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PubMed1999

Growth factors and their receptors in the olfactory system.

The olfactory epithelium is unique in the mammalian nervous system as it is a site of continual neurogenesis. Constant turnover of primary sensory neurons in the periphery results in continuous remodeling of neuronal circuits and synapses in the olfactory bulb throughout life. Most of the specific mechanisms and factors that control and modulate this process are not known. Recent studies suggest that growth factors, and their receptors, may play a crucial role in the development and continuous regeneration of olfactory neurons, i.e. particularly in neuronal proliferation, neurite outgrowth, fasciculation and synapse formation of the olfactory system. The potential role of the following factors and their receptors in different species are reviewed: Nerve growth factor (NGF); insulin-like growth factors (IGFs); fibroblast growth factors (FGFs); epidermal growth factor (EGF); transforming growth factor alpha (TGF alpha); amphiregulin (AR) and transforming growth factors beta (TGFs beta).

Animals↗
PubMed2003

Leiomyosarcoma of the kidney in a dog.

A leiomyosarcoma that occurred in the right kidney of a dog (7-year-old female Labrador retriever) was studied pathologically. On histological examination, tumour cells were spindle-shaped, the cell density was high, and complex fasciculated tumour cells showing longitudinal and transverse cross-sections were observed. Both ends of the nuclei were rounded, the nucleoli were clear and many images of nuclear division were observed. Immunohistochemically, tumour cells reacted intensely with anti-vimentin antibody and anti-actin smooth muscle antibody, and mildly with anti-desmin antibody. On electron microscopy, the nuclei of tumour cells were rounded at both ends and elongated elliptically, and a large number of microfibrils with focal density and dense patches were observed in the cytoplasm. This is a case report of a very rare leiomyosarcoma of the dog kidney.

Animals↗
PubMed2001

Overexpression of Fyn tyrosine kinase causes abnormal development of primary sensory neurons in Xenopus laevis embryos.

The expression and function of the Src family protein tyrosine kinase Fyn in Xenopus laevis embryos have been examined. In situ hybridization analysis demonstrated nervous system-specific expression of Fyn mRNA in tail-bud embryos. However, a class of primary sensory neurons; that is, Rohon-Beard (RB) neurons, which is positive for immunoglobulin superfamily cell adhesion molecules (CAM), neural cell adhesion molecule (N-CAM) and contactin, is devoid of Fyn expression. Injection of Fyn mRNA into one of the blastomeres at the 2-cell stage led to overexpression of Fyn in the injected half of the tail-bud embryos. Immunolabeling of the embryos with anti-HNK-1 antibody revealed that the peripheral axons of RB neurons were partially misguided and bound to each other to form abnormal subcutaneous fascicles. Similar abnormality was induced by injection of the Fyn overexpression vector. The incidence of abnormality appeared dose-dependent, being 68-92% of the injected embryos at 50-400 pg of mRNA. Co-injection of the contactin antisense vector depleted contactin mRNA accumulation without affecting Fyn overexpression and reduced the incidence of the abnormal RB-cell phenotype. However, the N-CAM antisense was ineffective in reducing this abnormality. These results suggest that Fyn can modify signals regulating axonal guidance or fasciculation in the developing X. laevis nervous system and that contactin may affect this action of Fyn.

Animals↗
PubMed1998

Differential patterns of semaphorin expression in the developing rat brain.

Semaphorins are a large family of cell-surface and secreted proteins that have been shown to function as chemorepellents or inhibitors of growth cones of peripheral neurons, yet little is known about their role in patterning central pathways. In order to examine whether semaphorins may be involved in guiding the formation of the reciprocal thalamocortical connections in the rat, we have analysed the spatial and temporal expression of five recently identified rodent semaphorins (semB, C, D, F and G) using in situ hybridization. Transcripts of all five genes were present throughout the period examined (E15-P7) and displayed highly specific spatiotemporal distributions. We have based our discussion of putative semaphorin effects on their known functions as chemorepellents and found their spatiotemporal expression patterns compatible with such a role in several developmental events. Specifically, semaphorins are in the position to: (i) prevent neurite extension into the ventricular neuroepithelium throughout the brain; (ii) confer non-permissive properties to the embryonic cortical plate, hence regulating the radial invasion of corticopetal afferents; (iii) confine axonal extension to the intermediate zone and subplate; (iv) maintain the fasciculated state of thalamocortical and corticothalamic axons, and prevent them from branching while they grow through the striatum; and (v) restrict the terminal arborizations of thalamic afferents to layer IV. The evidence that different semaphorin genes are often co-expressed further suggests that the various molecules might interact in synergistic ways. Taken together, our results support the hypothesis that semaphorins could act as guidance signals in the development of the thalamocortical projections and suggest that innervation specificity is achieved through the combined action of multiple guidance cues. Furthermore, these data provide a basis for the design of functional assays and the study of mice carrying knockouts in specific semaphorin genes.

