bluuebunny/crossref_metadata_2025 huggingface dataset:
LIPOPOLYSACCHARIDES OF A CAMPYLOBACTER COLI ISOLATE FROM A PATIENT WITH GUILLAIN‐BARRE SYNDROME DISPLAY GANGLIOSIDE MIMICRY
Authors: Bersudsky M , Rosenberg P , Rudensky B , Wirguin I.
Published: August 2010

Campylobacter coli was isolated from a patient with severe, axonal type Guillain‐Barre syndrome (GBS). The patient's serum was tested by ELISA for glycolipid antibodies and showed a high titer of IgG antibodies to asialo‐GM1 (GA1) and GD3. Campylobacter coli lipopolysaccharide (LPS) was extracted and analyzed by ELISA, immunoblot binding and blocking studies, and found to avidly bind cholera toxin and peanut agglutinin. The LPS from the patient's isolate also induced anti‐GA1 antibodies in a rat model. These findings suggest that the LPS from this bacterial isolate contains a ganglioside‐like epitope, which most likely resembles GA1. Thus, it appears that ganglioside cross‐reactivity is not unique to Campylobacter jejuni and seems to occur in all bacterial isolates from GBS cases so far analyzed.
QUALITY OF LIFE IN PATIENTS WITH AXONAL POLYNEUROPATHY
Authors: Teunissen Ll , Eurelings M , Notermans Nc , Hop Jw , Van Gijn J.
Published: August 2010

“Quality of life” (QOL) measurement reflects the impact of a disease on the daily life of a patient, and this can be used as an outcome measure in clinical trials. QOL measurements are rarely used in patients with neuromuscular disease. The aim of this study was to determine whether QOL is reduced in chronic polyneuropathy, whether there is a relationship between QOL and objective measures of disease severity, and whether measuring QOL is a useful addition to the assessment of severity of polyneuropathy. We measured QOL in 90 patients with chronic axonal polyneuropathy (33 with hereditary motor and sensory neuropathy type II and 57 with chronic idiopathic axonal polyneuropathy) using the RAND 36‐item Health Survey questionnaire (RAND‐36). We compared the results with the QOL of a reference population, with summed motor and sensory scores, and with the Rankin scale for handicap. Patients had worse scores than the reference population on seven of eight areas of the RAND‐36. Patients with both low motor and low sensory scores rated lower in physical and emotional areas than less impaired patients. A low Rankin score was related only to physical domains. We conclude that in patients with chronic axonal polyneuropathy the severity of disease can be assessed with a general QOL instrument, and that this provides additional information, particularly on areas related to emotional and social functioning.
ANTISULFATIDE ANTIBODIES IN NEUROPATHY—CLINICAL AND ELECTROPHYSIOLOGIC CORRELATES
Authors: Dabby R , Weimer Lh , Hays Ap , Olarte M , Latov N.
Published: August 2010

OBJECTIVE: To investigate the clinical and electrophysiologic characteristics of the neuropathy associated with elevated serum antisulfatide antibodies. METHODS: Clinical, electrophysiologic, morphologic, and laboratory data of 25 patients with significantly elevated (>25,600) antisulfatide antibodies were reviewed. RESULTS: Four groups were distinguished based on clinical and electrophysiologic data: Group 1, eight patients with predominantly small fiber sensory neuropathy (32%); Group 2, five patients with mixed large and small fiber sensory neuropathy (20%); Group 3, seven patients with axonal sensorimotor neuropathy (28%); and Group 4, three patients with demyelinating sensorimotor neuropathy (12%). One additional patient had mononeuritis multiplex and one had ALS. An immunoglobulin M (IgM) monoclonal gammopathy was found in 30% of the patients tested, but not in any of the Group 1 patients with small fiber sensory neuropathy. Serum IgM level was elevated in 12 patients, of whom six had a concomitant monoclonal gammopathy. Morphologic studies in five patients showed predominantly axonal degeneration, with three of the patients also exhibiting additional features of demyelination. CONCLUSIONS: Antisulfatide antibodies are associated with several subtypes of peripheral neuropathy. Predominantly sensory or sensorimotor axonal neuropathies are most common in this series, with the sensory component either small fiber or mixed fiber type. A smaller demyelinating group indistinguishable from patients with chronic inflammatory demyelinating polyradiculopathy was also seen. One third of patients had a concomitant IgM monoclonal gammopathy, and approximately one half had elevated serum IgM.
GLYCOSPHINGOLIPID ANTIBODIES AND BLOOD‐NERVE BARRIER IN AUTOIMMUNE DEMYELINATIVE NEUROPATHY
Authors: Kanda T , Yamawaki M , Iwasaki T , Mizusawa H.
Published: August 2010

OBJECTIVE: To evaluate morphologic changes in small endoneurial vessels in patients with autoimmune demyelinative neuropathy and antiglycosphyngolipid antibodies. BACKGROUND: Although a humoral immune cause has been postulated for various demyelinating neuropathies, the mechanism by which large molecules like immunoglobulins can traverse the blood‐nerve barrier (BNB) to enter the endoneurium is not understood. METHODS: We examined histologic and ultrastructural changes in small endoneurial vessels in sural nerve biopsy specimens from autoimmune demyelinative neuropathy patients, with or without anti‐glycosphingolipid (GSL) antibodies. Density of small endoneurial vessels, mean endothelial area, mean luminal area, and the percentage of endothelial cell junctions (that make up the BNB) that showed evidence of disruption were evaluated. RESULTS: Only junctional disruption showed a significant difference: autoimmune demyelinative neuropathy patients with anti‐GSL antibodies showed more BNB disruption than autoimmune demyelinative neuropathy patients without antibodies or control patients with nonautoimmune neuropathies. The most commonly observed endoneurial change in antibody‐positive autoimmune demyelinative neuropathy patients was the finding of continuous, patent spaces lacking tight junctions between endothelial cells. CONCLUSIONS: Brain endothelial cells and endoneurial endothelial cells share various GSL antigens, including GM1 and GD1b gangliosides, with peripheral nerve tissues. Circulating anti‐GSL antibodies could damage cell‐to‐cell attachments in endoneurial endothelium. This barrier disruption may permit the large molecules like immunoglobulins to enter the endoneurial space, contributing to development of autoimmune demyelinative neuropathy.
THE ROLE OF SOMATOSENSORY EVOKED POTENTIALS IN THE DIAGNOSIS OF AIDS‐ASSOCIATED MYELOPATHY
Authors: Tagliati M , Di Rocco A , Danisi F , Simpson Dm
Published: August 2010

