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Transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1[82] with a mutated NLS were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In a second series of transgenic mice, ataxin-1[77] containing a deletion within the self-association region was expressed within Purkinje cells nuclei. These mice developed ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice.

In this study we evaluate prognostic factors that predict local-regional control and survival following stereotactic radiosurgery (SRS) in patients with brain metastasis and establish guidelines for patient selection. Our evaluation is based on 73 patients with brain metastasis treated with SRS at the University of Minnesota between March 1991 and November 1995. The ability of stereotactic radiosurgery to improve local control in patients with brain metastases is confirmed in our study in which only 6 of 62 patients failed locally after SRS, with an actuarial local progression-free survival of 80% at 2 years. Variables that predicted worse prognosis were larger tumor size (p = 0.05) for local progression-free survival and multiplicity of metastasis (p = 0.03) and infratentorial location of metastases (p = 0.006) for regional progression-free survival. Absence of extracranial disease, KPS > or = 70, and single intracranial metastasis were significant predictors of longer survival. Patients who fulfill all three criteria will survive longer after SRS (MS = 17.7 months) and will most likely benefit from the increase local control in the brain achieved by SRS. Survival in patients who do not meet any of these criteria is very poor (MS = 1.5 months), and these patients are less likely to benefit from this treatment. Careful selection of patients for SRS is warranted.

Transgenic targeting of SV40 large T antigen (Tag) expression to murine cerebellar Purkinje cells induces these normally postmitotic neurons to undergo DNA synthesis and apoptosis. It has been proposed that these effects of Tag are due to the binding of Tag to pRb, which leads to the release and activation of the transcription factor E2F. Here it is reported that E2F and CDC2, the protein product of a gene regulated by E2F, were detectable in the Purkinje cell nuclei of Tag expressing transgenic animals. To directly test whether E2F-1 is part of the mechanism of Tag-induced Purkinje cell degeneration, transgenic mice that overexpress E2F-1 specifically in cerebellar Purkinje cells were generated. Although E2F-1 itself did not affect Purkinje cells, it did accelerate Tag-induced ataxia and Purkinje cell loss, suggesting that E2F-1 can contribute to the mechanism of Tag-induced Purkinje cell degeneration., (Copyright 1998 Academic Press.)

We used transgenic mice with Purkinje cell dysfunction (PO3 line) to study the role of these neurons in the increase in cerebellar blood flow (BFcrb) produced by stimulation of the cerebellar parallel fibers (PF). Mice (age 8-10 wk) were anesthetized (halothane) and artificially ventilated. Arterial pressure and end-tidal CO2 were monitored continuously. Arterial blood gases were measured. The PF were stimulated electrically (100 microA, 30 Hz; 40 s), and the increases in BFcrb were monitored by a laser-Doppler flow probe. First, we characterized the increases in BFcrb and the field potentials produced by PF stimulation in normal mice. PF stimulation evoked the typical field potentials and increased BFcrb by 60 +/- 4% (100 microA, 30 Hz; n = 10). The increases in BFcrb were attenuated by the broad-spectrum glutamate receptor antagonist kynurenate (-84 +/- 3%; P < 0.05 analysis of variance; n = 5), by the DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (-62 +/- 6%; P < 0.05; n = 5), and by the nitric oxide synthase inhibitor N omega-nitro-L-arginine (-46 +/- 7%; P < 0.05; n = 5). In PO3 transgenic mice, the increases in BFcrb produced by PF stimulation were reduced (P < 0.001) at every stimulus intensity and frequency tested (residual increase at 100 microA, 30 Hz: 19 +/- 2%; n = 6). The field potentials evoked by PF stimulation also were abnormal in that they lacked the late negative wave (n = 6), a finding consistent with lack of depolarization of Purkinje cells. The residual flow response in the transgenics was abolished by N omega-nitro-L-arginine (n = 5; P > 0.05). Ultrastructural studies showed that the density of PF-Purkinje cell synapses is reduced in PO3 mice, whereas the morphology of molecular layer interneurons (stellate cells) is normal. The findings suggest that Purkinje cells are responsible for a sizable component of the flow response whereas molecular layer interneurons mediate the remainder of the response. The study provides evidence that mouse mutants with spontaneous or genetically engineered cerebellar abnormalities could be useful to study the cellular and molecular correlates of functional hyperemia in the central nervous system.

