bluuebunny/crossref_metadata_2025 huggingface dataset:
Secondary Succession and Natural Habitat Restoration in Abandoned Rice Fields of Central Korea
Authors: Lee Chang‐Seok , You Young‐Han , Robinson George R.
Published: March 2003

Floristic composition and soil characteristics (moisture, pH, nutrient contents) in abandoned upland rice paddies of different ages were analyzed to clarify the regenerative aspects of succession as a tool for habitat restoration. The study sites represented five seral stages: newly abandoned paddy fields; successional paddy fields abandoned for 3, 7, and 10 years; and a 50‐year‐old Alnus japonica forest. A vegetation sere was apparent in changes of dominant plant species in the order Alopecurus aequalis var. amurensis (annual grass), Aneilema keisak (annual forb), Juncus effusus var. decipiens (rush), Salix koriyanagi (willow), and Alnus japonica (alder) communities. These temporal stages resemble the spatial zonation of vegetation in local riparian floodplain ecosystems, indicating a hydrosere, with soil moisture decreasing over time. Age distributions and life forms of the dominant plant species support a “tolerance” model of secondary succession, in which the established species persist into later successional stages. Persistence of earlier colonizers led to a net cumulative increase in species richness and a more even distribution of species cover with increasing field age. Between 10 and 50 years, vegetation stabilizes as an alder community. Soil moisture content decreased steadily with paddy field age after an initial rise immediately after their abandonment, whereas pools of organic matter, N, P, K, Ca, and Mg, increased with field age. The pace and direction of recovery of native vegetation and natural soil properties in these abandoned rice paddies resembled classic old field succession, a form of secondary succession that often serves as a template for guiding restoration efforts. Active intervention, in particular dismantling artificial levees, could accelerate the recovery process, but natural habitat recovery generally appears sufficiently robust to achieve “passive” restoration of this rare community without intervention.
Use of Shallow Basins to Restore Cutover Peatlands: Hydrology
Authors: Price Jonathan S. , Rochefort Line , Campeau Suzanne
Published: March 2003

Basins 20‐, 10‐, and 4‐m wide were excavated 15 to 20 cm into cutover peat fields near Lac Saint Jean, Québec, Canada to facilitate the establishment of Sphagnum mosses. Sphagnum diaspores (fragments) and straw mulch were spread over the excavated surfaces, a control peat field, and a mulch‐protected site without basins. Mean water tables in the 20‐, 10‐, and 4‐m wide basins and the mulch‐protected site were 27.2, 8.3, 11.4, and 9.7 cm higher, respectively, than in the control peat field in May to August 1996. Similar improvements were observed in 1997 (a drier summer). The higher water table was due to lowering of the peat surface with respect to the local water table, retention of meltwater and stormwater by the peripheral ridges formed during excavation, retention of water during drier periods by the groundwater mound beneath the ridges, and mulch. Soil moisture was always higher in the experimental basins than in the control peat field or in the mulch‐protected site, demonstrating the superior soil wetness characteristic of sites with basins and straw mulch. Water tension data signaled the absence of the capillary fringe (i.e., capillary drainage) near the surface for some finite period, thus possibly limiting water for best Sphagnum growth. At the experimental basins and mulch‐protected site, 100% of these periods lasted four or fewer days. In the control peat field, 20% of the periods when capillary drainage had occurred lasted more than four days, with one period of 17 days. The mulch protection alone provided considerable improvement in hydrological conditions compared with the control peat field, but the additional water retained in the experimental basins protected against Sphagnum desiccation and loss during more extreme dry periods.
Post reinnervation maturation of myelinated nerve fibers in the cat tibial nerve: chronic electrophysiological and morphometric studies
Authors: Fugleholm Kåre , Schmalbruch Henning , Krarup Christian
Published: March 2003

The extent to which the long‐term recovery of nerve fibers differs according to the cause of Wallerian degeneration is not clear, although outgrowth of axons is better after lesions with continuity of basal lamina of the Schwann cell tubes (nerve crush) compared with lesions with interruption of basal lamina (nerve section). Post‐reinnervation maturation of myelinated nerve fibers of the cat tibial nerve was followed in chronic electrophysiologic studies after crushing, sectioning, and section+freeze lesions, and compared with morphometric analysis of the same nerves. The amplitudes of the compound nerve action potentials (CNAPs) recovered to a much lesser extent after sectioning than after crushing the nerve. This difference could be related to a smaller number of large fibers, a greater degree of sprouting after sectioning than after crushing, or less synchronization of conduction in regenerated fibers. In comparison, the compound muscle action potentials (CMAPs) recovered to a greater extent than the CNAP after sectioning and section+freeze, though not to the same degree or as fast as after crushing. The difference between the recovery of the CNAP and the CMAP could be due to better regeneration of motor fibers, to differences in the size of motor units or to a better summation of motor unit action potentials. The maximal conduction velocities (CV) in mixed nerve and in motor fibers increased faster after crushing than after sectioning and section+freeze to 60%–70% of control values. The diameters of the largest myelinated fibers increased in all lesions to about 80% of controls. The relation between fiber diameter and CV was influenced by remodeling of myelin during maturation. Hence, long‐term functional recovery is influenced by the nature of the nerve lesion, and a smaller proportion of fibers recovered functionally after nerve section than after crush.
Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN‐ADM)
Authors: Müller Harald D. , Mugler Michael , Ramaekers Vincent T. , Schröder J. Michael
Published: March 2003

