Fiber Dysfunction Research Articles

The Clinical Features of Painful Small-Fiber Neuropathy Suggesting an Origin Linked to Primary Sjögren's Syndrome.

We attempted to determine whether clinical features could differentiate painful small-fiber neuropathy related to primary Sj€ogren's syndrome (pSS-SFN) from idiopathic SFN (idio-SFN). Validated clinical questionnaires and neurophysiological investigations specific for pain and SFN assessment were performed in 25 patients with pSS-SFN and 25 patients with idio-SFN. Patients with idio-SFN had more frequent severe burning sensations and higher mean anxiety scores and daily pain intensity compared to patients with pSSSFN. Conversely, patients with pSS-SFN had reduced electrochemical skin conductance measured by Sudoscan_, and almost half of them had the sensation of walking on cotton wool. Our results suggest that idio-SFN more specifically involved small sensory fibers than pSS-SFN, in which subtle dysfunction of larger sensory fibers and damage of distal autonomic sudomotor innervation may occur. A practical algorithm is proposed to help to differentiate SFN associated with pSS from idio-SFN, based on information very easy to obtain by clinical interview.

Dysmetabolic neuropathy in children with diabetes type I

Neuropathy is the most frequent symptomatic complication of diabetes. Diabetic polyneuropathy (DPN) is the most common variety of neuropathy, which represents chronic symmetrical sensorimotor polyneuropathy. (DPN) typically begins as a generalized asymptomatic dysfunction of peripheral nerve fibers, which may be revealed by electromyography. However, nerve conduction study (NCS) is a sensitive method for early detecting of peripheral neuropathy. We have performed NCS in 69 children with poorly compensated diabetes type I aged 7-18 y. Study protocol included testing of peripheral motor and sensory nerve conduction velocities (NCVs) and compound motor and sensory nerve action potential amplitudes. We revealed subclinical abnormalities, which were symmetric, suggestive of DPN and reflecting disorders of predominantly motor, rather than sensory nerves. In addition, nerve conduction abnormalities were correlated with high HbA1c level, patient age and disease (diabetes) duration. Poor metabolic control was the most important contributor to abnormal electrophysiological parameters.

Potency of descending pain modulatory system is linked with peripheral sensory dysfunction in fibromyalgia: An exploratory study.

Fibromyalgia (FM) is characterized by chronic widespread pain whose pathophysiological mechanism is related to central and peripheral nervous system dysfunction. Neuropathy of small nerve fibers has been implicated due to related pain descriptors, psychophysical pain, and neurophysiological testing, as well as skin biopsy studies. Nevertheless, this alteration alone has not been previously associated to the dysfunction in the descending pain modulatory system (DPMS) that is observed in FM. We hypothesize that they associated, thus, we conducted a cross-sectional exploratory study.To explore small fiber dysfunction using quantitative sensory testing (QST) is associated with the DPMS and other surrogates of nociceptive pathways alterations in FM.We run a cross-sectional study and recruited 41 women with FM, and 28 healthy female volunteers. We used the QST to measure the thermal heat threshold (HTT), heat pain threshold (HPT), heat pain tolerance (HPT), heat pain tolerance (HPTo), and conditional pain modulation task (CPM-task). Algometry was used to determine the pain pressure threshold (PPT). Scales to assess catastrophizing, anxiety, depression, and sleep disturbances were also applied. Serum brain-derived neurotrophic factor (BDNF) was measured as a marker of neuroplasticity. We run multivariate linear regression models by group to study their relationships.Samples differed in their psychophysical profile, where FM presented lower sensitivity and pain thresholds. In FM but not in the healthy subjects, regression models revealed that serum BDNF was related to HTT and CPM-Task (Hotelling Trace = 1.80, P < .001, power = 0.94, R2 = 0.64). HTT was directly related to CPM-Task (B = 0.98, P = .004, partial-η2 = 0.25), and to HPT (B = 1.61, P = .008, partial η2 = 0.21), but not to PPT. Meanwhile, BDNF relationship to CPM-Task was inverse (B = –0.04, P = .043, partial-η2 = 0.12), and to HPT was direct (B = –0.08, P = .03, partial-η2 = 0.14).These findings high spot that in FM the disinhibition of the DPMS is positively correlated with the dysfunction in peripheral sensory neurons assessed by QST and conversely with serum BDNF.

