Epidermal Nerve Research Articles

LepVax, a defined subunit vaccine that provides effective pre-exposure and post-exposure prophylaxis of M. leprae infection

Sustained elimination of leprosy as a global health concern likely requires a vaccine. The current standard, BCG, confers only partial protection and precipitates paucibacillary (PB) disease in some instances. When injected into mice with the T helper 1 (Th1)-biasing adjuvant formulation Glucopyranosyl Lipid Adjuvant in stable emulsion (GLA-SE), a cocktail of three prioritized antigens (ML2055, ML2380 and ML2028) reduced M. leprae infection levels. Recognition and protective efficacy of a single chimeric fusion protein incorporating these antigens, LEP-F1, was confirmed in similar experiments. The impact of post-exposure immunization was then assessed in nine-banded armadillos that demonstrate a functional recapitulation of leprosy. Armadillos were infected with M. leprae 1 month before the initiation of post-exposure prophylaxis. While BCG precipitated motor nerve conduction abnormalities more rapidly and severely than observed for control infected armadillos, motor nerve injury in armadillos treated three times, at monthly intervals with LepVax was appreciably delayed. Biopsy of cutaneous nerves indicated that epidermal nerve fiber density was not significantly altered in M. leprae-infected animals although Remak Schwann cells of the cutaneous nerves in the distal leg were denser in the infected armadillos. Importantly, LepVax immunization did not exacerbate cutaneous nerve involvement due to M. leprae infection, indicating its safe use. There was no intraneural inflammation but a reduction of intra axonal edema suggested that LepVax treatment might restore some early sensory axonal function. These data indicate that post-exposure prophylaxis with LepVax not only appears safe but, unlike BCG, alleviates and delays the neurologic disruptions caused by M. leprae infection.

Editors' note: A new potential biomarker for dementia with Lewy bodies: Skin nerve α-synuclein deposits

In “A new potential biomarker for dementia with Lewy bodies: Skin nerve α-synuclein deposits,” authors Donadio et al. studied phosphorylated α-synuclein (p-syn) deposits and epidermal nerve fiber (ENF) density in skin biopsies of patients with dementia with Lewy bodies (DLB). They detected p-syn in all patients with DLB. They also found reduced ENF in patients with DLB, especially in those with autonomic dysfunction. Commenting on the article, Dr. Khan asks whether synucleinopathies can be differentiated based on the skin biopsy (e.g., DLB from Parkinson disease, pure autonomic failure, or multiple system atrophy). Authors Donadio et al. agree that the possibility to differentiate different phenotypes of synucleinopathy by skin biopsy is an important aim, and is something they are working on. In “A new potential biomarker for dementia with Lewy bodies: Skin nerve α-synuclein deposits,” authors Donadio et al. studied phosphorylated α-synuclein (p-syn) deposits and epidermal nerve fiber (ENF) density in skin biopsies of patients with dementia with Lewy bodies (DLB). They detected p-syn in all patients with DLB. They also found reduced ENF in patients with DLB, especially in those with autonomic dysfunction.

Non-myelinated C-fibers, but not myelinated A-fibers, elongate into the epidermis in dry skin with itch

Chronic skin diseases with itch and dry skin show increased peripheral nerve fiber elongation into the epidermis. However, the characteristics of the elongated nerve fibers remain unclear. Therefore, we investigated the characteristics of the elongated nerve fibers using a dry skin mouse model with itch. In this mouse model, prepared via repetitive treatments with an acetone/ether mixture and water, the stratum corneum water content was decreased, whereas spontaneous scratching and epidermal hyperplasia were increased. In addition, the number of substance P (SP)- and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers (C-fibers) was increased in the epidermis of treated mice compared to that in non-treated control mice. However, neurofilament 200-immunoreactive nerve fibers (A-fibers) were not detected in the epidermis of treated mice. These results suggest that the elongated epidermal peripheral nerve fibers comprise SP/CGRP-containing C-fibers but not A-fibers. Thus, these fibers may be involved in the induction of dry skin pruritus.

