Modeling leukocyte trafficking at the human blood-nerve barrier in vitro and in vivo geared towards targeted molecular therapies for peripheral neuroinflammation.

Peripheral neuroinflammation is characterized by hematogenous mononuclear leukocyte infiltration into peripheral nerves. Despite significant clinical knowledge, advancements in molecular biology and progress in developing specific drugs for inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis, there are currently no specific therapies that modulate pathogenic peripheral nerve inflammation. Modeling leukocyte trafficking at the blood-nerve barrier using a reliable human in vitro model and potential intravital microscopy techniques in representative animal models guided by human observational data should facilitate the targeted modulation of the complex inflammatory cascade needed to develop safe and efficacious therapeutics for immune-mediated neuropathies and chronic neuropathic pain.

Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses.

Distinguishing between hereditary and inflammatory neuropathy is usually straightforward on clinical grounds with the help of a family history. There are nevertheless cases where the distinction is less clear. The advent of molecular genetics has in the past several years aided confirmatory diagnosis for an increasing proportion of patients with genetic neuropathy. Various reports have described associations of Charcot-Marie-Tooth disease with a suspected or confirmed inflammatory neuropathy occasionally responding to immunotherapy. Possible predisposition to an inflammatory component was suggested in a subset of patients. Such reports have, however, been relatively few in number, suggesting the rarity of such associations and of such a predisposition if it exists. There have been a number of publications detailing clinical presentations suggestive of inflammatory neuropathy in patients with a known or later proven genetic aetiology, and subsequently felt to be part of the phenotype rather than representing an association. A number of genetically mediated multisystemic diseases with neuropathy have otherwise been reported as mimicking chronic inflammatory demyelinating polyneuropathy (CIDP). The most common example is that of familial amyloid polyneuropathy, of particular concern for the clinician when misdiagnosed as CIDP, in view of the therapeutic implications. We review the literature on reported associations, mimics and misdiagnoses of hereditary and inflammatory neuropathy and attempt to determine a practical approach to the problem in clinical practice using clinical features, electrophysiology, histopathology and targeted early genetic testing. The issue of attempting immunomodulatory therapy is discussed in view of the published literature.

Dissecting the role of sortilin receptor signaling in neurodegeneration induced by NGF deprivation.

Sortilin is a member of the family of vacuolar protein sorting 10 protein domain receptors which has emerged as a co-receptor in cell death and neurodegeneration processes mediated by proneurotrophins. Here we tested the possibility that sortilin deficiency interferes with behavioral and neuropathological endpoints in a chronic Nerve Growth factor (NGF)-deprivation model of Alzheimer's disease (AD), the AD10 anti-NGF mouse. AD10 mice show cholinergic deficit, increased APP processing and tau hyper-phosphorylation, resulting in behavioral deficits in learning and memory paradigms assessed by novel object recognition and Morris water maze tests. Sort1(-/-) mice were crossed with AD10 anti-NGF mice and the neurodegenerative phenotype was studied. We found that the loss of sortilin partially protected AD10 anti-NGF mice from neurodegeneration. A protective effect was observed on non-spatial memory as assessed by novel object recognition, and histopathologically at the level of Aß and BFCNs, while the phosphotau increase was unaltered by knocking out sortilin. We suggest that sortilin might be involved in different aspects of neurodegeneration in a complex way, supporting the view that sortilin functions in the CNS are broader than being a co-receptor in proneurotrophin and neurotrophin signaling.

Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation.

