Biomedical subjects

Ellen Gelpi

Publications and source records attributed to Ellen Gelpi.

At least 19 recordsLinked to original sources

PubMed2006

The brain-specific protein TPPP/p25 in pathological protein deposits of neurodegenerative diseases.

Immunohistochemical detection of protein components of pathological inclusions is widely used for neuropathological diagnosis of neurodegenerative disorders. However, different antibodies and antigen unmasking methods may account for variability between research studies and thus may affect diagnostic accuracy. Using two different antibodies raised against either a segment (184-200 aa) or the full length of human recombinant brain-specific tubulin polymerization promoting protein TPPP/p25, we immunohistochemically screened neurodegenerative disorders, both with and without pathological alpha-synuclein structures. We tested three different epitope unmasking methods, we applied laser confocal microscopy to evaluate double immunolabelling, and we compared the amount of structures exhibiting TPPP/p25 and alpha-synuclein immunoreactivity. We demonstrate that there are a variety of staining patterns depending on the epitope retrieval method and antibody used. The antibody raised against aa 184-200 segment of TPPP/p25 is better in immunolabelling the majority of alpha-synuclein immunopositive neuronal and glial pathological profiles detectable in Parkinson's disease, diffuse Lewy-body disease, and multiple system atrophy, in addition to immunostaining some extracellular huntingtin immunoreactive structures, lipofuscin, and neuromelanin particles. In contrast, the one raised against the full-length human recombinant TPPP/p25 is more suitable to immunodetect normal oligodendrocytes. Exposition of the segment aa 184-200 of TPPP/p25 in the aggregates of pathological inclusions renders this antibody a reliable marker of all types of alpha-synucleinopathies and suggests a role for TPPP/p25 in the aggregation process of some neurodegenerative conditions.

Adult↗

PubMed2006

Human transmissible spongiform encephalopathies in eleven countries: diagnostic pattern across time, 1993-2002.

BACKGROUND: The objective of this study was to describe the diagnostic panorama of human transmissible spongiform encephalopathies across 11 countries. METHODS: From data collected for surveillance purposes, we describe annual proportions of deaths due to different human transmissible spongiform encephalopathies in eleven EUROCJD-consortium countries over the period 1993-2002, as well as variations in the use of diagnostic tests. Using logistic models we quantified international differences and changes across time. RESULTS: In general, pre-mortem use of diagnostic investigations increased with time. International differences in pathological confirmation of sporadic Creutzfeldt-Jakob disease, stable over time, were evident. Compared to their counterparts, some countries displayed remarkable patterns, such as: 1) the high proportion, increasing with time, of variant Creutzfeldt-Jakob disease in the United Kingdom, (OR 607.99 95% CI 84.72-4363.40), and France (OR 18.35, 95% CI 2.20-152.83); 2) high, decreasing proportions of iatrogenic Creutzfeldt-Jakob disease in France, (OR 5.81 95% CI 4.09-8.24), and the United Kingdom, (OR 1.54 95% CI 1.03-2.30); and, 3) high and stable ratios of genetic forms in Slovakia (OR 21.82 95% CI 12.42-38.33) and Italy (OR 2.12 95% CI 1.69-2.68). CONCLUSION: Considerable international variation in aetiological subtypes of human transmissible spongiform encephalopathies was evident over the observation period. With the exception of variant Creutzfeldt-Jakob disease and iatrogenic Creutzfeldt-Jakob disease in France and the United Kingdom, these differences persisted across time.

Australia↗

PubMed2006

Autopsy at 2 months after death: brain is satisfactorily preserved for neuropathology.

