A locus conferring tolerance to Theileria infection in African cattle.

East Coast fever, a tick-borne cattle disease caused by the Theileria parva parasite, is among the biggest natural killers of cattle in East Africa, leading to over 1 million deaths annually. Here we report on the genetic analysis of a cohort of Bos indicus (Boran) cattle demonstrating heritable tolerance to infection with T. parva (h2 = 0.65, s.e. 0.57). Through a linkage analysis we identify a 6 Mb genomic region on bovine chromosome 15 that is significantly associated with survival outcome following T. parva exposure. Testing this locus in an independent cohort of animals replicates this association with survival following T. parva infection. A stop gained variant in a paralogue of the FAF1 gene in this region was found to be highly associated with survival across both related and unrelated animals, with only one of the 20 homozygote carriers (T/T) of this change succumbing to the disease in contrast to 44 out of 97 animals homozygote for the reference allele (C/C). Consequently, we present a genetic locus linked to tolerance of one of Africa's most important cattle diseases, raising the promise of marker-assisted selection for cattle that are less susceptible to infection by T. parva.

The co-administration of live fowlpox and Newcastle disease vaccines by non-invasive routes to chickens reared by smallholders in Tanzania and Nepal.

The co-administration of commercial live fowlpox (FP) and Newcastle disease (ND) vaccines when given by non-invasive (needle-free) routes was demonstrated to be safe and to elicit immunity in two field studies, one in Tanzania the other in Nepal. Both studies were of a cluster-randomised controlled design in which birds were randomly assigned to one of five treatment groups: (i) administration with FP vaccine alone (feather follicle), (ii) administration with ND vaccine alone (eye-drop), (iii) concurrent administration of FP (feather follicle) and ND (eye-drop) vaccines, (iv) concurrent administration of FP (wing-web) and ND (eye-drop) vaccines, and (v) unvaccinated, acting as environmental sentinels. Data from a total of 1167 birds from seven villages in Hanang District of Tanzania together with 1037 birds from eleven villages in Dhading District of Nepal were collected over a period of 21 and 28 days, respectively. Immune responses to FP vaccination were evaluated by local take reactions, while those to ND vaccination were evaluated serologically by haemagglutination inhibition test. The two studies demonstrated that the concurrent vaccination of free-range, indigenous breeds of chicken with live FP and ND vaccines, both administered by non-invasive routes, was safe and induced immunity against FP and ND that were non-inferior to the administration of FP and ND vaccines alone. These findings are important to appropriately trained small-scale backyard poultry farmers as well as to paraprofessionals and community health workers helping to increase vaccine uptake and the control of both FP and ND in low- to middle-income countries.

Evaluation of new generation macrolides for the treatment and metaphylaxis of contagious bovine pleuropneumonia (CBPP) in cattle experimentally infected with Mycoplasma mycoides subspecies mycoides.

BACKGROUND: Contagious bovine pleuropneumonia (CBPP) caused by Mycoplasma mycoides subspecies mycoides (Mmm) is an important disease of cattle that causes serious economic losses. With the known effectiveness of new generation macrolides, tulathromycin and gamithromycin were assessed in comparison with oxytetracycline as a positive control and saline as a negative control for effectiveness in inhibiting lung lesion development, promoting resolution, preventing spread and bacteriological clearance in susceptible local cattle breeds in two separate studies in Kenya and Zambia. Animals were monitored for clinical signs, sero-conversion as well as detailed post-mortem examination for CBPP lesions. RESULTS: Using the Hudson and Turner score for lesion type and size, tulathromycin protected 90%, gamithromycin 80%, and oxytetracycline 88% of treated animals in Kenya. In Zambia, all animals (100%) treated with macrolides were free of lung lesions, while oxytetracycline protected 77.5%. Using the mean adapted Hudson and Turner score, which includes clinical signs, post-mortem findings and serology, tulathromycin protected 82%, gamithromycin 56% and oxytetracycline 80% of the animals in Kenya whereas in Zambia, tulathromycin protected 98%, gamithromycin 94% and oxytetracycline 80%. The saline-treated groups had 93 and 92% lesions in Kenya and Zambia respectively, with Mmm recovered from 5/14 in Kenya and 10/13 animals in Zambia. Whereas the groups treated with macrolides were free from lesions in Zambia, in Kenya 5/15 tulathromycin-treated animals and 6/15 gamithromycin-treated animals showed lesions. Oxytetracycline-treated animals showed similarities with 3/14 and 4/15 showing lesions in Zambia and Kenya respectively and Mmm recovery from one animal in Kenya and six in Zambia. In both studies, lesion scores of saline-treated groups were significantly higher than those of the antibiotic treated groups (p < 0.001). In sentinel animals, CBPP lesions were detected and Mmm recovered from one and two animals mixed with the saline-treated groups in Kenya and Zambia respectively. CONCLUSIONS: This study demonstrated that tulathromycin, a mycoplasmacidal, can achieve metaphylactic protection of up to 80%, while non-recovery of Mmm from sentinels suggests macrolides effectiveness in preventing spread of Mmm. It is recommended that further studies are conducted to evaluate strategies comparing vaccination alone or combining vaccination and antibiotics to control or eradicate CBPP.

