Jacqueline Pearson

Epidemiology and genetics of rheumatoid arthritis

Chapter summary The prevalence of rheumatoid arthritis (RA) is relatively constant in many populations, at 0.5–1.0%. However, a high prevalence of RA has been reported in the Pima Indians (5.3%) and in the Chippewa Indians (6.8%). In contrast, low occurrences have been reported in populations from China and Japan. These data support a genetic role in disease risk. Studies have so far shown that the familial recurrence risk in RA is small compared with other autoimmune diseases. The main genetic risk factor of RA is the HLA DRB1 alleles, and this has consistently been shown in many populations throughout the world. The strongest susceptibility factor so far has been the HLA DRB1*0404 allele. Tumour necrosis factor alleles have also been linked with RA. However, it is estimated that these genes can explain only 50% of the genetic effect. A number of other non-MHC genes have thus been investigated and linked with RA (e.g. corticotrophin releasing hormone, oestrogen synthase, IFN-γ and other cytokines). Environmental factors have also been studied in relation to RA. Female sex hormones may play a protective role in RA; for example, the use of the oral contraceptive pill and pregnancy are both associated with a decreased risk. However, the postpartum period has been highlighted as a risk period for the development of RA. Furthermore, breastfeeding after a first pregnancy poses the greatest risk. Exposure to infection may act as a trigger for RA, and a number of agents have been implicated (e.g. Epstein–Barr virus, parvovirus and some bacteria such as Proteus and Mycoplasma). However, the epidemiological data so far are inconclusive. There has recently been renewed interest in the link between cigarette smoking and RA, and the data presented so far are consistent with and suggestive of an increased risk.

Analytical aspects of biosensors

The aims of simplifying biochemical measurement and of extending assay reliability outside the con®nes of a central laboratory are present in many applied biology sectors, not just clinical chemistry. An increasing range of desktop analysers are commercially available that are economical both of sample and of operator time. A common theme running through many approaches is the exploitation of biological reagents, with the ultimate in simpli®cation being integration of biological and measurement elements into a simple, monolithic device. This is the basic concept of the biosensor, a biological sample-interactive phase in close contact with a physical or chemical transducer. A typical biosensor construct has three features ± a recognition element, a signal transducing structure and an ampli®cation/processing element (see Fig. 1). Various transduction mechanisms have been used: electrochemical, electrical, optical, thermal and piezoelectric, as summarized in Table 1. Most commonly, in a biosensor, a biorecognition phase (e.g. enzyme, antibody, receptor, single-stranded DNA) interacts with the analyte of interest to produce some chargebased or optical change at the local sensor± transducer interface. Through signal processing this interaction is converted into digital values that relate to the build-up of concentration or activity of the analyte in the vicinity of the device, which in turn relates to the ambient levels in the bulk sample under investigation. A biosensor is not necessarily a stand-alone entity, but should be considered as part of a general development in instrumentation, designed to address generic medical and non-medical measurement science problems. Biosensors, when deployed in a clinical setting, offer the advantage of extra-laboratory analysis of a variety of relevant substances, including hormones, drugs of abuse and metabolites (both in vivo and in vitro). Continuous realtime monitoring of analytes is also a possibility; for example, monitoring of metabolites in blood (where the sample matrix is inevitably optically opaque) in the critical care situation. Generally, biosensors permit the use of low cost, `clean’ technologywith reduced requirements for sample pre-treatment and large sample volume; ultimately, the user can be someone without prior laboratory skills. The `niche’ application is therefore extra-laboratory testing, as realized with conventional dry reagent dipsticks. This review provides basic descriptions of the main subtypes of biosensorwith an indication of their operational capability from a clinical chemistry perspective. Owing to a greater appreciation of the capabilities and limitations of biosensors and new input from the microfabrication and materials science ®elds, the direction of biosensor research is undergoing rapid change. The descriptions that follow are intended to re ect this change and illustrate the shift in emphasis from a preoccupation with bioreagent immobilization and chemistry to a renewed effort towards total system integration. A functionally ef®cient juxtaposition of sample and sensor remains essential for proper function, and the descriptions given provide some relevant examples.

Surface plasmon resonance: a study of the effect of biotinylation on the selection of antibodies for use in immunoassays

Surface plasmon resonance is a valuable optical phenomenon for monitoring biomolecular interactions in real time. In this project anti-mouse-Fc was coupled to the carboxymethyl dextran coating on the surface of a CM5 sensor chip (BIAcore) using amine coupling. Monoclonal antibodies (MAbs) to Luteinizing Hormone (LH) were then captured on this surface in the correct orientation for binding. LH (500 IU/l) was injected over the surface and the subsequent binding and dissociation events were monitored. The resulting optical response curves allowed fast analysis of the binding interactions of eight selected MAbs. It was possible to develop a two-site immunometric assay for LH using a pair of these MAbs. The effect of biotinylating the MAbs, using various biotin:antibody coupling ratios, on their subsequent binding to both LH and avidin conjugated alkaline phosphatase was also investigated. This approach has allowed rapid evaluation of the effect of changes in both reagent and reaction conditions on immunoassay performance and appears to be a valuable adjunct to immunosensor and immunoassay development.