Evidence of peripheral large nerve involvement in fibromyalgia: a retrospective review of EMG and nerve conduction findings in 55 FM subjects

Whereas small fiber neuropathy (SFN) is now a recognized part of fibromyalgia (FM), surprisingly little attention has been paid to any findings of large fiber neuropathy (LFN) in this disorder. Since 90% to 95% of FM subjects seen in our outpatient facility routinely undergo EMG and nerve conduction studies (NCS) we elected to retrospectively review the EMG/NCS results garnered from a large cohort of unselected subjects in order to describe the electrodiagnostic features of LFN in FM. Records from 100 consecutive, unselected clinic patients meeting the 1990 ACR criteria for FM, who had undergone EMG/NCS, were reviewed. The same electromyographer tested all subjects. After exclusion of FM patients with any other clinically relevant condition that might influence EMG results (e.g., familial neural degenerative conditions, diabetes mellitus, Vitamin B-12 deficiency, etc.) fifty-five FM subjects remained: 29 subjects with "FM Only," and 26 subjects with FM+Rheumatoid Arthritis ("FM+RA"). All subjects had also undergone ankle area skin biopsy for determination of epidermal nerve fiber density (ENFD). Fourteen other subjects, without FM or RA, examined by the same electromyographer, were used as an EMG/NCS comparison group. Ninety percent of the "FM Only" subjects demonstrated a demyelinating and/or axonal, sensorimotor polyneuropathy, and 63% had findings of SFN (ENFD ≤7 fibers/mm), suggesting a mixed fiber neuropathy in most. Furthermore, 61% of the "FM Only" subjects showed EMG findings suggestive of non-myotomal lower extremity axonal motor denervation, most likely due to a polyneuropathy, and 41% satisfied published criteria for "possible" chronic inflammatory demyelinating polyneuropathy (CIDP). There was surprisingly little difference in the EMG/NCS findings between the "FM Only" and the "FM+RA" groups. With the exception of carpal tunnel syndrome, our EMG/NCS comparison group showed few to none of these findings. Our review of the EMG/NCS results, gleaned from the largest FM cohort yet studied with these modalities, shows that electrodiagnostic features of polyneuropathy, muscle denervation, and CIDP are common in FM. Furthermore these electrodiagnostic findings are often seen coincident with SFN, and are not significantly influenced by the presence of RA. These results, particularly when taken as a whole, suggest that EMG/NCS may be clinically useful in detecting LFN in FM and help in better understanding the etiopathogenesis of this painful disorder.

Cytokine-mediated inflammation mediates painful neuropathy from metabolic syndrome.

Painful neuropathy (PN) is a prevalent condition in patients with metabolic syndrome (MetS). However, the pathogenic mechanisms of metabolic syndrome-associated painful neuropathy (MetSPN) remain unclear. In the current study, high-fat-fed mice (HF mice) were used to study MetSPN. HF mice developed MetS phenotypes, including increased body weight, elevated plasma cholesterol levels, and insulin resistance in comparison with control-fat-fed (CF) mice. Subsequently, HF mice developed mechanical allodynia and thermal hyperalgesia in hind paws after 8 wk of diet treatment. These pain behaviors coincided with increased densities of nociceptive epidermal nerve fibers and inflammatory cells such as Langerhans cells and macrophages in hind paw skin. To study the effect of MetS on profiles of cytokine expression in HF mice, we used a multiplex cytokine assay to study the protein expression of 12 pro-inflammatory and anti-inflammatory cytokines in dorsal root ganglion and serum samples. This method detected the elevated levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, and interleukin (IL)-6, IL-1β as well as reduced anti-inflammatory IL-10 in lumbar dorsal root ganglia (LDRG) of HF mice. Intraperitoneal administration of IL-10 reduced the upregulation of pro-inflammatory cytokines and alleviated pain behaviors in HF mice without affecting MetS phenotypes. Our findings suggested targeting HF-induced cytokine dysregulation could be an effective strategy for treating MetSPN.

