Human acoustic neurinomas: Nervous system specific biochemical parameters

Summary A series of 24 human acoustic neurinomas from 24 patients has been assayed for several biochemical parameters characteristic of the nervous system. S 100 protein, 2, 3-cyclic nucleotide 3-phosphohydrolase activity, and the myelin lipids galactosylceramide and sulfogalactosylceramide (sulfatide). Myelin basic protein was not detected. These findings further support the neuroectodermal origin of the human acoustic neurinoma, and provide additional biochemical markers for further study.     

Ultrastructural studies of concanavalin A receptors and 5′-nucleotidase localization in normal and injured mouse cerebral microvasculature

Summary Plant lectin concanavalin A conjugated with ferritin (Con A-F) injected i.v. was used for the detection of the specific monosaccharide residues (-d-mannosyl and -d-glucosyl) on the luminal surface of endothelial cells (ECs) in brain micro-blood vessels (MBVs). Both normal mice and animals with mechanically damaged blood-brain barrier (BBB) were used in this study. In addition, the activity of 5-nucleotidase (5N), the putative receptor for Con A, was studied cytochemically.Various methodologic experiments indicated that the reaction product formed on the luminal plasmalemma of ECs after incubation of samples in the cytochemical medium for the detection of 5N activity results from the action of unspecific phosphatase hydrolyzing both specific and nonspecific substrates. The abluminal side of the wall of MBVs seems to be a major location of 5N activity. Thus, no correlation between cytochemically demonstrable 5N activity and Con A receptor sites on the luminal surface of ECs was noted.After damage of the BBB, extensive internalization of the luminal plasmalemma forming the limiting membranes of pinocytotic vesicles, vacuoles, and endothelial channel-like structures was observed. This process was represented by a relatively rapid translocation of Con A receptors from luminal surface into the interior of the ECs and to the abluminal side of the vessel wall.Abbreviations AP Alkaline phosphatase - 5N 5-nucleotidase phate - AMP adenosine 5-monophosphate - CMP cytidine 5-monophosphate - GMP guanosine 5-monophosphate - UMP uridine 5-monophosphate - Con A concanavalin A - BBB blood-brain barrier - EC endothelial cell - HRP horseradish peroxidase - MBVs micro-blood vessels - NDPase nucleoside diphosphatase Supported in part by a grant from NINCDS No.17271-03     

S-100 protein and 2′,3′-cyclic nucleotide 3′-phosphohydrolase in human brain tumors

Summary Biopsy specimens from 23 human brain tumors have been analyzed for the nervous system specific protein S-100 and the membrane-associated enzyme 2,3-cyclic nucleotide 3-phosphohydrolase (CpNase). Biopsy specimens from an additional seven brain tumors were tested for either S-100 or CpNase alone.All astrocytomas and glioblastomas tested were found to contain S-100 and CpNase although there does not appear to be a strong correlation between the levels of these two markers in the 14 such tumors assayed for both. S-100 levels varied over a 19-fold range while CpNase varied over a 835-fold range. Postoperative survival in the astrocytoma and glioblastoma patients showed only a weak correlation with either tumor CpNase or S-100 levels.Two acoustic neurinomas, two oligodendrogliomas, one mixed glioma, and one choroid plexus papilloma were also assayed and found to have detectable levels of both S-100 and CpNase with the acoustic neurinomas and the mixed glioma having relatively high levels of each marker. All six meningiomas tested had low levels of CpNase. S-100 assays in three benign meningiomas were negative, while low levels of this protein were found in the one malignant meningioma tested.Tissue cultures were grown out from biopsy specimens of additional human brain tumors and tested at confluency for S-100. Of 15 astrocytoma and glioblastoma cultures tested, three had easily detectable amounts of S-100, two appeared to contain trace levels and ten were negative. The two acoustic neurinoma cultures tested were positive for S-100 while all three oligodendroglioma cultures were negative.     