Plasmodium falciparum variant erythrocyte surface antigens: a pilot study of antibody acquisition in recurrent natural infections.

BACKGROUND: During intra-erythrocytic replication Plasmodium falciparum escapes the human host immune system by switching expression of variant surface antigens (VSA). Piecemeal acquisition of variant specific antibody responses to these antigens as a result of exposure to multiple re-infections has been proposed to play a role in acquisition of naturally acquired immunity. METHODS: Immunofluorescence was used to explore the dynamics of anti-VSA IgG responses generated by children to (i) primary malaria episodes and (ii) recurrent P. falciparum infections. RESULTS: Consistent with previous studies on anti-VSA responses, sera from each child taken at the time of recovery from their respective primary infection tended to recognize their own secondary parasites poorly. Additionally, compared to patients with reinfections by parasites of new merozoite surface protein 2 (MSP2) genotypes, baseline sera sampled from patients with persistent infections (recrudescence) tended to have higher recognition of heterologous parasites. This is consistent with the prediction that anti-VSA IgG responses may play a role in promoting chronic asymptomatic infections. CONCLUSIONS: This pilot study validates the utility of recurrent natural malaria infections as a functional readout for examining the incremental acquisition of immunity to malaria.

A longitudinal assessment of the serological response to Theileria parva and other tick-borne parasites from birth to one year in a cohort of indigenous calves in western Kenya.

Tick-borne diseases are a major impediment to improved productivity of livestock in sub-Saharan Africa. Improved control of these diseases would be assisted by detailed epidemiological data. Here we used longitudinal, serological data to determine the patterns of exposure to Theileria parva, Theileria mutans, Babesia bigemina and Anaplasma marginale from 548 indigenous calves in western Kenya. The percentage of calves seropositive for the first three parasites declined from initial high levels due to maternal antibody until week 16, after which the percentage increased until the end of the study. In contrast, the percentage of calves seropositive for T. mutans increased from week 6 and reached a maximal level at week 16. Overall 423 (77%) calves seroconverted to T. parva, 451 (82%) to T. mutans, 195 (36%) to B. bigemina and 275 (50%) to A. marginale. Theileria parva antibody levels were sustained following infection, in contrast to those of the other three haemoparasites. Three times as many calves seroconverted to T. mutans before seroconverting to T. parva. No T. parva antibody response was detected in 25 calves that died of T. parva infection, suggesting that most deaths due to T. parva are the result of acute disease from primary exposure.

Parasite co-infections show synergistic and antagonistic interactions on growth performance of East African zebu cattle under one year.

The co-occurrence of different pathogen species and their simultaneous infection of hosts are common, and may affect host health outcomes. Co-infecting pathogens may interact synergistically (harming the host more) or antagonistically (harming the host less) compared with single infections. Here we have tested associations of infections and their co-infections with variation in growth rate using a subset of 455 animals of the Infectious Diseases of East Africa Livestock (IDEAL) cohort study surviving to one year. Data on live body weight, infections with helminth parasites and haemoparasites were collected every 5 weeks during the first year of life. Growth of zebu cattle during the first year of life was best described by a linear growth function. A large variation in daily weight gain with a range of 0·03-0·34 kg, and a mean of 0·135 kg (0·124, 0·146; 95% CI) was observed. After controlling for other significant covariates in mixed effects statistical models, the results revealed synergistic interactions (lower growth rates) with Theileria parva and Anaplasma marginale co-infections, and antagonistic interactions (relatively higher growth rates) with T. parva and Theileria mutans co-infections, compared with infections with T. parva only. Additionally, helminth infections can have a strong negative effect on the growth rates but this is burden-dependent, accounting for up to 30% decrease in growth rate in heavily infected animals. These findings present evidence of pathogen-pathogen interactions affecting host growth, and we discuss possible mechanisms that may explain observed directions of interactions as well as possible modifications to disease control strategies when co-infections are present.