Substance P restores normal skin architecture and reduces epidermal infiltration of sensory nerve fiber in TNCB-induced atopic dermatitis-like lesions in NC/Nga mice

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense pruritus and eczematous lesion. Substance P (SP) is an 11-amino-acid endogenous neuropeptide that belongs to the tachykinin family and several reports recently have supported the anti-inflammatory and tissue repairing roles of SP. ObjectiveIn this study, we investigated whether SP can improve AD symptoms, especially the impaired skin barrier function, in 2, 4, 6-trinitrochlorobenzene (TNCB)-induced chronic dermatitis of NC/Nga mice or not. MethodAD-like dermatitis was induced in NC/Nga mice by repeated sensitization with TNCB for 5 weeks. The experimental group designations and topical treatments were as follows: vehicle group (AD-VE); SP group (AD-SP); and SP with NK1R antagonist CP99994 (AD-SP-A) group. Histological analysis was performed to evaluate epidermal differentiation, dermal integrity, and epidermal nerve innervation in AD-like lesions. The skin barrier functions and pruritus of NC/Nga mice were evaluated by measuring transepidermal water loss (TEWL) and scratching behavior, respectively. ResultTopical SP treatment resulted in significant down-regulation of Ki67 and the abnormal-type keratins (K) K6, K16, and K17, restoration of filaggrin and claudin-1, marked reduction of TEWL, and restoration of basement membrane and dermal collagen deposition, even under continuous sensitization of low dose TNCB. In addition, SP significantly reduced innervation of itch-evoking nerve fibers, gelatinase activity and nerve growth factor (NGF) expression in the epidermis but upregulated semaphorin-3A (Sema3A) expression in the epidermis, along with reduced scratching behavior in TNCB-treated NC/Nga mice. All of these effects were completely reversed by co-treatment with the NK1R antagonist CP99994. In cultured human keratinocytes, SP treatment reduced expression of TGF-α, but upregulated TGF-β and Sema3A. ConclusionTopically administered SP can restore normal skin barrier function, reduce epidermal infiltration of itch-evoking nerve fibers in the AD-like skin lesions, and alleviate scratching behavior. Thus, SP may be proposed as a potential medication for chronic dermatitis and AD.

Small fiber neuropathy: Diagnosis, causes, and treatment

Small fiber neuropathy, which affects the sensory Aδ and C fibers, is now a major diagnostic and therapeutic challenge. Nearly 7% of the general population have chronic neuropathic pain responsible for severe quality-of-life impairments. Awareness must therefore be raised among clinicians of the somatosensory and autonomic symptoms that can reveal small fiber neuropathy, appropriate diagnostic investigations, most common causes, and best treatment options for each patient profile. To help achieve this goal, the present review article discusses the clinical presentation of neuropathic pain and paresthesia and/or autonomic dysfunction due to involvement of nerves supplying exocrine glands and smooth muscle; normal findings from standard electrophysiological investigations; most informative diagnostic tests (epidermal nerve fiber density in a skin biopsy, laser-evoked potentials, heat- and cold-detection thresholds, electrochemical skin conductance); main causes, which consist chiefly of metabolic diseases (diabetes mellitus, glucose intolerance), dysimmunity syndromes (Sjögren's syndrome, sarcoidosis, monoclonal gammopathy), and genetic abnormalities (familial amyloidosis due to a transthyretin mutation, Fabry disease, sodium channel diseases); and the available symptomatic and etiological treatments.

Less is More in Diabetic Neuropathy Diagnosis: Comparison of Quantitative Sudomotor Axon Reflex and Skin Biopsy.

To compare the frequency of abnormalities in epidermal nerve fiber density (ENFD) and quantitative sudomotor axon reflex (QSART) in patients with diabetic distal symmetric polyneuropathy (DSPN). Nerve conduction studies, ENFD, and QSART data were obtained pre- and postexercise, in patients enrolled in a prospective diabetic neuropathy study. McNemar's test was applied to compare the yield of ENFD and QSART. Eighteen patients (58 ± 4 years) were enrolled, with 36 data collection points. In diabetic DSPN and diabetic large fiber DSPN (DSPN-L), abnormal ENFD (77% and 100% respectively) is more frequent than abnormal QSART (39% and 35%, respectively) (P value = 0.001 in diabetic DSPN and P value = 0.0002 in diabetic DSPN-L), whereas in diabetic small fiber DSPN (DSPN-S), both tests have similar yields (47%). ENFD has a high diagnostic yield in diabetic DSPN and DSPN-L. Including QSART data adds little to the sensitivity of EFND in DSPN-S.

Clinical and Laboratory Profiles of Idiopathic Small Fiber Neuropathy in Children: Case Series.

