'Original antigenic sin', T cell memory, and malaria sporozoite immunity: an hypothesis for immune evasion

Prior to any exposure to malaria, most adults have T cells specific for malaria parasites and various malaria proteins. The protein for which this has been shown more than any other is the circumsporozoite protein (CSP) of Plasmo-dium falciparum. These T cells can be present in high frequency and appear to have arisen through exposure to other (non-malaria) organisms. Although T cells are thought to provide protection against sporozoites, these T cells specific for cross-reactive organisms are clearly unable to protect against malaria, and may be preferentially expanded following exposure to malaria sporozoites. Thus, cross-reactive organisms have the potential to skew the repertoire of sporozoite-induced T cells and affect the induction of protective immunity. This is analogous to the concept of 'original antigenic sin' whereby prior exposure to one strain of influenza virus was shown to be able to divert the antibody response to a second challenging strain to focus on the shared (cross-reactive) epitopes.     

Second international collaborative study evaluating performance characteristics of methods measuring the von Willebrand factor cleaving protease (ADAMTS-13)

Summary.  Background:  Over the last 4 years ADAMTS-13 measurement underwent dramatic progress with newer and simpler methods. Aims:  Blind evaluation of newer methods for their performance characteristics. Design:  The literature was searched for new methods and the authors invited to join the evaluation. Participants were provided with a set of 60 coded frozen plasmas that were prepared centrally by dilutions of one ADAMTS-13-deficient plasma (arbitrarily set at 0%) into one normal-pooled plasma (set at 100%). There were six different test plasmas ranging from 100% to 0%. Each plasma was tested 'blind' 10 times by each method and results expressed as percentage vs. the local and the common standard provided by the organizer. Results:  There were eight functional and three antigen assays. Linearity of observed-vs.-expected ADAMTS-13 levels assessed as r ² ranged from 0.931 to 0.998. Between-run reproducibility expressed as the (mean) CV for repeated measurements was below 10% for three methods, 10–15% for five methods and up to 20% for the remaining three. F -values (analysis of variance) calculated to assess the capacity to distinguish between ADAMTS-13 levels (the higher the F -value, the better the capacity) ranged from 3965 to 137. Between-method variability (CV) amounted to 24.8% when calculated vs. the local and to 20.5% when calculated vs. the common standard. Comparative analysis showed that functional assays employing modified von Willebrand factor peptides as substrate for ADAMTS-13 offer the best performance characteristics. Conclusions:  New assays for ADAMTS-13 have the potential to make the investigation/management of patients with thrombotic microangiopathies much easier than in the past.     

ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock

BACKGROUND: Insufficient control of von Willebrand factor (VWF) multimer size as a result of severely deficient ADAMTS-13 activity results in thrombotic thrombocytopenic purpura associated with microvascluar thrombosis and platelet consumption, features not seldom seen in severe sepsis and septic shock. METHODS: ADAMTS-13 activity and VWF parameters of 40 patients with severe sepsis or septic shock were compared with those of 40 healthy controls of the same age and gender and correlated with clinical findings and sepsis outcome. RESULTS: ADAMTS-13 activity was significantly lower in patients than in healthy controls [median 60% (range 27-160%) vs. 110% (range 63-200%); P < 0.001]. VWF parameters behaved reciprocally and both VWF ristocetin cofactor activity (RCo) and VWF antigen (VWF:Ag) were significantly (P < 0.001) higher in patients compared with controls. Neither ADAMTS-13 activity nor VWF parameters correlated with disease severity, organ dysfunction or outcome. However, a contribution of acute endothelial dysfunction to renal impairment in sepsis is suggested by the significantly higher VWF propeptide and soluble thrombomodulin levels in patients with increased creatinine values as well as by their strong positive correlations (creatinine and VWF propeptide r(s) = 0.484, P < 0.001; creatinine and soluble thrombomodulin r(s) = 0.596, P < 0.001). CONCLUSIONS: VWF parameters are reciprocally correlated with ADAMTS-13 activity in severe sepsis and septic shock but have no prognostic value regarding outcome.     

