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Extracellular vesicles (EVs), exhibiting their functional activity after internalization by recipient cells, are involved in the pathogenesis of drug-induced polyneuropathy (DIPN), a common complication of antitumor therapy. In this work, the internalization of EVs obtained from colorectal cancer patients undergoing polychemotherapy and its relationship with neurotoxicity were assessed using a model system of mononuclear leukocytes. Circulating EVs were isolated from 8 colorectal cancer patients who received antitumor therapy according to the FOLFOX or XELOX regimens before the start of chemotherapy (point 1) and after 3-4 courses (point 2). Mononuclear leukocytes of a healthy donor served as a cellular model system for EV internalization in vitro. EV internalization was assessed using fluorescence microscopy. It was shown that internalization of EVs obtained from colorectal cancer patients with high neurotoxicity was higher than in the group with low neurotoxicity. The ability of CD11b-positive (CD11b⁺) and CD11b-negative (CD11b⁻) mononuclear leukocytes of a healthy donor to internalize EVs obtained from patients before and after chemotherapy did not reveal significant differences. A direct relationship was found between the relative number of CD11b⁻ cells with internalized EVs and the integral index of neurotoxicity according to the NRS scale at the peak of its manifestation (point 2) (r=0.675, p.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTR-PN) results from specific TTR gene mutations. In this study, we generated two induced pluripotent stem cell (iPSC) lines derived from ATTR-PN patients with heterozygous TTR gene mutations (Ala97Ser and Phe64Leu). These iPSC lines exhibited normal morphology, karyotype, high pluripotency marker expression, and differentiation into cells representing all germ layers. The generation of these iPSC lines serve as a valuable tool for investigating the mechanisms of ATTR-PN across various cell types and facilitating patient-specific in vitro amyloidosis modeling., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph C. Wu reports a relationship with Greenstone Biosciences that includes: co-founder & scientific advisory board member. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Familial amyloid polyneuropathy (FAP) caused by a genetic mutation in transthyretin (TTR) is an autosomal dominant hereditary disease. The retrospective, observational case series study presents the ocular clinicopathological findings of five cases carrying the TTR mutation c.401A>G (p.Tyr134Cys). Multimodal retinal imaging and electrophysiological examination, Congo red staining and immunohistochemical analysis of specimens, and genetic analyses were performed. Cases 1 and 2 were symptomatic with vitreous and retinal amyloid deposition and poor visual recovery. Case 3 had a symptomatic vitreous haze in the left eye with good postoperative visual recovery. The right eye of case 3 and the eyes of cases 4 and 5 were asymptomatic. Thicker retinal nerve fiber layer, retinal venous tortuosity with prolonged arteriovenous passage time on fluorescein angiography and retinal dysfunction detected by multifocal electroretinogram occurred even in asymptomatic eyes. Moreover, the internal limiting membrane from patients with FAP was stained positive for Congo red and transforming growth factor-β1. The results highlight the amyloid deposition of mutant TTR in the optic disc and retina, even in the asymptomatic stage. The deposited amyloid leads to increased resistance to venous return and retinal functional abnormalities. Therefore, careful follow-up of structural and functional changes in the retina is needed, even in asymptomatic patients with FAP.

Introduction: Polyneuropathy is a debilitating condition characterized by distal sensory and motor deficits. Schwann cell dysfunction and axonal loss are integral factors in pathophysiology and disease progression of polyneuropathy., Aims: The aim of this study was the assessment of Schwann cell characteristics, nerve fibers and myelination parameters in polyneuropathy patients compared to controls., Methods: Nerve tissue was obtained from polyneuropathy patients (n = 10) undergoing diagnostic sural nerve biopsies. Biopsies of healthy peripheral nerves (n = 5) were harvested during elective sural nerve grafting for chronic peripheral nerve lesions. Exclusion criteria for the healthy control group were recent neurological trauma, diabetes, neurological and cardiovascular disease, as well as active malignancies and cytotoxic medication within the last 12 months. The over-all architecture of nerve sections and myelination parameters were histomorphometrically analyzed. Immunofluorescent imaging was used to evaluate Schwann cell phenotypes, senescence markers and myelination parameters., Results: Histomorphometric analysis of nerve biopsies showed significant axonal loss in polyneuropathy patients compared to controls, which was in accordance with the neuropathological findings. Immunofluorescent staining of Schwann cells and myelin basic protein indicated a significant impairment of myelination and lower Schwann cell counts compared to controls. Phenotypic alterations and increased numbers of non-myelinating p75-positive Schwann cells were found in polyneuropathy patients., Discussion: This study provided quantitative data of axonal loss, reduced myelination and Schwann cell dysfunction of polyneuropathy patients compared to neurologically healthy controls. Phenotypic alterations of Schwann cells were similar to those seen after peripheral nerve injury, highlighting the clinical relevance of Schwann cell dysfunction., Competing Interests: The authors have declared that no competing interests exist.

Acquired immune-mediated polyneuropathies are classified to some subtypes among them are acute and chronic inflammatory demyelinating polyradiculoneuropathies (AIDP and CIDP). These two conditions share some common signs and underlying mechanisms. Based on the roles of Suppressor of cytokine signaling ( SOCS ) genes in the modulation of immune system reactions, these genes might be involved in the pathogenesis of these conditions. We evaluated expression of SOCS1-3 and SOCS5 genes in the leukocytes of 32 cases of CIDP, 19 cases of AIDP and 40 age- and sex-matched controls using real time PCR method. The Bayesian regression model was used to estimate differences in mean values of genes expressions between cases and control group. Expression levels of SOCS1 and SOCS2 were significantly lower in male patients compared with controls. This sex-specific pattern was also observed for SOCS3 down-regulation. Based on the area under curve values in Receiver Operating Characteristics (ROC) curve, diagnostic powers of SOCS1 , SOCS2 , SOCS3 and SOCS5 genes in the mentioned disorder were 0.61, 0.73, 0.68 and 0.58, respectively. Expression of none of genes was correlated with age of enrolled cases. The current study shows evidences for participation of SOCS genes in the pathophysiology of acquired immune-mediated polyneuropathies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Taheri, Sangseifid, Shahani, Eftekharian, Arsang-Jang and Ghafouri-Fard.)

Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will eventually ensheath them. Myelin sheaths have evolved out of necessity to maintain rapid impulse propagation while accounting for body space constraints. However, myelinating SCs perform additional critical functions that are required to preserve axonal integrity including mitigating energy consumption by establishing the nodal architecture, regulating axon caliber by organizing axonal cytoskeleton networks, providing trophic and potentially metabolic support, possibly supplying genetic translation materials and protecting axons from toxic insults. The intermediate steps between the loss of these functions and the initiation of axon degeneration are unknown but the importance of these processes provides insightful clues. Prevalent demyelinating diseases of the PNS include the inherited neuropathies Charcot-Marie-Tooth Disease, Type 1 (CMT1) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and the inflammatory diseases Acute Inflammatory Demyelinating Polyneuropathy (AIDP) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Secondary axon degeneration is a common feature of demyelinating neuropathies and this process is often correlated with clinical deficits and long-lasting disability in patients. There is abundant electrophysiological and histological evidence for secondary axon degeneration in patients and rodent models of PNS demyelinating diseases. Fully understanding the involvement of secondary axon degeneration in these diseases is essential for expanding our knowledge of disease pathogenesis and prognosis, which will be essential for developing novel therapeutic strategies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy., Methods: In a cross-sectional study, serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n = 51) and without (n = 184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium., Results: Here, we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and, importantly, their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, the downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation., Conclusions: These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The nuclear membranes function as a barrier to separate the cell nucleus from the cytoplasm, but this barrier can be compromised by nuclear membrane ruptures, leading to intermixing of nuclear and cytoplasmic contents. Spontaneous nuclear membrane ruptures ( i.e ., ruptures occurring in the absence of mechanical stress) have been observed in cultured cells, but they are more frequent in the setting of defects or deficiencies in nuclear lamins and when cells are subjected to mechanical stress. Nuclear membrane ruptures in cultured cells have been linked to DNA damage, but the relevance of ruptures to developmental or physiologic processes in vivo has received little attention. Recently, we addressed that issue by examining neuronal migration in the cerebral cortex, a developmental process that subjects the cell nucleus to mechanical stress. In the setting of lamin B1 deficiency, we observed frequent nuclear membrane ruptures in migrating neurons in the developing cerebral cortex and showed that those ruptures are likely the cause of observed DNA damage, neuronal cell death, and profound neuropathology. In this review, we discuss the physiologic relevance of nuclear membrane ruptures, with a focus on migrating neurons in cell culture and in the cerebral cortex of genetically modified mice.

Lysophosphatidylserine (lyso-PS), a lysophospholipid derived from phosphatidylserine (PS), has emerged as a potent signaling lipid in mammalian physiology. In vivo , the metabolic serine hydrolases ABHD16A and ABHD12 are major lipases that biosynthesize and degrade lyso-PS, respectively. Of biomedical relevance, deleterious mutations to ABHD12 cause accumulation of lyso-PS in the brain, and this deregulated lyso-PS metabolism leads to the human genetic neurological disorder PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract). While the roles of ABHD16A and ABHD12 in lyso-PS metabolism in the mammalian brain are well established, the anatomical and (sub)cellular localizations of both lipases and the functional cross-talk between them with respect to regulating lyso-PS lipids remain under investigated. Here, using subcellular organelle fractionation, biochemical assays, and immunofluorescence-based high-resolution microscopy, we show that the PS lipase ABHD16A is an endoplasmic reticulum-localized enzyme, an organelle intricately regulating cellular PS levels. In addition, leveraging immunohistochemical analysis using genetic ABHD16A and ABHD12 knockout mice as important controls, we map the anatomical distribution of both of these lipases in tandem in the murine brain and show for the first time the distinct localization of these lipases to different regions and cells of the cerebellum. We complement the aforementioned immunohistochemical studies by quantitatively measuring lyso-PS concentrations in various brain regions using mass spectrometry and find that the cerebellar lyso-PS levels are most affected by deletion of ABHD16A (decreased) or ABHD12 (increased). Taken together, our studies provide new insights into lyso-PS signaling in the cerebellum, the most atrophic brain region in human PHARC subjects.

Objective: To investigate the expression of axon guidance cues in skin and sural nerve biopsies of patients with polyneuropathies (PNP) as potential markers of nerve de- and regeneration and inflammation., Methods: We prospectively recruited 88 patients with PNP and compared data between patient subgroups and healthy controls. All patients underwent skin punch and/or sural nerve biopsy at the lower leg and proximal thigh. We characterized gene expression profiles of netrin family members as target genes involved in neuronal de- and regeneration [netrin 1, deleted in colorectal cancer (DCC), uncoordinated5H2, neogenin 1 (NEO1), netrin G1, netrin G2] using quantitative real-time PCR., Results: Gene expression of netrin 1 (p < 0.05 in proximal skin), DCC (p < 0.001 in distal skin), NEO1 (p < 0.05 in distal skin), netrin G1 (p < 0.05 in proximal and p < 0.01 in distal skin), and netrin G2 (p < 0.001 in distal skin) was lower in skin biopsies of patients with neuropathy compared to healthy controls. Gene expression of NEO1 (p < 0.05 in distal skin), netrin G2 (p < 0.05 in distal skin), and DCC (p < 0.05 in sural nerve) was lower in samples of patients with painful compared to painless PNP and also correlated positively with intraepidermal nerve fiber density. Skin and sural nerve gene expression of the investigated target genes did not differ between neuropathies of different etiologies., Conclusion: We show reduced cutaneous and neural axon guide expression, which may contribute to a dysregulation of nerve fiber de- and regeneration.

Spontaneous autoimmune peripheral polyneuropathy (SAPP) is a reproducible mouse model of chronic inflammatory peripheral neuropathy in female non-obese diabetic mice deficient in co-stimulatory molecule, B7-2 (also known as CD86). There is evidence that SAPP is an interferon-γ, CD4+ T-cell-mediated disorder, with autoreactive T-cells and autoantibodies directed against myelin protein zero involved in its immunopathogenesis. Precise mechanisms leading to peripheral nerve system inflammation and nerve injury including demyelination in this model are not well defined. We examined the role of activating Fc-gamma receptors (FcγRs) by genetically ablating Fcγ-common chain (Fcer1g) shared by all activating FcγRs in the pathogenesis of this model. We have generated B7-2/ Fcer1g-double null animals for these studies and found that the neuropathic disease is substantially ameliorated in these animals as assessed by behavior, electrophysiology, immunocytochemistry, and morphometry. Our current studies focused on characterizing systemic and endoneurial inflammation in B7-2-null and B7-2/ Fcer1g-double nulls. We found that accumulation of endoneurial inflammatory cells was significantly attenuated in B7-2/ Fcer1g-double nulls compared to B7-2-single nulls. Whereas, systemically the frequency of CD4+ regulatory T cells and expression of immunosuppressive cytokine, IL-10, were significantly enhanced in B7-2/ Fcer1g-double nulls. Overall, these findings suggest that elimination of activating FcγRs modulate nerve injury by altering endoneurial and systemic inflammation. These observations raise the possibility of targeting activating FcγRs as a treatment strategy in acquired inflammatory demyelinating neuropathies., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Polyneuropathy in the critically ill patient was defined as a generalized weakness, acquired during Intensive Care Unit (ICU) admittance and attributed to lesion of the peripheral nerve. Research in this field progressed over time, revealing the crucial role of muscle injury in this disease, to the point of re-naming the disorder as ICU adquired weakness (ICUAW). Muscle damage is common in severe illness, and may be classified in qualitative (weakness) or quantitative (decrease in mass) muscle loss. The most frequent scenario in these patients, is simultaneous change in quality and quantity of muscle; resulting in a challenging and delayed recovery during hospital admittance and after discharge. Multiple causes have been identified in the pathogenesis of this disorder, such as: prolonged bed rest, inadequate intake of nutrients and exposure to drugs that affect muscle structure and contraction. The assessment of muscle mass using images provided by ultrasound or computerized tomography may guide follow up. The prevention and treatment of ICUAW requires a multimodal approach: early mobilization and exercise, appropriate nutritional prescription and, occasionally, muscle protein synthesis stimulants. Further studies will clarify more aspects regarding critically ill patients suffering from muscle injury, in order to better address prevention and treatment of ICUAW.

