Study of the potential toxicity of adrenaline to neurons, using the SH-SY5Y human cellular model

Abstract Prolonged overexposure to catecholamines causes toxicity, usually credited to continuous adrenoceptor stimulation, autoxidation, and the formation of reactive pro-oxidant species. Non-differentiated SH-SY5Y cells were used to study the possible contribution of oxidative stress in adrenaline (ADR)-induced neurotoxicity, as a model to predict the toxicity of this catecholamine to peripheral nerves. Cells were exposed to several concentrations of ADR (0.1, 0.25, 0.5 and 1mM) and two cytotoxicity assays [lactate dehydrogenase (LDH) release and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction] were performed at several time-points (24, 48, and 96h). The cytotoxicity of ADR was concentration- and time-dependent in both assays, since the lowest concentration tested (0.1mM) also caused significant cytotoxicity at 96h. N-acetyl-cysteine (1mM), a precursor of glutathione synthesis, prevented ADR-induced toxicity elicited by 0.5mM and 0.25mM ADR following a 96-h exposure, while the antioxidant Tiron (100µM) was non-protective. In conclusion, ADR led to mitochondrial distress and ultimately cell death in non-differentiated SH-SY5Y cells, possibly because of ADR oxidation products. The involvement of such processes in the catecholamine-induced peripheral neuropathy requires further analysis.

Value of shear wave elastography combined with the Toronto clinical scoring system in diagnosis of diabetic peripheral neuropathy.

ABSTRACT: To evaluate the diagnostic values of shear wave elastography (SWE) alone and in combination with the Toronto clinical scoring system (TCSS) on diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (T2DM).The study included 41 DPN patients, 42 non-DPN patients, and 21 healthy volunteers. Conventional ultrasonography and SWE were performed on the 2 sides of the tibial nerves, and cross-sectional area (CSA) and nerve stiffness were measured. TCSS was applied to all patients. A receiver operating characteristic curve analysis was performed.The stiffness of the tibial nerve, as measured as mean, minimum or maximum elasticity, was significantly higher in patients in the DPN group than the other groups (P < .05). The tibial nerve of subjects in the non-DPN group was significantly stiffer compared to the control group (P < .05). There was no significant difference of the tibial nerve CSA among the 3 groups (P > .05). Mean elasticity of the tibial nerve with a cutoff of 71.3 kPa was the most sensitive (68.3%) and had a higher area under the curve (0.712; 0.602-0.806) among the 3 shear elasticity indices for diagnosing DPN when used alone. When combining SWE with TCSS in diagnosing DPN, the most effective parameter was the EMax, which yielded a sensitivity of 100.00% and a specificity of 95.24%.SWE is a better diagnostic tool for DPN than the conventional ultrasonic parameter CSA, and a higher diagnostic value is attained when combining SWE with TCSS.

Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies. CMT patients typically show slowly progressive muscle weakness and sensory loss in a distal dominant pattern in childhood. The diagnosis of CMT is based on clinical symptoms, electrophysiological examinations, and genetic testing. Advances in genetic testing technology have revealed the genetic heterogeneity of CMT; more than 100 genes containing the disease causative mutations have been identified. Because a single genetic alteration in CMT leads to progressive neurodegeneration, studies of CMT patients and their respective models revealed the genotype-phenotype relationships of targeted genes. Conventionally, rodents and cell lines have often been used to study the pathogenesis of CMT. Recently, Drosophila has also attracted attention as a CMT model. In this review, we outline the clinical characteristics of CMT, describe the advantages and disadvantages of using Drosophila in CMT studies, and introduce recent advances in CMT research that successfully applied the use of Drosophila, in areas such as molecules associated with mitochondria, endosomes/lysosomes, transfer RNA, axonal transport, and glucose metabolism.

Validation of the Arabic Version of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool.

