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1.
Brain Res ; 1213: 152-65, 2008 Jun 05.
Article in English | MEDLINE | ID: mdl-18455153

ABSTRACT

In Alzheimer's disease (AD), cortical neurons develop neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau. The neurons eventually die. There are some hints that cortical neurons may also degenerate without the development of cytoskeletal changes. We investigated this possibility by comparing changes in APP staining and neuronal size with respect to the presence or absence of hyperphosphorylated tau. Adjacent sections of the medial temporal neocortex (Brodmann's area 22) of 5 male AD patients aged 60-88 years (Braak V-VI) and 5 age-matched male non-demented control subjects were i) stained with a modified Bielschowsky silver method in order to reveal NFTs and 'ghost' tangles, ii) single-stained with anti-APP, and iii) double-labeled with anti-APP and AT8. Anti-APP is directed against the beta-amyloid precursor protein and stains virtually all perikarya and proximal neurites of the cortical neurons. AT8 stains pre-tangles, NFTs and extracellular 'ghost' tangles due to the recognition of hyperphosphorylated tau. The study was focused on the supragranular cortical layers II-III, since these layers can be clearly delineated from the adjacent molecular and granular cell layers. The results showed that i) APP staining intensity in neurons was variable in the AD cortex, being clearly different from the invariably intense neuronal staining in all controls. Reduced cytoplasmic APP staining was observed, particular in small neurons, while lack of anti-APP staining in proximal neurites, too, was associated with AD. In addition, ii) cross-sectional area measurement on anti-APP-stained neurons revealed that in AD, as compared to controls, a clear decrease in the number of mainly large-sized neurons (>150 microm2) was accompanied by a significant increase in the percentage of neurons in the smaller size classes, indicating that many large-sized neurons became smaller in AD. iii) Reduced APP staining and decreased neuronal size were not necessarily associated with the presence or absence of hyperphosphorylated tau in these cells. iv) Twenty-six percent of the neurons contained hyperphosphorylated tau, while the level of NFT-related neuronal loss was low in AD. The present study suggests that non-tau based neuronal degeneration is a major phenomenon in the AD neocortex.


Subject(s)
Alzheimer Disease/complications , Alzheimer Disease/pathology , Neocortex/pathology , Nerve Degeneration/etiology , Nerve Degeneration/metabolism , tau Proteins/metabolism , Aged , Aged, 80 and over , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Case-Control Studies , Humans , Male , Middle Aged , Neurofibrillary Tangles/pathology , Neurofilament Proteins/metabolism , Plaque, Amyloid/pathology
2.
Ultrastruct Pathol ; 30(5): 387-91, 2006.
Article in English | MEDLINE | ID: mdl-17090518

ABSTRACT

The ultrastructure of lipofuscin (Lf) was studied in hippocampal and neocortical neurons of children and youngsters between 3 months and 24 years of age. As a standard, regions CA1 and CA4 of Ammon's horn and the gyrus centralis anterior of the left hemisphere were examined, and the ratio of the two components of Lf, the pigment part, and the usually droplet-like lipid part was looked at. Few and small granules with typical linear structures in the pigment part and little lipid droplets were found as early as at the age of 3 months in all brain regions. There were no morphological differences of Lf in the areas of Ammon's horn up to 3 years, but the Lf ultrastructure in Ammon's horn differed clearly from that in the neocortical region. Differences of Lf between the areas CA1 and CA4 were found to appear at the age of 6-8 years, to have a rather variable pattern between age 11 and about 20 years, and to be relatively constant thereafter. The Lf pigment part consisted of irregularly arranged three laminar linear structures. Some varieties could be seen in the size and shape of the Lf granules and in the lipid/pigment ratio. As to the question of Lf being an "age pigment," the findings that the number of Lf granules did not further increase after the period of early adolescence was not consistent with the age pigment hypothesis. No regional or age-dependent differences were found in the Lf of astro- and oligodendroglia.