Abstract  Hereditary motor and sensory neuropathy (HMSN) with autosomal recessive inheritance represents a genetically heterogeneous group of disorders with variable clinical, pathologic and electrophysiologic manifestations. A new variant of autosomal recessive HMSN, clinically defined by sensorimotor polyneuropathy associated with deafness and mental retardation, has recently been described. We report on the first autopsy case with this type of HMSN: a girl of non‐consanguineous parents with a presumably autosomal recessive type of motor and sensory neuropathy clinically associated with deafness, mental retardation, and epilepsy. The autopsy showed complete absence of large myelinated fibers in peripheral motor and sensory nerves corresponding to a lack of large neurons in dorsal root ganglia and anterior horns of the spinal cord, moderate neurogenic muscle atrophy, and nearly complete absence of neurons in the dentate nucleus of the cerebellum. Molecular genetic analyses in our case revealed neither genetic alterations in the survival motor neuron gene nor in the PMP‐22 gene.
Signal Transduction By Stress‐Activated Map Kinases
Authors: Davis Rj
Published: March 2003

The JNK group of stress‐activated MAP kinases consists of ten protein kinases that phosphorylate the NH2‐terminal activation domain of c‐Jun on Ser‐63 and Ser‐73 causing increased transcriptional activity. JNK protein kinase activity is increased in response to treatment of cells with pro‐inflammatory cytokines or exposure to environmental stress. Activated JNK is phosphorylated on Thr and Tyr within the tripeptide motif Thr‐Pro‐Tyr located in kinase sub‐domain VIII. Mutational analysis demonstrates that JNK activation requires the phosphorylation of both Thr and Tyr within this motif. This phosphorylation is mediated by dual specificity protein kinases, including MKK4 and MKK7. The function of the JNK signaling pathway has been studied using a combination of biochemical and genetic approaches. Genetic analysis of JNK signaling in Drosophila demonstrates that the JNK signaling pathway is required for early embryonic morphogenesis. Similarly, disruption of the JNK signaling pathway in mice using homologous recombination demonstrates that JNK signaling is required for embryonic viability. In contrast, mice with genetically engineered selective defects in JNK signaling are viable, but exhibit changes in stress‐induced gene expression and apoptosis. These studies provide insight into the role of the JNK stress‐activated MAP kinase pathway in the cellular response to environmental stress, including radiation.
Sural Nerve Pathology In Asymptomatic Minimally Neuropathic Diabetic Patients
Authors: Malik Ra , Tesfaye S , Walker D , Newrick Pg , Bandhari R , Siddique I , Boulton Ajm , Ward Jd
Published: March 2003

12 diabetic patients aged 47.5 ± 9.4 yr., duration of diabetes (14.6 ± 10.3 yr.) and 15 control subjects were studied. In diabetic patients neuropathy symptom score =0, neuropathy deficit score = 4.5 + 0.7/30, vibration = 12.0 + 1.8 V, thermal perception (2.0 + 0.8°C), heart rate variation during deep breathing (17.8 + 2.3), 30:15 ratio (1.31 + 0.07) was normal. Baseline (n=12) and repeat neurophysiology (n=10) performed 8.7 + 0.6 years after sural nerve biopsy demonstrated normal values at baseline, with progression of neuropathy (peroneal motor nerve conduction velocity (ms−1) (42.3 + 2.9 v 39.4 +2.0), sural nerve conduction velocity (45.4 + 3.7 v 43.6 + 1.7). Myelinated fibre density, fibre and axonal area and g‐ratio were not significantly reduced. Teased fibre studies showed paranodal abnormalities (p < 0.001), segmental demyelination (P < 0.01) with remyelination (P < 0.01) without axonal degeneration. Unassociated Schwann cell profile density (p < 0.04) and axon density (P < 0.001) were increased and axon diameter was decreased (P < 0.007) with a shift of the size frequency distribution to the left (skewness‐ 0.89 v 0.64, P < 0.03) suggestive of unmyelinated axonal atrophy/regeneration. Endoneurial capillary basement membrane thickening (P < 0.006), endothelial cell hyperplasia (P < 0.004) and luminal narrowing (P < 0.007) occurred. Current measures of neuropathy are too insensitive to detect significant nerve fibre pathology. The presence of microangiopathy provides support for a microvascular basis of diabetic neuropathy.
Map Kinases p38 And JNK Constitute Retrograde Stress Signals In Diabetic Neuropathy?
Authors: Fernyhough P , J‐D Delcroix , Jude Eb , Boulton Ajm , Tomlinson Dr
Published: March 2003

Stress‐activated protein kinases (SAPKs—p38 MAPK and JNK) are activated by high glucose or experimental diabetes. They are also carried from the periphery to the soma by retrograde axonal transport in sensory neurones. This study examined SAPK activation in nerve from diabetic patients and retrograde transport of activated SAPKs in diabetic rats. Sural nerve specimens were obtained from diabetic and roughly matched non‐diabetic individuals at amputation. Proteins were extracted for western blotting and blots exposed to antibodies raised against activated (phosphorylated on Ser/Thr) or all forms of JNK or p38, plus their common substrate, the transcription factor, ATF2. Retrograde transported SAPKs were collected distal to a 6h sciatic nerve crush in control and 8 wk streptozotocin diabetic rats. These were exposed to antibodies as described for human tissues. In human tissues, phosphorylation of JNK, p38 and ATF2 was increased between 2‐ to 4‐fold compared to controls. In rats, retrograde transport of phospho‐p38 (arbitrary units ± SD) was massively increased in diabetic rats (60.8 ± 11.8 versus controls, 18.8 ± 1.9) as was transport of ATF2 (20.9 ± 3.8 versus controls, 6.7 ± 0.8). One of the isoforms of phospho—JNK‐p46—showed a modest increase in retrograde transport in diabetic rats (13.7 ± 0.9 versus 8.1 ± 0.4), though the other isoforms (p54 and p56) were unaffected. These observations indicate a powerful retrograde signal in sensory neurones of diabetic rats in the form of exaggerated phosphorylation, and hence activation, of the SAPKs and one of their substrates, the transcription factor ATF2. This signal comes from some influence on the peripheral projection of these neurones and is a viable candidate for an early transcription‐dependent change in neuronal phenotype—perhaps a forerunner of diabetic neuropathy.
The Molecular Mechanism Of The Organelle Transports In Neurons; Kinesin Superfamily Proteins (Kifs), Structure, Gene, And Function
Authors: Hirokawa N.
Published: March 2003

