Biomedical subjects

J Bohl

Publications and source records attributed to J Bohl.

At least 19 recordsLinked to original sources

PubMed2000

Competitive binding to a charged leucine motif represses transformation by a papillomavirus E6 oncoprotein.

E6 oncoproteins from HPV-16 and bovine papillomavirus type 1 (BPV-1) bind to similar leucine-rich peptides termed charged leucine motifs found on the cellular focal adhesion protein paxillin and the E3 ubiquitin ligase E6AP. BPV-1 E6 (BE6) mutants that do not bind to paxillin are defective at inducing cellular transformation. It is possible, however, that BE6 mutants that do not bind paxillin are defective for transformation for an unrelated reason than the ability to bind to charged leucine motifs. To address the role of BE6 interaction with charged leucine motifs, we fused a BE6-binding charged leucine motif to the amino terminus of BE6, thereby creating an autoinhibitory binding domain. We found that the fusion protein failed to bind to paxillin or transform murine C127 cells. Mutation of the amino terminal binding motif in the fusion protein restored both interaction with paxillin and transformation. This demonstrates that BE6 transformation requires binding to charged leucine motifs on particular cellular proteins and that transformation by papillomavirus oncoproteins can be repressed by competitive interactions with charged leucine motifs.

Amino Acid Sequence↗

PubMed2000

Distribution of SNAP-25 in transient neuronal circuitries of the developing human forebrain.

The distribution of SNAP-25 is demonstrated within prominent transient structures in the developing human forebrain. During early fetal development SNAP-25 is mainly expressed in axons of the intermediate zone and the internal capsule. The fibers appear directed towards the mantle zone of the ganglionic eminence and the perireticular nucleus located within the internal capsule. Cells of these two areas are shown to interact with SNAP-25 immunoreactive structures with the aid of double-labellings. The SNAP-25 immunoreactive fibers may represent corticofugal axons which contact the perireticular nucleus and ganglionic eminence which are regarded as intermediate targets providing a scaffold for growing axons. Anti-SNAP-25, thus, is an appropriate marker of intermediate targets which are involved in brain injuries of preterm infants.

Adult↗

PubMed2000

[Clinical aspects of "argyrophilic grain disease"].

Argyrophilic grain disease (AGD) is a frequently occurring degenerative illness of the aging human brain. It is accompanied by progressive pathological alterations of the cytsokeleton which are traceable to an abnormal phosphorylation of the microtubule associated tau protein. Histologically, it is possible with the help of suitable staining techniques to identify pathognomonic spindle-shaped cellular inclusions (argyrophilic grains). These cellular inclusions display a typical cortical as well as subcortical distribution pattern. The goal of the present study is the retrospective evaluation of the clinical findings from 53 individuals with neuropathologically demonstrable AGD-related changes of the brain. Nearly one-half of the cases (49%) was classifiable as demented in accordance with DSM IV-criteria. Moreover, the frequency of the dementia increased significantly in relation to the growing severity of the AGD-associated pathological cytoskeletal degeneration. These results confirm the assumption that AGD can cause degenerative changes ranging from cognitive impairment all the way to dementia. They also underscore the necessity of further prospective studies pertaining to the clinical aspects of this still enigmatic disease.

Aged↗

PubMed2000

Pathological changes in the parahippocampal region in select non-Alzheimer's dementias.

The transentorhinal and entorhinal regions of the human brain extend over the ambient gyrus and anterior portions of the parahippocampal gyrus. They are important components of the limbic loop which receives its major afferents from the neocortical sensory association areas and generates powerful efferent projections both directly and via intermediary relay stations to the prefrontal cortex. The bilateral structural preservation of limbic loop components is a prerequisite for the maintenance of intact memory functions. In progressive neurodegenerative diseases, such as Alzheimer's disease, argyrophilic grain disease, Pick's disease, idiopathic Parkinson syndrome, and Huntington's disease, the transentorhinal and entorhinal regions are particularly susceptible to severe pathological changes. The transentorhinal region typically registers the initial alterations and becomes the most severely involved. From this transitional region of the mesocortex, the alterations usually invade with decreasing severity both the entorhinal region and temporal proneocortex. Each type of lesion that develops in the above-mentioned neurodegenerative disorders hampers or even interrupts data-transport from the sensory neocortex to the prefrontal neocortex, thereby contributing to the insidious development of progressive changes in personality, cognitive decline, and, ultimately, dementia.

Alzheimer Disease↗

PubMed2000

Identification of a second transforming function in bovine papillomavirus type 1 E6 and the role of E6 interactions with paxillin, E6BP, and E6AP.