Animals↗
PubMed1999

The interaction between F3 immunoglobulin domains and protein tyrosine phosphatases zeta/beta triggers bidirectional signalling between neurons and glial cells.

F3, a mouse glycosyl-phosphatidylinositol anchored molecule of the immunoglobulin superfamily, is known to influence axonal growth and fasciculation via multiple interactions of its modular immunoglobulin-like domains. We prepared an Fc chimeric molecule (F3IgFc) to identify molecules interacting with these domains and characterize the functional impact of the interactions. We affinity-isolated tenascin-C and isoforms of the proteoglycan-type protein tyrosine phosphatases zeta/beta (PTPzeta/RPTPbeta) from extracts of developing mouse brain. We showed that both PTPzeta/RPTPbeta and tenascin-C can bind directly to F3, possibly in an exclusive manner, with the highest affinity for the F3-PTPzeta/RPTPbeta interaction. We observed a strong binding of F3IgFc-coated fluorospheres to astrocytes in neural primary cultures and to C6 astrocytoma cells, and demonstrated, in antibody perturbation experiments, that F3-Ig binding on astrocytes depends on its interaction with PTPzeta/RPTPbeta. We also found by confocal analysis that tenascin-C and PTPzeta/RPTPbeta were colocalized on astrocytes which suggests a complex interplay of interactions between PTPzeta/RPTPbeta, tenascin-C and F3. We showed that the interaction between PTPzeta/RPTPbeta and F3-Ig-like domains can trigger bidirectional signalling. C6 glia-expressed PTPzeta/RPTPbeta stimulated neurite outgrowth by cortical and cerebellar neurons, whereas preclustered F3IgFc specifically modified the distribution of phosphotyrosine labelling in these glial cells. Both effects could be prevented and/or mimicked by anti-F3 and anti-6B4PG antibodies. These results identify F3 and PTPzeta/RPTPbeta as potential mediators of a reciprocal exchange of information between glia and neurons.

Animals↗
PubMed2000

Comparative study of the lamina cribrosa and the pial septa in the vertebrate optic nerve and their relationship to the myelinated axons.

The optic nerve contains the connective tissues, i.e. the lamina cribrosa and pial septa. This report presents a histological comparison of the lamina cribrosa and pial septa in the five classes (mammals, birds, reptiles, amphibians and teleosts) of vertebrates. Furthermore, the distribution of myelinated fibers was observed from the optic nerve through the retina in the same animals. The lamina cribrosa is found in mammals except for mice, and in birds. Structural complexity of the lamina was different in animals but generally dependent of the optic nerve thickness. The pial septa were present in the optic nerve proper of the mammals except for the mice, in birds and in a part of teleosts. Fasciculation of the optic nerve by the pial septa tended to be more prominent as the optic nerve become thicker. The optic nerve consisted of largely myelinated fibers in vertebrates. The retina contained some myelinated fibers in submammals but was thoroughly devoid of myelinated fibers in mammals. The borderline between myelinated and unmyelinated portions in the optic nerve of different species did not related to the lamina cribrosa. Amphibians had exceptionally only a few myelinated fibers in the optic nerve and no myelinated fibers in the retina.

Amphibians↗
PubMed2001

A comparative histopathologic and immunohistopathologic evaluation of cremaster muscles from boys with various inguinoscrotal pathologies.

