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J Neuhaus

Publications and source records attributed to J Neuhaus.

35 records · Page 2Linked to original sources
PubMed1997

Neurotoxic consequences of central long-term administration of interleukin-2 in rats.

Interleukin-2 is an immunoregulatory cytokine with several recently established CNS activities. Central effects of interleukin-2 include growth promotion for neuronal and glial cells as well as modulatory influences on neurotransmission and hormone release. However, little is known about the consequences in the CNS of chronically elevated levels of interleukin-2. Alterations in the interleukin-2/interleukin-2 receptor system are not only associated with CNS trauma, inflammation and certain neuropathologies; elevated interleukin-2 concentrations are especially induced during the therapeutic use of interleukin-2 in cancer treatments. In the present study, intracerebroventricular (i.c.v.) interleukin-2 infusions (5 15 U/h) were performed in Sprague Dawley rats for up to 14 days. Interleukin-2-treated animals showed significantly increased plasma levels of corticosterone indicating an hyperfunctioning of the hypothalamic-pituitary-adrenocortical axis that lasted over the 14 day infusion period. Moreover, the performance of interleukin-2-treated animals in the Morris swim maze task was transiently impaired. Quantitative receptor autoradiographic analyses revealed changes in the binding levels of cholinergic M1 and M2 as well as dopaminergic D1 and D2 receptors in selected brain areas in which interleukin-2 was shown to modulate neurotransmission and which are enriched with interleukin-2 receptor expression. Decreased receptor binding levels were observed in the frontoparietal cortex (M2, D1, D2), hippocampal CA1 region (M1, M2) and the nucleus accumbens (D2). Histological and immunohistochemical examination of the brains of interleukin-2-treated animals revealed multiple alterations. Interleukin-2 treatment resulted in an intracranial accumulation of non-neural, MHC class II-positive cells as well as T and B lymphocytes within the infused brain hemisphere. Cellular infiltrates were associated with angiogenesis and the deposition of extracellular matrix material, such as fibronectin. Adjacent brain regions that were partly invaded and dislodged by the cellular masses were characterized by reactive astrogliosis, microglial activation, endothelial upregulation of adhesion molecules, myelin damage and neuronal loss. Together the data suggest that persistently elevated central levels of interleukin-2 can interfere with several CNS functions and may lead to nervous tissue injury. These findings could be relevant to CNS pathologies characterized by abnormal interleukin-2 production and to central responses to interleukin-2 treatments.

Animals↗
PubMed1996

Electrical coupling among Bergmann glial cells and its modulation by glutamate receptor activation.

We studied the characteristics of electrical coupling between Bergmann glial cells in mouse cerebellar slices using Lucifer Yellow injection, patch-clamping cell pairs, and ultrastructural inspection. While early postnatal cells (days 5-7) were not coupled, coupling was abundant at postnatal days 20-24. Coupled cells were arranged perpendicular to the parallel fibers in a parasagittal section, forming a string, rather than a cluster of cells. Electron microscopy revealed that gap junctions were abundant in the distal parts of the processes. Gap junctions between cell bodies and processes were very rare, and no gap junctions were found between cell bodies of adjacent Bergmann glial cells. The junctional conductance was voltage and time independent and could be markedly reduced by halothane. Alkalization of cells (by applying NH4+) increased the junctional conductance to 150%, while acidification of the cell interior (by removing NH4+) led to a decrease to 70%. Activation of AMPA receptors induced a blockade of the junctional conductance to 30% of the control. This link is most likely mediated by the influx of Ca2+ via the receptor since this effect was not observed in Ca(2+)-free medium, suggesting that Ca2+ entry via the kainate receptor pore led to the closure of gap junctions. These studies indicate that electrical coupling between Bergmann glial cells is not only developmentally regulated but also controlled by physiological stimuli.

Aging↗
PubMed1996

Neurotoxicity induced by interleukin-2: involvement of infiltrating immune cells.

