Research letter: Predictive value of a self-reported history of varicella infection in determining immunity in adults

THE RECENT INTRODUCTION OF A VACCINE FOR VARICELLA has raised questions about whether, for adults, a patient''s history of varicella infection is useful in determining if vaccination is necessary. We report findings on 184 family medicine patients aged 18 to 65 years who were asked if they had a history of varicella infection and were subsequently tested for varicella antibodies. A history of infection was positive for 114 (62%) of the participants and negative or uncertain for 70 (38%). All 114 subjects who reported a varicella infection history were immune. All 4 subjects who were not immune reported an uncertain or negative infection history. Except for people who are at increased risk of varicella infection or complications from infection, serologic testing may not be required for adults in the general population who have a history of varicella infection. Varicella infection (chickenpox) is highly contagious¹ and is spread by respiratory droplets or direct contact. Varicella can occur in nonimmune adults, in whom severity of the infection increases with age,² often causing serious morbidity and loss of work time. In Canada, 70% of 53 reported deaths caused by varicella between 1987 and 1996 occurred in adolescents and adults.³ When acquired during pregnancy, varicella can cause significant maternal, perinatal and infant morbidity.³ After varicella infection, more than 95% of people develop antibodies,⁴ which are detected by serologic testing and indicate lifelong immunity.The recent introduction of a vaccine for varicella means that nonimmune adults may benefit from vaccination.⁵ This has led to studies to determine whether a self-reported history of varicella infection is an accurate indication of the presence of antibodies. Studies to date have yielded disparate conclusions and recommendations,^{6,7,8,9,10,11} and no study has yet investigated this question for adults in a primary care population. Our objective was to determine, in an adult primary care population, the accuracy of a self-reported history of varicella infection in determining immunity.St. Michael''s Hospital Family Practice Unit serves a population with a wide range of socioeconomic groups and countries of origin. The mean patient age is 44 years, and 60% of patients are female. On randomly selected clinic dates between October and December 2000 we enrolled patients aged 18 to 65 years who were having blood taken for reasons other than serologic testing for varicella antibodies. Using a structured interview, patients were asked about their history of varicella infection (Box 1), and their blood samples were analyzed for antibody titres using the VZVscan latex agglutination test (Becton Dickinson, Cockeysville, Md.). We excluded patients with psychiatric or medical conditions impairing memory, a history of varicella vaccination or active varicella infection. All patients gave informed consent, and the study was approved by the St. Michael''s Hospital Research Ethics Board.Open in a separate windowBox 1A sample size of 200 patients provides power to detect a 95% confidence interval (CI) of ± 3% if the baseline positive predictive value of a history of varicella is 95%.Of 204 participants enrolled, 184 had a serologic test for varicella antibodies. For unknown reasons, the serologic test was not performed in the remaining 20 cases.Of the 184 participants whose blood sample was tested for varicella antibodies, 101 (55%) were women, 117 (64%) were born in North America, and 107 (58%) had postsecondary education. The mean age was 43 (standard deviation 12.8) years. Participants for whom serologic testing was not done had similar characteristics.All 114 (62%) of the subjects who reported a history of varicella infection were immune, for a positive predictive value of 100% (95% CI 97%–100%) (Open in a separate windowIn this study, a self-reported history of varicella infection was a highly accurate indicator of immunity to the pathogen. The 98% (180/184) seroprevalence of varicella–zoster virus antibodies in our study population was slightly higher than other population estimates,² and consequently a large majority of those who were uncertain of or reported no past infection were also immune.Although we recruited participants from only 1 family medicine clinic in an urban teaching centre, the patient population of the clinic is diverse in terms of patient country of origin, socioeconomic status and demographic characteristics.Whether particular vaccination strategies are appropriate or cost-effective depends on the population examined and their circumstances. The costs of serologic testing and vaccination and the potential financial, social and medical consequences of infection should be considered.For people who are at increased risk of varicella infection or for whom it is crucial to establish immunity, such as health care workers,^9,10,12,13 pregnant women^7,11,14 and household contacts of immunocompromised people, it may be prudent to have them undergo routine serologic testing regardless of their self-reported infection history.In this primary care setting, a positive history of varicella infection was an accurate indicator of the presence of antibodies. Except for people at high risk of varicella infection, serologic testing may not be required for adults in the general population who have had the infection. Vaccination should be offered to nonimmune patients.     

