Varicella-Zoster viruses associated with post-herpetic neuralgia induce sodium current density increases in the ND7-23 Nav-1.8 neuroblastoma cell line

Post-herpetic neuralgia (PHN) is the most significant complication of herpes zoster caused by reactivation of latent Varicella-Zoster virus (VZV). We undertook a heterologous infection in vitro study to determine whether PHN-associated VZV isolates induce changes in sodium ion channel currents known to be associated with neuropathic pain. Twenty VZV isolates were studied blind from 11 PHN and 9 non-PHN subjects. Viruses were propagated in the MeWo cell line from which cell-free virus was harvested and applied to the ND7/23-Nav1.8 rat DRG x mouse neuroblastoma hybrid cell line which showed constitutive expression of the exogenous Nav 1.8, and endogenous expression of Nav 1.6 and Nav 1.7 genes all encoding sodium ion channels the dysregulation of which is associated with a range of neuropathic pain syndromes. After 72 hrs all three classes of VZV gene transcripts were detected in the absence of infectious virus. Single cell sodium ion channel recording was performed after 72 hr by voltage-clamping. PHN-associated VZV significantly increased sodium current amplitude in the cell line when compared with non-PHN VZV, wild-type (Dumas) or vaccine VZV strains ((POka, Merck and GSK). These sodium current increases were unaffected by acyclovir pre-treatment but were abolished by exposure to Tetrodotoxin (TTX) which blocks the TTX-sensitive fast Nav 1.6 and Nav 1.7 channels but not the TTX-resistant slow Nav 1.8 channel. PHN-associated VZV sodium current increases were therefore mediated in part by the Nav 1.6 and Nav 1.7 sodium ion channels. An additional observation was a modest increase in message levels of both Nav1.6 and Nav1.7 mRNA but not Nav 1.8 in PHN virally infected cells

A Rare Case of Fungal Necrotising Otitis Externa Centred on the Left Temporomandibular Joint

Introduction. Necrotising otitis externa (NOE) is a rare life-threatening complication of simple otitis externa which can be difficult to diagnose and manage. It is very rarely centred on the temporomandibular joint (TMJ). Fungi cause NOE in approximately 5–20% of patients, and a high index of suspicion is required for diagnosis, particularly when there is no improvement with prolonged topical and intravenous antibiotic therapy. Objective. To report a novel case of fungal NOE centred on the left TMJ in an immunocompromised adult male with a focus on investigations and optimal management. Case Report. A 67-year-old male with comorbid chronic renal impairment presented to our otolaryngology department with prolonged left otalgia and otorrhoea. Subsequent cross-sectional imaging demonstrated left NOE centred on the TMJ. Poor resolution with prolonged courses of systemic and topical anti-pseudomonal antibiotics prompted maxillofacial surgical input for left TMJ exploration, washout, and biopsy from the joint capsule. The causative organism was identified as Aspergillus flavus on PCR analysis. The patient was successfully treated with oral posaconazole and repeated topical insertions of amphotericin B-soaked ribbon gauze to the left ear. Discussion. A combination of various imaging modalities including CT, MRI, Tc-99, and gallium-67 are utilised in clinical practice both to diagnose NOE and subsequently monitor disease progression or resolution. Immunocompromised patients with confirmed fungal NOE may require a combination of treatments including surgical debridement and prolonged antifungal therapy for a number of months, if not lifelong, treatment. Initiating empirical antifungal therapy may be justified in some patients. However, this should be judged on a case-by-case basis and guided by discussion with the local microbiology and infectious diseases departments. However, there is no national guideline or consensus regarding treatment of these patients, especially in cases of fungal NOE

Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain

A distal symmetrical sensory peripheral neuropathy is frequently observed in people living with Human Immunodeficiency Virus Type 1 (HIV-1). This neuropathy can be associated with viral infection alone, probably involving a role for the envelope glycoprotein gp120; or a drug-induced toxic neuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors as a component of highly active anti-retroviral therapy. In order to elucidate the mechanisms underlying drug-induced neuropathy in the context of HIV infection, we have characterized pathological events in the peripheral and central nervous system following systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). Systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity (33% decrease in limb withdrawal threshold) that when combined with perineural HIV-gp120 is exacerbated (48% decrease in threshold) and both treatments result in thigmotactic (anxiety-like) behaviour. Immunohistochemical studies revealed little ddC-associated alteration in DRG phenotype, as compared with known changes following perineural HIV-gp120. However, the chemokine CCL2 is significantly expressed in the DRG of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fibre density, comparable to that seen in herpes zoster infection. Moreover, a spinal gliosis is apparent at times of peak behavioural sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone. Treatment with the microglial inhibitor, minocycline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120+ddC model and reversal of some measures of thigmotaxis. Finally, the hypersensitivity to mechanical stimuli was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. These data suggests that both neuropathic pain models display many features of HIV- and anti-retroviral-related peripheral neuropathy. They therefore merit further investigation for the elucidation of underlying mechanisms and may prove useful for preclinical assessment of drugs for the treatment of HIV-related peripheral neuropathic pain

A Clinical Decision Support Tool for Familial Hypercholesterolemia Based on Physician Input

Objective: To develop clinical decision support (CDS) for familial hypercholesterolemia (FH), based on physician input obtained by a mixed methods approach. Introduction: Awareness, detection, and control of FH—a relatively common genetic disorder—is low. Clinical decision support could address knowledge gaps and provide point-of-care guidance for the management of FH. Methods: A 16-question survey that assessed familiarity with FH and sought input on potential content of the CDS tool was emailed to 1161 clinicians including 208 cardiologists. In addition, 4 physician focus groups were held to gather input on the structure and form of the CDS tool. This study took place between September 12, 2016, and January 16, 2017. Results: The response rate to the survey was 18.1%. Clinicians were overwhelmingly (97.6%) in favor of a CDS tool that assists in managing patients with FH at the point of care and this was confirmed in the focus group discussions. Key themes emerged during the focus groups including providers' knowledge and understanding of FH, facilitators and barriers to implementing a CDS tool, and suggestions for its design and content. Conclusion: Clinicians were supportive of development of a CDS tool to assist with the evaluation and treatment of FH and provided feedback related to the design and implementation of such a tool