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At least 1,207 records · Page 67Linked to original sources
PubMed2001

Has basic research contributed to chronic pain treatment?

Our understanding of nociceptive processing and of plastic changes after persistent noxious input has increased immensely within the last two decades. It is now clear that long-lasting noxious stimulation or damage to the nervous system give rise to a neuronal hyperexcitability and that this sensitisation of the nervous system plays an important role for development and maintenance of chronic pain. The manifestations of such hyperexcitability are numerous and include among others: increased neuronal response to a suprathreshold stimulus, expansion of the peripheral areas from where a central neurone can be activated and the recruitment of previous non-responding nociceptive neurones. Furthermore, it has been possible to modulate this neuronal hyperexcitability by the discovery of molecular targets for pain, by sequencing DNA of ion channels and receptors and by development of new molecules that exert their effects on these molecular targets. The changes in responsiveness appear to be partly time and intensity dependent and partly dependent on the cause of injury. Whereas relatively short-lasting and moderate noxious input leads to reversible plastic changes, more intense and long-lasting noxious stimulation implies a risk for persistent and more profound alterations in transmitters, receptors, ion channels and in neuronal connectivity. Despite the explosion of new knowledge in pain processing and in molecular background for neuroplasticity, this progress has unfortunately not resulted in a corresponding improvement of our ability to treat chronic pain. The number of patients with chronic unrelieved pain is still high and newer types of treatment have so far not resulted in a substantially better treatment. Nevertheless, there is now an ongoing systematic research in which chronic pain conditions are assessed in a fashion so that mechanisms underlying pain can be dissected. Moreover, controlled clinical trials together with systematic reviews are carried out which in the future should permit formulation of treatment algorithms for chronic pain. Finally, it is likely that the development of new specific types of treatment will show efficacy if they are evaluated and analysed not on the global pain experience, but more specifically on those targets and elements of the pain experience they are aimed to deal with.

Animals↗
PubMed2004

[Perioperative targeting brachytherapy for lung cancer invading the chest wall].

We evaluated the efficacy of perioperative targeting brachytherapy for lung cancer invading the chest wall. Between 1998 and 2003, 7 patients underwent perioperative targeting brachytherapy for lung cancer invading the chest wall. There were 5 male and 2 female patients. The mean age was 63.3 years, with a range of 45 to 77 years. All patients underwent complete resection including the chest wall combined resection. During the operation, plastic afterloading catheters fixed on the Vicryl mesh at interval of 1 cm were placed on the site of chest wall resection. From the third to sixth day after the operation, 15 to 32 Gy of radiation was delivered over 3 or 4 days using a high dose rate remote afterloading system. The area targeted for brachytherapy was determined by a computed tomography (CT) scanner translator with a computer program for radiation planning. The median postoperative hospital stay was 35 days. Local recurrences were observed in 2 patients, but there was no evidence of recurrence in the margin of the resected chest wall. We believe that this short period of treatment and the low side effects enhances the quality of the patients. Prevention of local recurrence was achieved in short term follow-up.

Aged↗
PubMed2006

Memory enhancement in healthy older adults using a brain plasticity-based training program: a randomized, controlled study.

Normal aging is associated with progressive functional losses in perception, cognition, and memory. Although the root causes of age-related cognitive decline are incompletely understood, psychophysical and neuropsychological evidence suggests that a significant contribution stems from poorer signal-to-noise conditions and down-regulated neuromodulatory system function in older brains. Because the brain retains a lifelong capacity for plasticity and adaptive reorganization, dimensions of negative reorganization should be at least partially reversible through the use of an appropriately designed training program. We report here results from such a training program targeting age-related cognitive decline. Data from a randomized, controlled trial using standardized measures of neuropsychological function as outcomes are presented. Significant improvements in assessments directly related to the training tasks and significant generalization of improvements to nonrelated standardized neuropsychological measures of memory (effect size of 0.25) were documented in the group using the training program. Memory enhancement appeared to be sustained after a 3-month no-contact follow-up period. Matched active control and no-contact control groups showed no significant change in memory function after training or at the 3-month follow-up. This study demonstrates that intensive, plasticity-engaging training can result in an enhancement of cognitive function in normal mature adults.