BACKGROUND: Although AIDS‐associated vacuolar myelopathy is detected in> 50% of autopsy cases, it is often unrecognized during life. The clinical assessment is often difficult because of concurrent peripheral neuropathy and lack of specific diagnostic markers. Somatosensory evoked potentials (SEPs) have been successfully used to evaluate central conduction in a number of diseases involving the spinal cord. OBJECTIVES: To assess the diagnostic yield of SEPs in AIDS‐associated myelopathy. METHODS: We recorded tibial and median nerve SEPs in 69 HIV‐infected subjects referred for evaluation of lower extremity neurologic abnormalities. Stimulation of the peroneal nerve at the popliteal fossa was performed in patients with absent response to ankle stimulation. RESULTS: HIV‐infected subjects had significantly delayed latencies of both peripheral and central potentials, suggesting a combination of peripheral and CNS abnormalities. Analysis of peripheral and central latencies allowed us to discriminate between neuropathy and myelopathy in individual patients. Abnormalities of tibial central conduction time (CCT) correlated with clinical diagnosis of myelopathy. There was no significant difference in median CCTs between patients and controls, suggesting that conduction abnormalities were restricted to the thoracolumbar spinal cord. A derived spinal conduction time was a sensitive indicator of central conduction abnormalities in AIDS patients with myelopathy. CONCLUSIONS: The combination of median, posterior tibial, and peroneal SEPs is a valuable tool in the diagnosis of AIDS‐associated myelopathy, particularly when myelopathy and peripheral neuropathy coexist. The use of a derived spinal conduction time improves the diagnostic yield of SEPs in AIDS‐associated myelopathy.
LINKAGE TO CHROMOSOME 13Q11‐12 OF AN AUTOSOMAL RECESSIVE CEREBELLAR ATAXIA IN A TUNISIAN FAMILY
Authors: Mrissa N , Belal S , Ben Hamida C , Amouri R , Turki I , Mrissa R , Ben Hamida M , Hentati F.
Published: August 2010

OBJECTIVE: To report the clinical findings and the genetic linkage mapping of an autosomal recessive cerebellar ataxia associated to peripheral neuropathy, showing an early onset cerebellar ataxia with retained tendon reflexes (EOCA) phenotype. BACKGROUND: EOCA is a clinical syndrome delimited by Harding distinguished from Friedreich's ataxia (FA) mainly by the preservation of tendon reflexes. Molecular genetic study of patients with EOCA has demonstrated genetic heterogeneity. A form of autosomal recessive spastic ataxia has been described in Charlevoix Saguenay area in Quebec (ARSACS); the gene responsible has been mapped to chromosome 13q. METHODS: Genetic linkage analysis was performed on 18 members of a large family including 8 of 9 members with EOCA. After exclusion of FA and ataxia with vitamin E deficiency loci as well as loci of autosomal dominant cerebellar ataxias, we performed a linkage analysis to markers of 13q11‐12 region. RESULTS: The 9 affected members of this family showed stereotyped clinical features with cerebellar ataxia, pyramidal syndrome, and a variable degree of axonal peripheral neuropathy. Linkage was detected between the disease locus and the microsatellite marker D13S232. Surrounding markers to D13S232 confirmed the linkage and showed the homozygosity of the affected members. CONCLUSION: The family reported here showed the same locus as autosomal recessive spastic ataxia Charlevoix Saguenay disease.
PATHOPHYSIOLOGY AND CLASSIFICATION OF THE VIBRATION WHITE FINGER
Authors: Noel B.
Published: August 2010

Skin, arteries and nerves of the upper extremities can be affected by vibration exposure. Recent advances in skin and vascular biology as well as new investigative methods, have shown that neurovascular symptoms may be due to different vascular and neurological disorders which should be differentiated if proper management is to be evaluated. Three types of vascular disorder can be observed in the vibration white finger: digital organic microangiopathy, a digital vasospastic phenomenon and arterial thrombosis in the upper extremities. An imbalance between endothelin‐l and calcitonin‐gene‐related peptide is probably responsible for the vasospastic phenomenon. Moreover, paresthesiae can be due to either a diffuse vibration neuropathy or a carpal tunnel syndrome. A precise diagnosis is then necessary to adapt the treatment to individual cases. A classification describing the type and severity of the vascular lesions is presented. Asymptomatic lesions are included for adequate epidemiological studies and risk assessment of vibrating tools. Monitoring of vibration exposed workers should include not only a questionnaire about symptoms, but also a clinical evaluation including diagnostic tests for the screening of early asymptomatic neurovascular injuries.
NERVE INJURY‐INDUCED MECHANICAL BUT NOT THERMAL HYPERALGESIA IS ATTENUATED IN NEUROKININ‐1 RECEPTOR KNOCKOUT MICE
Authors: Mansikka H , Sheth Rn , DeVries C , Lee H , Winchurch R , Raja Sn
Published: August 2010

