A role for NT-3 in the hyperinnervation of neonatally wounded skin

Neurotrophin-3 (NT-3) is a target-derived neurotrophic factor that regulates sensory neuronal survival and growth. Here we report that NT-3 plays a critical permissive role in cutaneous sensory nerve sprouting that contributes to pain and sensitivity following skin wounding in young animals. Sensory terminal sprouting in neonatally wounded dermis and epidermis is accompanied by increased NT-3 transcription, NT-3 protein levels, and NT-3 protein release 3-7 days post skin injury in newborn rats and mice. Functional blockade of NT-3 activity with specific antibodies greatly reduces sensory neurite outgrowth induced by wounded skin, but not by naïve skin, in dorsal root ganglion/skin co-cultures. The requirement for NT-3 for sensory terminal sprouting in vivo is confirmed by the absence of wound-induced hyperinnervation in heterozygous transgenic mice (NT-3+/−lacZ). We conclude that upregulation of NT-3 in neonatally wounded skin is a critical factor mediating the sensory nerve sprouting that underlies hypersensitivity and pain following skin injury

Molecular, cellular and developmental studies of sensory hyperinnervation following neonatal skin wounding.

A close interaction exists between the nervous system and the skin during development and injury. During development target derived factors are important for patterning the neuronal elements present in later life. After injury, at critical developmental time points this patterning is subject to change for long periods, and can subsequently affect pain processing. Sensory hyperinnervation is profound in the skin of postnatal animals wounded at birth (Reynolds & Fitzgerald 1995). Here I have examined the development of this sensory hyperinnervation and the neurotrophins as possible causal factors. In vitro models for this phenomenon and histochemical characterisation of neurite outgrowth has also been assessed. NGF, NT-3 and GDNF are all upregulated after skin wounding in the above circumstance. However, neither NGF nor NT-3 are solely responsible for the hyperinnervation (Reynolds et al. 1997; Alvares et al. 1999). In vitro studies have demonstrated that NT-3 may be partly responsible, although trkC IgG fusion proteins show no effect in vivo. In vitro models have also demonstrated the importance of the dermis/epidermis for determining extent of neurite outgrowth. To add a new dimension to this study, I have constructed a neonatal wounded/naive skin cDNA library. By using a differential screening approach with mPCR probes, genes regulated in the above situation have been isolated. Clones generated have been sequenced and Northerns, and in situ hybridisation studies undertaken for genes of interest. Clones of particular interest include an endoplasmic reticulum stress protein-like gene (Erp29), an alpha globin-like gene, an ephrin (EPHRIN-A4) and a guanine nucleotide releasing protein-like gene. In addition several novel clones have been isolated which have yet to be characterised. This research will provide further information and understanding to both wound healing in neonates, and the peripheral patterning of cutaneous innervation during development, and lead to the discovery of the essence of hyperinnervation a largely unexplored event

Characteristics of 698 patients with dissociative seizures: a UK multicenter study

Objective We aimed to characterize the demographics of adults with dissociative (nonepileptic) seizures, placing emphasis on distribution of age at onset, male:female ratio, levels of deprivation, and dissociative seizure semiology. Methods We collected demographic and clinical data from 698 adults with dissociative seizures recruited to the screening phase of the CODES (Cognitive Behavioural Therapy vs Standardised Medical Care for Adults With Dissociative Non‐Epileptic Seizures) trial from 27 neurology/specialist epilepsy clinics in the UK. We described the cohort in terms of age, age at onset of dissociative seizures, duration of seizure disorder, level of socioeconomic deprivation, and other social and clinical demographic characteristics and their associations. Results In what is, to date, the largest study of adults with dissociative seizures, the overall modal age at dissociative seizure onset was 19 years; median age at onset was 28 years. Although 74% of the sample was female, importantly the male:female ratio varied with age at onset, with 77% of female but only 59% of male participants developing dissociative seizures by the age of 40 years. The frequency of self‐reported previous epilepsy was 27%; nearly half of these epilepsy diagnoses were retrospectively considered erroneous by clinicians. Patients with predominantly hyperkinetic dissociative seizures had a shorter disorder duration prior to diagnosis in this study than patients with hypokinetic seizures (P < .001); dissociative seizure type was not associated with gender. Predominantly hyperkinetic seizures were most commonly seen in patients with symptom onset in their late teens. Thirty percent of the sample reported taking antiepileptic drugs; this was more common in men. More than 50% of the sample lived in areas characterized by the highest levels of deprivation, and more than two‐thirds were unemployed. Significance Females with dissociative seizures were more common at all ages, whereas the proportion of males increased with age at onset. This disorder was associated with socioeconomic deprivation. Those with hypokinetic dissociative seizures may be at risk for delayed diagnosis and treatment