Onchocerca ochengi male worms implanted in SCID mice and Gerbil: Relationship between microfilaridermia status of cows, nodular worm viability and fertility and worm survival in the rodents.

BACKGROUND: Current treatment options for onchocerciasis are sub-optimal, prompting research and development of a safe cure (macrofilaricide). Onchocerca ochengi, a parasite of cattle, is used as a close surrogate for the human parasite O. volvulus in a murine model for pre-clinical screening of macrofilaricides. Skin from naturally infected cattle have been used in previous studies as a reliable source of parasite material. However, there is limited knowledge on how source-related factors such as the microfilaridermia status of the cattle, the nodule load and nodular worm viability may affect survival of male O. ochengi worms implanted in the rodent hosts. Such relationships were investigated in this study. METHODS: Dermal tissue and nodules were obtained from Gudali cattle, dissected and cultured to obtain migrating microfilariae (mf) and male worms. Emerged male worms were implanted into SCID mice and Gerbils (Meriones unguiculatus) and recovery rates were determined upon 42 days post implantation. Finally, nodules were processed for histology and embryogram analyses to assess the nodular worm viability and fertility, respectively. RESULTS: Of the 69 cattle sampled, 24 (34.8%) were mf+ and 45 (65.2%) were mf-. The mean nodule loads were 180.5 ± 117.7 (mf+) and 110.6 ± 102.7 (mf-) (p = 0.0186). The mean male worm harvest from nodules were 76.8 ± 120.3 and 47.2 ± 33.4 (p = 0.2488) for mf+ and mf- cattle, respectively. The number of male worms per 100 nodules were 57/100 and 46/100 nodules for mf+ and mf- cows, respectively. Female worms from nodules of mf- cows had higher counts of both normal and abnormal embryos with higher proportions of dead nodular worms evinced by histology compared to those from mf+ cows. A total of 651 worms were implanted into mice and gerbils, out of which 129 (19.81%) were recovered. Logistic regression analysis indicated that the microfilaridermia status of the cattle (presence of mf) (OR = 4.3319; P = 0.001) is the single most important predictor of the success of male worm recovery after implantation into rodents. CONCLUSION: Microfilaridermic cattle provide a promising source of adult O. ochengi. Male worms from this group of cattle have a better success rate of survival in a murine implant model. Nevertheless, in the programmatic point of view, amicrofilaridermic Gudali cattle would still constitute an important source of O. ochengi male worms with relatively good viability after implantation into rodents.

A qualitative evaluation of hospital versus community-based management of patients on injectable treatments for tuberculosis.

BACKGROUND: Patients being treated for recurrent or multidrug-resistant tuberculosis (TB) require long courses of injectable anti-tuberculous agents. In order to maintain strong TB control programmes, it is vital that the experiences of people who receive long-term injectables for TB are well understood. To investigate the feasibility of a novel model of care delivery, a clinical trial (The TB-RROC Study) was conducted at two central hospitals in Malawi. Hospital-based care was compared to a community-based approach for patients on TB retreatment in which 'guardians' (patient-nominated lay people) were trained to deliver injections to patients at home. This study is the qualitative evaluation of the TB-RROC trial. It examines the experiences of people receiving injectables as part of TB treatment delivered in hospital and community-based settings. METHODS: A qualitative evaluation of the TB-RROC intervention was conducted using phenomenographic methods. Trial participants were purposively sampled, and in-depth interviews were conducted with patients and guardians in both arms of the trial. Key informant interviews and observations in the wards and community were performed. Thematic content analysis was used to derive analytical themes. RESULTS: Fourteen patients, 12 guardians and 9 key informants were interviewed. Three key themes relating to TB retreatment emerged: medical experiences (including symptoms, treatment, and HIV); the effects of the physical environment (conditions on the ward, disruption to daily routines and livelihoods); and trust (in other people, the community and in the health system). Experiences were affected by the nature of a person's prior role in their community and resulted in a range of emotional responses. Patients and guardians in the community benefited from better environment, social interactions and financial stability. Concerns were expressed about the potential for patients' health or relationships to be adversely affected in the community. These potential concerns were rarely realised. CONCLUSIONS: Guardian administered intramuscular injections were safe and well received. Community-based care offered many advantages over hospital-based care for patients receiving long-term injectable treatment for TB and their families.