Cyclic adenosine 3′,5′monophosphate in cerebrospinal fluid of multiple sclerosis patients

Summary Cyclic adenosine 3,5monophosphate (cAMP) was assayed in CSF and plasma obtained from patients with multiple sclerosis. Decreased CSF cAMP levels were found in more than half of the patients while plasma cAMP was normal. The decrease is correlated significantly with the disability of the patient and with the progression of the disease. A low CSF cAMP level can be considered as prognostically unfavorable, particularly in the early stage of the disease. There was no correlation between the cAMP levels and the duration of the disease or with bouts and remissions. ACTH therapy did not normalize the decreased values. Obviously the decrease of CSF cAMP is related to the demyelination and not to the intensity of the pathological immunoreactions.

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Zusammenfassung Es wurde das cyclische Adenosin-3,5monophosphat im Liquor von Patienten mit multipler Sklerose untersucht. Bei einem Teil der Patienten wurden auch die Vergleichswerte im Blutplasma bestimmt. Es zeigte sich bei mehr als der Hälfte der Patienten eine Verminderung der cAMP-Konzentration im Liquor bei normalem Plasmaspiegel. Diese cAMP-Verminderung erwies sich als signifikant abhängig von dem Schweregrad der Erkrankung bzw. der Erkrankungsprogredienz und ist besonders in frühen Erkrankungsfällen als prognostisch ungünstiges Zeichen anzusehen. Es fand sich kein Zusammenhang mit dem Krankheitsstadium, d.h. Schub bzw. Intervall, und mit der Erkrankungsdauer. Eine ACTH-Behandlung vermochte diese Verminderung der Werte nicht auszugleichen. Es wird die Wertigkeit dieser Befunde diskutiert.

     

Autoradiographic studies of protein turnover in motoneurons of IDPN-treated rats

Summary Autoradiography was performed in order to envisage the turnover of H³-leucin labeled protein in the perikarya of spinal motoneurons and in the axonal balloons formed after repeated administrations of IDPN (--iminodiproprionitrile) in rats.These results suggested that (1) there was no significant, if any,in situ protein synthesis within the axon balloons, (2) the protein turnover was not appreciably altered in the perikarya of the control and IDPN-intoxicated rats, and (3) the labeled protein collected in the axon balloons seemed to be transported from the perikarya to which they were linked with short axonal segments (30 in average length).Supported in part by U.S. NIH Institutional Research Grant (and Neurology Foundation).     

β,β′-Iminodipropionitrile toxicity in normal and congenitally neurofilament-deficient Japanese quails

Morphological effects of a neurotoxin, ,-iminodipropionitrile (IDPN) were analyzed in normal and cogenitally neurofilament (NF)-deficient Japanese quails. These quails (6 weeks old) were injected intraperitoneally with IDPN (0.2 g/kg body weight) three times every 3 days. They were necropsied at 10 to 12 days after the first injection. In normal quails, axonal swellings were observed histologically in the ventral motoneurons, ventral root, commissura grisea and spinal ganglion in the cervical and synsacral spinal cord. Electron microscopically, the changes consisted of increased NFs, with scattered mitochondria, smooth endoplasmic reticulum and microtubules. The myelin sheaths of the involved nerves were thinner than those of the normal axons. These lesions were similar to those induced by IDPN intoxication in mammalian experimental animals. In NF-deficient quails injected with IDPN, no axonal changes were detected. These findings suggested that IDPN selectively attacked the NFs.     

Regional serotonin transporter availability and depression are correlated in Wilson’s disease

Summary. In patients with Wilsons disease (WD), depression is a frequent psychiatric symptom. In vivo neuroimaging studies suggest that depression and other neuropsychiatric disorders are associated with central serotonergic deficits. However, in vivo measurements of serotonergic neurotransmission have not until now been performed in patients with this copper deposition disorder. The present prospective study revealed that depressive symptomatology is related to an alteration of presynaptic serotonin transporters (SERT) availability as measured by [¹²³I]-2-carbomethoxy-3-(iodophenyl)tropane ([¹²³I]-CIT) and high-resolution single-photon emission computed tomography (SPECT). SERT imaging with [¹²³I]-CIT-SPECT could therefore become a useful tool for diagnosis and therapy monitoring in depressed WD patients.Received December 10, 2001; accepted March 24, 2003 Published online June 10, 2003     

Induction of glutathione S-transferase,placental type in T9 glioma cells by dibutyryladenosine 3′,5′-cyclic monophosphate and modification of its expression by naturally occurring isothiocyanates