Age is the principal nonmodifiable risk factor for stroke. Over the past 10 years, suitable models for stroke in aged rats have been established. At genetic and cellular level there are significant differences in behavioral, cytological and genomics responses to injury in old animals as compared with the young ones. Behaviorally, the aged rats have the capacity to recover after cortical infarcts albeit to a lower extent than the younger counterparts. Similarly, the increased vulnerability of the aged brain to stroke, together with a decreased interhemisphere synchrony after stroke, assessed by different experimental methods (MRI, fMRI, in vivo microscopy, EEG) leads to unfavorable recovery of physical and cognitive functions in aged people and may have a prognostic value for the recovery of stroke patients. Furthermore, in elderly, comorbidities like diabetes or arterial hypertension are associated with higher risk of stroke, increased mortality and disability, and poorer functional status and quality of life. Aging brain reacts strongly to ischemia-reperfusion injury with an early inflammatory response. The process of cellular senescence can be an important additional contributor to chronic post-stroke by creating a "primed" inflammatory environment in the brain. Overall, these pro-inflammatory reactions promote early scar formation associated with tissue fibrosis and reduce functional recovery. A better understanding of molecular factors and signaling pathways underlying the contribution of comorbidities to stroke-induced pathological sequelae, may be translated into successful treatment or prevention therapies for age-associated diseases which would improve lifespan and quality of life.

Identification of QTLs that modify peripheral neuropathy in NOD.H2b-Pdcd1-/- mice.

The non-obese diabetic (NOD) mouse strain is prone to developing various autoimmune syndromes including type I diabetes mellitus (T1DM), sialadenitis, thyroiditis and pancreatitis. Although the genetic basis of T1DM has been extensively analyzed, genetic factors that modify the other autoimmune phenotypes are largely unknown. We have recently reported that NOD mice with anti-diabetogenic MHC haplotype (H-2(b)) and programmed cell death 1 (PD-1) deficiency (NOD.H2(b)-Pdcd1(-/-) mice) are protected from T1DM but develop various tissue-specific autoimmune diseases including peripheral neuropathy due to autoimmune neuritis, sialadenitis and gastritis. In the present study, we generated [(C57BL/6 x NOD.H2(b))(F1) x NOD-H2(b)](BC1)-Pdcd1(-/-) mice to screen non-MHC quantitative trait loci (QTLs) that modify autoimmune phenotypes other than T1DM. We identified seven QTLs for peripheral neuropathy and neuritis, one QTL for insulitis, four QTLs for gastritis, two QTLs for sialadenitis and seven QTLs for vasculitis throughout the genome and designated them as Annp loci for autoimmunity due to polymorphisms of non-MHC genes in NOD mice and PD-1 deficiency. Annp1, 5, 6 and 7 overlapped with reported loci for T1DM (Idd3, 9, 15 and 2, respectively), suggesting that these loci modify not only T1DM but also other autoimmune phenotypes. NOD allele was promotive at 9 of 14 Annp loci, while NOD allele was protective at the other loci. Half of Annp loci associated with a single phenotype, while the other seven loci associated with more than two phenotypes. These results indicate that NOD genetic background harbors various QTLs that modify autoimmune phenotypes either by organ-specific or by organ-non-specific manner.

Transcriptional profiling of the injured sciatic nerve of mice carrying the Wld(S) mutant gene: identification of genes involved in neuroprotection, neuroinflammation, and nerve regeneration.

Wallerian degeneration (WD) involves the fragmentation of axonal segments disconnected from their cell bodies, segmentation of the myelin sheath, and removal of debris by Schwann cells and immune cells. The removal and downregulation of myelin-associated inhibitors of axonal regeneration and synthesis of growth factors by these two cell types are critical responses to successful nerve repair. Here, we analyzed the transcriptome of the sciatic nerve of mice carrying the Wallerian degeneration slow (Wld(S)) mutant gene, a gene that confers axonal protection in the distal stump after injury, therefore causing significant delays in WD, neuroinflammation, and axonal regeneration. Of the thousands of genes analyzed by microarray, 719 transcripts were differentially expressed between Wld(S) and wild-type (wt) mice. Notably, the Nmnat1, a transcript contained within the sequence of the Wld(S) gene, was upregulated by five to eightfold in the sciatic nerve of naive Wld(S) mice compared with wt. The injured sciatic nerve of wt could be further distinguished from the one of Wld(S) mice by the preferential upregulation of genes involved in axonal processes and plasticity (Chl1, Epha5, Gadd45b, Jun, Nav2, Nptx1, Nrcam, Ntm, Sema4f), inflammation and immunity (Arg1, Lgals3, Megf10, Panx1), growth factors/cytokines and their receptors (Clcf1, Fgf5, Gdnf, Gfrα1, Il7r, Lif, Ngfr/p75(NTR), Shh), and cell adhesion and extracellular matrix (Adam8, Gpc1, Mmp9, Tnc). These results will help understand how the nervous and immune systems interact to modulate nerve repair, and identify the molecules that drive these responses.

Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder.

BACKGROUNDCytotoxic T lymphocyte antigen 4 (CTLA4) is essential for immune homeostasis. Genetic mutations causing haploinsufficiency (CTLA4h) lead to a phenotypically heterogenous, immune-mediated disease that can include neuroinflammation. The neurological manifestations of CTLA4h are poorly characterized.METHODSWe performed an observational natural history study of 50 patients with CTLA4h who were followed at the NIH. We analyzed clinical, radiological, immunological, and histopathological data.RESULTSEvidence for neuroinflammation was observed in 32% (n = 16 of 50) of patients in this cohort by magnetic resonance imaging (MRI) and/or by cerebrospinal fluid analysis. Clinical symptoms were commonly absent or mild in severity, with headaches as the leading complaint (n = 13 of 16). The most striking findings were relapsing, large, contrast-enhancing focal lesions in the brain and spinal cord observed on MRI. We detected inflammation in the cerebrospinal fluid and leptomeninges before the parenchyma. Brain biopsies of inflammatory lesions from 10 patients showed perivascular and intraparenchymal mixed cellular infiltrates with little accompanying demyelination or neuronal injury.CONCLUSIONSNeuroinflammation due to CTLA4h is mediated primarily by an infiltrative process with a distinct and striking dissociation between clinical symptoms and radiological findings in the majority of patients.FUNDINGNIAID, NIH, Division of Intramural Research, NINDS, NIH, Division of Intramural Research, and the National Multiple Sclerosis Society-American Brain Foundation.TRIAL REGISTRATIONClinicalTrials.gov NCT00001355.

Neurological manifestations of the Mendelian-inherited autoinflammatory syndromes.

Autoinflammatory syndromes include an expanding list of conditions characterized by unprovoked recurrent attacks of systemic inflammation with lack of auto-antibodies or autoreactive T cells. Many of these syndromes are genetic diseases with a Mendelian inheritance. Neurological manifestations may be one of the major clinical features and, in some cases, the presenting symptom of these syndromes. The purpose of this review is to increase the recognition among neurologists of the Mendelian-inherited autoinflammatory syndromes by highlighting the neurological manifestations in the context of other symptoms that should lead physicians to suspect these syndromes. Most important for neurologists are the cryopyrin-associated periodic syndromes that include familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease (called chronic infantile neurological cutaneous and articular syndrome in Europe). We also review other syndromes with less common neurological involvement, including familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and hyperimmunoglobulinemia D syndrome. Because these syndromes are often treatable and irreversible damage is prevented if they are treated early, it is important to recognize the features that may result in these syndromes presenting to a neurologist, especially in early childhood.

Adipocyte cannabinoid CB1 receptor deficiency alleviates high fat diet-induced memory deficit, depressive-like behavior, neuroinflammation and impairment in adult neurogenesis.