Garcinia xanthochymus Benzophenones Promote Hyphal Apoptosis and Potentiate Activity of Fluconazole against Candida albicans Biofilms.

Xanthochymol and garcinol, isoprenylated benzophenones purified from Garcinia xanthochymus fruits, showed multiple activities against Candida albicans biofilms. Both compounds effectively prevented emergence of fungal germ tubes and were also cytostatic, with MICs of 1 to 3 µM. The compounds therefore inhibited development of hyphae and subsequent biofilm maturation. Xanthochymol treatment of developing and mature biofilms induced cell death. In early biofilm development, killing had the characteristics of apoptosis, including externalization of phosphatidyl serine and DNA fragmentation, as evidenced by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) fluorescence. These activities resulted in failure of biofilm maturation and hyphal death in mature biofilms. In mature biofilms, xanthochymol and garcinol caused the death of biofilm hyphae, with 50% effective concentrations (EC50s) of 30 to 50 µM. Additionally, xanthochymol-mediated killing was complementary with fluconazole against mature biofilms, reducing the fluconazole EC50 from >1,024 µg/ml to 13 µg/ml. Therefore, xanthochymol has potential as an adjuvant for antifungal treatments as well as in studies of fungal apoptosis.

Generation of Loa loa infective larvae by experimental infection of the vector, Chrysops silacea.

Basic and translational research on loiasis, a filarial nematode infection of medical importance, is impeded by a lack of suitable Loa loa infection models and techniques of obtaining and culturing life cycle stages. We describe the development of a new method for routine production of infective third-stage larvae (L3) of L. loa from the natural intermediate arthropod vector host, Chrysops silacea, following experimental infection with purified microfilariae. At 14-days post-infection of C. silacea, the fly survival rate was 43%. Survival was significantly higher in flies injected with 50 mf (55.2%) than those that received 100 mf (31.0%). However, yield per surviving fly and total yield of L3 was markedly higher in the group of flies inoculated with 100 mf (3474 vs 2462 L3 produced). The abdominal segment hosted the highest percentage recovery of L3 (47.7%) followed by head (34.5%) and thorax (17.9%). L. loa larval survival was higher than 90% after 30 days of in vitro culture. The in vitro moulting success rate to the L4 larval stage was 59.1%. After experimental infection of RAG2-/-IL-2γc-/-mice, the average L. loa juvenile adult worm recovery rate was 10.5% at 62 dpi. More than 87% of the worms were recovered from the muscles and subcutaneous tissues. Worms recovered measured an average 24.3 mm and 11.4 mm in length for females (n = 5) and males (n = 5), respectively. In conclusion, L. loa mf injected into C. silacea intrathoracically develop into infective larvae that remain viable and infective comparable to L3 obtained through natural feeding on the human host. This technique further advances the development of a full laboratory life cycle of L. loa where mf derived from experimentally-infected animals may be utilized to passage life cycle generations via intrathoracic injections of wild-caught vector hosts.

Taxanes, microtubules and chemoresistant breast cancer.

The taxanes, paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics causing cell cycle arrest and apoptosis. However, the mechanisms underlying their action have yet to be fully elucidated. These agents have become widely recognized as active chemotherapeutic agents in the treatment of metastatic breast cancer and early-stage breast cancer with benefits gained in terms of overall survival (OS) and disease-free survival (DFS). However, even with response to taxane treatment the time to progression (TTP) is relatively short, prolonging life for a matter of months, with studies showing that patients treated with taxanes eventually relapse. This review focuses on chemoresistance to taxane treatment particularly in relation to the spindle assembly checkpoint (SAC) and dysfunctional regulation of apoptotic signaling. Since spindle microtubules are the primary drug targets for taxanes, important SAC proteins such as MAD2, BUBR1, Synuclein-gamma and Aurora A have emerged as potentially important predictive markers of taxane resistance, as have specific checkpoint proteins such as BRCA1. Moreover, overexpression of the drug efflux pump MDR-1/P-gp, altered expression of microtubule-associated proteins (MAPs) including tau, stathmin and MAP4 may help to identify those patients who are most at risk of recurrence and those patients most likely to benefit from taxane treatment.

