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PubMed1999

Parkinsonism, pyramidal signs, polyneuropathy, and cognitive decline after long-term occupational solvent exposure.

It is well known that exposure to manganese, solvents, or carbon monoxide in an occupational setting may lead to central nervous system damage and parkinsonism. The most important solvents in this respect are methanol, toluene, carbon disulfide, and n-hexane. We describe three patients who had been exposed to various solvents for more than 20 years (25, 34, and 46 years). They presented with parkinsonism, pyramidal signs, mild cognitive decline, and unresponsiveness to levodopa. Two patients had a predominantly axonal and sensory polyneuropathy of the lower legs with fasciculations in one of them. Parkinsonian features were progressive, even after the patients had stopped work. We present clinical data, neuropsychological findings, and results of brain computed tomography or magnetic resonance imaging, electroneuromyography, evoked potentials, single photon emission computed tomography, and positron-emission tomography. There is growing evidence that various organic solvents give rise to a parkinsonism syndrome with pyramidal features in susceptible individuals.

Aged↗
PubMed2004

Distribution of N-cadherin in human cerebral cortex during prenatal development.

An important subgroup of adhesion molecules is the superfamily of cadherins, which takes part in cell recognition and differentiation during development. To our knowledge only one study describing N-cadherin expression in developing human brain has been performed so far. Our aim is to identify N-cadherin expression to establish a relationship between its expression and function in human cerebral cortex during prenatal development. In the present study, localization and intensity of N-cadherin was investigated in developing cerebral cortex. Fetuses from spontaneous abortions (n=13) were obtained from first, second, and third trimesters. Western blot analysis revealed three bands and the third trimester samples showed the strongest bands for N-cadherin. Cell processes, axon bundles, and some of the developing neurons revealed immunoreactivity for N-cadherin throughout pregnancy. The immunoreactivity increased in the developing neocortex and expanded from the ventricular layer toward the marginal zone as development progressed. Moreover, the immunoreactivity was strong in vascular endothelium during all three trimesters. We conclude that N-cadherin is dynamically related to the organization of cerebral cortex layers during prenatal development. The dynamic expression pattern implicates N-cadherin as a potential regulator of cell migration, axon extension and fasciculation, the establishment of synaptic contacts, and neurovascular angiogenesis in the developing human cerebral cortex.

Abortion, Spontaneous↗
PubMed2002

Mercury intoxication from skin ointment containing mercuric ammonium chloride.

OBJECTIVE: A one-year follow-up was performed of a 21-year-old man with a 16-year history of diabetes mellitus type I, who had been using ointment containing 10% mercuric ammonium chloride (hydrargyrum amidochloratum; HgNH(2)Cl) for eczema for approximately 3 weeks. Tiredness, fasciculations on the extremities and poor control of diabetes appeared after the end of the ointment treatment. Nephrotic syndrome and hypertension were diagnosed 1 month later. Two months after the ointment application the patient was very weak with tremors of the hands, almost unable to walk, and had lost 20 kg of body weight. He had severe neurasthenic symptoms and his behaviour suggested acute psychosis. METHODS: Internal, neurological and neuropsychological examinations were performed. Mercury in urine was determined by flameless atomic absorption spectrometry. RESULTS: The urine mercury level on admission was 252.0 microg/l. He was treated with Dimaval, sodium (2,3)-dimercaptopropane(-1)-sulphonate capsules for 12 days (total dose 6.3 g). The highest urine mercury excretion during antidote treatment was 2336.0 microg/24 h. The patient had proteinuria of up to 11.10 g/24 h, and renal biopsy revealed diffuse membranous glomerulonephritis of the 1st stage without apparent diabetic nephropathy. Similarly, neuropathy did not have typical signs of diabetic neuropathy. His clinical condition started to improve during the first 2 weeks. Further follow-up has shown slow normalisation of renal functions. After 1 year, proteinuria decreased to 0.62 g/24 h and body weight normalised. Neuropsychological and electromyographic findings became almost normal. CONCLUSION: Severe intoxication developed after a short period of ointment application. Most signs of damage disappeared in the course of 1 year, except mild proteinuria and neuropathy. The evolution was favourable and confirmed the primary role of mercury intoxication in the severe deterioration of the clinical status of the patient.

Administration, Topical↗
PubMed2000

Patterning defects in the primary axonal scaffolds caused by the mutations of the extradenticle and homothorax genes in the embryonic Drosophila brain.