The role of autoimmune mechanisms in idiopathic small fiber neuropathy (SFN) is not completely understood. Serum IgM binding to trisulfated disaccharide IdoA2S-GlcNS-6S (TS-HDS) and IgG to fibroblast growth factor receptor 3 were associated with sensory motor polyneuropathies and sensory neuronopathy among others. In this retrospective case review, we describe the clinical and laboratory findings of idiopathic SFN in a small cohort of pediatric patients. Eight children were diagnosed with SFN clinically and confirmed by reduced epidermal nerve fiber density. No involvement of large fibers was confirmed by clinical examination and electrophysiological tests. Possible triggering factors were infectious mononucleosis in 4 patients and human papilloma virus vaccination in 1 patient. Tilt table test was positive in 1 patient, and clinical autonomic dysfunctions were noted in 6 patients. Five patients had positive IgM against TS-HDS, 3 of whom had lower extremity predominant paresthesia. In conclusion, a high proportion of patients with idiopathic SFN in our cohort had a positive IgM TS-HDS antibody.

Chronic pain in Gaucher disease: skeletal or neuropathic origin?

BackgoundPain is one of the most disabling symptoms of Gaucher disease. It is referred by the majority of Gaucher patients and often persists despite long-term enzyme replacement treatment. It has been mainly considered as nociceptive pain secondary to skeletal involvement but it is described even in the absence of bone disease without a clear explanation. In the last years an increasing number of reports have described the presence of neurological manifestation in Gaucher type 1 patients, including subclinical large fibre neuropathy. In our Gaucher clinic we have observed the recurrence of painful symptoms in a group of type 1 Gaucher patients even after a long-term enzyme replacement therapy.MethodsA cross-sectional study was designed to investigate the pathophysiology of pain in a cohort of 25 Gaucher patients (13 females, 12 males). Twenty-two patients received enzyme replacement therapy for a period of time ranging from 10 to >20 years, while three were new diagnosis. Pain was classified as bone or neurologic related on the basis of anamnestic data, clinical and electrophysilogical examinations. Intensity and quality of pain were recorded by Douleur Neuropathique en 4 questionnaire and Neuropathic Pain Symptom Inventory. Neuroalgological evaluation, quantitative sensory testing, nerve conduction studies and evaluation of epidermal nerve fibres density were performed. Comorbidities for peripheral neuropathy were excluded.ResultsThirteen patients complained of pain suggestive of neuropathic origin with proximal patchy distribution, six manifested severe pain paroxysmal, nine pinprick hypoesthesia and 17 thermal hypoesthesia. At quantitative sensory testing, all of them showed high cold thresholds with errata sensation (burning instead of cold), paradoxical heat sensation and mechanic hypoesthesia; three patients showed pressure pain hyperalgesia. Epidermal denervation was present in 19 patients, 12 of them with non-length dependent pattern.ConclusionsThese results confirm the role of peripheral neuropathy in Gaucher pain and demonstrate that skin denervation is as a constitutive feature of the disorder. In addition, they further confirm the existence of a continuum Gaucher phenotype, and provide a new interpretation of pain origin that should be considered for an appropriate disease management and to avoid unnecessary dose escalations of enzyme therapy.

The reduction of intraepidermal P2X3 nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury-induced pain.

Skin biopsies from patients with neuropathic pain often show changes in epidermal innervation, although it remains to be elucidated to what extent such changes can be linked to a particular subgroup of nerve fibers and how these changes are correlated with pain intensity. Here, we investigated to what extent behavioral signs of hyperalgesia are correlated with immunohistochemical changes of peptidergic and non-peptidergic epidermal nerve fibers in a rat model of nerve injury-induced pain. Rats subjected to unilateral partial ligation of the sciatic nerve developed significant mechanical and thermal hyperalgesia as tested by the withdrawal responses of the ipsilateral footpad to von Frey hairs and hotplate stimulation. At day 14, epidermal nerve fiber density and total epidermal nerve fiber length/mm2 were significantly and consistently reduced compared to the contralateral side, following testing and re-testing by two blinded observers. The expression of calcitonin gene-related peptide, a marker for peptidergic nerve fibers, was not significantly changed on the ipsilateral side. In contrast, the expression of the P2X3 receptor, a marker for non-peptidergic nerve fibers, was not only significantly reduced but could also be correlated with behavioral hyperalgesia. When labeling both peptidergic and non-peptidergic nerve fibers with the pan-neuronal marker PGP9.5, the expression was significantly reduced, albeit without a significant correlation with behavioral hyperalgesia. In conjunction, our data suggest that the pathology of the P2X3 epidermal nerve fibers can be selectively linked to neuropathy, highlighting the possibility that it is the degeneration of these fibers that drives hyperalgesia.