Subject(s)
Aging/physiology , Hippocampus/ultrastructure , Lipofuscin/metabolism , Neurons/ultrastructure , Adolescent , Adult , Child , Child, Preschool , Hippocampus/metabolism , Humans , Infant , Microscopy, Electron, Transmission , Neurons/metabolism
3.
Clin Neuropathol ; 25(1): 48-56, 2006.
Article in English | MEDLINE | ID: mdl-16465775

ABSTRACT

AIM: The differentiation between low-grade astrocytomas and anaplastic astrocytomas is susceptible to considerable inter-observer variability. In order to contribute to a better standardization of astrocytoma-grading based on quantitative data, the present study focuses on two important aspects not being considered in previous morphometric studies: elaboration of a decision flow chart for tumor grading based on morphometric parameters and appropriate cut-off-values, easily performed using low-cost equipment such as measuring oculars; investigation of the distribution (histograms) of parameters describing nuclear size and internuclear distance, which had been represented in previous studies by their mean and standard deviation only. MATERIAL AND METHODS: At least 300 tumor cell nuclei per case were investigated in paraffin sections from surgical specimen of 75 patients with astrocytomas WHO grade II (n = 23) and anaplastic astrocytomas WHO grade III (n = 52) by means of a digital image analysis system. RESULTS: The morphometric data showed significant differences between both groups of tumors. According to multivariate analysis, the best contribution to tumor grading was achieved by means of parameters concerning the distribution of values for nuclear diameters and internuclear distances. A decision tree was constructed using a knowledge based algorithm, which provided astrocytoma grading based on the distribution of values for nuclear diameter, as well as the numerical nuclear density and proliferation index. Measurements using a measuring ocular took an acceptable amount of time (1.5 hour per case) and showed good reproducibility when compared with measurement by means of digital image analysis. CONCLUSION: The study demonstrates that a morphometric examination of tumor cell nuclei in paraffin sections supports the clinically important differential diagnosis between low-grade and high-grade astrocytomas. The method for classification and the data published in the present study constitute a good basis for a standardized and reproducible grading procedure for astrocytomas, which can be performed in any histologic laboratory even without a digital image analysis system.


Subject(s)
Astrocytoma/classification , Astrocytoma/pathology , Brain Neoplasms/classification , Brain Neoplasms/pathology , Cell Nucleus/ultrastructure , Algorithms , Astrocytoma/ultrastructure , Brain Neoplasms/ultrastructure , Decision Trees , Humans , Image Processing, Computer-Assisted , Reproducibility of Results
4.
Clin Neuropathol ; 24(6): 276-83, 2005.
Article in English | MEDLINE | ID: mdl-16320823

ABSTRACT

Cerebrotendinous xanthomathosis (CTX) is a rare autosomal-recessively transmitted disease of the lipid storage system with an array of general and neurological symptoms, based on the pathological storage of cholestanol and cholesterol. The histologic manifestations are foamy cell granulomata and cholesterol crystals within various tissues, associated with a loss of both nerve cells and demyelination inside the CNS. We present a case of CTX with clinical progression as well as the pathomorphologic autopsy findings. The CNS affection in our case will be demonstrated and the pathogenesis be discussed. Medical treatment of CTX is possible but with variable success. In the case shown, the patient profited only marginally from a long-term application of chenodeoxycholic acid.


Subject(s)
Xanthomatosis, Cerebrotendinous/pathology , Adult , Chenodeoxycholic Acid/therapeutic use , Gastrointestinal Agents/therapeutic use , Humans , Male , Xanthomatosis, Cerebrotendinous/complications , Xanthomatosis, Cerebrotendinous/drug therapy
5.
Neuropathol Appl Neurobiol ; 31(1): 34-44, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15634229

ABSTRACT

Although tumour cell nuclei are important histological structures for grading of astrocytomas according to the WHO-classification of brain tumours, there is no reported morphometric study of astrocytomas which describes quantitatively the four main morphologic criteria of tumour cell nuclei: size, shape, texture (densitometric characteristics) and spatial relationships between the nuclei (topometric analysis). Using a set of morphometric parameters describing these criteria as well as the Ki67-proliferation index, 74 astrocytomas from 74 patients were studied by means of a digital image analysis system. The objective of the study was to test, if these morphometric parameters were sufficient for statistical discrimination between pilocytic astrocytomas WHO-grade I, astrocytomas grade II and anaplastic astrocytomas grade III. Our results showed a correct reclassification of 97.3% (72/74) of the cases with respect to the tumour grade by means of cross-validated discriminant analysis. Morphometric parameters characterizing nuclear shape (shape factors, Fourier-amplitudes) showed the most prominent differences between the three groups of cases, followed by topometric parameters (number of neighbours per nucleus, distances between the nuclei). Less pronounced differences between the tumour grades were found for parameters characterizing nuclear size, nuclear texture and the Ki67-proliferation index. In conclusion, the present morphometric procedure provided good discrimination between the tumour grades, supporting the view that histomorphometry of tumour cell nuclei could be a valuable tool for grading of astrocytomas.


