H. P. Williams

The immune response to primary EBV infection: a role for natural killer cells

The role of antigen‐specific CD3+CD8+ cytotoxic T cells in the control of primary Epstein–Barr Virus (EBV) infection is well established. However, time is required for the antigen‐specific immune response to develop and expand. In contrast, innate immune responses, such as natural killer (NK) cells, are considered vital early in the infection process. We analysed the scale, phenotype and function of the NK cell response during symptomatic primary EBV infection, infectious mononucleosis (IM) and showed that NK cell numbers were significantly elevated both at diagnosis of IM and in the first month following diagnosis. There were also significant changes in cell phenotype and function, an increase in the proportion of CD56bright cells at diagnosis, and freshly isolated cells showing an enhanced ability to kill EBV‐infected cell lines. Moreover, in our cohort of IM patients higher NK cell counts were associated with significantly lower viral load in peripheral blood. Our results suggest NK cells have an important role in the control of primary EBV infection by eliminating infected B cells and augmenting the antigen‐specific T cell response via release of immunomodulatory cytokines. The magnitude of the NK cell response may ultimately determine whether primary EBV infection has a clinical outcome.

HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

Infectious mononucleosis (IM) is an immunopathological disease caused by EBV that occurs in young adults and is a risk factor for Hodgkin lymphoma (HL). An association between EBV-positive HL and genetic markers in the HLA class I locus has been identified, indicating that genetic differences in the HLA class I locus may alter disease phenotypes associated with EBV infection. To further determine whether HLA class I alleles may affect development of EBV-associated diseases, we analyzed 2 microsatellite markers and 2 SNPs located near the HLA class I locus in patients with acute IM and in asymptomatic EBV-seropositive and -seronegative individuals. Alleles of both microsatellite markers were significantly associated with development of IM. Specific alleles of the 2 SNPs were also significantly more frequent in patients with IM than in EBV-seronegative individuals. IM patients possessing the associated microsatellite allele had fewer lymphocytes and increased neutrophils relative to IM patients lacking the allele. These patients also displayed higher EBV titers and milder IM symptoms. The results of this study indicate that HLA class I polymorphisms may predispose patients to development of IM upon primary EBV infection, suggesting that genetic variation in T cell responses can influence the nature of primary EBV infection and the level of viral persistence.

A survey of different integer programming formulations of the travelling salesman problem

Eight distinct (and in some cases little known) formulations of the Travelling Salesman Problem as an Integer Programme are given. Apart from the standard formulation all the formulations are ‘compact’ in the sense that the number of constraints and variables is a polynomial function of the number of cities in the problem. Comparisons of the formulations are made by projecting out variables in order to produce polytopes in the same space. It is then possible to compare the strengths of the Linear Programming relaxations. These results are illustrated by computational results on a small problem

Sexual History and Epstein-Barr Virus Infection

To determine the role of sexual contact in transmission of Epstein-Barr virus (EBV) and occurrence of infectious mononucleosis (IM), a cross-sectional study was undertaken of EBV serologic testing and histories of IM and sexual behavior among 1006 new students at Edinburgh University. Prevalence of EBV seropositivity was significantly greater among women (79.2%) than among men (67.4%; P<.001) and among those who had ever been sexually active (82.7%) than among those who had not (63.7%; P<.001). Having a greater number of sex partners was a highly significant risk factor for EBV seropositivity. Two thirds of IM cases, but only a tenth of asymptomatic primary EBV infections, were statistically attributable to sexual intercourse. The findings suggest that EBV transmission occurs during sexual intercourse or closely associated behaviors. Transmission in this way appears to account for most cases of IM but for only a minority of cases of asymptomatic EBV infection, which mainly occur at younger ages.

Analysis of Immune Activation and Clinical Events in Acute Infectious Mononucleosis

The symptoms of infectious mononucleosis (IM) are thought to be caused by T cell activation and cytokine production. Surface lymphocyte activation marker (SLAM)-associated protein (SAP) regulates lymphocyte activation via signals from cell-surface CD244 (2B4) and SLAM (CD150). We followed T cell activation via this SAP/SLAM/CD244 pathway in IM and analyzed whether the results were associated with clinical severity. At diagnosis, SAP, SLAM, and CD244 were significantly up-regulated on CD4 and CD8 T cells; expression decreased during IM, but CD244 and SLAM levels remained higher on CD8 cells 40 days later. There were significantly more lymphocytes expressing CD8 and CD244/CD8 in patients with severe sore throat. The expression of CD8 alone and CD244 on CD8 cells correlated with increased virus load. We suggest that T cells expressing CD244 and SLAM are responsible for the clinical features of IM but that the control of activation is maintained by parallel increased expression of SAP.

