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Chemotherapy-induced peripheral neuropathy (CIPN) is widely recognized as a potentially severe toxicity that often leads to dose reduction or discontinuation of cancer treatment. Symptoms may persist despite discontinuation of chemotherapy and quality of life can be severely compromised. The clinical symptoms of CIPN, and the cellular and molecular targets involved in CIPN, are just as diverse as the wide variety of anticancer agents that cause peripheral neurotoxicity. There is an urgent need for extensive molecular and functional investigations aimed at understanding the mechanisms of CIPN. Furthermore, a reliable human cell culture system that recapitulates the diversity of neuronal modalities found in vivo and the pathophysiological changes that underlie CIPN would serve to advance the understanding of the pathogenesis of CIPN. The demonstration of experimental reproducibility in a human peripheral neuronal cell system will increase confidence that such an in vitro model is clinically useful, ultimately resulting in deeper exploration for the prevention and treatment of CIPN. Herein, we review current in vitro models with a focus on key characteristics and attributes desirable for an ideal human cell culture model relevant for CIPN investigations.

COPD is a common chronic disease with genetic predisposition. TRPV1 is mainly expressed in peripheral neuron which widely exists in entire respiratory tract. In present study, we aimed to study the relationship between single nucleotide polymorphisms (SNPs) of transient receptor potential vanilloid-1 (TRPV1) and the risk of chronic obstructive pulmonary disease (COPD) or COPD combined with pulmonary hypertension (PH) in Chinese Han population. A total of 1019 individuals, including 506 healthy volunteers and 513 COPD patients (150 patients combined with PH among them) were recruited in this study. Genomic DNA were extracted and sequenced. Genotype and allele frequencies of the TRPV1 SNPs among COPD, COPD combined with PH and control groups were compared. Then, the association of TRPV1 SNPs and smoking status were analyzed. Genotype frequencies of SNP rs3744683 had a significant difference in COPD patients with PH patients compared with control (p = 0.006) or COPD patients without PH patients (p = 0.016). Likewise, SNP rs3744683 was remarkedly associated with the risk of COPD (p = 0.004) in current-smoker groups which phenomenon was not observed in nonsmoker or former-smoker groups. Compared with the control group, there was a significant difference for the distribution of SNP rs4790521 alleles in the COPD group (p = 0.041). For further, logical regression analysis showed that SNP rs3744683 genotype of “TC” was a protective factor for PH in COPD patients compared with the genotype of “TT” (OR = 0.364, 95%CI = 0.159–0.829, p = 0.016). Our findings firstly revealed the relevance between TRPV1 SNPs and the risk for COPD/COPD combined with PH.

Highlights • New techniques emerge to study peripheral sensory neurons in iPS-cell derived models. • Genetic pain syndromes, e.g. gain- and loss-of-function mutations in Nav-channels are helpful. • Individualized treatment for neuropathic pain can be identified with iPS-cell derived nociceptors., In this concise Mini-Review we will summarize ongoing developments of new techniques to study physiology and pathophysiology of the peripheral sensory nervous system in human stem cell derived models. We will focus on recent developments of reprogramming somatic cells into induced pluripotent stem cells, neural differentiation towards neuronal progenitors and human sensory neurons. We will sum up the high potential of this new technique for disease modelling of human neuropathies with a focus on genetic pain syndromes, such as gain- and loss-of-function mutations in voltage-gated sodium channels. The stem cell derived human sensory neurons are used for drug testing and we will summarize their usefulness for individualized treatment identification in patients with neuropathic pain. The review will give an outlook on potential application of this technique as companion diagnostics and for personalized medicine.

In this study, we propose a novel method for inducing neuronal cells by briefly exposing them to small-molecule cocktails in a step-by-step manner. Global gene expression analysis with immunohistochemical staining and calcium flux assays reveal the generation of neurons from mouse embryonic fibroblasts. In addition, time-lapse imaging of neural precursor-specific enhancer expression and global gene expression analyses show that the neurons are generated by passing through a neural crest-like precursor stage. Consistent with these results, the neural crest-like cells are able to differentiate into neural crest lineage cells, such as sympathetic neurons, adipocytes, osteocytes, and smooth muscle cells. Therefore, these results indicate that brief exposure to chemical compounds could expand and induce a substantial multipotent cell population without viral transduction.