BACKGROUND: Obesity is a low-grade inflammation condition that facilitates the development of numerous comorbidities and the dysregulation of brain homeostasis. Additionally, obesity also causes distinct behavioral alterations both in humans and rodents. Here, we investigated the effect of inducible genetic deletion of the cannabinoid type 1 receptor (CB1) in adipocytes (Ati-CB1-KO mice) on obesity-induced memory deficits, depressive-like behavior, neuroinflammation and adult neurogenesis. METHODS: Behavioral, mRNA expression and immunohistochemical studies were performed in Ati-CB1-KO mice and corresponding wild-type controls under standard and high-fat diet. RESULTS: Adipocyte-specific CB1 deletion reversed metabolic disturbances associated with an obese condition confirming previous studies. As compared to obese mice, the metabolic amelioration in Ati-CB1-KO mice was associated with an improvement of mood-related behavior and recognition memory, concomitantly with an increase in cell proliferation in metabolic relevant neurogenic niches in hippocampus and hypothalamus. In mutant mice, these changes were related to an increased neuronal maturation/survival in the hippocampus. Furthermore, CB1 deletion in adipocytes was sufficient to reduce obesity-induced inflammation, gliosis and apoptosis in a brain region-specific manner. CONCLUSIONS: Overall our data provide compelling evidence of the physiological relevance of the adipocyte-brain crosstalk where adipocyte-specific CB1 influences obesity-related cognitive deficits and depression-like behavior, concomitantly with brain remodeling, such as adult neurogenesis and neuroinflammation in the hippocampus and hypothalamus.

Deficiency of α1,6-fucosyltransferase promotes neuroinflammation by increasing the sensitivity of glial cells to inflammatory mediators.

BACKGROUND: α1,6-Fucosyltransferase-deficient (Fut8-/-) mice displayed increased locomotion and schizophrenia-like behaviors. Since neuroinflammation is a common pathological change in most brain diseases, this study was focused on investigating the effects of Fut8 in microglia and astrocytes. METHODS: Brain tissues were analyzed using immunohistochemical staining. Core fucosylation and protein expression were analyzed using lectin blot and western blot, respectively. Fut8-knockout (KO) cells were established by the CRISPR/Cas9 system. RESULTS: The number of Iba-1 positive cells and GFAP positive cells were significantly increased in both untreated and lipopolysaccharide stimulated inflammatory conditional Fut8-/- mice by comparison with both wild-type (Fut8+/+) and hetero (Fut8+/-) mice. Stimulation with pro-inflammatory factors, such as IFN-γ and IL-6, induced expression levels of fucosylation in primary microglia and astrocytes, as well as in glial cell lines. Cell motility and iNOS expression were easily induced by IFN-γ in Fut8-KO BV-2 cells compared with wild-type (WT) cells. In a similar manner, both Fut8-KO C6 cells and primary astrocytes treated with 2-fluoro-L-fucose, a specific inhibitor for fucosylation, showed a higher response to IL-6-stimulated phospho-STAT3 signaling, compared with WT cells. CONCLUSIONS: Core fucosylation negatively regulates the states of neuroinflammation by modulating the sensitivity of microglia and astrocytes to inflammatory mediators. The disorders of Fut8-/- mice are caused not only by neurons but also by glial cell dysfunction. GENERAL SIGNIFICANCE: Core fucose is a novel regulator for neuroinflammation in the central nervous system.

Cytokine genotype suggests a role for inflammation in nucleoside analog-associated sensory neuropathy (NRTI-SN) and predicts an individual's NRTI-SN risk.

