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Summary Cultured ovine oligodendrocytes (OLGs) express a number of voltage-dependent potassium currents after they attach to a substratum and as they begin to develop processes. At 24–48 hours following plating, an outward potassium current can be identified that represents a composite response of a rapidly inactivating component and a steady-state or noninactivating component. After 4–7 days in culture, OLGs also develop an inward rectifier current. We studied the effects of forskolin and phorbol 12-myristate 13-acetate (PMA) on OLG outward currents. These compounds are known to alter the myelinogenic metabolism of OLGs. PMA, an activator of protein kinase C (PK-C), has been shown to enhance myelin basic protein phosphorylation while forskolin acting on adenylate cyclase, and thereby increasing cAMP, inhibits it. Both forskolin and PMA increase the phosphorylation of 2′3′-cyclic nucleotide phosphodiesterase, an OLG/myelin protein. We found that forskolin decreased the steady-state outward current at 120 mV by 10% at 100nm, and by 72% at 25 μm from a holding potential of −80 mV. The time course of inactivation of the peak currents was decreased, affecting both the fast and slow time constants. There was no significant change in the steady-state parameters of current activation and inactivation. The effect of forskolin was attenuated when the adenylate cyclase inhibitor adenosine (2mm) was present in the intracellular/pipette filling solution. The results of PMA experiments were similar to those obtained with forskolin. Whereas the amplitude of the currents in the presence of PMA was reduced by 28% at 1.5nm and 60% and 600nm, the decay phase of the peak currents was less affected. The PMA effect could still be seen when the intracellular Ca2+ was reduced to ≤10nm with 5mm BAPTA, but was inhibited when the cells were pre-exposed to 50 μm psychosine, a PK-C inhibitor. It is postulated that the potassium currents in OLG can be physiologically modulated by two distinct second-messenger systems, perhaps converging at the level of a common phosphorylated enzyme or regulatory protein.

The molecular size and stability of the nerve growth factor (NGF) secreted in culture by L cells have been studied by sedimentation and gel filtration chromatography. Results indicate that L cell NGF has a molecular weight of 160,000. It contains as part of its structure a protein component that is biologically, immunologically, and electrophoretically indistinguishable from the biologically active factor purified from mouse submandibular glands. However, unlike pure gland NGF, L cell NGF is highly stable in solution, and this finding indicates that L cell NGF is a form of the factor different from that previously described.

The presence of three distinct cholinergic receptors on human lymphocytes was suggested by the effects of carbamoylcholine on lymphocyte proliferation in vitro. The cells responded to both 0.1 nM and 1 microM carbamoylcholine by increased proliferation which was blocked by the muscarinic antagonist atropine. This effect occurred in both mitogen-stimulated cells (maximum effect at 24 hr) and nonstimulated cells (maximum effect at 72 hr). In contrast, 1--10 nM carbamoylcholine produced diminished in vitro proliferation, an effect which was blocked by the nicotinic antagonists alpha-bungarotoxin and d-tubocurarine.

Rat skeletal muscle cells and a cloned myogenic cell line synthesize and secrete in culture a molecule that is immunologically and biologically indistinguishable from the active form of nerve growth factor (NGF) from mouse submandibular gland. This protein can be detected in medium conditioned by muscle cells both before and after fusion and in the soluble fraction of muscle cell homogenates. Chromatographic data also reveal that the molecular properties of muscle cell NGF differ from those of the growth factor purified from mouse submandibular glands. Muscle cell NGF has a molecular weight between 140,000 and 160,000, whereas purified mouse gland NGF has a molecular weight of 26,000. The biologic function of muscle cell NGF is not known, although it could be that it plays some role relating to the association of nerves and muscle in vivo.

