Biomedical subjects

J A Hainfellner

Publications and source records attributed to J A Hainfellner.

At least 19 recordsLinked to original sources

PubMed2002

DNA topoisomerase IIalpha expression in optic pathway gliomas of childhood.

DNA topoisomerase IIalpha (Topo IIalpha) is linked to tumour cell growth and chemoresistance. We examined immunohistochemically Topo IIalpha expression levels in a series of 36 consecutive paediatric optic pathway glioma (OPG) patients. Topo IIalpha labelling index (LI) ranged from 0.0 to 11.6 and was significantly associated with patient age, with higher levels of Topo IIalpha in children < or = 3 years (P=0.031). Topo IIalpha expression did not correlate with patient survival. Topo IIalpha LI was not significantly increased in specimens of repeat surgery. Topo IIalpha LI closely correlated with MIB-1 LI (R=0.781, P<0.001). We conclude that Topo IIalpha expression correlates with tumour cell proliferation in paediatric OPGs. Assessment of cell proliferation, however, does not assist in refining prognostic predictions. Enhanced Topo IIalpha expression in children < or = 3.0 years suggests that Topo IIalpha-interfering anticancer compounds for adjuvant treatment of OPGs may be of particular benefit to young children.

Adolescent↗

PubMed2002

Fibrous meningeal tumours with extensive non-calcifying collagenous whorls and glial fibrillary acidic protein expression: the whorling-sclerosing variant of meningioma.

Meningiomas comprise a wide range of morphological patterns. We describe unusual fibrous meningeal tumours in two patients, composed of extensive non-calcifying collagenous whorls of varying size, resembling non-calcified psammoma bodies, while interposed tumour cells are sparse. Immunohistochemistry showed expression of S-100, vimentin and glial fibrillary acidic protein, whereas only single tumour cells stained for epithelial membrane antigen. Electron microscopy detected desmosomes or desmosome-like structures in both specimens. We conclude that these tumours represent a peculiar whorling-sclerosing variant of fibrous meningioma. Recognition of this meningioma variant is important in the differential diagnosis of meningioma versus other fibrous tumours of the meninges, including solitary fibrous tumours of the meninges, unusual forms of desmoplastic gliomas or chondroid tumours.

Aged↗

PubMed2001

Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: its impact on prognosis and on neoangiogenesis.

BACKGROUND: Hypoxia-inducible factor (HIF)1 alpha is considered to play a key role in the adaptation of cells to hypoxia by stimulating angiogenesis via regulation of vascular endothelial growth factor and by metabolic adaptation to O(2) deprivation. METHODS: Expression of HIF-1 alpha protein and p53 was investigated by immunohistochemistry in 51 specimens of supratentorial pure oligodendrogliomas. Microvessels density (MVD) was determined by anti-CD34 immunostaining. The influence of HIF-1 alpha expression on survival was investigated using univariate and multivariate analysis. RESULTS: Strong expression of HIF-1 alpha was observed in 12 (23.5%) specimens, moderate in 21 (41.2%) specimens, and weak in 8 (15.7%) cases, and no expression was found in 10 samples (19.6%). There was no correlation of HIF-1 alpha expression with histologic grading (P = 0.428, Mann-Whitney test). Hypoxia-inducible factor-1 alpha expression and MVD showed a strong correlation (P < 0.001, r = 0.735, Spearman coefficient of correlation). Overexpression of p53 was observed in only two cases. Patients with strong or moderate expression of HIF-1 alpha had a significantly shorter overall survival rate compared with those with low or no expression in univariate (P = 0.0434; log-rank test) and multivariate analysis (P = 0.0187). CONCLUSIONS: Overexpression of HIF-1 alpha indicates a diminished prognosis in oligodendrogliomas, independent of p53 status. This finding may be explained by the strong vascularization of these tumors that prevents hypoxia and allows O(2) diffusion and henceforth tumor progression.

Adult↗

PubMed2001

Serotonergic nuclei of the raphe are not affected in human ageing.

