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Stem cell self-renewal implies proliferation under continued maintenance of multipotency. Small changes in numbers of stem cells may lead to large differences in differentiated cell numbers, resulting in significant physiological... more
Stem cell self-renewal implies proliferation under continued maintenance of multipotency. Small changes in numbers of stem cells may lead to large differences in differentiated cell numbers, resulting in significant physiological consequences. Proliferation is typically regulated in the G1 phase, which is associated with differentiation and cell cycle arrest 1 . However, embryonic stem (ES) cells may lack a G1 checkpoint 2,3 . Regulation of proliferation in the ‘DNA damage’ S/G2 cell cycle checkpoint pathway is known for its role in the maintenance of chromatin structural integrity 4 . Here we show that autocrine/paracrine c-aminobutyric acid (GABA) signalling by means of GABAA receptors negatively controls ES cell and peripheral neural crest stem (NCS) cell proliferation, preimplantation embryonic growth and proliferation in the boundary-cap stem cell niche, resulting in an attenuation of neuronal progenies from this stem cell niche. Activation of GABAA receptors leads to hyperpola...
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Fast Adapting Mechanoreceptors are Important for Force Control in Precision Grip but not 1 for Sensorimotor Memory 2 3 4 Susanna B. Park1,3, Marco Davare1, Marika Falla1,4, William R. Kennedy2, Mona M. Selim2, 5 Gwen Wendelschafer-Crabb2,... more
Fast Adapting Mechanoreceptors are Important for Force Control in Precision Grip but not 1 for Sensorimotor Memory 2 3 4 Susanna B. Park1,3, Marco Davare1, Marika Falla1,4, William R. Kennedy2, Mona M. Selim2, 5 Gwen Wendelschafer-Crabb2, Martin Koltzenburg1 6 1 Institute of Neurology, University College London, London, United Kingdom; 2 Department 7 of Neurology, University of Minnesota, Minneapolis, Minnesota, United States of America; 3 8 Brain and Mind Centre, University of Sydney, Sydney, Australia; 4 Department of Neurology 9 and Psychiatry, Sapienza University, Rome, Italy 10 11 Correspondence to: 12 Professor Martin Koltzenburg 13 UCL Institute of Neurology 14 Queen Square London WC1N 3BG 15 Phone: +44 20 7905 2701 16 E-mail: [email protected] 17 18 19 Running title: Fast adapting mechanoreceptors in precision grip 20
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Research Interests: Chronic Pain and Medicine
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Koltzenburg, Martin and Gary R. Lewin. Receptive properties of embryonic chick sensory neurons innervating skin. J. Neurophysiol. 78: 2560–2568, 1997. We describe a new in vitro skin-nerve preparation from chick embryos that allows... more
Koltzenburg, Martin and Gary R. Lewin. Receptive properties of embryonic chick sensory neurons innervating skin. J. Neurophysiol. 78: 2560–2568, 1997. We describe a new in vitro skin-nerve preparation from chick embryos that allows detailed study of the functional properties of developing sensory neurons innervating skin. Functionally single sensory afferents were isolated by recording from their axons in microdissected filaments of the cutaneous femoralis medialis nerve, which innervates skin of the thigh. A total of 157 single neurons were characterized from embryos [embryonic days 17–21 ( E17–E21), n = 115] and hatchlings up to 3 wk old ( n = 42). Neurons were initially classified on the basis of their conduction velocity; those conducting below 1.0 m/s were being classified as C fibers and faster conducting fibers as A fibers. The proportions of A and C fibers encountered in embryonic and hatchling preparations were not very different, indicating that myelination and axon growth...