Adult↗
PubMed1988

Lysis of colonic epithelial cells by allogeneic mononuclear and lymphokine activated killer cells derived from peripheral blood and intestinal mucosa: evidence against a pathogenic role in inflammatory bowel disease.

A sensitive 4 h 51Cr-release cytotoxicity assay has been developed using as targets colonic epithelial cells obtained by Dispase-collagenase digestion of resected mucosa or colonoscopic biopsies. Peripheral blood mononuclear cells (MNC) from most healthy donors showed low, but significant levels of cytotoxicity for normal epithelial cell target cells of 8.7 (4.4) % (mean (SD] and similar levels were found in 14 ulcerative colitis (6.5 (4.4) %) and 16 Crohn's disease (6.2 (5.2) %) patients. Neither drug therapy nor disease activity influenced the results. The sensitivity of colonic epithelial cells isolated from inflamed and histologically normal mucosa to lysis by peripheral blood MNC from a single donor was not affected by the underlying disease. Anti-epithelial cell activity did not correlate with anti-K562 activity and the cytotoxic cell was plastic non-adherent and Leu-11b-. None of 15 MNC populations isolated from mucosa of normal, tumour bearing, or chronically inflamed intestine exhibited significant lysis of colonic epithelial cells despite killing of K562 target cells in 10. Lymphokine activated killer (LAK) cells, generated by interleukin-2 stimulation in vitro of nine intestinal and seven peripheral blood MNC populations, exhibited high levels of lysis of K562 cells but, on every occasion, failed to lyse colonic epithelial cells. These data indicate that spontaneously cytotoxic or LAK cells are unlikely to play a role in the generation of colonic epithelial cell injury by direct cytotoxicity in inflammatory bowel disease.

Adolescent↗
PubMed2003

Non-synaptic interaction between neurons in the brain, an analog system: far from Cajal-Sherringtons's galaxy.

The functional interactions between neurons without synaptic contacts are specialized to function on a time scale of seconds (minutes) and a distance scale of hundreds of micrometers. These nonsynaptic receptors and transporters are of high affinity, have many implications for psychiatry for understanding e.g. depression, changes in mood, in appetite, affective illnesses etc. It is, therefore, suggested that many drugs applied in psychiatric diseases, exert their effects after diffusion through extracellular spaces and may mimic the mode, or may influence the effect of endogenous ligands. The nonsynaptic chemical communication between neurons, and between neurones and target cells, via both pre- and postsynaptic sites, seems likely to achieve growing recognition. This system has a similar degree of selectivity to that of synaptic circuitry but have, in addition, a domain of versatility and plasticity in "hardwired" circuitry. The brain is a wired instrument, but its neurons, besides cabled information processing (through synapses), are able to talk to each other without synaptic contact. It is suggested, therefore that the nonsynaptic tonic presynaptic modulation of chemical transmission, plays a physiological role in the brain in shaping emotion, behaviour or learning processes, or in controlling the balance between sympathetic and parasympathetic nervous system, or the nonsynaptic released transmitter is able to produce responses of the target cells and a local fine tuning of cytokine production (cf. Elenkov et al., 2000), steroid secretion and possible many other functions not yet discovered. The spatial and temporal effect of transmitters on nonsynaptic receptors located on axon terminals, adopts the strength of transmission to a given situation. This will not only influence the function of the neurons system in health and disease, but also therapeutic and untoward effects of drugs that bind these nonsynaptic receptors and transporters (Vizi, 2000).

Animals↗
PubMed2006

Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons.

