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Biomedical subjects

R Mirsky

Publications and source records attributed to R Mirsky.

At least 37 records · Page 2Linked to original sources
PubMed1998

An integrated multipurpose lesion-making electrode.

PURPOSE: Although excellent results are reported from centers using microelectrode mapping during stereotactic pallidotomy, the recording methods used are time-consuming and technically cumbersome. We sought to develop a new electrode concept that may, when eventually applied in clinical practice, improve the efficiency and safety of microelectrode-guided functional neurosurgical procedures. CONCEPT: The scout electrode uses a recently developed research technique for simultaneously obtaining multiple microelectrode recordings along the shaft of a macroelectrode. RATIONALE: By positioning recording sites on either side of a lesion-making contact, it is possible to functionally "scout" the brain tissue surrounding the proposed lesion site, thus eliminating the need for serial movements and electrode interchanges. DISCUSSION: The feasibility of the scout electrode concept was tested using prototypes placed into cat medial geniculate nucleus. High-quality unit recordings were simultaneously obtained from different regions within the medial geniculate nucleus. This ability to physiologically map sites above and below the lesion-making contact facilitated precise placement of radiofrequency lesions in the center of the medial geniculate nucleus. These results suggest that it may be possible to develop clinically useful devices based on this novel concept.

Action Potentials↗
PubMed1998

An illuminating retractor for intracranial microneurosurgery.

During certain microneurosurgical procedures, the illumination provided by current coaxial microscope light sources is suboptimal. One potential solution is the surgical light blade (SLB), a malleable retractor incorporating a flat fiberoptic bundle along its surface. The SLB provides intense illumination within the surgical field without decreasing the amount of limited operating space. A prototype of the SLB was tested in six patients. Results suggest that with further development the SLB could become useful for intracranial microneurosurgery.

Brain Diseases↗
PubMed1998

Posterior ventricular catheter burr-hole localizer. Technical note.

Proper ventricular catheter placements are associated with improved shunt performance. When placing ventricular catheters via the posterior approach, the surgeon must determine an optimum trajectory and then pass a catheter along that trajectory. The incidence of optimal posterior catheter placements is increased by using a posterior catheter guide (PCG); however, errors may still occur because of poor selection of a posterior burr-hole site. In this report an easy-to-use posterior burr-hole localizer (Localizer) is described that defines the optimum burr-hole location based on geometric relationships involving the ear and supraorbital rims. The basic design principle of the Localizer was formulated and tested by using neuronavigational imaging tools to examine normal adult ventricular anatomy in relation to surface landmarks and by reviewing imaging studies obtained in 50 adult patients with hydrocephalus. Subsequently, the Localizer was used in 28 consecutive patients scheduled to undergo shunt surgery performed by using the PCG. In all cases the catheter entered the ventricle on the first pass and postoperative imaging studies demonstrated successful placement in the ipsilateral anterior horn. There were no catheter-related complications. These early results indicate that the Localizer and PCG devices may be safe and effective when used in combination for placement of posterior ventricular catheters.

Adult↗
PubMed1998

The Neuron-Glia Signal beta Neuregulin Induces Sustained CREB Phosphorylation on Ser-133 in Cultured Rat Schwann Cells.

beta neuregulins (also called NDF, GGF, ARIA, and heregulins) are neuron-derived molecules that are likely to be responsible for Schwann cell precursor survival, proliferation, and maturation in vivo and in vitro. Although the receptors to which beta neuregulins bind have been defined, little is known about the transcription factors these important ligands activate. Using antibodies, quantitative imaging methods and Western blotting, we show that beta neuregulin induces a high level of phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) on Ser-133 in cultured rat Schwann cells and that the phosphorylation is prolonged over several hours. In contrast, neurotrophins, CNTF, FGF-2, EGF, and TGFbeta induce little or no phosphorylation of CREB despite the fact that receptors for these factors are present on Schwann cells. As expected CREB phosphorylation was detected following cAMP elevation, and it was also induced by elevation of cytoplasmic Ca2+, endothelin 1, and PDGF-BB. The signal was lower than that seen in response to beta neuregulin, and transient, unlike the sustained CREB activation induced by beta neuregulin. Our results suggest that the sustained phosphorylation of CREB on Ser-133 may contribute to the broad spectrum of effects that beta neuregulins have on cells of the Schwann cell lineage and that the CREB pathway may be important for transduction of neuregulin signals in Schwann cells. Copyright 1998 Academic Press.