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Mice that overexpress nerve growth factor (NGF-OE) in the skin have double the normal number of cutaneous sensory neurons, have increased innervation of the skin and spinal cord, and are hyperalgesic. Here, we have asked whether the... more
Mice that overexpress nerve growth factor (NGF-OE) in the skin have double the normal number of cutaneous sensory neurons, have increased innervation of the skin and spinal cord, and are hyperalgesic. Here, we have asked whether the increased cutaneous NGF level results in a selective survival of only certain functional types of neurons and whether it changes the properties of cutaneous neurons. Using electron microscopy, we show that the number of both myelinated and unmyelinated nociceptors increases substantially in NGF-OE mice by a factor of 3.3 and 1.5, respectively. Using extracellular recordings from single units, we demonstrate that large myelinated (Aβ) fibers are unchanged in prevalence and receptive properties. In contrast, among thin myelinated (Aδ) fibers, the percentage of nociceptors increased from a normal 65 to 97%, consistent with a selective survival of nociceptors during embryogenesis. These afferents showed a twofold increase in their mechanical responsiveness, ...
Research Interests: Neuroscience, Chemistry, Electron Microscopy, Medicine, Mice, and 15 moreAnimals, Sensory Neuron, Programmed cell death, Functional Type, Nociception, Nerve Growth Factor, Axons, Nociceptors, Keratins, Functional Properties, Psychology and Cognitive Sciences, extracellular recording, Medical and Health Sciences, In Vitro Techniques, and Nerve fibers
Mice with a targeted deletion of the low-affinity neurotrophin receptor p75 (p75−/−) exhibit a 50% loss of large- and small-diameter sensory neurons in the dorsal root ganglion. Using neurophysiological recording techniques, we now show... more
Mice with a targeted deletion of the low-affinity neurotrophin receptor p75 (p75−/−) exhibit a 50% loss of large- and small-diameter sensory neurons in the dorsal root ganglion. Using neurophysiological recording techniques, we now show that p75 is not required for the survival of specific, functionally defined subpopulations of sensory neurons. Rather, p75−/− mice exhibit losses of neurons that subserve nociceptive as well as non-nociceptive functions. The receptive properties of large myelinated afferent fibers were normal in p75−/− mice. However, the receptive properties of subpopulations of afferent fibers with thin myelinated or unmyelinated axons were strikingly impaired in mice lacking p75. Furthermore, the presence of p75 is required for normal mechanotransduction in C fibers and D-hair receptors and normal heat sensitivity in A-fiber nociceptors.
Research Interests: Neuroscience, Chemistry, Electrophysiology, Apoptosis, Medicine, and 15 moreMutagenesis, Mice, Female, Animals, Male, Mechanoreceptors, Nociception, Receptor, Cell Survival, Nociceptors, Neuroprotective Agents, Psychology and Cognitive Sciences, Medical and Health Sciences, Electric stimulation, and Cold Temperature
1. The present study has investigated the receptive properties of myelinated mechanoreceptive primary afferents innervating the inflamed urinary bladder of the cat. In 15 experiments, 20 units were recorded from the dorsal and 3 from the... more
1. The present study has investigated the receptive properties of myelinated mechanoreceptive primary afferents innervating the inflamed urinary bladder of the cat. In 15 experiments, 20 units were recorded from the dorsal and 3 from the ventral root S2. Before inflammation the afferents had no resting activity and responded consistently to increases of intravesical pressure evoked by isotonic distension or isovolumetric contractions. All units were studied before and after the onset of an acute inflammation induced by intraluminal injection of mustard (1-2.5%) or turpentine oil (50%), which are known to induce an acute cystitis. 2. Eleven out of 14 units tested with mustard oil and 5/9 units tested with turpentine oil were activated at short latency. The response could not be explained by a concomitant increase of intraluminal pressure resulting from the intravesical injection of the irritant. This suggests that a large proportion of mechanosensitive afferents has an additional che...
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1. The purpose of the present study was to compare the responsiveness unmyelinated cutaneous units in vivo and in vitro and to determine the proportion of primary afferents innervating the rat hairy skin that do not respond to transient... more
1. The purpose of the present study was to compare the responsiveness unmyelinated cutaneous units in vivo and in vitro and to determine the proportion of primary afferents innervating the rat hairy skin that do not respond to transient mechanical or thermal stimuli. We have adopted electrical search strategies to locate the terminal arborization of unmyelinated fibers before testing the sensitivity to adequate stimuli. 2. A total of 144 unmyelinated units were studied, of which 31 were obtained from in vivo and 113 from in vitro experiments. 55 afferents were investigated after chronic surgical sympathectomy. Units recorded from sympathectomized rats did not differ in their conduction velocity, electrical thresholds, or receptive properties from units in intact animals. 3. There were only minor differences between the properties of units recorded in vivo and in vitro. This probably reflects technical differences of the setups rather than biological changes introduced by the in vitr...