Disclosure of neurological disorders by neuropathological examination may be one important aim of forensic autopsies. There are insufficient data on human brain tissue preservation after prolonged postmortem periods. Here, we describe neuropathological findings in a brain of a 77-year-old woman that was fixed at autopsy 2 months after death. The body had been stored in a cooling chamber at 3 degrees C temperature. Gross inspection of the brain was satisfactorily possible. Histomorphology was excellently preserved. Many histochemical and immunohistochemical stains allowed satisfactory neuropathological evaluation of brain tissue and the diagnosis of Alzheimer's disease. Nevertheless, some immunohistochemical stainings repeatedly yielded negative or suboptimal results. We conclude that neuropathological examination of human brain tissue extracted from the skull and fixed after prolonged body storage in a cool environment is feasible for forensic diagnosis of neurological disorders even several months after death. However, in such cases the significance of negative immunohistochemical staining results must be interpreted with caution.

Aged↗

PubMed2006

Histopathologic assessment of hot-spot microvessel density and vascular patterns in glioblastoma: Poor observer agreement limits clinical utility as prognostic factors: a translational research project of the European Organization for Research and Treatment of Cancer Brain Tumor Group.

BACKGROUND: Hot-spot microvessel density (MVD) and vascular patterns have been reported as histopathologic factors that influence prognosis in retrospective series of malignant gliomas. To investigate clinical utility, the authors systematically studied observer agreement on MVD and vascular patterns and the influence of repeatedly assessed data on patient outcomes in 2 independent glioblastoma series. METHODS: MVD and vascular patterns were assessed retrospectively by 5 observers in 1) a retrospectively compiled glioblastoma series that included 110 patients and 2) a glioblastoma series that included 233 patients who were treated within a randomized trial. MVD was determined in the field of greatest density ("hot-spot"). Predominantly classic or bizarre vascular patterns were determined by using a previously defined algorithm. RESULTS: Observer agreement on MVD was highly variable (range of kappa values, 0.464-0.901). The worst observer agreement was achieved when both the selection of hot-spots and MVD counts were performed independently. Survival analysis did not show a consistent association between repeatedly assessed MVD and patient outcome. Observer agreement on vascular patterns was poor (kappa = 0.297). Survival analysis did not show a consistent association between repeatedly assessed vascular patterns and patient outcome. CONCLUSIONS: Observer agreement on hot-spot MVD and vascular patterns in patients with glioblastoma was poor in independent assessments. MVD and vascular patterns were not associated consistently with patient outcome. Based on these findings, the authors concluded that poor observer agreement limits the clinical utility of histopathologically assessed hot-spot MVD and vascular patterns as prognostic factors in patients with glioblastoma. Improved methodologies for morphologic assessment of glioblastoma vascularization need to be identified.

Cohort Studies↗

PubMed2006

Successful heart failure therapy in mitochondrial disorder with noncompaction cardiomyopathy.

OBJECTIVE: Effective heart failure therapy with angiotensin-converting enzyme inhibitors and beta-blockers in a patient with mitochondrial disorder and asymptomatic previously stable hypertrophic cardiomyopathy and left ventricular noncompaction (NCCMP) has not been reported. CASE REPORT: In a 58-year-old male with juvenile seizures, impaired hearing, recurrent pancreatitis, diabetes, recurrent emesis and diarrhea, discrete weakness for hip flexion, general wasting, and reduced tendon reflexes, elevated muscle-enzymes, abnormal lactate-stress-test, and mitochondrial dysfunction on muscle biopsy, mitochondrial disorder was diagnosed at age 51 year. Echocardiography revealed myocardial thickening and NCCMP. Cardiac abnormalities did not progress upon repeated follow-ups. At age 57 year he developed acute heart failure during respiratory infection. Echocardiography additionally revealed reduced left ventricular systolic function, and a restrictive filling pattern. Within seven weeks of therapy with ramipril (2.5 mg/day) and bisoprolol (1.25 mg/day) the restrictive filling pattern disappeared and fractional shortening normalized. CONCLUSION: This case shows that heart failure in a patient with mitochondrial disorder and previously stable hypertrophic cardiomyopathy and NCCMP promptly resolves under therapy with angiotensin-converting enzyme inhibitors and beta-blockers.