Mice lacking the gene encoding for substance P and neurokinin A, or the NK‐1 receptor, exhibit alterations in behavior to various acute nociceptive stimuli. However, behavioral responses of NK‐1 mutant animals have not been well characterized in models of chronic pain. We studied the behavioral responses of NK‐1 knockout and wild‐type control mice to thermal and mechanical stimuli before and after inducing chronic neuropathic pain by unilateral ligation of the L5 spinal nerve. Mechanical hyperalgesia was evaluated by determining the frequency of withdrawal to von Frey monofilaments applied to the hind paws. Nerve injury‐induced hyperalgesia to thermal stimuli was examined by determining responses to radiant heat and cooling stimuli. The contribution of the sympathetic nervous system to mechanical hyperalgesia was evaluated by administering 3 mg/kg phentolamine, an alpha‐adrenergic antagonist, subcutaneously. Following spinal nerve injury, withdrawal frequencies to mechanical stimulation increased in wild‐type mice within 1 day and persisted during the g‐week observation period, whereas in the knockout mice, withdrawal frequencies did not increase significantly. In contrast, withdrawal latencies to radiant heat decreased up to 2 weeks after nerve injury in both the NK‐1 and the wild‐type mice. Similarly, the increase in withdrawal frequency to the cooling stimuli following the nerve injury was not different in the NK‐1 knockout and wild‐type mice. Mechanical hyperalgesia in the wild‐type mice was not reversed by systemic administration of phentolamine, suggesting that the pain is not sympathetically maintained. The results indicate that NK‐1 receptors contribute to the development of mechanical, but not thermal, hyperalgesia in neuropathic pain.
MULTISYSTEM INVOLVEMENT IN CONGENITAL INSENSITIVITY TO PAIN WITH ANHIDROSIS (CIPA), A NERVE GROWTH FACTOR RECEPTOR (TRK A)‐RELATED DISORDER
Authors: Toscano E , Della Casa R , Mardy S , Gaetaniello L , Sadile F , Indo Y , Pignata C , Andria G.
Published: August 2010

Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive disorder, is characterized by insensitivity to pain, self‐mutilating behaviour, anhidrosis and recurrent hyperpyrexia. It is a hereditary sensory and autonomic neuropathy, also classified as HSAN, due to a defect of the receptor for nerve growth factor. CIPA is the first human genetic disorder caused by a defect in the neurotrophin signal transduction system. This is the first clinical report of CIPA patients characterized on molecular grounds. The clinical phenotypes of our patients show that CIPA is characterized by a multisystem involvement besides the nervous system, including bone fracture with slow healing, immunologic abnormalities, such as low response to specific stimuli, chronic inflammatory state ending in systemic amyloidosis. The molecular characterization allows a better understanding of most of the clinical features.
THE PROTEOLIPID PROTEIN GENE AND MYELIN DISORDERS IN MAN AND ANIMAL MODELS
Authors: Yool Da , Edgar Jm , Montague P , Malcolm S.
Published: August 2010

The two proteins, proteolipid protein and DM20, which are encoded by alternative transcripts from the proteolipid protein (PLP) gene, are major components of central nervous system myelin. In man, mutations of these proteins cause Pelizaeus‐Merzbacher disease (PMD), an X‐linked dysmyelinating neuropathy. The mutations found are very varied, ranging from deletions, loss‐of‐function and missense mutations to additional copies of the gene. This same range of known genetic defects has been observed in animal models with spontaneous and engineered Pip gene mutations. The relationship between genotype and phenotype is remarkably close in the animal models and the PMD cases, making them useful models for studying the mechanisms of PLP gene‐related disease. As a result, it has become clear that the PLP gene plays a wider role in neural development in addition to its function as a structural component of myelin. It has also emerged that duplications of the PLP gene are the commonest mutation in PMD. Genetic disorders arising from a dosage effect may be more common than previously recognized. The study of the PLP gene in this rare disorder is, therefore, contributing both to our understanding of neural development and maintenance and to the mechanisms of human genetic disorders.
THE EXTRACELLULAR MATRIX OF PERIPHERAL NERVE IN DIABETIC POLYNEUROPATHY
Authors: Bradley Jl , King Rhm , Muddle Jr , Thomas Pk
Published: August 2010

The pattern of collagenisation in peripheral nerve in diabetic polyneuropathy was examined in nerve biopsy specimens from patients with diabetic polyneuropathy in comparison with organ donor control nerves and disease controls (other neuropathies). There was increased endoneurial collagenisation both in the diabetic polyneuropathy cases and the disease controls, this predominantly involving types I and III. Type II collagen was not detected in organ donor control nerves or in the diabetic and the disease control nerves. There was a relative increase in type VI collagen in the endoneurium in the diabetic nerves immediately surrounding groups of Schwann cells. This was not a feature in the other neuropathies. The quantity of types IV, V and VI collagen was increased around the endoneurial microvessels in the diabetic patients and, to a lesser extent, in those with hereditary motor and sensory neuropathy (HMSN). Increased deposition of types IV and V collagen was observed in the perineurium in the diabetic nerves, the latter being most evident in the innermost lamellae where the amount of laminin was possibly also increased. The diameter of the general endoneurial collagen fibrils was greater in the diabetic nerves, although this was not more than in a disease control (HMSN). The collagen fibrils that were present within the basal laminal tubes that had surrounded degenerated myelinated fibres in the diabetic nerves, and those within the onion bulbs of the HMSN cases, were of the normal endoneurial calibre. The expression of laminin by Bungner bands in diabetic neuropathy did not differ from that in disease control nerves, nor were any differences detected for fibronectin. Whether the changes observed are important for the impaired regenerative capacity in diabetic neuropathy requires further investigation.
THE DIABETIC FOOT
Authors: Tomas Mb , Patel M , Marwin Se , Palestro Cj
Published: August 2010