Nucleoside analog-associated sensory neuropathy (NRTI-SN) attributed to stavudine, didanosine, or zalcitabine (the dNRTIs) and distal sensory polyneuropathy (DSP) attributed to HIV are clinically indistinguishable. As inflammatory cytokines are involved in DSP, we addressed a role for inflammation in NRTI-SN by determining the alleles of immune-related genes carried by patients with and without NRTI-SN. Demographic details associated with risk of various neuropathies were included in the analysis. Alleles of 14 polymorphisms in 10 genes were determined in Australian HIV patients with definite NRTI-SN (symptom onset <6 months after first dNRTI exposure, n = 16), NRTI-SN-resistant patients (no neuropathy despite >6 months on dNRTIs, n = 20), patients with late onset NRTI-SN (neuropathy onset after >6 months of dNRTIs, n = 19), and HIV-negative controls. Carriage of TNFA-1031*2 was highest in NRTI-SN patients, suggesting potentiation of NRTI-SN. Carriage of IL12B (3' UTR)*2 was higher in NRTI-SN-resistant patients than controls or NRTI-SN patients, suggesting a protective role. BAT1 (intron 10)*2 was more common in NRTI-SN than resistant patients, but neither group differed from controls. This marks the conserved HLA-A1, B8, DR3 haplotype. Of the demographic details considered, increasing height was associated with NRTI-SN risk. A model including cytokine genotype and height predicted NRTI-SN status (p < 0.0001, R(2) = 0.54). Late onset NRTI-SN patients clustered genetically with NRTI-SN-resistant patients, so these patients may be genetically "protected." In addition to patient height, cytokine genotype influenced NRTI-SN risk following dNRTI exposure, suggesting inflammation contributes to NRTI-SN.

Neuro-inflammatory response in rats chronically exposed to (137)Cesium.

After the Chernobyl nuclear accident, behavioural disorders and central nervous system diseases were frequently observed in populations living in the areas contaminated by (137)Cs. Until now, these neurological disturbances were not elucidated, but the presence of a neuro-inflammatory response could be one explanation. Rats were exposed for 3 months to drinking water contaminated with (137)Cs at a dose of 400Bqkg(-1), which is similar to that ingested by the population living in contaminated areas in the former USSR countries. Pro-inflammatory and anti-inflammatory cytokine genes were assessed by real-time PCR in the frontal cortex and the hippocampus. At this level of exposure, gene expression of TNF-alpha and IL-6 increased in the hippocampus and gene expression of IL-10 increased in the frontal cortex. Concentration of TNF-alpha, measured by ELISA assays, was also increased in the hippocampus. The central NO-ergic pathway was also studied: iNOS gene expression and cNOS activity were significantly increased in the hippocampus. In conclusion, this study showed for the first time that sub-chronic exposure with post-accidental doses of (137)Cs leads to molecular modifications of pro- and anti-inflammatory cytokines and NO-ergic pathway in the brain. This neuro-inflammatory response could contribute to the electrophysiological and biochemical alterations observed after chronic exposure to (137)Cs.

Characterization of a cyclooxygenase-2-765G-->C promoter polymorphism in human neural cells.

Direct sequencing of the human cyclooxygenase-2 gene promoter revealed a common single nucleotide substitution, cyclooxygenase-2-765G-->C, in 24.5% of the populations analyzed. This change introduced a 20 base pair polypyrimidine/polypurine element and a partial recognition feature for RXRalpha, the 9-cis retinoic acid receptor, into the polymorphic promoter. Cyclooxygenase-2-765G-->C constructs, when transfected into human neural cells, exhibited a 1.4-fold higher level of basal expression, while the proinflammatory factors interleukin-1beta and 9-cis retinoic acid synergistically induced polymorphic promoter activity 2.4-fold over wild type. These results suggest that under specific conditions of cellular stress, a common variation in cyclooxygenase-2 promoter structure may enhance cyclooxygenase-2 transcription, and this may contribute to the proliferation of an inflammatory response in brain cells.

Acute multiple brachial neuropathy and Ehlers-Danlos syndrome.

Although acute brachial neuritis is a well-known syndrome, factors that contribute to its pathogenesis are not yet understood. Only once before has this syndrome been reported in connection with Ehlers-Danlos syndrome. We describe here a 24-year-old man who suddenly developed acute multiple brachial neuritis of the right shoulder and on neurologic examination showed an associated finding of Ehlers-Danlos syndrome. The latter syndrome was also confirmed in other members of his family. This combination may have been overlooked previously. Mechanical and traumatic factors may play an important role in both pathogenesis and therapy.

Expression of opioid receptors during peripheral inflammation.