A rapid receptor–ligand assay determination of estrogens using surface plasmon resonance

Abstract A rapid and simple assay has been developed for the determination of estrogen and estrogen like compounds using surface plasmon resonance (SPR) that might be of use in epidemiological studies and potentially may aid the diagnosis of male infertility. The interaction between hER and an immobilised estradiol-BSA conjugate can be suppressed if the receptor is pre-incubated with estradiol or with the estrogen mimic, diethylstilbesterol (DES). The binding response of hER to immobilised estradiol-BSA was 184±40 (n=3) resonance units (RU). When preincubated with either free estradiol or DES, the response was reduced to 93±8 and 103±19 RU, respectively (P≤0.018). There was no significant difference in the extent to which the level of binding was reduced when these two compounds were compared (P=0.47). When receptor was pre-incubated with estradiol to establish if binding of the receptor to a zearlenone-BSA (Z-BSA) conjugate also decreased, there was a substantial decrease in binding to Z-BSA, the difference in response being significant (P=0.034). The increased speed with which data may be obtained using SPR compared with traditional biological assays permits greater sample throughput and provides a more quantitative approach to defining levels of estrogen and estrogen like compounds in body fluids.

Books, my Greatest Joy: Constructing the Female Reader in 'The Lady's Magazine'

ABSTRACT The Ladys Magazine, the most popular and longest lasting periodical for women in the late eighteenth and early nineteenth centuries, brings to the fore issues of womens reading and concentrates on the figure of the woman reader to a quite remarkable extent. This is true both in editorial and other non‐fiction features and in fiction. As has been remarked, the juxtaposition of articles often causes oddly contradictory effects. These are studied in the context of the construction of the woman reader, relating them both to advertising and marketing strategies and to the contradictory quality of contemporary ideologies of gender and especially of womens reading. Far from being naive and conservative, as some critics have stated, the female reader constructed by/in the magazine had the ability to read both compliantly and resistingly, and was trained both in repetitive protocols and to be tolerant of contradiction. I argue that such a polyvalent model of reading might be potentially empowering for ...

“These Tags of Literature”: Some Uses of Allusion in the Early Novels of Angela Carter

Abstract Angela Carter has said that she is “in the demythologising business” (“Notes” 71); but, as Pauline Palmer has pointed out, that is only one aspect of her achievement, for her novels actually reveal “two antithetical impulses,” “demythologising” but also “celebratory and Utopian elements” (179). Carters novels create complex and mocking dualisms, as is suggested by some of her favorite words, like “ambivalent” and “ambiguous,”1 and recurrent images, like mirrors, doubles, dolls, puppets that resemble or become human beings, films, and pictures. In particular, a rich layering of literary allusiveness is one crucial technique by which Carter balances those “antithetical impulses.” As she has remarked, her “fiction is very often a kind of literary criticism” (Haffenden 79).

Whole blood assay of glucose-6-phosphate dehydrogenase: potential for simplified immunoassay

Enzyme labels combined with electrochemical product detection have considerable advantages in the development of non isotopic immunoassays. In particular, there is the possibility of signal detection in whole blood samples using cheap, robust and ultimately portable instrumentation. In this study the amperometric measurement, in whole blood, of glucose-6-phosphate dehydrogenase (G6PDH), an enzyme commonly employed in homogeneous immunoassays, has been investigated using a simple membrane covered electrode. On comparison of several compounds for electrochemical mediation of the enzyme cofactor NADH, in whole blood, napthoquinone sulphonic acid has been found to be optimal giving lower background responses (<1 nA vs. Ag/AgCl) whilst mediating effectively NADH detection at low overpotentials (≤0.15 V vs. Ag/AgCl). Employing this mediator it is possible to measure electrochemically NADH and subsequently G6PDH at concentrations down to 0.6 U ml−1 in the presence of whole blood. This simplified G6PDH detection system will facilitate greatly the development of dehydrogenase based amperometric immunoassays in whole blood.

DREADFUL NEWS FROM WAPPING (AND ELSEWHERE): GENDER, READING AND THE SUPERNATURAL IN EARLY MODERN ENGLAND

Scenes of books and reading are often prominent in accounts of early modern womens encounters with the supernatural. This reveals a number of significant things about the way reading was conceptualized in the period, especially about the anxieties on the part of (largely educated male) authors about the extension of reading to the young, the female, and the lower class, and the fantasies of these subjects to transgress a demandingly bibliocentric Protestant culture. In these narratives, three elements converge—the supernatural, the uncontrollable act of reading and the leaky female body—all of which raised anxieties about proper boundaries, rational subjectivity, and the power of the state and church to authorize meanings and control behaviour, leading to the representation of reading as essentially uncanny.

‘Then she asked it, what were its Sisters names?’: Reading between the lines in seventeenth-century pamphlets of the supernatural

Abstract In seventeenth-century cheap print on supernatural themes, the reader is often struck by gaps, silences, and things that do not quite add up. The article explores ways of reading between the lines to expose and perhaps make sense of these discontinuities. It asks what cultural work is performed by the supernatural in such texts, and speculates on the uses served by ghosts, fairies and demons both in the self-representation of subaltern, often female, individuals and in the textual strategies of the pamphlet writers.