Papillomavirus E6 oncoproteins transform mammalian cells through interaction with cellular proteins. Bovine papillomavirus type 1 E6 (BE6) interacts with three previously described cellular targets: the E6AP E3 ubiquitin ligase, the calcium-binding protein E6BP (also known as ERC-55), and paxillin, which is a focal adhesion adapter protein. BE6 interacts strongly with each of these proteins in vitro, binding to similar peptide sequences found in E6AP, E6BP, and paxillin. To determine which BE6 interactions are necessary for transformation by BE6, we used a novel selection strategy for temperature-sensitive BE6 mutants in yeast that could discriminate in their interaction between E6AP, E6BP, and paxillin. All BE6 mutants that retained transforming ability retained association with paxillin, while some mutants that were transformation positive failed to interact with E6AP or E6BP. This study demonstrates that oncogene mutants that are temperature sensitive for transformation can be selected in yeast and that the induction of anchorage-independent cell proliferation by BE6 does not require strong association of BE6 with either E6AP or E6BP. Of particular interest is the identification of a BE6 mutant that interacts strongly with the acidic charged leucine motifs of E6AP, E6BP, and paxillin but is devoid of transformation activity, thereby genetically identifying a second essential transformation function in BE6 that is independent of interaction with acidic charged leucine motifs.

Animals↗

PubMed2000

Transient structures of the human fetal brain: subplate, thalamic reticular complex, ganglionic eminence.

Morphological features of the subplate, the thalamic reticular complex and the ganglionic eminence, which represent three major transient structures of the human fetal forebrain, are summarized with special reference to their functional roles. The subplate harboring various neuronal types is an outstandingly wide zone subjacent to the cortical plate in the human fetal brain. Within the subplate various cortical afferents establish synaptic contacts for a prolonged period before entering the cortical plate. Therefore, the subplate is regarded as a "waiting compartment" which is required for the formation of mature cortical connections. Next to the thalamic reticular nucleus, within the fibers of internal capsule, the perireticular nucleus is located which has been established as a distinct entity during development. Its various neuronal types express a number of different neuroactive substances. Perinatally, the perireticular nucleus is drastically reduced in size. It is involved in the guidance of corticofugal and thalamocortical fibers. The ganglionic eminence is a conspicuous proliferative area that persists throughout nearly the entire fetal period. In the human fetal brain it extends medially upon the dorsal thalamic nuclei which receive precursor cells from the ganglionic eminence. Postmitotic cells in the marginal zone of the ganglionic eminence serve as an intermediate target for growing axons. On the whole, all three structures establish transient neural circuitries that may be essential for the formation of adult projections. The characteristics of the three transient structures are particularly relevant for developmental neuropathology as these structures may be damaged in disorders that preferentially occur in preterm infants.

Animals↗

PubMed1999

Neuropathology of Alzheimer's disease: what is new since A. Alzheimer?

Alzheimer's disease results from severe cytoskeletal alterations in only a few neuronal types within the human central nervous system. These intraneuronal changes take the form of neurofibrillary tangles and neuropil threads. Beginning in predisposed induction sites in the allocortex, the lesions follow a predictable sequence as they engulf other territories of the cerebral cortex and a specific set of subcortical nuclei. Some components of the brain are devastated, while others remain intact until the end phase of the disease. Assessment of the location of the afflicted neurons and the severity of the lesions allows the distinction of stages in the development of the disease. The degenerative process begins with the emergence of the first lesions, at whatever age it occurs. The illness remains subclinical for years, and proceeds inexorably, gradually laying waste to higher order limbic system centers. Clinical symptoms are observed only late in the course of the disease, and their appearance is usually concurrent with the encroachment of the destructive process upon neocortical association areas. The sequence of destruction bears a striking resemblance to the inverse sequence of cortical myelination. Late myelinating areas and layers develop the disease-related changes earlier and at higher densities than those which are myelinated early. The brain of the human adult is heavily laden with intraneuronal deposits of lipofuscin and neuromelanin pigment. The average density of neuronal pigmentation in given cortical areas mirrors the density of cytoskeletal lesions that develop in the course of the disease. Pigment-laden neuronal types giving rise to a single long, thin, unmyelinated or sparsely myelinated axon are particularly prone to developing Alzheimer's disease-related cytoskeletal changes.

Aged↗

PubMed1999

Apolipoprotein E isoforms and the development of low and high Braak stages of Alzheimer's disease-related lesions.