Many proteins are transported to their proper destination as membranous organelles or protein complexes after synthesis. Especially in highly polarized cells such as epithelial cells and neurons this transport is very important for the proper targeting of proteins to distinct parts of cells. Actually we visualized dynamics of membrane organelles carrying certain kinds of proteins in living cells using GFP technology. In order to understand the mechanism of this transport we identified 26 new members of microtubule based molecular motors, KIFs. Using multiple molecular cell biological and molecular genetical approaches we have characterized these new members. In this lecture I will focus on some of KIF members such as KIF1A, 1B, 3, C2 and 17. KIF1A is the fastest (1.5 μm/sec) anterograde monomeric motor for transport of precursor of synaptic vesicles and essential for neuronal function and survival while KIF1B is a unique monomeric anterograde motor (0.5 μm/sec) for transport of mitochondria. KIF3A and KIF3B, expressed ubiquitously, form a heterodimer associated with a protein, KAP3, and work as a new anterograde transporter for membranous organelles which are different from synaptic vesicle precursors and essential for neurite extension. KIFC2 is a neuron specific C‐terminal motor domain type KIF transporting multivesicular body‐like organelles to dendrites. Very recently we have identified new KIF17 which is expressed specifically in neurons and transport NMDA receptors in nerve dendrites. Thus, our studies revealed that transport of important functional molecules as various kinds of membrane organelles and protein complexes is accomplished very precisely by these new molecular motors.
Metabolic vs. Vascular Abnormalities In Diabetic Neuropathy
Authors: Greene D.
Published: March 2003

The DCCT clearly implicates hyperglycemia as an important contributory factor in the pathogenesis of diabetic polyneuropathy, a multifaceted set of clinical syndromes reflective of widespread damage to peripheral nerve fibers. The biochemical cascade stemming from hyperglycemia and responsible for this disorder remains controversial. Recently published clinical trials in diabetic neuropathy with aldose reductase inhibitors implicate the aldose reductase pathway as an important component in this process. Activation of the aldose reductase pathway by hyperglycemia produces secondary derangements in NAD(P)+:NAD(P)H ratios, depletion of alternative intracellular osmolytes such as taurine and myo‐inositol, and accelerated protein glycation. These biochemical alterations in turn can lead to the formation of reactive oxygen species (ROS), as can glucose‐related aldose‐reductase‐independent pathways such as auto‐oxidation and protein glycation. Aldose reductase‐dependent and aldose‐reductase‐independent ROS generation may directly damage end‐organ tissues or their vascular support, producing ischemia. Mitochondria are damaged by ROS, mitochondrial ROS generation is increased by imbalances in substrate and oxygen availability, and mitochondrial defense against ROS‐induced damage requires adequate energy supply. Hence metabolic oxidative stress from glucose and ischemic injury both target the mitochondria. Mitochondrial damage is an important initiator of programmed cell death, or apoptosis, through the release of mitochondrial cytochromes, and activation of caspase enzymes. This cascade of events, stemming from hyperglycemia, operating through aldose‐reductase‐dependent and aldose‐reductase‐independent generation of ROS, involving mitochondrial damage and impaired vascular support and tissue ischemia, and resulting in apoptosis, appears to play a potentially important role in the pathogenesis of chronic diabetic complications such as peripheral neuropathy.
Early Detection Of Autonomic Neuropathy In Diabetic Minipigs By Blood Pressure And Heart Rate Variability: Relationship With Changes In Vagus Nerve Morphometry
Authors: Mésangeau D , Laroche S , Laude D , Elghozi Jl , Malik Ra , Walker D , Siddique I , Tomlinson Dr
Published: March 2003

Early detection of cardiac autonomic neuropathy (CAN) is imperative for successful therapeutic intervention. The streptozotocin‐diabetic minipig is a suitable model to study cardiac function and determine the earliest markers of the condition. Blood Pressure (BP) and Heart Rate (HR) variability, analysed with spectral analysis and performed in control animals exhibited a mostly unique peak synchronized with respiration. The Respiratory Peak (RP) of HR was dramatically reduced by atropine, suggesting a vagal control of this oscillation. A pharmacological baroreflex curve was also constructed, and the gain of this curve was found significantly related (r = 0.70, p < 0.05) with the gain of the cross‐spectral analysis between SBP and HR. Diabetes significantly decreased BP at 3 and 6 months and increased HR at 6 months (77.4 ± 3.8 vs 66.6 ± 2.7 bpm). The RP of HR was significantly lowered at 3 months (3.2 ± 0.4 vs 5.6 ± 0.7 bpm) and was still decreased at 6 months (3.7 ± 0.5 vs 4.9 ± 0.7 bpm). The gain of the cross spectral analysis was also reduced at the early stage of the disease (1.1 ± 0.2 vs 1.6 ± 0.4 bpm/mmHg, p < 0.05). Morphometric analysis revealed abnormalities only in the proximal vagus nerve with a significant difference in the axon and fibre size frequency distribution between controls and diabetic animals (p = 0.05), due to a greater proportion of fibers with smaller axon sizes (<3 μm2) in diabetic minipigs. In conclusion this model exhibited CAN at an early stage of diabetes with an impairment of the baroreflex sensitivity associated with structural changes of proximal vagus nerve.
Activation Of Mitogen Activated Protein Kinases (Mapks) In Response To High Glucose In Primary Sensory Neurones
Authors: Purves T , Fernyhough P , Tomlinson Dr
Published: March 2003