Abstract 602: The α7 nicotinic acetylcholine receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy without enhancing the proliferation of lung cancer cells or interfering with paclitaxel-induced antitumor activity

Abstract While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, which can be a dose-limiting factor for chemotherapy or delay treatment. Our laboratories have previously shown that nicotine, the prototypical nicotinic acetylcholine receptor (nAChR) agonist, can prevent and reverse paclitaxel-induced peripheral neuropathy without increasing lung tumor growth in mice. Our current studies have demonstrated that the α7 nAChR silent agonist R-47 may be a promising preventative and therapeutic treatment for CIPN as well. R-47 (10 mg/kg, p.o.) was administered to male C57BL/6J mice treated with paclitaxel (8 mg/kg, i.p., every other day for a total of four injections). Von Frey filament testing revealed that R-47 can both prevent and reverse paclitaxel-induced mechanical allodynia; the latter effect can be inhibited by the α7 nAChR antagonist methyllycaconitine. In support of these findings, R-47 also prevents the reduction of intra-epidermal nerve fibers in the hind paws of paclitaxel-treated mice. In addition, α7 nAChR knockout mice exhibit a greater and sustained increase in mechanical allodynia after paclitaxel administration when compared to wild-type mice, suggesting the involvement of this receptor subtype in hindering CIPN development and/or maintenance. With regard to cancer, R-47 fails to increase A549 and H460 non-small cell lung cancer cell viability, colony formation, or proliferation alone, and does not interfere with paclitaxel-induced growth arrest, apoptosis, or DNA fragmentation. Most importantly, R-47 does not increase the growth of A549 tumors or interfere with the antitumor activity of paclitaxel in tumor-bearing mice. These data suggest that the use of an α7 nAChR silent agonist may be a safe and efficacious approach for the prevention and treatment of CIPN. Citation Format: S Lauren Kyte, Wisam Toma, Ganeshsingh Thakur, M Imad Damaj, David A. Gewirtz. The α7 nicotinic acetylcholine receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy without enhancing the proliferation of lung cancer cells or interfering with paclitaxel-induced antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 602.

Role of dietary amino acid balance in diet restriction-mediated lifespan extension, renoprotection, and muscle weakness in aged mice.

SummaryExtending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)‐induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age‐related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age‐dependent decrease in slow‐twitch muscle fiber function but reduced absolute fast‐twitch muscle fiber function. DR‐induced fast‐twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum‐fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet‐restricted aged mice, which were accompanied by a recovery in H2S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans‐sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.

The LDIFLARE and CCM Methods Demonstrate Early Nerve Fiber Abnormalities in Untreated Hypothyroidism: A Prospective Study.

Recent studies using skin biopsy suggest presence of small-fiber neuropathy in subclinical hypothyroidism. This study uses two noninvasive methods-the laser Doppler imager flare technique (LDIFLARE) and corneal confocal microscopy (CCM)-to assess small-fiber function (SFF) and small-fiber structure (SFS), respectively, in newly diagnosed hypothyroidism (HT) before and after adequate treatment. Single-center, prospective, intervention-based cohort study. Twenty patients with newly diagnosed HT (15 with primary HT and 5 with post-radioiodine HT) along with 20 age-matched healthy controls (HCs). Patients with HT and HCs were assessed neurologically at diagnosis and baseline, respectively. The HT group was reassessed after optimal replacement (defined as TSH level of 0.27 to 4.20 mIU/L) with levothyroxine (LT4) and HCs were reviewed after 1 year. Neurologic assessment for small fibers was performed by using LDIFLARE for SFF and CCM for SFS; large fibers were studied by sural nerve conduction velocity (SNCV) and sural nerve amplitude (SNAP). At baseline, both LDIFLARE (mean ± SD) (6.74 ± 1.20 vs 8.90 ± 1.75 cm2; P = 0.0002) and CCM nerve fiber density (CNFD) (expressed as number of fibers per mm2: 50.77 ± 6.54 vs 58.32 ± 6.54; P = 0.002) were significantly reduced in the HT group compared with HCs whereas neither SNCV nor SNAP was different (P ≥ 0.05). After optimal LT4 treatment, both LDIFLARE (7.72 ± 1.12 vs 6.74 ± 1.20 cm2; P ≤ 0.0001) and CNFD (54.43 ± 5.70 vs 50.77 ± 6.54 no./mm2; P = 0.02) improved significantly but remained significantly reduced compared to HCs (P = 0.008 and P = 0.01, respectively) despite normalization of TSH. This study demonstrates that dysfunction of small fibers precedes large neural fiber abnormalities in early HT. This can be reversed by replacement therapy to achieve a biochemically euthyroid state, but small-fiber neural outcomes continued to remain low compared with values in HCs.

