The intestinal immune response of the mouse to the tapeworm Hymenolepis diminuta

It is now conclusively evident that the intestinal tapeworm Hymenolepis diminuta in the mouse can establish successfully, but is thereafter rejected by an immunological mechanism that is thought to be thymus-dependent. The lack of damage to the small intestine in H. diminuta infection makes this an almost unique and potentially valuable model for the investigation of intestinal immune responses. The work presented in this thesis was undertaken to more fully characterise this host-parasite system, and the nature of the immune response of the mouse to H, diminuta was investigated in four different aspects. Firstly, the thymus-dependency of the response was confirmed, and the role of antibody in the expulsion of H. diminuta investigated; secondly, the source of the antigens which stimulate the protective response was investigated; thirdly, a study was made of the effect of an intestinal response to an unrelated parasite on H. diminuta and H. microstoma in rats and mice; fourthly, lymphocytes from the mesenteric lymph nodes of infected mice were tested for their ability to transfer immunity between mice, and to migrate to the small intestine of infected mice. The effects of pregnancy and lactation in the mouse were studied in relation to rejection of H. diminuta; both phases of the reproductive cycle are known to cause depression of T effector lymphocytes, whereas antibody responses are unaffected or enhanced. It was shown that pregnant and lactating mice reject H, diminuta more slowly than nulliparous mice, and that growth of the worms is much enhanced in comparison with worms from nulliparous mice. The delay in rejection caused by lactation was found to be greater than that observed during pregnancy, from which it can be concluded that immunodepression is more marked in lactating mice. The period of slowest rejection coincides with the period when greatest growth of the worms was noted (i.e. during mid-lactation), but the relative contributions of the immunodepression and the increased food intake of pregnant and lactating mice to the enhanced worm growth are far from clear. It was demonstrated that the immunological defect operating during pregnancy and lactation lies in the effector arm of the response, as sensitisation against H. diminuta occurred normally in these animals, but the response to reinfection of previously immunised animals was shown to be depressed during pregnancy and lactation. Experiments were carried out in which immunisation of mice with H, diminuta failed to provide any protection against H, diminuta infection in their offspring; antibody transferred in colostrum had no effect on either growth or survival of the worms in the young mice, which have little innate capacity to respond to the infection. From these and the above experiments, it was concluded that anti-worm antibody in the absence of effective T lymphocyte function has no measureable independent effect on H. diminuta. The relative roles of the scolex and strobila of H. diminuta in stimulating the immune response of the mouse were investigated by transplantation of worms with large or small weights of strobila into the duodenum of mice. It was found that the larger worms were rejected more quickly by the mice, and it is argued that this difference was not due to the smaller worms being more resistant to immunological attack, or to a time-related exposure of protective antigens, but to differences in size or surface area. Confirmation of this idea came from studies with stunted worms derived from heavily irradiated cysticercoids. At 35 krad and above, the worms excyst normally, but show little growth thereafter. These stunted worms, which cosist of a scolex and a stump of undifferentiated neck tissue, were rejected by mice via an immunological mechanism, but were shown to be poorly immunogenic; they are rejected slowly by mice, and stimulate poor immunological memory in comparison with normal worms. It was concluded that the protective antigen(s) arise from the tegument, but that the anterior end of the worm is more antigenic per unit weight than the posterior end. This theory is shown to fit many established observations, and brief discussion is made of the implications for vaccination studies, and of the possible nature of the protective antigens from the tegument of the worm. (Abstract shortened by ProQuest.)