In diabetes high glucose stresses cells as a prelude to complications. The MAPKs are serine‐threonine kinases, which are putative glucose stress transducers, comprising extracellular signal regulated kinases (ERKs), p38 and c‐Jun, n‐terminal kinases (JNKs). In 10 week streptozotocin‐induced diabetic rats JNK activation was increased when compared to age matched controls. This study aimed to determine the signaling pathways activated in response to high glucose in adult sensory neurones in vitro. Cultures of adult rat dorsal root ganglia (DRG) were treated with 10mM, 25mM and 50mM glucose for 16 hours. MAPK activation was examined in Western blots using antibodies raised against phosphorylated and non‐phosphorylated epitopes (results expressed as a ratio of phosphorylated to non‐phosphorylated kinase). Glucose caused a concentration‐dependent increase in phospho‐p38 with a 1.6 fold increase at 25mM (0.77 ± 1.04) and a 2.4 fold increase at 50mM (1.18 ± 1.44) when compared to 10mM (0.49 ± 0.60) glucose. Phosphorylation of the p56 JNK isoform increased 2.4 fold (4.37 ± 3.59) and the p46 isoform 2.2 fold (1.95 ± 1.35) at 50mM glucose when compared to 10mM (p56 1.80 ± 0.99, p46 0.88 ± 0.31). ERK phosphorylation remained unchanged in 3 different experiments. Immunocytochemistry located these changes to neurones, rather than the small percentage of non‐neurones that remain in culture. Transcription factor activation as a result of MAPK activation is being investigated using electrophoretic mobility shift assays. We conclude that the activation of MAPK pathways is involved in the response of neuronal cells to high glucose stress.
Impaired Motor Nerve Conduction Velocity (MNCV), Endoneurial Blood Flow (EBF), AND Acetylcholine‐Induced Vasodilation In Arterioles That Overlie The Sciatic Nerve In Diabetic Rats Is Prevented By Antioxidant Therapy
Authors: Yorek M , Coppey L , Davidson E , Dunlap J , Lund D.
Published: March 2003

Diabetes mellitus produces marked abnormalities in motor nerve conduction, but the mechanism is not clear. In the present study we hypothesized that in the streptozotocin‐induced diabetic rat impaired vasodilator function in arterioles that provide circulation to the sciatic nerve is associated with reduced EBF and that these defects precede slowing of MNCV, and thereby may contribute to nerve dysfunction. Three days after the induction of diabetes, EBF was reduced in the diabetic rat. After 1 week of diabetes, acetylcholine‐induced vasodilation was found to be impaired and was accompanied by an increase in the superoxide level in these arterioles. These changes preceded the slowing of MNCV. Treating diabetic rats weekly with hydroxyethyl starch‐conjugated deferoxamine (Biomedical Frontiers, MPLS, MN), an iron chelator and inhibitor of hydroxyl radical formation, partially prevented the formation of superoxide in these arterioles and reduced the diabetes‐induced deficits in MNCV, EBF and acetylcholine‐induced vasodilation. We conclude that the development of diabetic neuropathy in this rat model is due in part to the production of oxygen free radicals and impairment of vascular function.
Hypoxia Is Not A Cause Of Oxidative Stress In Diabetic Peripheral Nerve
Authors: Obrosova Ig , Van Huysen C , Fathallah L , Stevens Mj
Published: March 2003

Severe ischemia and hypoxia in the neural tissues are associated with free radical production. The purpose of our study was to explore the contribution of endoneurial hypoxia vs hyperglycemia to oxidative stress in early experimental diabetic neuropathy. This was achieved by evaluating α1‐adrenoceptor antagonist prazosin (5 mg/kg in the drinking water, for 3 wks from induction of diabetes), on diabetes‐induced changes in endoneurial vascular conductance (VC), biochemical markers of nerve hypoxia, lipid peroxidation and antioxidative defense. Diabetes‐induced decrease in VC as well as free NAD+/NADH ratios in mitochondrial cristae, matrix and cytosol, were completely (VC, free NAD+/NADH in mitochondrial matrix) or partially prevented by prazosin. Accumulation of lipid peroxidation products, depletion of GSH, ascorbate and taurine, increase in GSSG/GSH and DHAA/AA ratios were not affected by vasodilator therapy. Antioxidative defense enzyme activities were similar in control and diabetic rats treated with/without prazosin. Blood and nerve glucose concentrations were similarly elevated in prazosin‐treated and untreated diabetic rats. In conclusion, hyperglycemia, but not hypoxia, is a major cause of oxidative stress in diabetic peripheral nerve. Free radical production in PNS is dependent on the degree of hypoxia, and is not initiated by relatively mild hypoxia in early diabetes.
Early Detection Of Diminished Baroreflex Sensitivity In Diabetic Patients Without Evidence Of Cardiovascular Autonomic Neuropathy
Authors: Ziegler D , Laude D , Akila F , Elghozi J‐L
Published: March 2003