Activity-dependent plasticity in nociceptive pathways has been implicated in pathomechanisms of chronic pain syndromes. Calcitonin gene-related peptide (CGRP), which is expressed by trigeminal nociceptors, has recently been identified as a key player in the mechanism of migraine headaches. Here we show that CGRP is coexpressed with brain-derived neurotrophic factor (BDNF) in a large subset of adult rat trigeminal ganglion neurons in vivo. Using ELISA in situ, we show that CGRP (1-1000 nM) potently enhances BDNF release from cultured trigeminal neurons. The effect of CGRP is dose-dependent and abolished by pretreatment with CGRP receptor antagonist, CGRP(8-37). Intriguingly, CGRP-mediated BDNF release, unlike BDNF release evoked by physiological patterns of electrical stimulation, is independent of extracellular calcium. Depletion of intracellular calcium stores with thapsigargin blocks the CGRP-mediated BDNF release. Using transmission electron microscopy, our study also shows that BDNF-immunoreactivity is present in dense core vesicles of unmyelinated axons and axon terminals in the subnucleus caudalis of the spinal trigeminal nucleus, the primary central target of trigeminal nociceptors. Together, these results reveal a previously unknown role for CGRP in regulating BDNF availability, and point to BDNF as a candidate mediator of trigeminal nociceptive plasticity.

Animals↗
PubMed1994

Residual Ca2+ and short-term synaptic plasticity.

At many synapses, the amount of transmitter released by action potentials increases progressively during a train of spikes. This enhancement of evoked transmitter release grows during tetanic stimulation with several time constants, each bearing a different name (facilitation: tens to hundreds of milliseconds; augmentation: several seconds; potentiation: several minutes), and the enhancement of release to test spikes after a tetanus decays with similar time constants. All these processes depend on presynaptic Ca2+ influx during the conditioning tetanus. It has often been proposed that these forms of synaptic plasticity are due to residual Ca2+ present in nerve terminals following conditioning activity. We tested this idea directly by using photolabile Ca2+ chelators to reduce residual Ca2+ following conditioning stimulation or to generate an artificial elevation in Ca2+ concentration, and observed the effects on synaptic transmission at crayfish neuromuscular junctions. We found that facilitation, augmentation and potentiation are caused by the continuing action of residual Ca2+. Augmentation and potentiation seem to arise from Ca2+ acting at a separate site from facilitation, and these sites are different from the molecular target triggering neurosecretion.

Action Potentials↗
PubMed1984

Nonspecific cytotoxic cells in fish (Ictalurus punctatus). III. Biophysical and biochemical properties affecting cytolysis.

Nonspecific cytotoxic cells (NCC) from the catfish (Ictalurus punctatus) may comprise a population of cells that are responsible for cellular immunity in the fish. NCC kill a wide variety of transformed target cells, and previous studies have indicated that NCC share properties with mammalian natural killer cells. In the present study, many biophysical and biochemical properties of NCC were defined. NCC were nylon wool nonadherent and adherent. NCC activity was also enriched in plastic nonadherent cells. NCC were nonphagocytic (for carbonyl iron), and they did not bind to Sephadex G-10. Characterization of NCC by density gradient centrifugation indicated that they comprise a relatively homogenous population of cytolytic cells that band at 45.5% Percoll. Moderate to high doses (500-2500 R) of X-irradiation produced a stimulatory effect on NCC lysis of labeled target cells. Additional studies indicated that a soluble suppressor protein in catfish serum (CFS) regulated NCC activity. This S. aureus protein A binding component isolated from CFS suppressed NCC activity. Analysis by SDS-PAGE indicated that the soluble regulatory protein had properties similar to immunoglobulin. These data indicate that NCC share some biophysical properties with mammalian natural killer cells. In addition, NCC appear to be under partial cell regulation by a radiation sensitive suppressor cell and also by a soluble regulator serum immunoglobulin component.

Animals↗
PubMed1991

Reinnervation of cerebellar Purkinje cells by climbing fibres surviving a subtotal lesion of the inferior olive in the adult rat. I. Development of new collateral branches and terminal plexuses.