Rotational-echo double-resonance NMR-restrained model of the ternary complex of 5-enolpyruvylshikimate-3-phosphate synthase

The 46-kD enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase catalyzes the condensation of shikimate-3-phosphate (S3P) and phosphoenolpyruvate to form EPSP. The reaction is inhibited by N-(phosphonomethyl)-glycine (Glp), which, in the presence of S3P, binds to EPSP synthase to form a stable ternary complex. We have used solid-state NMR and molecular modeling to characterize the EPSP synthase-S3P-Glp ternary complex. Modeling began with the crystal coordinates of the unliganded protein, published distance restraints, and information from the chemical modification and mutagenesis literature on EPSP synthase. New inter-ligand and ligand-protein distances were obtained. These measurements utilized the native (31)P in S3P and Glp, biosynthetically (13)C-labeled S3P, specifically (13)C and (15)N labeled Glp, and a variety of protein-(15)N labels. Several models were investigated and tested for accuracy using the results of both new and previously published rotational-echo double resonance (REDOR) NMR experiments. The REDOR model is compared with the recently published X-ray crystal structure of the ternary complex, PDB code 1G6S. There is general agreement between the REDOR model and the crystal structure with respect to the global folding of the two domains of EPSP synthase and the relative positioning of S3P and Glp in the binding pocket. However, some of the REDOR data are in disagreement with predictions based on the coordinates of 1G6S, particularly those of the five arginines lining the binding site. We attribute these discrepancies to substantive differences in sample preparation for REDOR and X-ray crystallography. We applied the REDOR restraints to the 1G6S coordinates and created a REDOR-refined xray structure that agrees with the NMR results.     

Folate, homocysteine, endothelial function and cardiovascular disease

Evidence reported from numerous clinical studies over the past decade has revealed an association between increased plasma total homocysteine (tHcy) concentrations and cardiovascular disease (CVD). In addition, epidemiological studies have identified an inverse association between blood folate concentrations, folate intake and cardiovascular endpoints, that are independent of homocysteine. Folic acid supplementation can lower plasma tHcy concentrations safely and inexpensively. Furthermore, folic acid can reverse endothelial dysfunction observed in patients with CVD. This reversal in endothelial dysfunction with folic acid has been shown to be independent of plasma tHcy lowering, suggesting that folate has pleiotropic effects on the vasculature other than homocysteine lowering. In vitro evidence demonstrates that 5-methyltetrahydrofolate (5MeTHF) the main circulating metabolite of folate, can increase nitric oxide production and can directly scavenge superoxide radicals. The potential beneficial role of folic acid supplements on vascular disease are currently being tested in randomized placebo controlled studies.     

The Pseudomonas syringae type III effector AvrRpt2 functions downstream or independently of SA to promote virulence on Arabidopsis thaliana