Diabetic cardiovascular autonomic neuropathy (CAN) carries an increased risk of mortality. Decreased baroreflex sensitivity (BRS) has been identified as a predictor of increased mortality following myocardial infarction. We evaluated spontaneous BRS in 39 healthy control subjects (C: age (mean ± SEM): 41.5 ± 1.9 years) and 116 diabetic patients (64% Type 1, 36% Type 2; age: 45.8 ± 1.4 years; diabetes duration: 16.9 ± 1.0 years; HbA1c: 9.2 ± 0.2%) using cross‐spectral analysis between systolic blood pressure and heart rate in the low‐frequency (LF) and high‐frequency (HF) bands as well as time domain (sequence) analysis in the supine and standing positions over 10 min. According to previously suggested definitions based on autonomic function tests (AFTs), 36 patients had definite CAN (CAN+: 3 of 7 indices abnormal), 13 had borderline CAN (CAN[+]: 2 of 7 indices abnormal), and 64 had no evidence of CAN (CAN−: 1 of 7 indices abnormal). Maximum gain in cross‐spectral LF band (standing) was significantly reduced in CAN− as compared with C (5.2 ± 0.4 vs. 7.2 ± 0.8 ms/mmHg, p < 0.05). Moreover, maximum gain in cross‐spectral HF band was significantly lower in CAN− than in C (supine: 12.0 ± 1.2 vs. 17.9 ± 2.5 ms/mmHg, p < 0.05; standing: 4.9 ± 0.5 vs. 8.7 ± 1.0 ms/mmHg, p < 0.05). The slope of the regression line between defined increases or reductions in systolic blood pressure and R‐R intervals was significantly reduced in CAN− compared to C (supine: 10.6 ± 0.7 vs. 14.2 ± 1.6 ms/mmHg, p < 0.05; standing: 5.6 ± 0.4 vs. 8.1 ± 0.7 ms/mmHg, p < 0.05). Similar differences were obtained when comparing the CAN− and CAN[+] groups, the latter showing significantly reduced BRS by both techniques (p < 0.05). In contrast, no such differences were noted when comparing the CAN[+] and CAN+ groups. In conclusion, reduced spontaneous baroreflex sensitivity is an early marker of autonomic dysfunction at a stage when autonomic function tests do not yet indicate the presence of CAN, while cases with borderline CAN show a degree of BRS abnormality that is comparable to the level seen in definite CAN. Prospective studies are needed to evaluate whether reduced BRS is a predictor of mortality in diabetic patients.
Improvement Of Peripheral Nerve Structure By 15‐Month Aldose Reductase Inhibition With Fidarestat In Stz‐Induced Diabetic Rats
Authors: Kato N , Mizuno K , Makino M , Suzuki T , Yagihashi S.
Published: March 2003

There has been no report documenting the effects of long‐term aldose reductase (AR) inhibition one year or more on peripheral neuropathy of streptozotocin‐induced diabetic rats (STZ‐rats). Fidarestat (SNK‐860) is a potent AR inhibitor that possesses the beneficial effects on the nerve dysfunction in early stage of diabetic rats (1). In the present study, we investigated the effects of 15 months of treatment with fidarestat on functional, morphological and metabolic abnormalities in the peripheral nerve of STZ‐rats. Fidarestat treatment inhibited the slowing of F‐wave conduction velocity and motor nerve conduction velocity by about 70% and normalized the slowing of sensory nerve conduction velocity. Morphometric analysis of myelinated fibers demonstrated that the frequencies of abnormal fibers such as paranodal demyelination, Wallerian degeneration and axonal sequestration were reduced to the extent of normal levels by fidarestat. Axonal atrophy, reduction of myelin sheath thickness and ratio of large fibers were also inhibited. The effects of fidarestat on functional and morphological changes were accompanied by correction of the increased sorbitol, fructose and decreased myo‐inositol in nerve. It was thus demonstrated that long‐term inhibition of increased polyol pathway flux by fidarestat was beneficial for the development of functional and structural neuropathy in STZ‐rats.

(1) Mizuno, K., et al. (1999). J. Diab. Comp., 13,141‐150.
Power Spectral Analysis Of Heart Rate In Uremic Autonomic Neuropathy: Relation To Age
Authors: Di Leo R , Savica V , Bellinghieri G , Vita G.
Published: March 2003

Background: Autonomic derangement occurs frequently in chronic uremics. It is consistent with a parasympathetic and sympathetic damage, with some clinical sequelae. Power Spectral Analysis (PSA) of heart rate variability in frequency domain is an effective way for evaluating the autonomic function in different pathological conditions. The aim of the study was the evaluation of PSA variation in relation to age in chronic uremics. Materials and methods: We studied 24 uremic patients on intermittent haemodialysis, aged 34–75 years (mean age ± SD; 54.5 ± 14), and 24 age‐matched controls by PSA. Low frequency band (LF) is considered a marker of sympathetic component, high frequency band (HF) of parasympathetic control and LF/HF ratio reflects the sympatho‐vagal balance. Both control and uremic subjects were divided into two subgroups according to age under or above 65 years. Results: A significant reduction of LF components in middle age and elderly uremics was found when compared to controls, indicating a sympathetic pattern involvement. There was also a significant difference between middle age and elderly uremics for LF band. Comparing the linear regression models (age vs each test), correlation coefficient was significantly different in standing LF values between controls and uremics, while slope and intercept were not. Comment: Preliminary results indicate that aging is not a significant variable in uremic patients affected by autonomic neuropathy.
Gonosomal Mosaicism Of A Novel Heterozygous Mutation Of P Causes Charcot‐Marie‐Tooth Neuropathy Type 1b With Apparent Autosomal Recessive Inheritance
Authors: Fabrizi GM , Ferrarini M , Cavallaro T , Taioli F , Polo A , Jarre L , Rizzuto N.
Published: March 2003