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the alpha1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract. Work presented here describes the behavioral and neuropathological course seen in mutant SCA1 transgenic mice. Behavioral tests indicate that at 5 weeks of age mutant mice have an impaired performance on the rotating rod in the absence of deficits in balance and coordination. In contrast, these mutant SCA1 mice have an increased initial exploratory behavior. Thus, expression of the mutant SCA1 allele within cerebellar Purkinje cells has divergent effects on the motor behavior of juvenile animals: a compromise of rotating rod performance and a simultaneous enhancement of initial exploratory activity. With age, these animals develop incoordination with concomitant progressive Purkinje neuron dendritic and somatic atrophy but relatively little cell loss. Therefore, the eventual development of ataxia caused by the expression of a mutant SCA1 allele is not the result of cell death per se, but the result of cellular dysfunction and morphological alterations that occur before neuronal demise.

Expansions of CAG trinucleotide repeats encoding glutamine have been found to be the causative mutations of seven human neurodegenerative diseases. Similarities in the clinical, genetic, and molecular features of these disorders suggest they share a common mechanism of pathogenesis. Recent progress in the generation and characterization of transgenic mice expressing the genes containing expanded repeats associated with spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD/SCA3), and Huntington's disease (HD) is beginning to provide insight into the underlying mechanisms of these neurodegenerative disorders.

The most common mutation causing Gerstmann-Sträussler-Scheinker (GSS) disease is P102L in the prion protein. Previously, this mutation has only been found in coupling with methionine at residue 129. We describe a patient with GSS disease in whom the P102L mutation is in coupling with valine at residue 129. The clinical presentation in P102L-V129 differs greatly from that seen in P102-M129 patients.

Purkinje cells are uniquely susceptible to a number of physical, chemical, and genetic insults both during development and in the mature state. We have previously shown that when the postmitotic state of murine Purkinje cells is altered by inactivation of the retinoblastoma tumor susceptibility protein (pRb), immature as well as mature Purkinje cells undergo apoptosis. DNA synthesis and neuronal loss are induced in postmitotic Purkinje cells dependent upon the pRb-binding portion of SV40 large T antigen (T-ag). In the present study, Purkinje cell targeting of a mutant T-ag, PVU, which does not bind pRb, reveals disparate cerebellar phenotypes dependent upon temporal differences in transgene expression. Strong embryonic and postnatal transgene expression in three lines alters Purkinje cell development and function during the second postnatal week, causing ataxia without Purkinje cell loss. In contrast, two other transgenic lines reveal that PVU T-ag expression following normal Purkinje cell maturation causes rapid Purkinje cell degeneration. The second and third postnatal weeks of cerebellar development, which include the major period of synaptogenesis, appear to be the defining stage for the two PVU-induced phenotypes. These data indicate that Purkinje cell death susceptibility varies with developmental stage.

Spinocerebellar ataxia type 1 and Machado-Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicism, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.

We describe sequence similarity and immunologic cross-reactivity between a peptide of the mycobacterial hsp, HSP65, and the myelin protein 2',3' cyclic nucleotide 3' phosphodiesterase (CNP). We demonstrate that immunization with the homologous cross-reactive CNP peptide (hsp-CNP peptide) has significant biological consequences. Rats immunized with hsp-CNP peptide in either complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) produce large amounts of peptide-specific antibody. Isotypes of antibodies in animals immunized with peptide in CFA are IgG1 and IgG2a. Isotypes of antibodies in rats immunized with peptide in IFA are predominantly IgG1, with low titers of IgG2a. T cell proliferative responses to HSP65 are present in rats immunized with peptide in CFA. T cell responses to HSP65 initially are absent in rats immunized with peptide in IFA but develop over time. T cell proliferative responses to hsp-CNP peptide were not detected. None of the groups of rats developed clinical or histologic evidence of experimental autoimmune encephalomyelitis (EAE). To induce EAE, rats preimmunized with hsp-CNP peptide were challenged with guinea pig spinal cord (GPSC) emulsified in CFA. Rats preimmunized with peptide in CFA developed severe EAE. Rats preimmunized with hsp-CNP peptide in IFA were protected from EAE, with both a lower incidence and severity of disease. Injecting the murine monoclonal antibody recognizing the shared HSP65 and CNP epitope did not protect against EAE. Our data suggest that a Th2 pattern of immune response to a CNP peptide that itself is non-encephalitogenic protects against EAE. Immune responses to either hsp or myelin proteins cross-reactive with hsp may play an important role in the development of EAE.