T33. Electrochemical skin conductance as a marker of neuropathic pain in hereditary amyloid polyneuropathy related to transthyretin

Neuropathic pain (NP) is one of the most common symptoms of small fiber dysfunction in hereditary amyloid polyneuropathy related to transthyretin (hATTR-FAP), contributing to a poor quality of life in these patients. Despite being a common problem in many neurological conditions, there are few neurophysiological tests with high sensitivity to assess pain, with the notable exception of laser evoked potentials. Electrochemical skin conductance (ESC), measured by Sudoscan©, is a fast and reliable method capable of measuring sudomotor function, tested in various diseases. Since sudomotor function is mediated by post ganglionic sympathetic C fibers, we sought to assess the ESC in hATTR-FAP patients as a predictor of NP. 200 consecutive hATTR V30M amyloidosis patients (104 carriers, 96 symptomatic), with a mean age of 45.5 ± 13.6 years (118 females) were studied. ESC, measured by Sudoscan©, was recorded in both hands and feet. Neuropathy Impairment Scale (NIS) and Body mass index (BMI) were recorded. The presence of NP was evaluated by clinical signs and symptoms, and was graded in a 3 point scale (absent, moderate, severe). Independent-samples T test, One-Way ANOVA and Binary logistic regression were used for comparisons (level of significance set at 0.01). ROC curve analysis were also performed. Both feet and hands ESC were significantly lower in the symptomatic group when compared to carriers (75.8 ± 8.7 vs 38.1 ± 26.5 and 72.2 ± 10.3 vs 56.5 ± 21.2 respectively, p < 0.001). Feet ESC was significantly different between all degrees of NP (74.0 ± 12.9 vs 47.2 ± 27.7 vs 30.2 ± 22.7, p < 0.001), while hands ESC and NIS were only significantly lower in the severe NP group. In the regression model analysis, after adjustment for age, gender, BMI, stage of disease and NIS, feet ESC was a significant independent predictor for the presence of NP (B = 0.955 p = 0.005). The ROC curve of this model showed an area under the curve of 0.958 (p < 0.001). ROC curve analysis of Feet ESC as a predictor of NP showed an area under the curve of 0.850 (p < 0.001). ESC, measured by Sudoscan©, has already been acknowledged as a promising tool for small fiber dysfunction. In this study a clear relationship was demonstrated between NP and ESC values, independent of disease stage or neuropathy degree. ESC is a rapid and noninvasive neurophysiological tool for the evaluation of NP.

T84. Reduced amplitudes of pain-related evoked potentials in patients with neuropathic pain and normal small nerve fiber function and morphology

Cortical pain-related evoked potentials (PREP) are elicited by activation of the Aδ-fibers using cutaneous electrical stimulation and objectively reflect the Aδ-pathways. PREP were applied in an unselected patient population with acral neuropathic pain to explore its diagnostic usefulness in detecting small fiber impairment compared to quantitative sensory test (QST) and skin punch biopsy. Thirty-two patients (13 male and 19 female, median age 50 years, range 26–83) suffering from acral neuropathic pain were examined clinically and with nerve conduction studies, QST, skin punch biopsy and PREP. The study cohort consisted of 16 patients with small fiber neuropathy (SFN), 18 patients with mixed fiber neuropathy (MFN, i.e. large and small fiber neuropathy), and 8 patients with acral neuropathic pain without signs of a large fiber neuropathy or SFN. QST and skin biopsy were pathological in terms of elevated thermal thresholds and reduced distal skin innervation in patients with SFN and MFN, while patients with acral neuropathic pain had normal findings. PREP was the only method showing a pathological finding, namely reduced peak-to-peak amplitudes also in patients with acral neuropathic pain (p < 0.05). PREP was the only method revealing small fiber dysfunction in patients suffering from acral neuropathic pain with otherwise normal QST and skin biopsy. As a non-invasive test giving reproducible results, PREP may contribute to the diagnostic portfolio of small fiber tests in patients with neuropathic pain.