AIM: It has been hypothesized that the cremaster muscle (CM) might play a part in the pathogenesis of various inguinoscrotal pathologies such as undescended testis and hernia. A prospective study was carried out to determine if CM of boys with hydrocele, inguinal hernia, and undescended testis reveal any histopathological and immunohistopathological alterations. METHODS: Samples of CM from 29 patients presenting with inguinal hernia (15), undescended testis (9), and hydrocele (5), and CM from autopsies of boys without inguinal pathology (2), and samples of internal oblique muscles from patients undergoing laparotomy (3) were obtained. The biopsies were frozen in isopentane-cooled liquid nitrogen, cut in 6 micron sections and stored at -80 degrees C until processed. Sections were stained by hematoxylin-eosin, modified Gomori-trichrome, PAS, Oil Red-O, NADH, SDH and COX. All specimens were evaluated for seven parameters including variation in fibre size, presence of central nucleus, endomysial fibrosis, inflammation, presence of basophilic fibres, increase in perimysial connective tissue, and variation in fibre size between fascicules. The specimens were also evaluated for beta-spectrin, laminin alpha-1 chain, laminin alpha-2 chain, 43 kd distroglycan, and fetal myosin by immunofluorescence. The presence of each parameter was compared, individually and in combination, according to the ages and underlying pathologies. RESULTS: None of the internal oblique muscles were positive for any of the seven parameters. Only one of the two CM obtained during autopsy revealed a slight variation in fibre size. However, fibre size variation and increase in perimysial connective tissue were found in all but one CM from a patient with hernia. The presence or absence of parameters did not differ according to age. Comparison of the groups with inguinal hernia and undescended testis for each of the individual parameters did not reveal significant differences. However, the presence of four or more parameters in each CM was more commonly encountered among patients with undescended testis compared to patients with hernia (p < 0.05). The CM of patients with hydrocele suggested similar findings to patients with inguinal hernia. All of the specimens, regardless of origin, revealed normal sarcolemmal and basal laminal stainings, and fetal myosin was expressed in only two specimens which were obtained from an internal oblique muscle and the CM of a patient with an inguinal hernia. CONCLUSION: The CM of patients with inguinal hernia, hydrocele, and undescended testis reveal histopathological alterations. Furthermore, CM from patients with undescended testis reveal more profound alterations. Whether these alterations reflect a primary muscle pathology or a defect in innervation or changes secondary to inguinoscrotal pathology requires further study.

Child↗
PubMed2001

Clinical characteristics and management of ALS.

Amyotrophic lateral sclerosis (ALS) is the most common form of degenerative motor neuron disease in adulthood. The clinical picture was accurately described by Charcot over 125 years ago and consists of generalized fasciculations, progressive atrophy and weakness of the skeletal muscles, spasticity and pyramidal tract signs, dysarthria, dysphagia, and dyspnea. Pseudobulbar affect is common. Disease-specific treatment options are still unsatisfactory. However, therapeutic nihilism is not justified as a large array of palliative measures is available to enhance the quality of life of patients and their families. Palliative care in ALS is a multidisciplinary effort requiring careful coordination. An open and frank disclosure of the diagnosis is of paramount importance. Nutritional deficiency due to pronounced dysphagia can be relieved by a percutaneous endoscopic gastrostomy. Respiratory insufficiency can be effectively treated by noninvasive home mechanical ventilation. The terminal phase of the disease should be discussed, at the latest, when symptoms of dyspnea appear in order to prevent unwarranted fears of "choking to death." Collaboration with hospice and completion of advance directives can be of invaluable help in the terminal phase.

Adult↗
PubMed1988

Ectopic ACTH syndrome due to Grawitz tumor.

An extremely unusual case of adrenocorticotropin (ACTH)-producing Grawitz tumor is reported in a 56-year-old female. The clinical feature of the patient was compatible with Cushing's syndrome. The plasma levels of ACTH and cortisol were markedly elevated. At autopsy, a left renal tumor was demonstrated and its histopathological diagnosis was renal cell carcinoma (Grawitz tumor). The adrenal gland was bilaterally enlarged with diffuse hyperplasia of the fasciculate zone. The adenohypophyseal cells were atrophic and showed Crooke's degeneration. The tumor contained extremely high levels of ACTH, beta-lipotropin and beta-endorphin. The presence of large molecular weight forms of ACTH has also been demonstrated by a Sephadex G-50 gel filtration of the tumor extract. We authors believe that this is the first documented case of ACTH-producing Grawitz tumor in the literature.

