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The factors that determine persistence or clearance of hepatitis C virus (HCV) infection are poorly understood. The CD4 T cell responses to the HCV core protein were examined in a cohort of women infected with a single genotype of HCV. CD4 T cells from HCV-infected patients secreted interferon (IFN)-gamma in response to peptides from 4 immunodominant regions of the core protein, and these responses were stronger in persistently infected women. Interleukin (IL)-10 was also produced by CD4 T cells from HCV-infected subjects in response to the same core peptides. Furthermore, HCV core-specific CD4 T cell clones secreted either IFN-gamma or IL-10 but not IL-4. These findings demonstrate that T helper type 1 and regulatory T cells are induced against the same epitopes on the core protein during HCV infection.

The majority of hepatitis C virus (HCV) infections become chronic, despite the presence of HCV-specific cellular and humoral immune responses. We have previously suggested that IL-10-secreting antigen-specific regulatory T cells may contribute to viral persistence, and demonstrate here that peripheral blood mononuclear cells (PBMC) from chronically HCVinfected patients secrete IL-10, but not IFN-+ , in response to HCV nonstructural protein 4 (NS4). A neutralizing anti-IL-10 antibody restored this defective antigen-specific IFN-+ production in vitro. Furthermore, PBMC from normal individuals secreted IL-10 in response to NS4, suggesting that cells of the innate immune system, in addition to T cells, produced IL-10 in the HCV-infected patients. Cell separation experiments revealed that the innate IL-10 was produced by blood monocytes, but not dendritic cells (DC). In addition, NS4 inhibited IL-12 production by PBMC in response to LPS and IFN-+ , and Th1 responses to recall antigens in normal individuals. Furthermore, supernatants from NS4-stimulated monocytes inhibited LPS-induced maturation of DC and suppressed their capacity to stimulate proliferation and IFN-+ production by allospecific T cells. Our data suggest that HCV subverts cellular immunity by inducing IL-10 and inhibiting IL-12 production by monocytes, which in turn inhibits the activation of DC that drive the differentiation of Th1 cells.

Summary1. Upland heaths in the UK are of significant conservation importance. Large areas are managed through prescribed burning to improve habitat and grazing for red grouse Lagopus lagopus scoticus, deer Cervus elaphus and sheep Ovis aries. Previous research has identified trends in vegetation development following burning, but has not linked this to variation in fire behaviour and severity. 2. We burned 15 experimental fires on an area of Calluna vulgaris-dominated moorland, and recorded pre-and post-fire vegetation structure and composition, fire behaviour characteristics, and several 'proxy measures' of fire severity. 3. We distinguished measures of fire severity, describing the immediate physical effects of burning, from the long-term ecosystem responses of substrate development and Calluna regeneration. Proxy measures of fire severity did not relate strongly to fire behaviour or ecosystem response. 4. Post-fire regeneration was strongly linked to stand age and post-fire substrate type. Fire behaviour and severity had little effect, though fire-induced ground-surface heating may promote Calluna seedling establishment. Vegetative regeneration of Calluna was extremely poor in older stands, as was seedling establishment in areas where the post-fire substrate was dominated by live or dead pleurocarpous moss mats. 5. Synthesis and applications. Significant nonlinearities exist in fire severity on heathlands, with step changes related to the depth and moisture content of moss ⁄ litter layers and peat. Younger stands, less than c. 30 cm tall, should be the focus of management if the objective is to maximize Calluna regeneration. Burning older and uneven-aged stands is discouraged except for the purposes of fire hazard management. Managers should develop landscape-level burn plans to target burning effectively and create diverse fire regimes.

1. Calluna-dominated heaths occur throughout Europe but are in decline across their range. There is growing interest in using prescribed burning for their management, but environmental and social change will impact future fire regimes. Understanding fire behaviour is vital for the sustainable use of fire, but no robust models exist to inform management. 2. Shrub fuels display complex fire behaviour. This is particularly true in UK moorlands which are unusual in their fuel structure and moisture regime, being dominated by live fuel and an oceanic climate. 3. We burnt 27 experimental fires in the Scottish uplands during the legal burning season using a replicated experimental design. Plots were assigned to one of three commonly identified growth phases. We estimated a range of prefire fuel characteristics, including heterogeneity in fuel structure. We recorded wind speed and direction and estimated rate of spread (RoS). 4. Redundancy analysis was used to investigate the relationship between fire behaviour parameters as a whole and control variables. Fuel structure and heterogeneity, wind speed and canopy fuel moisture content were strongly related to variation in fire behaviour. 5. Best subsets regression was used to generate models of fire spread based on wind speed, vegetation height, canopy fuel moisture and an index of fuel heterogeneity. RoS was determined largely by wind speed, but this interacted strongly with vegetation structure. Changes in fuel horizontal continuity and vertical structure reduced rates of spread in low wind speeds. 6. Synthesis and applications. Live fuel moisture and fuel heterogeneity play an important role in dampening fire behaviour, aspects of shrub fuels that have previously not been examined in detail. Careful use of fire for moorland management increases habitat diversity and creates fire-safe landscapes. Escaped prescribed fires burn large areas, homogenize landscapes and have severe impacts on ecosystem services. The complex relationship between fuel structure and wind speed implies that changes in behaviour can be rapid and unexpected. Models can be used to assess fire hazard prior to prescribed burning and to choose fuels that can be burnt safely under prevailing or forecast conditions.