Protective effects of Enterococcus faecium strain R30 on transformation of slow to fast fiber under inactive condition

Inactivity results in the transformation of slow to fast fiber and mitochondria dysfunction in skeletal muscle. PGC‐1α, a transcriptional factor, can prevent transformation of slow to fast fiber and the reduced oxidative enzyme activity in skeletal muscle. We have confirmed that Enterococcus faecium strain R30 (R30) activated muscle sympathetic nerve and increased blood flow in muscle capillary in our previous study. Several studies report that the increased blood flow induces nitric oxide synthase (eNOS) expression via shear stress, and eNOS expression regulates PGC‐1α protein expression. Also, the activated sympathetic nerve activity increased PGC‐1α protein expression via activation of adrenergic receptor. Therefore, we examined the hypothesis that R30 might prevent the transformation of slow to fast fiber and the reduced oxidative enzyme activity via PGC‐1α protein expression in skeletal muscle under inactive condition. Fifteen male Sprague‐Dawley rats aged 11 weeks old were divided into three groups, that is, 1) control (CON; n = 5), 2) 2 weeks hindlimb unloading (HU; n = 5), and 3) HU+R30 (HU+R30; n = 5). In the experimental periods, we administered orally to R30 (500 mg/kg/day) in the HU+R30 group, and the same amount of physiological saline in the CON and HU groups. After 2 weeks hindlimb unloading, type I fiber composition ratio, citrate synthase (CS) activity, eNOS and PGC‐1α protein expression level were measured. Type I fiber composition ratio and CS activity were significantly higher in the HU+R30 than in the HU group. The expression levels of eNOS and PGC‐1α protein in the HU+R30 group were significantly higher than in the HU group. These results indicate that R30 supplementation could increase the levels of eNOS and PGC‐1α expression in soleus muscle, and prevent the transformation of slow to fast fiber and the reduced oxidative enzyme activity under inactive condition.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

P1-4-01. Evaluation of small fiber involvement using pain-related evoked potentials in patients with type 1 and type 2 diabetes

The pathophysiology of diabetic neuropathy presumably differs between type1 and type 2 diabetes mellitus (T1DM and T2DM), and neuropathic pain is more frequent in patients with T2DM than T1DM. To investigate difference in small fiber involvement, we studied painrelated evoked potentials (PREPs) using intraepidermal electrical stimulation (IES) selective to A-delta-fibers and C-fibers in patients with T1DM (n = 20) and T2DM (n = 20). IES was applied in the back of hand and foot, and PREPs were recorded from the Cz electrode referenced to the linked earlobes. We evaluated the thresholds, and PREP latencies and amplitudes. Nerve conduction studies were performed in the ipsilateral limbs. There were no significant differences in age and hemoglobin A1c levels between the groups, but disease duration was significantly longer in T1DM. In nerve conduction study, patients with T1DM showed significantly more severe large fiber dysfunction in the lower extremity, however less pain/paresthesia than T2DM patients. PREPs study showed no significant differences in all the parameters between T1DM and T2DM. Diabetic neuropathy in T1DM showed relatively mild small fiber involvement compared with large fiber dysfunction, and this characteristic pattern might be related to the difference in the pathophysiology or neuropathic symptoms.

Temporal and Spatial Quantification of Pain- Related Small Fiber Functionality Assessed Using Laser Speckle Contrast Analysis.