BACKGROUND: Chemotherapy-induced peripheral neuropathy results in multidimensional neurological and muscular symptoms, which interfere with the patients' daily life. AIM: Examine the psychometric properties of the Arabic version of the chemotherapy-induced peripheral neuropathy assessment tool (CIPNAT) among adult cancer patients. METHOD: A descriptive study design was used. A convenience sample of 210 patients was assigned to two groups: 135 who received chemotherapies of known neurotoxic potential and 75 who served as a comparison group. Translation and back-translation considering cross-cultural issues to produce the Arabic version of CIPNAT was used. Test-retest and internal consistency reliability were used to test the reliability of the tool, whereas for the validity, content and construct validity were assessed. RESULTS: Test-retest scores for the overall scale (r = 0.98, p = < .001), for the symptom experience subscale (r = 0.97, p = <.001), and for the interference subscale (r = 0.96, p = < .001) all showed evidence of reliability. Cronbach α coefficients were 0.97, 0.96, and 0.95 for the total scores, symptoms experience, and interference scales, respectively. Items to total correlation ranged from moderate to strong (0.55-0.81). The Content Validity Index was 0.83. The data support the evidence of discriminant validity, as significant differences were found between the groups with regard to symptom experience (t = 8.51, p = < .001), interference (t = 5.60, p = <.001), and total score (t = 7.88, p = < .001). CONCLUSIONS: The Arabic version of CIPNAT showed adequate reliability and validity to screen for chemotherapy-induced peripheral neuropathy symptoms and their interference in Arab countries. Further studies are needed to evaluate concurrent validity.

Chemotherapy-induced peripheral neuropathy among patients with ovarian cancer.

OBJECTIVE: To evaluate the course of chemotherapy-induced peripheral neuropathy (CIPN) among patients with ovarian cancer receiving taxanes. METHODS: In a retrospective case-control study conducted between January 1, 2016, and May 31, 2018, in Xiangya Hospital in Changsha, China, women with ovarian cancer received taxane and platinum-complex combination therapy. The European Organization for Research and Treatment of Cancer Quality of Life, Ovarian cancer module questionnaire, was used to assess the severity of neuropathy by telephone. RESULTS: Out of the 88 women included in the study, 61 (69.3%) reported CIPN. Twelve months after chemotherapy, the percentage was 19.3%. The percentage of patients suffering from sensory peripheral neuropathy (SPN) was higher than motor peripheral neuropathy at any time during the study. Sensory peripheral neuropathy was associated with the use of docetaxel and paclitaxel (docetaxel vs liposomal paclitaxel: odds ratio [OR] 4.39, 95% confidence interval [CI] 1.69-11.42, P<0.01; paclitaxel vs liposomal paclitaxel: OR 5.91, 95% CI 1.09-31.97, P=0.04). The average weakness score in acute CIPN was lower than chronic CIPN (1.46 vs 2.00, P=0.019). Patients treated with vitamin B1 and amifostine experienced better relief from CIPN. CONCLUSION: The present study showed a significant proportion of patients with ovarian cancer receiving taxanes suffered from long-term residual neuropathy, and the use of docetaxel and paclitaxel was associated with SPN. Vitamin B1 or amifostine may improve the symptoms of CIPN.

A Simplified Diagnostic Classification Scheme of Chemotherapy-Induced Peripheral Neuropathy.

Background and Objective. The main purpose of this study was to develop a simple automatic diagnostic classification scheme for chemotherapy-induced peripheral neuropathy. METHODS: This was a prospective cohort study that enrolled patients with colorectal or gynecologic cancer post chemotherapy for more than 1 year. The patients underwent laboratory examinations (nerve conduction studies and quantitative sensory tests), and a questionnaire about the quality of life. An unsupervised classification algorithm was used to classify the patients into groups using a small number of variables derived from the laboratory tests. A panel of five neurologists also diagnosed the types of neuropathies according to the laboratory tests. The results by the unsupervised classification algorithm and the neurologists were compared. RESULTS: The neurologists' diagnoses showed much higher rates of entrapment syndromes (66.1%) and radiculopathies (55.1%) than polyneuropathy (motor/sensory: 33.1%/29.7%). A multivariate analysis showed that the questionnaire was not significantly correlated with the results of quantitative sensory tests (r = 0.27) or the neurologists' diagnoses (r = 0.27) or the neurologists' diagnoses (. CONCLUSION: The results of our unsupervised classification algorithm based on three variables of laboratory tests correlated well with the neurologists' diagnoses.

Peripheral Nerve Vasculitis: Classification and Disease Associations.