Mitochondrial dysfunction causes various diseases. Mutations in the SLC25A46 gene have been identified in mitochondrial diseases that are sometimes classified as Charcot-Marie-Tooth disease type 2, optic atrophy, and Leigh syndrome. A homolog of SLC25A46 was identified in Drosophila and designated as dSLC25A46 (CG5755). We previously established mitochondrial disease model targeting of dSLC25A46, which causes locomotive dysfunction and morphological defects at neuromuscular junctions, such as reduced synaptic branch lengths and decreased numbers of boutons. The diverse symptoms of mitochondrial diseases carrying mutations in SLC25A46 may be associated with the dysregulation of some epigenetic regulators. To investigate the involvement of epigenetic regulators in mitochondrial diseases, we examined candidate epigenetic regulators that interact with human SLC25A46 by searching Gene Expression Omnibus (GEO). We discovered that HDAC1 binds to several SLC25A46 genomic regions in human cultured CD4 (+) cells, and attempted to prove this in an in vivo Drosophila model. By demonstrating that Rpd3, Drosophila HDAC1, regulates the histone H4K8 acetylation state in dSLC25A46 genomic regions, we confirmed that Rpd3 is a novel epigenetic regulator modifying the phenotypes observed with the mitochondrial disease model targeting of dSLC25A46. The functional reduction of Rpd3 rescued the deficient locomotive ability and aberrant morphology of motoneurons at presynaptic terminals induced by the dSLC25A46 knockdown. The present results suggest that the inhibition of HDAC1 suppresses the pathogenic processes that lead to the degeneration of motoneurons in mitochondrial diseases.

Graphene displays properties that make it appealing for neuroregenerative medicine, yet its interaction with peripheral neurons has been scarcely investigated. Here, we culture on graphene two established models for peripheral neurons: PC12 cells and DRG primary neurons. We perform a nano-resolved analysis of polymeric coatings on graphene and combine optical microscopy and viability assays to assess the material cytocompatibility and influence on differentiation. We find that differentiated PC12 cells display a remarkably increased neurite length on graphene (up to 27%) with respect to controls. Notably, DRG primary neurons survive both on bare and coated graphene. They present dense axonal networks on coated graphene, while they form cell islets characterized by dense axonal bundles on uncoated graphene. These findings indicate that graphene holds potential for nerve tissue regeneration and might pave the road to novel concepts of active nerve conduits.

Lower motoneuron degeneration are not among the characteristic features of Parkinson’s disease(PD), although there are single studies considering the peripheral neuron involvement in PD as a continuum of degenerative process. The aim of our study was to find out if possible lower motor neuron involvement in PD is reflected with the MUNE method (motor unit number estimation). Material and methods 41 patients with PD (mean age 62.6 yrs; 51%M) were included. The control group consisted of 45 healthy volunteers. MUNE with multipoint incremental method was calculated in the abductor pollicis brevis (APB), the abductor digiti minimi (ADM) and the extensor digitorum brevis (EDB). Results Significant difference in the number of motor units estimating by MUNE was found between groups aged 60 years or older in ADM comparing with control group (p Conclusions The loss of motor units in sporadic Parkinson’s disease revealed by the multipoint incremental MUNE method may be considered as a sign of lower motor neuron involvement and a feature of generalized neurodegeneration.

Professor Kazimiera Milanowska is a rehabilitation physician and academic scholar of international renown. She has extensive expert knowledge and scientific achievements in the fields of medical rehabilitation and physical culture sciences. The aim of the present biographical study was to present the development of Prof. Kazimiera Milanowska's career. As Head of the Rehabilitation Department at the Medical Academy in Poznan, she delivered lectures on the clinical foundations of rehabilitation and theory and philosophy of modern rehabilitation as well as numerous courses on methods of musculoskeletal compensation and adaptation, muscle reeducation, and rehabilitation following peripheral neuron injury. Kazimiera Milanowska has published numerous papers and books (221). She was the pioneer of combined electromyographic and ergometric diagnostics in Poland.

In this article the role of neurobiological, psychological and social factors in pathogenesis of chronic pain is analyzed. The chronic pain is considered not as a symptom of damage of tissue and as independent illness due to non-adequate neuroplasticity of systems involved into regulation of pain sensitivity. The major role in development and maintenance of chronic pain is devoted to the primary genetically determined and/or secondary disturbance of interaction between nociceptive and antinociceptive systems at various levels - from peripheral neuron to central structures – that provides pain perception and painful behaviour development.

