Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS.

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

HIV evolution: CTL escape mutation and reversion after transmission.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

Surface antigen expression on Plasmodium falciparum-infected erythrocytes is modified in alpha- and beta-thalassemia.

In an attempt to determine the mechanism whereby thalassemia in its milder forms may protect against malaria, we have examined the expression of neoantigen at the surface of Plasmodium falciparum-parasitized thalassemic red cells. Neoantigen expression was estimated by measurement of antibody bound after incubation in serum from adults living in a malaria-endemic area, using a quantitative radiometric antiglobulin assay. We found that P. falciparum-parasitized alpha- and beta-thalassemic red cells bind greater levels of antibody from endemic serum than controls: mean binding ratios (+/- SE), respectively, for alpha- and beta-thalassemia compared with controls were 1.69 +/- 0.12 and 1.23 +/- 0.06 on a cell for cell basis, and 1.97 +/- 0.11 and 1.47 +/- 0.08 after a correction for surface area differences. Binding of antibody increased exponentially during parasite maturation. In addition, we found a small but significant degree of binding of naturally occurring antibody to parasitized red cells, the extent of which was also greater in thalassemia. The apparent protective effect of thalassemia against malaria may be related to enhanced immune recognition and hence clearance of parasitized erythrocytes.

Patterns of immunodominance in HIV-1-specific cytotoxic T lymphocyte responses in two human histocompatibility leukocyte antigens (HLA)-identical siblings with HLA-A*0201 are influenced by epitope mutation.

Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201-restricted SLYNTVATL and HLA-A3-restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201-restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.

The male sexual pain syndromes.

Pain provoked by sexual intercourse in men is a well-recognized symptom that has received surprisingly little attention in the medical literature and has rarely been the subject of systematic study. Sexual pain disorders have generally been considered in the context of the sexual dysfunctions, and in men have received much less attention than in women. Reports of male sexual pain lack use of a uniform definition for the condition. Sexual pain, especially ejaculatory pain, is a common feature of chronic prostatitis/chronic pelvic pain syndrome (CPPS). However, a range of physical and medical causes for sexual pain in men has been reported, usually in the form of isolated clinical reports. Our understanding of the aetiology and pathogenesis of male sexual pain is very limited, and systematic evaluations of treatment approaches are lacking.

Chronic vulval ulceration--another immune reconstitution inflammatory syndrome?

We describe a patient who developed intractable chronic vulval ulceration that we believe was related to immune reconstitution following treatment of HIV infection with highly active antiretroviral treatment (HAART). Immune reconstitution inflammatory syndrome should be considered in the differential diagnosis of unexplained vulval ulceration that arises after starting HAART.

Protection by alpha-thalassaemia against Plasmodium falciparum malaria: modified surface antigen expression rather than impaired growth or cytoadherence.

We have attempted to determine the cellular mechanism by which alpha-thalassaemia may protect against Plasmodium falciparum malaria. Invasion and development of P. falciparum in the microcytic red cells of two-gene deletion forms of alpha-thalassaemia when measured morphologically or by [3H]hypoxanthine incorporation were normal compared to controls. Normal invasion rates were also observed following schizogony in thalassaemic red cells. Neither the addition of the oxidant menadione, 30% oxygen, nor modified medium, produced differential damage to parasites within thalassaemic cells. Furthermore, there were no significant differences in the binding of P. falciparum-parasitized alpha-thalassaemic and normal cells to C32 melanoma cells in vitro. However, when neoantigen expression on the surface of infected thalassaemic cells was estimated using a quantitative radiometric antiglobulin assay, clear differences were observed. It was found that alpha-thalassaemic cells bound higher levels of antibody from serum obtained from individuals living in a malaria endemic area than control normal red cells. The binding ratio for thalassaemic compared with controls was 1.69 on a cell-for-cell basis, and 1.97 when related to surface area. The binding of antibody from immune serum increased exponentially during parasite maturation. We also found increased binding of naturally occurring antibody present in non-immune serum to parasitized thalassaemic red cells which also increased during parasite maturation. We conclude that the protection afforded by thalassaemia against malaria may not reside in the ability of parasites to enter, grow or cytoadhere to endothelium in such cells, but may be related to immune recognition and subsequent clearance of parasitized red cells.

Usefulness of handgrip to improve ibutilide efficacy in organizing atrial electrical activity during atrial fibrillation.