Research Interests: Chemistry, Electrophysiology, Neurophysiology, Medicine, In Vitro, and 15 moreAnimals, Mechanoreceptors, Skin, In Vivo, Rats, Rat, Nociception, Stimulation, Nerve Endings, sympathectomy, Psychology and Cognitive Sciences, Medical and Health Sciences, Electric stimulation, Nerve fibers, and Cold Temperature
1. Conscious perception of noxious and innocuous distension of the colon as well as the reflex control of anal continence and defecation largely depend on an intact sacral primary afferent innervation. Here we have studied the functional... more
1. Conscious perception of noxious and innocuous distension of the colon as well as the reflex control of anal continence and defecation largely depend on an intact sacral primary afferent innervation. Here we have studied the functional properties of these visceral primary afferent neurons in the dorsal root S2 in 17 cats. Single fibers projecting into the pelvic nerve were identified electrically and studied with innocuous and noxious mechanical stimulation of colon and anal canal. 2. A total of 59 units responding to one of these stimuli were investigated and they could be separated into two subpopulations of afferents. Thirty-six fibers were reproducibly excited by distension of the colon, but not by mechanical stimulation of the anal canal. They were thin myelinated or unmyelinated fibers with a median conduction velocity of 3.2 m/s. The remaining 23 units had receptive fields in the mucosa of the anal canal and responded readily to an innocuous proximodistal shearing stimulus,...
Research Interests: Neurophysiology, Medicine, Cats, Anatomy, Intestinal Mucosa, and 15 moreFemale, Animals, Male, Anesthesia, Receptive Field, Reflex, Colon, Nerve Conduction Velocity, Urinary Bladder, Myelin Sheath, Psychology and Cognitive Sciences, Anal Canal, Medical and Health Sciences, Electric stimulation, and Distension
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Mice lacking the major Schwann cell myelin component P0 show a severe dysmyelination with pathological features reminiscent of the Déjérine-Sottas syndrome in humans. Previous morphological and electrophysiological studies on these mice... more
Mice lacking the major Schwann cell myelin component P0 show a severe dysmyelination with pathological features reminiscent of the Déjérine-Sottas syndrome in humans. Previous morphological and electrophysiological studies on these mice did not only demonstrate a compromised myelination and myelin maintenance, but were suggestive of an impairment of axons as well. Here, we studied the axonal pathology in P0-deficient mice by quantitative electron microscopy. In addition, we investigated epidermal receptor end organs by immunocytochemistry and muscle pathology by histochemistry.In proximal sections of facial and femoral nerves, axon calibers were significantly reduced, whereas the number of myelin-competent axons was not diminished in 5- and 17-month-old P0-deficient mice. However, in distal branches of the femoral and sciatic nerve (digital nerves innervating the skin of the first toe) the numbers of myelin-competent axons were reduced by 70% in 6-month-old P0-deficient mice. Immuno...
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We investigated the ability of human nociceptive primary afferent neurons to encode mechanical pain and to produce vasodilatation. Pain was induced by shooting a light metal cylinder (0.3 g) at different velocities (6–18 m/sec)... more
We investigated the ability of human nociceptive primary afferent neurons to encode mechanical pain and to produce vasodilatation. Pain was induced by shooting a light metal cylinder (0.3 g) at different velocities (6–18 m/sec) perpendicularly against the hairy skin of the hand. When single impact stimuli were applied, monotonically increasing stimulus-response functions were obtained in 10 psychophysical experiments using magnitude estimation techniques. In 35 microneurographic experiments nine unmyelinated afferents were recorded from the superficial radial nerve. All units responded readily to impact stimulation even at stimulus intensities that were not rated as painful. However, there was a close linear correlation between the number of action potentials evoked from the nociceptors and the psychophysical magnitude estimates of the perceived sensation or the stimulus intensity. This was also reflected by a corresponding increase of neurogenic vasodilatation. While two thin myeli...