Opioid receptors (OR) and their mRNA are present in the central and peripheral nervous system of mammals. In this review we examine the behavioral effects of opioids and the expression of their receptors during peripheral inflammation in two experimental models: the rat paw and the mouse intestine. Inflammation increased the antinociceptive (paw) and the inhibitory effects of opioids in the gut (transit, permeability and plasma extravasation) by interaction with OR located at peripheral sites. Based on agonist efficacy, micro > delta >> kappa-OR mediate the antinociceptive and antitransit effects of opioids during inflammation. Intestinal permeability is modulated by delta = micro >> kappa-OR, while kappa > delta >> micro-OR are involved in the inhibition of plasma extravasation. Intestinal inflammation increased the transcription of micro and delta-OR (but not kappa) genes in the gut, thus explaining the enhanced antitransit and antisecretory effects of micro and delta-OR agonists; however, the increased inhibitory effects of kappa-OR agonists on plasma extravasation could result from post-transcriptional regulation of the receptor. Similarly, the increased expression of peripheral micro-OR observed in the rat paw during inflammation, occurs at post-transcriptional levels and is related to an increased axonal transport from the dorsal root ganglia to peripheral terminals. The sites and mechanisms implicated in the increased transcription of micro and delta-OR during intestinal inflammation are under investigation.

Identification of a novel gene, OASIS, which encodes for a putative CREB/ATF family transcription factor in the long-term cultured astrocytes and gliotic tissue.

Gliosis is a characteristic response of astrocytes to inflammation and trauma of the central nervous system (CNS). To study the mechanisms underlying gliosis, we performed differential display screening for genes specifically induced in long-term cultured astrocytes used as an in vitro gliosis model. We identified and characterized a gene (named OASIS, for old astrocyte specifically-induced substance) expressed in long-term cultured mouse astrocytes, or 'old astrocytes (OA)'. The OASIS gene encoded a putative transcription factor belonging to the cyclic AMP responsive element binding protein/activating transcription factor (CREB/ATF) gene family, with homology to box B-binding factor-2 (BBF-2), a Drosophila transcription factor. Its expression was developmentally regulated; OASIS mRNA was primarily expressed in the salivary gland and cartilage in the mouse embryo and it was transiently upregulated in the brain during postnatal two weeks. The expression became weaker in the adult brain. We also demonstrated that an expression of the OASIS mRNA was induced in response to the cryo-injury of the mouse cerebral cortex. The distribution pattern of the OASIS-positive cells in the injured cortex was very similar to that of the glial fibrillary acidic protein (GFAP)-positive cells. These results suggest that OASIS protein may play a role in gliotic events.

Lipid abnormalities in hereditary neuropathy. Part 3. Plasma and erythrocyte lipids of HMSN-III (Dejerine-Sottas disease).

Plasma glucosylceramide levels of 5 patients with Hereditary Motor and Sensory Neuropathy Type III (Dejerine-Sottas disease) were approximately 50% higher than in controls. Erythrocyte glucosylceramides, however, were within the range of normal values. Elevated plasma glucosylceramide levels provide further evidence that an abnormality of lipid metabolism may underlie this recessively inherited hypertrophic neuropathy. No abnormality was observed among other glycosphingolipid fractions. An altered sphingomyelin fatty acid composition and reduced phosphatidylcholine level was also found, but this may not be disease-specific.

Phenotypic inflammation switch in rats shown by calcitonin gene-related peptide immunoreactive dorsal root ganglion neurons innervating the lumbar facet joints.