We analyzed the effect of handgrip on atrial electrical activity during atrial fibrillation (AF) by recording right and left atrial activity in 15 patients with persistent AF under baseline conditions and after saline and ibutilide infusions. The handgrip test for 15 seconds, which was always associated with a significant increase in mean atrial cycle length, was recorded in both atria (right atrium: saline vs saline + handgrip 141 +/- 29 vs 171 +/- 24 ms, p <0.001; ibutilide vs ibutilide + handgrip: 197 +/- 43 vs 221 +/- 39 ms, p <0.005). Handgrip favorably modifies atrial electrophysiologic properties during AF.

Effects of nadolol and its combination with atrial pacing on rate-enhanced ventricular premature complexes.

To explore the role of heart rate in the genesis of ventricular premature complexes whose incidence increases when the length of the preceding cardiac cycle decreases, we analyzed the effect of nadolol alone and together with atrial pacing in 4 patients. Nadolol lengthened the RR cycle and suppressed ventricular premature complexes; atrial pacing, restoring the baseline RR cycle lengths, led to the reappearance of ventricular premature complexes, suggesting the major role of heart rate.

Adverse effects of antimalarials. An update.

Various drugs are widely used in the prophylaxis and treatment of malaria. In the prevention of malaria in travellers, a careful risk-benefit analysis is required to balance the risk of acquiring potentially serious malaria against the risk of harm from the prophylactic agent. Unfortunately, the information needed to perform accurate analyses of this type is not available for most antimalarials. In the prophylaxis of malaria, chloroquine and proguanil have an excellent safety record, being very rarely associated with severe adverse reactions in the recommended dosages. However, in many parts of the world they are no longer effective prophylactic agents. Pyrimethamine-dapsone (Maloprim) is associated with agranulocytosis, especially if the recommended dose is exceeded, and should be reserved as a second-line agent for travellers to high risk areas. Pyrimethamine-sulfadoxine (Fansidar) and amodiaquine are associated with a relatively high incidence of potentially fatal reactions, and are no longer recommended for prophylaxis. Mefloquine, a relative newcomer, may provoke severe neuropsychiatric reactions with a frequency of 1 in 15,000 to 20,000 users at the prophylactic dosage. In the treatment of Plasmodium falciparum malaria, which has a high mortality if untreated, a greater risk of adverse reactions to antimalarial drugs is acceptable. As chloroquine resistance has become widespread, alternative agents including quinine, mefloquine, pyrimethamine-sulfadoxine, tetracyclines, halofantrine and artemisinin (qinghaosu) and its derivatives may be used in treatment regimens. The therapeutic ratios for chloroquine, quinine and mefloquine are narrow and toxicity is frequent when recommended treatment dosages are exceeded; parenteral administration above the recommended dose range is especially associated with the hazards of cardiac and neurological toxicity.

Brucellosis: imported and laboratory-acquired cases, and an overview of treatment trials.

Following the successful eradication of Brucella abortus infection in cattle, human brucellosis in England and Wales has become an uncommon imported disease. Culture of the organism presents a major laboratory hazard, and difficulties in identification may occur using a biochemical test-strip method. An overview of recent treatment trials of brucellosis indicates that regimens combining streptomycin and doxycycline are associated with a higher success rate (judged by the frequency of treatment failure and relapse following therapy) than combinations of rifampicin and doxycycline.

Acyclovir and postherpetic neuralgia.

Studies have demonstrated the benefit of acyclovir, given intravenously or orally, on the acute illness in herpes zoster (HZ). Whether or not such treatment influences the subsequent development of postherpetic neuralgia (PHN) has been the subject of recent controversy. Intravenous acyclovir has not been shown to influence PHN significantly in prospective studies. Oral acyclovir in large doses may reduce PHN during the 3 months after acute HZ, but this effect has not been observed consistently in well-designed studies. From 3 months onwards, no trial has demonstrated a significant effect of oral acyclovir in reducing PHN. The way forward is discussed.

Rat-bite acquired leptospirosis.

We report a case of leptospirosis in a boy following a rat-bite, an unusual mode of transmission for this infection. The use of antibiotics for fever following a rat-bite is discussed.

Chronic prostatitis/chronic pelvic pain syndrome: national survey of genitourinary medicine clinics.