We isolated and characterized the human beta-Trace protein (betaTP) gene promoter. betaTP, also known as prostaglandin D2 synthase, is a lipocalin secreted from the choroid plexus and meninges into cerebrospinal fluid. Basal transcription of the betaTP gene is directed from a core promoter found within the first 325 bases of the 5'-flanking sequence. The betaTP gene promoter is responsive to thyroid hormone (3,3',5-triiodothyronine, T3) and efficiently repressed by unliganded human thyroid hormone receptor beta (TRbeta). Functional analysis of the betaTP promoter in TE671 cells revealed that responsiveness to T3 occurs in sequences 2.5 kilobase pairs 5' of the start site. Within the hormone-responsive region we identified a thyroid hormone response element (TRE) located from -2576 to -2562 base pairs relative to the transcription start site. The betaTP TRE is composed of two directly repeated consensus half-sites separated by a 3-base pair space (DR3). The betaTP TRE forms specific complexes with TRbeta. We have shown that a gene active in the choroid plexus and meninges is responsive to T3. T3 may play a role in the regulated transport of substances into the cerebrospinal fluid and ultimately the brain.

Analyses of supernatant solutions from mouse C1300 neuroblastoma cultures by two independent immunoassays reveal that these cells secrete a factor which is immunochemically similar to mouse submaxillary gland nerve growth factor. The neuroblastoma factor is also biologically active in inducing neurite outgrowth from embryonic sensory ganglia-an effect that is completely blocked by specific antibody to nerve growth factor. Neuroblastoma cells are known to be functionally responsive to nerve growth factor, and the observation that they secrete a molecule like it may mean that these cells require or utilize the factor during growth in culture.

The effect of bovine glia maturation factor on the growth pattern of cancer cells was investigated in the rat glioma cell line 354A. When the cells were grown in the serum-free defined medium N2 in the absence of the factor, the cells proliferated with a doubling time of 24 hr without showing contact inhibition. After reaching confluency, the cell layer formed numerous foci from which heaps of cell colonies arose. The addition of glia maturation factor to the culture stimulated cell division in the logarithmic phase but prevented overgrowth once the cells arrived at confluency. The ability of glia maturation factor to restore contact inhibition suggests a regulatory role in normal and neoplastic cells.

A set of observations made on a patient with IgM? monoclonal gammopathy and neuropathy implicate humoral immunity in the pathogenesis of the neuropathy.

Bacteriophage immunoassays, radioimmunoassays, and biological assays have been used to measure levels of NGF in media conditioned by rat C-6 glioma cells in culture. By all three criteria, these cells secrete a macromolecule which is indistinguishable from mouse submandibular gland NGF.

Effects of the anti-T-cell monoclonal antibodies OKT3, OKT5, and OKT8 on T-cell surface properties and cell functions were evaluated. Incubation of mononuclear cells isolated from peripheral blood for 48 hr with each monoclonal antibody in the absence of complement resulted in modulation of their respective surface antigens; i.e., the number of cells detected by immunofluorescence as positive for the T3, T5, and T8 surface antigens was reduced. T3, T5, and T8 antigens modulated independently. A radiolabeled second antibody technique confirmed modulation by OKT3 and OKT8 and indicated that T-cell differentiation antigens can regenerate in culture. Incubation of mononuclear cells with OKT3 increased the number of sheep erythrocyte-binding lymphocytes (E+-rosetting cells) and markedly increased the number of avidly E+-rosetting cells. Incubation with OKT8 reduced the number of E+- and of avidly E+-rosetting cells. OKT3 induced both mitogenic reactivity and suppressor cell activity; cells modulated by OKT8 exhibited reduced mitogenic reactivity and reduced suppressor cell function. The decreases in total T cells, in avid T cells, in suppressor cell number, and in suppressor cell function that follow modulation by OKT8 mimic changes observed in multiple sclerosis patients.