In this study of an aged wolverine (Gulo gulo), we document neuropathologic lesions (cerebral amyloid angiopathy (CAA), neuritic plaques (NPs), neurofibrillary tangles (NFTs), and granulovacuolar degeneration strikingly similar to those present in aging and Alzheimer's disease (AD), with the additional finding of concurrent cerebral hemorrhage. A beta immunoreactive cerebral amyloid angiopathy and senile plaques (neuritic and diffuse) were present throughout the cerebral cortex and hippocampus. Ubiquitin immunoreactivity was noted in peripheral portions of some of the plaques. Argyrophilic intracellular neurofibrillary tangles containing abnormally phosphorylated (Ser 202) tau protein were present within cortical and hippocampal neurons. The wolverine should be added to the list of nonhuman species (dogs, nonhuman primates, polar bears) with amyloid deposits similar to those in aged humans and in humans with AD. The aged wolverine appears to be distinct from other nonhuman species in possessing plaques and NFTs, as well as other histologic cerebral lesions frequently associated with AD.

This study examines the impact of the Women's Intervention Services and Education (WISE) Project in serving substance-using pregnant and postpartum women through an array of case-managed services and supports. A descriptive analysis of multiple outcome indicators was performed on 152 women who had a minimum 6 months of exposure to WISE services at the time of the analysis. The variables used in the analysis to assess client and program outcomes included substance use, employment, arrests, incarceration, birthweight, and social support. This group of women showed statistically significant improvements across each of these multiple outcome indicators from pre-WISE to WISE discharge. Although the findings of this study are not conclusive because no control group was employed, the results are encouraging and supportive of a growing body of literature that suggests that pregnant and postpartum polydrug-using women can be responsive to case-managed, intensive intervention, with aftercare support.

We present a case report of a 17-year-old young man who developed fatal dissection of the middle cerebral artery after what appeared to be trivial trauma. The dissection was not evident on cerebral arteriogram but was identified at autopsy. Arterial dissection should be considered in the differential diagnosis of supraclinoid occlusion of the internal carotid artery seen by cerebral angiography.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant inherited disorder characterized by degeneration of cerebellar Purkinje cells, spinocerebellar tracts, and selective brainstem neurons owing to the expansion of an unstable CAG trinucleotide repeat. To gain insight into the pathogenesis of the SCA1 mutation and the intergenerational stability of trinucleotide repeats in mice, we have generated transgenic mice expressing the human SCA1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent to offspring transmissions. While all six transgenic lines expressing the unexpanded human SCA1 allele had normal Purkinje cells, transgenic animals from five of six lines with the expanded SCA1 allele developed ataxia and Purkinje cell degeneration. These data indicate that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrate that a mouse model can be established for neurodegeneration caused by CAG repeat expansions.

Radiation necrosis is a delayed complication of cranial irradiation, typically presenting as a single intracerebral mass that is radiographically indistinguishable from recurrent tumor. We describe 6 patients with a distinct radiographic syndrome of multifocal enhancing lesions on magnetic resonance images, and their variable clinical courses: some fluctuating, some spontaneously resolving, and some demonstrating fulminant progression to frank necrosis.

The product of the retinoblastoma susceptibility gene, pRb, is known to be an important regulator of cell division. Disrupted central nervous system development in RB null mice suggests a critical function for pRb in the proliferative arrest and initiation of terminal differentiation of certain neurons. Previously, we have shown that SV40 T-ag expression targeted to Purkinje neurons in transgenic mice causes cell-specific death. Here we describe that T-ag expression induces DNA synthesis and results in DNA fragmentation in Purkinje neurons. Characterization of transgenic mouse lines expressing mutant T-ags demonstrate that the pRb binding domain of T-ag is required for induction of Purkinje cell loss. These findings indicate that a pRb function is required well beyond the completion of Purkinje neuron differentiation and provide a link between cell cycle regulation and neurodegeneration in vivo.

A 29-year-old man presented with headache, confusion, word-finding difficulty, and a visual field deficit 16 months after complete removal of a sacrococcygeal chordoma. Magnetic resonance imaging of the head demonstrated two discrete enhancing left occipital lesions with associated cerebral edema. Both masses were surgically excised and their histological appearance was consistent with chordoma. Chordoma from the sacral region is known to metastasize to the lungs and the vertebral bodies but has rarely been shown to spread to the brain. Dissemination to the brain in this case may be related to the extent of the metastatic pulmonary disease and the anaplastic appearance of the primary tumor.