A comparison of approaches for association studies of polymorphisms and colorectal cancer risk.

AIM: Meta-analyses have been used to evaluate associations between polymorphisms and colorectal cancer risk, but the quality of individual studies used to inform them may vary substantially. Our aim was to apply well-established quality-control criteria to individual association studies and then compare the results of meta-analyses that included or excluded studies that did not meet these criteria. METHOD: We used meta-analyses of studies reporting a relationship between polymorphisms and colorectal cancer published between 1996 and 2008. Polymorphism-cancer associations were derived in separate meta-analyses including only those meeting the quality-control criteria. RESULTS: Relative ORs varied substantially between the open and restricted group meta-analyses for all variants except MTHFR 677 CT. However, the associations were modest and the direction of relative risk did not change after applying criteria. Publication bias was detected for all associations, except the restricted set of studies for GSTP1 GG. CONCLUSION: We observed variation in calculated relative risk and changes in tests for publication bias that were dependent on the inclusion criteria used for association studies of polymorphisms and colorectal cancer. Standardizing study inclusion criteria may reduce the variation in findings for meta-analyses of gene-association studies of common diseases such as colorectal cancer.

Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors.

The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n-3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was ∼20% lower in 488G and ∼20% higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30-60% higher residual COX activity; 511A also showed up to 70% higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in Vmax values with the two fatty acids: 488G showed ∼20% less and 511A showed ∼20% more discrimination against eicosapentaenoic acid. The Vmax value for eicosapentaenoate was not affected in 228H or 587R, nor were the Km values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n-3 fatty acids.

Control trial of porcine cysticercosis in Uganda using a combination of the TSOL18 vaccination and oxfendazole.

BACKGROUND: Neurocysticercosis caused by Taenia solium when the parasite lodges in the central nervous system, is an important cause of human seizures and mortality in sub-Saharan Africa. The parasite is prevalent in many regions of Uganda. Pigs are intermediate hosts for T. solium, and we evaluated a T. solium control program in pigs, involving vaccination of pigs with the TSOL18 vaccine and treatment with oxfendazole. METHODS: The study was conducted in two districts of Eastern Uganda involving the rural village communities of Bukedea (intervention area) and Kumi (control area) during 2016-2017. Seven hundred and thirty-four households were enrolled in the study. Pigs in the intervention area received intramuscular immunizations with TSOL18 (Cysvax™) and an oral medication with 30 mg/kg oxfendazole (Paranthic™) at approximately 3-monthly intervals for 18 months. Porcine cysticercosis was evaluated by post-mortem examination. At the beginning of the study, 111 pigs were examined. In an interim evaluation in the intervention area, 55 pigs were evaluated 12 months after starting the project. At the end of the study approximately 3 months after the final intervention, 55 pigs from the intervention area and 56 pigs from the control area were evaluated. RESULTS: The prevalence of porcine cysticercosis for the two sites was 16.2% at the beginning of the study (17.2% in the intervention area and 15.1% in the control area) with no statistically significant difference (P = 0.759) between the two study sites. Among the 110 animals assessed from the intervention site (55 at the interim evaluation and 55 at the final evaluation), no pig with viable T. solium cysts was found. There was a statistically significant difference between the prevalence at baseline (17.2%) and at the end of the study (0%) in the intervention area (P = 0.001) and a statistically significant difference between the intervention (0%) and control areas (5.4%) (P = 0.041) at the end of the study. CONCLUSIONS: Three-monthly concurrent vaccination of pigs with the TSOL18 vaccine and medication with oxfendazole eliminated T. solium transmission by the animals involved in the study. Application of vaccination with medication in pigs has the potential to reduce transmission of T. solium in Uganda and other endemic countries.

