带状疱疹后遗神经痛的动物模型及病理机制研究

带状疱疹后遗神经痛(postherpetic neuralgia,PHN)是带状疱疹最常见的并发症,其发生率随年龄的增加而增加,并且严重影响患者的生活质量。目前PHN的治疗多采用复合用药,但效果不佳。阻碍其治疗发展的关键是对PHN的发病机制不甚清楚,究其根本原因是缺乏与临床符合的动物模型。目的:综述带状疱疹病毒感染模型的改良和进展,使PHN的病理机制得到进一步揭示。内容:介绍与PHN相关的水痘-带状疱疹病毒潜伏感染模型、体外模型及慢性感染模型,综述与PHN发生发展有关的潜伏机制、与其他神经病理性痛相似的机制及近年来较为关注的中枢与外周损伤机制。趋向:进一步研究与人类水痘带状疱疹病毒感染更为相似的动物模型,并随其改良和进展,使发生PHN的机制得到进一步的阐释。     

Increased Incidence of Herpes Zoster and Postherpetic Neuralgia in Adult Patients following Traumatic Brain Injury: A Nationwide Population-Based Study in Taiwan

The aims of this study were to estimate the incidences of herpes zoster (HZ) and postherpetic neuralgia (PHN) in patients after traumatic brain injury (TBI). Furthermore, we aimed to explore the risk factors of the development of HZ and PHN in patients after TBI. This population-based, longitudinal analysis was conducted using the Taiwan National Health Insurance Research Database (consisting of 1,000,000 beneficiaries) from 1996 to 2010. Using the longitudinal National Health Insurance Research Database, we conducted a retrospective population-based cohort study to evaluate the incidence of HZ and PHN in adult TBI patients and controls. Kaplan-Meier analysis and Cox regression were used to compare differences in the development of HZ and PHN. The effects of gender, comorbidity and surgery on the risk of HZ and PHN development were assessed by subgroup analyses. Over a 15-year follow-up, the cumulative incidence of HZ in 28,234 TBI patients (604.00/100,000 person-years) was significantly higher than 34,085 controls (322.21/100,000 person-years) (P<0.0001, by log-rank test). Females showed a significantly higher incidence of HZ than males (p for interaction = 0.0010). The time to HZ development in the follow-up period was 5.9 years in TBI patients compared to 9.9 years in the control set (p <0.0001). TBI patients were 2.93 and 2.11 times likely to develop HZ and PHN, respectively, than the general population. The incidences of HZ and PHN in TBI patients were also significantly greater than for controls in the CCI = 0 subgroup. To our knowledge, this is the first population-based cohort study to reveal that TBI is an independent risk factor for HZ and PHN in TBI patients, especially in females. Physician should pay attention to the possibility of HZ and PHN in TBI patients and be aware that HZ vaccination early after brain trauma may lower the incidence of HZ and PHN.     

Spinal astrocytic activation is involved in a virally-induced rat model of neuropathic pain

Postherpetic neuralgia (PHN), the most common complication of herpes zoster (HZ), plays a major role in decreased life quality of HZ patients. However, the neural mechanisms underlying PHN remain unclear. Here, using a PHN rat model at 2 weeks after varicella zoster virus infection, we found that spinal astrocytes were dramatically activated. The mechanical allodynia and spinal central sensitization were significantly attenuated by intrathecally injected L-α-aminoadipate (astrocytic specific inhibitor) whereas minocycline (microglial specific inhibitor) had no effect, which indicated that spinal astrocyte but not microglia contributed to the chronic pain in PHN rat. Further study was taken to investigate the molecular mechanism of astrocyte-incudced allodynia in PHN rat at post-infection 2 weeks. Results showed that nitric oxide (NO) produced by inducible nitric oxide synthase mediated the development of spinal astrocytic activation, and activated astrocytes dramatically increased interleukin-1β expression which induced N-methyl-D-aspartic acid receptor (NMDAR) phosphorylation in spinal dorsal horn neurons to strengthen pain transmission. Taken together, these results suggest that spinal activated astrocytes may be one of the most important factors in the pathophysiology of PHN and "NO-Astrocyte-Cytokine-NMDAR-Neuron" pathway may be the detailed neural mechanisms underlying PHN. Thus, inhibiting spinal astrocytic activation may represent a novel therapeutic strategy for clinical management of PHN.     