We sought to determine current practice in the diagnosis and management of chronic prostatitis/chronic pelvic pain syndrome (CPPS) in genitourinary medicine departments in the UK, using a detailed questionnaire survey. Evaluable responses were received from 147 (69%) clinics. Seventy-nine (54%) clinics reported seeing >10 new CPPS patients per year. A broad range of investigations was reported to be used in the diagnosis of CPPS. Whilst 89 (61%) clinics reported using the four-glass test in diagnosis, 46 (32%) reported using the test in >90% of patients with CPPS, and 42 (29%) reported never using the test. In the treatment, doxycycline or ciprofloxacin were reported to be first line treatment by 98% clinics, mostly in 4-6 week courses; however, great variation was recorded in second-line choices and use of non-antibiotic approaches. This survey demonstrates that patients with CPPS are regularly diagnosed and managed in genitourinary clinics in the UK, with wide variations in diagnostic and treatment practices.

Collaborative approach to improve the detection and management of trichomoniasis in a low prevalence district.

We describe a simple collaborative approach developed by the departments of cytology, microbiology and genitourinary (GU) medicine for the detection, diagnosis and management of microbiologically confirmed Trichomonas vaginalis (TV) infection. Over a 2-year period, 54 (0.1%) of 52,440 cervical smears were reported to show TV, but microbiological confirmation was made in only 76% of 34 patients from whom a vaginal swab was subsequently taken. Trichomoniasis should not be diagnosed by cytology alone and clinicians need further education on the role of cytology in diagnosing sexually transmitted diseases (STDs). Over the same period, from a total of 96 cases of TV identified in the district, only 12 (13%) were first diagnosed in the department of GU medicine. Forty per cent of the other 84 patients were subsequently seen in the GU clinic for test of cure, contact tracing and screening for other STDs. Collaborations between departments may improve the management of trichomoniasis and other conditions in the community and their development should be encouraged.

The association of human papillomavirus infection with balanoposthitis: a description of five cases with proposals for treatment.

The features and clinical course of chronic balanitis in 5 patients are presented. In each case, histological examination of a cutaneous biopsy sample showed pronounced features of human papillomavirus (HPV) infection. In addition, HPV DNA was demonstrated in each biopsy specimen by a polymerase chain reaction and was found to be type 6 by Southern blot hybridization in 4 of the cases. Although the association of histological features of HPV infection with balanitis does not prove that HPV is causal, the failure to find other causes, the prolonged and distressing symptoms, and the ineffectiveness of topical steroids in improving symptoms, all suggest the importance of HPV infection. While effective treatment needs to be sought and developed, the response of one patient to oral isotretinoin suggests that this agent may be appropriate for a larger trial.

Treatment of neutropenic oral ulceration in human immunodeficiency virus infection with G-CSF.

We report the novel use of granulocyte colony-stimulating factor in the treatment of severe oral ulceration in human immunodeficiency virus-associated neutropenia. A 38-year-old man with acquired immunodeficiency syndrome developed severe refractory oral aphthous ulceration that persisted for 6 months despite a range of empirical treatments including corticosteroid. Rapid resolution of the ulceration occurred once the neutrophil count was restored to normal with granulocyte colony-stimulating factor.

Radiofrequency catheter ablation of atrio-ventricular accessory pathways.

Radiofrequency catheter ablation of accessory pathways may represent the treatment of choice for patients with symptomatic atrio-ventricular reentrant tachycardia or atrial fibrillation and a high ventricular response through the accessory pathways with short antegrade refractory period. Moreover, catheter ablation has contributed towards understanding anatomical and electrophysiological characteristics of accessory pathways. As far as anatomical characteristics accessory pathways may be classified into fibers with proximal insertion in right or left atrium and fibers with proximal insertion in the atrio-ventricular nodal junction. As far as electrophysiological properties are concerned, accessory pathways may be differentiated into non-decremental and decremental. In non-decremental by-pass tracts (the so-called Kent bundles) the impulse can be conducted antegradely, retrogradely and in both directions. Decremental accessory pathways generally show only antegrade conduction properties (the so-called Mahaim fibers) and can be classified in long and short pathways; in particular, catheter ablation has given considerable evidence that the vast majority (but not all) of them has a proximal insertion on the tricuspid anulus (atrio-ventricular pathways) or on the atrio-ventricular node (nodo-ventricular pathways). Decremental accessory pathways with only retrograde conduction properties are involved in the so called "Permanent Junctional Reciprocating Reentrant Tachycardia".

Community-acquired pneumonia due to Panton-Valentine leukocidin-producing Staphylococcus aureus in an HIV-2-infected patient.

Pneumonia caused by Panton-Valentine leukocidin-producing Staphylococcus aureus is associated with a high fatality rate. There have been few reported cases in HIV-1-co-infected patients. Here we report a fatal case of severe community-acquired pneumonia caused by Panton-Valentine leukocidin-producing S. aureus in a 45-year-old woman with HIV-2 infection.