Abstract: The results of geological, geochemical and isotopic investigations in the Hengill thermal area in Iceland are presented. This area may be regarded as typical of the Icelandic high temperature areas. The Hengill area is mainly built up of pillow lavas and hyaloclastites, which were piled up in subglacial eruptions. Its western half is traversed by a very active NE-SW trending fault zone about 5 km broad, within which are several eruptive fissures of postglacial age. The volcanic rocks are basalts of various kinds, but minor occurrences of intermediate and rhyolitic rocks are also found. Solfataras and fumaroles occur mainly at higher altitude. Within the fault zone they have a linear distribution along faults. Hot water springs are found in the lowlands on the southern border of the thermal area. The concentrations of chlorine, tritium and deuterium in the water indicate that the hot springs on the lowland are fed by a deep lying aquifer which receives water from a recharge area situated in the western branch of the active volcanic zone upto 70 km to the northeast. The hot springs at higher altitude are the outlets of a secondary circulation system fed by local rain water. This water derives its heat partly from the heat content of the rocks penetrated and partly by steam and gas boiled off from the deeper lying aquifer. Preliminary results from other high temperature areas in Iceland indicate the presence of similar hydrological systems.

Neuroelectric blocking activity, similar in nature to that previously observed in sera from patients with multiple sclerosis, has been observed in sera from 18 patients with amyotrophic lateral sclerosis. Results concerning the application of plasma exchange to this patient population are also described.

Eighteen black patients with narcolepsy underwent human leukocyte antigen (HLA) typing. Eleven of the 18 had cataplexy. Twelve patients (66.6) had HLA-DR2; 7 patients with cataplexy had DR2. All patients had DQwl. In contrast to white and Japanese patients studied to date, not all black narcoleptics have DR2.

Eosinophilia in the rat stomach was produced by immunization with isologous, homologous, and heterologous stomach extracts in Freund's adjuvant. Immunization with isologous, homologous, and heterologous liver extracts failed to evoke stomach eosinophilia. It is possible that production of autoantibodies directed against organ-specific antigens in the stomach extracts and interaction of these antibodies with organ-specific antigen in the stomach wall may be responsible for the stomach eosinophilia.

Chondrocytes in the fetal skull and visceral cartilage are considered to be of neural crest origin1while those found elsewhere in the body are thought to be derived from mesoderm2,3(mesodermal chondrocytes). Chondrocytes of pelvic rudiments from chick embryos are the only cells known to respond to nerve growth factor that are not of neuroectodermal origin4. In addition, embryonic spinal cord5and neural retina6of chickens synthesize type II collagen5,6, originally thought to be confined to cartilage. Here we report the presence of the S-100 protein (S-100) in chondrocytes of skull, vertebrae, ribs, sternum, larynx and long bones of the human fetus, and larynx and xiphoid process of the human adult. Mesodermal chondrocytes are the only cells which contain S-100 and yet are not considered to be of neuroectodermal origin, thus our results indicate that these chondrocytes may be developmentally closer to neuroectoderm than traditionally thought.

IT is generally admitted that mice undergoing graft-versus-host reaction reveal diminished immunological competence. In particular, the antibody production following antigenic challenge is known to be depressed1–3, although there is little conclusive evidence concerning the behaviour of immunoglobulins4,5. This particular aspect of the graft-versus-host reaction has been examined by us.

Lymph node cells from rats immunized with sciatic nerve in Freund's adjuvant demyelinate trigeminal ganglion cultures. Rabbit antiserum to rat immunoglobulin A blocks this cytodestructive event. The antiserum may act by combining with IgA on the lymphoid cell surface, preventing the interaction of cell-bound antibody and tissue antigen.

Bioseismic studies have previously documented the use of seismic stimuli as a method of communication in arthropods and small mammals. Seismic signals are used to communicate intraspecifically in many capacities such as mate finding, spacing, warning, resource assessing, and in group cohesion. Seismic signals are also used in interspecific mutualism and as a deterrent to predators. Although bioseismics is a significant mode of communication that is well documented for relatively small vertebrates, the potential for seismic communication has been all but ignored in large mammals. In this paper, we describe two modes of producing seismic waves with the potential for long distance transmission: 1) locomotion by animals causing percussion on the ground and 2) acoustic, seismic-evoking sounds that couple with the ground. We present recordings of several mammals, including lions, rhinoceroses, and elephants, showing that they generate similar acoustic and seismic vibrations. These large animals that produce high amplitude vocalizations are the most likely to produce seismic vibrations that propagate long distances. The elephant seems to be the most likely candidate to engage in long distance seismic communication due to its size and its high amplitude, low frequency, relatively monotonic vocalizations that propagate in the ground and have the potential to travel long distances. We review particular anatomical features of the elephant that would facilitate the detection of seismic waves. We also assess low frequency sounds in the environment such as thunder and the likelihood of seismic transmission. In addition, we present the potential role of seismic stimuli in human communication as well as the impact of modern anthropogenic effects on the seismic environment.

