity. Optical transmission measurements using multiplexer (a prototype device) reveal that POFs exhibited an early drop-off followed by a slow decline of transmission at 100°C with low humidity and nearly 100% loss of transmission at the early stages of exposure at 92°C with 95% relative humidity (RH) and at 120°C with low humidity. Fourier transform infrared (FTIR) and gel permeation chromatography (GPC) analysis data show no significant molecular changes in the PMMA core after climatic exposures. However, the attenuated total reflection (ATR)–FTIR data shows a few molecular changes in claddings due to degradation. Scanning electron microscopy (SEM) data illustrate the shrinkage and folding structure in claddings. The loss of the optical transmission at the early (initial) stages of exposure is attributed to the physical changes (like thermal expansion), and the same at the later stages mainly to chemical changes (e.g., oxidative degradation). The experiments conducted here show that the POFs optical transmission stability is strongly dependent on the chemical composition of claddings. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 860–870, 2007

Background: Recently, six molecular subtypes of sporadic CJD (sCJD) have been identified showing differences regarding the disease course, neuropathologic lesion patterns, and sensitivity to diagnostic tools. Only isolated cases of the rare VV1 type have been reported so far. Objective: To describe the clinical characteristics and neuropathologic lesion profiles in nine cases. Methods: In the years 1993 until late 2003, 571 definite neuropathologically confirmed cases of sporadic CJD were identified in Germany. Of these, nine were homozygous for valine and displayed type 1 of the pathologic PrP Sc in the brain (VV1 type). Results: The authors describe eight men and one woman belonging to the VV1 type. All patients were relatively young at disease onset (median 44 years vs 65 years in all sCJD) with prolonged disease duration (median 21 months vs 6 months in all sCJD). During the initial stages, their main clinical signs were personality changes and slowly progressive dementia as well as focal neurologic deficits. None of the nine VV1 patients had periodic sharp-wave complexes (PSWCs) in the EEG. Only two out of seven displayed the typical signal increase of the basal ganglia on MRI, whereas signal increase of the cortex was seen in all patients. The 14-3-3 protein levels were elevated in CSF in all cases tested. Conclusions: The clinical diagnosis of the VV1 type of sCJD can be best supported by the 14-3-3 test and cortical signal increase on MRI. Because of the young age at onset vCJD is sometimes suspected as a differential diagnosis. MRI plays an important role in differentiating these two disease types and should be performed early during the disease course.

Background: An international study of the epidemiologic characteristics of Creutzfeldt–Jakob disease (CJD) was established in 1993 and included national registries in France, Germany, Italy, the Netherlands, Slovakia, and the United Kingdom. In 1997, the study was extended to Australia, Austria, Canada, Spain, and Switzerland. Methods: Data were pooled from all participating countries for the years 1993 to 2002 and included deaths from definite or probable CJD of all etiologic subtypes. Results: Four thousand four hundred forty-one cases were available for analysis and included 3,720 cases of sporadic CJD, 455 genetic cases, 138 iatrogenic cases, and 128 variant cases. The overall annual mortality rate between 1999 and 2002 was 1.67 per million for all cases and 1.39 per million for sporadic CJD. Mortality rates were similar in all countries. There was heterogeneity in the distribution of cases by etiologic subtype with an excess of genetic cases in Italy and Slovakia, of iatrogenic cases in France and the UK, and of variant CJD in the UK. Conclusions: This study has established overall epidemiologic characteristics for Creutzfeldt–Jakob disease (CJD) of all types in a multinational population–based study. Intercountry comparisons did not suggest any relative change in the characteristics of sporadic CJD in the United Kingdom, and the evidence in this study does not suggest the occurrence of a novel form of human bovine spongiform encephalopathy infection other than variant CJD. However, this remains a possibility, and countries currently unaffected by variant CJD may yet have cases.