During early brain development in Drosophila a highly stereotyped pattern of axonal scaffolds evolves by precise pioneering and selective fasciculation of neural fibers in the newly formed brain neuromeres. Using an axonal marker, Fasciclin II, we show that the activities of the extradenticle (exd) and homothorax (hth) genes are essential to this axonal patterning in the embryonic brain. Both genes are expressed in the developing brain neurons, including many of the tract founder cluster cells. Consistent with their expression profiles, mutations of exd and hth strongly perturb the primary axonal scaffolds. Furthermore, we show that mutations of exd and hth result in profound patterning defects of the developing brain at the molecular level including stimulation of the orthodenticle gene and suppression of the empty spiracles and cervical homeotic genes. In addition, expression of a Drosophila Pax6 gene, eyeless, is significantly suppressed in the mutants except for the most anterior region. These results reveal that, in addition to their homeotic regulatory functions in trunk development, exd and hth have important roles in patterning the developing brain through coordinately regulating various nuclear regulatory genes, and imply molecular commonalities between the developmental mechanisms of the brain and trunk segments, which were conventionally considered to be largely independent.

Animals↗
PubMed2005

Macrophages during retina and optic nerve development in the mouse embryo: relationship to cell death and optic fibres.

We compared the spatial and temporal patterns of distribution of macrophages, with patterns of naturally occurring cell death and optic fibre growth during early retina and optic nerve development, in the mouse. We used embryos between day 10 of embryogenesis (E10; before the first optic fibres are generated in the retina) and E13 (when the first optic fibres have crossed the chiasmatic anlage). The macrophages and optic axons were identified by immunocytochemistry, and the apoptotic cells were detected by the TUNEL technique, which specifically labels fragmented DNA. Cell death was observed in the retina and the optic stalk long before the first optic axons appeared in either region. Subsequently, specialized F4/80-positive phagocytes were detected in chronological and topographical coincidence with cell death, which disappeared progressively. As development proceeded, the pioneer ganglion cell axons reached the regions where the macrophages were located. As the number of optic fibres increased, the macrophages disappeared. Therefore, cell death, accompanied by macrophages, preceded the growth of fibres in the retina and the optic nerve. Moreover, these macrophages synthesized NGF and the optic axons were p75 neurotrophin receptor (p75(NTR))- and TrkA-positive. These findings suggest that macrophages may be involved in optic axon guidance and fasciculation.

Animals↗
PubMed2000

Lectin cytochemical localisation of glycoconjugates in the olfactory system of the lizards Lacerta viridis and Podarcis sicula.

To investigate the presence of defined carbohydrate moieties on the cell surface of the olfactory and vomeronasal receptor cells and the projections of the latter into the olfactory bulbs, a lectin binding study was performed on the olfactory system of the lizards: Lacerta viridis and Podarcis sicula. Both lizards showed a high lectin binding for N-acetyl-glucosamine in the sensory neurons. The lectin binding patterns in Lacerta indicated that the main olfactory system possessed a moderate density of N-acetyl-galactosamine residues and detectable levels of galactose ones. The vomeronasal system on the other hand contained a high density of N-acetyl-galactosamine moieties and a moderate density of glucosamine ones. In Podarcis the main olfactory system and vomeronasal organ contained respectively detectable and moderate levels of galactose residues. The expression of specific glycoconjugates may be associated with outgrowth, guidance and fasciculation of olfactory and vomeronasal axons.

Acetylglucosamine↗
PubMed2005

The development of a long, coiled, optic nerve in the stalk-eyed fly Cyrtodiopsis whitei.

In the stalk-eyed fly Cyrtodiopsis whitei (Diopsidae; Diptera), the relatively long optic nerve develops within the tight lumen of a very short eyestalk. Axonal growth is generally considered in terms of path finding, selective fasciculation, and towing. Physical forces that are necessary for axon lengthening are generated either by the growth cone or by the growth of surrounding tissues. Therefore, it is surprising to encounter a loosely coiled nerve apparently lacking any attachments that could allow for pull, or towing, of the nerve. In this study, we used histological sections and whole-mount preparations to confirm that the optic nerve of the stalk-eyed fly indeed elongates without the external application of tension to the nerve. Secondly, we examined the distribution of cytoskeletal elements and selected proteins that may be involved in axon extension. Staining against the vesicle fusion proteins SNAP-24 and SNAP-25 consistently results in stronger staining in the rapidly extending optic nerve than in a control nerve, suggesting a possible role of these proteins in the extension process. On a gross morphological level, SNAP-24/25 as well as the cytoskeletal elements actin and tubulin are uniformly distributed throughout the lengths of the growing nerve, suggesting that nerve elongation is distributed rather than localized. Finally, we identified glia as a possible source for tension within the nerve bundle. Glia proliferate rapidly in the optic nerve but not in the control nerve. Much work continues to focus on the growth of axons in culture, but this study is one of the few that considers the dynamics of nerve bundle extension as a whole.