Subject(s)
Astrocytoma/pathology , Astrocytoma/ultrastructure , Brain Neoplasms/pathology , Brain Neoplasms/ultrastructure , Cell Nucleus/pathology , Cell Nucleus/ultrastructure , Algorithms , Densitometry , Humans , Image Processing, Computer-Assisted , Reproducibility of Results
6.
Neuropathol Appl Neurobiol ; 30(4): 315-28, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15305977

ABSTRACT

In this review, the results of previous histomorphometric studies of brain tumours are summarized and discussed with respect to their potential value for diagnostic purposes and for tumour research. In the majority of these studies, human gliomas were investigated. In a few studies, human meningiomas and other human or experimental tumour types were investigated. A computerized image analysis system was used for the morphometric analyses in most studies. The three main histologic structures examined were tumour cell nuclei, nucleolar organizer regions and tumour vessels. The current state of knowledge provides evidence that a diagnostic benefit could be provided by histomorphometric investigations of brain tumours, especially for grading of gliomas and with respect to independent prognostic information. Additional studies are necessary to delineate the spectrum of histomorphometric parameters and the investigation of their prognostic significance for cases with the same tumour type and tumour grade. Together with many recently published observations in this field, this review shows that histomorphometry is an important approach towards the investigation of brain tumour biology.


Subject(s)
Brain Neoplasms/pathology , Brain/pathology , Animals , Cell Nucleolus/ultrastructure , Cell Nucleus/chemistry , Cell Nucleus/genetics , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Glioma/pathology , Humans , Meningioma/pathology
7.
Clin Neuropathol ; 23(3): 113-9, 2004.
Article in English | MEDLINE | ID: mdl-15200289

ABSTRACT

Four cases of spontaneous intracranial hemorrhage (ICH) are described in which the diagnosis of a cerebral amyloid angiopathy (CAA) was made in the biopsy specimens. In one further case CAA was detected on autopsy after intracranial hemorrhage (ICH). Amyloidotic degeneration of the vessel walls appeared to be the most likely reason for the ICH which in these cases especially involved superficial neocortical regions. In all cases, co-deposition of A4beta-amyloid and ALlambda-amyloid was found in diseased leptomeningeal and cortical vessels. Besides CAA, all 5 patients suffered from other diseases which had affected the blood vessel walls such as atherosclerosis, diabetes mellitus or arterial hypertension. However, no signs of systemic amyloidosis could be detected in these cases. It is suggested that the observed co-deposition of 2 amyloid subtypes is based on the combination of 2 different diseases, one of which results in a local production of A4beta-amyloid in the tunica media of cerebral blood vessels and another one, e.g. arterial hypertension, which impairs the permeability of the blood vessels by affection of the tunica intima allowing for the pathological penetration of circulating immunoglobulin lambda-light chains into the vessel wall. Subsequently, the preexisting A4beta-amyloid might have induced the polymerization of the lambda-light chains to ALlambda-amyloid in the media of the vessels and could have aggravated the amyloidotic degeneration of the vessel walls.


Subject(s)
Blood Vessels/pathology , Brain/blood supply , Cerebral Amyloid Angiopathy/pathology , Intracranial Hemorrhages/pathology , Plaque, Amyloid/pathology , Adult , Aged , Amyloid beta-Peptides/metabolism , Blood Vessels/metabolism , Brain/diagnostic imaging , Brain/pathology , Cell Membrane Permeability/physiology , Cerebral Amyloid Angiopathy/complications , Cerebral Amyloid Angiopathy/metabolism , Cerebral Cortex/blood supply , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Fatal Outcome , Female , Humans , Hypertension/complications , Immunoglobulin lambda-Chains/metabolism , Intracranial Hemorrhages/etiology , Intracranial Hemorrhages/physiopathology , Male , Plaque, Amyloid/metabolism , Serum Amyloid A Protein/metabolism , Tomography, X-Ray Computed
8.
Ultrastruct Pathol ; 28(5-6): 341-51, 2004.
Article in English | MEDLINE | ID: mdl-15764582