带状疱疹后神经痛的射频治疗

带状疱疹后神经痛(postherpetic neuralgia,PHN)是带状疱疹的严重并发症,发病机制复杂,是一种难治性、顽固性的神经病理性疼痛,常见于老年患者或免疫功能低下的患者,严重影响日常生活。带状疱疹后神经痛的治疗方法包括药物治疗、神经刺激法、射频疗法以及神经阻滞法等。其中,射频疗法作为一项临床较为常用的治疗手段,已在各种慢性疼痛的治疗上取得了有效应用。本文将综合国内外近期的相关研究,对射频的机制、射频的分类、射频治疗PHN的疗效和治疗靶点的选择进行总结。     

Cooperative cocktail in a chemical defence mechanism of a trunkfish.

Pahutoxin a quaternary ammonium salt surfactant serves as an active ingredient in the defensive skin secretion of various marine trunkfish (Ostracociidae). In the defensive skin secretion of the Red Sea trunkfish, Ostracion cubicus the effect of PHN is amplified due to the existence of non toxic polypeptides which act as (a) PHN - chelators and (b) potentiators. The secretion of the Red Sea trunkfish includes an additional category of pharmacologically active polypeptides represented by boxin [7] which similarly to PHN they independently kill fish exclusively through medium application. By the aid of radiolabeled PHN and a fish gill membrane preparation a series of equilibrium saturation binding assays were carry out which demonstrate that PHN performs its biological defensive function via receptors and not due to its surface activity. The gill membranes of the trunkfish were shown to be devoid of PHNreceptors. The pharmacological, ecological and environmental implications of the above data are discussed.     

The PINE study: rationale and design of a randomised comparison of epidural injection of local anaesthetics and steroids versus care-as-usual to prevent postherpetic neuralgia in the elderly [ISRCTN32866390]

BACKGROUND: Postherpetic neuralgia (PHN) is by far the most common complication of herpes zoster (HZ) and one of the most intractable pain disorders. Since PHN is seen most often in the elderly, the number of patients with this disorder is expected to increase in our ageing society. PHN may last for months to years and has a high impact on the quality of life. The results of PHN treatment are rather disappointing. Epidural injection of local anaesthetics and steroids in the acute phase of HZ is a promising therapy for the prevention of PHN. Since randomised trials on the effectiveness of this intervention are lacking, the PINE (Prevention by epidural Injection of postherpetic Neuralgia in the Elderly) study was set up. The PINE study compares the effectiveness and cost-effectiveness of a single epidural injection of local anaesthetics and steroids during the acute phase of HZ with that of care-as-usual (i.e. antivirals and analgesics) in preventing PHN in elderly patients. METHODS / DESIGN: The PINE study is an open, multicenter clinical trial in which 550 elderly (age >/= 50 yr.) patients who consult their general practitioner in the acute phase of HZ (rash < 7 days) are randomised to one of the treatment groups. The primary clinical endpoint is the presence of HZ-related pain one month after the onset of the rash. Secondary endpoints include duration and severity of pain, re-interventions aiming to treat the existing pain, side effects, quality of life, and cost-effectiveness. CONCLUSION: The PINE study is aimed to quantify the (cost-) effectiveness of a single epidural injection during the acute phase of HZ on the prevention of PHN.     

Serial changes in urinary proteome profile of membranous nephropathy: implications for pathophysiology and biomarker discovery