The increasing use of crack-cocaine among addicted women and subsequent births of polydrug-exposed infants prompted the State of Florida to undertake initiatives to seek solutions to these problems. This study, focused on one of these initiatives, explored the relationship between service components of a comprehensive treatment program and substance-free time among 120 African American and Caucasian crack-cocaine addicted women. Findings from a multiple regression analysis indicated that aftercare management (p < .0001), vocational services (p < .02), and residential treatment (p < .03) were statistically significant services associated with substance-free time. Although these findings are not conclusive, they are supportive of a growing body of literature that suggests that crack-using and polydrug-using women can be responsive to treatment when it is tailored to their individual needs and includes long-term community support.

Carcinoid tumors constitute an uncommon source of metastatic lesions to the brain. We report the case of a 63-year-old man who initially sought treatment for proptosis 15 years before coming to our attention with a metastatic intracerebral left parietal carcinoid. The pathological features of the exenterated orbital mass were interpreted as undifferentiated carcinoma, and a lesion of the left lower lobe of the lung that had been removed 6 years earlier had been reported as metastatic malignant melanoma. The long duration between the initial diagnosis and the onset of neurological symptoms brought into question the original diagnosis, which, in retrospect, was most consistent with metastatic carcinoid. Staining for cytokeratin, neuron-specific enolase, and synaptophysin in the absence of staining for S-100 and HMB-45 supported the revised pathological diagnosis. Metastatic intracerebral carcinoid from an unrecognized bronchogenic source is a rare event, particularly after an orbital metastasis, but should be suspected when the clinical course is inconsistent with the more common causes of metastatic disease.

SV40 T antigen (Tag) expression directed to cerebellar Purkinje cells resulted in the generation of three transgenic mouse lines that displayed ataxia, a neurological phenotype characteristic of cerebellar dysfunction. Onset of symptoms and cerebellar pathology, characterized by specific Purkinje cell degeneration, appeared to be directly dependent upon transgene copy number. The SV5 line (containing > 30 transgene copies), exhibited embryonic transgene expression that caused selective death of immature Purkinje cells and a subsequent block in cerebellar development and ataxia at 2 weeks. The developmental effect of the disruption of Purkinje cells in SV5 mice suggests that a normal complement of these cells is required for early development of the cerebellar cortex, especially granule cell proliferation and migration from external to internal layers. Transgene expression in a second line, SV4 (10 copies), was detectable during the second postnatal week. Death of mature Purkinje cells in the SV4 line resulted in onset of ataxia at 9 weeks. Ataxia in a third line, SV6 (2 copies), was detected after 15 weeks. The distinct cerebellar phenotypes of the SV4-6 lines correlate with specific Tag-induced Purkinje cell ablation as opposed to tumorigenesis.

This study assessed the effects of a monthly peer support group for adolescents with cancer and other hematological diseases. These adolescents shared activities and experiences with nondisabled high school students. At the group's conclusion, the adolescents reported that the group helped them cope with their illness and improved the quality of their daily lives. Nondisabled students reported that the group favorably affected their attitudes about, and intended behavior toward, peers with chronic illnesses. These results suggest that such groups can provide important benefits for individuals with chronic illnesses as well as for their nondisabled peers.

The olfactory bulb (OB), with its comparatively simple and well-delineated connectivity, presents an interesting system for examining cell-specific pathology in neurologic degenerative disorders such as Alzheimer's disease (AD). We have found that in AD the large, efferently projecting neurons (mitral cells) of the OB degenerate, typically without classical Alzheimer neurofibrillary changes. In some cases, with less severe neocortical pathology, the terminal arborizations of olfactory nerve appear hyperplastic and are associated with focal accumulations of A-4 (beta-amyloid) immunoreactivity that are not detectable by standard amyloid stains. These abnormalities may represent a pathologic manifestation of normally occurring plasticity in the olfactory system.

The present study compared the relative effectiveness of a therapist-supported maintenance condition with a minimal contact maintenance condition in preventing relapse following an obesity treatment program. Thirty-two subjects who completed an initial 12-week cognitive/behavioral plus aerobic exercise treatment program were matched on absolute weight loss and randomly assigned to one of two maintenance conditions. Subjects were assessed at pretreatment, posttreatment, and 3, 6, and 12 months following posttreatment using measures of weight, blood pressure, and depression. Three- and six-month follow-up results indicated that subjects who participated in the therapist-supported maintenance group continued to lose weight and/or maintained therapy-induced weight loss to a greater degree than control subjects. At the 12-month follow-up assessment therapist-supported subjects maintained therapy-induced weight loss better than the control subjects. These findings suggest that maintenance programs which provide continued contact emphasizing relapse prevention training may be an important adjunct in the maintenance of therapy-induced weight loss.

