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PubMed1999

Postnatal development and adult organisation of the olivocerebellar projection map in the hypogranular cerebellum of the rat.

The olivocerebellar system is characterised by a precise topographical organisation, in which distinct subsets of inferior olivary axons project to neurochemically heterogeneous Purkinje cell subpopulations, arranged into parasagittally oriented compartments in the cerebellar cortex. Adult climbing fibres and Purkinje cells are linked by a one-to-one relationship, which is established during postnatal development after a transitory phase of multiple climbing fibre innervation. The elimination of redundant climbing fibre synapses is thought to be regulated by granule cell-mediated activity-dependent processes. In order to assess whether this developmental remodelling is also important for the construction of the mature olivocerebellar projection map, we examined the hypogranular cerebella of rats treated by means of methylazoxymethanol acetate (MAM) during early postnatal life, in which multiple climbing fibre innervation persists in the adult. In these animals we investigated the distribution of calcitonin gene-related peptide (CGRP)-immunoreactive olivocerebellar axons and arbours during early postnatal development, and the correspondence between climbing fibre strips and zebrin II-defined Purkinje cell bands in the adult. Our results show that: (1) the pattern of CGRP-immunoreactive climbing fibres observed during the first three postnatal weeks is not disrupted after granule cell degeneration; and (2) the alignment between olivocerebellar axon subsets and zebrin II+/- Purkinje cell compartments is normally achieved in adult rats. In contrast, the climbing fibre-Purkinje cell relationship is abnormal, and single arbours innervate restricted dendritic regions of several neighbouring target neurons. These results indicate that the normal distribution of olivocerebellar axon subsets to distinct cerebellar cortical compartments can be established independently from granule cell-mediated remodelling processes. Thus, the postnatal climbing fibre plasticity, which is needed to achieve the normal climbing fibre-Purkinje cell relationship, appears to be confined within the framework of a projection map established during earlier developmental phases.

Aging↗
PubMed2005

An autologous system for culturing head and neck squamous cell carcinomas for the assessment of cellular therapies on the chorioallantois membrane.

The evaluation of novel immunotherapeutic anti-cancer strategies requires target and effector cells from the autologous host to avoid false positive results because of allo-reactivity. Head and neck squamous cell carcinoma cells (HNSCC) do not proliferate under standard culture conditions in plastic ware. To create an autologous model, the chorioallantois membrane (CAM) of chicken embryos was employed to culture HNSCC and peripheral blood mononuclear cells (PBMC). Separated tumor cells were co-incubated with a cytostatic agent, PBMC, or mere cell culture medium as a control. Tumor cell lysis was assessed by acridine orange staining or by flow cytometry analysis of iodide marked cells after 24 and 48 h of co-incubation. Incubation with cisplatin resulted in a decrease of viable cells by 49% after 24 h and 48 h. In contrast, incubation with mere culture medium resulted in an increase of viable tumor cells by 5% after 24 h and a decrease of 4% after 48 h; the incubation of tumor cells and PBMC led to a non-significant decrease by 14% after 24 h and 16% after 48 h. Taken together, the CAM supports a favorable environment for the co-culture of HNSCC and PBMC, thus providing an approximated in vivo autologous model to assess the efficacy of new cell-therapeutical approaches.

Animals↗
PubMed1988

Antibody-mediated activation of T cell clones as a method for screening hybridomas producing antibodies to the T cell receptor.

In this study, supernatants (SN) of hybridomas established by fusing P3X63.Ag8.653 to spleen cells from C57L mice (V beta 8 family of T cell receptor (TcR) gene negative) immunized with the H-Y specific V beta 8 allotype positive helper T cell (HTL) clone OI6 were screened for the capacity to activate cloned T cells in the absence of interacting stimulator cells. In the first assay, SNs were mixed with V beta 8+ H-Y specific CTL OH2 and 51Cr-labelled non-specific B lymphoma (L10.A). In this system, antibodies (Ab) which can bind to L10.A by Fc-Fc receptor interaction and recognize TcR can facilitate lysis of L10.A target cells by OH2 CTL. In the second assay, OI6 clone cells were cultured in microtiter well, previously coated with hybridoma supernatants (SN). In this assay, Ab recognizing OI6 TcR complex and bound to plastic plates can stimulate OI6 cells to proliferate in the absence of stimulator cells. Using these two screening methods, nine hybridomas were established. Analysis of these hybridoma SN using surface staining, inhibition of T cell function and immunoprecipitation of radiolabelled surface molecules followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS/PAGE) showed that five Ab were directed to the allotypic determinant (V beta 8) of TcR and four Ab were specific to the clonotypic determinant of OI6 TcR. These results suggest that this Ab-mediated activation of T cell clone can be used for the screening of hybridomas secreting anti-TcR Ab and the immunogenicity of OI6 clonotypic determinants is similar to that of the V beta 8 allotypic determinant even in strains which do not express the V beta 8 TcR allotype.