Summary The effect of dibutyryladenosine 3,5-cyclic monophosphate (dibutyryl cAMP) on the expression of glutathione S-transferase placental type (GST-P) was examined in rat glioma cell line using an immunohistochemical technique. Cultured T9 glioma cells were negative for GST-P activity under normal conditions. However, treatment with 1 mM dibutyryl cAMP produced GST-P expression in about 50% of the cells, as well as some morphological changes. The expression of GST-P was increased with addition of dibutyryl cAMP together with 1 g/ml allyl isothiocyanate (AITC) or 0.1 g/ml benzyl isothiocyanate (BITC). With these combinated treatments, almost all cultured cells showed a strong positive reaction for GST-P, although AITC or BITC alone elicited GST-P in only 5% of the cultured cells. The results of the present study indicate that dibutyryl cAMP causes functional as well as morphological differentiation of T9 glioma cells.     

„Fingerprint inclusions” in muscle fibres in dystrophia myotonica

Summary Fingerprint inclusions were observed in numerous muscle fibres of 3 cases of dystrophia myotonica studied by electron microscopy in two different laboratories. They consist of parallel or concentric palisades of short electron dense linear elements. Identical fingerprint inclusions were reported in two other clinical conditions and cannot therefore be regarded as specific for a particular muscle disease. Their origin and significance remain obscure.     

L-DOPA biotransformation: correlations of dosage,erythrocyte catechol O-methyltransferase and platelet SULT1A3 activities with metabolic pathways in Parkinsonian patients

Summary. The objectives of this study were to determine (1) the effects of dose and drug absorption on pathways of biotransformation of L-DOPA in Parkinsonian patients treated with Sinemet, and (2) the extent to which genetically-determined variations in the activities of erythrocyte catechol O-methyltransferase and/or platelet phenol sulfotransferase might be reflected in individual differences in L-DOPA metabolism. In the 19 patients studied, there were negative correlations between dosage or absorption and extent of O-methylation and of sulfation of L-DOPA or its metabolites. Levels of activity for erythrocyte COMT were also reflected in individual variation in the metabolism of L-DOPA. In contrast, differences in platelet phenol sulfotransferase were not reflected in differences in sulfation of L-DOPA or of its metabolites. If such a relationship did exist, it might have been obscured by the effects of high dosage of L-DOPA, effects which might have resulted from a deficiency of the sulfation cosubstrate 3-phosphoadenosine 5-phosphosulfate in patients taking higher doses of drug.Received August 1, 2002; accepted March 1, 2003 Published online May 28, 2003     

Circadian variations of adrenergic receptors in the mammalian pineal gland: A review

Summary Pineal adrenergic receptor numbers show circadian variations in both rat and Syrian hamster. In the rat pineal -adrenergic receptor density reaches peak values either late in the light phase or at middark; the differences in the circadian phase seem related to the light:dark cycle to which the animals are exposed. No circadian rhythm of pineal -adrenergic receptors is documented in intact rats. In the Syrian hamster pineal -adrenergic receptor density is high throughout the light phase and drops to minimal values at the time of the nocturnal peak of melatonin production. The circadian rhythm of pineal -adrenergic receptor numbers runs parallel to the -adrenergic receptor variation, but is less pronounced.In the rat, pineal melatonin production is rapidly induced by -adrenergic agonists at any time during a 24-hour period, even when the pinealocyte -adrenergic receptor number is lowest (early in the light phase). In contrast, the Syrian hamster pineal seems most responsive to -adrenergic agonists in the late night while being less responsive during the day when -adrenergic receptor density is high. Interestingly, the human pineal gland is also not especially responsive to adrenergic stimulation during the light phase, possibly making the Syrian hamster pineal a better model than the rat pineal for determining neural/pineal interactions in humans. Comparison of the circadian variations in pineal adrenergic receptors leads to the conclusion that the functional differences between rat and hamster pineal are probably not explicable in terms of the adrenergic receptors, but are caused most likely by (a) intracellular mechanism(s) beyond the adrenergic receptors.     