Adrenergic beta-Antagonists↗

PubMed2006

Proteome profiling in the rat Harderian gland.

The Harderian gland is an orbital gland located behind the ocular bulb in most terrestrial vertebrates probably functioning for production of lipid secretion to protect the eye. We herein present a protein reference database of the rat Harderian gland that may serve as analytical tool for future proteomic work, report lipid and porphyrin handling cascades, address sequence conflicts and report structures that have not been so far described by proteomics methods.

Amino Acid Sequence↗

PubMed2006

Inflammatory response in human tick-borne encephalitis: analysis of postmortem brain tissue.

In Central European tick-borne encephalitis (TBE) mechanisms of tissue destruction are poorly understood. To evaluate the contribution of immunological mechanisms to tissue injury, the authors immunohistochemically analyzed paraffin-embedded autoptic brain tissue of 26 human TBE cases. In the parenchymal compartment, there was a predominance of macrophages/microglia and cytotoxic T cells. In addition, it was found that granzyme B-expressing lymphocytes were in close contact with TBE-expressing neurons up-regulating caspase-3. These findings indicate that cellular and humoral pathways of the immune system, especially granzyme B-releasing cytotoxic T cells and macrophages/microglia, mainly contribute to tissue destruction in TBE.

Adolescent↗

PubMed2006

Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo.

Prion diseases and Alzheimer disease (AD) share a variety of clinical and neuropathologic features (e.g. progressive dementia, accumulation of abnormally folded proteins in diseased tissue, and pronounced neuronal loss) as well as pathogenic mechanisms like generation of oxidative stress molecules and complement activation. Recently, it was suggested that neuronal death in AD may have its origin in the endoplasmic reticulum (ER). Cellular stress conditions can interfere with protein folding and subsequently cause accumulation of unfolded or misfolded proteins in the ER lumen. The ER responds to this by the activation of adaptive pathways, which are termed unfolded protein response (UPR). The UPR transducer PERK, which launches the most immediate response to ER stress (i.e. the transient attenuation of mRNA translation), and the downstream effector of PERK, eIF2alpha, were shown to be activated in AD. We demonstrate that neither in sporadic nor in infectiously acquired or inherited human prion diseases can the activated forms of PERK and eIF2alpha be detected, except when concomitant neurofibrillary pathology is present; whereas the distribution of phosphorylated PERK correlates with abnormally phosphorylated tau in AD. In brains of scrapie-affected mice and mice infected with sporadic or variant Creutzfeldt-Jakob disease, activated PERK is only very faintly expressed. The lack of prominent activation of the PERK-eIF2alpha pathway in prion diseases suggests that, in contrast to AD, ER stress does not play a crucial role in neuronal death in prion disorders.

Adult↗

PubMed2006

Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium.

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/Abeta) 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/Abeta (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.

Aged↗

PubMed2006

Mitochondrial disorder aggravated by propranolol.

Although there are indications that beta-blockers affect the skeletal muscle in therapeutic dosages, their influence on mitochondrial disorders is unknown. A 52-year-old woman developed double vision, myalgias, muscle cramps, and hip and thigh muscle stiffness. Clinical neurologic examination revealed ptosis, dysarthria, sore neck muscles, weakness and wasting of the thighs, and generally brisk tendon reflexes. Lactate stress testing was significantly abnormal. Needle electromyography was nonspecifically abnormal and myopathic. Muscle biopsy showed mild myopathic changes, target fibers, and a single COX-negative fiber. Probable mitochondrial disorder was diagnosed. The patient had been on 30 mg of propranolol during 7 years for arterial hypertension. Shortly after discontinuation of the drug, her double vision gradually disappeared, myalgias and muscle cramps gradually resolved, and the patient reported an increase in muscle mass on repeated follow-ups. Long-term administration of propranolol may aggravate a mitochondrial disorder. Discontinuation of propranolol may result in a gradual resolution of these adverse reactions.