Foot complications in diabetics often lead to amputation. Ulceration is the most common complication in the diabetic forefoot and underlies more than 90% of cases of pedal osteomyelitis. The diagnosis of osteomyelitis is, nevertheless, difficult, and imaging is an important part of the work‐up. Plain radiographs, although useful for anatomical information, are neither sensitive nor specific. Three‐phase bone scintigraphy is sensitive but not specific. Labeled leucocyte scintigraphy and MRI are both useful and are complementary to one another. Labeled leucocyte scintigraphy is valuable for diagnosis as well as follow‐up of pedal osteomyelitis. MRI offers exquisite anatomical detail, which is invaluable for guiding surgical management. The principal complication in the mid and hind foot is the neuropathic or Charcot joint. Although infection of the neuropathic joint is infrequent, its diagnosis is difficult. The extensive bony changes that accompany this disorder severely diminish the value of radiography and bone scintigraphy. It is not always possible to distinguish the marrow oedema of neuropathy from that of osteomyelitis and the role of MRI in the evaluation of this entity is still uncertain. Uptake of labeled leucocytes in the absence of infection may occur and is owing, at least in part, to haematopoietically active marrow. Combined leucocyte/marrow scintigraphy holds considerable promise for identifying the infected Charcot joint.
IGG ANTIGANGLIOSIDE ANTIBODIES IN GUILLAIN‐BARRE SYNDROME WITH BULBAR PALSY
Authors: Yoshino H , Harukawa H , Asano A.
Published: August 2010

Some patients with Guillain‐Barre syndrome (GBS) develop bulbar palsy, which may lead to serious complications during the acute phase of the illness. A serological marker that could predict the occurrence of bulbar palsy would be valuable for the treatment of acute GBS. We examined the serum levels of various IgG antiganglioside antibodies in the sera of 16 patients with GBS with bulbar palsy [GBS‐BP(+)] and 72 patients with CBS without bulbar palsy [GBS‐BP(‐)]. Anti‐GT1a antibodies were detected in a higher percentage of the GBS‐BP(+) patients (10/16, 63%) than the GBS‐BP(−) patients (2/72, 3%). In addition to GT1a, a new disialosylganglioside antigen was recognized by the sera of four GBS‐BP(+) patients. Anti‐GM1b antibodies were also frequently detected in the sera of the GBS‐BP(+) cases. However, anti‐GM1 and anti‐GalNAc‐GD1a antibodies, which are highly associated with acute axonal motor neuropathy (AMAN), were not detected in any of the GBS‐BP(+) cases, while anti‐GM1 antibodies were detected in 29% (21/72) and anti‐GalNAc‐GD1a antibodies were detected in 8% (6/73) of the GBS‐BP(−) cases. These findings suggest that the presence of particular antiganglioside antibodies might be related with certain clinical manifestations of GBS. In patients who are diagnosed with GBS, the presence or absence of anti‐GT1a and anti‐GM1b antibodies should be tested at the early stage of GBS so that appropriate therapies that prevent the development of bulbar palsy and improve the outcome of GBS, may be initiated.
NORMAL HUMAN PLASMA CONTAINS ANTIBODIES THAT SPECIFICALLY BLOCK NEUROPATHY‐ASSOCIATED HUMAN ANTI‐GM1 IGG‐ANTIBODIES
Authors: Lopez Phh , Irazoqui Fj , Nores Ga
Published: August 2010

Intravenous immunoglobulin (IVIg) is used in the treatment of a variety of autoimmune diseases. The blocking of disease‐associated antibodies by anti‐idiotype antibodies present in IVIg has been proposed as an action mechanism. Anti‐GM1 antibodies have been implicated in motor neuropathies. Although IVIg is frequently applied for these diseases, the presence in IVIg or in human plasma of anti‐idiotype antibodies that recognize anti‐GM1 antibodies has not been clearly demonstrated. Here we present evidence that normal human plasma contains antibodies that inhibit the binding of anti‐GM1 IgG‐antibodies from neuropathy patients but do not inhibit anti‐GM1 IgG‐antibodies of rabbit origin with the same fine specificity. The significance of these findings in the course of acute and chronic neuropathies is discussed.
PAINFUL NEUROPATHY DECREASES MEMBRANE CALCIUM CURRENT IN MAMMALIAN PRIMARY AFFERENT NEURONS
Authors: Hogan Qh , McCallum Jb , Sarantopoulos C , Aason M , Mynlieff M , Kwok Wm , Bosnjak Zj
Published: August 2010

Hyperexcitability of the primary afferent neuron leads to neuropathic pain following injury to peripheral axons. Changes in calcium channel function of sensory neurons following injury have not been directly examined at the channel level, even though calcium is a primary second messenger‐regulating neuronal function. We compared calcium currents (I‐Ca) in 101 acutely isolated dorsal root ganglion neurons from 31 rats with neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve, to cells from 25 rats with normal sensory function following sham surgery. Cells projecting to the sciatic nerve were identified with a fluorescent label applied at the CCI site. Membrane function was determined using patch‐clamp techniques in current clamp mode, and in voltage‐clamp mode using solutions and conditions designed to isolate I‐Ca. Somata of peripheral sensory neurons from hyperalgesic rats demonstrated decreased I‐Ca. Peak calcium channel current density was diminished by injury from 3.06 +/− 0.30 pS/pF to 2.22 +/− 0.26 pS/pF in medium neurons, and from 3.93 +/− 0.38 pS/ pF to 2.99 +/− 0.40 pS/pF in large neurons. Under these voltage and pharmacologic conditions, medium‐sized neuropathic cells lacked obvious T‐type calcium currents which were present in 25% of medium‐sized cells from control animals. Altered Ca2+ signalling in injured sensory neurons may contribute to hyperexcitability leading to neuropathic pain.
HYPERALGESIA DUE TO NERVE INJURY— ROLE OF PEROXYNITRITE
Authors: Liu T , Knight Kr , Tracey Dj
Published: August 2010