Background: Mutations in the N-myc downstream-regulated gene 1 (NDRG1) can cause degenerative polyneuropathy in humans, dogs, and rodents. In humans, this motor and sensory neuropathy is known as Charcot-Marie-Tooth disease type 4D, and it is assumed that analogous canine diseases can be used as models for this disease. NDRG1 is also regarded as a metastasis-suppressor in several malignancies. The tissue distribution of NDRG1 has been described in humans and rodents, but this has not been studied in the dog., Results: By immunolabeling and Western blotting, we present a detailed mapping of NDRG1 in dog tissues and primary canine Schwann cell cultures, with particular emphasis on peripheral nerves. High levels of phosphorylated NDRG1 appear in distinct subcellular localizations of the Schwann cells, suggesting signaling-driven rerouting of the protein. In a nerve from an Alaskan malamute homozygous for the disease-causing Gly98Val mutation in NDRG1, this signal was absent. Furthermore, NDRG1 is present in canine epithelial cells, predominantly in the cytosolic compartment, often with basolateral localization. Constitutive expression also occurs in mesenchymal cells, including developing spermatids that are transiently positive for NDRG1. In some cells, NDRG1 localize to centrosomes., Conclusions: Overall, canine NDRG1 shows a cell and context-dependent localization. Our data from peripheral nerves and primary Schwann cell cultures suggest that the subcellular localization of NDRG1 in Schwann cells is dynamically influenced by signaling events leading to reversible phosphorylation of the protein. We propose that disease-causing mutations in NDRG1 can disrupt signaling in myelinating Schwann cells, causing disturbance in myelin homeostasis and axonal-glial cross talk, thereby precipitating polyneuropathy.

Background: Diabetic Sensorimotor Polyneuropathy (DSPN) is a common complication of diabetes mellitus. Curcumin is the most important ingredient found in turmeric which has a very high potential for eliminating free radicals and inhibiting oxidative stress as an antioxidant agent. The aim of this study was to determine the effect of Nano-curcumin supplementation on the severity of sensorimotor polyneuropathy in patients with Type 2 diabetes mellitus (T2DM)., Method: This parallel, double-blind randomized, placebo-controlled clinical trial was conducted on 80 diabetic patients. Participants were allocated randomly to the intervention (n = 40) and the control group (n = 40). They received 80 mg of nano-curcumin or placebo capsules for 8 weeks. Anthropometric measurements, dietary intake, physical activity, glycemic indices and the severity of DSPN were measured before and after the intervention., Result: Supplementation of nano curcumin was accounted for a significant reduction in Glycated hemoglobin(HbA1c) (p < 0.001) and Fast Blood Sugar(FBS) (p = 0.004), total score of neuropathy (p < 0.001), total reflex score (p = 0.04) and temperature (p = 0.01) compared to placebo group., Conclusion: Our findings indicated that curcumin supplementation for 2 months improved and reduced the severity of DSPN in patients with T2DM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aims: Emerging evidence shows, that distal symmetric peripheral neuropathy (DSPN) also involves alterations in the central nervous system. Hence, the aims were to investigate brain metabolites in white matter of adults with diabetes and DSPN, and to compare any cerebral disparities with peripheral nerve characteristics., Methods: In type 1 diabetes, brain metabolites of 47 adults with confirmed DSPN were compared with 28 matched healthy controls using proton magnetic resonance spectroscopy (H-MRS) in the parietal region including the sensorimotor fiber tracts., Results: Adults with diabetes had 9.3% lower ratio of N-acetylaspartate/creatine (NAA/cre) in comparison to healthy (p < 0.001). Lower NAA/cre was associated with lower sural (p = 0.01) and tibial (p = 0.04) nerve amplitudes, longer diabetes duration (p = 0.03) and higher age (p = 0.03). In addition, NAA/cre was significantly lower in the subgroup with proliferative retinopathy as compared to the subgroup with non-proliferative retinopathy (p = 0.02)., Conclusions: The association to peripheral nerve dysfunction, indicates concomitant presence of DSPN and central neuropathies, supporting the increasing recognition of diabetic neuropathy being, at least partly, a disease leading to polyneuropathy. Decreased NAA, is a potential promising biomarker of central neuronal dysfunction or loss, and thus may be useful to measure progression of neuropathy in diabetes or other neurodegenerative diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Dysfunction of the blood-nerve barrier (BNB) plays important roles in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). The aim of the present study was to identify the candidate cytokines/chemokines that cause the breakdown of the BNB using sera from patients with CIDP and MMN., Methods: We determined the levels of 27 cytokines and chemokines in human peripheral nerve microvascular endothelial cells (PnMECs) after exposure to sera obtained from patients with CIDP variants (typical CIDP and multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]), MMN and amyotrophic lateral sclerosis (ALS), and healthy controls (HC), using a multiplexed fluorescent bead-based immunoassay system., Results: The induced protein (IP)10 level in the cells in both the MADSAM and MMN groups was markedly increased in comparison with the typical CIDP, ALS and HC groups. The other cytokines, including granulocyte colony-stimulating factor,vascular endothelial growth factor (VEGF) and interleukin-7, were also significantly upregulated in the MADSAM group. The increase of IP-10 produced by PnMECs was correlated with the presence of conduction block in both the MADSAM and MMN groups., Conclusion: The autocrine secretion of IP-10 induced by patient sera in PnMECs was markedly upregulated in both the MADSAM and MMN groups. The overproduction of IP-10 by PnMECs leads to the focal breakdown of the BNB and may help to mediate the transfer of pathogenic T cells across the BNB, thereby resulting in the appearance of conduction block in electrophysiological studies of patients with MADSAM and MMN., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the associations between different anthropometric measurements and development of distal sensorimotor polyneuropathy (DSPN) considering interaction effects with prediabetes/diabetes and to evaluate subclinical inflammation as a potential mediator., Research Design and Methods: This study was conducted among 513 participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (aged 62-81 years). Anthropometry was measured at baseline. Incident DSPN was defined by neuropathic impairments using the Michigan Neuropathy Screening Instrument at baseline and follow-up. Associations between anthropometric measurements and DSPN were estimated by multivariable logistic regression. Potential differences by diabetes status were assessed using interaction terms. Mediation analysis was conducted to determine the mediation effect of subclinical inflammation in these associations., Results: After a mean follow-up of 6.5 years, 127 cases with incident DSPN were detected. Both general and abdominal obesity were associated with development of DSPN. The odds ratios (95% CI) of DSPN were 3.06 (1.57; 5.97) for overweight, 3.47 (1.72; 7.00) for obesity (reference: normal BMI), and 1.22 (1.07; 1.38) for 5-cm differences in waist circumference, respectively. Interaction analyses did not indicate any differences by diabetes status. Two chemokines (C-C motif chemokine ligand 7 [CCL7] and C-X-C motif chemokine ligand 10 [CXCL10]) and one neuron-specific marker (Delta/Notch-like epidermal growth factor-related receptor [DNER]) were identified as potential mediators, which explained a proportion of the total effect up to 11% per biomarker., Conclusions: General and abdominal obesity were associated with incident DSPN among individuals with and without diabetes, and this association was partly mediated by inflammatory markers. However, further mechanisms and biomarkers should be investigated as additional mediators to explain the remainder of this association., (© 2018 by the American Diabetes Association.)