Journal Article↗
PubMed1997

Helix-loop-helix proteins in Schwann cells: a study of regulation and subcellular localization of Ids, REB, and E12/47 during embryonic and postnatal development.

Although basic helix-loop-helix (bHLH) proteins play an important role in transcriptional control in many cell types, the role of HLH proteins in Schwann cells has yet to be assessed. In this study, we have analyzed the expression of the dominant negative HLH genes, Id1 to Id4 and the class A gene REB, during Schwann cell development. We found that mRNA derived from these genes was present in the Schwann cell lineage throughout development including embryonic precursors and mature cells. The mRNA levels were not significantly regulated during development. Nevertheless, by using antibodies against the four different Id proteins, we found clear regulation of some of these genes at the protein level, in particular Id 2, 4, and REB, both in amount and nuclear/cytoplasmic localization. All these proteins are found in the nuclei of Schwann cell precursors but are not seen in nuclei of Schwann cells of newborn nerves. We observed extensive overlap in Id expression, especially in Schwann cell precursors that co-expressed all four Id proteins and REB. We also showed that Id 1 and 2 were up-regulated as Schwann cells progressed through the cell cycle. These data indicate that HLH transcription factors act as regulators of Schwann cell development and point to the existence of as yet unidentified cell type-specific bHLH proteins in these cells.

Aging↗
PubMed1997

Identification of transcriptionally regulated mRNAs from mouse Schwann cell precursors using modified RNA fingerprinting methods.

We have adopted RNA fingerprinting methods to screen for genes that are rapidly up- or down-regulated during normal mammalian development, comparing mRNA from early (embryo day 12) to late (embryo day 13) mouse Schwann cell precursors. The use of total RNA, a reduction of cDNA template for amplification, the detection of RT-PCR products with a sensitive DNA stain and polyacrylamide gel electrophoresis and rigid selection criteria involving three screening steps are significant improvements on previous methods. Of 19 differentially displayed bands, 15 represented novel genes. The four known cDNA fragments (interleukin enhancer binding factor 1, beta3 subunit of phospholipase C, brain beta-spectrin, and P21 polypeptide) consisted of coding sequences, indicating a high chance of obtaining coding regions. A semiquantitative RT-PCR analysis of three of the four known genes and a cDNA fragment randomly selected from the pool of 15 novel sequences, confirmed that they were regulated between embryo days 12 and 13, as predicted by the display gels. Our results suggest that the combination of methods described here will have wide applicability in studies of other developmental systems where precisely timed changes occur and where only small amounts of RNA can be obtained for analysis.

Animals↗
PubMed1997

Expression and regulation of alpha1beta1 integrin in Schwann cells.

The interaction of cells with the extracellular matrix plays a critical role in morphogenesis and cell differentiation. To define how Schwann cells might interact with the extracellular matrix, we chose to study the expression of the laminin/collagen receptor alpha1beta1 integrin during nerve development in the rat from embryonic day 14 to maturity. We found that this integrin is expressed predominantly on mature non-myelin-forming cells and only at very low levels on myelin-forming cells. Significant levels of this integrin were not detected on Schwann cell precursors or embryonic Schwann cells in vivo. Experiments using transected and crushed sciatic nerve showed that alpha1beta1 integrin expression is regulated at least in part by axonal contact. Furthermore, Schwann cell culture experiments showed that alpha1beta1 integrin levels are strongly upregulated by transforming growth factor-beta(s) and phorbol esters.