Mild acute hypertension was induced in rats pharmacologically and non-pharmacologically with metaraminol, angiotensin II or bilateral vagotomy. The extraction fraction of water (Ew) was measured in both hypertensive and normotensive animals. It was demonstrated that cerebral blood flow did not change during hypertensive states. Under constant flow conditions Ew becomes a direct index of the cerebral capillary permeability to water. Ew was significantly decreased (P less than 0.001) in all brain regions examined in the hypertensive animals as compared to normotensive controls. However, the decrease Ew induced by hypertension was not observed if the animal had previously received bilateral carotid sinus denervation. This observation indicated that the capillary permeability response induced by hypertension is mediated by a neurogenic mechanism involving information transfer from the peripheral baroreceptors in the carotid sinus along afferent connections into the central nervous system.

Twenty-eight gastric wall tumors classified by light microscopy as leiomyomas or leiomyosarcomas were reevaluated for histogenesis. Each case was analyzed for the presence of S-100 protein, a marker for cells derived from neuroectoderm, by the immunoperoxidase technique. Eight tumors contained cells with positive immunostaining for S-100 protein. Usually this staining was focal, but in one case staining was diffuse. In three additional cases the immunostaining outlined a nerve within the tumor. In contrast, two esophageal and 10 uterine leiomyomas, as well as normal gastric smooth muscle, gave negative reactions for S-100 protein. Twelve cases had tissue processed for electron microscopy. Only two of the tumors, one leiomyoma and one leiomyosarcoma, contained cytoplasmic myofilaments with densities expected in cells derived from smooth muscle; neither of these tumors stained for S-100 protein. In one case, the tumor with diffuse staining for S-100 protein, the cells resembled Schwann cells ultrastructurally. The remaining nine cases had neither smooth muscle nor Schwann cell features. They did contain interposed cell processes, primitive junctions, and large cytoplasmic vacuoles. The results of this study indicate that many gastric wall tumors are not derived from smooth muscle. The presence of S-100 protein suggests a nerve sheath origin in some cases. While the ultrastructure of many gastric tumors does not resemble nerve sheath cells in most peripheral nerves, the myenteric nervous system is a possible source for perineurial or mesenchymal nerve sheath cells with distinctive fine structure. Further study is needed to refine our knowledge of the histogenesis of gastric stromal tumors.

Markedly dilated dystrophic post-ganglionic sympathetic axons have been identified by dopamine-beta-hydroxylase immunohistochemistry in the paravascular ileal mesenteric nerves of rats with chronic streptozotocin diabetes. Many axons contained multiple dilatations with interposed axonal segments of near normal dimensions. These axonal abnormalities were absent in control animals. The time course of the development of the axonopathy and its distribution in the alimentary tract correlate with quantitative ultrastructural findings previously reported in this system.

A host of proteins was seen when the chloroform-methanol insoluble protein (CMIP) fraction of bovine brain myelin was transferred from polyacrylamide gels to cellulose nitrate sheets. Inoculation of rabbits with the CMIP fraction generated a number of antibodies which were demonstrated by the immunoblot technique. These antisera against CMIP contained antibodies which induced demyelination and inhibited myelin formation in central nervous system cultures. The demyelinating factor was specific for centrally myelinated fibers, and did not demyelinate peripherally myelinated axons.

Electron microscopic immunocytochemical studies were carried out to localize myelin basic protein and myelin proteolipid protein during the active period of myelination in the developing rat brain using antisera to purified rat brain myelin proteolipid protein and large basic protein. The anti-large basic protein serum was shown by the immunoblot technique to cross-react with all five forms of basic protein present in the myelin of 8-day-old rat brain. Basic protein was localized diffusely in oligodendrocytes and their processes at very early stages in myelination. The immunostaining for basic protein was not specifically associated with any subcellular structures or organelles. The ultrastructural localization of basic protein suggests that it may be involved in fusion of the cytoplasmic faces of the oligodendrocyte processes during compaction of myelin. Immunoreactivity in the oligodendrocyte and myelin due to proteolipid protein appeared at a later stage of myelination than did that due to basic protein. Staining for proteolipid protein in the oligodendrocyte was restricted to the membranes of the rough endoplasmic reticulum, the Golgi apparatus, and apparent Golgi vesicles. The early, uncompacted periaxonal wrappings of oligodendrocyte processes were well stained with antiserum to large basic protein whereas staining for proteolipid protein was visible only after the compaction of myelin sheaths had begun. Our evidence indicates that basic protein and proteolipid protein are processed differently by the oligodendrocytes with regard to their subcellular localization and their time of appearance in the developing myelin sheath.