Previous studies have indicated that the formation of stereotyped segmental nerves in leech embryos depends on the interactions between CNS projections and ingrowing afferents from peripheral neurons. Especially, CNS-ablation experiments have suggested that CNS-derived guidance cues are required for the correct navigation of several groups of peripheral sensory neurons. In order to directly test this hypothesis we have performed transplantations of CNS ganglia into ectopic sites in segments from which the resident ganglia have been removed. We find that the transplanted ganglia extend numerous axons distributed roughly equally in all directions. When these CNS projections reach and make contact with peripheral sensory axons they are used as guides for peripheral neurons to grow toward and into the ectopic ganglia even when this means following novel pathways that cross the midline and/or segmental boundaries. The peripheral sensory axons turn and grow toward the ectopic ganglia only when in physical contact with CNS axons, suggesting that diffusible chemoattractants are not a factor. These results demonstrate that the guidance cues provided by ectopic CNS projections are both necessary and sufficient to steer peripheral sensory neuron axons into the CNS.

Organophosphorus pesticides (OPs), one of the most popular classes of pesticides, are widely used all over the world especially in developing countries, such as China. There are many OPs, with thousands of trade names such as dimethoate, parathion and omethoate, most of which have been used for insect control in residential and agriculture settings. The acute toxicity of OPs are believed to be due primarily to the inhibition of acetylcholinesterase (AChE) resulting in an accumulation of acetylcholine (Ach) with a sustained overstimulation of Ach receptors in the clefts of central and peripheral neuron synapses. They can cause a progression of toxic signs, including hypersecretions, convulsions, respiratory distress, coma and death. However, the heavy usage of OPs has given rise to wide public concern on their chronic toxicity. Generally, long-tem exposure to OPs can be divided into occupational exposure and nonoccupational exposure. The former often involves farming population and workers employed in pesticide-related industries. And the latter is more for general population potentially exposed to OPs via a number of different routes including dietary, lifestyle or medicinal. China is a large country with large demand of pesticides. This means that there are much more Chinese people, both occupational and non-occupational population, whose health are under the threat of OPs exposure. The presence of common and specific metabolites of OPs in urine samples taken from the general population has demonstrated the widespread exposure to OPs in China. Moreover, workers engaged in OPs production are at high risk from OPs exposure, as confirmed by higher levels of OPs metabolites in biological samples compared to those present in individuals from non-agricultural communities. Therefore, a great deal of research has been conducted by Chinese scientists to understand the adverse effects of long-term, low-level exposure to OPs in both general and occupational population.

Perceptual multi-stability can be induced by either using some ambiguous figures (such as Neckar Cube or Face/ Vase figure) or showing different images to left and right eyes (binocular rivalry). The observer will experience a persistent switching between different perceptual representations of the same image. The switching process is spontaneous and irregular: time intervals between consequent switching would form some Gaussian-like distribution [1,2]. Switching is highly involuntary and usually human subjects cannot use their "will power" to control the process. Many behavioral experiments have been carried out. Levelt [3,4] found that during binocular rivalry, when the image brightness to one eye increased, the mean duration of perception from the other eye decreased (but little was change on the duration from the same eye). Leopold et al. [5] found that for ambiguous figures, the switching process would slow down if the figure appeared and disappeared periodically.

Intact pigeons (n = 64) were rotated in the dark in the horizontal plane at different orientations relative to the axis of rotation. The overall patterns of changes in nystagmus of the eyes arising as a result of displacement of the otolith membranes in several directions were analyzed. In ten pigeons, all changes in nystagmus (type 1 general patterns) could be explained in terms of the dynamics of peripheral neuron activity and non-specific (identical for all combinations of interacting inputs) central influences. In the remaining pigeons, part of the change in nystagmus (type 2 general patterns) was associated with central influences which were not identical for different combinations of interacting inputs. Repeated unusual combinations of vestibular stimuli and subsequent treatment with Nembutal transformed type 2 general patterns into type 1 general patterns. These data provide evidence for the fragmentary control of eye movements, whereby there is selective (fragmentary) modification of only some (individually specific) combinations of canal and otolith signals out of the whole set of vestibuloocular responses arising in response to stimulation of paired vestibular inputs; modification is mediated by changes in the sign of otolith influences on the canal components of these responses.