Cerebellar climbing fibres react by collateral sprouting after subtotal lesions of the inferior olive, and the newly formed branches are able to reinnervate neighbouring denervated Purkinje cells. In the present paper, we used the Phaseolus vulgaris leucoagglutinin (PHA-L) tracing technique to label the climbing fibres and study their plasticity in detail at the light microscopical level. The specific objectives were to study the time course and morphological aspects of their sprouting, to estimate their extent of growth, and to compare the newly formed terminal plexuses with normal climbing fibres. Intraperitoneal injection of 3-acetylpyridine induced degeneration of the majority of the olivary neurones, which terminate as climbing fibres in the cerebellar cortex. Regularly, small numbers of neurones survived in the inferior olive. In the cerebellar cortex scattered surviving climbing fibres were found, which were devoid of any sign of injury. Already 3 days after the lesion, surviving climbing fibres had emitted collateral branches, which elongated for some distance through the molecular layer and ended with a number of varicosities and very fine branchlets. By 7 days, it was possible to recognize new developing arbours which grew in the molecular layer with the same orientation as normal climbing fibres. At longer survival times, extensive terminal arbours had developed and double labelling experiments confirmed that they terminated around the proximal dendrites of Purkinje cells. The newly formed terminal plexuses resembled, in all essential aspects, normal climbing fibres. In addition, from 1 month onward, it was evident that every surviving climbing fibre was able to form several new terminal plexuses reinnervating a number of neighbouring Purkinje cells. The result of this process was the formation of large clusters of newly formed plexuses around the parental arborization. Quantitative estimates indicated that the domain of innervation of single surviving climbing fibres could be increased by more than six times. It is concluded that climbing fibres surviving a subtotal olivary lesion are capable of extensive sprouting, axonal growth, and formation of new terminal plexuses, which resemble normal climbing fibres. Previous electrophysiological evidence indicates that this reinnervation is functional. The high specificity with which sprouting olivary axons reinnervate the proximal Purkinje cell dendrites suggests the existence of precise interactions between the growing fibres and their target. This example of "homotypic" collateral sprouting and reinnervation may thus provide a useful model for the study of nerve-target interactions.

Animals↗
PubMed2003

IGF-1 induces neonatal climbing-fibre plasticity in the mature rat cerebellum.

Following unilateral transection (pedunculotomy) of the neonatal rat olivocerebellar pathway, the remaining inferior olive reinnervates the denervated hemicerebellum with correct topography. The critical period for this transcommissural reinnervation closes between postnatal days 7 and 10 but can be extended by injection of growth factors. Whether growth factor treatment can extend developmental plasticity into a mature, myelinated milieu remains unknown. Rats aged 11-30 days, underwent unilateral pedunculotomy followed 24 h later by injection of insulin-like growth factor 1 (IGF-1) into the denervated cerebellum. In all animals, IGF-1 induced transcommissural olivocerebellar reinnervation, which displayed organisation consistent with normal olivocerebellar topography even following pedunculotomy up to day 20. Thus IGF-1 can reproduce developmental neuroplasticity to promote appropriate target reinnervation in a mature myelinated environment.

Aging↗
PubMed1998

Chemokine receptors and human immunodeficiency virus infection.

Primate lentiviruses infect target cells by interacting with the cell surface protein, CD4 and additional molecules, termed coreceptors. Recently, HIV-1 coreceptors have been identified as seven transmembrane spanning, G-protein coupled receptors of the chemokine receptor family. Thus, expression of CD4 and an appropriate coreceptor is both necessary and sufficient to render target cell permissive for fusion with virions or infected cells. The spectrum of tissue tropisms exhibited by primate lentiviruses can be largely explained by differential utilization and distribution of coreceptors. This article reviews what is currently known about the selective utilization of particular coreceptors by primate lentiviruses and the nature of the envelope/coreceptor interaction, with particular reference to two important HIV-1 coreceptors, CCR-5 and CXCR-4. It has become clear that these interactions are somewhat 'plastic': Variability is evident, both in the selection of coreceptor and the way in which different viral strains interact with their cognate coreceptors. The implications of these findings both for attempts to block HIV infection with coreceptor targeted agents and for understanding HIV replication in vivo is discussed.

Animals↗
PubMed2004

Three-dimensional antennal lobe atlas of the male moth, Agrotis ipsilon: a tool to study structure-function correlation.