Unusual ‘Spike-wave stupor’ in a patient with manic-depressive psychosis treated with amitriptyline

Summary Spike-wave stupor was observed in a 58-year-old male patient with manic-depressive psychosis. Almost continuous atypical spike-wave activity was seen in conjunction with a stuporous episode with stereotyped automatism. Intravenous diazepam ended both the electroencephalographic epileptiform discharges and the clinical stupor. Before and during this episode the patient was treated with an average-dose amitriptyline monotherapy. There was no family history of epileptic seizures. The patient had had electroconvulsive therapy. The history suggests that the analeptic property of amitriptyline induced the spike-wave stupor in this patient.

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Zusammenfassung Während eines Stupors mit stereotypen Bewegungsabläufen und Reihensprechen, der im Rahmen einer depressiven Phase eines an einer manisch-depressiven Psychose erkrankten 58jährigen Patienten auftrat, wurde eine nahezu kontinuierliche unregelmäßige spike-wave- und sharp-wave-Aktivität im EEG abgeleitet. Der spike-wave-Stupor konnte durch eine intravenöse Applikation von Diazepam in seiner klinischen und elektroenzephalographischen Ausprägung rasch unterbrochen werden. Vor und während der stuporösen Attacke wurde der Patient mit Amitriptylin als Monotherapie in üblicher Dosierung behandelt. Die Eigen- und Familienanamnese ergab keinen Hinweis auf das Vorliegen einer Epilepsie. Epileptische Anfälle hatte der Patient nur aus therapeutischen Gründen im Rahmen einer Elektroschocktherapie. Die Analyse des Falles läßt in der analeptischen Wirkung von Amitriptylin die Ursache für das Auftreten des spike-wave-Stupors erkennen.

     

Group psychotherapy and the mosaic adolescent society

Discussion of the influence of peer group mores and values on the adolescent patient's dysfunctional behaviors and treatment outcome. When the group therapist thinks peer, the group will focus on important issues such as inclusion, acceptance and awareness of the contrasting beliefs of the numerous peer subcultures within adolescent society. Strategies and approaches to create a therapeutic group milieu and structure are outlined to enable unwanteds to enter peer groups which support rather than impede the attainment of treatment goals. The need for leadership to be responsive to group members who have not experienced negentropic or functional systems is emphasized.     

Occurrence of α-synuclein pathology in the cerebellum of Guamanian patients with parkinsonism-dementia complex

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disease affecting the indigenous Chamorro population of Guam. Neuropathologically, PDC is characterized by neuronal loss in the substantia nigra pars compacta with severe widespread neurofibrillary tangles (NFTs) similar to those observed in Alzheimers disease (AD), and is thus considered a tauopathy. Following reports of -synuclein pathology in PDC patients of Guam, PDC has also been neuropathologically classified as a synucleinopathy. Recently, the presence of -synuclein-positive bodies has been reported in the cerebellum of some patients with Parkinsons disease (PD), diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using immunohistochemical techniques, we investigated the deposition of -synuclein in the cerebellum of Guamanian PDC patients. Numerous -synuclein-immunoreactive spherical structures were found in the molecular layer of the cerebellum of 63.6% of PDC patients. These structures were only seen in patients showing -synuclein pathology in the amygdala. The average density of -synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients was almost an order of magnitude higher than in non-Guamanian PD patients, and this -synuclein pathology was much more pronounced in the hemisphere than in the vermis. In addition, double immunohistochemistry revealed that cerebellar -synuclein is co-localized with the neuronal marker calbindin and with glial-fibrillary acidic protein, suggesting the involvement of Purkinje cells and Bergmann glia. These findings demonstrate that the -synuclein pathology in PDC of Guam affects not only the amygdala, but also the cerebellum, where it appears to involve both Purkinje cells and specialized astrocytes.     

