A phase I trial of hypoxoside as an oral prodrug for cancer therapy - absence oftoxicity

No Abstract

Identification of Ehrlichia ruminantium proteins that activate cellular immune responses using a reverse vaccinology strategy

Ehrlichia ruminantium is an obligate intracellular bacterial pathogen which causes heartwater, a serious tick-borne disease of ruminants throughout sub-Saharan Africa. The development of promising recombinant vaccines has been reported previously, but none has been as effective as immunisation with live organisms. In this study we have used reverse vaccinology to identify proteins that elicit an in vitro cellular immune response similar to that induced by intact E. ruminantium. The experimental strategy involved four successive steps: (i) in silico selection of the most likely vaccine candidate genes from the annotated genome; (ii) cloning and expression of the selected genes; (iii) in vitro screening of the expressed proteins for their ability to induce interferon-gamma (IFN-ᵧ) production in E. ruminantium–immune lymphocytes; and (iv) further examination of the cytokine response profiles of those lymphocytes which tested positive for IFN-ᵧ induction. Based on their overall cytokine induction profiles the recombinant proteins were divided into four distinct groups. Eleven recombinant proteins induced a cytokine profile that was similar to the recall immune response induced by immune peripheral blood mononuclear cells (PBMC) stimulated with intact E. ruminantium. This response comprised the upregulation of cytokines associated with adaptive cellular immune responses as well as innate immunity. A successful vaccine may therefore need to contain a combination of recombinant proteins which induce both immune pathways to ensure protection against heartwater.The South African Department of Agriculture OV9/23/C167 grant and the FP6 EU INCO-DEV EPIGENEVAC FP6-003713 grant.http://www.elsevier.com/locate/vetimmab201

Efficacy of orally administered fluralaner (BravectoTM) or topically applied imidacloprid/moxidectin (Advocate®) against generalized demodicosis in dogs

BACKGROUND : This laboratory study compared the efficacy of Bravecto™ (fluralaner), formulated as a chewable tablet, with the efficacy of Advocate® (imidacloprid/moxidectin), formulated for topical administration, against naturally acquired generalized demodicosis in dogs. METHODS : Sixteen dogs, all diagnosed with generalized demodectic mange, were randomly allocated to two equal groups. Bravecto™ chewable tablets were administered once orally at a minimum dose of 25 mg fluralaner/kg body weight to one group of dogs, while the second group was treated topically on three occasions at 28-day intervals with Advocate® at a minimum dose of 10 mg imidacloprid/kg body weight and 2.5 mg moxidectin/kg body weight. Mites were counted in skin scrapings and demodectic lesions were evaluated on each dog before treatment and at 28-day intervals thereafter over a 12 week study period. Deep skin scrapings (~4 cm2) were made from the same five sites on each dog at each subsequent examination. RESULTS : After single oral administration of Bravecto™ chewable tablets, mite numbers in skin scrapings were reduced by 99.8% on Day 28 and by 100% on Days 56 and 84. Mite numbers in the dogs treated topically on three occasions at 28-day intervals with Advocate® were reduced by 98.0% on Day 28, by 96.5% on Day 56 and by 94.7% on Day 84. Statistically significantly (P ≤ 0.05) fewer mites were found on Days 56 and 84 on the Bravecto™ treated dogs compared to Advocate® treated dogs. A marked decrease was observed in the occurrence of erythematous patches, crusts, casts and scales in the dogs treated with Bravecto™ and in the occurrence of erythematous patches in the dogs treated with Advocate®. With the exception of one dog in each treated group, all dogs exhibited hair regrowth ≥ 90% at the end of the study in comparison with their hair-coat at study start. CONCLUSIONS : Single oral administration of Bravecto™ chewable tablets is highly effective against generalized demodicosis, with no mites detectable at 56 and 84 days following treatment. In comparison, Advocate®, administered three times at 28-day intervals, is also highly effective against generalized demodicosis, but most dogs still harboured mites at all assessment time points. Both treatments resulted in a marked reduction of skin lesions and increase of hair re-growth 12 weeks after the initial treatment.http://www.parasitesandvectors.comam201

Energy cost and return for hunting in African wild dogs and Cheetahs

African wild dogs (Lycaon pictus) are reported to hunt with energetically costly long chase distances. We used high-resolution GPS and inertial technology to record 1,119 high-speed chases of all members of a pack of six adult African wild dogs in northern Botswana. Dogs performed multiple short, high-speed, mostly unsuccessful chases to capture prey, while cheetahs (Acinonyx jubatus) undertook even shorter, higher-speed hunts. We used an energy balance model to show that the energy return from group hunting and feeding substantially outweighs the cost of multiple short chases, which indicates that African wild dogs are more energetically robust than previously believed. Comparison with cheetah illustrates the trade-off between sheer athleticism and high individual kill rate characteristic of cheetahs, and the energetic robustness of frequent opportunistic group hunting and feeding by African wild dogs

Sources of variation in quality of South African beef: Case studies in relation to the red meat classification system

Abstract The South African classification system describes beef carcasses in regard to visual fat cover, conformation and age by dentition. Animal age provides a fairly accurate description of expected eating quality in regard to tenderness in an industry where other sources of variation in tenderness are limited. Since deregulation in the beef industry in the 90s many changes have occurred in all parts of the value chain. This paper presents a number of case studies that focussed on the sources of variation in meat quality, but in particular on sources of changes in meat tenderness over the past two decades. These sources include feeding regime, the use of beta agonists, post mortem ageing and electrical stimulation. In some studies these factors are integrated with age or interactions among two or more of these factors are investigated

Women for science and science for women: Gaps, challenges and opportunities towards optimizing pre-exposure prophylaxis for HIV-1 prevention