ACTH Syndrome, Ectopic↗
PubMed1996

[Profile of the effect of succinylcholine after pre-curarization with atracurium, vecuronium or pancuronium].

OBJECTIVE: The depolarizing muscle relaxant succinylcholine (SCh) may cause several side effects including muscle fasciculations and postoperative myalgia. These can be attenuated or even prevented by prior administration of a non-depolarizing muscle relaxant. A study was conducted to detect any difference between clinically established approaches concerning the successful prevention of muscular side effects and the influence on the time profile of SCh action. METHODS: The study included 64 patients (ASA status I or II) who underwent elective surgery under general anesthesia. The patients were divided into four groups; the demographic data did not differ significantly between the groups (see table 1). Before the injection of SCh (1 mg/kg) for intubation, the control group received saline (K), the other groups 5 mg Atracurium (A), 1 mg Vecuronium (V), or 1 mg Pancuronium (P), respectively. Neuromuscular block was quantified after train-of-four (TOF) stimulation of the tibial nerve by accelerometry at the toe. The first response was used to determine the onset time, duration of effect, and recovery index. It was noted whether SCh led to muscular activity. Postoperatively, patients were asked whether they experienced any muscular sequelae. Statistical significance was assessed at the 5% probability level by the Mann-Whitney-U test and the CHi2 test (Fisher's exact test, if appropriate). RESULTS: SCh caused a complete neuromuscular block in all patients. Most patients in the control group exhibited muscular contractions than in the other groups (see table 2), but only two patients reported light myalgia. There was no statistically significant difference between the four groups in the onset time and the recovery index of SCh. The duration of the effect was significantly reduced by atracurium (7.5 min) or vecuronium (8.2 min) as compared to the placebo (11.8 min) and pancuronium (13.5 min) (see figure). CONCLUSION: The prolonged duration of the SCh effect after pancuronium is probably due to the known inhibition of cholinesterase by pancuronium. The short duration of action after Atracurium and Vecuronium can be explained by the competitive antagonism at the receptor causing an increased amount of unbound SCh. The duration of the SCh effect may be influenced according to clinical needs by the choice of the non-depolarizing muscle relaxant. The significantly reduced duration of complete neuromuscular block after Atracurium or Vecuronium as precurarizing agents may be advantageous in cases where a fast recovery of spontaneous breathing is essential. If a reduction of the SCh blockade has to be avoided, Pancuronium should be selected for prior administration.

Adult↗
PubMed1996

[Chronic progressive spinobulbar spasticity (primary lateral sclerosis)].

This paper presents an account of chronic-progressive Spinobulbar Spasticity (SBS) or Primary Lateral Sclerosis (PLS), a rare syndrome involving degeneration of the upper motoneuron, on the basis of 6 clinically examined cases. Individuals of both sexes can be affected. Onset of the syndrome occurs around the age of 54, but may sometimes be before 50. Early symptoms of the disease are spasticity on one leg and disturbance of motor skills in one hand. The symptoms generalize within two to three years into tetraspasticity accentuated in the legs, accompanied by pseudo-bulbar dysarthria and dysphagia, which, however, may also be present at the onset of the disease. Compulsive laughing and crying, optokinetic disturbances and facial stiffness develop as additional, though inconstant symptoms. Disease courses of 25 years were observed. Therapy is symptomatic. Fasciculation and muscular atrophy, which would indicate a transition to Amyotrophic Lateral Sclerosis (ALS), were not observed even if the disease was of longstanding. SBS differs from spastic spinal paralysis by virtue of its greater mean age of incidence, its tetraspasticity in conjunction with pseudobulbar signs, and-so far as can be established to date-its apparent non-hereditariness. An influence of exotoxic factors has not been demonstrated so far. The clinical syndrome results from a selective degeneration of the corticospinal and cortico-bulbar tracts up to the motor cortex, where loss of original pyramidal cells has been shown to occur (Pringle et al., 1992). The paper includes a survey of the clinical and neuropathological findings in cases of SBS published so far. Extensive anamnestic and clinical records including TCMS-studies, PET and NMR-CT scans performed in the parasagittal plane are essential for early diagnosis of the syndrome.