Adrenergic beta-Antagonists↗

PubMed2006

Creatine kinase elevation in creutzfeldt-jakob disease.

OBJECTIVES: Creutzfeldt-Jakob disease (CJD) is not only a disorder of the central nervous system but also affects the skeletal muscle. Subclinical skeletal muscle involvement, manifesting as hyper-creatine-kinase (CK)-emia, is rare. CASE REPORT: The patient, a 60-year-old male, developed progressive dementia, accompanied by dysphagia and bursts of aggression, disorientation and optic hallucinations. Five months after onset of the cognitive decline, hyper-CK-emia of 117 U/l (normal: <81 U/l) was noted for the first time. During 12 months until decease, hyper-CK-emia was permanently present and reached a maximum of 354 U/l. Hyper-CK-emia was attributed to subclinical involvement of the skeletal muscle in CJD. Hyper-CK-emia due to progressive brain damage, double trouble of an additional primary myopathy or due to excessive myoclonic jerking was excluded. CONCLUSIONS: This case shows that CJD may be present with mild hyper-CK-emia in individual patients, most likely due to concomitant undiagnosed involvement of the skeletal muscle in the primary disease.

Creatine Kinase↗

PubMed2005

Mass spectrometric identification of serine hydrolase OVCA2 in the medulloblastoma cell line DAOY.

OVCA2 is a putative serine-hydrolase. Performing protein profiling in human tumour cell lines, OVCA2 was detected in DAOY medulloblastoma cells as a high abundance protein. The protein was unambiguously identified by 2D gel-electrophoresis and MALDI-MS and MS/MS, its presence was confirmed by western blotting. Immunohistochemistry revealed expression in medulloblastoma and predominantly in oligodendrocytes. Computational approaches predicted functional motifs and domains, interaction with apoptosis-related protein BAG and 3D structure. In addition to the presence of OVCA2 in medulloblastoma, it was furthermore detectable in three out of 10 human tumour cell-lines as a high abundance protein probably suggesting a role in the tumour biology.

Amino Acid Sequence↗

PubMed2005

Extravasation of plasma proteins can confound interpretation of proteomic studies of brain: a lesson from apo A-I in mesial temporal lobe epilepsy.

Apolipoprotein A-I (apo A-I), a major component of high density lipoproteins, has been shown to be involved in lipid metabolism, cholesterol homeostasis and degeneration/regeneration of brain tissues and was proposed as a useful marker for the extent and severity of CNS injury. We searched for aberrant protein expression in hippocampus from patients with mesial temporal lobe epilepsy (MTLE) by an analytical method based on two-dimensional gel electrophoresis coupled with mass spectrometry (MALDI-TOF/TOF) and unambiguously identified 2 spots as apolipoprotein A-I forms in brain of MTLE patients with 7.5-fold increased levels (controls: 0.046 +/- 0.046; MTLE patients: 0.343 +/- 0.154, mean +/- SD, P = 0.003). Western blot analysis confirmed increased apo A-I levels in MTLE. Immunohistochemistry detected staining for apo A-I extracellularly in perivasal brain parenchyma, neuropil and areas with increased glial fibrillary acidic protein (GFAP) expression as well as some pyramidal neurons and subpial astrocytes. These findings indicate that the increase of apo A-I in MTLE was possibly not reflecting a pathogenetic role but was rather due to extravasates, bleedings or increase of microvascular endothelial cells known to synthesize apo A-I. Care has to be taken when protein expressional findings are to be interpreted in the presence of plasma proteins, including apo A-I, thus clearly representing a confounding factor.

Adult↗

PubMed2005

Intraventricular meningiomas: a report of 16 cases.