Charcot‐Marie‐Tooth neuropathy type 1 (CMT1) is the most common inherited demyelinating neuropathy. It has autosomal dominant inheritance associated with heterozygous mutations in the genes coding the peripheral myelin protein 22 (PMP22), the myelin protein zero (P0) and the early growth response 2 (EGR2) transcription factor. More severe, usually sporadic de‐hypomyelinating neuropathies of infancy are classified as Dejerine‐Sottas syndrome (DSS). Since the original description by Dejerine and Sottas of two affected siblings born of unaffected parents, DSS has long been considered to be autosomal recessive, but it is now known that DSS is also caused by heterozygous mutations that originate de novo in the forementioned genes. True autosomal recessive, usually severe, demyelinating neuropathies are rare and associated with still unknown genes. Two sisters born of unaffected parents suffered from a severe de‐remyelinating neuropathy of infancy consistent with CMT1. Both patients carried a novel heterozygous G308→A transition of P0 without any additional mutation of PMP22 and EGR. The mutation is predicted to cause a Gly74→Glu substitution in the extracellular domain of P0 (P0ex). Gly74Glu is pathogenic because: it was absent in healthy controls; it changes a phylogenetically conserved residue; it is functionally non‐conservative; based on the P0ex crystal, it is predicted to be structurally incompatible with the normal β‐sheet conformation of P0ex. The healthy mother carried a minor proportion of the G308→A transition in white blood cells (≅20 %), fibroblasts, buccal smear and hairs (≅30%). We concluded that she is actually a gonosomal mosaic harboring clones of mutant somatic and germline cells. The Gly74→Glu substitution originated early in the embryogenesis of the mother, before the commitment to germ cells.
Ulnar Neuropathy At Elbow (UNE): Clinical And Electrophysiological Study Of 279 Cases
Authors: Giannini F , Venturini E , Franci L , Marsili T , Ginanneschi F , Mondelli M.
Published: March 2003

We report a retrospective study on patients referred to EMG services of ASL 7 and Department of Neurosciences in the period 1.1.95 to 31.12.99. In agreement with recently developed AAEM‐AAN guidelines (Neurology 1999, 52:688–690), we recognized as affected by UNE all patients with symptoms and/or signs of ulnar nerve impairment associated with corresponding electrophysiological findings. The minimal electrophysiological criteria for diagnosis is the reduction of the ulnar MNCV in the segment above‐below elbow (<50 m/s) or the difference greater than 10 m/s between this value and the more distal MNCV (segment below elbow‐wrist). This finding may be associated with a reduction of the above/below elbow CMAP greater than 20%. For clinical assessment we utilized severity scale proposed by Antoniadis et al. (Neurosurgery 1997, 41:585–91): stage 1‐recent and mild symptoms of intermittent paresthesias and hypesthesias; stage 2‐persistent symptoms and varying degrees of weakness and intrinsic muscle atrophy; stage 3‐marked intrinsic muscle atrophy, weakness, and deformity. A global neurophysiological severity measurement is proposed, based on 13‐steps which takes into account 4 parameters: above/below elbow MNCV and CMAP difference, EMG findings of the first dorsal interosseous muscle and SNAP at wrist by fifth finger stimulation. Then, 279 UNE from 254 subjects (89 females and 165 males, mean age 58.7 and 55.8 years respectively) were diagnosed: 155 (55.5%) idiopathic cases, 45 (16.1%) post‐traumatic (18 with elbow fracture), 29 (10.4%) due to repetitive stress of the elbow, 28 (10%) with elbow arthropathy. Highest significant correlations have been founded between clinical severity and global neurophysiological score (p < 0.0001) on the one hand and symptoms duration (p < 0.001) on the other hand. Gender significant differences are lacking for age, symptoms duration and clinical severity, whereas the mean neurophysiological score in males results slightly greater than in females (p < 0.05).
Restless Legs Syndrome In Peripheral Neuropathy
Authors: Melli G , Marbini A , Grosso R , Inglese C , Gemignani F.
Published: March 2003