Dietary advice for reducing cardiovascular risk

Background Changes in population diet are likely to reduce cardiovascular disease and cancer, but the effect of dietary advice is uncertain. This review is an update of a previous review published in 2007. Objectives To assess the effects of providing dietary advice to achieve sustained dietary changes or improved cardiovascular risk profile among healthy adults. Search methods We searched the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects (DARE) and the HTA database on The Cochrane Library (Issue 4, 2010). We searched MEDLINE (Ovid) (1950 to week 2 October 2010) and EMBASE (Ovid) (1980 to Week 42 2010). Additional searches were done on CAB Health (1972 to December 1999), CVRCT registry (2000), CCT (2000) and SIGLE (1980 to 2000). Dissertation abstracts and reference lists of articles were checked and researchers were contacted. Selection criteria Randomised studies with no more than 20% loss to follow-up, lasting at least three months and involving healthy adults comparing dietary advice with no advice or minimal advice. Trials involving children, trials to reduce weight or those involving supplementation were excluded. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Main results Forty-four trials with 52 intervention arms (comparisons) comparing dietary advice with no advice were included in the review; 18,175 participants or clusters were randomised. Twenty-nine of the 44 included trials were conducted in the USA. Dietary advice reduced total serum cholesterol by 0.15 mmol/L (95% CI 0.06 to 0.23) and LDL cholesterol by 0.16 mmol/L (95% CI 0.08 to 0.24) after 3 to 24 months. Mean HDL cholesterol levels and triglyceride levels were unchanged. Dietary advice reduced blood pressure by 2.61 mm Hg systolic (95% CI 1.31 to 3.91) and 1.45 mm Hg diastolic (95% CI 0.68 to 2.22) and 24-hour urinary sodium excretion by 40.9 mmol (95% CI 25.3 to 56.5) after 3 to 36 months but there was heterogeneity between trials for the latter outcome. Three trials reported plasma antioxidants, where small increases were seen in lutein and β-cryptoxanthin, but there was heterogeneity in the trial effects. Self-reported dietary intake may be subject to reporting bias, and there was significant heterogeneity in all the following analyses. Compared to no advice, dietary advice increased fruit and vegetable intake by 1.18 servings/day (95% CI 0.65 to 1.71). Dietary fibre intake increased with advice by 6.5 g/day (95% CI 2.2 to 10.82), while total dietary fat as a percentage of total energy intake fell by 4.48% (95% CI 2.47 to 6.48) with dietary advice, and saturated fat intake fell by 2.39% (95% CI 1.4 to 3.37). Two trials analysed incident cardiovascular disease (CVD) events (TOHP I/II). Follow-up was 77% complete at 10 to 15 years after the end of the intervention period and estimates of event rates lacked precision but suggested that sodium restriction advice probably led to a reduction in cardiovascular events (combined fatal plus non-fatal events) plus revascularisation (TOHP I hazards ratio (HR) 0.59, 95% CI 0.33 to 1.08; TOHP II HR 0.81, 95% CI 0.59 to 1.12). Authors' conclusions Dietary advice appears to be effective in bringing about modest beneficial changes in diet and cardiovascular risk factors over approximately 12 months, but longer-term effects are not known

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Compartmentalisation of β-secretase (Asp2) into low-boyant density, non-caveolar lipid rafts

AbstractRecent epidemiological studies show a reduced prevalence of Alzheimer's disease (AD) in patients treated with inhibitors of cholesterol biosynthesis [1, 2]. Moreover, the cholesterol-transport protein, apolipoprotein E4, and elevated cholesterol are important risk factors for AD [3–5]. Additionally, in vitro and in vivo studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein (APP) to β-amyloid [6–11], the major constituent of senile plaques [12–14]. Cholesterol plays a crucial role in maintaining lipid rafts in a functional state [15]. Lipid rafts are cholesterol-enriched membrane microdomains implicated in signal transduction, protein trafficking, and proteolytic processing [15–18]. Since APP, β-amyloid, and the putative γ-secretase, presenilin-1 (PS-1), have all been found in lipid rafts [12, 19–21], we hypothesized that the recently identified β-secretase, Asp2 (BACE1) [13], might also be present in rafts. Here, we report that recombinant Asp2 expressed in three distinct cell lines is raft associated. Using both detergent and nondetergent methods, Asp2 protein and activity were found in a light membrane raft fraction that also contained other components of the amyloidogenic pathway. Immunoisolation of caveolin-containing vesicles indicated that Asp2 was present in a unique raft population distinct from caveolae. Finally, depletion of raft cholesterol abrogated association of Asp2 with the light membrane fraction. These observations are consistent with the raft localization of APP processing and suggest that the partitioning of Asp2 into lipid rafts may underlie the cholesterol sensitivity of β-amyloid production