Interleukin-2 (IL-2), a key regulator of immune functions, also has potent effects on neurons and glia. IL-2 modulates neural cell growth and survival and transmitter and hormone releases and is thought to mediate neuroimmune interactions. Investigating the neuroendocrine consequences of chronically elevated central nervous system (CNS) levels of IL-2, we recently observed marked neurotoxicity [Hanisch et al. (1994) Endocrinology 135:2465-2472]. In the present study, we characterize in detail the modifications in brain tissue architecture as they result in Sprague-Dawley rats from intracerebroventricular (i.c.v.) administration of low amounts of IL-2 (5 and 15 U/h, respectively, delivered by means of osmotic minipumps for up to 14 days). Histological inspection of the brains revealed massive cellular infiltrates in the ipsilateral hemisphere. The infiltrates were associated with pronounced angiogenesis and changes in the composition of the extracellular matrix. These anatomical changes apparently developed between day 7 and 14. They were specific for IL-2 and were not seen in animals treated, for example, with heat-inactivated IL-2 (controls). We further show that chronic central administration of IL-2 let to T and B lymphocyte invasion of the brain and an intracranial agglomeration of large numbers of MHC class II-positive cells. Immunocytochemistry revealed a widespread inundation of CNS tissue and a decoration of glial cells and neurons by endogenous antibodies. Tissue regions around the IL-2-induced infiltrates showed myelin destruction and neuronal cell loss. Chronically elevated CNS levels of IL-2 may, thus, not only interfere with neurotransmission and endocrine functions but also severely disturb tissue homeostasis. Therefore, the present findings could be relevant to brain injuries, CNS disorders, and clinical treatments associated with increased IL-2 levels or involving an immune component.

Animals↗
PubMed1995

Preferential localization of active mitochondria in process tips of immature retinal oligodendrocytes.

Active mitochondria were visualized with a laser scanning confocal microscope using the dye rhodamine 123, which is accumulated in mitochondria with a high respiratory activity. In glial precursor cells cultured from rabbit retina the fluorescence signal of active mitochondria was confined to the tips of processes, while in oligodendrocytes an even distribution was found. The developmental stage of cultured oligodendrocytes was determined by staining with O4 and O10 antibodies after the end of microfluorometric measurements. In glial precursor cells, the mitochondrial uncoupler CCCP generated an increase in the cytoplasmic calcium concentration ([Ca2+]i) in regions corresponding to those revealed by rhodamine 123 staining. In mature oligodendrocytes CCCP evoked [Ca2+]i elevation without significant spatial heterogeneity. However, electron microscopy did not reveal an uneven distribution of mitochondria in either immature or mature oligodendrocytes. We conclude that in the precursor cells, active mitochondria are confined to process tips and serve as a Ca2+ pool, while in oligodendrocytes such a spatial heterogeneity cannot be detected. This preferential localization of active mitochondria may play a role in the neurone-glia interaction during the formation of the contact between the myelinating glial process and the axonal membrane.

Aniline Compounds↗
PubMed1994

Development of microglia in mouse neopallial cell cultures.

Microglia develop in cultures initiated from disaggregated neopallial cells of newborn C3H/HeJ mice when the cultures are subjected to nutritional deprivation for 10 or more days (Hao et al: Int J Dev Neurosci 9:1-14, 1991). In the present experiments, the cultures were pulsed with BrdU for 3 hours at different times during incubation and then the cells were immunoreacted with antibodies against BrdU, GFAP, and CR3 receptor. The dividing cells (BrdU+) were found to be either GFAP+ or GFAP-, but not Mac-1+/BrdU+. Infection of proliferating cells after 2 or more days of incubation with replication-deficient retroviral vector containing E. coli lacZ reporter gene resulted in many labeled astroglia cell clones but no labeled microglia. However, when cells were infected right after disaggregation of neopallium, labeled Mac-1+ microglia were found. When Mac-1+ cells in a suspension of disaggregated neopallial cells were killed using complement mediated lysis before setting up the cultures, Mac-1+ microglia developed, in spite of the treatment. We conclude that in cultures initiated from mouse neopallium there are MAC-1-/GFAP- microglia progenitor cells which do not divide in nutritionally deprived cultures but can transform into Mac-1+ microglia under the influence of astroglia-derived trophic factors. Microglia, which become Mac-1+ (i.e., express CR3 receptor), proliferate extensively in the presence of CSF-1 (which is produced by astroglia).

Animals↗
PubMed1994

Modulation of tight junction structure in blood-brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes.