An analysis of health-related quality of life in the phase III PROSELICA and FIRSTANA studies assessing cabazitaxel in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Men with metastatic castration-resistant prostate cancer (mCRPC) are living longer, therefore optimizing health-related quality of life (HRQL), as well as survival outcomes, is important for optimal patient care. The aim of this study was to assess the HRQL in patients with mCRPC receiving docetaxel or cabazitaxel. PATIENTS AND METHODS: PROSELICA (NCT01308580) assessed the non-inferiority of cabazitaxel 20 mg/m2 (C20) versus 25 mg/m2 (C25) in patients with mCRPC after docetaxel. FIRSTANA (NCT01308567) assessed the superiority of C25 or C20 versus docetaxel 75 mg/m2 (D75) in patients with chemotherapy-naive mCRPC. HRQL and pain were analyzed using protocol-defined, prospectively collected, Functional Assessment of Cancer Therapy-Prostate (FACT-P) and McGill-Melzack questionnaires. Analyses included definitive improvements in HRQL, maintained or improved HRQL, and HRQL over time. RESULTS: In total, 2131 patients were evaluable for HRQL across the two studies. In PROSELICA, 38.8% and 40.5% of patients receiving C20 and C25, respectively, had definitive FACT-P total score (TS) improvements. In FIRSTANA, 43.4%, 49.7%, and 44.9% of patients receiving D75, C20, and C25, respectively, had definitive FACT-P TS improvements. In both trials, definitive improvements started after cycle 1 and were maintained for the majority of subsequent treatment cycles. More than two-thirds of patients maintained or improved their FACT-P TS. CONCLUSIONS: In PROSELICA and FIRSTANA, >40% of the 2131 evaluable patients with mCRPC had definitive FACT-P TS improvements; improvements occurred early and were maintained. More than 75% of patients maintained or improved their FACT-P TS.

Clinical Evaluation of Corridor Disease in Bos indicus (Boran) Cattle Naturally Infected With Buffalo-Derived Theileria parva.

Corridor disease (CD) is a fatal condition of cattle caused by buffalo-derived Theileria parva. Unlike the related condition, East Coast fever, which results from infection with cattle-derived T. parva, CD has not been extensively studied. We describe in detail the clinical and laboratory findings in cattle naturally infected with buffalo-derived T. parva. Forty-six cattle were exposed to buffalo-derived T. parva under field conditions at the Ol Pejeta Conservancy, Kenya, between 2013 and 2018. The first signs of disease observed in all animals were nasal discharge (mean day of onset was 9 days post-exposure), enlarged lymph nodes (10 days post-exposure), and pyrexia (13.7 days post-exposure). Coughing and labored breathing were observed in more than 50% of animals (14 days post-exposure). Less commonly observed signs, corneal edema (22%) and diarrhea (11%), were observed later in the disease progression (19 days post-exposure). All infections were considered clinically severe, and 42 animals succumbed to infection. The mean time to death across all studies was 18.4 days. The mean time from onset of clinical signs to death was 9 days and from pyrexia to death was 4.8 days, indicating a relatively short duration of clinical illness. There were significant relationships between days to death and the days to first temperature (chi2 = 4.00, p = 0.046), and days to peak temperature (chi2 = 25.81, p = 0.001), animals with earlier onset pyrexia died sooner. These clinical indicators may be useful for assessing the severity of disease in the future. All infections were confirmed by the presence of macroschizonts in lymph node biopsies (mean time to parasitosis was 11 days). Piroplasms were detected in the blood of two animals (4%) and 20 (43%) animals seroconverted. In this study, we demonstrate the successful approach to an experimental field study for CD in cattle. We also describe the clinical progression of CD in naturally infected cattle, including the onset and severity of clinical signs and pathology. Laboratory diagnoses based on examination of blood samples are unreliable, and alternatives may not be available to cattle keepers. The rapid development of CD requires recognition of the clinical signs, which may be useful for early diagnosis of the disease and effective intervention for affected animals.

Inherited Tolerance in Cattle to the Apicomplexan Protozoan Theileria parva is Associated with Decreased Proliferation of Parasite-Infected Lymphocytes.

Theileria parva is the causative agent of East Coast fever and Corridor disease, which are fatal, economically important diseases of cattle in eastern, central and southern Africa. Improved methods of control of the diseases are urgently required. The parasite transforms host lymphocytes, resulting in a rapid, clonal expansion of infected cells. Resistance to the disease has long been reported in cattle from T. parva-endemic areas. We reveal here that first- and second-generation descendants of a single Bos indicus bull survived severe challenge with T. parva, (overall survival rate 57.3% compared to 8.7% for unrelated animals) in a series of five field studies. Tolerant cattle displayed a delayed and less severe parasitosis and febrile response than unrelated animals. The in vitro proliferation of cells from surviving cattle was much reduced compared to those from animals that succumbed to infection. Additionally, some pro-inflammatory cytokines such as IL1ß, IL6, TNFα or TGFß which are usually strongly expressed in susceptible animals and are known to regulate cell growth or motility, remain low in tolerant animals. This correlates with the reduced proliferation and less severe clinical reactions observed in tolerant cattle. The results show for the first time that the inherited tolerance to T. parva is associated with decreased proliferation of infected lymphocytes. The results are discussed in terms of whether the reduced proliferation is the result of a perturbation of the transformation mechanism induced in infected cells or is due to an innate immune response present in the tolerant cattle.