Sleep disorders increase with ageing. The serotonergic system has been linked with sleep regulation. In fatal familial insomnia, a prion disease with insomnia as one major clinical feature, we recently observed a disturbance in the serotonergic system as likely substrate of typical symptoms. Using immunohistochemistry for the serotonin synthesizing enzyme, tryptophan hydroxylase, we investigated the serotonergic median raphe nuclei (dorsal raphe nucleus, superior central nucleus, and raphe obscurus nucleus) in brains of an older (n = 12; age range 62-84 years) and a younger group (n = 10; age range 5-29 years). We found no significant difference between age groups in the percentage of neurons able to synthesize serotonin. Other changes might relate to sleep disturbances in the elderly.

Adolescent↗

PubMed2001

Immunohistochemical detection of cell growth fraction in formalin-fixed and paraffin-embedded murine tissue.

Monoclonal antibody MIB-1 is a reliable tool for determining proliferating cells in human tissues, but does not react with the homologous mouse antigen and is therefore useless in experimental pathology using mice as model systems. Standard method for assessment of cellular proliferation in formalin-fixed, paraffin-embedded murine tissues is immunohistochemical detection of DNA synthesis using antibodies against exogenously injected 5-bromodeoxyuridine (BrdU), which is a tedious procedure and not useful for routine investigations. We tested monoclonal antibody MIB-5 and monoclonal and polyclonal anti-MCM3 antibodies as immunohistochemical proliferation markers for paraffin-embedded nonneoplastic and neoplastic tissues of wild-type and transgenic mice, compared to anti-BrdU immunostaining. Percentage of proliferating cells was determined with continuously decreasing antibody dilutions. Percentages of MIB-5 and anti-BrdU immunostained cells correlated strongly, as well as percentage of MIB-5-decorated cells and frequency of mitotic figures. Anti-MCM3 antibodies labeled significantly higher percentages of cells than anti-BrdU or MIB-5, and showed a linear decrease with increasing antibody dilutions. We conclude that MIB-5 detects reliably the cell growth fraction in formalin fixed, paraffin-embedded murine tissues, bypassing methodological drawbacks of BrdU. Anti-MCM3 antibodies are less useful for determination of proliferating cells although they might detect the fraction of cells remaining competent for proliferation.

Adenoma↗

PubMed2001

Intramyocardial hematoma mimicking abnormal left ventricular trabeculation.

Intramyocardial hematoma may present as a tumor or pseudoaneurysm on echocardiography. A 68-year-old man was admitted with a subacute posterior wall infarction complicated by ventricular fibrillation. Echocardiography showed isolated left ventricular abnormal trabeculations, a finding suggesting an associated skeletal muscle disorder, in the lateral wall. At cardiac surgery, performed 6 weeks later because of severe 3-vessel disease, an intramyocardial hematoma of the lateral wall was excised, and myocardial and skeletal muscle biopsies were taken, which showed neither isolated left ventricular abnormal trabeculations nor skeletal muscle disorder. Postoperatively, echocardiography revealed no abnormal trabeculations.

Aged↗

PubMed2001

Fibroblasts can express glial fibrillary acidic protein (GFAP) in vivo.

Neuropathologists use anti-glial fibrillary acidic protein (GFAP) antibodies as specific markers for glial cells, and neurobiologists use GFAP for targeting transgenes to glial cells. Since GFAP has also been detected in non-glial cells, we systematically analyzed GFAP expression in human and murine non-CNS tissues using a panel of anti-GFAP antibodies. In human tissues we confirm previously observed GFAP expression in Schwann cells, myoepithelial cells, and chondrocytes, and show for the first time GFAP expression in fibroblasts of epiglottic and auricular perichondrium, ligamentum flavum, and cardiac valves. In mice we show GFAP expression in Schwann cells, bone marrow stromal cells, chondrocytes, and in fibroblasts of dura mater, skull and spinal perichondrium, and periosteum, connective stroma of oral cavity, dental pulp, and cardiac valves. Anti-GFAP immunoblotting of human non-CNS tissues reveals protein bands with a molecular mass ranging between approximately 35 and approximately 42 kDa. In GFAP-v-src transgenic mice, whose oncogenic v-src transgene transforms GFAP expressing cells, non-CNS tumors originate from fibroblasts. We conclude that human and murine fibroblasts can express GFAP in vivo. The somatic distribution of GFAP expressing fibroblasts indicates origin from the neural crest. Development of non-CNS tumors from fibroblasts in GFAP-v-src mice functionally confirms GFAP expression in these cells.

Animals↗

PubMed2000

An autosomal dominant early adult-onset distal muscular dystrophy.