This study aimed to establish a practical method for assessing pain symptomatology and develop criteria for quantifying small fiber functions using laser speckle contrast analysis (LASCA). Axon flare responses, which reflect small fiber functions, were induced either by histamine or capsaicin applied to the volar surface of the skin of the left forearm. To inhibit small fiber function, local anesthetic cream was applied to the skin of right forearm. The effects on pain symptomatology (severity/timing) and axon flare responses (temporal/spatial characteristics) were measured using LASCA. To highlight the clinical relevance, this method was applied to 3 different types of patients with small fiber dysfunction. Forty-four forearms of 22 healthy volunteers were tested. Eutectic mixture local anesthetic cream reduced the severity and duration of pain, abolishing or prolonging the latency to reach 3-fold higher levels of basal skin microcirculation levels, and decreasing the area and intensity of flare responses. There were positive correlations between pain symptomatology and flare response characteristics in the control forearm. Similar results were confirmed in neuropathic pain patients. Pain-related small fiber functions and symptomatology (two-in-one method) can be assessed via histamine- or capsaicin-evoked axon flare responses in as little as 15 minutes. The reduction of small fiber functions are characterized by decrease in flare size/intensity at 5 minutes after stimulation and prolongation/abolishment of the latency to reach 3-fold higher levels of baseline skin microcirculation. LASCA may be applied in the clinic to aid early diagnosis, monitor disease progression, and objectively assess treatment efficacy in patients with neuropathic pain.

LEFT VENTRICULAR LONGITUDINAL FIBER DYSFUNCTION IN LEFT VENTRICULAR NON-COMPACTION CARDIOMYOPATHY

Longitudinal left ventricle (LV) fiber dysfunction may play a role in LV non-compaction cardiomyopathy (LVNC), due to the extensive involvement of the subendocardial myocardium. Mitral Annular Plane Systolic Excursion (MAPSE), using 2-D echo or MRI imaging, is an easily performed and replicable

How to diagnose neuropathy in diabetes mellitus?

Diabetic neuropathy is a common problem and can present various clinical presentations such as cranial neuropathy, radiculopathy, plexopathy, mononeuropathy, polyneuropathy and autonomic neuropathy. Clinical evaluation and use of scoring systems for the evaluation of diabetic polyneuropathy is an important step to get correct diagnosis. New informations about the diagnosis of diabetic neuropathy continue to emerge, which will lead to correct diagnosis and treatment as well. Diabetic length-dependent sensorimotor polyneuropathy (DSPN) and carpal tunnel syndrome are the most common seen problems. While acute and painful situations with motor weakness are mostly transient, sensory fibres are predominantly involved in chronic ones. Nerve conduction studies are needed to confirm diagnosis of any type of diabetic neuropathy, but they are normal in cases with small fiber involvement. The early diagnosis is crucial because it is well-known that subclinical diabetic neuropathy may be reversed or significantly improved with diabetes control. Because neuropathy at the stage in which only small fibers are affected can be reversed, it is important to diagnose DSPN in these stages. Skin biopsy taken from the dermatomal area of sural nerve, laser-doppler-imager flare technique, corneal confocal microscopy are used to assess small fibre dysfunction. The aim of the present review was to evaluate evidence-based diagnosis for any type of neuropathy seen in the patients with diabetes mellitus.

Method-of-limits; Cold and warm perception thresholds at proximal and distal body regions

ObjectiveThermal quantitative sensory testing with the ‘Method-of-Limits’ is an established rationale for detection of small nerve fiber dysfunction, but adequate reference values are crucial for such evaluations, regardless of the underlying cause. This study assessed reference data for cold- (CPT) and warm- (WPT) perception thresholds at both proximal and distal sites in eight body regions of the lower and upper extremities, all determined within the same test session for each subject. MethodsSeventy-five healthy subjects (aged 16–72 years) were tested according to the method-of-limit for CPT and WPT at the dorsum of the foot, the medial and lateral lower leg, the ventral thigh, the thenar eminence, the radial and ulnar part of the lower arm, and the anterior deltoid part of the upper arm. ResultsOverall, thermal perception thresholds (TPT) varied with test location, but were higher in the lower than in the upper part of the body, also WPT were generally higher than CPT. TPT at the dorsum foot highly correlated with age, while inconsistent correlations were noted between TPT and age or height at other tested locations. ConclusionThis study describes for the first time reference values at eight defined body regions, at both proximal and distal sites. SignificanceThe report enables refined evaluations of general small nerve fiber function, as assessed by quantitative thermal sensory testing with the Method-of-Limits.