Actins↗
PubMed1997

Genetic analysis of the role of Eph receptors in the development of the mammalian nervous system.

The Eph family of tyrosine protein kinase receptors and their cognate ligands, a family of membrane-bound molecules known as ephrins, have been implicated in diverse biological processes, such as axon guidance, the formation of topographic neural projections, axon fasciculation, the regionalization of the central nervous system, and cell migration. The recent generation of mutant mice lacking some of these receptors has made possible the dissection of the role that these molecules play in the development of the mammalian nervous system.

Animals↗
PubMed1997

The Eph family: a multitude of receptors that mediate cell recognition signals.

The Eph receptor tyrosine kinases are emerging as molecules that guide the migration of cells and growth cones during embryonic development. Based on their concentration in embryonic regions containing growing neuronal processes, the Eph receptors were suspected early on to have a role in regulating aspects of axon growth. The most distinctive role of the Eph receptors appears to be their ability to mediate cell-cell repulsion through the binding of a ligand on an adjacent cell surface. The repulsive interactions are presumably mediated by transient receptor activation at the boundaries of complementary regions of high ligand or receptor expression. In contrast, overlapping expression patterns may regulate cell adhesion and cytoskeletal organization with possible consequences on the overall growth and fasciculation of neuronal processes. A notable feature of Eph receptor signaling is that, upon receptor binding, responses may also be elicited in the ligand-expressing cells. A better understanding of Eph receptor function requires the elucidation of their signaling properties. Recent evidence suggests a functional interaction between the Eph receptor EphB2 and neural cell adhesion molecules of the L1 family, which have well-recognized roles in the formation of neuronal projections. Only a few cytoplasmic signaling molecules that bind to the activated Eph receptors have been identified. Several of these molecules are known to transduce signals regulating cytoskeletal organization and neurite outgrowth. It is currently unclear why there is a need for fourteen distinct Eph receptor genes, many of which appear to encode several variant forms with distinct functional properties, but it is tempting to speculate that such diversity is necessary to refine the spatial organization of embryonic structures.

Animals↗
PubMed1997

Cadherins and the formation of neural circuitry in the vertebrate CNS.

Cadherins are a family of calcium-dependent morphoregulatory molecules mediating cell-cell adhesion. More than a dozen cadherin subtypes are known to be expressed in the developing and mature CNS. Each of these subtypes shows a restricted and distinct expression pattern that differs from that of the other cadherins. During the formation of fiber tracts and neural circuits, each cadherin is expressed by a subset of neurite fascicles. The differential expression of cadherins provides a molecular code for the high degree of specificity and selectivity in neural circuit formation. This code may be a combinatorial one, since the expression of cadherins shows partial overlap. The expression data and experimental results available at present suggest a role for cadherins in aspects of axon outgrowth, axon navigation, axon fasciculation, axonal target recognition, and, finally, in synaptogenesis. However, the precise role of cadherins in some of these processes and their functional relationship to other molecules involved in neurite outgrowth remains to be experimentally established.

Animals↗
PubMed2001

Semaphorin-neuropilin-1 interactions in plasticity and regeneration of adult neurons.

During development, axonal growth cones are guided to their appropriate targets by many attractive and repulsive cues. It has become increasingly clear over the last few years that how the growth cone responds to these cues depends both on the molecular nature of the cue and on the internal state of the neuron. The unexpected result is that the same molecule can act as an attractor or as a repellent. A number of guidance cues used by neurons during development are retained in the adult nervous system, where their function is often still unclear. Most of these molecules are implicated in plasticity in the adult nervous system and can play a role (sometimes maladaptive) in neuronal regeneration after injury. A group of axonal guidance cues that has been well studied in development is the semaphorin family of secreted and membrane-anchored proteins, which has been implicated in axon steering, fasciculation, branching and synapse formation. This review focuses on semaphorin-3A (probably the best-characterized semaphorin) and its receptors (in particular neuropilin-1) in the adult nervous system and argues that semaphorin-3A plays a role in the maintenance and regeneration of adult sensory neurons.