Noradrenergic,purinergic, and cholinergic transmission in the mouse vas deferens: influence of field-stimulation parameters,reserpinization, 6-hydroxydopamine and 4-aminopyridine

Summary In the field-stimulated mouse vas deferens the twitch inhibiting potency of prazosin (1 M) and ,-methylene ATP (MeATP, 10 M) was studied, using two types of stimulation-response curves, (a) variation of frequency from 3 to 100 Hz at a constant pulse width of 0.1 ms and (b) variation of pulse width from 0.04 to 0.8 ms at a constant frequency of 15 Hz. Prazosin and MeATP reduced the twitch response by eliminating the noradrenergic and purinergic component, respectively. After the combined application of both compounds a small third twitch component remained that was most prominent at high frequencies. Reserpinization reduced the effect of prazosin but enhanced that of MeATP and increased the cholinergic component. 6-Hydroxydopamine enhanced the effects of prazosin and MeATP to the same extent, but left the cholinergic component intact. In vasa pre-loaded with [³H]-noradrenaline, field stimulation induced a larger release of tritium at high frequency and short pulse duration (100 Hz, 0.1ms) than at lower frequency and long pulse duration (15 Hz, 0.3 ms). Prazosin (1 M) augmented both the spontaneous and the stimulation-induced overflow of tritium, whereas MeATP (10 M) had only a negligible negative effect on the outflow of label. In conclusion, the twitch contraction of the mouse vas deferens has a small cholinergic component in addition to the noradrenergic and purinergic components. Adrenergic and purinergic transmission seem not to run strictly in parallel: the purinergic component dominates during stimulation at low frequency and long pulse duration, and after reserpinization; 4-aminopyridine enhances the adrenergic mechanism more than the purinergic one.     

The RAGE pathway in inflammatory myopathies and limb girdle muscular dystrophy

Oxidative stress and nuclear factor-B (NF-B) activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases. Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand N-carboxymethyllysine (CML) results in the activation of NF-B and the production of proinflammatory cytokines. To determine whether engagement of RAGE contributes to the pathogenesis of inflammatory myopathies, we performed immunohistochemical studies on the presence of CML-modified proteins, RAGE and activated NF-B in muscle biopsies of patients with polymyositis (PM, n=10), dermatomyositis (DM, n=10), limb girdle muscular dystrophy (LGMD, n=10) and in 10 controls with normal muscle biopsy results. In inflammatory myopathies CML, RAGE and NF-B were detected in mononuclear cells and in regenerating muscle fibers. CML, NF-B and, to a lesser extent, RAGE were also found in degenerating muscle fibers, but colocalization of CML, RAGE and NF-B was only seen in infiltrating mononuclear cells and regenerating muscle fibers. Immunofluorescence double labeling demonstrated an expression of CML, RAGE and NF-B in CD4-, CD8-, CD22- and CD68-positive mononuclear cells. Western blot analysis showed an increased immunoreactivity for CML-modified proteins in PM and DM. In LGMD, CML, RAGE and NF-B were found in regenerating muscle fibers and less frequently in degenerating muscle fibers, and with lower staining intensities than in inflammatory myopathies. Our data suggests that the CML-RAGE-NF-B pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM. RAGE-mediated NF-B activation may be involved in muscle fiber regeneration in inflammatory myopathies and LGMD.     

Die Bedeutung der diskontinuierlichen Zonierung des Immunglobulinbereiches für die Diagnose neurologischer Erkrankungen

Zusammenfassung 1. 340 Patienten, welche bei der agarelektrophoretischen Auftrennung der Liquorproteine eine diskontinuierliche Zonierung im Bereiche der -Globuline zeigten, wurden bezüglich Verteilung dieser clonalen -Zonen auf die verschiedenen neurologischen Erkrankungen untersucht.2. Bei der MS und den anderen entzündlichen neurologischen Erkrankungen findet sich eine Häufung der schnell wandernden Zone ₂ und der mittelschnell wandernden Zonen ₃ und ₄.3. Bei den Discushernien und den zentralnervös-nichtentzündlichen Erkrankungen ist die Zonenverteilung ziemlich flach und undifferenziert, wobei hier wie auch bei Tumoren und Polyneuritiden der relativ hohe ₀-Anteil auffällt als ein Phänomen, das bei zentralnervös-entzündlichen Prozessen nur selten anzutreffen ist. In den wenigen Tumorfällen mit -Zonierung scheint die ₄-Position deutlich zu überwiegen.4. In der Hälfte aller MS-Liquoren mit -Zonierung ist das Totalprotein, in einem Sechstel das Total--Globulin (rel%) normal, und nur bei zwei Dritteln finden sich Plasmazellen. Die elektrophoretische Feststellung von -Zonierung ist in der neurologischen Labordiagnostik folglich ein wichtiges Hilfskriterium.5. Mit zunehmendem Anstieg des -Globulin-Gehaltes im Liquor läßt sich bei MS-Patienten, nicht aber bei allen Krankheitsgruppen, eine Zunahme der Häufigkeit der -Zonierung nachweisen.6. Das Auftreten von -Zonierung ist bei den zentralnervös-entzündlichen Krankheiten und der MS sechsmal häufiger als bei den zentralnervös-nichtentzündlichen Krankheiten.7. -Zonierung scheint beim Gesunden, bei psychiatrischen Erkrankungen, Myopathien, bei gewissen Tumoren (Neurinomen) und metabolisch bedingten Polyneuritiden nicht vorzukommen.