High glucose up-regulates Semaphorin 3A expression via the mTOR signaling pathway in keratinocytes: A potential mechanism and therapeutic target for diabetic small fiber neuropathy.

Small fiber neuropathy (SFN) is a common complication in diabetes, and is characterized by decreased intraepidermal nerve fiber density (IENFD). Semaphorin 3A (Sema3A), which is produced by keratinocytes, has a chemorepulsive effect on intraepidermal nerve fibers. mTOR signaling can mediate local protein synthesis that is critical for growth of axons and dendrites. Therefore, this study aimed to investigate whether Sema3A is up-regulated in diabetic keratinocytes via the mTOR-mediated p70 S6K and 4E-BP1 signaling pathways, and furthermore whether it is involved in the pathogenesis of diabetic SFN. IENFD, expression of Sema3A, and mTOR signaling, were evaluated in the skin of diabetic patients with SFN as well as control subjects. Sema3A and mTOR signaling were also assessed in HaCaT cells which had been treated with high glucose (HG) or recombinant Sema3A (rSema3A) in the presence or absence of rapamycin. Small fiber dysfunction was evaluated by examining IENFD and using behavioral tests in control and streptozotocin-induced diabetic rats treated with or without rapamycin. We found that higher Sema3A expression and over-activation of mTOR signaling, was accompanied by reduced IENFD in the skin of diabetic patients compared with control subjects. The expression of Sema3A, and mTOR signaling were up-regulated in HaCaT cells incubated with HG or rSema3A, and this could be attenuated by rapamycin. Hyperalgesia, reduced IENFD, and up-regulated Sema3A and mTOR signaling were also detected in diabetic rats. These effects were ameliorated by rapamycin treatment. Our data indicate that HG up-regulates Sema3A expression by activating mTOR signaling in diabetic keratinocytes. This pathway may therefore play a critical role in diabetic SFN.

65. Laser evoked potentials and skin biopsy to evaluate small nerve fiber dysfunction in myotonic dystrophy type 1(DM1): A preliminary study

Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. We recruited 3 patients with previously diagnosed DM1 (mean age was 51 ± 8 years; height 166 ± 8 cm) who underwent leg skin biopsy and laser evoked potentials (LEP). The specific aim of this study is to ascertain the small nerve fiber involvement in DM1 by means of LEP and skin biopsy. Two patents showed abnormalities in both LEP and skin biopsy whereas one patient displayed abnormal skin biopsy but normal findings in LEP. Our data demonstrated a reasonable concordance between LEP and skin biopsy in evaluating small fiber loss in DM1. However, these are preliminary data and a larger number of patients must be recruited before to draw any definite conclusion.

Circulating miR-19b and miR-181b are potential biomarkers for diabetic cardiomyopathy

Diabetic cardiomyopathy is characterized by metabolic changes in the myocardium that promote a slow and silent dysfunction of muscle fibers, leading to myocardium remodelling and heart failure, independently of the presence of coronary artery diseases or hypertension. At present, no imaging methods allow an early diagnosis of this disease. Circulating miRNAs in plasma have been proposed as biomarkers in the prognosis of several cardiac diseases. This study aimed to determine whether circulating miRNAs could be potential biomarkers of diabetic cardiomyopathy. Mice that were fed with a high fat diet for 16 months, showed metabolic syndrome manifestations, cardiac hypertrophy (without hypertension) and a progressive cardiac function decline. At 16 months, when maximal degree of cardiac dysfunction was observed, 15 miRNAs from a miRNA microarray screening in myocardium were selected. Then, selected miRNAs expression in myocardium (at 4 and 16 months) and plasma (at 4, 12 and 16 months) were measured by RT-qPCR. Circulating miR-19b-3p and miR-181b-5p levels were associated with myocardium levels during the development of diabetic cardiomyopathy (in terms of cardiac dysfunction), suggesting that these miRNAs could be suitable biomarkers of this disease in asymptomatic diabetic patients.