Little attention has been given to how formal classroom instruction can be adapted to teach youths everyday skills such as the correct writing of biographic information frequently requested in transactions like applying for a job or a social security number and cashing a check. In this study, six youths in a special education classroom were taught to complete job application forms with the date, their name, signature, address, telephone number, date of birth, and a reference's name, address, and occupation. Each youth was trained on one item of biographic information at a time, after which he was tested on four application forms, including one on which he had not been trained. The tests show that after an item had been taught, it was correctly used in completing application forms on which the youths had been trained and forms on which they had never been trained. The study demonstrates the feasibility of teaching community-living, vocation-related skills to special-education youths in a classroom setting.

Immunohistochemical localization of tissue specific or cell-specific antigenic markers in neoplastic cells has become an increasingly important tool in the pathologic diagnosis of tumors. The myelin-specific proteins of peripheral nervous system myelin, because they are normally synthesized in Schwann cells, are potentially useful markers for neoplasms arising from peripheral nerves. The authors carried out immunohistochemical studies on 18 cases of Schwann cell neoplasms, including schwannomas, neurofibromas, and granular cell tumors, to determine whether two myelin-specific proteins, myelin basic protein and P2 protein, were present in neoplastic Schwann cells. None of these tumors showed immunostaining for either myelin basic protein or P2 protein in neoplastic cells. In contrast, S-100 protein, which is a well established marker for normal and neoplastic Schwann cells, was localized by immunohistochemistry to neoplastic cells in all 18 neoplasms. Therefore, although myelin basic protein and P2 protein are known to be Schwann-cell-specific proteins, they do not appear to be expressed commonly in neoplastic Schwann cells.

THIS ARTICLE REPORTS ON THE PRIMARY STEPS IN THE DEVELOPMENT OF PARENT ADVICE FOR POPULAR DISSEMINATION: (a) developing advice for one specific problem situation, family shopping trips; (b) testing the advice program for benefit to children and convenience to adults; and (c) packaging the advice so it can be used successfully by interested parents. Systematic observation of 12 families using the written advice package on shopping trips revealed its effectiveness in reducing child disruptions and increasing positive interactions between parents and children. These findings, along with interview information from families, showed that the package is usable, effective, and popular with both parents and children, and thus is ready for dissemination to a wide audience of parents-a step that in itself should involve research and evaluation.

Axotomy of sciatic nerve fibers in adult rats induces expression of NGF receptor in the entire population of Schwann cells located distal to the injury (Taniuchi et al., 1986b). In the present study we have used immunocytochemistry, with a monoclonal antibody directed against the rat NGF receptor, to examine axotomized peripheral nerves by light and electron microscopy. We have found that (1) the NGF receptor molecules were localized to the cell surface of Schwann cells forming bands of Bungner; (2) axonal regeneration into the distal portion of sciatic nerve coincided temporally and spatially with a decrease in Schwann cell expression of NGF receptor; (3) Schwann cell NGF receptor could be induced by axotomy of NGF-independent neurons, such as motoneurons and parasympathetic neurons; and (4) the presence of axon-Schwann cell contact was inversely related to expression of Schwann cell NGF receptor. Using biochemical assays we have found that, in striking contrast to peripheral nerves, there was no detectable induction of NGF receptor in the spinal cord and brain after axotomy of NGF receptor-bearing fibers. Filtration assays of 125I-NGF binding to the induced NGF receptors of Schwann cells measured a Kd of 1.5 nM and a fast dissociation rate, both characteristics of class II receptor sites. We conclude that Wallerian degeneration induces Schwann cells, but not central neuroglia, to produce and position upon their plasmalemmal surface the class II NGF receptor molecules. The induction is ubiquitous among Schwann cells, irrespective of the type of axon they originally ensheathed. Expression of Schwann cell NGF receptor is negatively regulated by axonal contact, being induced when axons degenerate and suppressed when regenerating axons grow out along the Schwann cell surface. We propose that the induced NGF receptors function to bind NGF molecules upon the Schwann cell surface and thereby provide a substratum laden with trophic support and chemotactic guidance for regenerating sensory and sympathetic neurons.

