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Previously, herpes zoster (HZ) was found to occur at a higher rate in the HIV population than the general population. However, there are limited data about the incidence, risk factors, and clinical outcomes of HZ in the current antiretroviral therapy (ART) era.We identified HZ episodes in an urban HIV clinic cohort between 2002 and 2009. Three controls were matched to each case, and conditional logistic regression was used to assess for risk factors associated with incident HZ cases. Logistic regression was used to assess for factors associated with complicated HZ.One hundred eighty-three new HZ cases were identified in 4353 patients with 19,752 person-years (PY) of follow-up—an incidence rate 9.3/1000 PY. Cases were majority men (62%) and African American (75%), with a mean age of 39 years (interquartile range, 32-44 years). Fifty patients (28%) had complicated HZ with 12% developing postherpetic neuralgia. In multivariate regression, factors associated with the increased risk of HZ were having started ART within 90 days of the episode [adjusted odds ratio (AOR), 4.02; 95% confidence interval (CI), 1.31 to 12.41], having a viral load of >400 copies per milliliter (AOR, 1.49; 95% CI, 1.00 to 2.24), and having a CD4 <350 cells per cubic millimeter (AOR, 2.46; 95% CI, 1.42 to 4.23) or 350 to 500 cells per cubic millimeter (AOR, 2.02; 95% CI, 1.14 to 3.57) as compared with CD4 >500 cells per cubic millimeter.The incidence of HZ is lower than previously reported in HIV cohorts but remains higher than the general population. Over one fourth of patients developed complicated HZ, which is remarkable given the young age of our population. Risk factors for HZ include markers of poor immune function, suggesting that appropriate ART may reduce the burden of HZ in this population. [ABSTRACT FROM AUTHOR]

SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain. [ABSTRACT FROM AUTHOR]

Background: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years. Methods: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004. Results: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen–inotersen) and 39 switched from placebo to inotersen (placebo–inotersen). The placebo–inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen–inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo–inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study. Conclusion: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy (PN) continues to be a major complication of human immunodeficiency virus (HIV) infection despite successful anti-retroviral therapy. Human HIV-PN can be recapitulated in a CD8-depleted, simian immunodeficiency virus (SIV)-infected rhesus macaque animal model, characterized by a loss of intraepidermal nerve fiber density (IENFD) and damage to the dorsal root ganglia (DRG). Increased monocyte traffic to the DRG has previously been associated with severe DRG pathology, as well as a loss in IENFD. Here, we sought to characterize the molecular signals associated with monocyte activation and trafficking to the DRGs.Methods: Eleven SIV-infected CD8-depleted rhesus macaques were compared to four uninfected control animals. sCD14, sCD163, sCD137, regulated on activation normal T cell expressed and secreted (RANTES), and monocyte chemoattractant protein 1 (MCP-1) were measured in plasma and the latter three proteins were also quantified in DRG tissue lysates. All SIV-infected animals received serial skin biopsies to measure IENFD loss as well as BrdU inoculations to measure monocyte turnover during the course of infection. The number of BrdU+ and CD14+ CD16+ peripheral blood monocytes was determined by flow cytometry. The number of MAC387+, CCR2+, CCR5+, and CD137+ cells in DRG tissue was quantified by immunohistochemistry.Results: sCD14, sCD163, MCP-1, and sCD137 increased significantly in plasma from pre-infection to necropsy. Plasma sCD163 and RANTES inversely correlated with IENFD. Additionally, sCD137 in DRG tissue lysate was elevated with severe DRG pathology and associated with the recruitment of MAC387+ cells to DRG. Elevated numbers of CCR5+ and CCR2+ satellite cells in the DRG were found, suggesting a chemotactic role of their ligands, RANTES, and MCP-1 in recruiting monocytes to the tissue.Conclusions: We characterized the role of systemic (plasma) and tissue-specific (DRG) monocyte activation and associated cytokines in the pathogenesis of SIV-PN. We identified sCD163 and RANTES as potential biomarkers for HIV-PN, as these were associated with a loss of IENFD. Additionally, we identified CD137 signaling to play a role in MAC387+ cell traffic to DRG and possibly contribute to severe pathology. These studies highlight the role of monocyte activation and traffic in the pathogenesis of SIV-PN, while identifying specific signaling proteins for future pharmacological blockade. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary transthyretin‐mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO‐TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients' neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score. Methods: Stage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks. Results: At 66 weeks, inotersen‐treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items. Discussion Inotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients' neuropathy experience in clinical practice. See article on pages 502–508 in this issue. [ABSTRACT FROM AUTHOR]

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials. [ABSTRACT FROM AUTHOR]

Cites a study about the incidence, risk factors and clinical sequelae of herpes zoster. Significance of the patients percentage with post-herpetic neuralgia on the zoster infection rates changes; Identification of patients with episode of herpes zoster; Assessment of factors associated with an initial episode of herpes zoster.

Diabetic peripheral neuropathy (DPN) is one of the most common complications in diabetic patients. Though the exact mechanism for DPN is unknown, it clearly involves metabolic dysfunction and energy failure in multiple cells within the peripheral nervous system. Lactate is an alternate source of metabolic energy that is increasingly recognized for its role in supporting neurons. The primary transporter for lactate in the nervous system, monocarboxylate transporter-1 (MCT1), has been shown to be critical for peripheral nerve regeneration and metabolic support to neurons/axons. In this study, MCT1 was reduced in both sciatic nerve and dorsal root ganglia in wild-type mice treated with streptozotocin (STZ), a common model of type-1 diabetes. Heterozygous MCT1 null mice that developed hyperglycemia following STZ treatment developed a more severe DPN compared to wild-type mice, as measured by greater axonal demyelination, decreased peripheral nerve function, and increased numbness to innocuous low-threshold mechanical stimulation. Given that MCT1 inhibitors are being developed as both immunosuppressive and chemotherapeutic medications, our results suggest that clinical development in patients with diabetes should proceed with caution. Collectively, our findings uncover an important role for MCT1 in DPN and provide a potential lead toward developing novel treatments for this currently untreatable disease. • MCT1 is reduced in sciatic nerve and DRG of streptozotocin-induced diabetic mice. • Reducing MCT1 worsens experimental diabetic neuropathy in mice. • Reducing MCT1 led to greater nerve demyelination after induction of diabetes. [ABSTRACT FROM AUTHOR]