Nicotine Prevents and Reverses Paclitaxel-Induced Mechanical Allodynia in a Mouse Model of CIPN.

Chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration, continues to be a dose-limiting and debilitating side effect during and/or after cancer chemotherapy. Paclitaxel, a taxane commonly used to treat breast, lung, and ovarian cancers, causes CIPN in 59-78% of cancer patients. Novel interventions are needed due to the current lack of effective CIPN treatments. Our studies were designed to investigate whether nicotine can prevent and/or reverse paclitaxel-induced peripheral neuropathy in a mouse model of CIPN, while ensuring that nicotine will not stimulate lung tumor cell proliferation or interfere with the antitumor properties of paclitaxel. Male C57BL/6J mice received paclitaxel every other day for a total of four injections (8 mg/kg, i.p.). Acute (0.3-0.9 mg/kg, i.p.) and chronic (24 mg/kg per day, s.c.) administration of nicotine respectively reversed and prevented paclitaxel-induced mechanical allodynia. Blockade of the antinociceptive effect of nicotine with mecamylamine and methyllycaconitine suggests that the reversal of paclitaxel-induced mechanical allodynia is primarily mediated by the α7 nicotinic acetylcholine receptor subtype. Chronic nicotine treatment also prevented paclitaxel-induced intraepidermal nerve fiber loss. Notably, nicotine neither promoted proliferation of A549 and H460 non-small cell lung cancer cells nor interfered with paclitaxel-induced antitumor effects, including apoptosis. Most importantly, chronic nicotine administration did not enhance Lewis lung carcinoma tumor growth in C57BL/6J mice. These data suggest that the nicotinic acetylcholine receptor-mediated pathways may be promising drug targets for the prevention and treatment of CIPN.

Neurophysiologic Studies in the Evaluation of Polyneuropathy.

This article provides core information on the clinical neurophysiology techniques available for the investigation of disorders of the peripheral nervous system. The role of small fiber dysfunction in some types of polyneuropathy is being increasingly appreciated, and neurophysiologic techniques for evaluating the autonomic components of peripheral axons have enhanced our understanding of small fiber dysfunction. The principles of nerve conduction studies and needle EMG are presented in this article, along with the patterns of abnormality encountered in patients with polyneuropathy due to large and small fiber involvement.

P.192 - Muscle fiber dysfunction contributes to clinical muscle weakness in inclusion body myositis

Inclusion body myositis (IBM) is the most common acquired muscle disorder in adults over 50 years old. It is characterized by progressive muscle weakness and marked muscle atrophy, most prominent in the finger flexors and quadriceps muscle. In addition to atrophy, fatty replacement of muscle tissue contributes to clinical muscle weakness and functional decline. This study aims to investigate the contractile performance of residual muscle tissue. We included 8 participants with IBM and 12 healthy controls. We measured individual health related quality of life, functional performance and muscle strength. In all participants, muscle contractile capacity was measured both in vivo, using quantitative muscle testing and MRI imaging, and ex vivo, using single fiber studies of the vastus lateralis as well as tibialis anterior muscle biopsies. Quadriceps specific force was calculated by correcting the voluntary maximum force (N) for the contractile cross-sectional area (CCSA). CCSA was calculated by multiplying the total cross-sectional area by the muscle fraction on MRI. Voluntary maximum force generation of the quadriceps muscle was significantly reduced in IBM participants (216.9 ± 57.6 N vs. 572.1 ± 53.1 N, p < .001). Quadriceps specific force was reduced in IBM participants. Muscle fiber specific force was also reduced in IBM patients compared to healthy controls (type 1 fibers: 158.3 ± 4.1 mN/mm2 in IBM vs. 178.9 ± 3.4 in controls, type 2 fibers: 180.3 ± 7.2 mN/mm2 in IBM vs. 213.7 ± 4.2 in controls, p = .036). Reduced muscle fiber specific force was equally present in vastus lateralis and tibialis anterior muscles. Contractile performance of residual muscle tissue is impaired in IBM patients, both in vivo and ex vivo. We conclude that sarcomeric dysfunction contributes to clinical muscle weakness in IBM.