Model Solving in Mathematical Programming.

19. Model Solving in Mathematical Programming. By H. P. Williams. ISBN 0 471 93772 3 (paperbound), 0 471 93581 6 (hardbound). Wiley, Chichester, 1993. 360 pp. £19.95 (paperbound), £39.95 (hardbound).

A study of risk factors for acquisition of Epstein‐Barr virus and its subtypes

BACKGROUND Risk factors for primary infection with Epstein-Barr virus (EBV) and its subtypes have not been fully investigated. METHODS Questionnaires and serum samples from a total of 2006 students who entered Edinburgh University in 1999-2000 were analyzed to examine risk factors for EBV seropositivity, both overall and by EBV type. RESULTS The prevalence of EBV seropositivity was significantly increased among females, older students, those who had lived in tropical countries, those with siblings, and those who were sexually active, particularly if they had had numerous sex partners. Risk was lower (1) among students who always used a condom than among those who had sexual intercourse without one and (2) among female oral-contraceptive users than among sexually active nonusers. Risk factors for type 1 EBV infection were similar to those for EBV overall. No associations were found between nonsexual risk factors and type 2 infection. Sexual activity increased the risk of type 2 infection, but the increase in risk with number of sex partners was less consistent than for type 1 infections. Dual infection was uncommon, but the patterns of risk appeared to be similar to those of type 1 infection. CONCLUSION This study provides further evidence that EBV may be sexually transmitted and some suggestion that the risk factors for type 1 and type 2 infection differ.

Infectious Mononucleosis in University Students in the United Kingdom: Evaluation of the Clinical Features and Consequences of the Disease

BACKGROUND Infectious mononucleosis (IM) is common among university students. We undertook to analyze the clinical features and sequelae of the disease in a cohort of students at Edinburgh University. METHODS Consecutive IM case patients were recruited from 2000 through 2002 at the University Health Service after diagnosis of IM. RESULTS IM resulted in marked reductions in student study time, physical exercise, and non-exercise-related social activities, and sustained increases in reported number of hours of sleep. The disease profile differed between the sexes, with significantly more females reporting fatigue, which was more likely to be prolonged (P = .003) and to lead to loss of study time (P = .013). Female case patients were more likely to discontinue their studies following IM (16% vs 0%; P = .056). Within the typically elevated lymphocyte counts in IM, we identified an elevated gammadelta T cell component that may contribute to the disease pathogenesis. CONCLUSIONS IM results in substantial morbidity among university students, reported as more profound in females, and affecting academic studies, physical exercise, and social activities. Immunization to prevent IM and strategies to reduce post-IM disability would be beneficial in this population.

Logic applied to integer programming and integer programming applied to logic

The many connections between the methods of Computational Logic and Integer Programming (IP) are surveyed. It is shown how computational problems arising in formal logic can be solved by IP. Also it is shown how the methods of logic are applicable both to modelling and solving IP models. It is shown how Fourier-Motzkin elimination for Linear Programming, when specialised to 0–1 IP models gives rise to the logic method of Resolution. Finally conventional IP methods are applied to solving logical inference problems.

Duality in mathematics and linear and integer programming

Linear programming (LP) duality is examined in the context of other dualities in mathematics. The mathematical and economic properties of LP duality are discussed and its uses are considered. These mathematical and economic properties are then examined in relation to possible integer programming (IP) dualities. A number of possible IP duals are considered in this light and shown to capture some but not all desirable properties. It is shown that inherent in IP models are inequality and congruence constraints, both of which give on their own well-defined duals. However, taken together, no totally satisfactory dual emerges. The superadditive dual based on the Gomory and Chvátal functions is then described, and its properties are contrasted with LP duals and other IP duals. Finally, possible practical uses of IP duals are considered.