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Koltzenburg, Martin, Cheryl L. Stucky, and Gary R. Lewin. Receptive properties of mouse sensory neurons innervating hairy skin. J. Neurophysiol. 78: 1841–1850, 1997. Using an in vitro nerve skin preparation and controlled mechanical or... more
Koltzenburg, Martin, Cheryl L. Stucky, and Gary R. Lewin. Receptive properties of mouse sensory neurons innervating hairy skin. J. Neurophysiol. 78: 1841–1850, 1997. Using an in vitro nerve skin preparation and controlled mechanical or thermal stimuli, we analyzed the receptive properties of 277 mechanosensitive single primary afferents with myelinated ( n = 251) or unmyelinated ( n = 26) axons innervating the hairy skin in adult or 2-wk-old mice. Afferents were recorded from small filaments of either sural or saphenous nerves in an outbred mice strain or in the inbred Balb/c strain. On the basis of their receptive properties and conduction velocity, several receptor types could be distinguished. In adult animals (>6 wk old), 54% of the large myelinated fibers (Aβ, n = 83) showed rapidly adapting (RA) discharges to constant force stimuli and probably innervated hair follicles, whereas 46% displayed a slowly adapting (SA) response and probably innervated Merkel cells in touch dome...
Research Interests: Neuroscience, Biology, Neurophysiology, Medicine, Mice, and 14 moreFemale, Animals, Male, Mechanoreceptors, Sensory Neuron, Receptive Field, Nociception, Nociceptors, Mechanosensitive Channels, Psychology and Cognitive Sciences, Somatosensory system, Medical and Health Sciences, In Vitro Techniques, and Nerve fibers
Sympathetic postganglionic neurons were allowed to reinnervate the hairless skin of the cat paw pad, normally supplied by the tibial nerve, after suturing the central stump of the superficial peroneal nerve (supplying both hairy and... more
Sympathetic postganglionic neurons were allowed to reinnervate the hairless skin of the cat paw pad, normally supplied by the tibial nerve, after suturing the central stump of the superficial peroneal nerve (supplying both hairy and hairless skin, eight animals) or of the sural nerve (supplying only hairy skin, seven animals) to the distal stump of the tibial nerve. Neural activation of sweat glands was studied by the starch iodine method and by recording the skin potential from the skin surface. Postganglionic neurons were activated by electrical stimulation of peripheral nerves or reflexly. There was good functional reinnervation of sweat glands by sudomotor neurons in all animals. The superficial peroneal nerve contains a few fibers that normally supply < 20% of the sweat glands on the foot pads. When this nerve regenerated into the innervation territory of the tibial nerve, sudomotor fibers consistently made functional contacts with sweat glands on the pads in all animals. These functional contacts were always weaker than those in the controls. Electrical stimulation of the sural nerve does not activate sweat glands in the paw pads of normal animals, indicating that this nerve does not contain postganglionic sudomotor axons. When the sural nerve regenerated into the foot pads, electrical stimulation activated some sweat glands in five of seven animals. We conclude that sudomotor neurons have a high capacity to functionally reinnervate sweat glands in the adult cat. There was also evidence that some noradrenergic vasoconstrictor neurons might take on "cholinergic features' in the adult animal when they reinnervate sweat glands suggesting that the peripheral target can specify the phenotypic properties of postganglionic neurons in the adult animal.
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Brain-derived neurotrophic factor (BDNF) is a survival factor for certain sensory neurons during development. Using electrophysiology in BDNF-deficient mice, we show here that slowly adapting mechanoreceptors (SAM), but not other types of... more
Brain-derived neurotrophic factor (BDNF) is a survival factor for certain sensory neurons during development. Using electrophysiology in BDNF-deficient mice, we show here that slowly adapting mechanoreceptors (SAM), but not other types of cutaneous afferents, require BDNF in postnatal life for normal mechanotransduction. Neurons lacking BDNF did not die, but instead showed a profound and specific reduction in their mechanical sensitivity, which was quantitatively the same in BDNF -/- and BDNF +/- animals. Postnatal treatment of BDNF +/- mice with recombinant BDNF completely rescued the mechanosensitivity deficit. Therefore BDNF is important for regulating SAM mechanosensitivity, independent of any survival-promoting function.