In this study we describe an autosomal dominant distal muscular dystrophy in a small Austrian family. The myopathy started in early adulthood with a slowly progressive weakness of the muscles of the anterior tibial compartment, followed by the long finger extensors and sternocleidomastoids in some family members. Other muscles were spared. Histopathology showed fiber size variation and autophagic vacuoles. This disease pattern is similar to Laing distal myopathy, which has been described previously in only one other family.

Adult↗

PubMed2000

Kynurenic acid metabolism in the brain of HIV-1 infected patients.

Patients who are infected with human immunodeficiency virus type 1 (HIV-1) frequently present with neurological and psychiatric symptoms. Kynurenic acid (KYNA), an intermediate metabolite of L-kynurenine (L-KYN), is a neuroprotectant and a broad-spectrum antagonist at excitatory amino acid (EAA) receptors. The present study examines the biosynthetic machinery of KYNA in the frontal cortex and cerebellum of 25 HIV-1 and 16 control (CO) patients. We measured the contents of L-KYN and KYNA and the activity of enzymes synthesizing KYNA, kynurenine aminotransferases I and II (KAT I and KAT II). The KYNA level was significantly increased in the frontal cortex (209 +/- 38% of CO; p < 0.05) and moderately increased in the cerebellum (164 +/- 31% of CO) of HIV-1 brains as compared with controls. The bioprecursor of KYNA, L-KYN, was increased in frontal cortex (188 +/- 45% of CO) and cerebellum (151 +/- 16% of CO; p < 0.05). The elevated KYNA in frontal cortex correlated with significant increases of KAT I (341 +/- 95% of CO; p < 0.05) and KAT II (141 +/- 8% of CO; p < 0.05). In the cerebellum, a high KYNA content was in the line with increased KAT I (262 +/- 52% of CO; p < 0.05) activity, while KAT II was in a control range (85 +/- 12% of CO). This study demonstrates that HIV-1 infection associates with elevated KYNA synthesis in the brain. In contrast to KAT II, KAT I was prominently increased in both brain regions investigated. Differences in neurochemical parameters of KYNA metabolism between frontal cortex and cerebellum suggests selective tissue damage. Drugs which influence the synthesis of the endogenous neuroprotectant KYNA may become useful in the therapy of neuropsychiatric manifestations of HIV-1 infected patients.

AIDS Dementia Complex↗

PubMed2000

Apoplexy of a pituitary macroadenoma with reversible third, fourth and sixth cranial nerve palsies following administration of hypothalamic releasing hormones: MR features.

Pituitary apoplexy in patients with pituitary macroadenomas can occur either spontaneously or following various interventions. We present a case of a 71-year-old woman who developed third, fourth, and sixth cranial nerve palsies following administration of the four hypothalamic releasing hormones for routine preoperative testing of pituitary function. The MR examination showed interval tumor growth with impression of the floor of the third ventricle. There were also changes in signal intensity characteristics of the mass, suggestive of intratumoral bleeding. A transsphenoidal surgery with subtotal resection of the pituitary adenoma was performed. Microscopical examination revealed large areas of necrosis and blood surrounded by adenomatous tissue. Third, fourth, and sixth cranial nerve palsies completely resolved within 4 months. We conclude that MR imaging is useful in the demonstration of pituitary apoplexy following preoperative stimulation tests, but we suggest that these tests should be abandoned in patients with pituitary macroadenomas.

Abducens Nerve Diseases↗

PubMed2000

Evidence of therapeutic efficacy of CCNU in recurrent choroid plexus papilloma.

A pregnant 33-year old woman developed nystagmus and cerebellar ataxia. A tumor in the roof of the fourth ventricle was diagnosed. The tumor was subtotally removed using microneurosurgical techniques. The histopathological diagnosis was choroid plexus papilloma (CPP). Twenty-one months later, the tumor recurred and was reoperated. Histologically the tumor displayed now increased mitotic activity and pleomorphism. Radiation therapy of the neuroaxis was performed. Within 59 months, the CPP recurred 3 more times with neuroradiological evidence of extensive spinal seeding. After several palliative irradiations, including 2 gamma-knife boosts, the patient was referred to chemotherapy. She was treated with CCNU (Lomustin) 100 mg/m2 orally (12 cycles, cumulative dosis 1440 mg/m2). Within 42 months, there was no new local recurrence and spinal seeding showed significant regression. Clinically the patient improved and stabilized, but needs continuous support because of persisting severe gait ataxia. The course of disease in our patient provides evidence for therapeutic efficacy of CCNU in recurrent CPP.

