Peripheral sensory function in non-freezing cold injury patients and matched controls.

NEW FINDINGS: What is the central question of this study? Is peripheral sensory function impaired in the chronic phase of non-freezing cold injury (NFCI)? What is the main finding and its importance? Warm and mechanical detection thresholds are elevated and intraepidermal nerve fibre density is reduced in individuals with NFCI in their feet when compared to matched controls. This indicates impaired sensory function in individuals with NFCI. Interindividual variation was observed in all groups, and therefore a diagnostic cut-off for NFCI has yet to be established. Longitudinal studies are required to follow NFCI progression from formation to resolution ABSTRACT: The aim of this study was to compare peripheral sensory neural function of individuals with non-freezing cold injury (NFCI) with matched controls (without NFCI) with either similar (COLD) or minimal previous cold exposure (CON). Thirteen individuals with chronic NFCI in their feet were matched with the control groups for sex, age, race, fitness, body mass index and foot volume. All undertook quantitative sensory testing (QST) on the foot. Intraepidermal nerve fibre density (IENFD) was assessed 10 cm above the lateral malleolus in nine NFCI and 12 COLD participants. Warm detection threshold was higher at the great toe in NFCI than COLD (NFCI 45.93 (4.71)°C vs. COLD 43.44 (2.72)°C, P = 0.046), but was non-significantly different from CON (CON 43.92 (5.01)°C, P = 0.295). Mechanical detection threshold on the dorsum of the foot was higher in NFCI (23.61 (33.59) mN) than in CON (3.83 (3.69) mN, P = 0.003), but was non-significantly different from COLD (10.49 (5.76) mN, P > 0.999). Remaining QST measures did not differ significantly between groups. IENFD was lower in NFCI than COLD (NFCI 8.47 (2.36) fibre/mm2 vs. COLD 11.93 (4.04) fibre/mm2 , P = 0.020). Elevated warm and mechanical detection thresholds may indicate hyposensitivity to sensory stimuli in the injured foot for individuals with NFCI and may be due to reduced innervation given the reduction in IENFD. Longitudinal studies are required to identify the progression of sensory neuropathy from the formation of injury to its resolution, with appropriate control groups employed.

Analysis of Macrophages and Peptidergic Fibers in the Skin of Patients With Painful Diabetic Polyneuropathy.

BACKGROUND AND OBJECTIVES: The mechanisms of pain in patients with diabetic polyneuropathy are unknown. Studies have suggested a role of inflammation and increased neuropeptides peripherally in pain generation. This study examined the possible skin markers of painful diabetic polyneuropathy (P-DPN): macrophages, substance P (SP), and calcitonin gene-related peptide (CGRP). METHODS: The participants were included from a large Danish cross-sectional clinical study of type 2 diabetes. We diagnosed definite diabetic polyneuropathy using the Toronto criteria and used the Neuropathic Pain Special Interest Group classification for defining P-DPN. We included 60 skin biopsies from patients with diabetic polyneuropathy-30 with P-DPN and 30 with nonpainful diabetic polyneuropathy (NP-DPN)-and 30 biopsies from healthy controls of similar age and sex. The biopsies were stained using PGP 9.5, IbA1, and SP and CGRP primary markers. RESULTS: There was increased macrophage density in patients with P-DPN (8.0%) compared with that in patients with NP-DPN (5.1%, p < 0.001), and there was increased macrophage density in patients with NP-DPN (5.1%) compared with that in healthy controls (3.1%, p < 0.001). When controlling for neuropathy severity, body mass index, age, and sex, there was still a difference in macrophage density between patients with P-DPN and patients with NP-DPN. Patients with P-DPN had higher median nerve fiber length density (274.5 and 155 mm-2 for SP and CGRP, respectively) compared with patients with NP-DPN (176 and 121 mm-2 for SP and CGRP, respectively, p = 0.009 and 0.04) and healthy controls (185.5 and 121.5 mm-2 for SP and CGRP, respectively), whereas there was no difference between patients with NP-DPN and controls without diabetes (p = 0.64 and 0.49, respectively). The difference between P-DPN and NP-DPN for SP and CGRP was significant only in female patients, although a trend was seen in male patients. DISCUSSION: The findings point to a possible involvement of the innate immune system in the pathogenesis of neuropathic pain in patients with DPN, although markers of activated macrophages were not measured in this study.

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy.

Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuropathy is likely to be a class side effect of these drugs, although its severity is largely variable, and it deserves to be further investigated, since the mechanisms of BTZ-induced peripheral neurotoxicity (BiPN) are still unknown.   In our study, we investigated in vivo and in vitro possible pathogenic events relevant to BiPN using a well-established rat model, with particular reference to the extent of proteasome inhibition and the effects on α-tubulin polymerization in sciatic nerves and dorsal root ganglia specimens obtained from animals treated with chronic regimens at a dose of 0.2 mg/kg intravenously. The same assessments were also performed after a single injection. Moreover, these studies were replicated in vitro using embryonic DRG neurons exposed to 100 nM BTZ and adult DRG neurons exposed to 10-50 nM BTZ for 24 h and 48 h. A significant increase in the polymerized fraction of α-tubulin and prolonged proteasome inhibition were observed after the chronic BTZ treatment in vivo. Recovery to physiological levels was observed after a 4-week follow-up post-treatment period. Proteasome inhibition and increased α-tubulin polymerization were also observed following BTZ treatment of both embryonic and adult DRG neurons in vitro. Our in vivo results suggest that proteasome inhibition and alteration of tubulin dynamics contribute to BiPN. The in vitro systems here described reliably replicate the in vivo results, and might therefore be used for further mechanistic studies on the effects of proteasome inhibitors on neurons.

Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia.

In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B H3 and H4 were not neurotoxic. Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.

The role of neuregulin-1 in the response to nerve injury.

Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types will not only give insight into peripheral nerve development, but also the reaction to and recovery from peripheral nerve injury. The type III isoform of neuregulin-1 (NRG1) has emerged as a key signaling factor that is expressed on axons and, through binding to erbB2/3 receptors on Schwann cells, regulates multiple phases of their development. In adulthood, NRG1 is dispensable for the maintenance of the myelin sheath; however, this factor is required for both axon regeneration and remyelination following nerve injury. The outcome of NRG1 signaling depends on interactions with other pathways within Schwann cells such as Notch, integrin and cAMP signaling. In certain circumstances, this signaling pathway may be maladaptive; for instance, direct binding of Mycobacterium leprae onto erbB2 receptors produces excessive activation and can actually promote demyelination. Attempts to modulate this pathway in order to promote nerve repair will therefore need to give consideration to the exact isoform used, as well as how it is processed and the context in which it is presented to the Schwann cell.

Identification of patients with neuropathic pain using electronic primary care records.

BACKGROUND: Chronic neuropathic pain is a common condition which is challenging to treat. Many people with neuropathic pain are managed in the community, so primary care records may allow more appropriate subjects to be recruited for clinical studies. OBJECTIVE: We investigated whether primary care records can be used to identify patients with diseases associated with neuropathic pain. METHOD: We analysed demographic, diagnostic and prescribing data from over 100 000 primary care electronic patient records in one part of London, UK. RESULTS: The prevalence of diagnoses associated with chronic neuropathic pain was 13 per 1000, with the elderly, women and white patients experiencing the greatest burden of disease. CONCLUSION: Computerised health records offer an excellent opportunity to improve the identification of patients for clinical research in complex conditions like chronic neuropathic pain. To make full use of data from these records, standardisation of clinical coding and consensus on diagnostic criteria are needed.