Using open-access taxonomic and spatial information to create a comprehensive database for the study of Mammalian and avian livestock and pet infections

AbstractWhat are all the species of pathogen that affect our livestock? As 6 out of every 10 human pathogens came from animals, with a good number from livestock and pets, it seems likely that the majority that emerge in the future, and which could threaten or devastate human health, will come from animals. Only 10 years ago, the first comprehensive pathogen list was compiled for humans; we still have no equivalent for animals. Here we describe the creation of a novel pathogen database, and present outputs from the database that demonstrate its value.The ENHanCEd Infectious Diseases database (EID2) is open-access and evidence-based, and it describes the pathogens of humans and animals, their host and vector species, and also their global occurrence. The EID2 systematically collates information on pathogens into a single resource using evidence from the NCBI Taxonomy database, the NCBI Nucleotide database, the NCBI MeSH (Medical Subject Headings) library and PubMed. Information about pathogens is assigned using data-mining of meta-data and semi-automated literature searches.Here we focus on 47 mammalian and avian hosts, including humans and animals commonly used in Europe as food or kept as pets. Currently, the EID2 evidence suggests that:•Within these host species, 793 (30.5%) pathogens were bacteria species, 395 (15.2%) fungi, 705 (27.1%) helminths, 372 (14.3%) protozoa and 332 (12.8%) viruses.•The odds of pathogens being emerging compared to not emerging differed by taxonomic division, and increased when pathogens had greater numbers of host species associated with them, and were zoonotic rather than non-zoonotic.•The odds of pathogens being zoonotic compared to non-zoonotic differed by taxonomic division and also increased when associated with greater host numbers.•The pathogens affecting the greatest number of hosts included: Escherichia coli, Giardia intestinalis, Toxoplasma gondii, Anaplasma phagocytophilum, Cryptosporidium parvum, Rabies virus, Staphylococcus aureus, Neospora caninum and Echinococcus granulosus.•The pathogens of humans and domestic animal hosts are characterised by 4223 interactions between pathogen and host species, with the greatest number found in: humans, sheep/goats, cattle, small mammals, pigs, dogs and equids.•The number of pathogen species varied by European country. The odds of a pathogen being found in Europe compared to the rest of the world differed by taxonomic division, and increased if they were emerging compared to not emerging, or had a larger number of host species associated with them

Global Proteotoxicity Caused by Human β2 Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans

Aggregation of β2 microglobulin (β2m) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type protein and its truncated variant, ΔN6 β2m, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the β2m variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of β2 microglobulin have been widely studied in vitro and in vivo, we lack a comparable understanding of the molecular mechanisms underlying toxicity in a cellular and organismal environment. Here, we established transgenic C. elegans lines expressing wild-type (WT) human β2m, or the two highly amyloidogenic naturally occurring variants, D76N β2m and ΔN6 β2m, in the C. elegans bodywall muscle. Nematodes expressing the D76N β2m and ΔN6 β2m variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both β2m variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of β2m reduces the capacity of C. elegans to cope with heat and endoplasmic reticulum (ER) stress, correlating with a deficiency to upregulate BiP/hsp-4 transcripts in response to ER stress in young adult animals. Interestingly, protein secretion in all β2m variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal β2m toxicity and a disrupted ER secretory metabolism

FDG‐PET/CT after two cycles of R‐CHOP in DLBCL predicts complete remission but has limited value in identifying patients with poor outcome – final result of a UK National Cancer Research Institute prospective study