Animals↗
PubMed1997

P0 is constitutively expressed in the rat neural crest and embryonic nerves and is negatively and positively regulated by axons to generate non-myelin-forming and myelin-forming Schwann cells, respectively.

We show that in the rat, the major gene of PNS myelin, P0, is expressed long before myelination in the neural crest, Schwann cell precursors, and embryonic Schwann cells irrespective of whether they will myelinate or not. This myelin-independent P0 expression is constitutive and likely to serve as a specific marker for the Schwann cell lineage. The much higher P0 expression accompanying myelination is therefore not new gene expression but strong up-regulation of preexisting basal levels. We provide new evidence that the up-regulation to myelination-related levels depends on positive extrinsic signals and therefore does not represent a constitutive phenotype. P0 mRNA is not detectable in mature non-myelin-forming Schwann cells of the sympathetic trunk, but is detectable after transection, indicating that there is a P0-inhibitory signal associated with mature unmyelinated axons. Thus, the regulation of the P0 gene is complex, encompassing extrinsically signaled amplification superimposed on a highly lineage-specific and constitutive basal expression.

Animals↗
PubMed1997

Embryonic Schwann cell development: the biology of Schwann cell precursors and early Schwann cells.

The cellular events leading to the generation of Schwann cells from the neural crest have recently been clarified and it is now possible to outline a relatively simple model of the Schwann cell lineage in the rat and mouse. Neural crest cells have to undergo 3 main developmental transitions to become mature Schwann cells. These are the formation of Schwann cell precursors from crest cells, the formation of immature Schwann cells from precursors and, lastly, the postnatal and reversible generation of non-myelin- and myelin-forming Schwann cells. Axonal signals involving neuregulins are important regulators of these events, in particular of the survival, proliferation and differentiation of Schwann cell precursors.

Animals↗
PubMed1997

Chronic microelectrode investigations of normal human brain physiology using a hybrid depth electrode.

Neurosurgeons have unique access to in vivo human brain tissue, and in the course of clinical treatment important scientific advances have been made that further our understanding of normal brain physiology. In the modern era, microelectrode recordings have been used to systematically investigate the cellular properties of lateral temporal cerebral cortex. The current report describes a hybrid depth electrode (HDE) recording technique that was developed to enable neurosurgeons to simultaneously investigate normal cellular physiology during chronic intracranial EEG recordings. The HDE combines microelectrode and EEG recordings sites on a single shaft. Multiple microelectrode recordings are obtained from MRI defined brain sites and single-unit activity is discriminated from these data. To date, over 60 HDEs have been placed in 20 epilepsy surgery patients. Unique physiologic data have been gathered from neurons in numerous brain regions, including amygdala, hippocampus, frontal lobe, insula and Heschl's gyrus. Functional activation studies were carried out without risking patient safety or comfort.

Action Potentials↗
PubMed1997

Response of Schwann cells to mitogens in vitro is determined by pre-exposure to serum, time in vitro, and developmental age.

We compared the mitogenic response of Schwann cells freshly isolated from adult, neonatal, and embryonic nerves, and compared these cells with cells that had been cultured in serum for 5 days. DNA synthesis in response to growth factors was measured using bromodeoxyuridine and immunocytochemistry. Freshly isolated adult Schwann cells were unresponsive to growth factors with or without forskolin to elevate intracellular cAMP levels. After 5 days of culture in serum, or alternatively in defined medium containing fibroblast growth factor 2 plus forskolin, or neu-differentiation factor beta2, adult cells were responsive to mitogens, whereas cells cultured in defined medium alone remained unresponsive. Serum also increased expression of type 1 fibroblast growth factor receptor. Freshly isolated embryonic and neonatal Schwann cells in contrast responded to growth factors even in the absence of forskolin. This responsiveness changed with time in culture. Neonatal cells cultured for 5 days in defined medium in the presence or absence of serum no longer responded to FGF alone, but required forskolin for a mitogenic response. Thus, the response of freshly isolated cells to mitogens is developmentally regulated; extrinsic signals are required to render adult cells responsive to mitogens; and with time in culture, neonatal cells develop a requirement for cAMP elevation for mitogenic response.