Meningiomas of the ventricle system are extremely rare. We report on a series of 16 intraventricular meningiomas (IVMs) treated at our institution between 1980 and 2004, with a special interest on the surgical outcome of using the intra/inter-parietal and parieto-occipital approach and the benefits of neuro-navigation. A retrospective analysis of the medical files for clinicoradiological findings, surgical interventions and surgical outcome was carried out. In 16 IVM patients with a female/male ratio of 11:5, age ranged from 24 years to 84 years (median 44 years). Duration of symptoms ranged from a few days to several years, and the cardinal symptoms were signs of increased intracranial pressure (86%), followed by corticospinal tract signs (43%), visual field defects (36%), cognitive changes (29%) and seizures (7%). The majority of tumours was located in the trigone (88%), and one was found in each the temporal horn and in the fourth ventricle. Tumour size ranged from 2.5 cm to 8 cm (median 5 cm), and the radiological appearance was uniform. The neuropathological workup revealed most IVMs as meningothelial, transitional (mixed) or lymphoplasmacyte-rich meningiomas (81%). Three tumours were classified as atypical (19%) and the MIB-1 proliferation index ranged from 1% to 40%. Complete resection was possible in all but one case. The trigonal IVMs were resected via an intraparietal/inter-parietal or parieto-occipital approach, and neuro-navigation was used in eight tumours. We encountered one perioperative death and one severely disabled patient. All other patients had a Glasgow outcome scale score of 5, and most of the pre-existing symptoms disappeared or improved after surgery. IVMs are a surgically curable tumour entity in most cases. The intraparietal/inter-parietal and parieto-occipital approach is very safe, and neuro-navigation allows early devascularisation of the tumour.

Adult↗

PubMed2005

Prion disease with a 144 base pair insertion: unusual cerebellar prion protein immunoreactivity.

Sporadic, acquired, and genetic human prion diseases are characterized neuropathologically by distinct deposition patterns of the abnormal, disease-associated form of the prion protein (PrP(sc)). In addition to mutations in the prion protein gene (PRNP), PrP(sc) immunostaining patterns correlate with molecular phenotypes of prion diseases defined by the PRNP polymorphism at codon 129 and with protease-resistant PrP classified by Western blotting. Some point or insertional PRNP mutations share similar clinical and neuropathological phenotypes, whereas others show great variability even within the same family. Here we report a patient who presented clinically as sporadic Creutzfeldt-Jakob disease (CJD). Histologically moderate spongiform change was seen in cerebral and cerebellar cortical areas. Neuronal loss was restricted mainly to the occipital cortex and the basal ganglia. Surprisingly, numerous eosinophilic globular structures were noted in the molecular layer and the parahippocampal gyrus. These globules showed intense PrP immunopositivity using anti-PrP antibodies against different epitopes. They were stained with PAS but lacked congophilia and birefringence in polarized light. Ultrastructurally, globules were composed of 21-nm-thick intermingled filaments without dense core. Genetic analysis revealed a PRNP 144 base pair insertion. Our case reinforces the importance of molecular genetic diagnosis, especially in those patients who lack a family history of prion disease and show unusual neuropathological changes. It also widens the phenotypic spectrum of prion diseases. The phenotypic variability within the same mutation suggests further, yet uncharacterized, genetic or epigenetic influence on phenotype in these diseases.

Aged↗

PubMed2005

Recurrent central neurocytomas.