Animals↗
PubMed1995

Activity-dependent remodeling of connections in the mammalian visual system.

The development of precise connections in the mammalian central nervous system requires neural activity. Synchronous patterns of afferent activity, and coincident afferent and target activity are required for specifying the neuronal connectivity that characterizes the adult visual pathway in mammals. During development, postsynaptic target neurons communicate with presynaptic afferents. Recent evidence suggests that the mechanisms that underlie activity-dependent development of connections in the visual system may share significant similarities with the mechanisms responsible for synaptic plasticity in the adult brain.

Afferent Pathways↗
PubMed2004

Neural cell adhesion molecule (NCAM) null mice do not show a deficit in odour discrimination learning.

Polysialylated neural cell adhesion molecule (PSA-NCAM) is predominantly expressed during development where it regulates biological functions including axon targeting and neuronal precursor cell migration. Although dramatically down regulated after birth in most regions of the nervous system, PSA-NCAM remains highly expressed into adulthood in areas that have ongoing regeneration and plasticity such as in the olfactory bulb and hippocampus. Consequently, lack of PSA-NCAM in NCAM null mice results in distinct morphological changes to these areas. The functional correlates of these changes are not well defined although there have been reports that learning is impaired in NCAM null mice. In the present study, we assessed the ability of old and young NCAM null mice to learn an odour discrimination task. We tested male and female experimental and control animals of two different ages: 30-60 days and 12-15 months. During 4 days of training, NCAM null and C57BL/6J received trials where one odour (CS+) was paired with sugar while another odour (CS-) was not. In a subsequent preference test, conducted in the absence of sugar, all animals, regardless of strain or age, spent significantly more time digging in the CS+ odour than in the CS- odour. In addition, there was no significant difference in digging behaviour in the CS+ between the NCAM null and the control animals. These data indicate that deletion of the NCAM gene may change the morphology of the olfactory bulb but does not interfere with the ability to learn an odour discrimination task.

Age Factors↗
PubMed2005

Glutamate- and GABA-based CNS therapeutics.

Glutamate- and GABA-releasing neurons form the basis for neurotransmission in the mammalian central nervous system (CNS). The co-ordination of these excitatory and inhibitory systems, together with intrinsic voltage-gated ion channels and G-protein-coupled receptor modulation, provides the diverse neuronal firing patterns, network activity and synaptic plasticity that are required for the complexity of CNS function. Virtually all of the known molecular components of the gamma-aminobutyric acid (GABA) and glutamate neurotransmitter systems have been considered as potential therapeutic targets. Positive allosteric modulators of GABAA receptors, such as the benzodiazepines, have found wide clinical use, and the N-methyl-D-aspartate receptor antagonists ketamine and memantine have therapeutic utility. In these fundamental neurotransmitter systems, drugs that provide allosteric modulation of ligand-gated ion channels or G-protein-coupled receptors, or seek to selectively target receptor subtypes, appear to hold the greatest promise for the desired balance of efficacy and tolerability. This might also be achieved through targeting transporter subtypes. A large number of compounds based on these strategies are currently in clinical trials for diseases that span a wide range of CNS disorders.

Animals↗
PubMed2005

Origin and immunolesioning of cholinergic basal forebrain innervation of cat primary auditory cortex.

Numerous studies have implicated the cholinergic basal forebrain (cBF) in the modulation of auditory cortical responses. This study aimed to accurately define the sources of cBF input to primary auditory cortex (AI) and to assess the efficacy of a cholinergic immunotoxin in cat. Three anaesthetized cats received multiple injections of horseradish-peroxidase conjugated wheatgerm-agglutin into physiologically identified AI. Following one to two days survival, tetramethylbenzidine histochemistry revealed the greatest number of retrogradely labeled cells in ipsilateral putamen, globus pallidus and internal capsule, and smaller numbers in more medial nuclei of the basal forebrain (BF). Concurrent choline acetyltransferase immunohistochemistry showed that almost 80% of the retrogradely labeled cells in BF were cholinergic, with the vast majority of these cells arising from the more lateral BF nuclei identified above. In the second part of the study, unilateral intraparenchymal injections of the cholinergic immunotoxin ME20.4-SAP were made into the putamen/globus pallidus nuclei of six cats. Immuno- and histochemistry revealed a massive reduction in the number of cholinergic cells in and around the targeted area, and a corresponding reduction in the density of cholinergic fibers in auditory cortex. These results are discussed in terms of their implications for investigations of the role of the cBF in cortical plasticity.