UMMARY Electrophysiological examinations were performed on 32 children aged three to 17 years who had typical clinical manifestations of ataxia-telangiectasia (AT). EMG findings demonstrated neurogenic lesions, more pronounced in the distal leg muscles of older children where they resembled the picture characteristic of motor neuron disease. Electrophysiological and nerve conduction results showed that generalised, progressive, sensory nervous system degeneration, with neurogenic amyotrophy affecting the distal part of the lower limbs, is an established feature of this disease and can be considered one of the diagnostic characteristics of AT. This allows the syndrome to be classified as an hereditary spinocerebellar degeneration. RESUME Degeneration neuronale peripherique progressive dans I'ataxie/telangiectasie: etude electrophysiologique chez I'enfant Des examens electrophysiologiques ont ete realises chez 32 enfants ages de trois a 17 ans, presentant les signes cliniques manifestes d'une ataxie-telangiectasie (AT). Les donnees EMG demontrerent l'existence de lesions neurogeniques, plus prononcees sur les muscles distaux des jambes, chez les enfants les plus ages, evoquant les images caracteristiques d'affections du neurone moteur. Les resultats de l'electrophysiologie et de la conduction nerveuse revelerent qu'une degeneration generalisee, du systeme nerveux sensoriel avec amyotrophie neurogenique affectant la partie distale des membres inferieurs est une donnee etablie de la maladie et peut etre consideree comme une caracteristique diagnostique de l'AT. Cela permet de classer le syndrome comme une degeneration hereditaire spino-cerebelleuse. ZUSAMMENFASSUNG Progressive periphere Neurodegeneration bei der Ataxia-Teleangiectasia: eine elektrophysiologicshe Untersuchung bei Kindern Bei 32 Kindern in Alter zwischen drei und 17 Jahren, die typische klinische Merkmale einer Ataxia-Telangiectasia (AT) hatten, wurden elektrophysiologische Untersuchungen durchgefuhrt. Die EMG-Befunde zeigten neurogene Lasionen, die bei alteren Kindern in den distalen Beinmuskeln ausgepragter waren und dem charakteristischen Bild einer Erkrankung des Motorneurons ahnelten. Die elektrophysiologischen Befunde und die Nervenleitgeschwindigkeiten zeigten, daβ eine generalisierte, progressive Degeneration des sensiblen Nervensystems mit neurogener Amyotrophie des distalen Anteils der unteren Extremitaten ein sicheres Merkmal dieser Erkrankung ist und als eins der diagnostischen Charakteristika fur die AT angesehen werden kann. Damit kann das Syndrom als eine hereditare spinocerebellare Degeneration klassifiziert werden. RESUMEN Degeneracion neuronal periferica progresiva en la ataxia telangiectasis Se relizaron examenes electrofisiologicos en 32 ninos de tres a 17 anos, que tenian manifestaciones clinicas tipicas de ataxia-teleangiectasia (AT). Los hallazgos EMG demostraron una lesion neurogenica mas pronunciada en los musculos distales de la pierna en los ninos mayores, que se parecia al cuadro caracteristico de la enfermedad neuronal motora. Los resultados electrofisiologicos y de la conduccion nerviosa mostraron que la degeneracion del sistema nervioso sensorial generalizada y progresiva con amiotrofia neurogenica, afectando la parte distal de las extremidades inferiores, constituye una caracteristica de esta enfermedad y que puede ser considerada como una caracteristica diagnostica de la AT. Esto permite clasificar el sindrome como una degeneracion espinocerebelosa hereditaria.

To the Editor. —Chronic inflammatory demyelinating polyneuropathy is a disease of the peripheral neuron with unknown cause. Management of the disorder is still a subject of study. Recently, several studies 1-5 have demonstrated that treatment with high-dose intravenous immunoglobulin has a clear effect on chronic inflammatory demyelinating polyneuropathy. Repeated treatments for a long period are common. 5 In some cases, it might be better to use plasma exchange. 6 We present a patient with chronic inflammatory demyelinating polyneuropathy who was treated with high-dose intravenous immunoglobulin several times, resulting in short-term amelioration with rapid new deterioration with an initially unknown cause; plasma exchange caused rapid improvement without new deterioration. Report of a Case. —A 66-year-old man was admitted with paresthesia of the lower limbs that had appeared rather suddenly. Later on, progressive weakness of the legs developed, which gradually extended to the arms over a period of several weeks. There were