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1. The ventral roots of the spinal cord contain a large number of unmyelinated primary afferent neurones. There is some controversy, however, about the function of these fibres and the route of their central projection. Here we have used... more
1. The ventral roots of the spinal cord contain a large number of unmyelinated primary afferent neurones. There is some controversy, however, about the function of these fibres and the route of their central projection. Here we have used electrophysiological techniques to quantify the central projection patterns of these neurones in the segment S2 of adult chloralose‐anaesthesized cats. 2. A total of 1185 single unmyelinated units were recorded in small filaments isolated from intact and de‐efferented ventral roots or intact dorsal roots of the segment S2 in nineteen cats. The projection patterns of these neurones were tested using supramaximal electrical stimulation of the pelvic and pudendal nerve (the main tributaries of the spinal nerve of this segment) and of the segmental companion root (dorsal or ventral as appropriate). 3. The principal finding of this study is that 85% of unmyelinated afferent axons in the ventral root are direct and exclusive projections. They constitute a...
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Research Interests: Psychology and Medicine
Research Interests: Psychology, Histology, Medicine, Anatomy, Electromyography, and 3 moreDenervation, Lesion, and Sciatic Nerve
elbow-4cm proximal to the elbow segment (AE6-AE4) in 9 arms (9.8%), 2cm distal to the elbow-4cm distal to the elbow segment (BE2-BE4)in 8 arms (8.6%) and 4cm distal to the elbow-6cm distal to the elbow segment (BE4-BE6) in 6 arms (6.5%)... more
elbow-4cm proximal to the elbow segment (AE6-AE4) in 9 arms (9.8%), 2cm distal to the elbow-4cm distal to the elbow segment (BE2-BE4)in 8 arms (8.6%) and 4cm distal to the elbow-6cm distal to the elbow segment (BE4-BE6) in 6 arms (6.5%) respectively. Conclusion: The SSCSs are more sensitive significantly in detecting CubTS than the conventional long segmental motor conduction studies. It could localize the entrapment leisions precisely in the patients with CubTS. It is a useful tool for the detection of ulnar mononeuropathy at the elbow, especially in diagnosing the patients with CubTS who have no clinical features or a normal long segmental nerve conduction findings.
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Viscero-sympathetic reflex responses to mechanical stimulation of urinary bladder and colon were studied in cutaneous vasoconstrictor (CVC) neurones supplying hairy skin, in muscle vasoconstrictor (MVC) neurones supplying skeletal muscle... more
Viscero-sympathetic reflex responses to mechanical stimulation of urinary bladder and colon were studied in cutaneous vasoconstrictor (CVC) neurones supplying hairy skin, in muscle vasoconstrictor (MVC) neurones supplying skeletal muscle and in sudomotor (SM) neurones supplying the sweat glands of the central paw pad of the cat hindlimb. The cats were anaesthetized, paralysed and artificially ventilated. The vasoconstrictor activity was recorded from the axons of the postganglionic fibres that were isolated in filaments from the respective peripheral hindlimb nerves. The activity in the sudomotor neurones was monitored by recording the fast skin potential changes occurring on the surface of the central paw pad. Afferents from the urinary bladder and from the colon were stimulated by isotonic distension and isovolumetric contraction of the organs. Most CVC neurones with ongoing activity were inhibited by these stimuli; only a few CVC neurones were excited. The MVC and SM neurones were generally excited by the visceral stimuli, yet the size of the evoked skin potential changes was variable. The reflex responses elicited in the sympathetic outflow to the cat hindlimb by stimulation of visceral afferents from the pelvic organs are uniform with respect to the different types of afferent input system but differentiated with respect to the efferent output systems. Graded stimulation of the visceral afferents from the urinary bladder by isotonic pressure steps elicited graded reflex responses in CVC (threshold less than 30 mmHg) and MVC neurones (threshold less than 20 mmHg) and a graded increase of the arterial blood pressure (threshold less than 20 mmHg). These graded reflex responses are closely related to the quantitative activation of sacral afferent neurones with thin myelinated axons innervating the urinary bladder that are also responsible for eliciting the micturition reflex, but not to the quantitative activation of sacral afferent neurones with unmyelinated axons. The latter have thresholds of 40-50 mmHg intravesical pressure at which the size of the vesico-sympathetic reflexes in the vasoconstrictor neurones was about 50% of maximal size. This does not exclude the fact that activation of unmyelinated vesical afferents contributes to the vesico-sympathetic reflexes.