Adult↗
PubMed2001

Developmentally regulated expression of brain-specific chondroitin sulfate proteoglycans, neurocan and phosphacan, in the postnatal rat hippocampus.

Developmental changes in the distribution of brain-specific chondroitin sulfate proteoglycans, neurocan and phosphacan/RPTPzeta/beta, in the hippocampus of the Sprague-Dawley rat were examined using monoclonal antibodies 1G2 and 6B4. The 1G2 immunoreactivity was predominant in the neonatal hippocampus while the 6B4 immunoreactivity was predominant in the mature hippocampus. Moderate 1G2 immunoreactivity was detected in the dentate gyrus and subiculum immediately after birth. Immunoreactivity reached a peak on postnatal days 7-10 (P7-P10) when intense 1G2 labeling was present throughout the neuropil layers of the hippocampus except the mossy fiber tract. 6B4 immunoreactivity was limited in the stratum lacunosum moleculare of CA1 in the neonatal hippocampus. It gradually increased by P21 when diffuse 6B4 immunoreactivity was detected in the stratum oriens and radiatum of Ammon's horn, and in the hilus and inner one-third molecular layer of the dentate gyrus, while 1G2 immunoreactivity decreased after P21. In the adult hippocampus, moderate 6B4 immunoreactivity was present in the stratum oriens and radiatum of Ammon's horn, and in the hilus and inner one-third molecular layer of the dentate gyrus, but not in the mossy fiber tract. In addition, strong 6B4 labeling appeared around a subset of neurons after P21. The results suggest that neurocan may have a role in the development of neuronal organization, while phosphacan/RPTPzeta/beta may contribute to the maintenance and plasticity of synaptic structure and function. Furthermore, the absence of 1G2 and 6B4 immunoreactivities in the stratum lucidum suggests that neurocan and phosphacan/RPTPzeta/beta may function as a barrier for the extension of mossy fibers and provide an environment permissive for fasciculation of the mossy fibers.

Animals↗
PubMed2006

[Referred pain from amputation stump trigger points into the phantom limb].

OBJECTIVES: The aim of the study was to examine whether/how myofascial stump trigger points (TPs) after lower leg amputations are able to produce stump pain (SP), phantom pain (PP), and sensations (PS) in the phantom limb. METHODS: Palpation of the 5 most striking stump TPs of 30 leg amputees (12 transfemoral, 18 transtibial) was documented in a standardized manner. Patients were asked to localize SP, PP, and PS. RESULTS: Of 150 TPs, 14 produced involuntary stump movements and 10 stump fasciculations. Dorsal PP after ventral TP palpation occurred as well as PP in the toes from TPs near the hip. Of 30 patients, 20 reported PS and 8 PP; 60 of 150 TPs produced PS and 17 PP. Phantom phenomena were localized in 62.8% in the toes (1st toe 19.8%, toes 2-5 about 10% each), 17.9% midfoot, and the rest were more proximal. TPs were localized more in the lateral/dorsal stump than medial/ventral. About 70% of the TPs were found between 3 and 7 cm from the stump end, those with toe projections more distal than those with tibial projections. CONCLUSIONS: Myofascial TPs in amputation stumps are common and able to produce sensations and pain in the phantom limb. Most reported experiences were localized in the toes, as phantom pain usually is. There seems to be a "stump representation" and it seems possible that "referred TP pain" and "phantom pain" may develop from similar origin.

Humans↗
PubMed2006

Immunolocalization of a candidate pheromone receptor in the antenna of the male moth, Heliothis virescens.

Pheromone recognition in insects is thought to involve distinct receptor proteins in the dendritic membrane of antennal sensory neurons. We have generated antibodies directed against a peptide derived from the sequence of the candidate pheromone receptor HR13 from Heliothis virescens. The antibodies specifically labelled the cell bodies of a distinct neuron population housed in male-specific pheromone-sensitive sensilla. Combining antibody staining with in situ hybridization the reactive cells were found to express the HR13 gene. In addition, dendrites projecting into sensilla hairs as well as the axonal processes of immunoreactive cells were labelled. Labelling of axons has allowed visualization of their fasciculation within antennal segments and permits tracking of axons as they merge into the antennal nerve. The HR13 protein was first detected 1 day before eclosion. Thus, the distribution of HR13 protein in the antennal neurons of the male moth strongly suggests a role of the HR13 receptor in recognition of pheromones.

Animals↗
PubMed2002

[Dermatofibrosarcoma protuberans of the breast: a case report].