AvrRpt2, a Pseudomonas syringae type III effector protein, functions from inside plant cells to promote the virulence of P. syringae pv. tomato strain DC3000 (PstDC3000) on Arabidopsis thaliana plants lacking a functional copy of the corresponding RPS2 resistance gene. In this study, we extended our understanding of AvrRpt2 virulence activity by exploring the hypothesis that AvrRpt2 promotes PstDC3000 virulence by suppressing plant defenses. When delivered by PstDC3000, AvrRpt2 suppresses pathogen-related (PR) gene expression during infection, suggesting that AvrRpt2 suppresses defenses mediated by salicylic acid (SA). However, AvrRpt2 promotes PstDC3000 growth on transgenic plants expressing the SA-degrading enzyme NahG, indicating that AvrRpt2 does not promote bacterial virulence by modulating SA levels during infection. AvrRpt2 general virulence activity does not depend on the RPM1 resistance gene, as mutations in RPM1 had no effect on AvrRpt2-induced phenotypes. Transgenic plants expressing AvrRpt2 displayed enhanced susceptibility to PstDC3000 strains defective in type III secretion, indicating that enhanced susceptibility of these plants is not because of suppression of defense responses elicited by other type III effectors. Additionally, avrRpt2 transgenic plants did not exhibit increased susceptibility to Peronospora parasitica and Erysiphe cichoracearum, suggesting that AvrRpt2 virulence activity is specific to P. syringae.     

Gene expression signatures from three genetically separable resistance gene signaling pathways for downy mildew resistance

Resistance gene-dependent disease resistance to pathogenic microorganisms is mediated by genetically separable regulatory pathways. Using the GeneChip Arabidopsis genome array, we compared the expression profiles of approximately 8,000 Arabidopsis genes following activation of three RPP genes directed against the pathogenic oomycete Peronospora parasitica. Judicious choice of P. parasitica isolates and loss of resistance plant mutants allowed us to compare the responses controlled by three genetically distinct resistance gene-mediated signaling pathways. We found that all three pathways can converge, leading to up-regulation of common sets of target genes. At least two temporal patterns of gene activation are triggered by two of the pathways examined. Many genes defined by their early and transient increases in expression encode proteins that execute defense biochemistry, while genes exhibiting a sustained or delayed expression increase predominantly encode putative signaling proteins. Previously defined and novel sequence motifs were found to be enriched in the promoters of genes coregulated by the local defense-signaling network. These putative promoter elements may operate downstream from signal convergence points.     

N-Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: structure-activity relationship of the benzoyl moiety

o-Bromobenzoyl l-tryptophan 1 inhibits the association of LFA-1 with ICAM-1 with an IC(50) of 1.7microM. Evaluation of the structure-activity relationship of the benzoyl moiety shows that 2,6-di-substitutions greatly enhance potency of this class of inhibitors. Electronegative substitutions that favor a 90 degrees angle between the benzoyl ring and the amide bond yield the most potent compounds. There is a strong correlation between the potency of the compounds and the difference between the ab initio energy at 90 degrees and the global minima energy for given compounds. Combining the favored benzoyl substitutions with l-histidine and l-asparagine resulted in a 15-fold increase in potency over compound 1.     

Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's beta-secretase

Cleavage of amyloid precursor protein (APP) by the Alzheimer's beta-secretase (BACE1) is a key step in generating amyloid beta-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with beta-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates. Inhibitory activity is dependent on saccharide size and specific structural characteristics, and the mechanism of action involves blocking access of substrate to the active site. In cellular assays, HS specifically inhibits BACE1 cleavage of APP but not alternative cleavage by alpha-secretase. Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action. Furthermore, inhibition of cellular HS synthesis results in enhanced BACE1 activity. Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing.     

Merging aquatic and terrestrial perspectives of nutrient biogeochemistry

Although biogeochemistry is an integrative discipline, terrestrial and aquatic subdisciplines have developed somewhat independently of each other. Physical and biological differences between aquatic and terrestrial ecosystems explain this history. In both aquatic and terrestrial biogeochemistry, key questions and concepts arise from a focus on nutrient limitation, ecosystem nutrient retention, and controls of nutrient transformations. Current understanding is captured in conceptual models for different ecosystem types, which share some features and diverge in other ways. Distinctiveness of subdisciplines has been appropriate in some respects and has fostered important advances in theory. On the other hand, lack of integration between aquatic and terrestrial biogeochemistry limits our ability to deal with biogeochemical phenomena across large landscapes in which connections between terrestrial and aquatic elements are important. Separation of the two approaches also has not served attempts to scale up or to estimate fluxes from large areas based on plot measurements. Understanding connectivity between the two system types and scaling up biogeochemical information will rely on coupled hydrologic and ecological models, and may be critical for addressing environmental problems associated with locally, regionally, and globally altered biogeochemical cycles.We dedicate this paper to the memory of Catherine Lisa Dent, a member of our working group who contributed much to the ideas presented herein, and to the joy of developing them together.Due to an error in the citation line, this revised PDF (published in December 2003) deviates from the printed version, and is the correct and authoritative version of the paper.     