Cat scratch disease: a diagnostic conundrum.

We report the case of a patient who presented to a clinic for evaluation of inguinal lymphadenopathy. Histology of the lymph nodes revealed micoabscess formation suggesting infection with Lymphogranuloma venereum (LGV) or Bartonella henselae--the causative agent in cat scratch disease (CSD). The patient recalled no preceding animal exposure. Clinical and serological findings initially suggested early LGV but convalescent serology supported CSD. This serves as an important reminder that B. henselae infection should be considered a cause of regional lymphadenopathy in individuals suspected of having LGV.

Mouse models of Loa loa.

Elimination of the helminth disease, river blindness, remains challenging due to ivermectin treatment-associated adverse reactions in loiasis co-infected patients. Here, we address a deficit in preclinical research tools for filarial translational research by developing Loa loa mouse infection models. We demonstrate that adult Loa loa worms in subcutaneous tissues, circulating microfilariae (mf) and presence of filarial biomarkers in sera occur following experimental infections of lymphopenic mice deficient in interleukin (IL)-2/7 gamma-chain signaling. A microfilaraemic infection model is also achievable, utilizing immune-competent or -deficient mice infused with purified Loa mf. Ivermectin but not benzimidazole treatments induce rapid decline (>90%) in parasitaemias in microfilaraemic mice. We identify up-regulation of inflammatory markers associated with allergic type-2 immune responses and eosinophilia post-ivermectin treatment. Thus, we provide validation of murine research models to identify loiasis biomarkers, to counter-screen candidate river blindness cures and to interrogate the inflammatory etiology of loiasis ivermectin-associated adverse reactions.

Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models.

The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve a matching efficacious exposure profile.

Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections.

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targets Wolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination of Wolbachia in the in vivo Litomosoides sigmodontis filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantify Wolbachia elimination in Brugia pahangi filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed in L. sigmodontis, Brugia malayi, and Onchocerca ochengi in vivo preclinical models of filarial disease and in vitro selectivity against Loa loa (a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.

Amyloid-Like ß-Aggregates as Force-Sensitive Switches in Fungal Biofilms and Infections.

Cellular aggregation is an essential step in the formation of biofilms, which promote fungal survival and persistence in hosts. In many of the known yeast cell adhesion proteins, there are amino acid sequences predicted to form amyloid-like ß-aggregates. These sequences mediate amyloid formation in vitro. In vivo, these sequences mediate a phase transition from a disordered state to a partially ordered state to create patches of adhesins on the cell surface. These ß-aggregated protein patches are called adhesin nanodomains, and their presence greatly increases and strengthens cell-cell interactions in fungal cell aggregation. Nanodomain formation is slow (with molecular response in minutes and the consequences being evident for hours), and strong interactions lead to enhanced biofilm formation. Unique among functional amyloids, fungal adhesin ß-aggregation can be triggered by the application of physical shear force, leading to cellular responses to flow-induced stress and the formation of robust biofilms that persist under flow. Bioinformatics analysis suggests that this phenomenon may be widespread. Analysis of fungal abscesses shows the presence of surface amyloids in situ, a finding which supports the idea that phase changes to an amyloid-like state occur in vivo. The amyloid-coated fungi bind the damage-associated molecular pattern receptor serum amyloid P component, and there may be a consequential modulation of innate immune responses to the fungi. Structural data now suggest mechanisms for the force-mediated induction of the phase change. We summarize and discuss evidence that the sequences function as triggers for protein aggregation and subsequent cellular aggregation, both in vitro and in vivo.