In this report we describe the transfer of chronic relapsing experimental allergic encephalomyelitis (EAE) with in vitro-stimulated lymph node cells (LNC) from SJL/J mice immunized with human myelin proteolipid protein (PLP). No additional immune enhancing procedures were applied in the transfer recipients. Clinical and histological EAE was transferred with 10-30 X 10(6) LNC to 27/28 mice. The LNC proliferated in vitro to PLP, but not to myelin basic protein (MBP), and induced delayed-type hypersensitivity. Enrichment for lymphoblasts by Ficoll centrifugation was essential for the disease development. The clinical course usually showed an early episode of acute paralytic illness, followed by chronic relapsing disease, and resembled the transfer of EAE using MBP-specific cells, both clinically and histologically.

The effect of acrylamide on the sympathetic innervation of the rat pineal gland was examined by using ultrastructural, immunohistological, biochemical, and physiological methods. Separation of sympathetic terminals from perivascular pineocyte processes was facilitated by administration of the false neurotransmitter 5-hydroxydopamine, which preferentially labeled sympathetic terminals, shortly before sacrifice. Administration of acrylamide (50 mg/kg/day, intraperitoneally) for 1 to 2 weeks resulted in the near-total loss of pineal parenchymal perivascular axons and axons intercalated between individual pineocytes. More proximal portions of these sympathetic axons located within the capsule of the pineal gland developed markedly enlarged swellings containing neurofilaments and tubulovesicular elements. The ultrastructural appearance of axons swollen by tubulovesicular elements resembled that of regenerating axons and axons whose regenerative progress had been frustrated. The activity of pineal dopamine-beta-hydroxylase, a noradrenergic marker enzyme confined to sympathetic axons and their terminals and absent in pineocytes, was determined in an attempt to develop a quantitative measure of the extent of sympathetic denervation. The loss of 50% of pineal dopamine-beta-hydroxylase activity underestimated the extent of parenchymal denervation due to the marked engorgement of remaining capsular sympathetic axons by immunoreactive dopamine-beta-hydroxylase. The daily rhythm of pineal serotonin N-acetyltransferase (NATase) activity, which is dependent on the circadian variation in the activity of pineal sympathetic axons, was decreased 90% by chronic acrylamide administration. Pineal NATase activity increased 25- to 50-fold in acrylamide intoxicated rats in which isoproterenol was used to stimulate pineocyte beta-adrenergic receptors directly, which is evidence against a nonspecific toxic effect of acrylamide on pineocytes. Administration of N,N'methylene-bis-acrylamide, a non-neurotoxic analog of acrylamide, was without effect on pineal ultrastructure or NATase activity.

Using two methods of immunization (A and B), 5/10 (A) and 27/45 (B), BALB/c by J mice immunized with human myelin proteolipid protein developed a demyelinating disease with a spectrum of chronic progressive to relapsing-remitting courses. Demyelinative lesions were seen histopathologically in all clinically affected animals that were examined. Many of the clinically unaffected animals also had histopathologic evidence of demyelination. Some of the animals had evidence of multiple ages of foci of activity. Evidence is presented that contamination with myelin basic protein could not account for the disease. This is a new model for multiple sclerosis in mice.

Immunohistochemical localization of nervous system antigens is becoming an increasingly useful tool in the diagnosis of neuropathologic lesions. Use of antigen markers specific for certain cell types, when properly employed, can confirm suspected diagnoses or solve difficult differential diagnoses. Presently the most useful markers are the glial antigens, glial fibrillary acid protein and S-100 protein, but a number of other markers, such as neurofilament proteins and neuron-specific enolase, have shown some diagnostic utility.

An intravenous injection method to measure cerebral vascular extraction fractions of highly diffusible substances in the rat is described. The brain extraction fractions of 3H-labeled water (Ew) and ethanol (Ee) were defined as the ratio of either of those tracers to the freely diffusible reference tracer, 14C-butanol, in the brain, divided by the ratio of the tracers available for the extraction during the time between simultaneous intravenous injection of the tracers and decapitation of the rat. Ew and Ee were measured in five regions of brain, including brainstem and cerebellum, under PaCO2 conditions ranging from 15 to 85 mm Hg. The extraction fractions for both test tracers were shown to vary with PaCO2-induced flow changes according to the equation, ln(1 - E) = -PS/F. When PS/F values calculated from regional measurements of Ew and Ee were plotted versus PaCO2, least squares regression equations of the plots could be used to compare permeabilities of both tracers at any given PaCO2 value. Ratios of the permeabilities of water and ethanol varied regionally but were relatively constant in a given region under different flow states. This intravenous injection method allows for accurate measurement of the extraction fractions of even highly diffusible tracers under varied flow conditions in all brain regions regardless of arterial blood supply.