Adult↗

PubMed2000

No tissue damage by chronic deep brain stimulation in Parkinson's disease.

We report on the pathological findings in the brains of 8 Parkinson's disease patients treated with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (6 cases) and subthalamic nucleus (2 cases). DBS was performed continuously for up to 70 months. All brains showed well-preserved neural parenchyma and only mild gliosis around the lead track compatible with reactive changes due to surgical placement of the electrode. We conclude that chronic DBS does not cause damage to adjacent brain tissue.

Brain↗

PubMed2000

Alteration of the serotonergic nervous system in fatal familial insomnia.

Fatal familial insomnia (FFI) is a unique hereditary prion disease with characteristic disturbances of sleep. We studied the serotonergic system in 8 FFI-affected subjects by immunohistochemistry for the serotonin-synthesizing enzyme, tryptophan hydroxylase (TH). Quantification of neurons in median raphe nuclei showed no total neuronal loss in FFI but a substantial increase of TH+ neurons (approximately 62%) in FFI subjects compared with controls. Our data indicate an alteration of the serotonergic system that might represent the functional substrate of some typical symptoms of FFI.

Adult↗

PubMed1999

Deposition of disease-associated prion protein involves the peripheral nervous system in experimental scrapie.

There is some evidence that the peripheral nervous system (PNS) is involved in the pathogenesis of transmissible spongiform encephalopathies (TSEs). The TSE-specific abnormal prion protein (PrP(sc)) is considered as surrogate marker for infectivity. We traced the deposition of PrP(sc) by immunocytochemistry in sheep and hamsters inoculated intraperitoneally with scrapie. The trigeminal, dorsal root, celiac, thoracic, and nodose ganglia contained ganglion cells and fewer satellite cells with prominent granular PrP(sc) deposition. As a novel deposition pattern, punctate deposits in adaxonal location were seen along nerve fibers of peripheral nerve adjacent to ganglia. Such prominent involvement of the PNS in two different experimental scrapie models emphasizes the need to consider the PNS in natural scrapie and other TSEs including bovine spongiform encephalopathy as potential source of infectivity.

Animals↗

PubMed1999

Disease associated prion protein may deposit in the peripheral nervous system in human transmissible spongiform encephalopathies.

There is increasing evidence indicating involvement of the peripheral nervous system (PNS) in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Immunocytochemically detectable deposits of TSE-specific abnormal prion protein (PrP(sc)) are considered as a surrogate marker for infectivity. We used anti-PrP immunocytochemistry to trace PrP(sc) deposition in spinal and enteric ganglia, and peripheral nerve in Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia. Discrete PrP(sc) deposits were detectable only in a few posterior root nerve fibers in an adaxonal location in one of nine CJD and the one GSS patients examined. Follicular dendritic cells of the gut and enteric nervous system were not labeled. Thus, PrP(sc) may spread to the PNS in different forms of human prion disease. In contrast to our observations in experimental scrapie (Groschup et al., Acta Neuropathol, this issue), the deposits were scant. Possible explanations for this discrepancy comprise strain difference, or centripetal (experimental scrapie) versus centrifugal (sporadic and genetic human prion diseases) spread of PrP(sc), resulting in different patterns and amounts of PrP(sc) accumulation in the PNS.

Adult↗

PubMed1999

Deposition of the prion protein (PrP) during the evolution of experimental Creutzfeldt-Jakob disease.