Sexual and reproductive health in HIV-positive women: a dedicated clinic improves service.

We run a one-stop clinic for HIV-positive women, offering sexually transmitted infection screening, cervical cytology and family planning. We completed an audit cycle, and showed that all aspects of our care had improved since the introduction of this integrated service.

TB and HIV stigma compounded by threatened masculinity: implications for TB health-care seeking in Malawi.

SETTING: Urban Blantyre, Malawi. OBJECTIVE: To understand why men with tuberculosis (TB) in the community remain undiagnosed. DESIGN: A multi-method qualitative study applying a modified grounded theory approach. Data were gathered from March 2011 to March 2012 from 134 men and women taking part in 1) focus group discussions with community members (n = 6) and health care workers (n = 2), and 2) in-depth interviews with TB patients (n = 20, females n = 14) and chronic coughers (n = 20, women n = 8). Data were analysed inductively to identify, refine and consolidate, and verify emerging concepts and themes. RESULTS: Two emerging themes highlighting compound stigma in this high human immunodeficiency virus (HIV) prevalence, low-income setting are presented. First, cough or any illness that portended a 'serious' condition were accompanied by portrayals of cough, TB and HIV as being interchangeable. Chronic coughers and TB patients described their illness in ways that foregrounded bodily decimation and rupture of social life and masculine identity. Second, 'resistance strategies' entailed resisting classification as (seriously) ill by evading or ambivalently approaching health care, or acknowledging the 'ill' status then actively pursuing health-appropriate behaviours, including changing lifestyle or adopting non-normative gender roles. CONCLUSIONS: Managing patients requires 1) going beyond syndromic management based on vital signs and clinical indicators to recognising and intervening on health care-seeking related tensions to retain individuals in care, and 2) understanding and addressing TB stigma as it manifests and affects men and women differently in specific settings.

Primary care and the National Strategy for Sexual Health and HIV: an evaluation of one primary care trust.

Windsor, Ascot, Maidenhead (WAM) primary care trust (PCT) currently has no specialist sexual health services. We researched the level of sexual health service provision in WAM compared with targets set out in the National Strategy for Sexual Health and HIV and assessed support for level 2 service expansion. We found practices were already providing much of level 1 and parts of level 2 services. Gaps centred on male and asymptomatic female screening and sexual health promotion. Ten out of 22 practices expressed interest for service development within the PCT, but obstacles cited included lack of resources, training and prioritization of the strategy. The study has identified strengths and weaknesses across the PCT that have guided recent initiatives. This model could be used by other PCTs to ascertain their needs and acknowledge their achievements.

The Human Disease-Associated Aß Amyloid Core Sequence Forms Functional Amyloids in a Fungal Adhesin.

UNLABELLED: There is increasing evidence that many amyloids in living cells have physiological functions. On the surfaces of fungal cells, amyloid core sequences in adhesins can aggregate into 100- to 1,000-nm-wide patches to form high-avidity adhesion nanodomains on the cell surface. The nanodomains form through interactions that have amyloid-like properties: binding of amyloid dyes, perturbation by antiamyloid agents, and interaction with homologous sequences. To test whether these functional interactions are mediated by typical amyloid interactions, we substituted an amyloid core sequence, LVFFA, from human Aß protein for the native sequence IVIVA in the 1,419-residue Candida albicans adhesin Als5p. The chimeric protein formed cell surface nanodomains and mediated cellular aggregation. The native sequence and chimeric adhesins responded similarly to the amyloid dye thioflavin T and to amyloid perturbants. However, unlike the native protein, the nanodomains formed by the chimeric protein were not force activated and formed less-robust aggregates under flow. These results showed the similarity of amyloid interactions in the amyloid core sequences of native Als5p and Aß, but they also highlighted emergent properties of the native sequence. Also, a peptide composed of the Aß amyloid sequence flanked by amino acids from the adhesin formed two-dimensional sheets with sizes similar to the cell surface patches of the adhesins. These results inform an initial model for the structure of fungal cell surface amyloid nanodomains. IMPORTANCE: Protein amyloid aggregates are markers of neurodegenerative diseases such as Alzheimer's and Parkinsonism. Nevertheless, there are also functional amyloids, including biofilm-associated amyloids in bacteria and fungi. In fungi, glycoprotein adhesins aggregate into cell surface patches through amyloid-like interactions, and the adhesin clustering strengthens cell-cell binding. These fungal surface amyloid nanodomains mediate biofilm persistence under flow, and they also moderate host inflammatory responses in fungal infections. To determine whether the amyloid-like properties of fungal surface nanodomains are sequence specific, we ask whether a disease-associated amyloid core sequence has properties equivalent to those of the native sequence in a fungal adhesin. A chimeric adhesin with an amyloid sequence from the Alzheimer's disease protein Aß instead of its native sequence effectively clustered the adhesins on the cell surface, but it showed a different response to hydrodynamic shear. These results begin an analysis of the sequence dependence for newly discovered activities for fungal surface amyloid nanodomains.