BACKGROUND: Since the first description of Central neurocytomas (CNs) as a benign tumor entity in 1982, there has been great enthusiasm regarding the benign course and the curative surgical approach to this disease. The current study was performed to investigate the frequency of disease recurrence during long-term follow-up. METHODS: A retrospective analysis of the medical files with emphasis on clinicoradiologic findings and histologic and immunohistochemical features was performed. RESULTS: Between 1985-2003. surgical resection was performed in 14 patients with CNs ages 16-43 years (7 were female and 7 were male). Two patients (14%) died postoperatively and one patient had a malignant disease course (7%). In the remaining 11 patients, one patient with an incompletely resected CN had disease progression after 37 months but at the time of last follow-up had had stable disease for 10 years. In addition, the authors reported 5 patients with disease recurrence occurring at a median of 67 months after surgery (range, 51-79 months after surgery), all of which occurred after complete surgical resection was performed. The observation period for the remaining 5 patients was short (median of 34 months [range, 5-44 months]). Extensive histologic and immunohistochemical workup did not identify any significant prognostic parameters. The MIB-1 proliferation index ranged from 0.8-11% (median of 4.6%), but was reported to be 46.8% in the malignant transformed tumor. All patients with disease recurrence responded well to different forms of focal radiation therapy (gamma knife radiosurgery in three patients and interstitial irradiation in one patient) and for one patient with a recently detected recurrence, gamma knife radiosurgery was planned. CONCLUSIONS: CNs appear to have a higher tendency to recur during long-term follow-up than previously reported, even after complete resection. Therefore, periodic neuroradiologic follow-up examinations should be considered mandatory in all patients, even after several years.

Adolescent↗

PubMed2005

Megadolichobasilar anomaly with thrombosis in a family with Fabry's disease and a novel mutation in the alpha-galactosidase A gene.

Fabry's disease is an X-linked lysosomal storage disorder. alpha-Galactosidase deficiency leads to accumulation of globotriaosylceramide mainly in endothelial and smooth muscle cells. Cerebrovascular symptoms with predominant affection of the vertebrobasilar circulation are one of the major sources of morbidity in Fabry's disease. We present a Hungarian family with Fabry's disease caused by a new mutation in the alpha-galactosidase A gene (GLA), and describe a variant expression of the disease. Megadolichobasilar anomaly was diagnosed in two male patients in the family who died of thrombosis. In another female patient who had suffered from disturbance of the vertebrobasilar circulation, a strongly dilated basilar artery without thrombosis was found at autopsy. Another three family members had basilar strokes and large and elongated basilar arteries on MRI. Genetic analysis disclosed a c.47T-->C missense mutation resulting in L16P in the amino acid sequence of the alpha-galactosidase protein. This report suggests that megadolichobasilar anomaly is potentially life-threatening, and that L16P is a disease-causing mutation in patients with Fabry's disease. Early enzyme replacement therapy may prevent the development of these irreversible cerebrovascular complications.

Adult↗

PubMed2005

No prognostic impact of survivin expression in glioblastoma.

Survivin is a member of a novel protein family of inhibitors of apoptosis, and also plays a role as a potent regulator of mitosis. In semiquantitative Western blot analysis of glioblastomas, survivin expression was shown to be a prognostically significant factor. In the present study we investigated the immunohistochemical expression of survivin and its prognostic impact in a large glioblastoma series comprising 104 consecutive adult patients undergoing a first operation for glioblastoma. We analyzed survivin, Ki-67, and topoisomerase-II-alpha expression in paraffin-embedded tissue, and correlated patient age, Karnofsky performance score, vascular pattern and survivin-, Ki-67-, topoisomerase-II-alpha-, and apoptotic indices with patient outcome using univariate and multivariate survival analysis. Survivin was expressed in all glioblastoma samples, and was prominent in a fraction of nuclei of tumor cells and vascular cells. Further, survivin labeled spindle- and chromosomal material of mitotic figures. Faint cytoplasmic expression was also seen. The survivin index showed significant correlation with Ki-67 and Topo-II-alpha indices. On average, 58.85% of Ki-67 and 91.08% of survivin-expressing nuclei co-expressed Ki-67 and survivin. The survivin index did not correlate significantly with overall survival, whereas patient age, Karnofsky performance score, vascular pattern, and Ki-67 and topoisomerase-II-alpha indices were associated with patient outcome. In summary, in glioblastoma, survivin is expressed predominantly in proliferating tumor cell nuclei. In contrast to Ki-67 and topoisomerase-II-alpha, survivin expression does not influence patient outcome. So, in contrast to Ki-67, survivin does not seem to be useful as prognostic factor in the clinical setting.

Adult↗