Membranous nephropathy is one of the most common causes of primary glomerular diseases worldwide. The present study adopted a gel-based proteomics approach to better understand the pathophysiology and define biomarker candidates of human membranous nephropathy using an animal model of passive Heymann nephritis (PHN). Clinical characteristics of Sprague-Dawley rats injected with rabbit anti-Fx1A antiserum mimicked those of human membranous nephropathy. Serial urine samples were collected at Days 0, 10, 20, 30, 40, and 50 after the injection with anti-Fx1A (number of rats = 6; total number of gels = 36). Urinary proteome profiles were examined using 2D-PAGE and SYPRO Ruby staining. Quantitative intensity analysis and ANOVA with Tukey post-hoc multiple comparisons revealed 37 differentially expressed proteins among 6 different time-points. These altered proteins were successfully identified by MALDI-TOF MS and classified into 6 categories: (i) proteins with decreased urinary excretion during PHN; (ii) proteins with increased urinary excretion during PHN; (iii) proteins with increased urinary excretion during PHN, but which finally returned to basal levels; (iv) proteins with increased urinary excretion during PHN, but which finally declined below basal levels; (v) proteins with undetectable levels in the urine during PHN; and (vi) proteins that were detectable in the urine only during PHN. Most of these altered proteins have functional significance in signaling pathways, glomerular trafficking, and controlling the glomerular permeability. The ones in categories (v) and (vi) may serve as biomarkers for detecting or monitoring membranous nephropathy. After normalization of the data with 24-h urine creatinine excretion, changes in 34 of initially 37 differentially expressed proteins remained statistically significant. These data underscore the significant impact of urinary proteomics in unraveling disease pathophysiology and biomarker discovery.     

Allodynic skin in post-herpetic neuralgia: histological correlates

Most post-herpetic neuralgia (PHN) patients suffer from tactile allodynia (pain evoked by lightly touching the skin) and it is frequently the dominant clinical manifestation. The pathophysiology of tactile allodynia in PHN patients is poorly understood and this is one of the major limits to the development of appropriate therapies. Epidermal nerve fibres (ENFs) are free nerve endings of small-diameter A-delta and C primary afferents, which can easily be assessed by neurodiagnostic skin biopsy (NSB). The aim of this study was to establish the correlation between the residual epidermal innervation of the allodynic skin and the intensity of tactile allodynia in that area. Twenty-five patients (13 males and 12 females) with PHN were enrolled. Eighteen patients had PHN in the thoracic dermatome, four in the cervical, two in the trigeminal and one in the lumbar. The severity of allodynia evoked by a paintbrush was graded according to an eleven-point numerical scale. A skin biopsy was obtained from the maximal allodynia area and from the contralateral skin. Nerve fibres were labelled with indirect immunofluorescence. Results showed that epidermal innervation was lower in the allodynic skin than in the contralateral skin, although there was great variability among patients. There was no correlation between severity of allodynia and epidermal innervation of the PHN skin. In conclusion, the present study further indicates peripheral nervous system involvement in PHN but does not support a direct correlation between epidermal innervation changes and tactile allodynia.     

带状疱疹后神经痛患者杏仁核的功能连接改变研究

带状疱疹后神经痛(postherpetic neuralgia,PHN)是一种常见的神经病理性疼痛,但其中枢机制尚不明了.杏仁核在疼痛反应中的作用近年来受到关注.本研究的目的在于通过功能磁共振成像,研究带状疱疹后神经痛患者杏仁核各个亚区功能连接(functional connectivity,FC)的改变,探索慢性神经病理性疼痛的中枢机制.8位带状疱疹后神经痛患者和8位健康者进行了普通核磁共振和静息态功能磁共振扫描.将杏仁核各个亚区分别进行的功能连接分析,并将功能连接和被试者的病程、视觉模拟评分(visual analog scale,VAS)进行了相关分析.与健康志愿者相比,PHN患者杏仁核的基底外侧部(laterobasal groups,LB)和皮质部(superficial groups,SF)与多个脑区的FC表现出增强,主要位于颞叶和额叶.同时SF与多个区域的FC出现减低,主要位于额叶和顶叶.颞叶和额叶部分区域与LB的FC强度、与病程长短和VAS评分表现出关联性.研究结果提示,PHN患者杏仁核功能连接的改变提示了在慢性神经病理性疼痛的产生和发展中,杏仁核以及多个涉及情绪、认知、注意的脑区发挥了重要作用.     