SOCIOLOGICAL THEORY AND PHARMACY PRACTICE RESEARCH: (2) An introduction to functionalist sociology: Talcott Parsons' concept of the “sick role”

This article, the second in a series highlighting the relevance of sociological theory to pharmacy practice, provides an introduction to functionalist sociology through a discussion of the work of the influential sociologist Talcott Parsons. As we noted in the first paper,¹ the discipline of sociology consists of a number of competing perspectives which seek to understand the nature of the social world: functionalism is one perspective that has had an enduring influence. Drawing on metaphors from biology, functionalist sociologists view societies as wholes or systems, which consist of interacting and self‐regulating elements. Each of the elements works to maintain the whole, so ensuring the stability or order of the system. Parsons focused on one of the elements within the social system — medicine — and, specifically, on the doctor‐patient relationship, in order to illustrate his ideas. In this article, we will be discussing Parsons' contribution to functionalist sociology, his depiction of the relationships between health professionals and patients and his assertion that these play an important role in sustaining order within society. We provide a critique of his ideas before assessing his relevance to the contemporary health services and pharmacy practice research agenda. A reading list is supplied at the end of the article for those who wish to follow up his ideas. As we suggested in the first paper,¹ our aim for this series is to stimulate critical engagement with key sociological concepts among pharmacy practice researchers, with the hope of strengthening the inter‐disciplinary explanatory capacity of this body of work.²     

Lactation inhibition by the dopamine agonist CV 205–502

Summary. In an open pilot study with a parallel group design 30 bottle feeding women were randomly assigned in a two to one ratio to receive either the new dopamine agonist CV 205–502 or bromocriptine for lactation inhibition. Ten women who intended to breast feed served as normal controls. All treated women reached prepregnant prolactin levels within 72 h with once-daily 0.075 mg of CV 205–502 or twice-daily 2.5 mg of bromocriptine, at starting doses of 0.05 mg and 2.5 mg respectively. Fifteen of the 20 women treated with CV 205–502 reported breast symptoms, 50% occurring on days 3 and 4 of treatment. Three of the 10 women treated with bromocriptine had breast symptoms between days 2 and 28. Overall efficacy and tolerance in the two groups was very good. Side effects did not differ between the groups, with the exception of pulse rate in the standing position, which was significantly higher in the bromocriptine treated group than in either the CV 205–502 group (  P = 0.02  ) or the breast feeding group (   P < 0.01  ). The coagulation tests (fibrinogen, AT III, PTT and APTT) showed no significant differences between the three groups.     

Quantitative Tissue Doppler Echocardiography: Physiological Nonuniformity of Left Ventricular Transmural Myocardial Wall-Motion Velocities and Gradients

Tissue Doppler echocardiography (TDE) is a new method by which transmural myocardial function can be studied noninvasively. In order to investigate physiology and reproducibility, 24 young, healthy volunteers were examined by M-mode TDE. Nonuniformity of transmural tissue layer velocities became apparent: Subendocardial and subepicardial velocities of the anteroseptal myocardial wall (AW) were 3.5 ± 0.7 and 1.3 ± 0.5 cm/sec (P < 0.0001 , t- test), whereas in the posterolateral wall (PW) values of 3.6 ± 0.6 and 1.2 ± 0.4 cm/sec (P < 0.0001 , t- test ), respectively, were revealed. The ratios, termed "myocardial velocity gradients" as a new indicator of left ventricular performance, were 3.1 ± 1.0 and 3.4 ± 1.1, respectively. AW and PW did not differ (N.S.). Tolerance borders did not overlap, and intraobserver variability did not reach intersubject variability (P < 0.0001, F-ratio test). TDE provides new and more sophisticated insights into left ventricular performance. It seems to be accurate and reliable and therefore worth introducing into the clinical arena.