The UK National Cancer Research Institute initiated a prospective study (UKCRN‐ID 1760) to assess the prognostic value of early fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/computed tomography (CT) in diffuse large B‐cell lymphoma (DLBCL). In total, 189 patients with DLBCL treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) had baseline and post‐cycle‐2 PET (PET2) within a quality assurance framework. Treatment decisions were based on CT; PET2 was archived for central blinded reporting after treatment completion. The association of PET2 response with end‐of‐treatment CT, progression‐free (PFS) and overall survival (OS) was explored. The end‐of‐treatment complete response rate on CT was 83·9%, 75·0%, 70·5%, 40·4% and 36·4% for Deauville score (DS) 1 (n = 34), 2 (n = 39), 3 (n = 46), 4 (n = 56) and 5 (n = 14) (P < 0·001); and 64·1% and 50·0% for the maximum standardised uptake value (∆SUVmax) of ≥66% (n = 168) and <66% (n = 21), respectively (P = 0·25). After a median 5·4 years of follow‐up, the 5‐year PFS was 69·4%, 72·8%, 76·7%, 71·2% and 47·6% by DS 1–5 (P = 0·01); and 72·6% and 57·1% by ∆SUVmax of ≥66% and <66% (P = 0·03), respectively. The association with DS remained in multivariable analyses, and was consistent for OS. Early complete metabolic response (DS 1–3) at interim PET/CT after two cycles of R‐CHOP in DLBCL was associated with a higher end‐of‐treatment complete and overall response rate; however, only DS‐5 patients had inferior PFS and OS

Detection of genotoxic and non-genotoxic renal carcinogens in vitro in NRK-52E cells using a transcriptomics approach. (2012).

There is a need to develop quick, cheap, sensitive and specific methods to detect the carcinogenic potential of chemicals. Currently there is no in vitro model system for reliable detection of non-genotoxic carcinogens (NGTX) and current tests for detection of genotoxic carcinogens (GTX) can have low specificity. A transcriptomics approach holds promise and a few studies have utilised this technique. However, the majority of these studies have examined liver carcinogens with little work on renal carcinogens which may act via renal-specific NGTX mechanisms. In this study the normal rat renal cell line (NRK-52E) was exposed to sub-toxic concentrations of selected rat renal carcinogens and non-carcinogens (NC) for 6 h, 24 h and 72 h. Renal carcinogens were classified based on their presumed mode of action into GTX and NGTX classes. A whole-genome transcriptomics approach was used to determined genes and pathways as potential signatures for GTX, NGTX and those common to both carcinogenic events in vitro. For some of the GTX compounds an S9 drug metabolising system was included to aid pro-carcinogen activation. Only three genes were commonly deregulated after carcinogen (GTX + NGTX) exposure, one Mdm2 with a detection rate of 67%, and p21 and Cd55 with a detection rate of 56%. However, examination of enriched pathways showed that 3 out of 4 NGTX carcinogens and 4 out of 5 GTX carcinogens were related to known pathways involved in carcinogenesis giving a detection rate of 78%. In contrast, none of the NC chemicals induced any of the above genes or well-established carcinogenic pathways. Additionally, five genes (Lingo1, Hmox1, Ssu72, Lyrm and Usp9x) were commonly altered with 3 out of 4 NGTX carcinogens but not with NC or GTX carcinogens. However, there was no clear separation of GTX and NGTX carcinogens using pathway analysis with several pathways being common to both classes. The findings presented here indicate that the NRK-52E cell line has the potential to detect carcinogenic chemicals, although a much larger number of chemicals need to be used to confirm these findings

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial

Background: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. Patients and methods: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. Results: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. Conclusion: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. ClinicalTrials.gov: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34

Effectiveness of low-Dye taping for the short-term treatment of plantar heel pain: a randomised trial

BACKGROUND: Plantar heel pain is one of the most common musculoskeletal disorders of the foot and ankle. Treatment of the condition is usually conservative, however the effectiveness of many treatments frequently used in clinical practice, including supportive taping of the foot, has not been established. We performed a participant-blinded randomised trial to assess the effectiveness of low-Dye taping, a commonly used short-term treatment for plantar heel pain. METHODS: Ninety-two participants with plantar heel pain (mean age 50 ± 14 years; mean body mass index 30 ± 6; and median self-reported duration of symptoms 10 months, range of 2 to 240 months) were recruited from the general public between February and June 2005. Participants were randomly allocated to (i) low-Dye taping and sham ultrasound or (ii) sham ultrasound alone. The duration of follow-up for each participant was one week. No participants were lost to follow-up. Outcome measures included 'first-step' pain (measured on a 100 mm Visual Analogue Scale) and the Foot Health Status Questionnaire domains of foot pain, foot function and general foot health. RESULTS: Participants treated with low-Dye taping reported a small improvement in 'first-step' pain after one week of treatment compared to those who did not receive taping. The estimate of effect on 'first-step' pain favoured the low-Dye tape (ANCOVA adjusted mean difference -12.3 mm; 95% CI -22.4 to -2.2; P = 0.017). There were no other statistically significant differences between groups. Thirteen participants in the taping group experienced an adverse event however most were mild to moderate and short-lived. CONCLUSION: When used for the short-term treatment of plantar heel pain, low-Dye taping provides a small improvement in 'first-step' pain compared with a sham intervention after a one-week period