Acetylcholine↗
PubMed2003

New approaches to study the development of morphine tolerance and dependence.

Morphine is now believed not to cause tolerance and dependence when it is appropriately used in clinic. However, in terminal cancer pain, patients' analgesic tolerance to morphine is developed due to the use of high doses of morphine for complete blockade of pain. At higher doses, morphine has more opportunity to show serious side effects, which worsens quality of life (QOL), and leads to the use of potent analgesic adjuvants to reduce the morphine dosage. Here we attempt to summarize recent studies of the molecular basis of morphine tolerance and dependence, and to discuss whether these mechanisms could provide new molecular targets as analgesic adjuvants. They include protein kinase C inhibitor, opioid agonist with low RAVE value, and antagonists of antiopioid receptors (GluRepsilon1 or nociceptin/OFQ receptor). In addition, we demonstrate new approaches to find further candidates of such molecular targets. These approaches include the visualization of neuronal networks in the downstream of opioid neurons by use of the WGA transgene technique and the single cell dissection technique to get new genes involved in plasticity during morphine tolerance and dependence.

Analgesics, Opioid↗
PubMed2006

Possible key role of granzyme B in keratoacanthoma regression.

It is still controversial whether keratoacanthoma is to be considered as a well differentiated variant of squamous cell-carcinoma or a separate entity. As opposed to malignant potential of squamous cell-carcinoma, keratoacanthoma is characterized by a spontaneous regression. However, in some cases, otherwise typical keratoacanthoma can behave aggressively showing the signs of perineural and perivascular invasion and metastases in regional lymph nodes. The most important feature that separates these two closely related entities is a tendency of keratoacanthoma to regress. Causes and detailed mechanism of this regression are still not completely elucidated. Within the past few years, it has become evident that the molecular events regulating cell survival and apoptosis are important contributors to the overall kinetics of benign and malignant cell growth. Immunological mechanisms have been implicated in a phenomenon of spontaneous tumor regression. Recent studies suggested that the tumor regression is dependent mainly on the immune response mediated by cytotoxic T lymphocytes (CD8+), together with helper T cells (CD4+). Cytotoxic T lymphocytes can kill tumor cells and mediate tumor regression in vivo through two distinct molecular mechanisms: Fas/Fas ligand and granzyme B/perforin mediated pathways. Tumor cells are capable of developing different escape mechanisms in order to overcome their sensitivity to apoptotic signals. However, granzyme B, contained in cytolytic granules released upon target cell recognition, can also cause tumor cell death and consequently tumor regression by direct damage to non-nuclear structures through a caspase-independent pathway. Therefore, we propose a key role of plasticity in the granzyme B mediated cell death pathway in the killing of changed tumor cells, resulting in keratoacanthoma regression through apoptosis or direct damage of tumor cells. On the other hand, insufficient activation of cytotoxic T lymphocytes and decreased release or activity of granzyme B could be responsible for squamous cell-carcinoma progression and occasional aggressive behavior in keratoacanthomas. As a first step in confirming or refuting our hypothesis, we suggest a thorough immunohistochemical study of the presence of granzyme B and its activity in keratoacanthoma and squamous cell-carcinoma samples. To our knowledge, no such study has been performed so far.

Animals↗
PubMed1998

The Cyclops effect in adults: sighting without visual feedback.

When asked to look through a tube, younger children place it at the bridge of the nose, and not over one eye: the Cyclops effect. This is a natural response to a median plane egocenter. With maturity, the Cyclops effect disappears as we learn to overcome the consequences of an egocenter between the two eyes, and instead, to use the "preferred" eye. We videotaped adults (n = 14) and children with normal vision (n = 30), children with comitant strabismus (n = 14), and adults and children (n = 14) with one eye enucleated as they attempted to look through a plastic tube. Immediately in front of the face was a liquid crystal window that could be either transparent or opaque. As the tube was raised, the window was made opaque--blocking sight of the target, their hands, and the tube. Most binocular observers placed the tube approximately at the bridge of the nose. This was significantly different from the response of the enucleated observers who put the tube 75% of the way to the remaining eye (P = 0.0001). All observers align, on average, with the measured location of their egocenter when asked to perform a monocular task without visual cues. Deprived of visual feedback, binocular observers show the Cyclops effect, regardless of age.