Use of a marker organism to model the spread of central nervous system tissue in cattle and the abattoir environment during commercial stunning and carcass dressing

Due to concerns about a link between variant Creutzfeldt-Jakob disease in humans and similar prion protein-induced disease in cattle, i.e., bovine spongiform encephalopathy (BSE), strict controls are in place to exclude BSE-positive animals and/or specified risk materials including bovine central nervous system (CNS) tissue from the human food chain. However, current slaughter practice, using captive bolt guns, may induce disruption of brain tissues and mobilize CNS tissues into the bovine circulatory system, leading to the dispersion of CNS tissues (including prion proteins) throughout the derived carcass. This project used a marker (antibiotic-resistant) strain of Pseudomonas fluorescens to model the effects of commercial captive bolt stunning procedures on the movement of mobilized CNS material within slaughtered animals and the abattoir environment. The marker organism, introduced by injection through the bolt entry aperture or directly using a cartridge-fired captive bolt, was detected in the slaughter environment immediately after stunning and in the abattoir environment at each subsequent stage of the slaughter-dressing process. The marker organism was also detected on the hands of operatives; on slaughter equipment; and in samples of blood, organs, and musculature of inoculated animals. There were no significant differences between the results obtained by the two inoculation methods (P < 0.05). This study demonstrates that material present in, or introduced into, the CNS of cattle during commercial captive bolt stunning may become widely dispersed across the many animate and inanimate elements of the slaughter-dressing environment and within derived carcasses including meat entering the human food chain.     

A Cross-System Comparison of Bacterial and Fungal Biomass in Detritus Pools of Headwater Streams

The absolute amount of microbial biomass and relative contribution of fungi and bacteria are expected to vary among types of organic matter (OM) within a stream and will vary among streams because of differences in organic matter quality and quantity. Common types of benthic detritus [leaves, small wood, and fine benthic organic matter (FBOM)] were sampled in 9 small (1st-3rd order) streams selected to represent a range of important controlling factors such as surrounding vegetation, detritus standing stocks, and water chemistry. Direct counts of bacteria and measurements of ergosterol (a fungal sterol) were used to describe variation in bacterial and fungal biomass. There were significant differences in bacterial abundance among types of organic matter with higher densities per unit mass of organic matter on fine particles relative to either leaves or wood surfaces. In contrast, ergosterol concentrations were significantly greater on leaves and wood, confirming the predominance of fungal biomass in these larger size classes. In general, bacterial abundance per unit organic matter was less variable than fungal biomass, suggesting bacteria will be a more predictable component of stream microbial communities. For 7 of the 9 streams, the standing stock of fine benthic organic matter was large enough that habitat-weighted reach-scale bacterial biomass was equal to or greater than fungal biomass. The quantities of leaves and small wood varied among streams such that the relative contribution of reach-scale fungal biomass ranged from 10% to as much as 90% of microbial biomass. Ergosterol concentrations were positively associated with substrate C:N ratio while bacterial abundance was negatively correlated with C:N. Both these relationships are confounded by particle size, i.e., leaves and wood had higher C:N than fine benthic organic matter. There was a weak positive relationship between bacterial abundance and streamwater soluble reactive phosphorus concentration, but no apparent pattern between either bacteria or fungi and streamwater dissolved inorganic nitrogen. The variation in microbial biomass per unit organic matter and the relative abundance of different types of organic matter contributed equally to driving differences in total microbial biomass at the reach scale.