Article abstract-Results of a double-blind, placebo-controlled study in ambulatory patients with relapsing-remitting MS showed that interferon beta-1b reduced the rate of exacerbations by one-third compared with placebo and limited new disease activity in the brain as evidenced by MRI. Interferon beta-1b, administered subcutaneously at a dosage of 0.25 mg (8 million IU) every other day is indicated for the treatment of ambulatory patients with relapsing-remitting MS. Interferon beta-1b may help a wider range of patients, but it should be prescribed only for patients with a diagnosis of clinically definite or laboratory-supported definite MS. The decision to treat a patient with interferon beta-1b should be individualized; that is, based on each patient's clinical presentation and course of MS. The most common adverse effects include (1) injection-site reactions and (2) flulike symptoms, which are generally manageable and usually abate after the first few months of treatment. Spasticity may increase. Patients with severe depression or suicidal ideation should be monitored carefully, and symptomatic treatment should be pursued. Interferon beta-1b is contraindicated in pregnant and nursing women. Interferon beta-1b is effective in reducing the progression of total disease burden as seen on MRI in patients with MS. Its use is relatively straightforward and generally does not require alteration in the symptomatic treatment of MS. Patient education and support remain the mainstays of maintaining compliance through the early phases of therapy.

Based on scientific literature and interviews with clinicians and patients, we developed a quality of life instrument for use with people with MS called the Functional Assessment of Multiple Sclerosis (FAMS).The initial item pool consisted of 88 questions: 28 from the general version of the Functional Assessment of Cancer Therapy quality of life instrument, plus 60 generated by patients, providers, and literature review. The validation samples comprised a mail survey cohort (N = 377) and a clinical cohort (N = 56). Both cohorts provided evidence for internal consistency of the derived subscales, test-retest reliability, content validity, concurrent validity, and construct validity. Principal components and Rasch measurement model analyses were applied sequentially to survey sample data, reducing test length to 44 questions, divided into six subscales: mobility, symptoms, emotional well-being (depression), general contentment, thinking/fatigue, and family/social well-being. Fifteen initially rejected questions were added back as miscellaneous (unscored) questions for their potential clinical and empirical value. The mobility subscale was strongly predictive of the Kurtzke Extended Disability Status Scale and the Scripps Neurologic Rating Scales. The other five subscales were not, indicating they measure aspects of patient quality of life not captured by the neurologic exam. The final 59-item English language instrument (FAMS version 2) is available for inclusion in clinical trials and clinical practice.

We assessed neuropsychological function longitudinally in 30 MS patients who participated in the pivotal trial of interferon beta-1b (IFN-beta-1b). Nine patients received high-dose IFN-beta-1b (8.0 million units), eight low-dose IFN-beta-1b (1.6 MIU), and 13 placebo. There was significant improvement in Wechsler Memory Scale Visual Reproduction-Delayed Recall scores between years 2 and 4 of the trial in MS subjects receiving high-dose IFN-beta-1b. Motoric performance, MRI lesion area, and depression rating scores did not correlate with this finding. Comparison of MRI at baseline and at years 2 and 4 revealed significant changes over time for the total cohort (p < 0.02). Mean lesion area in the high-dose group did not change over time, whereas the low-dose and placebo groups had increases in total lesion area of 28 and 36%, respectively, at year 4. Expanded disability status scale scores did not change significantly between years 2 and 4 of the trial, nor did they correlate with MRI lesion area at any assessment point. We conclude that high-dose IFN-beta-1b improves delayed visual reproduction test performance in MS patients, a finding unlikely to be explained by practice effects or brain lesion area.