We studied the immunocytochemical distribution of the prion or proteinase-resistant protein (PrP) during the evolution of experimental Creutzfeldt-Jakob disease (CJD) in mice. Fifty-one brains were collected up to 22 weeks following intracerebral inoculation with the Fujisaki strain of the CJD agent. Slides were also immunostained for apolipoprotein E (apoE) and glial fibrillary acidic protein. Vacuolar changes with focal astrocytosis first occurred around the needle track at week 2 and later spread along white matter tracks. Until week 12, changes were asymmetrical, affecting more the side of inoculation. Spongiform change and astrogliosis spread subsequently to the gray matter. Time course and intensity of spongiform change and immunocytochemistry for PrP were discrepant: in most brain regions, severe vacuolation preceded immunocytochemically detectable PrP accumulation. PrP deposits in form of small dots were first detectable at week 6 in the area surrounding the needle track. After week 7, plaque-like amorphous PrP deposits were observed in white matter pathways. Finally, PrP was detectable also in basal ganglia and in the dorsal hippocampus (week 13) and in the neocortex (week 17), as the synaptic type of PrP immunopositivity. In the hippocampus, diffuse PrP deposits paralleled spongiform change, while in the cortex severe vacuolation was accompanied only by weak synaptic PrP deposits. Immunocytochemically detectable apoE was restricted to compact plaque-type PrP deposits after week 15. We conclude that disease-specific neuropathology spreads from the needle track along white matter pathways towards the gray matter; in this model, there is some discrepancy between development of tissue pathology and immunocytochemically detectable deposition of PrP. Immunocytochemically detectable apoE deposition follows PrP accumulation.

Animals↗

PubMed1999

Fatal familial insomnia: a new Austrian family.

We present clinical, pathological and molecular features of the first Austrian family with fatal familial insomnia. Detailed clinical data are available in five patients and autopsy in four patients. Age at onset of disease ranged between 20 and 60 years, and disease duration between 8 and 20 months. Severe loss of weight was an early symptom in all five patients. Four patients developed insomnia and/or autonomic dysfunction, and all five patients developed motor abnormalities. Analysis of the prion protein (PrP) gene revealed the codon 178 point mutation and methionine homozygosity at position 129. In all brains, neuropathology showed widespread cortical astrogliosis, widespread brainstem nuclei and tract degeneration, and olivary 'pseudohypertrophy' with vacuolated neurons, in addition to neuropathological features described previously, such as thalamic and olivary degeneration. Western blotting of one brain and immunocytochemistry in four brains revealed quantitative and regional dissociation between PrP(res)(the protease resistant form of PrP) deposition and histopathology. In the cerebellar cortex of one patient, PrP(res) deposits were prominent in the molecular layer and displayed a peculiar patchy and strip-like pattern with perpendicular orientation to the surface. In another patient, a single vacuolated neuron in the inferior olivary nuclei contained prominent intravacuolar granular PrP(res) deposits, resembling changes of brainstem neurons in bovine spongiform encephalopathy.

Adult↗

PubMed1999

No complementation between TP53 or RB-1 and v-src in astrocytomas of GFAP-v-src transgenic mice.

Human low-grade astrocytomas frequently recur and progress to states of higher malignancy. During tumor progression TP53 alterations are among the first genetic changes, while derangement of the p16/p14ARF/RB-1 system occurs later. To probe the pathogenetic significance of TP53 and RB-1 alterations, we introduced a v-src transgene driven by glial fibrillary acidic protein (GFAP) regulatory elements (which causes preneoplastic astrocytic lesions and stochastically astrocytomas of varying degrees of malignancy) into TP53+/- or RB-1+/- mice. Hemizygosity for TP53 or RB-1 did not increase the incidence or shorten the latency of astrocytic tumors in GFAP-v-src mice over a period of up to 76 weeks. Single strand conformation analysis of exons 5 to 8 of non-ablated TP53 alleles revealed altered migration patterns in only 3/16 tumors analyzed. Wild-type RB-1 alleles were retained in all RB-1+/-GFAP-v-src mice-derived astrocytic tumors analyzed, and pRb immunostaining revealed protein expression in all tumors. Conversely, the GFAP-v-src transgene did not influence the development of extraneural tumors related to TP53 or RB-1 hemizygosity. Therefore, the present study indicates that neither loss of RB-1 nor of TP53 confer a growth advantage in vivo to preneoplastic astrocytes expressing v-src, and suggests that RB-1 and TP53 belong to one single complementation group along with v-src in this transgenic model of astrocytoma development. The stochastic development of astrocytic tumors in GFAP-v-src, TP53+/- GFAP-v-src, and RB-1+/- GFAP-v-src transgenic mice indicates that additional hitherto unknown genetic lesions of astrocytes contribute to tumorigenesis, whose elucidation may prove important for our understanding of astrocytoma initiation and progression.

Animals↗