A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective chemopreventive agents for colorectal neoplasia. Polymorphisms in NSAID targets or metabolizing enzymes may affect NSAID efficacy or toxicity. We conducted a literature review to summarize current evidence of gene-drug interactions between NSAID use and polymorphisms in COX1, COX2, ODC, UGT1A6 and CYP2C9 on risk of colorectal neoplasia by searching OVID and PubMed. Of 134 relevant search results, thirteen investigated an interaction. One study reported a significant interaction between NSAID use and the COX1 Pro17Leu polymorphism (P=0.03) whereby the risk reduction associated with NSAID use among homozygous wild-type genotypes was not observed among NSAID users with variant alleles. Recent pharmacodynamic data support the potential for gene-drug interactions for COX1 Pro17Leu. Statistically significant interactions have also been reported for ODC (315G>A), UGT1A6 (Thr181Ala+Arg184Ser or Arg184Ser alone), and CYP2C9 (*2/*3). No statistically significant interactions have been reported for polymorphisms in COX2; however, an interaction with COX2 -765G>C approached significance (P=0.07) in one study. Among seven remaining studies, reported interactions were not statistically significant for COX1, COX2 and ODC gene polymorphisms. Most studies were of limited sample size. Definitions of NSAID use differed substantially between studies. The literature on NSAID-gene interactions to date is limited. Reliable detection of gene-NSAID interactions will require greater sample sizes, consistent definitions of NSAID use and evaluation of clinical trial subjects of chemoprevention studies.

Metabolomic analysis of 92 pulmonary embolism patients from a nested case-control study identifies metabolites associated with adverse clinical outcomes.

Essentials Risk-stratification often fails to predict clinical deterioration in pulmonary embolism (PE). First-ever high-throughput metabolomics analysis of risk-stratified PE patients. Changes in circulating metabolites reflect a compromised energy metabolism in PE. Metabolites play a key role in the pathophysiology and risk stratification of PE. SUMMARY: Background Patients with acute pulmonary embolism (PE) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low-risk and high-risk PE is limited, so current risk-stratification efforts often fail to predict clinical deterioration and are insufficient to guide management. Objectives To improve our understanding of the physiology differentiating low-risk from high-risk PE, we conducted the first-ever high-throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case-control study. Patients/methods We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 h of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk-strata. Results When we compared 46 low-risk with 46 intermediate/high-risk PEs, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: tricarboxylic acid (TCA) cycle, fatty acid metabolism (acyl carnitine) and purine metabolism, (hypo)xanthine/inosine containing. Additionally, energy, nucleotide and amino acid pathways were downregulated in intermediate/high-risk PE patients. When we compared 28 intermediate-risk with 18 high-risk PE patients, 41 metabolites differed at a nominal P-value level. These metabolites were enriched in fatty acid metabolism (acyl cholines), and hemoglobin and porphyrin metabolism. Conclusion Our results suggest that high-throughput metabolomics can provide insight into the pathophysiology of PE. Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high-risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE.

Plasma inflammatory cytokines and survival of pancreatic cancer patients.

OBJECTIVES: Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome. METHODS: We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study. Hazard ratios (HRs) and 95% confidence intervals (CI) for death were estimated using multivariate Cox proportional hazards models. RESULTS: Overall mortality was significantly increased in patients in the top quartile of CRP (HR = 2.52, 95% CI: 1.82-3.49), IL-6 (HR = 2.78, 95% CI: 2.03-3.81), sTNF-RII (HR = 2.00, 95% CI: 1.46-2.72), and MIC-1 (HR = 2.53, 95% CI: 1.83-3.50), compared to those in the bottom quartile (P-trend <0.0001 for all four comparisons). Furthermore, patients with higher circulating concentrations of all four cytokines had a median survival of 3.7 months; whereas, those with lower levels had a median survival of 19.2 months (HR = 4.55, 95% CI: 2.87-7.20, P-trend <0.0001). CONCLUSION: Individual elevated plasma inflammatory cytokines are associated with significant and dramatic reductions in pancreatic cancer patient survival. Furthermore, we observed an independent combined effect of those cytokines on patient survival, suggesting that multiple inflammatory pathways are likely involved in PDAC progression. Future research efforts to target the inflammatory state using combination strategies in pancreatic cancer patients are warranted.