ABSTRACT

Lipofuscin represents an integral part of neurons and glial cells in mammals and in submammalian species. It is a special lysosomal organelle, takes part of cellular metabolism, and is a structural expression of catabolic pathways. Species-specific differences of lipofuscin indicate metabolic differences of the relevant neurons. The authors have studied the ultrastructure of neuronal lipofuscin in the hippocampus and cerebral neocortex of dogs, horses, cows, elephants, rats, mice, apes, and humans to answer the question of species-specific differences of this organelle. Paraffin sections of formalin-fixed material were investigated by hematoxylin-eosin and PAS staining, by fluorescence microscopy for autofluorescence, with a laser scanning confocal microscope and by electron microscopy. In the animals studied and in humans the lipofuscin displayed, in addition to the general trilaminar substructure, species-specific appearances. No differences were found in the lipofuscin structure between neocortical and hippocampal neurons of the separate animal species. In contrast, in humans, neurons of the hippocampus showed a particular lipofuscin structure, not only different from the neocortical one, but also with differences between CA1 and CA3/4 sectors. Interestingly, in apes a transitional situation was found with slight differences between neocortical and hippocampal lipofuscin, especially in the rhesus monkey. This peculiarity was corroborated by the distribution of special pentilaminar linear structures in the lipofuscin pigment in all animals, only sparsely in the rhesus monkey and not in humans. The results indicate that lipofuscin ultrastructure of neocortical and hippocampal neurons is species specific and that lipofuscin in the human hippocampal neurons displays structures characteristic of man differing from the neocortical neuronal lipofuscin. The neuronal lipofuscin of apes, especially of the rhesus monkey displays structures in between humans and lower mammals. Nothing is known about the functional significance of these findings. They may indicate metabolic and/or functional characteristics of the relevant neurons.


Subject(s)
Hippocampus/metabolism , Lipofuscin/metabolism , Mammals/metabolism , Neocortex/metabolism , Neurons/metabolism , Adult , Animals , Cattle , Dogs , Hippocampus/ultrastructure , Humans , Mammals/anatomy & histology , Mice , Microscopy, Confocal , Microscopy, Electron, Transmission , Neocortex/ultrastructure , Neurons/ultrastructure , Periodic Acid-Schiff Reaction , Rats , Rats, Sprague-Dawley , Species Specificity
9.
J Neurol Neurosurg Psychiatry ; 74(8): 1142-4, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12876257

ABSTRACT

A case of biopsy verified progressive multifocal leucoencephalopathy (PML) in an HIV patient is presented. Imaging and histological examination confirmed remarkable inflammatory activity accompanied by an unusually benign clinical course despite no clear evidence of immune reconstitution after the start of antiretroviral treatment. This case not only raises several questions regarding the pathophysiology of PML, but gives also evidence that AIDS associated inflammatory PML must be considered another clinical entity in the expanding range of diseases now commonly referred to as the immune reconstitution syndrome.


Subject(s)
AIDS Dementia Complex/drug therapy , AIDS-Related Opportunistic Infections/drug therapy , Antiretroviral Therapy, Highly Active , Encephalitis/immunology , Leukoencephalopathy, Progressive Multifocal/drug therapy , AIDS Dementia Complex/diagnosis , AIDS Dementia Complex/immunology , AIDS Dementia Complex/pathology , AIDS-Related Opportunistic Infections/diagnosis , AIDS-Related Opportunistic Infections/immunology , AIDS-Related Opportunistic Infections/pathology , Antiretroviral Therapy, Highly Active/adverse effects , Biopsy , Brain/immunology , Brain/pathology , CD4 Lymphocyte Count , Encephalitis/pathology , Follow-Up Studies , Humans , Image Enhancement , Leukoencephalopathy, Progressive Multifocal/diagnosis , Leukoencephalopathy, Progressive Multifocal/immunology , Leukoencephalopathy, Progressive Multifocal/pathology , Lymphocytes/immunology , Lymphocytes/pathology , Macrophages/immunology , Macrophages/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology
10.
Clin Neuropathol ; 22(3): 101-9, 2003.
Article in English | MEDLINE | ID: mdl-12809352

ABSTRACT

A female patient started to suffer from transient ischemic attacks when she was 47 years of age, followed by increasing predominantly left-side spastic tetraparesis, generalized seizures and progressive dementia over a period of 11 years. She died when she was 58 years of age. On gross examination the brain showed enlarged ventricles and arteriosclerotic changes of large extracerebral vessels of the circulus arteriosus. Microscopic examination of the atrophic brain showed innumerable incomplete microinfarcts in the white and gray matter throughout all parts of the brain. In the white matter these lesions were characterized by small foci of demyelination and loss of oligodendrocytes while occasionally some scavenger cells were seen. Axons seemed to be unaffected or displayed irregular axonal regeneratory growth. Any inflammatory reaction failed. In the cerebral cortex and subcortical nuclei the lesions showed loss of neurons and decrease in synaptophysin expression. Intracerebral arteries showed fibrosis or fibrohyalinosis of the entire intracerebral small-vessel network. In addition, numerous uncommon clusters of angioma-like telangiectatic vessels were observed. Medium-sized ischemic infarcts were found in the right putamen and adjacent internal capsule region, left-side dorsolateral brain stem and cerebellar hemisphere as well as a left-side pyramidal tract degeneration. Contralateral pseudohypertrophy of the inferior olivary nucleus was seen. The clinical and the neuropathologic observations made in this patient are compatible with small vessel disease characterized by a multicentric special and not yet described type of incomplete mini-infarcts in cerebral cortex and white matter accompanied by some larger ischemic infarcts of the common type in brain stem and cerebellum.