Animals↗
PubMed1996

Oct-6 (SCIP/Tst-1) is expressed in Schwann cell precursors, embryonic Schwann cells, and postnatal myelinating Schwann cells: comparison with Oct-1, Krox-20, and Pax-3.

The POU domain transcription factor Oct-6 (SCIP/Tst-1) is likely to control important stages of Schwann cell development, including the initiation of myelination around birth. Here, we use immunocytochemical and reverse transcriptase-polymerase chain reaction techniques to examine Oct-6 earlier in nerve development, to test the idea that Oct-6 has an additional role in Schwann cell precursors or early embryonic Schwann cells, a possibility raised by previous studies on transgenic mice. Consistent with this, we find low but unambiguous levels of Oct-6 mRNA and protein in Schwann cell precursors of mouse and rat (nerves from 12- and 14-day-old embryos, respectively), with expression levels gradually increasing during early Schwann cell development and towards birth. Unexpectedly, Oct-6 immunoreactivity is clearly present in nuclei of most myelinating cells at least as late as postnatal day 12. Furthermore, many nonmyelinating Schwann cells express Oct-6 in adult life. A comparison of Oct-6 mRNA with other Schwann cell transcription factors-namely, Oct-1, Krox-20, and Pax-3-reveals that each factor exhibits strong developmental regulation and a unique expression pattern in embryonic nerves. Therefore, they are likely to play distinct regulatory roles in early development of the Schwann cell lineage.

Animals↗
PubMed1996

Schwann cell development, differentiation and myelination.

Neu-differentiation factor (glial growth factor) has been established as an important regulator of early Schwann cell development, and the lineage relationship between immature Schwann cells and the neural crest has been clarified by the identification of the Schwann cell precursor. Progress has been made in identifying transcription factors that control Schwann cell development and in defining molecules that positively and negatively regulate myelin differentiation pathways. The tetraspan group has emerged as a set of proteins with prominent functions in Schwann cell biology.

Animals↗
PubMed1996

Regulation of rat Schwann cell Po expression and DNA synthesis by insulin-like growth factors in vitro.

Myelination by Schwann cells is likely to be regulated in vivo by positive and negative epigenetic factors. In vitro, the positive regulation of myelin differentiation, in particular expression of the major myelin protein Po, can be mimicked by cAMP elevating agents, while serum, transforming growth factor (TGF) beta s, and fibroblast growth factor (FGF)2 have been shown to exert a negative effect on this differentiation. Growth factors which promote Po induction have not, however, been identified previously. Using a forskolin concentration (0.4 microM) which alone produces little Po mRNA or protein induction, we show that insulin-like growth factor (IGF)-I, IGF-II and high concentrations of insulin promote high levels of Po induction, although in the absence of forskolin they have no effect. Another event related to Schwann cell differentiation, induction of galactocerebroside expression in response to cAMP analogues, is also potentiated by IGFs. In a different context, IGFs regulate Schwann cell DNA synthesis. We find that in defined medium forskolin plus FGF2, TGF beta or platelet-derived growth factor (PDGF) BB causes minimal DNA synthesis in the absence of IGFs and that IGFs act as potent mitogens under these conditions. IGFs also potentiate DNA synthesis induced by beta isoforms of neu-differentiation factors (NDFs), although in this case considerable DNA synthesis occurs even in the absence of IGF. These results show that IGFs can act as powerful stimulators of both proliferation and differentiation in Schwann cells, and that the total growth factor input determines which of these pathways IGFs will promote.

Animals↗
PubMed1996

Development and differentiation of Schwann cells.