"The vasculitic neuropathies encompass a wide range of disorders characterized by ischemic injury to the vasa nervorum. Patients with vasculitic neuropathies develop progressive, painful sensory or sensorimotor deficits that are typically multifocal or asymmetric. Depending on the underlying etiology, the vasculitis may be confined to the peripheral nervous system; may be one manifestation of a primary systemic vasculitis; or one manifestation of a systemic vasculitis that is secondary to underlying connective tissue disease, drug exposure, viral infection, or paraneoplastic syndrome. This article reviews the classification, clinical presentation, diagnostic approach, etiologies, and treatment of the vasculitic neuropathies."

Pharmacokinetic and toxicodynamic evaluation of oxaliplatin-induced neuropathy and hematological toxicity in rats.

PURPOSE: Oxaliplatin (L-OHP) is a third-generation, platinum-based chemotherapeutic agent and is widely used in gastroenterological cancer regimens. It is important to complete chemotherapy cycles to improve treatment efficacy for cancer patients. However, undesirable side effects, including acute and chronic neuropathies, and myelosuppression, lead to the discontinuation of chemotherapy in some treatment regimens. To predict and prevent the onset of side effects, and to establish appropriate dose adjustment, pharmacokinetic and toxicodynamic studies were performed to investigate the effects of L-OHP in rats. METHODS: Rats were administered intravenous L-OHP, once a week for 4 weeks, at doses of 3, 5, or 8 mg/kg. Pharmacokinetic profiles were observed on Day 1 and Day 22. Acute and chronic neuropathies were evaluated over 4 weeks; cold allodynia was evaluated using an acetone test and mechanical allodynia using the von Frey test. Hematological parameters were also investigated during the same period. RESULTS: The mean AUC0-∞ values for L-OHP were 0.4 ± 0.2, 2.4 ± 0.4, and 3.5 ± 0.9 ng h/mL, increasing dose-dependently on Day 1. The accumulation of L-OHP on Day 22 was observed after repeated administration of L-OHP, as shown by mean AUC0-∞ values of 0.6 ± 0.2, 4.0 ± 1.0, and 14.1 ± 9.8 ng·h/mL, for the three doses. Cold allodynia was observed from Day 3 in the 5 and 8 mg/kg groups, and the extent of this response was dose-dependent. Mechanical allodynia was also observed from Day 10 in the 5 and 8 mg/kg groups. Moreover, the platelet count was the most sensitive among the hematological parameters. CONCLUSION: These results provide useful experimental data for clinical cancer patients undergoing chemotherapy, to establish a pharmacokinetic and toxicodynamic model of L-OHP for adequate dose adjustment.

[Peripheral neuropathies: Diagnostic strategy]. / Neuropathies périphériques : démarche diagnostique.

Diagnosing a peripheral neuropathy is sometimes challenging, as the causes are diverse and the clinical pictures heterogeneous. Overall, diagnosing a patient with peripheral neuropathy will require some knowledge in almost every field of medicine. Therefore, it appears crucial to adopt a diagnostic strategy that is based on solid clinical and neurophysiological grounds. The present paper describes a three-step diagnostic strategy: (1) to delineate a clinico-pathologic entity from clinical and electrodiagnostic findings; (2) to propose a list of plausible causes based on step one, history and clinical context; (3) to use appropriate workup in order to determine the cause or mechanism of the neuropathy. The three steps of this diagnostic strategy necessitate a high level of expertise and interaction between physicians is highly desirable. Finally, an aggressive course and a severe impairment should lead to relentlessly look for a curable cause.

Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer.

CONTEXT: Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. OBJECTIVE: The objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. METHODS: Chemotherapy-naive colorectal cancer patients (N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc©), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510-520 mg/m2 (T1) and 1020-1040 mg/m2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts. RESULTS: Latent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs (n = 54); low symptoms and intermediate signs (n = 44); low symptoms and high signs (n = 21); and high symptoms and high signs (n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. CONCLUSION: We identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.

Working hand syndrome: A new definition of non-classified polyneuropathy condition.