We carried out a partial ligation of the sciatic nerve in rats to induce nerve injury and neuropathic hyperalgesia. We showed that nitrotyrosine, a marker of peroxynitrite activity, was formed after partial nerve injury. Double‐labelling immunohistochemistry showed that nitrotyrosine‐immunoreactive cells were mainly macrophages and Schwann cells. Daily treatment with uric acid, a scavenger of peroxynitrite, decreased nitrotyrosine formation in the injured sciatic nerve, and produced concomitant alleviation of thermal hyperalgesia and Wallerian degeneration. These results provide the first evidence that peroxynitrite is formed after partial nerve injury, and contributes to the initiation of thermal hyperalgesia and Wallerian degeneration. We hypothesize that uric acid alleviates hyperalgesia and Wallerian degeneration by inhibiting oxidative damage caused by peroxynitrite and possibly also by decreasing the production of other inflammatory mediators such as prostaglandins.
EFFECTS OF MIDAZOLAM IN THE SPINAL NERVE LIGATION MODEL OF NEUROPATHIC PAIN IN RATS
Authors: Kontinen Vk , Dickenson Ah
Published: August 2010

Potential changes in the spinal GABAergic activity after nerve injury were studied by comparing the effects of systemic administration of the benzodiazepine midazolam on the noxious evoked responses of dorsal horn in rats with spinal nerve ligation of neuropathy and control animals. The tight ligation of the L5 and L6 spinal nerves was performed in adult male Sprague‐Dawley rats and resulting mechanical and cold allodynia were assessed with von Frey hairs and the acetone drop test. Single unit extracellular recordings of dorsal horn neurones were performed 15‐18 days after the surgery under halothane anaesthesia using transcutaneous electrical stimulation of the receptive field at three times the C‐fibre threshold. The rats in the spinal nerve ligation group, but not in the sham‐operated control group developed mechanical and cold allodynia. Subcutaneous administration of midazolam 0.1–3.0 mg/kg reduced the A delta‐fibre evoked activity in a dose‐related manner in all study groups, but the C‐fibre evoked activity was significantly reduced only in the spinal nerve ligation group. The inhibitory effects of s.c. midazolam were significantly reversed by i.t. administration of flumazenil, suggesting a spinal site of action. Midazolam reduced C‐fibre evoked firing significantly more in the spinal nerve ligation model than in the non‐operated or sham controls. These results indicate changes in the spinal GABAergic system in the neuropathic animals and could be of importance in the development of new treatments for neuropathic pain.
CONNEXIN CHANNELS IN SCHWANN CELLS AND THE DEVELOPMENT OF THE X‐LINKED FORM OF CHARCOT‐MARIE‐TOOTH DISEASE
Authors: Ressot C , Bruzzone R.
Published: August 2010

Charcot‐Marie‐Tooth disease comprises a group of genetically heterogeneous disorders of the peripheral nervous system. The X‐linked form of Charcot‐Marie‐Tooth (CMTX) is associated with mutations in the gene encoding the gap junction protein connexin 32 (Cx32), which is expressed in Schwann cells. Immunocytochemical evidence suggests that Cx32 is localized to the incisures of Schmidt‐Lantermann and the paranodes of myelinating Schwann cells, where it appears to form reflexive gap junctions. It is currently thought that this cytoplasmic continuity provides a much shorter diffusion pathway for the transport of ions, metabolites and second messenger molecules through intracellular channels between the adaxonal and perinuclear regions of Schwann cells, across the myelin sheath. This review summarizes our current understanding of the role of connexins in Schwann cells and focuses on the lessons for channel function and disease pathophysiology derived from the functional analysis of Cx32 mutations. One of the most intriguing aspects emerging from this work is that several mutations retain functional competence, although the mutated channels exhibit altered Sating properties. This suggests that partial and/or selective disruption of the radial communication pathway formed by Cx32 is sufficient to cause a functional deficit and lead to the development of CMTX. The next challenge will be to define, at the molecular level, the sequence of events involved in the disease process. The presence of a group of functional mutations should help understand the cellular basis of CMTX, by allowing the identification of the specific molecules that need to be exchanged through Cx32 channels, but are excluded from the mutated ones.
EXPERIMENTAL ALLERGIC NEURITIS IN THE SJL/J MOUSE: INDUCTION OF SEVERE AND REPRODUCIBLE DISEASE WITH BOVINE PERIPHERAL NERVE MYELIN AND PERTUSSIS TOXIN WITH OR WITHOUT INTERLEUKIN‐12
Authors: Calida Dm , Kremlev Sg , Fujioka T , Hilliard B , Ventura E , Constantinescu Cs , Lavi E , Rostami A.
Published: August 2010

We report a reproducible model of experimental allergic neuritis (EAN) with severe clinical signs and consistent pathological features in mice. Pertussis toxin (PT) in the presence or absence of murine recombinant interleukin‐12 (mrIL‐12) was used as an adjuvant with bovine peripheral nerve myelin (BPNM) to induce clinical EAN in SJL/J mice. After immunization with a combination of BPNM in complete Freund's adjuvant (CFA) and PT, mice developed severe consistent signs of EAN. The additional treatment of immunized mice with mrIL‐12 prolonged the course of EAN characterized by earlier clinical signs of the disease and delayed the recovery stage. Mice injected with BPNM and CFA without PT developed mild clinical signs. Histological examination of the caudae equinae and the sciatic nerves taken from mice with clinical signs of EAN during the recovery stage revealed severe demyelination, remyelination and remnants of mononuclear cell infiltration. Moderate to severe EAN can be induced in SJL/J mice by the injection of a combination of BPNM in CFA and PT. This model can provide a better understanding of mechanism of demyelination in infiltrating peripheral neuropathy.
RELATIONSHIP BETWEEN FASCICLE SIZE AND PERINEURIAL COLLAGEN IV CONTENT IN DIABETIC AND CONTROL HUMAN PERIPHERAL NERVE
Authors: Williams Pe , Lowry A , Hill R , Masson E.
Published: August 2010