The possibility of concomitant immunity and its potential mechanisms in Onchocerca volvulus infection were examined by analyzing cytokine and antibody responses to infective larval (third-stage larvae [L3] and molting L3 [mL3]), adult female worm (F-OvAg), and skin microfilaria (Smf) antigens in infected individuals in a region of hyperendemicity in Cameroon as a function of age. Peripheral blood mononuclear cell interleukin 5 (IL-5) responses to F-OvAg and Smf declined significantly with age (equivalent to years of exposure to O. volvulus). In contrast, IL-5 secretion in response to L3 and mL3 remained elevated with increasing age. Gamma interferon responses to L3, mL3, and F-OvAg were low or suppressed and unrelated to age, except for responses to Smf in older subjects. IL-10 levels were uniformly elevated, regardless of age, in response to L3, mL3, and F-OvAg but not to Smf, for which levels declined with age. A total of 49 to 60% of subjects had granulocytemacrophage colony-stimulating factor responses to all O. volvulus antigens unrelated to age. Analysis of levels of stage-specific immunoglobulin G3 (IgG3) and IgE revealed a striking, age-dependent dissociation between antibody responses to larval antigens (L3 and a recombinant L3-specific protein, O. volvulus ALT-1) which were significantly increased or maintained with age and antibody responses to F-OvAg, which decreased. Levels of IgG1 to L3 and F-OvAg were elevated regardless of age, and levels of IgG4 increased significantly with age, although not to O. volvulus ALT-1, which may have unique L3-specific epitopes. Immunofluorescence staining of whole larvae showed that total anti-L3 immunoglobulin levels also increased with the age of the serum donor. The separate and distinct cytokine and antibody responses to adult and infective larval stages of O. volvulus which are age related are consistent with the acquisition of concomitant immunity in infected individuals.The filarial parasite Onchocerca volvulus infects about 18 million people, and a further 100 million live in areas in which O. volvulus is endemic in Africa and Latin America. The resulting disease, onchocerciasis, is characterized by severe dermatitis and blindness (21). There is epidemiological evidence that acquired immunity against O. volvulus infection occurs in humans. For example, in regions of high endemicity, despite constant exposure to infected Simulium flies, 1 to 5% of the population exhibits no clinical manifestations of disease. These individuals are considered to be immune to infection and are referred to as putatively immune (PI) (15,17,46,47). Furthermore, in chronically infected (INF) individuals, the number of skin microfilariae (mf) tends to level off between the ages of 20 and 40 years, suggesting that these individuals have developed a means of limiting acquired infections (11). It has been suggested that the means of limiting acquired infections is through concomitant immunity (36), whereby newly introduced infective-stage larvae (third-stage larvae [L3]) are eliminated ...

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BackgroundOptimal surgical intervention for low-grade haemorrhoids is unknown. Rubber band ligation (RBL) is probably the most common intervention. Haemorrhoidal artery ligation (HAL) is a novel alternative that may be more efficacious.ObjectiveThe comparison of HAL with RBL for the treatment of grade II/III haemorrhoids.DesignA multicentre, parallel-group randomised controlled trial.PerspectiveUK NHS and Personal Social Services.Setting17 NHS Trusts.ParticipantsPatients aged ≥ 18 years presenting with grade II/III (second- and third-degree) haemorrhoids, including those who have undergone previous RBL.InterventionsHAL with Doppler probe compared with RBL.OutcomesPrimary outcome – recurrence at 1 year post procedure; secondary outcomes – recurrence at 6 weeks; haemorrhoid severity score; European Quality of Life-5 Dimensions, 5-level version (EQ-5D-5L); Vaizey incontinence score; pain assessment; complications; and cost-effectiveness.ResultsA total of 370 participants entered the trial. At 1 year post procedure, 30% of the HAL group had evidence of recurrence compared with 49% after RBL [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) 1.42 to 3.51;p = 0.0005]. The main reason for the difference was the number of extra procedures required to achieve improvement/cure. If a single HAL is compared with multiple RBLs then only 37.5% recurred in the RBL arm (adjusted OR 1.35, 95% CI 0.85 to 2.15;p = 0.20). Persistence of significant symptoms at 6 weeks was lower in both arms than at 1 year (9% HAL and 29% RBL), suggesting significant deterioration in both groups over the year. Symptom score, EQ-5D-5L and Vaizey score improved in both groups compared with baseline, but there was no difference between interventions. Pain was less severe and of shorter duration in the RBL group; most of the HAL group who had pain had mild to moderate pain, resolving by 3 weeks. Complications were low frequency and not significantly different between groups. It appeared that HAL was not cost-effective compared with RBL. In the base-case analysis, the difference in mean total costs was £1027 higher for HAL. Quality-adjusted life-years (QALYs) were higher for HAL; however, the difference was very small (0.01) resulting in an incremental cost-effectiveness ratio of £104,427 per additional QALY.ConclusionsAt 1 year, although HAL resulted in fewer recurrences, recurrence was similar to repeat RBL. Symptom scores, complications, EQ-5D-5L and continence score were no different, and patients had more pain in the early postoperative period after HAL. HAL is more expensive and unlikely to be cost-effective in terms of incremental cost per QALY.LimitationsBlinding of participants and site staff was not possible.Future workThe incidence of recurrence may continue to increase with time. Further follow-up would add to the evidence regarding long-term clinical effectiveness and cost-effectiveness. The polysymptomatic nature of haemorrhoidal disease requires a validated scoring system, and the data from this trial will allow further assessment of validity of such a system. These data add to the literature regarding treatment of grade II/III haemorrhoids. The results dovetail with results from the eTHoS study [Watson AJM, Hudson J, Wood J, Kilonzo M, Brown SR, McDonald A,et al.Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomised controlled trial.Lancet2016, in press.] comparing stapled haemorrhoidectomy with excisional haemorrhoidectomy. Combined results will allow expansion of analysis, allowing surgeons to tailor their treatment options to individual patients.Trial registrationCurrent Controlled Trials ISRCTN41394716.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 88. See the NIHR Journals Library website for further project information.