Force Sensitivity in Saccharomyces cerevisiae Flocculins.

Many fungal adhesins have short, ß-aggregation-prone sequences that play important functional roles, and in the Candida albicans adhesin Als5p, these sequences cluster the adhesins after exposure to shear force. Here, we report that Saccharomyces cerevisiae flocculins Flo11p and Flo1p have similar ß-aggregation-prone sequences and are similarly stimulated by shear force, despite being nonhomologous. Shear from vortex mixing induced the formation of small flocs in cells expressing either adhesin. After the addition of Ca(2+), yeast cells from vortex-sheared populations showed greatly enhanced flocculation and displayed more pronounced thioflavin-bright surface nanodomains. At high concentrations, amyloidophilic dyes inhibited Flo1p- and Flo11p-mediated agar invasion and the shear-induced increase in flocculation. Consistent with these results, atomic force microscopy of Flo11p showed successive force-distance peaks characteristic of sequentially unfolding tandem repeat domains, like Flo1p and Als5p. Flo11p-expressing cells bound together through homophilic interactions with adhesion forces of up to 700 pN and rupture lengths of up to 600 nm. These results are consistent with the potentiation of yeast flocculation by shear-induced formation of high-avidity domains of clustered adhesins at the cell surface, similar to the activation of Candida albicans adhesin Als5p. Thus, yeast adhesins from three independent gene families use similar force-dependent interactions to drive cell adhesion. IMPORTANCE The Saccharomyces cerevisiae flocculins mediate the formation of cellular aggregates and biofilm-like mats, useful in clearing yeast from fermentations. An important property of fungal adhesion proteins, including flocculins, is the ability to form catch bonds, i.e., bonds that strengthen under tension. This strengthening is based, at least in part, on increased avidity of binding due to clustering of adhesins in cell surface nanodomains. This clustering depends on amyloid-like ß-aggregation of short amino acid sequences in the adhesins. In Candida albicans adhesin Als5, shear stress from vortex mixing can unfold part of the protein to expose aggregation-prone sequences, and then adhesins aggregate into nanodomains. We therefore tested whether shear stress from mixing can increase flocculation activity by potentiating similar protein remodeling and aggregation in the flocculins. The results demonstrate the applicability of the Als adhesin model and provide a rational framework for the enhancement or inhibition of flocculation in industrial applications.

The enigmatic protein kinase Cdelta: complex roles in cell proliferation and survival.

Protein kinase Cdelta (PKCdelta) has been implicated both as a tumor suppressor and a positive regulator of cell cycle progression. PKCdelta has also been reported to positively and negatively regulate apoptotic programs. This has led to conflicting hypotheses on the role of PKCdelta in the control of cell proliferation and survival. Surprisingly, PKCdelta mice develop normally and are fertile, indicating that PKCdelta is not critical for normal cell proliferation during development. However, PKCdelta may play important roles in neoplastic cell proliferation. In this review, we have summarized the apparent multifunctional properties of this enigmatic protein with regard to its role in the regulation of cell cycle progression and cell survival. It is proposed that PKCdelta has both tumor suppressor and proliferation capabilities that can be recruited as a backup kinase for both gatekeeper tumor suppression and as an activator of the Ras/Raf/MEK/MAP kinase signaling pathway in cell proliferation.