AIM: The relationship between perineurial collagen IV content and fascicle size was determined in diabetic and control human peripheral nerve. METHODS AND RESULTS: Age‐matched diabetic and control sural nerve samples were immunostained using antibodies to collagen IV. The number of cell layers and the perimeter of the fascicle were measured and the collagen IV content of the perineurium determined. Using this method, a comparison could be made of collagen IV content in the perineuria of fascicles of different size. A positive linear relationship was found between fascicle size and the amount of collagen IV per unit of perineurium. The number of perineurial cell layers and the collagen IV content of the diabetic nerve did not differ from control values. CONCLUSIONS: The linear relationship between fascicle size and perineurial collagen IV content per unit of perineurium underlines the importance of taking fascicle size into account when determining changes in basement membrane components associated with neuropathy. The results indicate that increased deposition of collagen IV is not involved in the early changes in the perineurial cell basement membrane and is thus not the primary factor involved in altered nerve function associated with diabetic neuropathy.
ENLARGEMENT OF THE RECEPTIVE FIELD SIZE TO LOW INTENSITY MECHANICAL STIMULATION IN THE RAT SPINAL NERVE LIGATION MODEL OF NEUROPATHY
Authors: Suzuki R , Kontinen Vk , Matthews E , Williams E , Dickenson Ah
Published: August 2010

One characteristic of plasticity after peripheral tissue or nerve damage is receptive field reorganization, and enlargement of receptive field size has been suggested to occur in certain models of neuropathic pain. The aim of the present study was to explore whether enlargement of neuronal receptive fields could contribute to the mechanical allodynia found on the ipsilateral paw in the spinal nerve ligation model of neuropathy. After ligation of L‐5‐L‐6 spinal nerves, all rats developed behavioral signs of mechanical allodynia, while the sham‐operated control group displayed no such changes. The characteristics of the evoked responses of the neurones recorded in the dorsal horn of the rats were similar between the spinal nerve ligation, the sham operated control group, and the nonoperated control group, except for spontaneous activity, which was significantly increased in the spinal nerve ligation group. The mean size of the receptive field on the ipsilateral hindpaw, mapped using low‐intensity stimulation with 9‐g von Frey hair, was significantly increased in the spinal nerve ligation group, as compared to the sham‐operated group. No significant difference was seen with 15‐ or 75‐g von Frey hairs. The distribution of the receptive fields over the plantar surface of the paw was similar between the study groups. The enlargement of receptive field for nonnoxious touch could be an indication of central sensitization in this model.
ALTERED TONIC CONDUCTANCES IN AXONS OF TRANSGENIC MOUSE EXPRESSING THE HUMAN NEUROFILAMENT HEAVY GENE: A MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS
Authors: Kriz J , Meier J , Julien Jp , Padjen Al
Published: August 2010

Neurofilaments (NFs; made by copolymerization of three intermediate filament proteins NF‐L, NF‐M, and NF‐H, for light, medium, and heavy) constitute the most abundant cytoskeletal structure in large myelinated axons. The presence of aberrant NF accumulation has been associated with neurodegenerative diseases (such as ALS). The possible causal role of NF in neurodegeneration has been supported by studies on recently available transgenic mice in which expression of human NF‐H (hNF‐H +/+) leads to overt neuropathy. We have examined electrophysiological properties of myelinated axons in hNF‐H +/+ mice using intraaxonal microelectrode recording from isolated sciatic and tibial nerves. Transgenic mice showed several deficits in physiological properties of low threshold myelinated fibers: conduction velocity and resting membrane potential were significantly decreased (20 +/− 1.6 vs 40 +/− 2 m/s; −71.3 +/− 0.9 vs −75.5 +/− 0.5 m/s; mean +/− SE; n = 25; 22 degrees C). While the amplitude of action potentials was of comparable size (82 +/− 5 vs 86 +/− 3 mV) duration of action potential (at half‐amplitude, AP/2) in hNF‐H +/+ was significantly prolonged (0.82 +/− 0.02 vs 0.65 +/− 0.02 ms). Voltage‐current properties of axonal membrane indicate a significant decrease in inward and outward rectification. Occasionally, impaled axons of hNF‐H +/+ showed membrane oscillations and repetitive activity (reminiscent of fasciculations) never observed in normal animals. These results are compatible with an imbalance between ion conductances in axons from transgenic animals (an increase in Na+ and a decrease in K+ conductances), in agreement with recent suggestion based on clinical studies on ALS patients (H. Bostock et al., 1995, Brain 118, 217–225). One may hypothesize that these changes could contribute to neurodegenerative processes (i.e., via an increase in [Na+](i)), as well as clinical symptoms (fasciculations) observed in patients with degenerative motor neuron diseases.
TREATMENT OF POSTHERPETIC NEURALGIA—AN UPDATE
Authors: Kanazi Ge , Johnson Rw , Dworkin Rh
Published: August 2010