The aim of this paper was to define an unexplained non-classified polyneuropathy condition as a new neurological disease. This new diagnosis of occupation related polyneuropathy has been named as "WORKING HAND SYNDROME (WHS)."This study collected and compared clinic and electrophysiological analyze data from healthy controls, WHS patients, carpal tunnel syndrome (CTS) patients and polyneuropathy patients. The WHS patients presented to the clinic with pain, numbness, tingling, and burning sensations in their hands that increased significantly during rest and nighttime. However, there was no weakness in the muscles, and the deep tendon reflexes were normal in this disease. The patients had all been working in physically demanding jobs requiring the use of their hands/arms for at least 1 year, but no vibrating tools were used by the patients. All of the cases were men. I supposed that overload caused by an action repeated chronically by the hand/arm may impair the sensory nerves in mentioned hand/arm. In patients with these complaints, for a definitive diagnosis, similar diseases must be excluded. Nonetheless, the specific electrophysiological finding that the sural nerves are normal on the lower sides, as well as the occurrence of sensory axonal polyneuropathy in the sensory nerves without a significant effect on velocity and latency in the work-ups of the upper extremity are enough to make a diagnosis.In conclusion, WHS has been defined as a polyneuropathy and occupational disease. Patients with WHS present with pain, numbness, tingling, and burning sensations in their hands that increases significantly during rest and nighttime. They also use their arms/hands for jobs that require heavy labor. The neurological examinations of patients with WHS are normal. Only the sensory nerves in the upper extremities are affected. This article is suggested to serve as a resource for patients, health care professionals, and members of the neurology community at large.

Neuropathic Minimally Invasive Surgeries (NEMESIS):: Percutaneous Diabetic Foot Surgery and Reconstruction.

Patients with peripheral neuropathy associated with ulceration are the nemesis of the orthopedic foot and ankle surgeon. Diabetic foot syndrome is the leading cause of peripheral neuropathy, and its prevalence continues to increase at an alarming rate. Poor wound healing, nonunion, infection, and risk of amputation contribute to the understandable caution toward this patient group. Significant metalwork is required to hold these technically challenging deformities. Neuropathic Minimally Invasive Surgeries is an addition to the toolbox of management of the diabetic foot. It may potentially reduce the risk associated with large wounds and bony correction in this patient group.

Acid-Sensing Ion Channels as Potential Pharmacological Targets in Peripheral and Central Nervous System Diseases.

Acid-sensing ion channels (ASICs) are widely expressed in the body and represent good sensors for detecting protons. The pH drop in the nervous system is equivalent to ischemia and acidosis, and ASICs are very good detectors in discriminating slight changes in acidity. ASICs are important pharmacological targets being involved in a variety of pathophysiological processes affecting both the peripheral nervous system (e.g., peripheral pain, diabetic neuropathy) and the central nervous system (e.g., stroke, epilepsy, migraine, anxiety, fear, depression, neurodegenerative diseases, etc.). This review discusses the role played by ASICs in different pathologies and the pharmacological agents acting on ASICs that might represent promising drugs. As the majority of above-mentioned pathologies involve not only neuronal dysfunctions but also microvascular alterations, in the next future, ASICs may be also considered as potential pharmacological targets at the vasculature level. Perspectives and limitations in the use of ASICs antagonists and modulators as pharmaceutical agents are also discussed.

Muscle relaxants--the current position in the treatment of spasticity in orthopedics.

Muscle tone often exists concomitantly with pain symptoms in different neurological and orthopaedic disease entities. In order to overcome that painful symptom, it is crucial to integrate painkillers with adjunctive therapy using muscle relaxants which decrease the muscle tone. Muscle relaxants available in pharmaceutical trade suppress motor outflow through different mechanisms of action, these include drugs such as: Tizanidine, botulinum toxin, Baclofen, Tolperisone, Methocarbamol. Combining muscle relaxants with analgesics significantly improves the effectiveness of the treatment and allows to reduce drugs doses.

The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review.

IMPORTANCE: Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination but has limited diagnostic evaluation. However, rare localizations of peripheral neuropathy often require more extensive diagnostic testing and different treatments. OBJECTIVE: To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. EVIDENCE REVIEW: References were identified from PubMed searches conducted on May 29, 2015, with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the authors' own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. FINDINGS: Diffuse, nonlength-dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, nonlength-dependent neuropathies are Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and amyotrophic lateral sclerosis. Effective disease-modifying therapies exist for many diffuse, nonlength-dependent neuropathies including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyotrophy (radiculoplexus neuropathy) is lacking. CONCLUSIONS AND RELEVANCE: Recognition of rare localizations of peripheral neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the diagnostic evaluation and provide information on the localization and pathophysiology of nerve injury.

