The matrix metalloproteinase-3 (MMP-3) 5A/6A promoter polymorphism is not associated with ischaemic heart disease: analysis employing a family based approach

Matrix metalloproteinase-3 (MMP-3) has been proposed as an important mediator of the atherosclerotic process. The possible role of the functional -1612 5A/6A polymorphism of the MMP-3 gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family based tests of association. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test (PDT), no association between the MMP-3 -1612 5A/6A polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the MMP-3 -1612 5A/6A polymorphism is not associated with IHD.     

A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice

Studies in gene-targeted mice have demonstrated that factor B of the alternative complement pathway plays an important role in several disease models, but an exogenous inhibitor of factor B has not previously been available. We have developed an inhibitory monoclonal antibody directed against a critical epitope on mouse factor B and have tested it in a model of antiphospholipid (aPL) antibody (Ab)-induced fetal loss. Gene-targeted factor B-deficient mice (fB-/-) were injected with a fusion protein comprised of the second and third short consensus repeat (SCR) domains of mouse factor B linked to a mouse IgG1 Fc domain. Hybridomas were made from splenocytes of the immunized mouse. One mAb, designated 1379, produced an IgG1 antibody that inhibited alternative pathway activation in vitro and in vivo by preventing formation of the C3bBb complex. Strikingly, this mAb inhibited alternative pathway activation in serum from mice, rats, humans, monkeys, pigs and horses. Fab fragments made from this mAb also inhibited alternative pathway activation. Epitope mapping demonstrated that this antibody binds to factor B within the third SCR domain. When mAb 1379 was administered to mice that also received human IgG containing antiphospholipid antibodies, it provided significant protection from antiphospholipid antibody-induced complement activation and fetal loss. Thus, this mAb to factor B has broad species reactivity and effectively inhibits alternative pathway activation. The mAb protects mice in an in vivo model of antiphospholipid antibody syndrome, demonstrating the therapeutic potential for the inhibition of factor B in this disease.     

A contribution of cellular immunity to protection against influenza in man

The degree of lymphocyte transformations and leukocyte migration inhibition (LMI) in the presence of inactivated A/Scotland/74 (H3N2) influenza virus vaccine was measured in blood samples collected from 56 medical student volunteers. At the same time the volunteers were skin tested, using the same vaccine. Using the antigenically similar WRL 105 (H3N2), recombinant influenza virus, the level of haemagglutination-inhibiting (HI) antibodies in serum, and neutralizing antibodies in nasal washings collected from the volunteers, were also determined. Each volunteer was then inoculated with live, attenuated WRL 105 influenza virus vaccine and infections demonstrated by virus isolations and serology.Correlations between the ability to infect the volunteers and the various parameters of humoral and cellular immunity were then determined. The results showed a good correlation between the level of serum HI antibody and infection. Thus 16 of 20 volunteers with serum HI antibody titres of 110, but only 6 of 20 volunteers with antibody levels of 130, showed evidence of infection. No direct correlation was observed between any of the other parameters measured and infection by WRL 105 virus. However, when the LMI and serum HI antibody levels were considered together, a contribution of cellular immunity, as measured by the LMI test, could be found. Of 19 volunteers with low serum HI antibody and low LMI levels, 16 were infected, whereas of 13 volunteers with low HI antibody, but with high LMI levels, only 6 showed evidence of infection with WRL 105 influenza virus.     

A Third Route for Reading? Implications from a Case of Phonological Dyslexia

Models of reading in the neuropsychological literature sometimes only include two routes from print to sound, a lexical semantic route and a sublexical phonological route. Other researchers hypothesize an additional route that involves a direct connection between lexical orthographic representations and lexical phonological representations. This so-called ‘third route’ has been invoked to account for the preserved oral reading of some patients who show severe semantic impairments and a disruption of the sublexical phonological route. In their summation hypothesis, Hillis and Caramazza proposed that reading in these cases could result from a combination of partial lexical semantic information and partial sublexical phonological information, thus obviating the need for the third route. The present study examined the case of a phonological dyslexic patient (ML) who exhibited preserved word reading, even for items he could not name, along with a non-word reading impairment. The relationship between ML’s naming and reading, and the influence of semantic variables on his reading were examined. The results of this examination are interpreted as supporting the existence of the third route.     

Ablation of Complex Fractionated Atrial Electrograms in Catheter Ablation for AF; Where have we been and where are we going?

Catheter ablation for persistent AF remains a challenge to the ablator as the disease is now outside the veins and cannot be tackled by pulmonary vein isolation alone. In this article we describe targeting complex fractionated atrial electrograms (CFAE) as a method to guide atrial substrate modification.     

Sunao Tawara : further musings on his tribulations in providing the basis for the modern-day understanding of cardiac electrophysiology

Sunao Tawara, who was born in 1873 and died in 1952, is considered the father of modern cardiac electrophysiology. He published his monumental monograph de     

Pregnancy and the orthopaedic patient

Pregnancy presents unique challenges to both the Orthopaedic surgeon, and the patient. Uniquely there exists not one, but two patients necessitating consideration in each decision process. Physiological changes serve to contribute to the presentation of a number of orthopaedic conditions unique to pregnancy, as well as impacting upon the management of trauma involving the pregnant patient. While elective orthopaedic procedures can generally be postponed until after delivery, trauma usually demands more urgent intervention. A planned and reasoned approach to managing such trauma scenarios is beneficial. In this review article we firstly discuss some of the physiological changes in pregnancy that make the patient susceptible to orthopaedic disease or injury. Secondly, we look at the management of orthopaedic trauma in the pregnant patient. An overview of some of the orthopaedic conditions encountered during pregnancy is presented.