Postherpetic neuralgia (PHN) is a chronic pain syndrome that is often refractory to treatment and can last for years, causing physical and social disability, psychological distress, and increased use of the healthcare system. In this paper we provide an update on recent developments in the treatment of PHN. We emphasize the results of recent studies that provide an evidence‐based approach for treating PHN that was not available until very recently. In randomised, controlled clinical trials, the topical lidocaine patch, gabapentin, and controlled release oxycodone have been shown to provide superior pain relief in patients with PHN when compared with placebo. It has also recently been demonstrated that the tricyclic antidepressant nortriptyline provides equivalent analgesic benefit when compared with amitriptyline, but is better tolerated. Based on these results, nortriptyline can now be considered the preferred antidepressant for the treatment of PHN, although desipramine may be used if the patient experiences unacceptable sedation from nortriptyline. The topical lidocaine patch, gabapentin and controlled release oxycodone all appear to be as effective as tricyclic antidepressants in the treatment of patients with PHN, and the results of these recent studies suggest that each of these treatments should be considered early in the course of treatment. Additional controlled trials are needed to compare the efficacy and tolerability of these 4 treatments—tricyclic antidepressants, gabapentin, the topical lidocaine patch and controlled release opioid analgesics—used singly and in various combinations in the treatment of patients with PHN.
EFFECTS OF NEUTRALIZING ANTIBODIES TO TNF‐ALPHA ON PAIN‐RELATED BEHAVIOR AND NERVE REGENERATION IN MICE WITH CHRONIC CONSTRICTION INJURY
Authors: Lindenlaub T , Teuteberg P , Hartung T , Sommer C.
Published: August 2010

Inhibition of proinflammatory cytokines reduces hyperalgesia in animal models of painful neuropathy. We set out to investigate the consequences of this treatment for nerve regeneration. Here we examined the sequels of epineurial application of neutralizing antibodies to tumor necrosis factor‐alpha (TNF) in chronic constriction injury (CCI) of the sciatic nerve in C57/BL 6 mice. The mice were tested behaviorally for manifestations of thermal hyperalgesia and mechanical allodynia. Nerve regeneration was assessed by morphometry of myelinated nerve fibers in the sciatic nerve and of the epidermal innervation density in the glabrous skin of the hindpaws. Antibodies to TNF reduced thermal hyperalgesia and mechanical allodynia after CCI. Myelinated fiber density in the sciatic nerve was reduced to 30% of normal on day 7 after surgery, and reached 60% on day 45, with no difference between antibody‐treated and untreated animals. Epidermal innervation density as shown by PGP 9.5 and CGRP immunohistochemistry was reduced to 25–47% at both time points after CCI, again without differences between antibody treated and untreated mice. Myelinated fiber density but not epidermal innervation density was correlated to thermal and mechanical withdrawal thresholds. We conclude that neutralization of endoneurial TNF attenuates pain related behavior but has no effect on nerve regeneration. Furthermore, the number of epidermal nerve fibers is not relevant to the magnitude of behavioral hyperalgesia in CCI.
CIGUATERA AND PERIPHERAL NEUROPATHY: A CASE REPORT
Authors: Derouiche F , Cohen E , Rodier G , Boulay C , Courtois S.
Published: August 2010

Ciguatera is the most frequently observed form of tropical fish poisoning. It appears as a syndrome associating general signs, gastrointestinal, cardiac and neurological problems. Peripheral and central nervous system signs may be observed. We report a case of a 60‐year‐old man who developed Ciguatera poisoning with diarrhea, facial paresthesia, myalgia, cramps and weakness. Physical examination revealed a motor distal deficit of the four limbs, myokymia and ataxia. EMG testing was in favor of an axonal neuropathy. Neurologic symptoms persisted for two months. This case illustrates a new pathophysiological mechanism of neuropathy: “axonal channelopathy”. Abnormalities of peripheral nerve sodium and potassium channels result in clinical and electrophysiological manifestations unrelated to axonal degeneration or demyelinization. The ciguatoxin mainly acts on sodium channels. Prolonged sodium channel activation results in repetitive axon firing. Recently ciguatoxin was demonstrated to have a novel action, blocking the sodium channel leading to slowed nerve conduction and decreased motor and sensory action potential amplitudes.
MUTATION‐DEPENDENT ALTERATION IN CELLULAR DISTRIBUTION OF PERIPHERAL MYELIN PROTEIN 22 IN NERVE BIOPSIES FROM CHARCOT‐MARIE‐TOOTH TYPE 1A
Authors: Hanemann Co , D'urso D , Gabreels‐Festen Aawm , Muller Hw
Published: August 2010

The hereditary demyelinating neuropathy Charcot‐Marie‐Tooth type 1A is caused by duplication or by point mutations of the PMP22 gene. Histopathological differences in these genotypes suggest distinct disease mechanisms. In the present investigation we demonstrate a pathologically altered cellular distribution of PMP22 in sural nerve biopsies of patients with PMP22 point mutations. In these patients, in contrast to findings in patients with PMP22 duplication, PMP22 partially accumulates in the Schwann cells instead of being inserted in the myelin sheath. These findings may explain the different histopathology and may suggest different mechanisms of pathogenesis in these genotypes.
ATP‐SENSITIVE K+ CHANNEL EFFECTS ON NERVE FUNCTION, NA+, K+ ATPASE, AND GLUTATHIONE IN DIABETIC RATS
Authors: Hohman Tc , Cotter Ma , Cameron Ne
Published: August 2010