Tight junctions between endothelial cells of brain capillaries are the most important structural elements of the blood-brain barrier. Cultured brain endothelial cells are known to loose tight junction-dependent blood-brain barrier characteristics such as macromolecular impermeability and high electrical resistance. We have directly analyzed the structure and function of tight junctions in primary cultures of bovine brain endothelial cells using quantitative freeze-fracture electron microscopy, and ion and inulin permeability. The complexity of tight junctions, defined as the number of branch points per unit length of tight junctional strands, decreased 5 hours after culture but thereafter remained almost constant. In contrast, the association of tight junction particles with the cytoplasmic leaflet of the endothelial membrane bilayer (P-face) decreased continuously with a major drop between 16 hours and 24 hours. The complexity of tight junctions could be increased by elevation of intracellular cAMP levels while phorbol esters had the opposite effect. On the other hand, the P-face association of tight junction particles was enhanced by elevation of cAMP levels and by coculture of endothelial cells with astrocytes or exposure to astrocyte-conditioned medium. The latter effect on P-face association was induced by astrocytes but not fibroblasts. Elevation of cAMP levels together with astrocyte-conditioned medium synergistically increased transendothelial electrical resistance and decreased inulin permeability of primary cultures, thus confirming the effects on tight junction structure and barrier function. P-face association of tight junction particles in brain endothelial cells may therefore be a critical feature of blood-brain barrier function that can be specifically modulated by astrocytes and cAMP levels. Our results suggest an important functional role for the cytoplasmic anchorage of tight junction particles for brain endothelial barrier function in particular and probably paracellular permeability in general.

Animals↗
PubMed1990

Stability of orthogonal arrays of particles in murine skeletal muscle and astrocytes after circulatory arrest, and human gliomas.

The effect of hypoxic conditions on the maintenance of orthogonal arrays of particles (OAP) in the plasma membranes of brain astrocytes, skeletal muscle cells of the mouse and of human glioma cells was investigated by means of freeze-fracturing. Pieces of tissue were put in a moist chamber at 20 and 37 degrees C and fixed after different intervals up to 2 h. Muscle cell OAP are demonstrated 2 h after circulatory arrest irrespective of temperature. Astrocytic OAP are shown to be as stable as those in muscle cells at 20 degrees C. Also at 37 degrees C, intact OAP were observed although the membranes were strongly lesioned. We conclude that OAP in astrocytes are essentially more stable than reported in the literature.

Animals↗
PubMed1990

Orthogonal arrays of particles in astroglial cells: quantitative analysis of their density, size, and correlation with intramembranous particles.

Astroglial cells were investigated by means of freeze-fracture in normal rat and mouse brain, cell culture and human gliomas. Membranes of these cells were quantitatively analyzed for their intramembranous particles (IMPs) and orthogonal arrays of particles (OAPs). Measurement of the size of OAPs and IMPs has permitted the search for a correlation between the 7-nm IMPs, which are distributed randomly in the membrane, and the subunits of OAPs (OAP-Su, also 7 nm in diameter). Using cultured astroglial cells treated with basic fibroblast growth factor (bFGF), arginine vasopressin, or sorbitol, good evidence for a relationship between the density of 7-nm IMPs and the size of OAPs can be demonstrated. These findings led to a hypothetical model of OAP modulation. A preliminary report has been published elsewhere (Neuhaus and Wolburg, 1989).

Animals↗
PubMed1987

Relationship between orthogonal arrays of particles and tight junctions as demonstrated in cells of the ventricular wall of the rat brain.

Ependymal cells in the ventricular wall and in several circumventricular organs of the rat were compared by means of freeze-fracturing. In principle, tight junctions and orthogonal arrays of particles (OAP) do not coexist in the cells bordering the ventricular wall: (1) Ordinary ependymal cells of the rat possess OAP and are devoid of tight junctions. (2) Epithelial cells of the rat choroid plexus are connected by tight junctions; OAP are lacking here. In some cases, however, tight junctions and OAP coexist in the same cell. In the boundary zone between choroid plexus and ependyma of the rat, the density of OAP is very low, whereas the tight junctions are well developed. In the subfornical and the subcommissural organ (SCO) of the rat both structures are poorly developed; in the SCO they occur segregated in different membranous areas. An overview of the literature confirms that tight junctions and OAP mostly exclude each other. The possibility that in astrocytes and ependymal cells tight junctions may have been replaced by OAP during phylogeny is briefly discussed.