原发性三叉神经痛和疱疹后三叉神经痛临床特征及射频热凝术后效果分析

摘要 目的：探讨原发性三叉神经痛（PTN）和疱疹后三叉神经痛（PHN）的临床特征,并比较经卵圆孔射频热凝术（RF-TC）治疗PTN和PHN的临床疗效。方法：随机选取2019年1月至2020年8月在我院治疗的三叉神经痛患者123例,其中原发性三叉神经痛90例,带状疱疹后神经痛33例。所有患者均通过RF-TC进行治疗,治疗后通过视觉模拟量表（VAS）、巴罗神经研究所疼痛强度量表对面部疼痛评分进行疼痛评估,通过巴罗神经研究所麻木评分进行麻木评定,通过健康问卷-9对患者抑郁情况进行评估,通过匹斯堡睡眠质量指数测量患者心理状态。结果：PTN患者发病年龄显著低于PHN患者（P<0.05）,而病程显著高于PHN患者（P<0.05）;PHN患者的眼支发生率高于PTN患者（39.39% vs 8.89%, P<0.05）。两组患者经RF-TC治疗前后VAS评分无显著差异（P>0.05）。PHN组从轻度到重度影响睡眠质量的比例显著高于PTN组（30.30% vs 10.00%, P<0.05）。PTN组患者治疗后中重度抑郁患者比例显著高于PHN组患者（21.11% vs 9.09%, P<0.05）。两组患者经RF-TC治疗后,临床治疗有效率、面麻木程度以及巴罗神经研究所疼痛强度量表评定的面部疼痛无显著差异（P>0.05）。结论：经卵圆孔射频热凝术治疗原发性三叉神经痛和带状疱疹后三叉神经痛是安全有效的,但治疗后疱疹后三叉神经痛失眠的发生率较高,而原发性三叉神经痛的抑郁发生率较高。     

Markedly increased urinary preprohaptoglobin and haptoglobin in passive Heymann nephritis: a differential proteomics approach

Membranous nephropathy (MN), a common cause of idiopathic nephrotic syndrome in adults, remains a potentially devastating problem worldwide. At present, there is no reliable noninvasive method for predicting and/or monitoring this glomerular disease, and its pathophysiology remains poorly understood. In the present study, the urinary proteome profile of rats after 10 days of an induction of passive Heymann nephritis (PHN), which resembles human MN, was compared to that of the baseline (control) urine prior to the induction of PHN by anti-Fx1A injection. Each pool of PHN and control urine samples (n = 10 each) was labeled with different fluorescent dyes (Cy3 or Cy5), and equal amounts of the labeled proteins of both pools were resolved in the same 2D gel, together with an internal standard labeled with Cy2. Two-dimensional difference gel electrophoresis revealed a number of protein spots whose expression levels were altered during PHN. Eighteen protein spots with >1.5-fold changes and p < 0.05 were selected for subsequent identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. They were successfully identified as serum albumin precursor, alpha-1-antitrypsin, preprohaptoglobin, liver-regeneration-related protein, and transthyretin (which increased during PHN) and E-cadherin, MPP7, tropomyosin beta, kallikrein, and alpha-2u globulin (which decreased in the PHN urine). Among these proteins, the increase in urinary preprohaptoglobin has particularly drawn our attention because of its byproduct, haptoglobin (Hp), which is involved in the protection of tissue damage from hemoglobin-induced oxidative stress. Western blotting and enzyme-linked immunosorbent assay clearly showed a markedly increased level of Hp in the urine, but not in the serum, of the PHN animals. Our findings may lead to a significant advance in the attempt to define a new therapeutic target and/or novel biomarker for human MN.     

Intracellular depolymerase activity in isolated inclusion bodies containing polyhydroxyalkanoates with long alkyl and functional substituents in the side chain.

The in vitro degradation of isolated Pseudomonas oleovorans inclusion bodies containing either poly-3-hydroxynonanoate (PHN), or poly(-3-hydroxy-5-phenylvalerate) (PHPV), or a mixture of these two polymers was investigated. When incubated at 30 degrees C and pH 9, inclusion bodies containing either polyhydroxyoctanoate (PHO), PHN or PHPV exhibited similar degradation rates of approximately 0.94 (+/- 3%) mg/h. The PHN and PHPV components for inclusion bodies containing a mixture of PHN and PHPV showed similar degradation rates; that is the ratios showed little change and remained at approximately 50 wt.% (+/- 3%) for each component. These results contrast markedly with in vivo studies for similar inclusion bodies in whole cells. The results suggest that the synthesis and degradation of these novel polyhydroxyalkanoates by P. oleovorans proceeds by the same enzymatic pathway. In addition, comparisons between the in vivo and in vitro polymer degradation suggest that the activity of the intracellular depolymerase does not control the rate limiting step of PHPV degradation in vivo. Instead, the presence of an aromatic group in the repeating units of this polymer may inhibit the utilization of the monomeric units of PHPV as a reserve carbon source by the cells.     