The Ultrasound pattern sum score - UPSS. A new method to differentiate acute and subacute neuropathies using ultrasound of the peripheral nerves.

OBJECTIVE: Ultrasound differentiation of neuropathies is a great challenge. We, therefore, suggest a standardized score to operationalize differentiation between several acute and subacute onset neuropathies. METHOD: We retrospectively analyzed the ultrasound data of 61 patients with acute or subacute neuropathies, e.g. chronic immune-mediated neuropathies, Guillain-Barré syndrome (GBS), and axonal/vasculitic neuropathies. We compared these data to 28 healthy controls. Based on these results an ultrasound pattern sum score (UPSS) with three sub-scores (UPS-A for the sensorimotor nerves, UPS-B for the cervical roots and the vagal nerve and UPS-C for the sural nerve) was developed. Afterwards, the applicability of the score was prospectively validated in 10 patients with chronic neuropathies and in 14 patients with unknown acute and subacute PNP before performing additional tests. RESULTS: UPS-A and UPSS were significantly higher in CIDP than in other neuropathies and controls (p<0.001). UPS-B was significantly more often pathologic in GBS than in CIDP and other neuropathies (p<0.001). Using receiver operation characteristics curve analysis boundary values for each score were defined. Positive predictive value (PPV) of these scores for CIDP and GBS was >85%. Vasculitic neuropathies showed an intermediate type of UPSS compared to other axonal neuropathies (p<0.001). In the prospective application the pattern score could be used with good accuracy in several types of neuropathy. CONCLUSION: UPS-A and UPSS operationalize to diagnose acute and subacute-onset CIDP and its variants with high sensitivity, specificity, and PPV. An increased UPS-B with normal UPSS and other sub scores may point to the diagnosis of GBS with high PPV and enables the differentiation from CIDP. SIGNIFICANCE: Using the UPSS and its sub-scores gives a new diagnostic power to the method of the peripheral nerve ultrasound.

[Chemotherapy-induced peripheral neuropathy; impact on quality of life]. / Chemotherapie-geïnduceerde perifere neuropathie; invloed op kwaliteit van leven.

Peripheral neuropathy is a frequently occurring side-effect of chemotherapy as a cancer treatment. The incidence of chemotherapy-induced peripheral neuropathy (CIPN) is increasing as a consequence of better treatment of cancer becoming available and increasing use of chemotherapy, and because CIPN occurs more frequently with use of new chemotherapeutics. The diagnosis 'CIPN' is made principally on clinical grounds, and it is characterized by predominantly sensory symptoms. The National Cancer Institute Common Toxicity Criteria (NCI-CTC) are commonly used to grade CIPN, but the reliability of these criteria is debated. If CIPN occurs, the only effective strategies are dose reduction or discontinuation of chemotherapy. CIPN impairs quality of life. It is important to evaluate the symptoms of CIPN, as well as the impact on daily living.

A clinical decision support system with an integrated EMR for diagnosis of peripheral neuropathy.

The prevalence of peripheral neuropathy in general population is ever increasing. The diagnosis and classification of peripheral neuropathies is often difficult as it involves careful clinical and electro-diagnostic examination by an expert neurologist. In developing countries a large percentage of the disease remains undiagnosed due to lack of adequate number of experts. In this study a novel clinical decision support system has been developed using a fuzzy expert system. The study was done to provide a solution to the demand of systems that can improve health care by accurate diagnosis in limited time, in the absence of specialists. It employs a graphical user interface and a fuzzy logic controller with rule viewer for identification of the type of peripheral neuropathy. An integrated medical records database is also developed for the storage and retrieval of the data. The system consists of 24 input fields, which includes the clinical values of the diagnostic test and the clinical symptoms. The output field is the disease diagnosis, whether it is Motor (Demyelinating/Axonopathy) neuropathy, sensory (Demyelinating/Axonopathy) neuropathy, mixed type or a normal case. The results obtained were compared with the expert's opinion and the system showed 93.27 % accuracy. The study aims at showing that Fuzzy Expert Systems may prove useful in providing diagnostic and predictive medical opinions. It enables the clinicians to arrive at a better diagnosis as it keeps the expert knowledge in an intelligent system to be used efficiently and effectively.