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The location of a sensory cortex for temperature perception remains a topic of substantial debate. Both the parietal–opercular (SII) and posterior insula have been consistently implicated in thermosensory processing, but neither region... more
The location of a sensory cortex for temperature perception remains a topic of substantial debate. Both the parietal–opercular (SII) and posterior insula have been consistently implicated in thermosensory processing, but neither region has yet been identified as the locus of fine temperature discrimination. Using a perceptual learning paradigm in male and female humans, we show improvement in discrimination accuracy for subdegree changes in both warmth and cool detection over 5 d of repetitive training. We found that increases in discriminative accuracy were specific to the temperature (cold or warm) being trained. Using structural imaging to look for plastic changes associated with perceptual learning, we identified symmetrical increases in gray matter volume in the SII cortex. Furthermore, we observed distinct, adjacent regions for cold and warm discrimination, with cold discrimination having a more anterior locus than warm. The results suggest that thermosensory discrimination is...
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Sensory feedback from cutaneous mechanoreceptors in the fingertips is important in effective object manipulation, allowing appropriate scaling of grip and load forces during precision grip. However, the role of mechanoreceptor subtypes in... more
Sensory feedback from cutaneous mechanoreceptors in the fingertips is important in effective object manipulation, allowing appropriate scaling of grip and load forces during precision grip. However, the role of mechanoreceptor subtypes in these tasks remains incompletely understood. To address this issue, psychophysical tasks that may specifically assess function of type I fast-adapting (FAI) and slowly adapting (SAI) mechanoreceptors were used with object manipulation experiments to examine the regulation of grip force control in an experimental model of graded reduction in tactile sensitivity (healthy volunteers wearing 2 layers of latex gloves). With gloves, tactile sensitivity decreased significantly from 1.9 ± 0.4 to 12.3 ± 2.2 μm in the Bumps task assessing function of FAI afferents but not in a grating orientation task assessing SAI afferents (1.6 ± 0.1 to 1.8 ± 0.2 mm). Six axis force/torque sensors measured peak grip (PGF) and load (PLF) forces generated by the fingertips d...
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Research Interests: Medicine and Denervation
Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in... more
Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifyin...
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1. We examined the functional properties of unmyelinated primary afferent neurones innervating the pelvic viscera in twenty‐five anaesthetized cats. The axons were isolated from the intact dorsal root and the intact or chronically... more
1. We examined the functional properties of unmyelinated primary afferent neurones innervating the pelvic viscera in twenty‐five anaesthetized cats. The axons were isolated from the intact dorsal root and the intact or chronically de‐efferented ventral root of the segment S2. All units were electrically identified with electrical stimulation of the pelvic nerve. 2. The responses of the neurones were studied with natural stimulation of the urinary bladder using innocuous and noxious increases of intravesical pressure and at the onset of an acute artificial inflammation induced by intraluminal injection of mustard or turpentine oil. 3. Out of 297 unmyelinated afferent units isolated from the dorsal root, seven were excited by an increase of the intravesical pressure during contractions and distension of the urinary bladder. These units were silent when the bladder was empty and had thresholds of 30‐50 mmHg which are presumed to be noxious. Further increases of the intravesical pressur...