The glomerular structure of the primary olfactory neuropil has long been thought to play an important role in odour coding. In insects, the number of glomeruli in the antennal lobe is limited in most species to fewer than 100 compared with more than 1,000 in vertebrates, making it possible to identify individual glomeruli. A complete three-dimensional atlas of the glomeruli within the antennal lobe of the male noctuid moth Agrotis ipsilon was constructed. All 66 glomeruli were singly identifiable in both antennal lobes of the three brains investigated. Further, six antennal lobes containing intracellularly stained projection neurones were reconstructed. By using the atlas, the respective target glomerulus of each projection neurone could be identified. The importance of the glomerular atlas as a tool to study central olfactory processing and its plasticity is discussed.

Action Potentials↗
PubMed1990

Rat ventral mesencephalon grown as organotypic slice cultures and co-cultured with striatum, hippocampus, and cerebellum.

Tissue slices of rat ventral mesencephalon (VM), striatum, hippocampus and cerebellum were prepared from late fetal (E21) to 7 day old (P7) rats and cultured for 3 to 60 days by the roller tube technique before they were stained immunocytochemically for tyrosine hydroxylase (TH), a marker of dopaminergic (DA) neurons and fibres. The TH immunoreactive (TH-i), DA neurons retained their morphological in vivo characteristics in the VM slice cultures consisting of the substantia nigra (SN) and the ventral tegmental area (VTA). The general morphology of the described neuronal cell types did not appear to change when the VM slices were co-cultured with striatal tissue, a major normal target of the DA neurons, but an extensive innervation of the striatum by TH-i nerve fibres was observed. In co-cultures of VM and hippocampus, a minor target organ of DA fibres, growth of TH-i nerve fibres was observed mainly into the opposing edge of the hippocampal slice. In co-cultures of VM and cerebellum, which is normally devoid of DA fibres, no significant growth of TH-i nerve fibres into the cerebellar slices was observed. Besides suggesting a target orientated growth of ventral mesencephalic DA fibres, the results point to the further use of VM slice cultures in the study of the developmental, plastic and regenerative properties of DA neurons.

Aging↗
PubMedDate not supplied

Effect of lipopolysaccharides, lipid A and interferon on the cell-mediated cytotoxicity of human leukocytes against K-562 tumor cells.

The effect of lipopolysaccharides (LPS), lipid A and interferon on cell-mediated cytotoxicity was investigated using 51Cr-labeled K-562 tumor cells as targets. As effectors, peripheral blood mononuclear cells from healthy blood donors were obtained by Ficoll gradient centrifugation: mononuclear phagocytes were eliminated by iron phagocytosis and plastic adherence. A T cell-enriched population was obtained by passing mononuclear phagocyte-depleted mononuclear cells through nylon wool columns. LPS and lipid A augmented cell-mediated cytotoxicity provided mononuclear phagocytes were present. Supernatants from LPS-treated mononuclear phagocytes and T cells enhanced mononuclear phagocyte-mediated cytotoxicity to a higher degree than LPS and lipid A alone. This finding suggests the participation of a lymphokine. In contrast, the interferon preparation increased the cell-mediated cytotoxicity both of mononuclear phagocyte-containing and of mononuclear phagocyte-depleted effectors. Here, the participation of natural killer cells as effectors is suggested.

Cell Line↗
PubMed1996

Locally advanced rectal cancer: resection and intraoperative radiotherapy using the flab method combined with preoperative or postoperative radiochemotherapy.