Animals↗
PubMed1986

Decrease in the density of orthogonal arrays of particles in membranes of cultured rat astroglial cells by the brain fibroblast growth factor.

The effect of brain-derived basic fibroblast growth factor (bFGF) on the membrane structure of cultured rat astroglial cells was investigated by quantitative freeze-fracture replica examination. In the presence of bFGF the number of the orthogonal arrays of particles (OAP), which are characteristic compounds of the membrane of mammalian astrocytes, is clearly reduced. This finding is discussed in the framework on current views about neuro-glial interactions and their implications in the process of fiber regeneration in the central nervous system.

Animals↗
PubMedDate not supplied

Recruitment and retention of healthy minority women into community-based longitudinal research.

This report examines the impact of individualized, population-based recruitment and retention approaches on the development of a subject pool, enrollment, and retention at 12 months of healthy, community-based women in three ethnic groups: African Americans, non-Hispanic European Americans, and Mexicans/Central Americans. Of 722 women contacted and screened, 346 (48%) were eligible and consented to participate. Attrition at 12 months was low (10%) compared with other published reports. The largest group of potential subjects was identified through broadcast media approaches, but this method produced the highest number of ineligible women and highest rate of attrition. Printed matter produced the next largest group of potential subjects, but ineligibility was high (53%). Face-to-face interactions enrolled the highest proportion of eligible women (84%) and lowest overall attrition (7%). Direct referral yielded fairly efficient enrollments (57%) and average attrition. Multiple approaches for recruitment can produce a diverse sample of healthy, community-based women. Face-to-face recruitment results in the highest yield of participants with the lowest attribution but is presumed to require more resources.

Adult↗
PubMedDate not supplied

Are prior head injuries or diagnostic X-rays associated with glioma in adults? The effects of control selection bias.

The causes of glioma, the most common type of primary malignant brain tumors, are poorly understood. This study compares personal histories of head injury and diagnostic radiation procedures of the head and neck among 476 adults newly diagnosed with glioma in the San Francisco Bay Area between August of 1991 and April of 1994 (82% of all those diagnosed during that time period) with 462 age-, gender-, and ethnicity-frequency-matched controls (63% of those eligible from random digit dialing). In addition, limited information was obtained from 101 controls during a brief telephone interview conducted with controls who declined participation in the lengthy in-person interview. Controls who participated in the full interview were much more likely than controls who only completed the telephone interview to report head injury [odds ratios (OR) and 95% confidence intervals (CI) were 2.3 (1.0-4.9) and 3.0 (1.6-5.8) for women and men, respectively]. The OR for any head injury in cases versus controls who completed the full interview was 0.9. However, OR for any head injury in cases versus both control groups was 1.3, 95% CI (1.0-1.7), and the OR for head injury for which the subject sought medical attention was 1.1, 95% CI (0.8-1.4). Among subjects completing the full interview, cases who responded by self-report were less likely than controls to report prior non-dental head and neck X-rays (OR = 0.7; 95% CI: 0.5-1.0). However, stratification by respondents' history of head injury indicated no difference in history of head and neck X-ray among those without prior head injury; OR 0.9; 95% CI (0.6-1.2). Cases and controls shared a very similar history of dental procedures and frequency of dental visits. These results suggest that head injury requiring medical attention, dental visits, or non-dental diagnostic X-rays to the head and neck are not important contributors to the risk of adult glioma and reveal some of the methodological obstacles encountered in forming convincing conclusions about these risk factors for brain tumors.

Adult↗
PubMedDate not supplied

The glio-axonal interaction and the problem of regeneration of axons in the central nervous system--concept and perspectives.

Lesion of the central nervous system in man is generally believed to be incurable. However, in the last time evidence accumulated that axonal growth occurs after a lesion if the growing neurites encounter a permissive environment. Since astrocytes play a considerable role as environmental factor in the CNS, the astrocytes from regenerative as well as from non-regenerative species were compared. The concept proposed here postulates that interactions between astrocytes and axons are of basic significance for fiber regeneration and have changed qualitatively during phylogeny: in lower vertebrates astrocytes guide growing and regenerating axons; in higher vertebrates including man the glioaxonal interactions were possibly deteriorated by the appearance of new compounds in the astrocytic membrane.

Animals↗