Subject(s)
Alzheimer Disease/pathology , Brain/blood supply , Brain/pathology , Cerebral Arteries/pathology , Dementia, Vascular/pathology , Ischemic Attack, Transient/pathology , Brain/diagnostic imaging , Dementia, Vascular/etiology , Dementia, Vascular/physiopathology , Diagnosis, Differential , Female , Humans , Intracranial Arteriosclerosis/complications , Intracranial Arteriosclerosis/pathology , Ischemic Attack, Transient/etiology , Ischemic Attack, Transient/physiopathology , Magnetic Resonance Imaging , Middle Aged , Quadriplegia/etiology , Seizures/etiology , Tomography, X-Ray Computed
11.
Clin Neuropathol ; 22(3): 129-36, 2003.
Article in English | MEDLINE | ID: mdl-12809355

ABSTRACT

OBJECTIVE: To investigate the influence of nuclear morphology of tumor cells on survival time of patients with primary glioblastomas. STUDY DESIGN: Tumor cell nuclei have been measured in paraffin sections from 51 glioblastomas (Ki-67 immunostaining). In each tumor, the region with the highest proliferative activity has been selected for performing the morphometric analysis. Nuclear area, shape variables (roundness factor, Fourier amplitudes) and the proliferation index Ki-67 have been determined. Statistical relationships between these variables have been tested by principal component analysis and Spearman's correlation analysis. The survival time has been tested using Kaplan-Meier analysis. The influence of morphometric variables on survival time and on the time until recurrence has been tested by Cox analysis. RESULTS: There is a significant correlation of mean value and standard deviation of nuclear area with shape variables. Cox analysis showed a significant influence of the quantitative morphologic variables on survival time for patients with and without complete surgical resection. For patients with complete surgical resection, there was a distinct influence of mean nuclear area on survival time. Patients with incomplete surgical resection of the tumors had a significantly shorter survival. No significant influence of the variables on the time from surgery to recurrence could be shown. CONCLUSION: Quantitative morphology of tumor cell nuclei in our set of glioblastoma cases showed a statistically significant relation with the survival time of the patients, indicating the biological significance of nuclear morphology in glioblastomas.


Subject(s)
Brain Neoplasms/pathology , Brain Neoplasms/ultrastructure , Cell Nucleus/pathology , Glioblastoma/mortality , Glioblastoma/pathology , Adult , Aged , Brain Neoplasms/metabolism , Fourier Analysis , Glioblastoma/metabolism , Glioblastoma/surgery , Glioblastoma/ultrastructure , Humans , Immunohistochemistry , Ki-67 Antigen/metabolism , Middle Aged , Proportional Hazards Models
12.
Clin Neuropathol ; 22(3): 119-28, 2003.
Article in English | MEDLINE | ID: mdl-12809354

ABSTRACT

In 2 cases of tuberous sclerosis complex (TSC), a disseminated distribution of atypical cells throughout the white matter and cortex of the telencephalon has been found. No cortical tubera were observed. In 1 of the cases, ventricular wall tumors (giant astrocytomas) were present. Stripes and candle guttering excrescences of groups of atypical cells perpendicular to the ventricular wall and to the cortical surface indicate erroneous genetic information in sets of neuroepithelial germ cells. This is compatible with the somatic second hit hypothesis effective in addition to the basic defect of TSC1 and TSC2 genes. The normal age-correspondend corticogenesis with regular layering and regular differentiation of neurons and glia without any cortical malformation or dysplasia and the sparing of allocortical parts of the telencephalon (hippocampus) as well as of basal ganglia, cerebellum, brain stem and spinal cord point to the rather late appearance of atypical cells which manifest in loco and do not interfere with corticogenesis. The bidirectional potential of atypical cells is obvious by their strong GFAP and APP surface staining. This coexpression indicates glial as well as neuronal features and emphasizes the relatively low level of differentiation of these cells. In their disseminated localization in our cases, these cells do not form tumors in the telencephalic white matter or cortex thus escaping sonographic detection before birth.