Restless legs syndrome (RLS) is increasingly recognized as a manifestation of various forms of peripheral neuropathy, and in particular in association with amyloidosis, uremia, diabetes, cryoglobulinemia, and Charcot‐Marie‐Tooth disease type 2. A previous study demonstrated a 5% prevalence of RLS in unselected neuropathies, but did not elucidate factors influencing the occurrence, or not, of RLS in peripheral neuropathy. We studied a series of unselected neuropathic patients to assess the prevalence of RLS, and to define the features of peripheral neuropathy associated with RLS. In a population of 70 consecutive patients with various forms of peripheral neuropathy (polyneuropathy in 65 cases, multiple mononeuropathy in 5 cases) we found RLS in 20 cases (28.6%). In particular, RLS was more often associated with cryoglubolinemic neuropathy (5/13), diabetic neuropathy (4/12), Charcot‐Marie‐Tooth disease (4/18), and chronic idiopathic axonal polyneuropathy (2/6). RLS was usually associated with a neuropathy of axonal type, and the onset of RLS was 0–10 (median 1) years after the onset of neuropathy; in 9 cases, RLS was an initial manifestation of neuropathy. Patients with pure sensory or mainly sensory neuropathy had RLS more often than patients with other patterns of neuropathy (13/37 vs. 7/33). Severity of neuropathy, as judged by Rankin score, did not differ in patients with or without RLS (13/20 with Rankin grade 2 or more, vs. 36/50). Prevalence of RLS in our population of neuropathic patients was higher than previously reported. Thus RLS may be viewed as a quite common manifestation of peripheral neuropathy in general, although more common in some forms, and it represents a treatable neuropathic symptom. Mechanisms of RLS are elusive, however a role of sensory inputs is supported by its greater incidence in association with sensory neuropathies.
PMP22 Mutations In DÉJÈRine‐Sottas Disease: A Mutational “Hot Spot” On Codon 72
Authors: Milani M , Milani N , Pareyson D , Gorni K , Merlini L , Mostacciuolo ML , Taroni F.
Published: March 2003

Increased dosage of the gene encoding the peripheral myelin protein PMP22 is the most common molecular mechanism underlying the demyelinating form of Charcot‐Marie‐Tooth disease (CMT1A). It results from the duplication of a 1.5‐Mb tract on chr. 17p11.2 which encompasses the PMP22 gene. Mutations in this gene can also cause CMT1A and are often associated with more severe phenotypes such as Déjèrine‐Sottas disease (DSD) and congenital hypomyelinating neuropathy (CHN). We have analyzed the PMP22 gene in 20 unrelated patients affected with a severe form of demyelinating motor and sensory neuropathy (severe CMT1 or DSD). All the patients had been found negative for the common CMT1A duplication and for mutations in the myelin protein P0 gene (MPZ). Direct sequence analysis of PMP22 uncovered the presence of missense mutations in 3 patients diagnosed as having DSD. In each case, the mutation was heterozygous and was not carried by any of the nonaffected parents, thus indicating that it was a de novo dominant mutation. Patient #1, a 3‐y‐old boy, carried a C‐to‐T transition in PMP22 exon 4 which would result in the amino acid substitution of Leu‐80 with Pro in the 2nd transmembrane domain of the protein. This mutation had been previously observed in another DSD patient (Tyson, 1997). Patient #2, a 3‐y‐old girl, and patient #3 carried the same mutation, the 215C‐to‐T transition in exon 4. Interestingly, patient #3 was a 35‐y‐old man born of consanguineous healthy parents. The disease had started during the first years of life and the patient had become wheelchair‐bound at the age of 28 y. The 215C‐to‐T mutation eliminates a TaqI restriction site and results in the substitution of Ser‐72 (TCG) with Leu (TTG) in the 2nd transmembrane domain of PMP22. Approx. 40 different PMP22 mutations are currently listed in the European CMT Consortium Database. In the majority of cases, the mutations have been identified in single or very few patients, with the only exception of the Ser72Leu substitution. Including the two unrelated patients reported here, this mutation has been thus far described in a total of 7 patients. The mutation, which occurs within a CpG dinucleotide, exhibits phenotypic heterogeneity and has been observed in both DSD (6) and CHN (1) cases. In conclusion, PMP22 mutations are rare causes of genetic neuropathies. Given the limited number of such mutations, the recurrence of substitutions at codon 72 would indicate that this may represent a mutational “hot spot”. We therefore suggest that sequence analysis of PMP22 exon 4 should routinely precede analysis of the remaining exons and intron/exon boundaries.
A Useful Electrophysiologic Test For Diagnosis Of Minimal Conduction Block
Authors: Padua L , Aprile I , Sabatelli M , D'Amico P , Caliandro P , Tonali P.
Published: March 2003

The concept of motor nerve conduction block has gained more importance with the identification of new disease entities. In fact, the presence of motor conduction block greatly influences the diagnostic and therapeutical approach of neuropathies. In spite of the generally good sensitivity of the conventional nerve conduction evaluation, normal findings are still observed in a number of patients with clinical data strongly suggesting the presence of conduction block. We have developed a simple technique for the detection of conduction block by using SFEMG electrode. This test is based on the concept that from stimulation proximal and distal to a partial conduction block, several registrations from few muscle fibers could show some “blocked” fibers (innervated by “blocked” axons). To evaluate the usefulness, sensitivity and specificity of a new neurophysiological test for partial conduction block we studied 17 patients (17 nerves) with clinical picture strongly suggesting the presence of motor conduction block and 20 healthy subjects (40 nerves). Motor nerve conduction studies were performed with conventional surface technique and with the new technique we developed. Moreover, we also evaluated patients with other neurological diseases. According to recent AAEM consensus criteria, 5/17 cases presented “definite” partial conduction block and 6 presented “probable” partial conduction block. In contrast, 16/17 cases (94%) presented an evidence of conduction block at SFEMG conduction block test. The 5/6 cases that were not filled in the AAEM criteria and that presented abnormal findings at SFEMG nerve conduction test could be considered affected by “minimal conduction block.” The sensitivity of this new test was greater than the conventional test. The specificity was 100% (no abnormal findings in healthy subjects or patients with other diseases than neuropathy). SFEMG conduction block test is a sensitive, complementary technique for diagnosis of minimal conduction block in patients with normal findings in standard nerve conduction studies.
A New Simple Neurophysiological Method (Through Conventional Electrical Stimulation) To Assess Function Of Tactile Receptors And Related Nerve Fibers
Authors: Padua L , Aprile I , Tonali P , Meloni A , Stalberg E.
Published: March 2003

