Complete mapping of a novel HLA A*6801-restricted HIV-1 Tat epitope directly with a rapid modified enzyme-linked immunospot assay

We identified a novel HLA A*6801-restricted HIV-1 Tat-derived cytotoxic T lymphocyte (CTL) epitope using an adapted enzyme-linked immunospot assay that allows the rapid ex vivo identification of CTL epitopes together with their associated HLA Class I restriction elements. The optimal 11 amino acid residue Tat epitope efficiently stabilized the refolding of monomeric peptide-HLA A6801 complexes in vitro and fluorochrome-labelled, tetrameric peptide-HLA A6801 complexes stained CD8 T cells specific for this epitope directly ex vivo.     

Eye injuries in squash: a preventable disease.

As more Canadians are taking up squash the incidence of eye injuries is increasing dramatically. Over 2-1/2 years, 23 cases from one urban practice were examined. Almost half of the group required inhospital treatment. Five patients sustained a permanent decrease in vision; these cases involved three corneal scars, one cataract and one macular cyst. Patients wearing glasses or hard contact lenses appear to be more susceptible to serious eye injury. Experience does not appear to reduce the likelihood of eye injuries; the patients in this study had played squash for 5.6 years on the average. Consequently the medical profession must take the lead by encouraging squash players to use protective equipment now available to reduce the incidence of these injuries that pose so much personal hazard.     

Cytotoxic T lymphocytes and viral evolution in primary HIV-1 infection

Efforts to develop immune-based therapies for HIV infection have been impeded by incomplete definition of the immunological correlates of protection. Despite many precedents demonstrating that CD8(+) cytotoxic T lymphocytes are key mediators of protective anti-viral immunity in non-human animal models, direct evidence that these effector cells control viral replication in HIV-1 infection has remained elusive. The first part of this paper describes a detailed immunological and genetic study founded on evolutionary considerations. Following infection with HIV-1, virus variants which escaped recognition by autologous cytotoxic T lymphocytes were shown to possess a selection advantage within the host environment. Cytotoxic T lymphocytes therefore exert anti-viral pressure in vivo. This observation provides compelling evidence that cytotoxic T lymphocytes comprise a significant element of anti-retroviral immunity. Subsequently, the quantification of peripheral cytotoxic T lymphocyte frequencies utilizing peptide-(human leucocyte antigen class I) tetrameric complexes is described. Five patients with qualitatively similar immunodominant cytotoxic T lymphocyte responses during symptomatic primary HIV-1 infection were studied longitudinally. Expansions of virus-specific CD8(+) lymphocytes comprising up to 2% of the total CD8(+) T cell population were observed in the acute phase of infection. Antigenic load was identified as an important determinant of circulating HIV-1-specific CD8(+) lymphocyte levels; however, significant numbers of such cells were also found to persist following prolonged therapeutic suppression of plasma viraemia. In addition, an analysis of antigenic sequence variation with time in this case series suggests that the early administration of combination anti-retroviral therapy may limit HIV-1 mutational escape from host cytolytic specificities. The implications of these preliminary data are discussed. The data presented suggest that vaccination protocols should aim to elicit vigorous cytotoxic T lymphocyte responses to HIV-1. Attempts to stimulate polyvalent responses to mutationally intolerant epitopes are likely to be most effective. Optimal management of HIV-1 infection requires an understanding of dynamic host-virus interactions, and may involve strategies designed to enhance cytotoxic T lymphocyte activity following periods of anti-retroviral drug therapy.     

Rural background and clinical rural rotations during medical training: effect on practice location

BACKGROUND: Providing health care services in rural communities in Canada remains a challenge. What affects a family medicine resident's decision concerning practice location? Does the resident's background or exposure to rural practice during clinical rotations affect that decision? METHODS: Cross-sectional mail survey of 159 physicians who graduated from the Family Medicine Program at Queen's University, Kingston, Ont., between 1977 and 1991. The outcome variables of interest were the size of community in which the graduate chose to practise on completion of training (rural [population less than 10,000] v. nonrural [population 10,000 or more]) and the size of community of practice when the survey was conducted (1993). The predictor or independent variables were age, sex, number of years in practice, exposure to rural practice during undergraduate and residency training, and size of hometown. RESULTS: Physicians who were raised in rural communities were 2.3 times more likely than those from nonrural communities to choose to practise in a rural community immediately after graduation (95% confidence interval 1.43-3.69, p = 0.001). They were also 2.5 times more likely to still be in rural practice at the time of the survey (95% confidence interval 1.53-4.01, p = 0.001). There was no association between exposure to rural practice during undergraduate or residency training and choosing to practise in a rural community. INTERPRETATION: Physicians who have roots in rural Canada are more likely to practise in rural Canada than those without such a background.     

Racial and ethnic differences in outcome in zidovudine-treated patients with advanced HIV disease. Zidovudine Epidemiology Study Group

OBJECTIVES--To determine if racial-ethnic differences exist in survival, disease progression, and development of myelosuppression in zidovudine-treated patients with advanced human immunodeficiency virus (HIV) disease. DESIGN--Prospective observational study. SETTING.-Hospital and private clinics in 12 metropolitan centers. PATIENTS.-The study included 754 non-Hispanic white, 165 black, and 106 Hispanic patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex (ARC) who received up to 2 years of zidovudine therapy. OUTCOME MEASURES--Survival, development of Pneumocystis carinii pneumonia (PCP), other opportunistic infections, and myelosuppression. RESULTS--At initiation of zidovudine therapy, Hispanic and particularly black patients had more advanced HIV disease than white patients, as indicated by lower baseline CD4+ counts, hematocrits, and AIDS-defining diagnoses. Black patients with AIDS also had a worse prognosis compared with white and Hispanic patients with AIDS. The product-limit survival rates at 2 years for white, black, and Hispanic patients with AIDS were 40%, 27%, and 39%, respectively (black vs white, P = .01; Hispanic vs white, P = .32, by the log-rank test). The respective proportions of patients who developed PCP at 2 years were 46%, 66%, and 44% (black vs white, P = .0001; Hispanic vs white, P = .86) and for other opportunistic infections the proportions were 56%, 63%, and 63%, respectively (black vs white, P = .03; Hispanic vs white, P = .09). There were no significant racial-ethnic differences in survival or in the development of opportunistic infections for patients with ARC, and there were no differences in the incidence of myelosuppression or dose reduction or suspension for patients with either ARC or AIDS. After adjusting for more advanced HIV disease (mainly low CD4+ counts and hematocrits), black race was no longer a significant independent predictor of survival. Adjustment for racial differences in the use of PCP prophylaxis accounted for most of the excess risk for the development of PCP in black patients compared with white patients with AIDS. CONCLUSIONS--Racial differences in survival and the development of opportunistic infections are mainly due to the more advanced HIV disease in black patients when zidovudine therapy is started and to their less frequent use of PCP prophylaxis. Innovative approaches are needed to ensure more widespread use of and earlier access to zidovudine therapy and PCP prophylaxis.     

Lymphoma simulating uveitis (masquerade syndrome)

The authors present three recent cases of intraocular lymphoma. All three patients presented with apparent hypopyon and uveitis. Although the diagnosis was a difficult one to make, an aspiration of the anterior chamber with appropriate cytologic studies was conclusive in one case. The neoplasm may masquerade as any type of intraocular inflammation, anterior or posterior. We discuss the management and prognosis of these patients and review 68 cases from the world literature. Radiation therapy plays an important palliative role in this condition.