Aged↗
PubMed1990

Spinal muscular atrophy in African children.

Forty-five African children with SMA were seen over a period of five years. Fifteen had severe infantile form (Group 1), 19 intermediate (Group 2), 9 juvenile (Group 3) and 2 cervical type. A positive family history was obtained in only 9% of patients. The female/male ratio was 1:1.7. The age of onset was under four months in Group 1, between 5-24 months in Group 2. In 77% of Group 3 onset was between 5-24 months, 22% between 25-48 months. The lower limbs were more severely affected than upper limbs in all except the two patients with cervical SMA, proximal muscles more than distal in 82% and proximal and distal muscle were equally affected in 18%. Bulbar weakness was present in 73% and facial weakness in 80% of Group 1 patients only. Fasciculation of tongue occurred in 50% of Group 1, 42% of Group 2 and 44% of Group 3 patients. Tremor of hands was seen in none of the patients in Group 1, 58% in Group 2 and 66% in Group 3. Tendon reflexes were absent or depressed in all except one patient in Group 2 and were normal in the legs of the two patients with cervical SMA. The blood CK was elevated in 26% of patients. An ECG "tremor" was present in 26% of patients in Group 1, 68% in Group 2 and 66% in Group 3. Four patients (all in Group 1) died of pneumonia; the outcome in the others is not known.(ABSTRACT TRUNCATED AT 250 WORDS)

Africa↗
PubMed1977

Azorean disease of the nervous system.

We studied a family of Portuguese ancestry from the Azores who suffered a progressive neurologic disease characterized by gait ataxia, features similar to Parkinson's disease in some patients, limitation of eye movements, widespread fasciculations of muscles, loss of reflexes in the lower limbs, followed by nystagmus, mild cerebellar tremor and extensor plantar responses. Two post-mortem examinations revealed loss of neurons and gliosis in the substantia nigra, nuclei pontis (and in the putamen in one case) as well as in the nuclei of the vestibular and other cranial nerves, columns of Clarke and anterior horns, in the spinal cord there were also loss of fibers in the fasciculi gracilis and mild changes in the pyramidal tracts. Comparison of the disease in this family with the findings reported in three families of similar ancestry, previously thought to have different disorders, suggests that they may all represent a single genetic entity with variable expression.

Adolescent↗
PubMed2000

Oral ulcerations as the first sign of a foramen magnum meningioma.

We report the case of a patient with oral ulcerations that were likely traumatic in origin caused by biting of the tongue. Physical examination showed only deviation, fasciculations, and hemiatrophy of the right side of the tongue. Neurologic examination disclosed an isolated XII nerve palsy. A magnetic resonance image showed a lesion in the posterior fossa displacing the brain stem at a bulbar level. This was consistent with the diagnosis of a meningioma, later confirmed by the histopathologic study. It is very unusual that a meningioma produces a selective involvement of the XII nerve. Early diagnosis of a foramen magnum meningioma is important, both to improve prognosis and to avoid neurologic sequelae.

Aged↗
PubMed2007

Axon guidance genes identified in a large-scale RNAi screen using the RNAi-hypersensitive Caenorhabditis elegans strain nre-1(hd20) lin-15b(hd126).

The navigation of axons toward their targets is a highly dynamic and precisely regulated process during nervous system development. The molecular basis of this navigation process is only partly understood. In Caenorhabditis elegans, we isolated the RNAi-hypersensitive strain nre-1(hd20) lin-15b(hd126), which allows us to phenocopy axon guidance defects of known genes by feeding RNAi. We used this mutant strain to systematically screen 4,577 genes on chromosomes I and III for axon guidance phenotypes. We identified 93 genes whose down-regulation led to penetrant ventral cord fasciculation defects or motoneuron commissure outgrowth defects. These genes encode various classes of proteins, ranging from secreted or putative cell surface proteins to transcription factors controlling gene expression. A majority of the genes is evolutionary conserved and previously uncharacterized. In addition, we found axon guidance functions for known genes like pry-1, a component of the Wnt-signaling pathway, and ced-1, a receptor required for the engulfment of neurons undergoing apoptosis during development. Our screen provides insights into molecular pathways operating during the generation of neuronal circuits and provides a basis for a more detailed analysis of gene networks regulating axon navigation.