Chronic idiopathic axonal polyneuropathy (CIAP) is a disorder with insidious onset and slow progression, where no etiology is identified despite appropriate investigations. We aimed to investigate the role of oxidative stress as a risk factor for the pathogenesis of CIAP. Sera of patients with CIAP were tested for protein carbonyl (PC) and 8-hydroxydeoxyguanosine (8H). As a control group, we recruited patients with gluten neuropathy. Twenty-one patients with CIAP and 21 controls were recruited. The two groups did not differ significantly regarding demographics or clinical characteristics (i.e., neuropathy type or disease severity). After adjusting for gender, having CIAP was positively correlated with both the 8H titer (standardized beta coefficient 0.349, p = 0.013) and the PC titer (standardized beta coefficient 0.469, p = 0.001). Oxidative stress appears to be increased in CIAP and might have a role in the pathogenesis of the disease.

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a rare genetic human neurological disorder caused by null mutations to the Abhd12 gene, which encodes the integral membrane serine hydrolase enzyme ABHD12. Although the role that ABHD12 plays in PHARC is understood, the thorough biochemical characterization of ABHD12 is lacking. Here, we report the facile synthesis of mono-1-(fatty)acyl-glycerol lipids of varying chain lengths and unsaturation and use this lipid substrate library to biochemically characterize recombinant mammalian ABHD12. The substrate profiling study for ABHD12 suggested that this enzyme requires glycosylation for optimal activity and that it has a strong preference for very-long-chain lipid substrates. We further validated this substrate profile against brain membrane lysates generated from WT and ABHD12 knockout mice. Finally, using cellular organelle fractionation and immunofluorescence assays, we show that mammalian ABHD12 is enriched on the endoplasmic reticulum membrane, where most of the very-long-chain fatty acids are biosynthesized in cells. Taken together, our findings provide a biochemical explanation for why very-long-chain lipids (such as lysophosphatidylserine lipids) accumulate in the brains of ABHD12 knockout mice, which is a murine model of PHARC., (© 2018 Joshi et al.)

Objective: To improve understanding of disease pathophysiology in anti-myelin-associated glycoprotein (anti-MAG) neuropathy to guide further treatment approaches., Methods: Anti-MAG neuropathy patients underwent clinical assessments, nerve conduction and excitability studies, and ultrasound assessment., Results: Patients demonstrated a distinctive axonal excitability profile characterised by a reduction in superexcitability [MAG: -14.2 ± 1.6% vs healthy controls (HC): -21.8 ± 1.2%; p < 0.01] without alterations in most other excitability parameters. Mathematical modelling of nerve excitability recordings suggested that changes in axonal function could be explained by a 72.5% increase in juxtaparanodal fast potassium channel activation and an accompanying hyperpolarization of resting membrane potential (by 0.3 mV) resulting in a 94.2% reduction in discrepancy between anti-MAG data and the healthy control model. Superexcitability changes correlated strongly with clinical and neurophysiological parameters. Furthermore, structural assessments demonstrated a proximal pattern of nerve enlargement (C6 nerve root cross-sectional area: 15.9 ± 8.1 mm 2 vs HC: 9.1 ± 2.3 mm 2 ; p < 0.05)., Conclusions: The imaging and neurophysiological results support the pathogenicity of anti-MAG IgM. Widening between adjacent loops of paranodal myelin due to antibodies would expand the pathway from the node to the juxtaparanode, increasing activation of juxtaparanodal fast potassium channels, thereby impairing saltatory conduction., Significance: Potassium channel blockers may prove beneficial in restoring conduction closer to its normal state and improving nerve function in anti-MAG neuropathy., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Distal symmetric polyneuropathy, represented by chronic inflammatory demyelinating polyneuropathy, is a popular neurological condition. Some cases are known to be associated with genetic mutations or serum auto-antibodies, but the exact mechanisms in most cases are unknown. Recently, osmotic factors have been suggested to trigger some neurological disorders, such as neuromyelitis optica. The aim of the present study was to assess the possible association of osmotic factors in the pathogenesis of distal polyneuropathy. We prospectively measured the serum levels of osmolality, electrolytes, total protein, albumin, blood urea nitrogen, glucose, and osmolality gap in the patients with acute distal polyneuropathy before treatments (n = 12) and those with other comprehensive neurological disorders such as multiple sclerosis and neurodegenerative diseases (n = 176). Then, we compared each osmotic fraction between the two groups. As a result, all of the 12 patients with acute distal polyneuropathy, including 4 patients with chronic inflammatory demyelinating polyneuropathy, showed abnormally high or low values of osmolality gap, compared to the others (p < 0.0001, F-test). In the patients with other diseases, there were 2 patients with abnormally high osmolality gap values, which were attributable to their hyperlipidemia or high titer of serum autoantibody unrelated to polyneuropathy. In conclusion, serum osmolality gap would be elevated or decreased in the acute phase of distal symmetric polyneuropathy. Osmotic imbalance between the serum and nerve cells, based on abnormal excess or deficit of some unidentified serum osmolytes, may be one of the mechanisms in symmetric polyneuropathy with unknown causes.