STUDY DESIGN: The changes in dorsal root ganglion neurons innervating the L5-L6 facet joint were studied using the retrograde neurotransport method and the immunohistochemistry of calcitonin gene-related peptide in an inflammatory model of rats. OBJECTIVES: To determine by inflammatory stimulation the changes in calcitonin gene-related peptide-immunoreactive dorsal root ganglion neurons innervating the L5-L6 facet. SUMMARY OF BACKGROUND DATA: The rat L5-L6 facet joint is innervated from L1-L5 dorsal root ganglia. The presence of calcitonin gene-related peptide-immunoreactive dorsal root ganglion neurons innervating the L5-L6 facet joint has been confirmed, but the changes in the number and distribution of these neurons caused by inflammation have not been studied. METHODS: Retrograde transport of fluorogold was used in 20 rats: 10 in the control group and 10 in the inflammatory group. Using the dorsal approach, fluorogold crystals were injected into the left L5-L6 facet joint. Then 5 days after application, complete Freund's adjuvant (50 microg Mycobacterium butyricum in oil saline emulsion) was injected into the same L5-L6 facet joint (inflammatory group). Of the total fluorogold-labeled dorsal root ganglion neurons from T13-L6, the number and cross-sectional area of the cell profiles of fluorogold-labeled, calcitonin gene-related peptide-immunoreactive neurons in the bilateral dorsal root ganglia of both groups were evaluated. RESULTS: Fluorogold-labeled neurons were distributed throughout the ipsilateral dorsal root ganglia from L1-L5 in both groups. Of the fluorogold-labeled neurons, the ratios of the calcitonin gene-related peptide-immunoreactive L1, L2, L3, L4, and L5 dorsal root ganglion neurons, respectively, were 17%, 24%, 44%, 56%, and 50% in the control group and 50%, 39%, 51%, 61%, and 56% in the inflammatory group. The ratios of the calcitonin gene-related peptide-immunoreactive L1 and L2 dorsal root ganglion neurons labeled by fluorogold were significantly higher in the inflammatory group than in the control group (P < 0.05). The mean cross-sectional area of fluorogold-labeled, calcitonin gene-related peptide-immunoreactive cells from L1-L5 dorsal root ganglia increased from 621 +/- 64 microm2 to 893 +/- 63 microm2 in the inflammatory group (P < 0.01). CONCLUSIONS: The ratio of fluorogold-labeled, calcitonin gene-related peptide-immunoreactive neurons was significantly higher in the L1 and L2 dorsal root ganglia of the inflammatory group than in those of the control group, and the average cross-sectional area of the cells from L1-L5 dorsal root ganglion increased. Associated with the inflammation in the facet joints, the change in calcitonin gene-related peptide-immunoreactive neuron distribution and the phenotypic switch to large neurons may complicate the mechanism of facet joint inflammatory pain.

[Electrophysiological study of a family of subjects presenting primary hypertrophic neuritis]. / Etude électrophysiologique d'une famille de sujets présentant une névrite hypertrophique primitive.

Primary hypertrophic neuritis (hereditary motor and sensory neuropathy types I and III) can easily be characterized in affected families by nerve conduction measurement. Such a study is reported in a family with two affected subjects from two successive generations, a man and one of his daughters (type I). Nerve conduction velocities (NCV) were dramatically low (down to 10 m/sec) in three other subjects from the second generation without any obvious clinical symptom. These cases show again the lack of correlation between electrophysiological data and clinical features in these affections. They emphasize the usefulness of electrophysiological diagnosis among subjects without any obvious clinical sign.

[Familial hypertrophic neuropathies. Conceptual and critical outline. Report of a family with Dyck and Lambert's type IV disease (author's transl)]. / Neuropatías hipertróficas familiares. Delimitación conceptual y crítica. Aportación de un grupo familiar tipo IV de Dyck y Lambert.

The authors make a historical and critical summary of the clinical development of hypertrophic neuropathies up to the classification established by Dick and Lambert, based on its clinical, electrophysiological and genetic study. Until more light is shed on the etiology of these diseases by the metabolic studies already initiated, the use of such classification is recommended. Based on this point of view the clinical, electrophysiological and pathological study of five members of a peculiar family is presented. The affected members presented clinically with different stages of evolution of the uncommon form defined as type IV by Dick and Lambert.