Some vasodilators correct nerve conduction velocity and endoneurial blood flow deficits in diabetic rats. It is not known whether vasa nervorum has ATP‐sensitive K+ (K‐ATP) channels that mediate vasodilation, or whether K‐ATP channels could modulate peripheral nerve function. Therefore, we examined the effects of 2 weeks treatment with the K‐ATP channel openers, celikalim and WAY135201 (R‐4‐[3, 4‐dioxo‐2‐(1, 2, 2‐trimethyl‐propylamino)‐cyclobut‐1‐1‐enylamino]‐3‐methoxy‐benzonitrile), on sciatic nerve blood flow, conduction velocity, Na+‐K+ ATPase activity and glutathione content after 6 weeks of untreated streptozotocin‐diabetes in rats. Blood flow and motor conduction velocity, 47.6% and 20.3% reduced by diabetes, respectively, were completely restored by both celikalim and WAY135201 treatments. Diabetes diminished sciatic Na+‐K+ ATPase activity by 47.6% and this was 80–90% corrected by the K‐ATP channel openers. Sciatic nerve glutathione content, 30.3% reduced by diabetes, was unaffected by celikalim or WAY135201. Thus, K‐ATP channel openers had marked beneficial effects on nerve perfusion and function in experimental diabetic neuropathy, and may be suitable for further study in clinical trials.
QUANTITATIVE SENSORY TESTING: EFFECT OF SITE AND PRESSURE ON VIBRATION THRESHOLDS
Authors: Hagander Lg , Midani Ha , Kuskowski Ma , Parry Gjg
Published: August 2010

OBJECTIVE: To determine the effect of different sites and locally applied pressure on vibration thresholds. METHODS: Vibration thresholds were compared in 47 normal volunteers at 3 sites of the index finger (pulp, dorsum of the middle phalanx and nail) and at two sites of the great toe (dorsum of the proximal phalanx and nail). The effect of local pressure (30, 50 and 100 g/1.22 cm(2)) were compared in 41 subjects at the dorsum of the middle phalanx of the index finger and the proximal phalanx of the great toe. RESULTS: The hand was more sensitive than the foot for vibration. There were no significant differences in vibration thresholds at different sites of the index finger and different sites of the great toe. The pulp of the index finger yielded the least inter‐individual variation. Testing under 30 and 50 g/1.22 cm(2) of pressure yielded equal vibration thresholds. Vibration threshold was higher when tested under 100 g/1.22 cm(2) at the index finger but not the great toe. This difference was small and clinically negligible. CONCLUSION: Testing of vibration thresholds in normal subjects can be adequately conducted at several sites of the index finger and the great toe. The test can be adequately done under low pressure of 30–50 g/1.22 cm(2).
ANTIBODIES TO GM1(NEUGC) IN GUILLAIN‐BARRE SYNDROME AFTER GANGLIOSIDE THERAPY
Authors: Odaka M , Yuki N , Nobile‐Orazio E , Carpo M , Hirata K.
Published: August 2010

N‐Glycolyneuraminic acid‐containing GM1 [GM1(Gc)] is a molecule for serum antibodies in patients with Guillain‐Barre syndrome (GBS). To clarify the pathogenesis of GBS after treatment with bovine brain ganglioside, we investigated the presence of anti‐GM 1(Gc) antibody in patients who developed GBS after ganglioside injection. Serum samples were taken from nine Italian patients with GBS after ganglioside therapy as well as from untreated Italian (n = 30) and Japanese (n = 131) GBS patients. Bovine brain gangliosides fractionated in a column were used as antigens, and binding of serum IgG or IgM was examined. An absorption study of IgG anti‐GM1(Gc) antibody was made with CMI, asialo‐GM1, GM2, CD1a, and GD1b. Four of the nine patients who developed GBS after being administered gangliosides had IgG anti‐GM1(Gc) antibodies. Anti‐GM1(Gc) IgG antibody frequencies were higher in patients with GBS after ganglioside therapy than in those who were untreated. Rates of absorption of IgG anti‐GM1(Gc) antibodies by GM1 were significantly higher (except for asialo‐GM1 and GD1b) than by GM2 and GD1a. The presence of GM 1(Gc) was confirmed in bovine brain immunochemically using cholera toxin and Hanganutziu‐Deicher antibody. Secondary ion mass spectra showed that the structure of the ganglioside was consistent with that of GM1(Gc). GM1(Gc) was recognized more frequently in sera from patients who developed GBS after ganglioside therapy than in sera from untreated GBS patients. Because N‐glycolylneuraminic acid‐containing gangliosides seem to be highly immunogenic in humans, GM1(Gc) may act as an immunogen in some patients who develop GBS following ganglioside therapy.
Hyperbaric oxygen treatment has different effects on nerve regeneration in acellular nerve and muscle grafts
Authors: Nishiura Yasumasa , Haapaniemi Tomas , Dahlin Lars B.
Published: August 2010

Abstract  Effects of hyperbaric oxygen treatment (HBO) on nerve regeneration in acellular nerve and muscle grafts were investigated in rats. Nerve and muscle grafts were made acellular by freeze‐thawing and the obtained grafts were used to bridge a 10‐mm gap in the sciatic nerve on the left and right sides, respectively. Rats were treated with HBO (100% oxygen for 90 minutes at 2.5 atmospheres absolute pressure ATA) twice a day for 7 days. Axonal outgrowth, Schwann cell migration and invasion of macrophages were examined 10 days after the graft procedure by staining neurofilaments, S‐100 proteins and the macrophage antibodies ED1 and ED2, respectively. Axonal outgrowth and Schwann cell migration in acellular nerve grafts were superior to that found in the acellular muscle grafts. However, there was no difference between HBO‐treated and non‐treated rats in acellular nerve grafts. Such a difference was found in acellular muscle grafts concerning both axonal outgrowth and Schwann cell migration from the proximal nerve end. No differences in the content of macrophages or neovascularization (alkaline phosphatase staining) in either of the grafts and treatments were seen. It is concluded that there is a differential effect of HBO‐treatment in acellular nerve and muscle grafts and that HBO‐treatment has no effect on the regeneration process in acellular nerve grafts, in contrast to fresh cellular nerve grafts where a beneficial effect has previously been reported.