Preventing new HIV infections remains a global challenge. Young women continue to bear a disproportionate burden of infection. Oral pre-exposure prophylaxis (PrEP), offers a novel women-initiated prevention technology and PrEP trials completed to date underscore the importance of their inclusion early in trials evaluating new HIV PrEP technologies. Data from completed topical and systemic PrEP trials highlight the role of gender specific physiological and social factors that impact PrEP uptake, adherence and efficacy. Here we review the past and current developments of HIV-1 prevention options for women with special focus on PrEP considering the diverse factors that can impact PrEP efficacy. Furthermore, we highlight the importance of inclusion of female scientists, clinicians, and community advocates in scientific efforts to further improve HIV prevention strategies

Anaplasma marginale outer membrane protein vaccine candidates are conserved in North American and South African strains

Bovine anaplasmosis is a globally economically important tick-borne disease caused by the obligate intraerythrocytic rickettsia, Anaplasma marginale. A live Anaplasma centrale blood-based vaccine is available, but it does not protect against all A. marginale field strains and may also transmit other blood-borne pathogens. Five potential outer membrane protein (OMP) vaccine candidates have been well-characterised in A. marginale strains from the USA, however, their levels of conservation in other countries must be ascertained in order to inform their use in a vaccine with regional or global efficacy. This study assessed the amino acid variation in vaccine candidate OMPs in South African strains of A. marginale, and also compared the immunogenic properties between South African and US strains. OMP genes Am779, Am854, omp7, omp8 and omp9 were amplified and sequenced from a set of genetically diverse South African samples with different msp1α-genotypes. OMPs Am854 and Am779 were highly conserved, with 99–100 % amino acid identity, while Omp7, Omp8 and Omp9 had 79–100 % identity with US strains. As has been shown previously, Omp7–9 possess conserved N- and C- termini, a central variable region, and a highly conserved CD4 T-cell epitope, FLLVDDA(I/V)V, in the N-terminal region. Western blot analysis of recombinant OMPs indicates strong antigenic conservation between South African and US strains of A. marginale, suggesting that they are good candidates for use in a novel global vaccine cocktail, although further work on the best formulation and delivery methods will be necessary.The National Research Foundation (NRF) (Nicola Collins, grant number 81840) and Technology Innovation Agency, Tshwane Animal Health Cluster (Marinda Oosthuizen, grant number TAHC12-00037).http://www.elsevier.com/locate/ttbdis2021-04-18hj2020Veterinary Tropical Disease

Game fence presence and permeability influences the local movement and distribution of South African mammals

Fences are utilized throughout the world to restrict the movements of wildlife, protecting them from threats and reducing human-wildlife conflict. In South Africa the number of privately-owned fenced game reserves has greatly increased in recent years, but little is known about how fencing affects the distribution and movements of target and non-target mammals. We surveyed 2m either side of the complete fence line of a recently established commercial game reserve in South Africa, identifying signs of animal presence (spoor, scat, foraging or other field signs) while also recording damage (holes) to the fence. Every 250m we carried out 100m perpendicular transects either side of the fence, recording vegetation cover and height at 10m intervals along the transect. We found that livestock (largely cattle) were excluded from the reserve. However, 12% of records of large animal species were recorded outside of the fence line. These species had been introduced to the reserve, strongly suggesting that they had crossed the boundary into the surrounding farmland. Sixteen naturally present wild species were found on both sides of the fence, but we found more evidence of their presence inside the reserve. Observational evidence suggests that they were regularly crossing the boundary, particularly where the fence was damaged, with hole size affecting species recorded. We also found evidence that the construction of the fence had led to a difference in vegetation structure with plant diversity and percentage of non-woody plant cover significantly higher inside the fence. While fencing was highly effective at preventing movement of livestock, introduced and wild animals were able to cross the boundary, via holes in the fence. This work shows that the efficacy of the most common approach to preventing animal movement around protected areas depends on the species being considered and fence condition

Fatal Human Infection with Rabies-related Duvenhage Virus, South Africa

Duvenhage virus was isolated from a patient who died of a rabieslike disease after being scratched by a bat early in 2006. This occurred ≈80 km from the site where the only other known human infection with the virus had occurred 36 years earlier

Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel

The impact of topical antiretrovirals for pre-exposure prophylaxis on humoral responses following HIV infection is unknown. Using a binding antibody multiplex assay, we investigated HIV-specific IgG and IgA responses to envelope glycoproteins, p24 Gag and p66, in the genital tract (GT) and plasma following HIV acquisition in women assigned to tenofovir gel (n=24) and placebo gel (n=24) in the CAPRISA 004 microbicide trial to assess if this topical antiretroviral had an impact on mucosal and systemic antibody responses. Linear mixed effect modeling and partial least squares discriminant analysis was used to identify multivariate antibody signatures associated with tenofovir use. There were significantly higher response rates to gp120 Env (P=0.03), p24 (P=0.002), and p66 (P=0.009) in plasma and GT in women assigned to tenofovir than placebo gel at multiple time points post infection. Notably, p66 IgA titers in the GT and plasma were significantly higher in the tenofovir compared with the placebo arm (P<0.05). Plasma titers for 9 of the 10 HIV-IgG specificities predicted GT levels. Taken together, these data suggest that humoral immune responses are increased in blood and GT of individuals who acquire HIV infection in the presence of tenofovir gel.United States. National Institutes of Health (AI51794)United States. National Institutes of Health (AI104387)United States. National Institutes of Health (AI115981)United States. National Institutes of Health (AI116086)United States. Agency for International Development (GP00-08-00005-00 subproject agreement PPA-09-046