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1. The present study has investigated the reflex organization of sympathetic neurones and its control of autonomic effector organs following nerve injury and repair. A well‐defined population of vasoconstrictor neurones supplying blood... more
1. The present study has investigated the reflex organization of sympathetic neurones and its control of autonomic effector organs following nerve injury and repair. A well‐defined population of vasoconstrictor neurones supplying blood vessels of the hairy skin was forced to innervate a territory that contained some appropriate, but mainly inappropriate autonomic effector organs. For this purpose the central stump of the cut sural nerve was sutured to the peripheral stump of the cut tibial nerve 11‐12 months prior to the terminal experiment. 2. The activity of postganglionic sympathetic neurones was recorded from fine strands of the sural nerve proximal to the nerve lesion. Using a laser‐Doppler device cutaneous blood flow was measured in the hairless skin of the hindpaw that was now reinnervated by the sural nerve. The results show a qualitative change of the reflex organization of sympathetic neurones following cross‐union of these nerves. 3. Stimulation of arterial chemoreceptors...
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The neurophysiological basis of visceral sensations in general and pain in particular have been mainly studied with short-lasting stimuli that simulate the acute events of visceral organ function. Pelvic viscera are supplied by spinal... more
The neurophysiological basis of visceral sensations in general and pain in particular have been mainly studied with short-lasting stimuli that simulate the acute events of visceral organ function. Pelvic viscera are supplied by spinal afferents which are involved in the coordinated reflex regulation of continence and evacuation of bowel and bladder and are capable of signalling impending or frank tissue damage. Typically, each afferent neuron innervates one viscus only. The organ-specific subtypes are functionally homogenous and encode by their discharge frequency the information for organ regulation, non-painful and painful sensations. Thus, pain elicited from these organs under physiological conditions is probably not elicited by a specific set of nociceptive visceral afferents. While the use of brief stimuli has yielded invaluable neurophysiological information for normal, healthy viscera, it has fallen somewhat short of providing information about the neuronal basis of chronic visceral pain states. Using pathological models such as experimental inflammation of the urinary bladder and ischaemia of the colon we have shown that the receptor properties of most afferents change dramatically. Of particular interest is the discovery of a novel type of visceral receptor which is not excited by extreme noxious mechanical stimuli applied to the healthy tissue but which is vigorously activated at the onset of an inflammation. This means that the number of functionally active primary afferents is not immutable, but critically depends on the state of the tissue. This new principle of plasticity in the peripheral nervous system bears some considerable importance for the understanding of the genesis of chronic visceral pain states.(ABSTRACT TRUNCATED AT 250 WORDS)
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Clinicamente, la mayoria de las enfermedades que afectan al sistema nervioso periferico no causan dolor cronico sino, mas bien, sintomas y signos neurologicos negativos. Las enfermedades que lesionan el sistema nervioso, paradojicamente... more
Clinicamente, la mayoria de las enfermedades que afectan al sistema nervioso periferico no causan dolor cronico sino, mas bien, sintomas y signos neurologicos negativos. Las enfermedades que lesionan el sistema nervioso, paradojicamente no cursan con dolor, puesto que la alteracion de las fibras nerviosas que transportan la informacion nociceptiva del sistema nervioso central o periferico hace que se disminuya la sensibilidad al dolor. Las neuropatias sensitivas son un grupo heterogeneo de enfermedades que suelen presentarse de forma independiente al estimulo, con dolor continuo e hiperalgesia tras estimulos. Como en muchos otros dolores cronicos, existe una comorbilidad importante, como alteracion del sueno, depresion y ansiedad. El dolor neuropatico no es una enfermedad en sentido estricto sino el sintoma de una patologia subyacente, y eso hace que deba diagnosticarse tras una cuidadosa exploracion neurologica y las pruebas diagnosticas apropiadas. Los resultados de los estudios realizados con pacientes afectados de neuropatias sensitivas cronicas coinciden en senalar la importancia de las alteraciones en el fenotipo de las aferencias nociceptivas primarias. La clasificacion actual divide las neuropatias sensitivas en: polineuropatias simetricas y mononeuropatias u oligoneuropatias asimetricas.
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Page 127. Chapter 5 Mechanisms of peripheral neuropathic pain Martin Koltzenburg 5.1 Introduction It is common clinical experience that most lesions of the peripheral PNS or central nervous system do not produce chronic pain. ...