We describe a dermatofibrosarcoma protuberans (DFSP) of the breast and briefly report about such cases previously mentioned in the literature. A 27-year-old woman was referred because of the progressive increase, during pregnancy, of a mammary nodule located between the internal quadrants of the right breast. Its clinical and radiologic features suggested a fibroadenoma. Lumpectomy revealed a 3-cm, gray-whitish, fasciculated nodule. Histological examination showed a neoplasm characterized by a highly and monomorphic cellular proliferation of spindle-shaped cells, arranged in bundles displaying repetitive storiform growth pattern and infiltrating the adjacent mammary tissue. Lack of necrosis and low mitotic rate was observed. At immunohistochemistry the tumor cells were diffusely positive for vimentin and CD34, but negatively stained with CD99, bc-2, desmin, smooth-muscle actin, S100 protein and cytokeratins. A diagnosis of mammary dermatofibrosarcoma protuberans (DF-SP) was posed. Neoplastic involvement of surgical margins led to a subsequent quadrantectomy without regional lymphadenectomy. The patient was alive and disease-free at the 8-month follow-up. Mammary DFSP is rare. Its preoperative diagnosis is extremely difficult, particularly when radiologic images show an intraparenchymal lesion with round borders. We report such a case and briefly review the pertinent literature. Morphologic parameters to distinguish DFSP from other spindle cell lesions of the breast are discussed.

Adult↗
PubMed2006

The role of cytoplasmic serine residues of the cell adhesion molecule L1 in neurite outgrowth, endocytosis, and cell migration.

1. The cell adhesion molecule L1 has been implicated in adhesion and migration of cells, in axon growth, guidance, and fasciculation, in myelination and synaptic plasticity. The cytoplasmic domain of neuronal L1 is highly conserved between species and has been shown to be phosphorylated at serine and tyrosine residues. 2. To investigate the significance of L1 serine phosphorylation, mutants of L1 were generated in which ser-1152, ser-1181, ser-1204, and ser-1248 were exchanged for leucine and rat B35 neuroblastoma cells were stably transfected with the L1-cDNA constructs. 3. Neurite outgrowth on poly-L-lysine (PLL) as substrate was determined either with or without differentiation into a neuronal phenotype with dbcAMP. In addition, antibody-induced endocytosis and cell migration were examined. 4. Our observations indicate that phosphorylation of single serine residues of the cytoplasmic domain of L1 contributes to neurite outgrowth through different mechanisms. Neurite growth is increased when ser-1152 or ser-1181 is replaced by a non-phosphorylatable leucine and decreased when ser-1204 or ser-1248 is mutated to leucine. Furthermore, mutation of ser-1181 to leucine results in strongly enhanced antibody-induced endocytosis of L1 and also in enhanced cell migration.

Amino Acid Sequence↗
PubMed1985

Pyramidal tract deficits and polyneuropathy in hyperthyroidism, Combination clinically mimicking amyotrophic lateral sclerosis.

Generalized weakness, intermittent dysphagia, and a 40-pound weight loss developed in an elderly man over a six-month period. Examination revealed weakness, atrophy and fasciculations of extremity musculature, pseudobulbar speech, hyperactive upper extremity reflexes, and extensor toe signs without sensory loss. Results of electrodiagnostic studies were consistent with an axonal polyneuropathy. Endocrinologic results were compatible with hyperthyroidism. Radioiodine therapy resulted in resolution of clinical neurologic symptoms and signs within seven months. This case illustrates a previously undescribed concurrence of hyperthyroid associated polyneuropathy and pyramidal tract dysfunction that led to an initial clinical diagnosis of amyotrophic lateral sclerosis.

Aged↗
PubMed1986

Subacute neurotoxicity following long-term exposure to carbaryl.

Carbaryl, a widely used insecticide, is reputed to have a wide safety margin. It can induce acute cholinesterase poisoning, which is rapidly reversible on discontinuation of exposure. Long-term sequelae from long-term exposure have not previously been described in humans. This report describes the experience of a 75-year-old man who had long-term excessive exposure to carbaryl and in whom a debilitating syndrome, including headaches, memory loss, proximal muscle weakness, muscle fasciculation, muscle cramps, and anorexia with marked weight loss, developed. At the time of diagnosis, serum pseudocholinesterase levels were low, and his major symptoms resolved on termination of exposure. Late clinical features were sleep apnea and progressive development of a peripheral neuropathy. The difficulty in diagnosing the cause of a group of relatively nonspecific symptoms raises the question of whether chronic carbaryl neurotoxicity might be occurring more frequently than previously suspected.

Aged↗