Targeting the latent cytomegalovirus reservoir with an antiviral fusion toxin protein.

Reactivation of human cytomegalovirus (HCMV) in transplant recipients can cause life-threatening disease. Consequently, for transplant recipients, killing latently infected cells could have far-reaching clinical benefits. In vivo, myeloid cells and their progenitors are an important site of HCMV latency, and one viral gene expressed by latently infected myeloid cells is US28. This viral gene encodes a cell surface G protein-coupled receptor (GPCR) that binds chemokines, triggering its endocytosis. We show that the expression of US28 on the surface of latently infected cells allows monocytes and their progenitor CD34+ cells to be targeted and killed by F49A-FTP, a highly specific fusion toxin protein that binds this viral GPCR. As expected, this specific targeting of latently infected cells by F49A-FTP also robustly reduces virus reactivation in vitro. Consequently, such specific fusion toxin proteins could form the basis of a therapeutic strategy for eliminating latently infected cells before haematopoietic stem cell transplantation.

Sero-prevalence of Taenia spp. cysticercosis in rural and urban smallholder pig production settings in Uganda.

The pork tapeworm, Taenia solium, is prevalent in Uganda although the prevalence has not been determined in all areas of the country. A cross-sectional study, to determine the sero-prevalence of the parasite in pigs kept under rural and urban production settings, was carried out in three Ugandan districts, Masaka, Mukono and Kamuli. Serum samples from 1185 pigs were tested for the presence of T. solium cysticercosis antigen using the HP10 antigen-ELISA (Ag-ELISA) and the ApDia Ag-ELISA assays. Using parallel interpretation of the two tests showed lower levels of observed prevalence of T. solium in rural production settings (10.8%) compared to urban (17.1%). Additionally, Maximum Likelihood Estimation for evaluating assays in the absence of a gold standard, using TAGS on the R platform, estimated the true sero-prevalence to be lower in rural production setting, 0.0% [0.0-3.2%; 95% confidence interval (CI)] than in urban production setting, 12.3% (4.2-77.5% CI). When the sensitivity/specificity (Se/Sp) of the assays were estimated, assuming conditional independence of the tests, HP10 Ag-ELISA was more sensitive and specific [(Se=53.9%; 10.1-100% CI), (Sp=97.0%; 95.9-100% CI)] than the ApDia assay [(Se=20.2%; 1.5-47.7% CI), (Sp=92.2%; 90.5-93.9% CI)]. Subject to parasitological verification, these results indicate there may be a need to implement appropriate control measures for T. solium in the study areas.

Corrigendum to "Exposure of vaccinated and naive cattle to natural challenge from buffalo-derived Theileria parva" [Int. J. Parasitol. Parasites Wildl. 4(2) (2015) 244-251].

[This corrects the article DOI: 10.1016/j.ijppaw.2015.04.006.].

Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells.

Human cytomegalovirus (HCMV) latency in the myeloid lineage is maintained by repressive histone modifications around the major immediate early promoter (MIEP), which results in inhibition of the lytic viral life cycle. We now show that pharmacological inhibition of histone deacetylases (HDACs) relieves this repression of the MIEP and induces transient expression of the viral lytic immediate early (IE) antigens but, importantly, not full virus reactivation. In turn, these latently infected cells now become targets for IE-specific cytotoxic T cells (CTLs) which are present at high frequency in all normal healthy HCMV positive carriers but would normally be unable to target latent (lytic antigen-negative) cells. This approach of transiently inducing viral lytic gene expression by HDAC inhibition, in otherwise latently infected cells, offers a window of opportunity to target and purge the latent myeloid cell reservoir by making these normally immunologically undetectable cells visible to pre-existing host immune responses to viral lytic antigens.

Release factors and their role as decoding proteins: specificity and fidelity for termination of protein synthesis.

The decoding of stop signals in mRNA requires protein release factors. Two classes of factor are found in both prokaryotes and eukaryotes, a decoding factor and a stimulatory recycling factor. These factors form complexes at the active centre of the ribosome and mimic in overall shape the complexes found at other stages of protein synthesis. The decoding release factor is shaped like a tRNA and has a domain for codon recognition at the decoding site of the ribosome, and a domain for peptidyl-tRNA hydrolysis that is inferred to be near the peptidyltransferase centre. Initial interaction of the decoding factor with the ribosome is a low fidelity event involving multiple contacts with the ribosomal components. A subsequent discrimination step, at present poorly defined, ensures high fidelity of codon recognition.