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Sympathetic reflex responses were elicited in human volunteers by sustained selective excitation of nociceptors by noxious chemicals, namely topical application of mustard oil which elicited burning pain, or histamine which induced... more
Sympathetic reflex responses were elicited in human volunteers by sustained selective excitation of nociceptors by noxious chemicals, namely topical application of mustard oil which elicited burning pain, or histamine which induced itching in a skin area of 5 cm2 on the volar aspect of one forearm. Stimulus-related sympathetic reflex responses were studied by means of computer-assisted infrared thermography of the palmar aspects of both hands. Nociceptive stimulation induced a decrease of skin surface temperature in both hands interpreted as vasoconstriction. The magnitude of the reflex cooling was correlated with the magnitude of the sensation (r = 0.49), but independent of the quality of sensation (itch or pain). The temperature reduction was maintained for more than 30 min and its time-course matched the time-courses of pain or itch sensations. It is concluded that the sustained and selective excitation of nociceptors elicits a sustained sympathetic reflex response, which adapts very slowly. The time-course of the reflexes suggests that these are not arousal responses, but may be indicators of nociceptive processing in conscious humans. Contralateral temperature decreases were consistently smaller than ipsilateral ones. Thus, sustained nociceptive-specific vasoconstrictor reflexes may be somatotopically organised with an emphasis on areas close to the painful stimulus (homotopic), which has so far only been shown in animals. The study thus demonstrates for the first time in humans the presence of a sympathetic reflex asymmetry, which is specific for nociceptive afferent input.
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MR changes in denervated muscles have been reported to occur within days up to several weeks after peripheral nerve damage. The purpose of this experimental study was to investigate the longitudinal changes in denervated muscles by using... more
MR changes in denervated muscles have been reported to occur within days up to several weeks after peripheral nerve damage. The purpose of this experimental study was to investigate the longitudinal changes in denervated muscles by using MR imaging. In 12 Lewis rats, the left sciatic nerve was transected at the level of the proximal thigh. MR imaging of both legs was performed before and 1 hour, 24 hours, 48 hours, 7 days, 14 days, 28 days, and 2 months after the procedure. The MR protocol included T1-weighted spin-echo, T2-weighted double turbo spin-echo, and turbo inversion recovery magnitude (TIRM) sequences obtained in the axial plane. Signal intensities (T2-weighted double turbo spin-echo and TIRM sequences) and the T2 TR (T2-weighted double turbo spin-echo sequence) were recorded for the soleus, peroneal, and gracilis muscles of both sides. Moreover, the circumferences of both lower legs were determined on the basis of T1-weighted images. Twenty-four hours after denervation, a...
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RNA amplification is necessary for profiling gene expression from small tissue samples. Previous studies have shown that the T7 based amplification techniques are reproducible but may distort the true abundance of targets. However, the... more
RNA amplification is necessary for profiling gene expression from small tissue samples. Previous studies have shown that the T7 based amplification techniques are reproducible but may distort the true abundance of targets. However, the consequences of such distortions on the ability to detect biological variation in expression have not been explored sufficiently to define the true extent of usability and limitations of such amplification techniques. We show that expression ratios are occasionally distorted by amplification using the Affymetrix small sample protocol version 2 due to a disproportional shift in intensity across biological samples. This occurs when a shift in one sample cannot be reflected in the other sample because the intensity would lie outside the dynamic range of the scanner. Interestingly, such distortions most commonly result in smaller ratios with the consequence of reducing the statistical significance of the ratios. This becomes more critical for less pronoun...
Research Interests: RNA, Statistical Analysis, Biology, Medicine, Gene expression, and 15 moreLinear models, Biological Sciences, Mice, Animals, Spinal Cord, Male, Statistical Significance, Gene, Microarray Analysis, Reproducibility of Results, Bayes Theorem, Gene expression profiling, Dynamic Range, Statistics as Topic, and Medical and Health Sciences
Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we... more
Mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system in humans, described clinically as Charcot-Marie-Tooth type 2D or distal spinal muscular atrophy type V. Here, we characterise a new mouse mutant, Gars(C201R), with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however...