带状疱疹后遗神经痛患者脑基础活动改变的功能核磁共振研究

带状疱疹后遗神经痛(postherpetic neuralgia,PHN)是临床上一种慢性顽固性神经病理性疼痛,然而,对于其潜在的中枢机制还知之甚少.为了进一步探讨带状疱疹后遗神经痛患者的相关脑区活动,利用功能核磁共振成像低频振幅振荡(ALFF)技术观察带状疱疹后遗神经痛患者的基础脑区活动.8名带状疱疹后遗神经痛患者与8名性别、年龄相匹配的健康者行静息态功能磁共振(f MRI)成像扫描,用SPM8中的多重回归分析,在控制被试年龄、性别、教育年限的影响下,将每个体素的ALFF值同每个被试的病程、视觉模拟评分(visual analog scale,VAS)进行相关分析.与健康志愿者相比,PHN组与VAS评分相关的ALFF值增高的脑区有:右侧小脑后叶、前额叶背外侧区域(BA11/46/47)、右侧顶叶(BA40)、右侧舌回(BA17/18/19);与VAS评分相关的ALFF值降低的脑区有:右侧颞中回(BA21)、左侧舌回(BA17/18)、右侧小脑前叶、左侧后扣带回(BA30/19)和右侧中央前回(BA3/4/6);PHN组与病程相关的ALFF值增高的脑区有:右侧小脑后叶、前额叶背外侧区域(BA9/10/11/47)、左侧颞上回(BA38)、右侧顶叶和右侧舌回(BA17/18/19);与病程相关ALFF值降低的脑区有:左侧海马旁回(BA28)、右侧小脑前叶、左侧扣带回(BA24)、右侧颞上回(BA13)、左侧中央前回和右侧顶下小叶(BA39/40).研究结果提示,涉及疼痛的情绪、警觉行为、注意的脑区在带状疱疹后遗痛慢性疼痛的产生和维持中发挥重要作用.     

Proteomic analysis of the nuclear matrix in the early stages of rat liver carcinogenesis: Identification of differentially expressed and MAR-binding proteins

Tumor progression is characterized by definite changes in the protein composition of the nuclear matrix (NM). The interactions of chromatin with the NM occur via specific DNA sequences called MARs (matrix attachment regions). In the present study, we applied a proteomic approach along with a Southwestern assay to detect both differentially expressed and MAR-binding NM proteins, in persistent hepatocyte nodules (PHN) in respect with normal hepatocytes (NH). In PHN, the NM undergoes changes both in morphology and in protein composition. We detected over 500 protein spots in each two dimensional map and 44 spots were identified. Twenty-three proteins were differentially expressed; among these, 15 spots were under-expressed and 8 spots were over-expressed in PHN compared to NH. These changes were synchronous with several modifications in both NM morphology and the ability of NM proteins to bind nuclear RNA and/or DNA containing MARs sequences. In PHN, we observed a general decrease in the expression of the basic proteins that bound nuclear RNA and the over-expression of two species of Mw 135 kDa and 81 kDa and pI 6.7-7.0 and 6.2-7.4, respectively, which exclusively bind to MARs. These results suggest that the deregulated expression of these species might be related to large-scale chromatin reorganization observed in the process of carcinogenesis by modulating the interaction between MARs and the scaffold structure.     

Effect of duration of postherpetic neuralgia on efficacy analyses in a multicenter,randomized, controlled study of NGX-4010, an 8% capsaicin patch evaluated for the treatment of postherpetic neuralgia

Background

Postherpetic neuralgia (PHN) is a painful and difficult to treat complication of acute herpes zoster. Current treatment options provide only partial relief and are often limited by poor tolerability. We evaluated the safety and efficacy of a single 60-minute application of NGX-4010, an 8% capsaicin patch, in patients with PHN.

Methods

This multicenter, double-blind, controlled study randomized 155 patients 2:1 to receive either NGX-4010 or a 0.04% capsaicin control patch. Patients were at least 18 years old with PHN for at least 3 months, and an average Numeric Pain Rating Scale (NPRS) score of 3 to 9. The primary efficacy endpoint was the percentage change in NPRS score from baseline to weeks 2-8.