In recent research, apolipoprotein-E (apoE) polymorphism has been shown to influence the formation of neurofibrillary changes and the accumulation of beta/A4-amyloid, the histopathological hallmarks of Alzheimer's disease (AD). Clinical studies associate the apoE allele epsilon4 with earlier onset of the disease, although the clinical speed of progression remains unchanged. Time course estimates have also provided evidence which indicates that the clinical phase of AD constitutes only 10-20% of the total time span needed for the development of this slowly progressing degenerative brain disorder. Due to the lack of reliable clinical tests for the detection of pre-symptomatic stages of AD, we set out with an autopsy approach to monitor neuropathology of the long pre-clinical phase of AD. This study examined beta/A4-peptide deposition and the formation of neurofibrillary changes staged according to the Braaks' classification in groups of individuals matched for age and sex with different genotypes. In comparison with epsilon3 homozygotes, the presence of the epsilon4 allele is statistically associated with a higher stage of beta/A4-peptide deposition and neurofibrillary change formation (chi2-test, P<0.01 for beta/A4-stage and P<0.001 for neurofibrillary changes). The effect of the epsilon2 allele differs. Its presence is associated with a lower stage of neurofibrillary pathology in individuals below the age of 80 but with a higher stage thereafter compared to age- and sex-matched epsilon3 homozygotes. Accordingly, the statistical juxtaposition of individuals over 80 years with epsilon4 alleles and those with epsilon2 alleles showed no significant difference with respect to the stages. Our findings indicate that apoE-variants have different effects on the speed of histopathology formation, even in the pre-clinical stages of AD. This suggests that clinical onset, course and pathogenesis of AD are influenced by the apoE genotype.

Alleles↗

PubMed1999

Alterations in the organization of the isocortical layer I in trisomy 22.

The isocortical layer I of human fetal brains obtained from different cases of chromosomal abnormalities (trisomy 18, 21, 22) and controls without pathological disturbances were investigated histologically and immunohistochemically by using the antibodies SMI 311, SMI 35 and SMI 81 (SNAP 25) as well as antibodies against GAP 43 and calretinin. In cases of trisomy 22 the Cajal-Retzius cells in Nissl-sections and in SMI 311-immunopreparations do not reveal any alterations regarding their location or morphology. However, the axonal plexus, selectively labelled with SMI 35, normally located in layer Ib, is malpositioned in Ia. Likewise, SNAP 25- and GAP 43-immunoreactive structures, which were taken as signs of synaptogenesis, are displaced and appear in Ia instead of Ib. Cases of trisomy 18 and 21 show no changes within the organization of layer I. In trisomy 22 the isocortical layer I reveals malpositioned axonal plexus and a corresponding displacement of synaptic proteins. The possible significance of this alteration in the developmental process of the isocortex is discussed.

Brain↗

PubMed1999

Leptomeningeal carcinomatosis and cranial nerve palsy as presenting symptoms of a clinically inapparent gallbladder carcinoma.

We present an occult metastatic signet-ring cell gallbladder carcinoma in a 78-year-old woman, who complained of recurrent headaches, dysarthria, and paresis of the tongue. Cranial imaging showed contrast enhancement of the basal leptomeninges, and the cerebrospinal fluid displayed clusters of adenocarcinoma cells proposed as leptomeningeal carcinomatosis of the breast, lung or gut. However, postmortem examination revealed the gallbladder as the site of the primary carcinoma with focal signet-ring cell differentiation. In patients with progressive neurologic deterioration due to leptomeningeal carcinomatosis, adenocarcinomas from the gastrointestinal and hepatic systems should be considered. It is likely that signet-ring cell carcinomas display an increased affinity to leptomeningeal spread.

Aged↗

PubMed1999

Distribution patterns of vimentin-immunoreactive structures in the human prosencephalon during the second half of gestation.

Neuronal migration is guided by long radially oriented glial fibres. During late stages of development radial glial cells are transformed into astrocytes. A predominant intermediate filament protein within radial glial cells and immature astrocytes is vimentin. In this study fetal brain sections were used to demonstrate the transient features of vimentin-positive radial glia. In the lower half of the cerebral wall of the 6th gestational month bundles, curvature, and crossing of vimentin-positive fibres are regularly seen. Moreover, fibres terminating on vessels are observed. In the upper half fibres are radially oriented; when ascending towards the pial surface the number and diameter of fibres appears conspicuously decreased. Radially aligned fibres display numerous varicosities. In the 8th month the bulk of vimentin-positive fibres is encountered next to the ganglionic eminence and below isocortical cerebral fissures. The dentate gyrus is conspicuous due to its high amount of immunolabelled fibres. Furthermore, densely packed fibres are visible within the internal and external capsule and in the vicinity of the anterior commissure. Radial glial somata are found in the proliferative areas as well as in the adjacent white matter. In the latter location bipolar, monopolar and stellate vimentin-positive cells are present. The results demonstrate an area-specific distribution pattern of vimentin-positive structures which can be correlated with migrational events. Areas maturing late in development for instance, reveal dense immunolabelling in the 8th month. The orientation and position of radial fibres point to an additional developmental role of these fibres, i.e. their involvement in the guidance of growing axons. Moreover, the arrangement and morphology of vimentin-positive fibres, such as retraction of fibres or occurrence of varicosities, are indicative of degenerative events. Accordingly, a transformation of radial glial somata, their displacement towards the white matter and finally the growth of stellate processes can clearly be demonstrated.