Three retarded and four economically disadvantaged children were taught, through modelling and reinforcement procedures, to produce complete sentences in response to three types of questions involving changes in verb inflections. To evaluate generalization of training, new but similar questions were periodically asked, answers to which were never modelled or reinforced. Modelling and reinforcement effectively taught correct sentence answers to training questions and produced new sentence answers to questions for which no specific training had been given.

Chronic treatment of rats with amitriptyline (AMI) induced a persistent increase in the diffusibility of water into the brain (EW). This effect was observable 12 h after the last dose. AMI induces this alteration at plasma drug concentrations of 71 +/- 13 ng/ml (the therapeutic range for man is 100--250 ng/ml). Furthermore, chronic treatment potentiated the increase observed after acute drug administration and resulted in a 350% enhancement in the permeability of water across the cerebral capillary. Thus, long-term antidepressant administration can chronically influence cerebral function by affecting capillary permeability.

Hemorrhage into areas of periventricular leukomalacia may occur and range in size from microscopic to massive. Hitherto, the definitive diagnosis has been made only at autopsy. A case is described in which the diagnosis of hemorrhagic periventricular leukomalacia was made antemortem by real-time ultrasound scanning and confirmed at autopsy. Periventricular/intraventricular hemorrhage, a more common hemorrhagic lesion, may extend into periventricular with matter in a location ventral and medial to hemorrhagic periventricular leukomalacia. Real-time ultrasound scanning is a safe and reliable means of defining the topography of these two hemorrhagic lesions and, thereby, of suggesting the correct diagnosis.

Immunoblot analysis of antiserum to rat central nervous system (CNS) myelin revealed antibodies to myelin basic protein (MBP), proteolipid protein (PLP), and numerous high molecular weight proteins. In addition, anti-CNS myelin serum exclusively immunostained 4 basic proteins of rat peripheral nervous system (PNS) myelin. Similarly, anti-PNS myelin sera immunostained many high molecular weight proteins in both CNS and PNS myelin in addition to P0 and 4 basic proteins. Purified MBP and PLP were immunostained by anti-CNS myelin sera and MBP and P0 by anti-PNS myelin sera, indicating that antigenic sites are preserved during protein purification. Immunohistochemical localization with antisera was confined to the myelin sheath except that antisera to CNS myelin also stained oligodendrocytes during the active period of myelination. While anti-CNS myelin sera specifically demyelinated centrally myelinated fibers in culture, none of the anti-PNS myelin sera used here demyelinated organotypic spinal cord-dorsal root ganglion cultures.

A small volume (5 microliters) common carotid arterial injection method is described for the quantitation of cerebral vascular extraction fractions (Et) of diffusion limited tracer molecules in the rat. The method is a modification of a technique introduced by Oldendorf and widely used for the study of blood-brain barrier phenomena. While the Oldendorf technique has proven valuable for estimating the relative permeabilities of substances, it is limited in measuring Et under conditions of physiologically or pharmacologically altered permeability or blood flow. The method described in this paper--using a small volume (5 microliters) common carotid injection, a freely diffusible reference tracer, [14C]butanol, and a 5 sec circulation time--allows for measurements of Et that reflect changes in blood flow and small differences in permeability. The modified method is important for the study of the regulation of cerebral vascular permeability and flow in an inexpensive animal model.

NGF acts on responsive neurons by binding to specific NGF receptors on axonal termini, after which a critical biochemical signal is retrogradely transported to the cell body. The identity of the signal(s) is unknown; candidates include NGF itself or some other "second messenger." A possible second messenger is the NGF receptor. As a first step in assessing the possible role of NGF receptor in the generation of the NGF-dependent signal, and in understanding the economy of NGF receptor synthesis and utilization, we determined whether the NGF receptor is retrogradely transported. Using immunohistochemical staining with a monoclonal antibody (192-IgG) against rat NGF receptor, we looked for accumulation of NGF receptor molecules distal (retrograde transport), as well as proximal (anterograde transport), to sites of axonal ligation or transection. By 10-12 hr in both the ligated sciatic nerve and the lesioned fimbria-fornix, accumulated NGF receptor was detected proximal and distal to the ligation/lesion site. The transported receptor presumably was located in sympathetic and sensory neurons in the sciatic nerve and in forebrain cholinergic neurons projecting from the medial septum to the hippocampus. In both anatomical sites, accumulation of NGF receptor on the proximal (anterograde) side occurred in streams of fine axonal processes, whereas staining on the distal (retrograde) side occurred in varicose or granular configurations. These results raise the possibility that the NGF receptor has a role in the mechanism of NGF beyond the initial binding event at the plasma membrane of the axonal terminus.