204 Voluntary Exercise Modulates Macrophage Polarization Following Sciatic Nerve Injury and Improves Functional Recovery in Mice

Abstract INTRODUCTION Peripheral nerve injury is associated with trauma and is often amenable to surgery. Functional recovery remains a challenging clinical problem that often leads to significant morbidity. Therapies that augment surgical repair may be beneficial in functional outcomes. Macrophages are responsible for the breakdown of debris following injury as well as promotion of regenerative signals. Macrophage polarization is the process by which macrophages take on phenotypically distinct functions based on the local environment and signaling cues. Exercise has been shown to drive macrophage polarization from a pro-inflammatory M1 phenotype towards an anti-inflammatory M2 phenotype in numerous tissues, but remains uninvestigated in the peripheral nervous system. METHODS The purpose of our study was to identify how exercise affects macrophage polarization, motor and sensory function, and neuroregeneration following sciatic nerve crush. Male and female C57BL/6 mice underwent sciatic nerve crush injury and were then given access to running wheels (exercised) or not given access to running wheels (sedentary) for 4 weeks. Analysis included behavioral assessments, anatomical studies, and in vitro studies. RESULTS >Exercised mice ran an average of 2.9 km per night. Injured exercised mice were protected from the development of thermal hyperalgesia. Exercised mice had fewer paw slips on beam walk testing compared to sedentary mice. No differences were measured in mechanical sensitivity or motor coordination and balance. Motor nerve conduction velocities from injured exercised animals were significantly higher than injured sedentary animals suggesting improved nerve recovery with exercise. Injured sciatic nerves from exercised mice demonstrated increased M2 macrophages compared to sciatic nerves from injured sedentary mice. The behavioral changes and altered macrophage polarization correlated with increased epidermal nerve fiber density, improved myelination, and increased in vitro neurite outgrowth from injured exercised animals. CONCLUSION Exercise alters macrophage polarization towards an anti-inflammatory phenotype which improves repair and recovery of the injured peripheral nerve.

Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis.

Psoriasis is often accompanied by itch, but the mechanisms behind this symptom remain elusive. Dynamic changes in epidermal innervation have been observed under chronic itch conditions. Therefore, we investigated whether epidermal innervation is altered in the imiquimod-induced psoriasis mouse model, whether blockade of neurotrophic growth factor signaling can reduce these changes, and whether this system can impact psoriatic itch. Over the 7-day time course of imiquimod treatment, the density of epidermal nonpeptidergic nerves significantly increased, whereas the density of peptidergic nerves significantly decreased. The nonpeptidergic epidermal nerves expressed glial cell line-derived neurotrophic factor (GDNF) family receptor GFRα-1 and GFRα-2, the ligand-binding domains for GDNF and neurturin (NRTN). The NRTN mRNA expression was elevated in the skin of imiquimod-treated mice, whereas the GDNF mRNA expression was decreased. Treatment of imiquimod-challenged mice with an NRTN-neutralizing antibody significantly reduced nonpeptidergic nerve density as well as spontaneous scratching. These results indicate that NRTN contributes to an increase in the epidermal density of nonpeptidergic nerves in the imiquimod-induced psoriasis model, and this increase may be a factor in chronic itch for these mice. Therefore, inhibition of NRTN could be a potential treatment for chronic itch in psoriasis.