Adolescent↗
PubMed2006

Role of the urothelium in urinary bladder dysfunction following spinal cord injury.

A consequence of spinal cord injury is a change in bladder reflex pathways resulting in the emergence of detrusor hyperreflexia and increased activity of the urethral sphincter. A basis for some of these alterations could be changes in the environment of bladder sensory nerve endings at the target organ. Recent evidence suggests that the urothelium (the lining of the urinary bladder) plays a prominent role in modulating bladder sensory nerve ending excitability. It is conceivable that factors and processes affecting the plasticity of bladder neurons after spinal cord injury may be partly due to changes occurring in the urothelium. Although the urothelium has classically been thought of as a passive barrier to ions/solutes, a number of novel properties have been recently attributed to these cells. Our work and that of others clearly demonstrates that the urothelium exhibits both "sensor" (expression of sensor molecules or response to thermal, mechanical and chemical stimuli) as well as "transducer" (release of factors/transmitters) properties. Taken together, these and other findings discussed in this chapter suggest a sensory function for the urothelium and that alterations in urothelial properties may contribute to afferent abnormalities following spinal cord injury.

Botulinum Toxins↗
PubMed1998

The high-LET radiation component measured during the EUROMIR-94 mission.

Stacks of CR-39 plastic nuclear track detectors were mounted inside the MIR-station during the EUROMIR-94-mission. We present LET-spectra determined separately for long range cosmic ray heavy ions and for short range target fragments produced in nuclear interactions of cosmic rays and measured charge distributions for relativistic and stopping particles.

Cosmic Radiation↗
PubMed2003

Effect of polymer concentration on partitioning and molecular recognition in plasticized poly(vinyl chloride).

Mixtures of poly(vinyl chloride) (PVC) with plasticizers have been used in ion-selective electrodes for many years. The same material has proven useful in solid-phase microextraction (SPME), both with and without artificial receptors. We hypothesized that by changing the polymer concentration in plasticized PVC membranes containing artificial receptor from the standard 33 wt %, the selectivity of the extraction of barbiturates over similar molecules could be improved. Partition coefficients and receptor-substrate formation constants of a target species, phenobarbital, in membranes with various polymer concentrations were determined. Diffusion coefficients of the solute phenobarbital in receptor-free membranes were also determined. Kamlet-Taft solvatochromic properties beta and pi* were measured for the PVC/dioctyl sebacate materials. Cohesive energy densities were calculated for the same materials. Partition coefficients for phenobarbital (from aqueous solution to membrane) decrease as [PVC] increases, while the formation constants for the complex of the solute with its receptor increase. Diffusion coefficients decrease as the polymer concentration increases as well. The increase in polymer concentration brings about a decrease in hydrogen-bonding basicity and an increase in dipolarity and cohesive energy density. The values of the solvatochromic parameters determined at various compositions are highly correlated; thus, it is impossible to calculate how much each factor contributes to the changes associated with partition and complex formation. The solvatochromic "polarizability correction factor" has been determined to be 0 for PVC. In SPME experiments at 30%, 40%, and 50% (w/w) PVC, as polymer concentration increases, selectivity for barbiturate extraction over other cyclic imides becomes better in the presence of barbiturate receptor and worse without receptor.

Journal Article↗
PubMed2001

Bone marrow cells regenerate infarcted myocardium.

Myocardial infarction leads to loss of tissue and impairment of cardiac performance. The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time. Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation; these events promote structural and functional repair. This high degree of stem cell plasticity prompted us to test whether dead myocardium could be restored by transplanting bone marrow cells in infarcted mice. We sorted lineage-negative (Lin-) bone marrow cells from transgenic mice expressing enhanced green fluorescent protein by fluorescence-activated cell sorting on the basis of c-kit expression. Shortly after coronary ligation, Lin- c-kitPOS cells were injected in the contracting wall bordering the infarct. Here we report that newly formed myocardium occupied 68% of the infarcted portion of the ventricle 9 days after transplanting the bone marrow cells. The developing tissue comprised proliferating myocytes and vascular structures. Our studies indicate that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease.

Animals↗
PubMed2000

Cytokine and growth factor involvement in schizophrenia--support for the developmental model.