Results

The mean percent reduction in "average pain for the past 24 hours" NPRS scores from baseline to weeks 2-8 was greater in the NGX-4010 group (36.5%) compared with control (29.9%) although the difference was not significant (p = 0.296). PGIC analysis demonstrated that more NGX-4010 recipients considered themselves improved (much, or very much) compared with control at weeks 8 and 12, but the differences did not reach statistical significance. Post hoc analyses of patients with PHN for at least 6 months showed significantly greater reductions in "average pain for the past 24 hours" NPRS scores from baseline to weeks 2-8 in NGX-4010 patients compared to controls (37.6% versus 23.4%; p = 0.0291). PGIC analysis in this subgroup demonstrated that significantly more NGX-4010 recipients considered themselves much or very much improved compared with control at week 12 (40% versus 20%; p = 0.0403;).

Conclusions

Although treatment appeared to be safe and well tolerated, a single 60-minute application of NGX-4010 failed to show efficacy in this study which included patients with PHN for less than 6 months. Large reductions in pain observed among control patients with pain for less than 6 months may have been due to spontaneous resolution of PHN, may have confounded the results of the prespecified analyses, and should be taken into account when designing PHN studies.

Trial Registration

NCT00068081

     

The Calcineurin Inhibitor Tacrolimus Reduces Proteinuria in Membranous Nephropathy Accompanied by a Decrease in Angiopoietin-Like-4

Tacrolimus is an anticalcineurinic agent with potent immunosuppressive activity that has recently been shown to have the added benefit of reducing proteinuria in membranous nephropathy (MN) patients. However, its potential mechanisms remain unknown. To reveal the mechanism, rat cohorts were administered tacrolimus or vehicle from days 7 to 28 after the induction of passive Heymann nephritis (PHN). PHN induction resulted in heavy proteinuria and increased expression of desmin, a marker of injured podocytes. We also showed that the glomerular expression of angiopoietin-like-4 (Angptl4) was markedly upregulated in PHN rats and human MN followed by an increase in urine Angptl4 excretion. In addition, increased Angptl4 expression may be related to podocyte injury and proteinuria. Furthermore, upregulated Angptl4 expression primarily colocalized with podocytes rather than endothelial or mesangial cells, indicating that podocytes may be the source of Angptl4, which then gradually migrated to the glomerular basement membrane over time. However, tacrolimus treatment markedly reduced glomerular and urinary Angptl4, accompanied by a reduction in the established proteinuria and the promotion of podocyte repair. Additionally, glomerular immune deposits and circulating IgG levels induced by PHN clearly decreased following tacrolimus treatment. In conclusion, this is the first demonstration that the calcineurin inhibitor tacrolimus can reduce Angptl4 in podocytes accompanied by a decrease in established proteinuria and promotion of podocyte repair in MN.     

Metalloprotease meprin beta in rat kidney: glomerular localization and differential expression in glomerulonephritis

Meprin (EC 3.4.24.18) is an oligomeric metalloendopeptidase found in microvillar membranes of kidney proximal tubular epithelial cells. Here, we present the first report on the expression of meprin beta in rat glomerular epithelial cells and suggest a potential involvement in experimental glomerular disease. We detected meprin beta in glomeruli of immunostained rat kidney sections on the protein level and by quantitative RT-PCR of laser-capture microdissected glomeruli on the mRNA level. Using immuno-gold staining we identified the membrane of podocyte foot processes as the main site of meprin beta expression. The glomerular meprin beta expression pattern was altered in anti-Thy 1.1 and passive Heymann nephritis (PHN). In addition, the meprin beta staining pattern in the latter was reminiscent of immunostaining with the sheep anti-Fx1A antiserum, commonly used in PHN induction. Using Western blot and immunoprecipitation assays we demonstrated that meprin beta is recognized by Fx1A antiserum and may therefore represent an auto-antigen in PHN. In anti-Thy 1.1 glomerulonephritis we observed a striking redistribution of meprin beta in tubular epithelial cells from the apical to the basolateral side and the cytosol. This might point to an involvement of meprin beta in this form of glomerulonephritis.     