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The significance of discontinuous zonation of electrophoretically separated globulins for the diagnosis of neurological diseases

Summary 1. 340 patients in whom discontinuous zonation of the globulin region was observed after electrophoretic separation of the CSF proteins were examined to see how the distribution of these clonal zones is correlated with different neurological diseases.2. In multiple sclerosis (MS) and other inflammatory diseases of the CNS, zones are most frequently found in the medium positions: ₂, ₃ and ₄.3. In disk hernias and the noninflammatory diseases of the CNS, the dispersion of zone frequency is rather undifferentiated. In these conditions and in tumors of the CNS and polyneuritis, the relatively high proportion of ₀ zones is a conspicuous feature; it is scarcely encountered in inflammatory processes of the CNS. The rare cases of tumors with zonation show a preponderance of the ₄ zone.4. The total protein content is normal in half of all MS fluids with zonation; in one sixth the relative amount of total globulin is also normal, whereas plasma cells are demonstrable in only two thirds. The electrophoretic evaluation of zonation is, therefore, an important tool in neurological laboratory work.5. Increased amounts of globulin in CSF are accompanied by an increased frequency of zonation in some diseases, such as MS, but not in tumors or vascular processes.6. The incidence of zonation is about 6 times higher in MS than in noninflammatory diseases of the CNS.7. zonation seems not to be present in healthy persons, in psychiatric diseases, myopathies, some tumors (neurinoma) and polyneuritis of metabolic-toxic etiology.

     

Intelligence and temperament as protective factors for mental health. A cross-sectional and prospective epidemiological study

The Sjöbring system of personality dimensions measuring intellectual capacity, activity, impulsivity and sociability was used to study possible salutogenic (i.e. causes of health) effects. The study comprised 590 subjects investigated in 1947, 1957, 1972 and 1988–1989 in the Lundby project, an epidemiological study in Sweden. Psychiatric diagnoses were made in 1947, 1957 and 1972. Mental health was estimated in 1988–1989 using the concept love well, work well, play well and expect well. The Sjöbring dimensions were clinically assessed in 1972. Both in the concurrent study in 1972 and in the prospective study in 1988–1989 super capacity (high intellectual function), super validity (high activity level) and super solidity (low impulsivity) were statistically associated with lower frequencies of certain psychiatric diagnoses and a higher frequency of positive mental health. These variables are proposed to increase coping capacity, and therefore increase stress resilience.     

Golgi-like demonstration of “dark” neurons with an argyrophil III method for experimental neuropathology

Summary A silver method is proposed for the selective, well-contrasted and reproducible demonstration of dark neurons in frozen, vibratome and paraffin sections cut at a thickness of 5 to 200 m from aldehyde-fixed brains. The Golgi-like staining of the dendrites enables asorting of dark neurons according to characteristic neuron classifications. The staining procedure includes an esterification with 1-propanol, a treatment with diluted acetic acid and development. The esterification strongly increases the argyrophilia of both dark neurons and mitochondria. Unwanted co-staining of mitochondria is suppressed by the acetic acid treatment, while a special developer is used to render the staining controllable. The applicability of the method to experimental neuropathology is demonstrated by Golgi-like staining of dark neurons in rat brains exposed, before transcardial perfusion-fixation and delayed autopsy, to various pathological conditions including ischemia, hypoglycemia, trauma, status epilepticus, deafferentation and poisoning with kainic acid, colchicine and sodium azide, respectively.