Astrocytes↗

PubMed1999

Distribution of GAP-43-immunoreactive structures in the human fetal amygdala.

The growth-associated protein GAP-43 is a developmentally regulated protein which is involved in the formation of neuronal contacts. In immunohistochemical studies, GAP-43 is detected within axons during their elongation; thus a fibrous immunoreactivity is visible. After axonal growth is completed there is a shift from a fibrous to a punctate immunoreactivity. The latter has been shown to correlate with synaptogenesis. In the amygdala of the 5th gestational month, a fibrous GAP-43-immunoreactivity is seen in the basolateral nuclei, whereas the corticomedial nuclei exclusively show a punctate immunoreactivity. In the 7th month, all amygdaloid nuclei display immunoreactive puncta, but no fibers. In the 9th month GAP-43-immunoreactivity is no longer visible within the amygdala. The results demonstrate the differential distribution of GAP-43-immunoreactive structures in the amygdaloid nuclei. The nuclear specific immunostaining and its changes may indicate the sequential appearance of the monoaminergic innervation of the amygdala, as GAP-43 is known to occur in monoaminergic systems. Nuclei involved in high levels of the cortical processing hierarchy such as the lateral or basal nucleus display a late occurrence of GAP-43-immunoreactivity. In general, anti-GAP-43 has been shown to be an appropriate tool to investigate axonal growth and synaptogenesis in the developing human brain.

Aged↗

PubMed1998

Evolution of Alzheimer's disease related cortical lesions.

Alzheimer's disease is an immutably progressing dementing disorder. Its major pathologic hallmark is the gradual development of neurofibrillary changes in a few susceptible nerve cell types. The cortical changes do not occur inevitably with advancing age. Once the disease has begun, spontaneous recovery or remissions are not observed. The initial changes develop in poorly myelinated areas of the temporal lobe. The destructive process then follows a predictable pattern as it extends into other cortical areas. Advanced age is not a prerequisite for the evolution of the lesions. Alzheimer's disease is thus an age-related, but not an age-dependent disease. The spread of the neurofibrillary changes resembles the process of cortical myelination, however in reverse order.

Aging↗

PubMed1998

Monoclonal antibodies SMI 311 and SMI 312 as tools to investigate the maturation of nerve cells and axonal patterns in human fetal brain.

Neurofilaments, which are exclusively found in nerve cells, are one of the earliest recognizable features of the maturing nervous system. The differential distribution of neurofilament proteins in varying degrees of phosphorylation within a neuron provides the possibility of selectively demonstrating either somata and dendrites or axons. Non-phosphorylated neurofilaments typical of somata and dendrites can be visualized with the aid of monoclonal antibody SMI 311, whereas antibody SMI 312 is directed against highly phosphorylated axonal epitopes of neurofilaments. The maturation of neuronal types, the development of area-specific axonal networks, and the gradients of maturation can thus be demonstrated. Optimal immunostaining with SMI 311 and SMI 312 is achieved when specimens are fixed in a mixture of paraformaldehyde and picric acid for up to 3 days and sections are incubated free-floating. Neurons, with their dendritic domains immunostained by SMI 311 in a Golgi-like manner, can be completely visualized in relatively thick sections. The limitations of Golgi-preparations, such as glia-labeling, artifacts, and the staining of only a small non-representative percentage of existing neurons, are not apparent in SMI preparations, which additionally provide the possibility of selectively staining axonal networks. The results achieved in normal fetal brain provide the basis for studies of developmental disturbances.

Abortion, Induced↗

PubMed1998

Transient features of the thalamic reticular nucleus in the human foetal brain.