Subject(s)
Biomarkers, Tumor/metabolism , Cerebral Cortex/embryology , Neurons/pathology , Telencephalon/pathology , Tuberous Sclerosis/etiology , Tuberous Sclerosis/pathology , Cerebral Cortex/growth & development , Female , Humans , Infant, Newborn , Male , Pregnancy , Telencephalon/metabolism
13.
Neurology ; 60(6): 983-7, 2003 Mar 25.
Article in English | MEDLINE | ID: mdl-12654964

ABSTRACT

OBJECTIVE: Classic infantile spinal muscular atrophy (SMA) is believed to be a purely motor disorder, affecting neurons of the spinal anterior horn and nuclei of the lower cranial nerves. Other organ malformations or peripheral nerve involvement have been regarded as exclusion criteria for infantile SMA. Whether SMN protein deficiency can also lead to loss of sensory neurons has not been systematically addressed. METHODS: The authors evaluated the sural nerve biopsies of 19 patients with infantile SMA of varying severity. The diagnosis of SMA was confirmed by the presence of a homozygous deletion of the SMN1 gene in all patients. RESULTS: In seven unrelated infants with SMA type I, axonal degeneration of the sural nerve was noted. Five patients showed abnormal sensory conduction, thus prompting sural nerve biopsy. Sural nerves showed different degrees of axonal loss: fiber density ranged from 3.482 to 22.076/mm2 and was markedly reduced in four patients. There was no evidence of primary demyelination: the ratio of total myelinated fiber thickness to axon diameter (g-ratio) was normal in the patients examined. In seven patients with SMA II and five patients with SMA III, no sural nerve alterations were seen, and conduction velocity was normal. In addition to SMN1 gene deletions, homozygous NAIP gene deletions were detected in six out of seven infants with peripheral neuropathy, whereas there was no evidence of a large deletion including the multicopy markers C212 and Ag1-CA in two out of three families tested. CONCLUSIONS: In this series of patients with SMA I through III who underwent sural nerve biopsy, there was significant sensory nerve pathology in severely affected patients with SMA type I, whereas there were no sensory nerve alterations clinically or morphologically in patients with milder SMA type II or III.


Subject(s)
Nerve Tissue Proteins/deficiency , Neurons, Afferent/pathology , Sensation Disorders/etiology , Spinal Muscular Atrophies of Childhood/complications , Axons/ultrastructure , Cyclic AMP Response Element-Binding Protein , Exons/genetics , Female , Genes, Recessive , Genetic Heterogeneity , Humans , Infant , Infant, Newborn , Male , Nerve Fibers, Myelinated/pathology , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Neuronal Apoptosis-Inhibitory Protein , Phenotype , RNA-Binding Proteins , SMN Complex Proteins , Spinal Muscular Atrophies of Childhood/classification , Spinal Muscular Atrophies of Childhood/genetics , Sural Nerve/pathology , Survival of Motor Neuron 1 Protein , Wallerian Degeneration
14.
Pathologe ; 23(4): 252-9, 2002 Jul.
Article in German | MEDLINE | ID: mdl-12185779

ABSTRACT

To detect a possible correlation between the neurology and duration of Creutzfeldt-Jakob disease (CJD) and cerebral pathology, we studied 22 autopsy cases by histological and immunohistochemical methods. The duration of disease ranged between 1 and 15 months with an average of 5.2 months. Only in 11 cases was the EEG typical for CJD. Morphologically the changes varied from minimal spongy changes to severe neuronal loss and brain atrophy. For the three cortical regions examined semiquantitatively, there was no correlation between the severity of spongiform changes and the duration of disease or the pattern of neurological symptoms. The study shows that more extensive sampling for the detection of regional heterogeneity of changes is mandatory in spongiform encephalopathies, and that complicating changes such as intermittent infections may play a role for the survival time as well. Moreover, genetic determinants, prion protein polymorphisms and the mode of exposure have to be considered as possible modulating factors.