Medical treatment with various cytokines can provoke psychiatric symptoms. Conversely, psychiatric patients can display abnormalities in cytokine and neurotrophic factor expression. Such observations have pointed to the potential contribution of cytokines and growth factors to schizophrenic pathology and/or etiology. The cellular targets of the relevant factors and the nature of their actions remain to be explored in mental illness, however. Recent physiological studies demonstrate that cytokines and neurotrophic factors can markedly influence synaptic transmission and plasticity upon acute or chronic application. Moreover, many of the molecular alterations observed in the schizophrenic brain are consistent with abnormalities in cytokine and neurotrophic factor regulation of these molecules. In this review, we summarize these molecular pathology findings for schizophrenia and highlight the neurodevelopmental activities of cytokines and neurotrophic factors that may contribute to the etiology or pathology of this illness.

Animals↗
PubMed2001

Laser transmission through transparent membranes used in cutaneous laser treatment.

BACKGROUND: Some clinicians perform cutaneous laser treatments through transparent membranes to protect themselves and the surroundings from contamination by ejected tissue particles. Transmissibility of these membranes influences the tissue irradiance. OBJECTIVE: We compared the optical transmissibility of 8 membranes. METHODS: In part 1, a Schwartz Electro-Optics Q-switched alexandrite laser (wavelength of 720-800 nm, beam diameter of 3 mm) was directed through 8 membranes. A Molectron JD 2000 Joulemeter Ratiometer obtained measurements of percent loss of laser energy (for calculation of percent transmission) through each. To evaluate other wavelengths used in skin treatment, an SLM Aminco UV-VIS model 2000 spectrophotometer measured variance of transmission over a spectral region from 350 to 900 nm in 4 of the membranes. RESULTS: The samples listed in order of increasing amounts of light energy lost across the membrane as compared with control (direct irradiation) were as follows: (1) Handi Wrap plastic wrap: 7% loss, 93% transmission; (2) glass slide: 8% loss; (3) Bioclusive transparent dressing: 11% loss; (4) Tegaderm transparent dressing: 26% loss; (5) Vigilon dressing without plastic backing: 34% loss; (6) Vigilon dressing with one layer of plastic backing: 37% loss; (7) Acuderm dressing: 41% loss; and (8) OpSite IV: 48% loss. CONCLUSIONS: Transmissibility of the interposed membranes must be considered when determining the dosimetry of light energy required by the target tissue.

Laser Therapy↗
PubMed2005

Differential localization of ErbB receptor ensembles influences their signaling in hippocampal neurons.

Our studies indicate that ErbB complexes participate in both survival and synaptic plasticity signals of hippocampal neurons but in a manner that depends on the subcellular localization of the receptor ensembles. Using dissociated hippocampal cultures, we found that neurons, rather than glial cells, are the primary targets of ErbB receptor ligands such as epidermal growth factor and heregulin. Further investigation demonstrated that ErbB receptors distribute differentially in hippocampal neurons with the epidermal growth factor receptor confined to neural cell bodies and the p185(c-neu) and ErbB4 receptors distributed to both neural soma and neurites. Activation of ErbB receptor and downstream signaling molecules were observed in neurites only after heregulin stimulation. The receptor complex which mediated neurite located signals was the p185(c-neu)/ErbB4 heterodimer. Colocalization of p185(c-neu), but not epidermal growth factor receptor, with postsynaptic density protein 95 suggests that the heregulin signaling contributes to synapse specific activities. However, the epidermal growth factor receptor complex mediates physiological survival signals, as neuronal survival was enhanced by epidermal growth factor, rather than heregulin. Collectively, these studies indicate that different ErbB ensembles localize to different locations on the neuron to mediate distinct signals and functions.

Animals↗
PubMedDate not supplied

Controlled and localized genetic manipulation in the brain.

Brain structure and function are determined in part through experience and in part through our inherited genes. A powerful approach for unravelling the balance between activity-dependent neuronal plasticity and genetic programs is to directly manipulate the genome. Such molecular genetic studies have been greatly aided by the remarkable progress of large-scale genome sequencing efforts. Sophisticated mouse genetic manipulations allow targeted point-mutations, deletions and additions to the mouse genome. These can be regulated through inducible promoters expressing in genetically specified neuronal cell types. However, despite significant progress it remains difficult to target specific brain regions through transgenesis alone. Recent work suggests that transduction vectors, like lentiviruses and adeno-associated viruses, may provide suitable additional tools for localized and controlled genetic manipulation. Furthermore, studies with such vectors may aid the development of human genetic therapies for brain diseases.

Animals↗