The architectonic organization and neuronal types of the human foetal reticular nucleus (RN)--with special reference to transient characteristics--have been investigated using antisera against calretinin, parvalbumin and neurofilament epitopes of somata and dendrites (SMI 311). The RN consists of four subdivisions (clearly distinguishable in the 6/7th gestational month): The main portion appears as a prominent structure on account of its extension and high packing density of neurons which coexpress calretinin and parvalbumin. These two calcium-binding proteins are also expressed by the perireticular nucleus forming a conspicuous grey within the internal capsule. Perireticular cells form clusters which are in continuity with the main portion, globus pallidus, ganglionic eminence and pregeniculate nucleus. In double-labellings, a medial subnucleus stands out distinctly as it only expresses calretinin. SMI 311-immunopreparations show neurons revealing a high degree of diversification and elaborated dendritic trees. Several transient characteristics become obvious: the perireticular nucleus, not visible in the adult, represents a distinct entity in the human foetal brain. The main portion and the pregeniculate nucleus appearing as prominent greys are dramatically reduced in size later on. The percentage of RN-neurons expressing calretinin, the diversity of neuronal types and elaborated dendritic trees are reduced. The transient features can be correlated with the RN's putative functional roles in development: early RN-afferents to the dorsal thalamus may represent pioneer fibres providing guiding cues for outgrowing axons from or into the thalamus. Moreover, the RN may serve as an intermediate target for growing axons which are sorted and directed towards different final targets.

Antibodies, Monoclonal↗

PubMed1998

Transient architectonic features in the basolateral amygdala of the human fetal brain.

The architectonical differentiation in the basolateral nuclei of the human fetal amygdala - with special reference to transient structures - was studied using series of relatively thick Nissl-stained sections. These architectonic features were correlated with the process of migration. Radial glial fibers providing the scaffold of migratory routes can reliably be marked with the aid of antivimentin. In the 5th gestational month a transient feature is conspicuous in the inferior portions of the basolateral nuclei bordering upon the ganglionic eminence (proliferative zone): columnar cell clusters, separated by cell-sparse septa, extend from the poliferative zone to the nuclei. The width of the cell columns vary considerably between the different nuclei. In vimentin immunopreparations fibers are found inside these cell columns. So they most probably reflect clustered migratory streams. Two months later, instead of this merging area between the ganglionic eminence and the amygdaloid nuclei a cell-free capsule envelopes the nuclei and clearly separates them from the ganglionic eminence. Changes in cytoarchitectonics are accompanied by a distinct rearrangement of radial glial fibers. A basket-like arrangement of the vimentin-immunoreactive fibers around the cell columns inside the cell sparse septa is found. Towards the end of pregnancy radial glial fibers gradually vanish. A comparison of Nissl and vimentin preparations reveals that transient architectonic characteristics as visible in relatively thick Nissl sections may be correlated with migrational routes.

Amygdala↗

PubMed1997

Neurofibrillary tangles and neuropil threads as a cause of dementia in Parkinson's disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related degenerative disorders of the human brain. Both diseases involve multiple neuronal systems and are the consequences of cytoskeletal abnormalities. In AD susceptible neurons produce neurofibrillary changes, while in Parkinson's disease, they develop Lewy bodies. In AD six developmental stages can be distinguished on account of the predictable manner in which the neurofibrillary changes spread across the cerebral cortex. During the course of PD numerous limbic determined parts of the brain undergo specific lesions regulating endocrine and autonomic functions. In general, the extranigral destructions are in themselves not sufficient to produce overt intellectual deterioration. Fully developed Parkinson's disease with concurring incipient Alzheimer's disease is likely to cause impaired cognition.

Dementia↗

PubMed1997

Cerebral haemorrhage in long-term survivors of childhood acute lymphoblastic leukaemia.

Modern treatment of childhood acute lymphoblastic leukaemia (ALL) has dramatically improved the prognosis for children with this disease. Therapeutic approaches consist of multimodal chemotherapy and radiotherapy with significant long-term side-effects. We report on 4 children out of a group of 120 newly diagnosed patients with ALL, who survived the disease for more than 2 years and developed a cerebral haemorrhage after chemotherapy and fractionated cranial irradiation. Following a period of 2-12 years the four children presented with acute neurological signs and symptoms. i.e. seizures, ataxia and hemiparesis. CT and MRI revealed intracerebral mass lesions, interpreted as haemorrhage. After neurosurgery the patients neurological state improved. Histological examination confirmed the suspected diagnosis of bleeding cavernous haemangioma or capillary telangiectases. There are two possibilities to explain these rare alterations: they may be pre-existent to the disease and therapy or they may be caused by irradiation. CONCLUSION Acute neurological symptoms in patients treated for ALL may be caused by spontaneous cerebral haemorrhaging of cavernous haemangiomas or capillary telangiectases induced by chemotherapy and/or radiotherapy.

Adolescent↗