PURPOSE: Surgery often fails to achieve local control in advanced rectal cancer. Additional measures are necessary to prevent local recurrence. The aim of this study was to evaluate intraoperative radiation therapy (IORT) (flab technique) combined with preoperative or postoperative radiochemotherapy. PATIENTS/METHODS: IORT is performed using a flexible flab containing hollow plastic tubes that are connected to a multichannel afterloading device with a 370 Gbq-192-Ir source. Patients receive an intraoperative dose of 15 Gy. Target volumes were measured in a cadaver experiment. From 1989 to 1993, 38 patients were included in this study. Nineteen patients were staged as T3 tumors by preoperative endosonography (Group I) and 19 as T4 tumors (Group II). Patients in Group I underwent resection (abdominoperineal resection (APR), 16; anterior resection, 3) and IORT, followed by postoperative radiochemotherapy (50 Gy/5-fluorouracil), whereas patients in Group II received preoperative radiochemotherapy (40 Gy/5-fluorouracil) followed by resection (APR, 18; anterior resection, 1) and IORT. Mean follow-up was 25.5 months. RESULTS: Operative radicality in Group I was RO (13), R1 (3), and R2 (3), and in Group II it was RO (14), R1 (3), R2 (2). R2 resections were attributable to preoperative undetected distant metastases. Perioperative mortality was 0 percent in Group I and 10.5 percent (n = 2) in Group II. Postoperative morbidity was 53 percent (n = 10) in Group I and 84 percent (n = 16) in Group II with delayed sacral wound healing being the predominant problem. Stenosis of the ureter occurred in two patients (Group II). Late or persistent therapy-related complications were seen in two patients in Group I and in six patients in Group II. Local recurrence developed in three patients in Group I (15.8 percent) and in two patients in Group II (10.5 percent). Survival data do not reach statistical significance between the two groups because of small numbers but show a favorable trend for the preoperative radiochemotherapy group. When compared with a matched historical control group of patients receiving resection only, adjuvant/neoadjuvant radiotherapy with resection/IORT improves survival significantly. CONCLUSION: The flab method is a simple but especially practical technique for IORT in the pelvis. Adjuvant/neoadjuvant therapy combined with resection/IORT is associated with high morbidity but acceptable mortality. Preliminary survival data are encouraging and call for a controlled prospective randomized trial.

Antimetabolites, Antineoplastic↗
PubMed2005

Mechanism of antitumor activity of bone marrow natural suppressor cells.

Co-culturing of P-815 tumor cell strain and intact mouse bone marrow cells nonadherent to plastic resulted in the appearance of soluble mediators with antitumor activity. Bone marrow cells start releasing these antiproliferative factors only after signal exchange with the target tumor cells. The cell-cell contact is an important factor for the induction of antitumor activity. Antitumor activity of bone marrow cells (similarly as immunosuppressive activity) is realized through suppressor factors; the appearance of these factors is induced by target tumor cells.

Animals↗
PubMed2004

Regulated transcripts in the hippocampus following transections of the entorhinal afferents.

Based on the data from a cDNA microarray experiment which was carried out to screen the differential expressed genes in the rat hippocampus 10 days after removal of the entorhinal afferents, we confirmed the increase of expression of eight transcripts encoding protein osteonectin, thymosin-beta4, gelsolin, MHC I, MHC II, beta2-microglobulin, and interferon-gamma receptor using Northern blot. In situ hybridization revealed that the up-regulation of all these 8 transcripts localized specifically in the denervated target areas, the hippocampal stratum lacunosum-moleculare, and the dentate outer molecular layer. The results suggest that these molecules may have roles in the plasticity events in the hippocampus after entorhinal deafferentation.

Adaptation, Physiological↗
PubMed2005

Common molecular pathways mediate long-term potentiation of synaptic excitation and slow synaptic inhibition.

Synaptic plasticity, the cellular correlate for learning and memory, involves signaling cascades in the dendritic spine. Extensive studies have shown that long-term potentiation (LTP) of the excitatory postsynaptic current (EPSC) through glutamate receptors is induced by activation of N-methyl-D-asparate receptor (NMDA-R)--the coincidence detector--and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Here we report that the same signaling pathway in the postsynaptic CA1 pyramidal neuron also causes LTP of the slow inhibitory postsynaptic current (sIPSC) mediated by metabotropic GABA(B) receptors (GABA(B)-Rs) and G protein-activated inwardly rectifying K(+) (GIRK) channels, both residing in dendritic spines as well as shafts. Indicative of intriguing differences in the regulatory mechanisms for excitatory and inhibitory synaptic plasticity, LTP of sIPSC but not EPSC was abolished in mice lacking Nova-2, a neuronal-specific RNA binding protein that is an autoimmune target in paraneoplastic opsoclonus myoclonus ataxia (POMA) patients with latent cancer, reduced inhibitory control of movements, and dementia.

Animals↗