Using the rat sciatic nerve as a model for the study of Schwann cell differentiation we have identified a Schwann cell precursor, a distinct cell type present in developing nerves at a time when they are projecting to their target tissues. These cells develop into Schwann cells over a relatively short time in vivo. In vitro, they can generate Schwann cells if they are cultured in neuron-conditioned medium or in the presence of neu-differentiation factors (NDF) (neuregulins, heregulins, glial growth factor), a recently discovered family of growth factors expressed at high levels in neurons. Thus neu-differentiation factors may be important neuro-glia signalling molecules in the Schwann cell lineage. Later stages in the development of Schann cells, such as differentiation towards a myelin phenotype, can be studied using cultured Schwann cells. These cells dedifferentiate both in vivo and in vitro when they are deprived of axonal contact. Elevation of intracellular cyclic AMP levels in the absence of cell division causes high levels of expression of Po, the major myelin glycoprotein. TGF beta s and FGFs suppress this induction, while IGFs promote it.

Animals↗
PubMed1995

TGF-beta s and cAMP regulate GAP-43 expression in Schwann cells and reveal the association of this protein with the trans-Golgi network.

We have shown previously that growth-associated protein 43 (GAP-43) is expressed by rat Schwann cells and is restricted to non-myelin-forming Schwann cells in vivo. Here we examined the regulation of GAP-43 using agents that are known to control Schwann cell differentiation in vitro. GAP-43 protein and mRNA levels are decreased by forskolin and other agents that elevate intracellular cAMP (and promote expression of the myelinating Schwann cell phenotype). We also found that expression of GAP-43 protein but not mRNA is down-regulated by transforming growth factor betas (TGF-beta s). Moreover, TGF-beta treatment of Schwann cells results in cell clumping, process retraction and disappearance of GAP-43 from the plasma membrane, revealing that GAP-43 is associated with the Golgi apparatus. This association was confirmed by partial overlap of GAP-43 with the trans-Golgi network marker (23c) and the disruption of the Golgi with brefeldin A or monensin leading to altered GAP-43 distribution. Golgi-associated GAP-43 appeared to have the same molecular weight as the plasma membrane-associated GAP-43. Thus these results show that GAP-43 expression in Schwann cells is subject to regulation by both extracellular and intracellular signalling molecules and that Schwann cell GAP-43 is often associated with the Golgi apparatus.

Animals↗
PubMed1995

Expression of endopeptidase-24.11 (common acute lymphoblastic leukaemia antigen CD10) in the sciatic nerve of the adult rat after lesion and during regeneration.

Endopeptidase-24.11, which is identical with the common acute lymphoblastic leukaemia antigen CD10 (CALLA), is a cell surface Zn2+ metalloprotease that regulates peptide-induced responses in different tissues, including the nervous and immune systems. In the peripheral nervous system, high levels of the enzyme are present in all neonatal and early postnatal Schwann cells, while as myelination proceeds it is gradually suppressed in the majority of cells that form myelin but retained in non-myelin-forming cells in the adult animal. In the present study we have investigated the effects of transection, crush and regeneration of the adult rat sciatic nerve on the expression of the endopeptidase by Schwann cells in situ. Endopeptidase-24.11 was monitored by immunocytochemistry using the monoclonal anti-endopeptidase antibody 23B11. For comparison, a parallel study was carried out with a monoclonal antibody directed against the rat nerve growth factor receptor. We found that (i) all Schwann cells of the distal segment re-expressed endopeptidase-24.11 as early as 4 days after axotomy, the level of immunostaining reaching a maximum after 2 weeks, (ii) axonal regeneration repressed Schwann cell expression of endopeptidase-24.11, and (iii) the induction of the nerve growth factor receptor followed a similar pattern to that of endopeptidase-24.11 in the transected and crushed nerve. Enzymatic amplification of endopeptidase-24.11 cDNA from normal and axotomized adult rat sciatic nerve confirmed the expression of endopeptidase-24.11 in these tissues. Our results show that the expression of endopeptidase-24.11 in Schwann cells, as is the case with the nerve growth factor receptor, is induced by the loss of the normal axon-Schwann cell contact. The significant increase in the expression of endopeptidase-24.11 by Schwann cells after axonal damage suggests that the enzyme could play a role in axonal regeneration.

Animals↗