Objective: The objective of this study is to examine thiol-disulphide homeostasis in patients with polyneuropathy dominated by diabetic or non-diabetic axonal degeneration., Materials-Methods: Fifty-four patients diagnosed with polyneuropathy dominated by axonal damage and 41 healthy subjects were included in the study. The patients were grouped into two groups according to whether or not they had diabetes. The native thiol and total thiol concentrations were measured with the newly developed automated method., Results: While there was no significant difference between the patients with diabetic and non-diabetic polyneuropathy in terms of native thiol and total thiol levels (p > 0.05), the native thiol and total thiol levels of the groups with both diabetic polyneuropathy and non-diabetic polyneuropathy were significantly low compared to the control group (p < 0.01). The level of disulphides in the patients with diabetic polyneuropathy was significantly higher than that of the patients with non-diabetic polyneuropathy and the healthy individuals (p < 0.05). The loss in the sural nerve sensory neural action potential amplitude was positively correlated with the decrease in the levels of both native thiol and total thiol (p < 0.05)., Discussion: In our study, we observed that the thiol-disulphide balance was also impaired in patients with non-diabetic polyneuropathy similar to patients with diabetic polyneuropathy, and we therefore considered that impaired the thiol-disulphide homeostasis could be the last common path in patients with polyneuropathy with axonal damage, regardless of the aetiology. Therefore, fortification of thiol deficiency with N-acetyl cysteine or alpha-lipoic acid can fix the thiol-disulphide balance and help decelerate the axonal damage.

α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing αSyn and Tau. The identified neuropathological features closely resembled those in brains of p.A53T patients. Small molecules targeting αSyn reverted the degenerative phenotype under both basal and induced stress conditions, indicating a treatment strategy for PD and other synucleinopathies. Furthermore, mutant neurons showed disrupted synaptic connectivity and widespread transcriptional alterations in genes involved in synaptic signaling, a number of which have been previously linked to mental disorders, raising intriguing implications for potentially converging disease mechanisms., Competing Interests: The authors declare no conflict of interest.

Introduction:: The purpose of this study was to evaluate the prevalence of peripheral polyneuropathy (PPN) in subjects with grade II and III obesity (Ob-II,III) and metabolic syndrome (MetS) but without diabetes and to investigate possible associated factors., Method:: A cross-sectional study was performed in non-diabetic Ob-II,III,MetS patients using the Michigan Neuropathy Screening Instrument (MNSI) to assess the presence of PPN., Results:: A total of 24 of 218 non-diabetic Ob-II,III,MetS patients had PPN. Based on univariate analysis, serum levels of LDL-cholesterol (p=0.046) were significantly associated with PPN, while serum triglycerides (p=0.118) and low HDL-cholesterol (p=0.057) showed a tendency toward this association. On a Poisson regression analysis, when the three possible associations were included, low HDL-cholesterol (p=0.047) remained independently associated., Conclusion:: In non-diabetic Ob-II,III,MetS patients, PPN defined by the MNSI showed a high prevalence and was associated with low levels of HDL-cholesterol. In order to diagnose that complication, neurological evaluation should be performed in these patients.

Background: Tafamidis, a non-NSAID highly specific transthyretin stabilizer, delayed neurologic disease progression as measured by Neuropathy Impairment Score-Lower Limbs (NIS-LL) in an 18-month, double-blind, placebo-controlled randomized trial in 128 patients with early-stage transthyretin V30M familial amyloid polyneuropathy (ATTRV30M-FAP). The current post hoc analyses aimed to further evaluate the effects of tafamidis in delaying ATTRV30M-FAP progression in this trial., Methods: Pre-specified, repeated-measures analysis of change from baseline in NIS-LL in this trial (ClinicalTrials.gov NCT00409175) was repeated with addition of baseline as covariate and multiple imputation analysis for missing data by treatment group. Change in NIS-LL plus three small-fiber nerve tests (NIS-LL + Σ3) and NIS-LL plus seven nerve tests (NIS-LL + Σ7) were assessed without baseline as covariate. Treatment outcomes over the NIS-LL, Σ3, Σ7, modified body mass index and Norfolk Quality of Life-Diabetic Neuropathy Total Quality of Life Score were also examined using multivariate analysis techniques., Results: Neuropathy progression based on NIS-LL change from baseline to Month 18 remained significantly reduced for tafamidis versus placebo in the baseline-adjusted and multiple imputation analyses. NIS-LL + Σ3 and NIS-LL + Σ7 captured significant treatment group differences. Multivariate analyses provided strong statistical evidence for a superior tafamidis treatment effect., Conclusions: These supportive analyses confirm that tafamidis delays neurologic progression in early-stage ATTRV30M-FAP., Trial Registration Number: NCT00409175.

Aim: Chronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive, predominantly sensory, axonal polyneuropathy, with no aetiology being identified despite extensive investigations. We studied the potential role of the metabolic syndrome, neurotoxic 1-deoxysphingolipids (1-deoxySLs), microangiopathy and inflammation in sural nerve biopsies., Methods: We included 30 CIAP-patients, 28 with diabetic distal symmetrical polyneuropathy (DSPN) and 31 healthy controls. We assessed standardised scales, tested for the metabolic syndrome, measured 1-deoxySLs in plasma, performed electroneurography and studied 17 sural nerve biopsies (10 CIAP; 7 DSPN)., Results: One third of the CIAP-patients had a metabolic syndrome, significantly less frequent than DSPN-patients (89%). Although the metabolic syndrome was not significantly more prevalent in CIAP compared to healthy controls, hypercholesterolemia did occur significantly more frequent. 1-deoxySLs were significantly and equally elevated in both patient groups compared to healthy controls. Mean basal lamina thickness of small endoneurial vessels and the number of CD68- or CD8-positive cells in biopsies of CIAP- and DSPN-patients did not differ significantly. However, the number of leucocyte-common-antigen positive cells was significantly increased in CIAP., Conclusions: A non-significant trend towards a higher occurrence of the metabolic syndrome in CIAP-patients compared to healthy controls was found. 1-deoxySLs were significantly increased in plasma of CIAP-patients. Microangiopathy and an inflammatory component were present in CIAP-biopsies., Competing Interests: The authors have declared that no competing interests exist.

Comparative evaluation of clinical, neurophysiologic and laboratory data changes in 154 workers exposed to vibration in mining industry helped to identify the most informative criteria of vibration disease diagnosis. Scientifically justified use of neurospecific parameters - S100B protein and neurospecific enolase - was aimed to evaluate vibration disease severity.