In-vivo reflectance confocal microscopy of Meissner's corpuscles in diabetic distal symmetric polyneuropathy

ObjectiveTo evaluate in-vivo reflectance confocal microscopy (RCM) of Meissner's corpuscles (MC) in diabetic distal symmetric polyneuropathy (DSP). MethodsForty-three adults with diabetes and 21 control subjects underwent RCM of MC density at the fingertip of digit V, thenar eminence (TE), and arch of the foot, ankle skin biopsy for epidermal nerve fiber density (ENFD), electrophysiological studies, monofilament threshold testing, and timed vibration at the toe. Subjects with diabetes were subdivided into groups with and without clinical DSP using the American Academy of Neurology (AAN) case definition and neuropathy outcomes were compared across groups. ResultsBoth diabetic groups (with and without AAN clinical DSP criteria) had objective evidence of peripheral sensory involvement using conventional sensory measures, although those with clinical DSP criteria had greater abnormalities. MC densities were lower in the entire diabetic group at the TE and digit V relative to controls. MC densities at all imaging sites were associated with corresponding conventional sensory measures. MC densities were reduced in subjects without AAN clinical DSP criteria at the TE and digit V compared to controls whereas conventional upper limb sensory measures did not differ between these groups. ConclusionsIn-vivo RCM of MC density at digit V is a non-invasive, painless, objective marker in diabetes that offers a window into early large fiber sensory nerve terminal loss. Further studies are needed to determine whether RCM of MCs can identify quantitative changes in DSP associated with disease progression or treatment.

253 Novel injectable coolant for treatment of pain

Cutaneous pain is a major clinical problem. Current treatments have limitations and undesirable side effects. There is a need for a novel, safe, long-lasting means of relieving pain. Previously, we showed that controlled topical cooling of human skin via cryolipolysis leads to prolonged hypoesthesia lasting up to 8 weeks. Quantification of nerve fiber density in the cooled area demonstrated significant reduction of unmyelinated epidermal and myelinated dermal nerve fibers. In order to target deeper sensory nerves at any anatomic location a more direct and efficient method of nerve cooling was needed. Injection of a “heat sink”, such as an injectable coolant, can cool the target tissue directly with increased efficacy. We invented a novel, sterile, biocompatible injectable coolant and tested its safety and efficacy in swine and rat models. Using the swine model we demonstrated that our injectable coolant is safe and more effective in cooling tissue than the conventional cryolipolysis. Using a rat model, we studied the feasibility of this novel injectable coolant in selectively targeting the sciatic nerve. The coolant was injected into skin, muscle and around the sciatic nerve. Gross observation, photography, intense monitoring and histology showed excellent safety and tolerability. Histology and coherent anti-Stokes Raman scattering (CARS) microscopy showed myelin degradation starting at day 7 post-injection, followed by recovery at day 49. Thus, the injectable coolant is safe in reversibly targeting the rat sciatic nerve. While further studies are needed to determine clinical efficacy for the treatment of pain, initial safety and imaging data are encouraging.

867 A comparison of epidermal nerve fiber density and subepidermal neuropeptides in patients with symptomatic scalp vs. controls

867 A comparison of epidermal nerve fiber density and subepidermal neuropeptides in patients with symptomatic scalp vs. controls

Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy

Oxaliplatin use as chemotherapeutic agent is frequently limited by cumulative neurotoxicity which may compromise quality of life. Reports relate this neurotoxic effect to oxidative stress and mitochondrial dysfunction in peripheral nerves and dorsal root ganglion (DRG). Carvedilol is an antihypertensive drug, has also been appreciated for its antioxidant and mitoprotective properties. Carvedilol co-treatment did not reduce the anti-tumor effects of oxaliplatin in human colon cancer cells (HT-29), but exhibited free radical scavenging activity against oxaliplatin-induced oxidative stress in neuronal cells (Neuro-2a). Hence, the present study was designed to investigate the effect of carvedilol in the experimental model of oxaliplatin-induced peripheral neuropathy (OIPN) in Sprague-Dawley rats. Oxaliplatin reduced the sensory nerve conduction velocity and produced the thermal and mechanical nociception. Carvedilol significantly (P<0.001) attenuated these functional and sensorimotor deficits. It also counteracted oxidative/nitrosative stress by reducing the levels of nitrotyrosine and improving the mitochondrial superoxide dismutase expression in both sciatic nerve and DRG tissues. It improved the mitochondrial function and prevented the oxaliplatin-induced alteration in mitochondrial membrane potential in sciatic nerve thus prevented loss of intra epidermal nerve fiber density in the foot pads. Together the results prompt the use of carvedilol along with chemotherapy with oxaliplatin to prevent the peripheral neuropathy.

Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy.

Oxaliplatin, an organoplatinum compound, is used in the treatment of colorectal cancer, but its clinical use can be limited due to the development of peripheral neuropathy. Whilst mitochondrial dysfunction has been implicated as a major pathomechanism for oxaliplatin-induced neurotoxicity, the prevention of autophagy may also aggravate neuronal cell death. Melatonin, a well-known mitoprotectant and autophagy inducer, was used to examine its neuroprotective role in oxaliplatin-induced peripheral neuropathy (OIPN). Melatonin prevented the loss of mitochondrial membrane potential (Ψm) and promoted neuritogenesis in oxaliplatin-challenged neuro-2a cells. It did not interfere with the cytotoxic activity of oxaliplatin in human colon cancer cell line, HT-29. Melatonin treatment significantly alleviated oxaliplatin-induced pain behavior and neuropathic deficits in rats. It also ameliorated nitro-oxidative stress mediated by oxaliplatin, thus prevented nitrosylation of proteins and loss of antioxidant enzymes, and therefore, it improved mitochondrial electron transport chain function and maintained cellular bioenergetics by improving the ATP levels. The protective effects of melatonin were attributed to preventing oxaliplatin-induced neuronal apoptosis by increasing the autophagy pathway (via LC3A/3B) in peripheral nerves and dorsal root ganglion (DRG). Hence, it preserved the epidermal nerve fiber density in oxaliplatin-induced neuropathic rats. Taken together, we provide detailed molecular mechanisms for the neuroprotective effect of melatonin and suggest it has translational potential for oxaliplatin-induced neuropathy.

A combined model reduction algorithm for controlled biochemical systems

BackgroundSystems Biology continues to produce increasingly large models of complex biochemical reaction networks. In applications requiring, for example, parameter estimation, the use of agent-based modelling approaches, or real-time simulation, this growing model complexity can present a significant hurdle. Often, however, not all portions of a model are of equal interest in a given setting. In such situations methods of model reduction offer one possible approach for addressing the issue of complexity by seeking to eliminate those portions of a pathway that can be shown to have the least effect upon the properties of interest.MethodsIn this paper a model reduction algorithm bringing together the complementary aspects of proper lumping and empirical balanced truncation is presented. Additional contributions include the development of a criterion for the selection of state-variable elimination via conservation analysis and use of an ‘averaged’ lumping inverse. This combined algorithm is highly automatable and of particular applicability in the context of ‘controlled’ biochemical networks.ResultsThe algorithm is demonstrated here via application to two examples; an 11 dimensional model of bacterial chemotaxis in Escherichia coli and a 99 dimensional model of extracellular regulatory kinase activation (ERK) mediated via the epidermal growth factor (EGF) and nerve growth factor (NGF) receptor pathways. In the case of the chemotaxis model the algorithm was able to reduce the model to 2 state-variables producing a maximal relative error between the dynamics of the original and reduced models of only 2.8% whilst yielding a 26 fold speed up in simulation time. For the ERK activation model the algorithm was able to reduce the system to 7 state-variables, incurring a maximal relative error of 4.8%, and producing an approximately 10 fold speed up in the rate of simulation. Indices of controllability and observability are additionally developed and demonstrated throughout the paper. These provide insight into the relative importance of individual reactants in mediating a biochemical system’s input-output response even for highly complex networks.ConclusionsThrough application, this paper demonstrates that combined model reduction methods can produce a significant simplification of complex Systems Biology models whilst retaining a high degree of predictive accuracy. In particular, it is shown that by combining the methods of proper lumping and empirical balanced truncation it is often possible to produce more accurate reductions than can be obtained by the use of either method in isolation.

Neuropsychiatric factors in sensitive skin

Sensitive skin is a syndrome defined by the occurrence of unpleasant sensations (stinging, burning, pain, pruritus, and tingling sensations) in response to stimuli that normally should not provoke such sensations. The worldwide prevalence of sensitive skin is approximately 40%. Clinical, histologic, biochemical, and therapeutic data show that this condition is related to changes in epidermal nerve endings with subsequent hyperreactivity and neurogenic inflammation; hence, sensitive skin is not a psychosomatic disorder, although psychologic consequences are possible.