Sirs, Prion diseases are transmissible diseases that include sporadic, acquired and familial disorders. More than 30 point mutations and insert mutations of the prion protein gene (PRNP) are thought to cause familial prion diseases, i.e. familial Creutzfeldt-Jakob disease (fCJD), GerstmannStraussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Clinical and pathological changes may be similar or indistinguishable from sporadic CJD (sCJD) as in fCJD associated with the E200K mutation, or may be quite different from sCJD as in the P102L mutation that is associated with GSS [1]. The clinical and pathological appearance of sCJD is linked to a methionine–valine polymorphism at codon 129 of PRNP and the biochemical isoform of PrP [2]. The influence of the codon 129 polymorphism in familial prion diseases depends on the particular pathogenic mutation and can be significant. Here we report on a CJD case with an R148H mutation. This patient underwent surgery for hysterectomy when she was 82 years old. After surgery she recovered, but was found somewhat fearful. Five months later she developed a rapidly progressive depressive, anxious disorder, and her state of awareness deteriorated within two weeks. She was admitted to a psychiatric ward. On admission she was disoriented, apprehensive, mistrustful and mute; Babinski’s sign on the right was positive. Within days the patient became somnolent and reacted with a defence reaction to painful stimuli. An evident ‘gegenhalten’ of all extremities was found, and the patient developed myoclonic jerks. She had to be fed by tube. The first EEG showed generalized pathologic alterations, but later periodic sharp wave complexes appeared. In the CT mild cortical atrophy was seen. T2-weighted MRI images revealed symmetric multiple hyperintense lesions in subcortical and periventricular locations. Examinations of the CSF was positive for the 143-3 protein and showed an increased tau protein level (>1,500 pg/ml). The patient was diagnosed with probable sCJD [3]. There was only limited information on her family, but no disease similar to CJD was known in the family. She succumbed six months after the onset of disease and an autopsy was performed. Genomic DNAwas extracted from peripheral blood and was investigated as described [4]. For Western blotting the brain was kept frozen at −80°C until use. Tissue from the frontal cortex and cerebellum was homogenised in 9 volumes (wt./vol) of lysis buffer (0.5% Nonidet P-40, 0.5% DOC, 10 mM EDTA, 100 mM NaCl, 100 mM Tris, pH 7.4) and further processed as described [2]. After PK digestion (50 μg/ml, 1 h at 37°C) cleared homogenates were subjected to SDS-PAGE and blotted on PVDF membranes. Monoclonal antibodies 6H4, 3F4 and L42 were used for immunodetection [5–7]. Blots were developed using NBT-BCIP according to standard protocols. Quantification of band intensities was performed with software TotalLab 1D Gel Analysis, version 2.0. For microscopic investigation the right half of the brain was fixed in formalin and processed for histology, immunohistochemistry and paraffin-embedded tissue (PET) blotting [8]. The monoclonal antibodies L42 and 12F10 were used for immunohistochemistry and PET blotting respectively. B. Krebs . R.-M. Lederer . O. Windl . E.-M. Grasbon-Frodl . H. A. Kretzschmar (*) Institut fur Neuropathologie, LMU Munchen, Feodor-Lynen-Strasse 23, 81377 Munich, Germany e-mail: Hans.Kretzschmar@med.uni-muenchen.de

Objectives – Cerebrospinal fluid (CSF) pattern in patients with neuropathologically diagnosed Creutzfeldt–Jakob disease was analyzed. Material and methods – Routine tests included white blood cells count, protein, albumin, immunoglobulins and the presence of oligoclonal immunoglobulin G (IgG) in the CSF as well as the calculation of intrathecal synthesis of immunoglobulins by standard methods. In addition, antibodies against neurotropic viruses such as measles, rubella, varicella zoster and herpes simplex were measured and the specific antibody index was calculated. Results – A blood–CSF barrier dysfunction was observed in six of 25 cases. In CSF/serum quotient diagrams, no patient had intrathecally synthesized immunoglobulins, but in two of 25 patients oligoclonal bands were detected. Two patients had intrathecally synthesized antibodies against varicella zoster and three against herpes simplex virus. Conclusion – In conclusion, in the routine diagnosis, the CSF in CJD is normal in most cases. In some patients, abnormalities include the blood–CSF barrier dysfunction, mild pleocytosis, oligoclonal bands and intrathecally synthesized viral antibodies.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disease with the greatest incidence occurring in patients between 60 and 70 years old. Younger patients may also be affected. In this study, we used all case material available from 52 patients with sCJD aged 50 years or younger at disease onset, who were identified between 1993 and 2003 in Germany. The objective of this study was to describe the psychiatric and neurological features of these young patients with emphasis on the different codon 129 genotypes and PrP types, and to compare them with elder patients with sCJD and patients with variant CJD. We also gave particular attention to electroencephalogram, magnetic resonance imaging, and 14-3-3 results, as well as to the neuropathological lesion profile. The clinical syndrome in young patients differs from elder patients with CJD with respect to clinical signs, disease duration, technical investigations, and neuropathological lesion profile. The psychiatric symptoms in young patients with sCJD are similar to the psychiatric symptoms expressed by patients with variant CJD; however, in contrast with the variant cases, young patients with sCJD experience development of prominent dementia early in the disease course.