Objective: We investigated the pathogenicity of immunoglobulin M (IgM) anti-GM1 antibodies in serum from patients with multifocal motor neuropathy (MMN) using human induced pluripotent stem cell (iPSC)-derived motor neurons (MNs)., Methods: iPSCs were generated from fibroblasts and differentiated into MNs. We studied the binding of IgM to MNs, their complement-activating properties, and effects on structural integrity using fluorescence and electron microscopy. Live cell imaging was used to study effects of antibody binding on MNs in the presence and absence of complement., Results: IgM antibody binding to MNs was detected using sera from MMN patients with and without detectable anti-GM1 IgM antibody titers in enzyme-linked immunosorbent assay, but not with sera from (disease) controls. Competition and depletion experiments showed that antibodies specifically bound to GM1 on iPSC-derived MNs. Binding of these antibodies disrupted calcium homeostasis by both complement-dependent and complement-independent pathways. MNs showed marked axonal damage after complement activation, and reduced antibody pathogenicity following treatment with immunoglobulin preparations., Interpretation: Our data provide evidence for the pathogenicity of anti-GM1 IgM antibodies in MMN patients and link their presence to the clinical characteristics of axonal damage and immunoglobulin responsiveness. This iPSC-derived disease model will facilitate diagnosis, studies on autoantibody pathogenicity, drug development, and screening in immune-mediated neuropathies. Ann Neurol 2016;80:71-88., (© 2016 American Neurological Association.)

Aim: To investigate whether Aδ and C fibre pain threshold values, measured using intra-epidermal electrical stimulation (IES), in people with and without Type 2 diabetes are useful in evaluating diabetic polyneuropathy (DPN) severity., Methods: Aδ and C fibre pain threshold values were measured in Japanese people with (n = 120) and without (n = 76) Type 2 diabetes by IES. Nerve conduction studies and other tests were performed to evaluate diabetic complications., Results: Aδ and C fibre pain threshold values were high in people with diabetes compared with control subjects (Aδ fibre: 0.050 vs. 0.030 mA, P < 0.01; C fibre: 0.180 vs. 0.070 mA, P < 0.01). Participants with diabetes and neuropathy had significantly higher Aδ and C fibre pain threshold values than participants without neuropathy (Aδ fibres 0.063 vs. 0.039 mA, P < 0.01; C fibres 0.202 vs. 0.098 mA, P < 0.05). C fibre pain threshold values were significantly higher in participants with diabetes and diabetic microvascular complications than in participants without complications. Threshold values increased with complication progression. When DPN was diagnosed according to the Diabetic Neuropathy Study Group in Japan criteria, the cut-off for the C fibre pain threshold values was 0.125 mA (area under the curve 0.758, sensitivity 81.5%, specificity 61.5%). The IES test took less time (P < 0.01) and was less invasive (P < 0.01) than the nerve conduction studies., Conclusions: Intra-epidermal electrical stimulation is a non-invasive and easy measurement of small fibre pain threshold values. It may be clinically useful for C fibre measurement to diagnose early DPN as defined by the Diabetic Neuropathy Study Group in Japan criteria., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)

Aims: Sepsis patients and other patients in the critical care settings are at very high risk of mortality due to the primary illness. However, a fraction of patients, even after showing initial clinical improvement, deteriorates relentlessly at later stages. Increasingly, it is being identified that this is mostly due to dysfunction of the neurological system., Main Methods: We obtained peripheral nerve biopsies from the sural nerve from ICU patients. Nav1.6 expression was significantly diminished. The expression of cellular membrane anchoring protein for Nav1.6, ankyrin, remained unaffected, suggesting that genomic repression may be responsible for the diminished expression of the sodium channels. We examined the expression of two regulatory transcription factors: (a) a positive regulator YY1 that binds to the promoter region of sodium channels and (b) an upstream negative neuronal regulator REST., Key Findings: REST expression was significantly elevated, while YY1 expression was diminished. Finally, we also observed that the cholinergic synthetic enzyme acyltransferase was also significantly diminished in sensory nerve lysates. Finally, circulating antibodies was detected in the peripheral blood against all the major sodium channels Nav1.6, 1.8 and 1.9, which contribute to the development and propagation of action potentials., Significance: This may potentially explain why its dysfunction affects neurological functions across all systems of the body during critical illness. The underlying mechanism of why the expression of the REST transcriptional factor is affected in critical illnesses remains our future goals of investigation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.

Background: Development of polyneuropathy (PNP) under treatment for tuberculosis (TB), including isoniazid (INH), is a highly relevant adverse drug effect. The NAT2 acetylation status is a predictor of potential toxic effects of INH. The question as to whether individual risk stratification by genotyping is useful to avoid suffering of patients and to lower costs for the health care system is of considerable clinical importance., Case Presentation: After drug treatment for TB, including INH, a 23-year-old man developed severe PNP. During the treatment, laboratory results have been indicating incipient liver and renal injury. Later, molecular genetic analyses were performed and revealed a variation in the NAT2 gene and the c1/c2 genotype of the CYP2E1 gene, both described to contribute to an elevated risk for anti-tuberculostatic-induced liver damages (ATIL)., Conclusion: The combination of metabolizer genotypes should be taken into account as a cause for toxic effects and the development of PNP. Individual genotyping, performed before medication or at least if an elevation of liver parameters is observed, may reduce the risk of severe cases of PNP by early adjustment of treatment. Our case study indicates that evaluation of individual risk stratification with systematic pharmacogenetic genotyping of metabolizer gene combinations in the context of TB treatment should be addressed in clinical studies with larger cohorts.

Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models., (Copyright © 2015 the American Physiological Society.)

Background: Mononeuropathies (MNs: nerve ligation) and polyneuropathies (PNs: cisplatin) produce unilateral and bilateral tactile allodynia, respectively. We examined the effects of intraplantar (IPLT) and intrathecal (IT) botulinum toxin B (BoNT-B) on this allodynia., Methods: Mice (male c57Bl/6) were prepared with an L5 nerve ligation. Others received cisplatin (IP 2.3 mg/kg/d, every other day for 6 injections). Saline and BoNT-B were administered through the IPLT or IT route. We examined mechanical allodynia (von Frey hairs) before and at intervals after BoNT. As a control, we injected IPLT BoNT-B treated with dithiothreitol to cleave heavy chain from light chain. We measured motor function using acute thermal escape and sensorimotor tests., Results: MN and PN mice showed a persistent ipsilateral and bilateral allodynia, respectively. IPLT BoNT-B resulted in an ipsilateral dorsal horn reduction in the synaptic protein target of BoNT-B (vesicle-associated membrane protein) and a long-lasting (up to approximately 17 days) reversal of allodynia in PN and MN models. The predominant effect after IPLT delivery was ipsilateral to IPLT BoNT. The effects of IPLT BoNT-B in MN mice were blocked by prior reduction of BoNT-B with dithiothreitol. IT BoNT-B in mice with PN resulted in a bilateral reversal of allodynia. With these dosing parameters, hind paw placing and stepping reflexes were unaltered, and there were no changes in thermal escape latencies. After cisplatin, dorsal root ganglions displayed increases in activation transcription factor 3, which were reduced by IT, but not IPLT BoNT-B., Conclusions: BoNT-B given IPLT and IT yields a long-lasting attenuation of the allodynia in mice displaying MN and PN allodynia.

Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes., Competing Interests: The authors have declared that no competing interests exist.

Vitamin B6 intoxication can result in a sensory ataxic neuropathy, but the association with a milder predominantly sensory or sensorimotor phenotype in chronic idiopathic axonal polyneuropathy (CIAP) remains unclear. A total of 381 patients with CIAP and 140 healthy controls were prospectively included. In a standardized fashion the use of vitamin B6 containing supplements and vitamin B6 levels were compared between patients and controls. On follow-up, patients were questioned about cessation of supplement use and the impact on the symptoms of polyneuropathy. Vitamin B6 levels in patients (median: 99 nmol/l, range: 38-2,967 nmol) were not significantly higher than in controls (median: 109 nmol/l, range: 41-2,373 nmol/l, p = 0.58), nor were daily dose, cumulative dose or duration of supplement use. However, more patients (31%) than controls (22%) used vitamin B6 containing supplements (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.0-2.7, p = 0.032). Follow-up of patients confirming the cessation of supplements showed slow progression of symptoms in 64%, stabilization in 26%, and regression in 10%. On the basis of our prospective case-control study and review of the literature, an association between CIAP and vitamin B6 exposure or elevated vitamin B6 levels appears unlikely., (© 2014 Peripheral Nerve Society.)

Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [Ki (nM)/EC50 (nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 µg/kg after intravenous and 25.1 µg/kg after oral administration. In comparison with selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol's duration of action is long (up to 7 hours after intravenous 12 µg/kg; >9 hours after oral 55 µg/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equianalgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side effect profile.

Objective: In multifocal motor neuropathy (MMN), the destruction of the blood-nerve barrier (BNB) has been considered to be the key step in the disease process. The purpose of the present study was to ascertain whether sera from patients with MMN can open the BNB, and which component of patient sera is the most important for this disruption., Methods: We evaluated the effects of sera from patients with MMN, patients with amyotrophic lateral sclerosis, and control subjects on the expression of tight junction proteins and vascular cell adhesion molecule-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human peripheral nerve microvascular endothelial cells (PnMECs)., Results: The sera from patients with MMN decreased the claudin-5 protein expression and the TEER in PnMECs. However, this effect was reversed after application of an anti-vascular endothelial growth factor (anti-VEGF) neutralising antibody. The VEGF secreted by PnMECs was significantly increased after exposure to the sera from patients with MMN. The sera from patients with MMN also increased the VCAM-1 protein expression by upregulating the nuclear factor kappa-B (NF-κB) signalling. The immunoglobulin G purified from MMN sera decreased the expression of claudin-5 and increased the VCAM-1 expression in PnMECs., Conclusions: The sera from MMN patients may disrupt the BNB function via the autocrine secretion of VEGF in PnMECs, or the exposure to autoantibodies against PnMECs that are contained in the MMN sera. Autoantibodies against PnMECs in MMN sera may activate the BNB by upregulating the VCAM-1 expression, thereby allowing for the entry of a large number of circulating inflammatory cells into the peripheral nervous system.

Complex evaluation covered parameters pro- and antioxidant system in some somatic diseases, mostly in arthrosis and polyneuropathies due to occupational factor of functional overstrain. The results obtained prove influence of prolonged occupational functional overstrain causing excessive free oxidative radicals formation, strain of antioxidant status and subsequent oxidant stress--that is clinically manifested with "mutual burden" syndrome in combined occupational diseases.

PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts) is a recently described autosomal-recessive neurodegenerative disease caused by mutations in the α-β-hydrolase domain-containing 12 gene (ABHD12). Only five homozygous ABHD12 mutations have been reported and the pathogenesis of PHARC remains unclear. We evaluated a woman who manifested short stature as well as the typical features of PHARC. Sequence analysis of ABHD12 revealed a novel heterozygous c.1129A>T (p.Lys377*) mutation. Targeted comparative genomic hybridization detected a 59-kb deletion that encompasses exon 1 of ABHD12 and exons 1-4 of an adjacent gene, GINS1, and includes the promoters of both genes. The heterozygous deletion was also carried by the patient's asymptomatic mother. Quantitative reverse transcription-PCR demonstrated ∼50% decreased expression of ABHD12 RNA in lymphoblastoid cell lines from both individuals. Activity-based protein profiling of serine hydrolases revealed absence of ABHD12 hydrolase activity in the patient and 50% reduction in her mother. This is the first report of compound heterozygosity in PHARC and the first study to describe how a mutation might affect ABHD12 expression and function. The possible involvement of haploinsufficiency for GINS1, a DNA replication complex protein, in the short stature of the patient and her mother requires further studies., (© 2013 WILEY PERIODICALS, INC.)

The autosomal dominant disorder neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome caused by inactivation of the NF2 tumor suppressor gene, encoding merlin. Apart from tumors affecting the peripheral and central nervous systems, most NF2 patients develop peripheral neuropathies. This peripheral nerve disease can occur in the absence of nerve-damaging tumors, suggesting an etiology that is independent of gross tumor burden. We discovered that merlin isoform 2 (merlin-iso2) has a specific function in maintaining axonal integrity and propose that reduced axonal NF2 gene dosage leads to NF2-associated polyneuropathy. We identified a merlin-iso2-dependent complex that promotes activation of the GTPase RhoA, enabling downstream Rho-associated kinase to promote neurofilament heavy chain phosphorylation. Merlin-iso2-deficient mice exhibited impaired locomotor capacities, delayed sensory reactions and electrophysiological signs of axonal neuropathy. Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons.

Advances in human genetics are leading to the discovery of new disease-causing mutations at a remarkable rate. Many such mutations, however, occur in genes that encode for proteins of unknown function, which limits our molecular understanding of, and ability to devise treatments for, human disease. Here, we use untargeted metabolomics combined with a genetic mouse model to determine that the poorly characterized serine hydrolase α/β-hydrolase domain-containing (ABHD)12, mutations in which cause the human neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract), is a principal lysophosphatidylserine (LPS) lipase in the mammalian brain. ABHD12(-/-) mice display massive increases in a rare set of very long chain LPS lipids that have been previously reported as Toll-like receptor 2 activators. We confirm that recombinant ABHD12 protein exhibits robust LPS lipase activity, which is also substantially reduced in ABHD12(-/-) brain tissue. Notably, elevations in brain LPS lipids in ABHD12(-/-) mice occur early in life (2-6 mo) and are followed by age-dependent increases in microglial activation and auditory and motor defects that resemble the behavioral phenotypes of human PHARC patients. Taken together, our data provide a molecular model for PHARC, where disruption of ABHD12 causes deregulated LPS metabolism and the accumulation of proinflammatory lipids that promote microglial and neurobehavioral abnormalities.