Prognostic indices in diffuse large B-cell lymphoma in the rituximab era: an analysis of the UK National Cancer Research Institute R-CHOP 14 versus 21 phase 3 trial

We compared the International Prognostic Index (IPI), Revised (R)‐IPI and age‐adjusted (aa)‐IPI as prognostic indices for patients with diffuse large B‐cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R‐CHOP 14 versus 21 trial (N = 1080). The R‐IPI and aa‐IPI showed no marked improvement compared to the IPI for overall and progression‐free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)‐IPI, where baseline β2‐microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high‐risk DLBCL group in the rituximab era is needed

Transcriptomic alterations induced by Monuron in rat and human renal proximal tubule cells in vitro and comparison to rat renal-cortex in vivo

Monuron (1,1-dimethyl-3-(4-chlorophenyl)urea) is a non-selective phenylurea herbicide, widely used in developing countries although concerns have been raised about its toxicity and carcinogenicity. Monuron was evaluated by the National Toxicology Program in 1988 and shown to be a male rat-specific renal carcinogen. We report that oral administration of Monuron to male rats for 3 days, leads to a larger number of genes being differentially expressed in the renal-cortex than in the liver. Further, we observed up-regulation of cell cycle genes and genes involved in cell proliferation in the renal-cortex while in the liver xenobiotic metabolising enzymes were up-regulated. We also identified one commonly down-regulated gene in both organs – fragile histidine triad gene (Fhit), a putative tumour suppressor gene; however the down-regulation was only significant at the protein level in the liver. In addition, we conducted in vitro whole-genome transcriptomics studies with human and rat renal cortical cells. Rat cells exposed to Monuron showed down-regulation of sterol biosynthesis, spliceosome and cell cycle genes and up-regulation of genes involved in amino acid metabolism and transport. No genes were found to be differentially expressed in human cells exposed to Monuron. Overall, the findings from the in vitro studies showed very little overlap with the whole animal findings

A randomized controlled trial of mycophenolate mofetil in patients with IgA nephropathy [ISRCTN62574616]

BACKGROUND: IgAN is the most common type of glomerulonephritis in the world. Between 15 and 40 percent of adults and children diagnosed with IgAN eventually progress to ESRD. Despite the need for effective treatment strategies, very few RCTs for IgAN have been performed. The most effective therapies for IgAN appear to be corticosteroids, ACEi, and FOS that contain a high concentration of omega 3 fatty acids. While ACEi and FOS are generally well tolerated with minimal side effects, the use of high dose steroids over a long course of therapy is often associated with significant morbidity. OBJECTIVE OF THE STUDY: The objective of the study is to test the hypothesis that treatment with the immunosuppressive agent, MMF, will lead to significant and sustained improvement in urinary protein excretion in patients with IgAN who have been pre-treated (and continue to be treated) with ACE(i )and FOS compared to a placebo control group of patients receiving comparable doses of ACEi and FOS without MMF. DESIGN: After a three month treatment period with the ACEi, lisinopril and the FOS, Omacor(®), 100 (2 × 50) patients with IgAN and a urinary P/C ratio ≥ 0.6 (males) and ≥ 0.8 (females) and an estGFR ≥ 40 ml/min/1.73 m2 will be randomized to treatment with either MMF or placebo for one year. All patients will be followed off study drug for a second year, but will continue treatment with lisinopril and Omacor(® )for the two year duration of the study. The primary outcome measure of change in urine P/C ratio will be assessed at the end of years one and two