Subject(s)
Cerebral Cortex/pathology , Creutzfeldt-Jakob Syndrome/pathology , Creutzfeldt-Jakob Syndrome/physiopathology , Aged , Autopsy , Brain/pathology , Child , Female , Humans , Male , Middle Aged
15.
Clin Neuropathol ; 21(4): 139-44, 2002.
Article in English | MEDLINE | ID: mdl-12143924

ABSTRACT

The clinical course and the postmortal pathological findings in a female newborn showing parental consanguinity are presented. One week afterbirth, the infant developed fever, hepatosplenomegaly and polyserositis. Rapidly progressing immunodeficiency due to pancytopenia led to pneumonia and untreatable respiratory distress with fatal outcome after 2 weeks. Autopsy findings revealed multisystem lymphohistiocytic infiltration with marked erythrophagocytosis. Neuropathological findings included lymphohistiocytic leptomeningitis, perivascular cuffing by lymphohistiocytic infiltrations in the cerebral white matter, predominantly in subependymal location, and multifocal lymphohistiocytic infiltrations of the cerebral grey matter and the cervical spinal cord. Erythrophagocytosis was the histopathological hallmark at all sites. Regarding the fatal clinical course, the medical history of parental consanguinity and the histopathological features, postmortem diagnosis was familial erythrophagocytic lymphohistiocytosis (FEL, Farquhar's disease). The present case is discussed with focus on CNS involvement in FEL by reviewing the relevant literature.


Subject(s)
Central Nervous System/pathology , Histiocytosis, Non-Langerhans-Cell/genetics , Histiocytosis, Non-Langerhans-Cell/pathology , Polycythemia/genetics , Polycythemia/pathology , Central Nervous System/physiopathology , Female , Histiocytosis, Non-Langerhans-Cell/physiopathology , Humans , Infant, Newborn , Polycythemia/physiopathology
16.
Neuropediatrics ; 32(5): 267-70, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11748499

ABSTRACT

A premature boy with a congenital form of nemaline myopathy due to mutation in the ACTA1-gene showed decreased carnitine levels in the eighth week of life. After sufficient oral carnitine substitution he improved gradually. In the first 15 months of life he made good progress; he reached full head control, learned to sit unsupported and was able to raise objects. At that time the carnitine levels were normal without substitution. Nemaline myopathy is clinically and genetically heterogenous. The pathogenesis of the muscle weakness is poorly understood. Disturbances of carnitine metabolism in this group of patients as one possibility are conceivable. Further investigations of carnitine metabolism in patients with nemaline myopathy may shed light on the pathogenesis of this entity.


Subject(s)
Bacterial Proteins/genetics , Carnitine/deficiency , Membrane Proteins/genetics , Mutation/genetics , Myopathies, Nemaline/genetics , Biopsy , Follow-Up Studies , Humans , Infant , Infant, Newborn , Male , Microscopy, Electron , Muscle, Skeletal/pathology , Myopathies, Nemaline/diagnosis , Myopathies, Nemaline/pathology
17.
Mamm Genome ; 12(9): 678-86, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11641715

ABSTRACT

Lines of mice selected for many generations for high or low growth in several laboratories around the world have been collected, and from these, inbred lines are being developed by recurrent full-sib mating in Edinburgh. There are seven high selected lines and four low lines (each low line is from the same base population as one of the high lines), and the histories of each are summarized. Mean body weight of males at 70 days of age in the Edinburgh laboratory in the heaviest inbred line (77 g) is 4.8-fold higher than in the lightest line (16 g), and 1.9-fold higher than in the least extreme high line (41 g). Litter size, food intake, and fat content also differ substantially. These inbred extreme selected lines are a uniquely valuable resource for QTL or gene mapping, candidate gene identification, and elucidation of epistatic effects.


Subject(s)
Chromosome Mapping , Growth/genetics , Mice, Inbred Strains/growth & development , Animals , Body Weight , Crosses, Genetic , Eating , Female , Genetic Linkage , Male , Mice , Quantitative Trait, Heritable , Selection, Genetic
18.
Clin Neuropathol ; 20(5): 200-11, 2001.
Article in English | MEDLINE | ID: mdl-11594505

ABSTRACT

The giant axonal neuropathy (GAN) is morphologically characterized by axonal swellings and accumulations of neurofilaments in giant axons and other cell types. Curly hair is not a constant finding. The clinical course is progressive and mostly starts in early childhood. We report the case of a boy aged 6 years at the time of sural nerve and muscle biopsy. Suralis nerve showed a reduced numerical density of myelinated fibres with a consecutive endoneural fibrosis. Morphometric investigation revealed a pronounced reduction of fibres measuring 8-12 microm in diameter. Giant axons were seen in relatively low number and were not very large with a maximum diameter of 18 microm. They had a relatively thin myelin sheet proved also by the high G ratio in the histogram. Many onion bulb formations of Schwann cells were present. There are only few reports of giant axons with such low maximum diameter in cases with GAN, the lowest maximum diameters being reported in case reports on Japanese children. Up to now, this is the first report of a non-Japanese patient with a low maximum diameter of giant axons of less than 20 microm in peripheral nerve biopsy. Ultrastructurally, typical accumulations of neurofilaments and osmiophilic aggregates were found in giant axons. Other diagnoses with occurrence of giant axons could be excluded in view of the absence of specific findings. Sporadic or familial cases with giant axons are discussed. Sceletal muscle biopsy (M. quadriceps femoris) showed neurogenic affection with presence of small angulated atrophic muscle fibres.