To establish the role of the metabolic state in the pathogenesis of polyneuropathy, an age- and sex-matched, longitudinal study in rats fed high-fat and high-sucrose diets (HFSD) or high-fat, high-sucrose and high-salt diets (HFSSD) relative to controls was performed. Time courses of body weight, systolic blood pressure, fasting plasma glucose (FPG), insulin, free fatty acids (FFA), homeostasis model assessment-insulin resistance index (HOMA-IR), thermal and mechanical sensitivity and motor coordination were measured in parallel. Finally, large and small myelinated fibers (LMF, SMF) as well as unmyelinated fibers (UMF) in the sciatic nerves and ascending fibers in the spinal dorsal column were quantitatively assessed under electron microscopy. The results showed that early metabolic syndrome (hyperinsulinemia, dyslipidemia, and hypertension) and prediabetic conditions (impaired fasting glucose) could be induced by high energy diet, and these animals later developed painful polyneuropathy characterized by myelin breakdown and LMF loss in both peripheral and central nervous system. In contrast SMF and UMF in the sciatic nerves were changed little, in the same animals. Therefore the phenomenon that high energy diets induce bilateral mechanical, but not thermal, pain hypersensitivity is reflected by severe damage to LMF, but mild damage to SMF and UMF. Moreover, dietary sodium (high-salt) deteriorates the neuropathic pathological process induced by high energy diets, but paradoxically high salt consumption, may reduce, at least temporarily, chronic pain perception in these animals.

Gene transfer to target delivery of neurotrophic factors to the primary sensory afferent for treatment of polyneuropathy, or of inhibitory neurotransmitters for relief of chronic pain, offers the possibility of a highly selective targeted release of bioactive molecules within the nervous system. Preclinical studies with non-replicating herpes simplex virus (HSV)-based vectors injected into the skin to transduce neurons in the dorsal root ganglion have demonstrated efficacy in reducing-pain related behaviors in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer, and in preventing progression of sensory neuropathy caused by toxins, chemotherapeutic drugs or resulting from diabetes. Successful completion of the first phase 1 clinical trial of HSV-mediated gene transfer in patients with intractable pain from cancer has set the stage for further clinical trials of this approach., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Systemic vascular endothelial growth factor inhibition, in combination with chemotherapy, improves the outcome of patients with metastatic cancer. Peripheral sensory neuropathies occurring in patients receiving both drugs are attributed to the chemotherapy. Here, we provide unprecedented evidence that vascular endothelial growth factor receptor inhibitors trigger a painful neuropathy and aggravate paclitaxel-induced neuropathies in mice. By using transgenic mice with altered neuronal vascular endothelial growth factor receptor expression, systemic inhibition of vascular endothelial growth factor receptors was shown to interfere with the endogenous neuroprotective activities of vascular endothelial growth factor on sensory neurons. In vitro, vascular endothelial growth factor prevented primary dorsal root ganglion cultures from paclitaxel-induced neuronal stress and cell death by counteracting mitochondrial membrane potential decreases and normalizing hyperacetylation of α-tubulin. In contrast, vascular endothelial growth factor receptor inhibitors exerted opposite effects. Intriguingly, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors exerted their effects through a mechanism whereby Hdac6, through Hsp90, controls vascular endothelial growth factor receptor-2-mediated expression of the anti-apoptotic Bcl2. Our observations that systemic anti-vascular endothelial growth factor therapies interfere with the neuroprotective activities of vascular endothelial growth factor may have important implications for the application of anti-vascular endothelial growth factor therapies in cancer patients.

Given the availability of effective but costly treatment for acquired demyelinating neuropathies, biomarkers for these disorders are urgently needed. Here we aimed to quantify morphological abnormalities of myelinated fibers in skin biopsies from the proximal leg of patients with neuropathies to determine a potential diagnostic role of this method. We used double immunofluorescence to detect myelinated and unmyelinated fibers in thigh skin from 81 patients with polyneuropathy, 19 patients with small fiber neuropathy, and 25 controls. Dermal myelinated fibers were reduced 6.8-fold in patients with polyneuropathy (p < 0.0001). The number of dermal nerve bundles with myelinated fibers was reduced 2.7-fold (p = 0.0025). In small fiber neuropathy, myelinated fibers in dermal nerve bundles were only reduced in the length-dependent type, indicating that this subgroup may represent an early stage of generalized polyneuropathy. Elongated nodes of Ranvier were detectable in demyelinating neuropathies only. Our data suggest that changes in the number and morphology of myelinated fibers in the proximal leg can confirm the diagnosis of neuropathy, and may help to distinguish between demyelinating and axonal neuropathy, and to differentiate pure small fiber neuropathy from early polyneuropathy.

The events leading to the degradation of the endogenous PrP(C) (normal cellular prion protein) have been the subject of numerous studies. Two cleavage processes, α-cleavage and β-cleavage, are responsible for the main C- and N-terminal fragments produced from PrP(C). Both cleavage processes occur within the N-terminus of PrP(C), a region that is significant in terms of function. α-Cleavage, an enzymatic event that occurs at amino acid residues 110 and 111 on PrP(C), interferes with the conversion of PrP(C) into the prion disease-associated isoform, PrP(Sc) (abnormal disease-specific conformation of prion protein). This processing is seen as a positive event in terms of disease development. The study of β-cleavage has taken some surprising turns. β-Cleavage is brought about by ROS (reactive oxygen species). The C-terminal fragment produced, C2, may provide the seed for the abnormal conversion process, as it resembles in size the fragments isolated from prion-infected brains. There is, however, strong evidence that β-cleavage provides an essential process to reduce oxidative stress. β-Cleavage may act as a double-edged sword. By β-cleavage, PrP(C) may try to balance the ROS levels produced during prion infection, but the C2 produced may provide a PrP(Sc) seed that maintains the prion conversion process.

Serum antibodies to different gangliosides have been identified in some Guillain-Barré (GBS) subtypes and variants. In the January issue of Experimental Neurology Susuki and colleagues (2012) showed that in experimental neuropathies associated with antibodies to GM1, GD1a and GD1b the common mechanism is a complement mediated dysfunction and disruption of the nodes of Ranvier which causes a pathophysiological continuum from early reversible conduction failure to axonal degeneration. These observations, correlated and integrated with electrophysiological and pathological findings in humans indicate that the GBS subtypes acute motor conduction block neuropathy, acute motor axonal neuropathy, acute motor and sensory neuropathy and acute sensory neuropathy and possibly also a chronic disorder as multifocal motor neuropathy represent a spectrum of the same immunopathologic process. Being the nodal axolemma and the paranode the focus of the nerve injury, these immune mediated neuropathies could be more properly classified as nodo-paranodopathies., (Copyright © 2012 Elsevier Inc. All rights reserved.)