The impact of the 2011 UK post-exposure prophylaxis for HIV following sexual exposure guidelines: a regional retrospective audit.

A re-audit of prescribing of post-exposure prophylaxis for HIV following sexual exposure in the Thames Valley demonstrated that an updated proforma has led to significant improvements in clinician-led outcomes, but had no impact on completion or follow-up rates.

Quantitative Analyses of Force-Induced Amyloid Formation in Candida albicans Als5p: Activation by Standard Laboratory Procedures.

Candida albicans adhesins have amyloid-forming sequences. In Als5p, these amyloid sequences cluster cell surface adhesins to create high avidity surface adhesion nanodomains. Such nanodomains form after force is applied to the cell surface by atomic force microscopy or laminar flow. Here we report centrifuging and resuspending S. cerevisiae cells expressing Als5p led to 1.7-fold increase in initial rate of adhesion to ligand coated beads. Furthermore, mechanical stress from vortex-mixing of Als5p cells or C. albicans cells also induced additional formation of amyloid nanodomains and consequent activation of adhesion. Vortex-mixing for 60 seconds increased the initial rate of adhesion 1.6-fold. The effects of vortex-mixing were replicated in heat-killed cells as well. Activation was accompanied by increases in thioflavin T cell surface fluorescence measured by flow cytometry or by confocal microscopy. There was no adhesion activation in cells expressing amyloid-impaired Als5pV326N or in cells incubated with inhibitory concentrations of anti-amyloid dyes. Together these results demonstrated the activation of cell surface amyloid nanodomains in yeast expressing Als adhesins, and further delineate the forces that can activate adhesion in vivo. Consequently there is quantitative support for the hypothesis that amyloid forming adhesins act as both force sensors and effectors.

Disease progression and survival following specific AIDS-defining conditions: a retrospective cohort study of 2048 HIV-infected persons in London.

OBJECTIVE: To assess the impact of specific AIDS-defining conditions on survival in HIV-infected persons, with emphasis on the effect of tuberculosis. METHODS: A retrospective cohort analysis of HIV-infected Africans and non-Africans attending 11 specialist HIV/AIDS units in London enrolled for a comparison of the natural history of HIV/AIDS in different ethnic groups. RESULTS: A total of 2048 patients were studied of whom 627 (31%) developed 1306 different AIDS indicator diseases. Pneumocystis carinii pneumonia accounted for 159 (25%) of initial AIDS episodes and tuberculosis for 103 (16%). In patients with HIV disease, tuberculosis had the lowest risk [relative risk (RR), 1.11; 95% confidence interval (CI), 0.75-1.63], and high-grade lymphoma had the highest risk (RR, 20.56; 95% CI, 2.70-156.54) for death. For patients with a prior AIDS-defining illness, the development of subsequent AIDS indicator diseases such as Pneumocystis carinii pneumonia (RR, 1.18; 95% CI, 0.77-1.83) and tuberculosis (RR, 1.36; 95% CI, 0.76-2.47) had the best survival, and non-Hodgkin's lymphoma had the worst survival (RR, 9.67; 95% CI, 1.26-74.33). Patients with tuberculosis had a lower incidence of subsequent AIDS-defining conditions than persons with other initial AIDS diagnoses (rate ratio, 0.47; 95% CI, 0.37-0.59). CONCLUSIONS: Considerable variation exists in the relative risk of death following different AIDS-defining conditions. The development of any subsequent AIDS-defining condition is associated with an increased risk of death that differs between diseases, and this risk should be considered when evaluating the impact of specific conditions. Like other AIDS-defining conditions, incident tuberculosis was associated with adverse outcome compared with the absence of an AIDS-defining event, but we found no evidence of major acceleration of HIV disease attributable to tuberculosis.