During 1965 to 1968, 80 workers who had been engaged in the production of 2, 4, 5-sodium trichlorphenoxyacetate and butylester of trichlorphenoxyacetate acid became ill. The cause of the illness was 2, 4, 7, 8-tetrachlordibenzo-p-dioxin. A 10-yr study has been conducted for 55 exposed individuals. The majority of the patients developed chloracne, and 11 manifested porphyria cutanea tarda. Approximately one-half of the patients suffered from metabolic disturbances, i.e., pathologically elevated lipids with abnormalities in the lipoprotein spectrum, and two-fifths of the patients had pathological changes in the glucose tolerance test. One-third of the patients had biochemical deviations indicative of a mild liver lesion. Histological examination revealed light steatosis, or periportal fibrosis, or activation of Kupffer cells. Fluorescence of the liver tissues was present in ultraviolet light. In 17 persons symptoms of nervous system focal damage existed, with predominance of peripheral neuron lesion of the lower extremities (verified by EMG examination). The majority of patients suffered from various psychological disorders. As of this date, two patients have died of bronchogenic lung carcinoma; one of liver cirrhosis; one of a rapidly developed, extremely unusual type of atherosclerosis precipue cerebri; and two patients have died in traffic accidents. The conditions of most other patients have improved.

(1) 17 cases of intoxication polyneuritis occurred in 17 workers exposed to n-hexane vapour in recent years, from 1960 to 1962, in Japan. (2) 6 cases of those occurred in 3 small polyethylene laminating plants. In these plans, in the first process, gravure printed cellophane sheet was smeared with n-hexane solution containing 5% organic titan, tetra isopropyl titan or tetra buthyl titan. Solvent n-hexane was vapourized with warm air and n-hexane vapour contaminated the air of the workroom. Organic titan, remained on the printed surfarce of cellophane sheet, was rapidly hydrolized with water in the air to titan oxide. In the second process, fused polyethylene was painted thinly on this surface. Titan oxide on this surface accelerated adhesion of polyethylene with cellophane, and cellophane sheet was laminated fast with polyethylene. This laminated sheet had the character of clear printed colour and water-proof, and was used widely as packing materials of foods, confectionery and others. Concentration of n-hexane vapour in the air around the machine in the first process was 1000s2500 ppm. N-hexane used in these plants contained impurties, i.e. methyl pentane (16%) methyl cyclopentane (20%). Titan was not detected in the air. Working time was 10s12 hours and workers became drausy in half or one hour and went outdoor to inspire fresh air for 10 to 15 minutes. (3) 11 cases of those occurred in a great pharmaceutical plant. In this plant, 95% n-hexane was used as a remover of grease on the surface of tablets. Tablets in wire netting were immersed for 5 minutes in n-hexane within the immersion box, and tablets in wire netting were dried on the shelf. N-hexane vapourized from the surface of the tablets and the immersion box. Concentration of n-hexane vapour was 1000 ppm around the immersion box and 500 ppm at the center of the workroom. Workers stayed in this room for 8 hours except for the noon recess. (4) In all cases symptoms of intoxican began with the same subjective complaints. The first complaint was fatigue in all cases and loss of appetite in some cases, followed by paresthesia in distal parts of the extremities, weakness, and difficulty in walking. Symptoms and signs advanced during the exposure and this progress was arrested finally three months after removing from the exposure, and the symptoms gradually improved throughout the period between six and thiry months. This characteristic process of development and improvement of symptoms was not such as usually seen in common polyneuritis. All diagnosis of these cases by clinical and hygienic examinations was intoxication polyneuritis of the mixed form. (5) In the first case, n-hexane, impurities in n-hexane and organic titan were suspected of the causes of intoxication. But in the second case, the cause was only n-hexane. N-hexane causes undoubtedly intoxication polyneuritis in man. One of my co-workers, Miyagaki proved experimentally the occurrence of intoxication neuritis due to n-hexane in rats. (6) Till now, n-hexane was regarded as of lowtoxic solvent owing to its low toxicity on the hematopoiesis and the liver function. But the present result showed that toxicity of n-hexane on the peripheral neuron was not insignificant.

Historical review. The clinical classification of cases studied. The microscopic changes of central neuritis. Report of cases. The symptom-complex of central neuritis. Neurologic symptoms. Systemic symptoms. Mental symptoms. The etiology of central neuritis. Possible etiologic factors. Axonal injury. Toxins, endogenous and exogenous. Infection. Type of terminal illness. Starvation. Theoretical considerations. A new name for central neuritis. Summary. Conclusions. The pathologic process known as "central neuritis" involves particularly the ganglion cells and resembles the change found in the cell body of a peripheral neuron after injury to its axon. As the involvement frequently seems severe enough to interfere with function, one would expect that its presence could be detected during life. Although central neuritis is found in many different diseases, there must be a common etiologic factor. In this study, I investigated central neuritis from two points of view: (1) diagnosis during life, and (2) etiology. HISTORICAL REVIEW Central neuritis was