Animals↗
PubMed2007

Differences in protein mobility between pioneer versus follower growth cones.

Navigating growth cones need to integrate, process and respond to guidance signals, requiring dynamic information transfer within and between different compartments. Studies have shown that, faced with different navigation challenges, growth cones display dynamic changes in growth kinetics and morphologies. However, it remains unknown whether these are paralleled by differences in their internal molecular dynamics. To examine whether there are protein mobility differences during guidance, we developed multiphoton fluorescence recovery after photobleaching methods to determine molecular diffusion rates in pathfinding growth cones in vivo. Actively navigating growth cones (leaders) have consistently longer recovery times than growth cones that are fasciculated and less actively navigating (followers). Pharmacological perturbations of the cytoskeleton point to actin as the primary modulator of diffusion in differently behaving growth cones. This approach provides a powerful means to quantify mobility of specific proteins in neurons in vivo and reveals that diffusion is important during axon navigation.

Actins↗
PubMed1972

Temporal pattern of neurogenesis in spinal cord: cytoarchitecture and directed growth of axons.

Neurogenesis was studied in rat spinal cord by correlation of the observations from [(3)H]thymidine autoradiography and Golgi techniques. The temporal pattern of the origin of neurons systematically lagged along the ventro-dorsal and rostro-caudal axes. The temporal pattern was correlated with the topographic pattern of the release and segregation of the newly formed neuroblasts from the neuroepithelium. These temporal and topographic patterns of neuroblast genesis imparted an order to the settling of the neuroblasts. Further, the emerging cytoarchitecture of the differentiating neuroblasts resulted in the formation of oriented interfaces along which the axons grew. The "pioneering" fibers grew along the interfaces formed by the regressed neuroepithelium and the assembled neuroblasts. As development progressed, the axons formed later "selectively fasciculated" along the "pioneering" fibers in a staggered pattern as a result of their differential times of origin. These temporal and topographic patterns occurred in a manner such that the preexisting structure served as an "organizing structure" or foundation upon which the axonal processes formed later in the developmental sequence were oriented and assembled.

Animals↗
PubMed1981

Distinct calcium-independent and calcium-dependent adhesion systems of chicken embryo cells.

Three criteria have been used to distinguish among different systems of embryonic cell adhesion: dependence on Ca2+, involvement of particular cell-surface molecules, and binding specificity. The characterization of the adhesion with respect to cell-surface molecules was carried out by using specific antibodies against the neural and liver cell adhesion molecules (N-CAM and L-CAM) and antibodies raised against retinal cells prepared by limited trypsinization in the presence of Ca2+ (called "T/Ca cells"). Aggregation of cells prepared from retina or brain without Ca2+ did not require Ca2+ and was inhibited by anti-(N-CAM) antibodies but not by anti-(L-CAM) or anti-T/Ca cell antibodies. In contrast, cells obtained from the same tissues in the presence of Ca2+ did require Ca2+ to aggregate. This aggregation was inhibited by anti-T/Ca cell antibodies but not by anti-(N-CAM) or anti-(L-CAM) antibodies. Hepatocyte aggregation also required Ca2+ and was inhibited only by anti-(L-CAM) antibodies. These results define three antigenically distinct cell adhesion systems in the embryo and raise the possibility that additional systems will be found. The neural Ca2+-independent system displayed a limited tissue specificity, mediating binding to neural but not liver cells. In contrast, the Ca2+-dependent systems of both neural and liver cells caused binding to all cell types tested. The Ca2+-dependent system was most active in retinal cells from 6-7 day embryos, whereas the Ca2+-independent system was most active at later times during development. In addition, treatments that inhibited the Ca2+-independent or Ca2+-dependent systems had very different effects on the fasciculation of neurites from dorsal root ganglia. All of the results suggest that Ca2+-independent and Ca2+-dependent adhesion systems play different functional roles during embryogenesis.

Animals↗