Herpes Zoster Vaccine Effectiveness against Incident Herpes Zoster and Post-herpetic Neuralgia in an Older US Population: A Cohort Study

Background

Herpes zoster is common and has serious consequences, notably post-herpetic neuralgia (PHN). Vaccine efficacy against incident zoster and PHN has been demonstrated in clinical trials, but effectiveness has not been studied in unselected general populations unrestricted by region, full health insurance coverage, or immune status. Our objective was to assess zoster vaccine effectiveness (VE) against incident zoster and PHN in a general population-based setting.

Methods and Findings

A cohort study of 766,330 fully eligible individuals aged ≥65 years was undertaken in a 5% random sample of Medicare who received and did not receive zoster vaccination between 1st January 2007 and 31st December 2009.Incidence rates and hazard ratios for zoster and PHN were determined in vaccinated and unvaccinated individuals. Analyses were adjusted for age, gender, race, low income, immunosuppression, and important comorbidities associated with zoster, and then stratified by immunosuppression status. Adjusted hazard ratios were estimated using time-updated Cox proportional hazards models.Vaccine uptake was low (3.9%) particularly among black people (0.3%) and those with evidence of low income (0.6%). 13,112 US Medicare beneficiaries developed incident zoster; the overall zoster incidence rate was 10.0 (9.8–10.2) per 1,000 person-years in the unvaccinated group and 5.4 (95% CI 4.6–6.4) per 1,000 person-years in vaccinees, giving an adjusted VE against incident zoster of 0.48 (95% CI 0.39–0.56). In immunosuppressed individuals, VE against zoster was 0.37 (95% CI 0.06–0.58). VE against PHN was 0.59 (95% CI 0.21–0.79).

Conclusions

Vaccine uptake was low with variation in specific patient groups. In a general population cohort of older individuals, zoster vaccination was associated with reduction in incident zoster, including among those with immunosuppression. Importantly, this study demonstrates that zoster vaccination is associated with a reduction in PHN. Please see later in the article for the Editors'' Summary     

Semantics-Based Composition of Integrated Cardiomyocyte Models Motivated by Real-World Use Cases

Semantics-based model composition is an approach for generating complex biosimulation models from existing components that relies on capturing the biological meaning of model elements in a machine-readable fashion. This approach allows the user to work at the biological rather than computational level of abstraction and helps minimize the amount of manual effort required for model composition. To support this compositional approach, we have developed the SemGen software, and here report on SemGen’s semantics-based merging capabilities using real-world modeling use cases. We successfully reproduced a large, manually-encoded, multi-model merge: the “Pandit-Hinch-Niederer” (PHN) cardiomyocyte excitation-contraction model, previously developed using CellML. We describe our approach for annotating the three component models used in the PHN composition and for merging them at the biological level of abstraction within SemGen. We demonstrate that we were able to reproduce the original PHN model results in a semi-automated, semantics-based fashion and also rapidly generate a second, novel cardiomyocyte model composed using an alternative, independently-developed tension generation component. We discuss the time-saving features of our compositional approach in the context of these merging exercises, the limitations we encountered, and potential solutions for enhancing the approach.     

Local and Systemic Cytokine Expression in Patients with Postherpetic Neuralgia

Background

Postherpetic neuralgia (PHN) is the painful complication of a varicella zoster virus reactivation. We investigated the systemic and local gene expression of pro- and anti-inflammatory cytokine expression in patients with PHN.

Methods

Thirteen patients with PHN at the torso (Th4-S1) were recruited. Skin punch biopsies were obtained from the painful and the contralateral painless body area for intraepidermal nerve fiber density (IENFD) and cytokine profiling. Additionally, blood was withdrawn for systemic cytokine expression and compared to blood values of healthy controls. We analyzed the gene expression of selected pro- and anti-inflammatory cytokines (tumor necrosis factor-alpha [TNF] and interleukins [IL]-1β, IL-2, and IL-8).

Results

IENFD was lower in affected skin compared to unaffected skin (p<0.05), while local gene expression of pro- and anti-inflammatory cytokines did not differ except for two patients who had 7fold higher IL-6 and 10fold higher IL-10 gene expression in the affected skin compared to the contralateral unaffected skin sample. Also, the systemic expression of cytokines in patients with PHN and in healthy controls was similar.

Conclusion

While the systemic and local expression of the investigated pro- and anti-inflammatory cytokines was not different from controls, this may have been influenced by study limitations like the low number of patients and different disease durations. Furthermore, other cytokines or pain mediators need to be considered.