Subject(s)
Axons/pathology , Gait Disorders, Neurologic/pathology , Hereditary Sensory and Motor Neuropathy/pathology , Retrograde Degeneration/pathology , Biopsy , Child , Child, Preschool , Diagnosis, Differential , Disease Progression , Electromyography , Follow-Up Studies , Gait Disorders, Neurologic/diagnosis , Gait Disorders, Neurologic/genetics , Hereditary Sensory and Motor Neuropathy/diagnosis , Hereditary Sensory and Motor Neuropathy/genetics , Humans , Male , Microscopy, Electron , Neurofibrils/pathology , Neurologic Examination , Schwann Cells/pathology , Sural Nerve/pathology
19.
Clin Neuropathol ; 20(2): 80-6, 2001.
Article in English | MEDLINE | ID: mdl-11327302

ABSTRACT

Giant cell arteritis (GCA) is a disease chiefly found in elderly patients. Intracranial vessels are rarely involved in GCA. Here we report the case of a 19-year-old woman with GCA in the basilar and vertebral arteries. Two weeks after the first symptoms, she developed an aneurysmatical dilatation of the right vertebral artery which ruptured leading to subarachnoid hemorrhage. Although the ruptured right vertebral artery was clipped neurosurgically, she died two days later. Autopsy revealed GCA with focal medial necrosis and intimal thickening of the vertebral arteries and the basilar artery. No other arteries were affected. In the involved vessels, the media exhibited C1q immunoreactivity. At the intimal site of the internal elastic lamina there were increased levels of elastase. Other arterial diseases showing the pattern of GCA were excluded. This case demonstrates that GCA is not necessarily restricted to elderly people. Moreover, this case shows that a GCA-induced aneurysm is a very rare reason for subarachnoid hemorrhage even in young adults.


Subject(s)
Aneurysm, Ruptured/pathology , Giant Cell Arteritis/pathology , Vertebral Artery/pathology , Vertebrobasilar Insufficiency/pathology , Adult , Basilar Artery/pathology , Brain Stem/pathology , Diagnosis, Differential , Fatal Outcome , Female , Humans , Postoperative Complications/pathology , Subarachnoid Hemorrhage/pathology
20.
Anal Quant Cytol Histol ; 23(2): 135-43, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11332080

ABSTRACT

OBJECTIVE: To confirm a relationship between histomorphology of glioblastomas and amplification of the gene for the epidermal growth factor receptor (EGFR) as the most important molecular biologic alteration in these tumors. STUDY DESIGN: In paraffin sections of surgical specimens from 71 primary resected glioblastomas, tumor cell nuclei in the region with the highest proliferative activity (Ki-67 immunostaining) were investigated morphometrically. Shape variables (roundness factor, Fourier amplitudes) and nuclear area were measured. Additionally, the numerical density of Ki-67-positive tumor cell nuclei was estimated. Differential polymerase chain reaction (PCR) was performed from paraffin sections of the same tumor area. The signals for the EGFR gene and IFN gamma reference gene were quantified densitometrically. RESULTS: Cases with distinct EGFR gene amplification (EGFR/IFN ratios > 5) revealed significantly lower mean values for several Fourier amplitudes, indicating a more regular nuclear shape when compared with cases without evidence of EGFR gene amplification (EGFR/IFN-ratios < or = 1). The Ki-67 index and nuclear area showed no significant differences between these groups. Although a large variation in nuclear morphology was observed for cases without evidence of EGFR gene amplification, discriminant analysis based on morphometric variables provided a good separation of these cases from cases with distinct EGFR gene amplification, with a high percentage of statistically correct reclassified cases. CONCLUSION: Our results provide evidence of a relationship between genetic alterations and histomorphology of glioblastomas.


Subject(s)
Brain Neoplasms/pathology , Cell Nucleus/pathology , ErbB Receptors/genetics , Gene Amplification , Genes, erbB-1 , Glioblastoma/genetics , Glioblastoma/pathology , Ki-67 Antigen/analysis , Adult , Aged , Cell Division/physiology , Densitometry , Fourier Analysis , Humans , Middle Aged , Polymerase Chain Reaction
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