Sometimes standard sensory nerve conduction studies show normal results in patients with definite symptoms of sensory polyneuropathy. This is usually explained because standard neurophysiological tests evaluate only large myelinated fibers and do not assess the slowest conducting fibers, more distal segments of the nerves and tactile receptors. Tactile stimulation is a test, not routinely available, that assesses the function of tactile receptors and conduction of fibers that are depolarized by these receptors. During conventional sensory nerve conduction studies (in patients and healthy subjects) through surface electrodes, where we slowly increased the intensity of the stimulus, we occasionally observed a sensory response characterized by a particular morphology with two peaks. After several experiments (performed in the neurophysiological laboratories of Catholic University of Rome and of University of Uppsala) we argued that the double component of the response is the expression of the stimulation of tactile receptors (and depolarization of their related fibers). Therefore an electrical stimulation through conventional EMG equipment allows us to assess function of tactile receptors (and related nerve fibers). This observation may have important diagnostic application in clinical practice to evaluate suspected polyneuropathies negative to neurophysiological conduction studies.
Abnormal Schwann Cell‐Axon Interaction In EBF‐2 “Knock Out” Mice
Authors: Previtali SC , Corradi A , Croci L , Zanoni F , Broccoli V , Consalez GG , Quattrini A.
Published: March 2003

Ebf‐2 belongs to the Ebf gene family which has been implicated in various aspects of neural development. In the peripheral nervous system, Ebf‐2 is highly expressed in immature Schwann cells. Ebf‐2 expression is maintained in non myelin‐forming Schwann cells, whereas it is down‐regulated in myelin‐forming Schwann cells. Although its exact role is still unclear, putative target genes include molecules involved in Schwann cell differentiation and maturation such as SCIP, N‐CAM, L1, laminin, and the intermediate filament GFAP. Disruption of Ebf‐2 affects nerve development and results in a defective Schwann cell‐axon interaction. Deficient sorting of large calibre axons that lie in bundles in non‐myelin‐forming Schwann cells, associated in some cases with abnormal myelination, are the main characteristic features. This is likely the result of an aberrant communication between Schwann cells and axons.
Myelinated Nerve Fibers In Glabrous Digital Skin
Authors: Provitera V , Nolano M , Stancanelli A , Crisci C , Santoro L.
Published: March 2003

In the last decade, applying multiple immunolabeling with highly specific antibodies and confocal microscopy to skin biopsies, it has been possible to study extensively cutaneous innervation. This technique has proved to be reliable and even more sensitive than sural nerve biopsy to investigate mild dying back neuropathies with only a very distal involvement of nerve fibers. So far it has been used mainly on hairy skin to evaluate small fiber anomalies in congenital, acquired and idiopathic sensory neuropathies. Compared to hairy skin, glabrous skin has a peculiar characteristic: it is rich in mechanoreceptors and myelinated Aβ fibers. To study these structures we selected a group of healthy volunteers and recruited a group of patients affected by hereditary or acquired sensory neuropathies. Skin biopsy was performed using a three mm disposable punch in all subjects on fingertip. We stained the cutaneous samples with a panel of antibodies identifying different neural structures such as the axon, the myelin sheath, the Schwann cell, and the Meissner corpuscle capsula. Three‐D digitized images were acquired using a confocal microscope. We studied Meissner and intrapapillar myelinated nerve fiber density and using a dedicated software we measured in normal and neuropathic subjects area and density of innervation of Meissner corpuscles and thickness, internodal and Ranvier node length of the sensory fibers approaching the mechanoreceptors.
Interferon Alpha May Benefit Cidp Patients Refractory To Standard Therapies: Description Of Long‐Term Results On 12 Patients
Authors: Sabatelli M , Quaranta L , Madia F , Lippi G , Tonali P.
Published: March 2003

Although most patients affected by CIDP improve with Corticosteroids, Intravenous Immunoglobulins or Plasma‐Exchange, about 20–30% show poor or no response and 7–10% die due to the disease. We describe 12 CIDP patients unresponsive to standard therapies who were treated with Interferon alpha. Follow‐up period ranged from 4 months to 8 years. Six patients showed a marked and sustained improvement: three recovered completely; the others, who had a severe quadriparesis (Rankin 5) before treatment disclosed a score 2–3 at last follow up. Beginning of improvement was observed within 2–4 days since starting therapy in most patients. In the remaining 6 patients no improvement was observed and two of them died with quadriplegia and respiratory failure. No significant adverse effects were observed. Over the last decade Interferons have been used in the treatment of CIDP. Some authors reported no significant improvement (Hadden et al., Neurology 1999, 53:57; Kuntzer et al., Neurology 1999, 53:1364) while others documented a clear benefit (Engel and Adornato, Neurology 1992, 42:467; Sabatelli, J Neurol Neurosurg Psych 1995, 58:638; Gorson et al., Neurology 1997, 48:777; Gorson et al., Neurology 1998, 50:84; Harada et al., 2000, MN:295; Ueda et al., Rinsho Shink 2000, 40:155). The ever present problem in clinical studies on CIDP, selection bias, may explain this discrepancy. However, the type of Interferon employed may be crucial because only patients receiving IFN alpha improved. Our data show that 50% of patients treated with IFN alpha disclose a significant improvement thus suggesting that this therapy may represent an effective option in otherwise intractable CIDP patients.